**Part 2**

## **Treatment of Thyroid and Parathyroid Diseases**

132 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Sokic, S.I., Adanja, B.J., Vlajinac, H.D., Jankovic, R.R., Marinkovic, J.P., Zivaljevic, V.R.

Tunbridge W.M., Evered D.C., Hall R., Appleton D., Brewis M., Clark F., Evans J.G., Young

Tuttle R.M., Lemar H., & Burch H.B. (1998). Clinical Features Associated with an Increased

Vander J.B., Gaston E.A., & Dawber T.R. (1968). The significance of nontoxic thyroid

Wiest P.W., Hartshorne M.F., Inskip P.D., Crooks L.A., Vela B.S., & Telepak R.J. (1998).

E., Bird T., & Smith P.A. (1977). The spectrum of thyroid disease in a community:

Risk of Thyroid Malignancy in Patients with Follicular Neoplasia by Fine-Needle

nodules. Final report of a 15-year study of the incidence of thyroid malignancy.

Thyroid palpation versus high-resolution thyroid ultrasonography in the detection

(1994). Risk factors for thyroid cancer. *Neoplasma*, 41, 371-374.

the Whickham survey. *Clin Endocrinol* (Oxf), 7:481–493.

Sherman SI. (2003). Thyroid carcinoma. *Lancet* 361:501–511.

Aspiration. *Thyroid*, 8(5):377-383.

of nodules. *J Ultrasound Med*;17:487-96.

Zar J. (1999). *Biostatistical analysis*, 4th ed. New Jersey: Prebtice-Hall.

*Ann Intern Med,* 69:537–540

**10**

*USA* 

**Minimally-Invasive Parathyroid Surgery** 

Parathyroid surgery was first performed to correct primary hyperparathyroidism less than 100 years ago, and surgical treatment remains the only successful and durable cure for the disorder. 1,2 Techniques have evolved over the past century and continue to change and develop to this day. The conventional technique of bilateral neck exploration, though effective, has the disadvantage of being an invasive procedure, resulting in greater pain, poorer cosmesis, longer operative time, and longer hospitalization. More recently, developments in adjunctive technologies have allowed the development of less invasive techniques to achieve the same end result. This chapter will briefly discuss the conventional surgical treatment of primary hyperparathyroidism followed by a look at the minimally

Knowledge of the anatomy and embryology of the parathyroid glands is paramount to the success of surgery, regardless of the techniques employed. The variability in gland position can make localization difficult both pre-operatively and intra-operatively. The parathyroids are endocrine glands that develop from the endoderm of the 3rd and 4th pharyngeal pouches beginning in the 5th week of gestation. They migrate from this position inferiorly, reaching their final locations by the 7th week. The 3rd pharyngeal pouch develops into both the thymus and the inferior parathyroids, while the 4th arch becomes the superior glands.1-3 Parathyroid glands are usually about 5 x 3 x 1 mm in size with an average weight of 35 mg,

Normally, each set of glands is paired, resulting in 2 superior and 2 inferior glands. This is the case in 84% of patients. About 3% of patients will have only 3 glands, and 13% of patients may have 5 or more glands. The superior parathyroid glands normally reside postero-medial to the superior thyroid lobes, near the cricothyroid junction, while the inferior glands tend to be on the postero-lateral side of the inferior thyroid lobe, inferior to where the recurrent laryngeal nerve and inferior thyroid artery cross. The inferior parathyroids are usually found within 2 cm of the lower pole of the thyroid. This anatomic arrangement of glands is true in about 80% of patients. However, aberrant migration is common, and the glands can be found in ectopic locations in many cases. Ectopic superior parathyroid glands may be retroesophageal, intrathyroidal, or in the posterior mediastinum. Inferior parathyroid glands have more variable ectopic sites as a

invasive techniques that are being developed and used today.

although adenomatous glands may be much larger.3

**2. Anatomy and embryology** 

**1. Introduction** 

David Rosen, Joseph Sciarrino and Edmund A. Pribitkin

*Thomas Jefferson University, Philadelphia, PA* 

### **Minimally-Invasive Parathyroid Surgery**

David Rosen, Joseph Sciarrino and Edmund A. Pribitkin *Thomas Jefferson University, Philadelphia, PA* 

*USA* 

#### **1. Introduction**

Parathyroid surgery was first performed to correct primary hyperparathyroidism less than 100 years ago, and surgical treatment remains the only successful and durable cure for the disorder. 1,2 Techniques have evolved over the past century and continue to change and develop to this day. The conventional technique of bilateral neck exploration, though effective, has the disadvantage of being an invasive procedure, resulting in greater pain, poorer cosmesis, longer operative time, and longer hospitalization. More recently, developments in adjunctive technologies have allowed the development of less invasive techniques to achieve the same end result. This chapter will briefly discuss the conventional surgical treatment of primary hyperparathyroidism followed by a look at the minimally invasive techniques that are being developed and used today.

#### **2. Anatomy and embryology**

Knowledge of the anatomy and embryology of the parathyroid glands is paramount to the success of surgery, regardless of the techniques employed. The variability in gland position can make localization difficult both pre-operatively and intra-operatively. The parathyroids are endocrine glands that develop from the endoderm of the 3rd and 4th pharyngeal pouches beginning in the 5th week of gestation. They migrate from this position inferiorly, reaching their final locations by the 7th week. The 3rd pharyngeal pouch develops into both the thymus and the inferior parathyroids, while the 4th arch becomes the superior glands.1-3 Parathyroid glands are usually about 5 x 3 x 1 mm in size with an average weight of 35 mg, although adenomatous glands may be much larger.3

Normally, each set of glands is paired, resulting in 2 superior and 2 inferior glands. This is the case in 84% of patients. About 3% of patients will have only 3 glands, and 13% of patients may have 5 or more glands. The superior parathyroid glands normally reside postero-medial to the superior thyroid lobes, near the cricothyroid junction, while the inferior glands tend to be on the postero-lateral side of the inferior thyroid lobe, inferior to where the recurrent laryngeal nerve and inferior thyroid artery cross. The inferior parathyroids are usually found within 2 cm of the lower pole of the thyroid. This anatomic arrangement of glands is true in about 80% of patients. However, aberrant migration is common, and the glands can be found in ectopic locations in many cases. Ectopic superior parathyroid glands may be retroesophageal, intrathyroidal, or in the posterior mediastinum. Inferior parathyroid glands have more variable ectopic sites as a

Minimally-Invasive Parathyroid Surgery 137

known as a 3.5 gland resection is accomplished by resecting 3 abnormal glands, and approximately ½ of the most normal-appearing gland, leaving approximately 50 mg of parathyroid tissue. This approach removes the majority, but not all of the PTH secreting tissue in an attempt to allow the patient to become normocalcemic without needing chronic vitamin D and calcium supplementation. A total resection with autotransplantation involves resecting all found glands and then implanting small sections of the gland into a distant site; typically 12-24 sites within the subcutaneous tissue or the brachioradialis of the nondominant forearm. Again, this maintains functioning parathyroid tissue to reduce the risk of lifetime supplementation and permits titration of hormone level by future selective removal

Intraoperative PTH monitoring is frequently used to determine completeness of resection of abnormal tissue. If PTH does not drop to <50% of the pre-operative level, then the exploration is continued in the neck and mediastinum to look for ectopic tissue. If all ectopic sites have been explored and the Miami criterion has not been met, the operation is

Cure rates have been reported at >95% with a single operation, and complications at <4%. 1,2,5 Complications include recurrent laryngeal nerve (RLN) paresis, persistent hypocalcemia, and hematoma. Postoperatively patients are admitted at least overnight, and postoperative calcium levels are followed to screen for hypocalcemia. Patients are typically placed on

Despite the decrease in its incidence (10% of endocrine surgeons surveyed in 2008 used BNE as their primary technique, as opposed to 74% in 19983), bilateral exploration is still the preferred primary technique in cases of MEN, non-MEN familial isolated hyperparathyroidism (both of which carry an increased risk of multi-gland disease), and non-localizing pre-op imaging.2 Additionally, a minimally invasive technique failure may

The term "minimally invasive" is applied to several different techniques. These techniques share the objectives of reduced dissection, operative time, and duration of hospitalization as well as an improvements in patient comfort and cosmesis through smaller or more discretely located incisions. Technological advancements in imaging, laboratory, and operative techniques have made these approaches possible. These adjuncts will be

This imaging technique uses a radiotracer (usually 99mTc-sestamibi) injected intravenously to locate the parathyroid glands. 99mTc-sestamibi preferentially distributes to cells with high concentrations of mitochondria, resulting in greater concentration in cells of thyroid, heart, liver, salivary gland, and parathyroid tissue. Parathyroid glands that are hyperplastic or adenomatous tend to concentrate sestamibi to levels significant for detection, while normal

concluded and further work-up postoperatively with imaging must be done.1-3,6,7

vitamin D and calcium postoperatively and go home on this supplementation.1

need to be converted to a bilateral neck exploration to achieve a cure.

discussed, followed by an explanation of the techniques themselves.

of auto-transplanted parathyroid tissue. 1,2,5

**5. Minimally invasive techniques** 

**6. Preoperative localization studies** 

**6.1 Parathyroid scintigraphy** 

result of their longer migration. These sites include the thyrothymic tissue, thyroid, thymus, anterior mediastinum, and within the carotid sheath. Understanding of this anatomic variability is important in interpreting preoperative imaging and directing operative exploration.1-3

#### **3. Pathophysiology**

Overproduction of parathyroid hormone (PTH) is the defining feature of hyperparathyroidism. Hyperparathyroidism may be caused by a single parathyroid adenoma, multi-gland hyperplasia, double adenomas, or parathyroid carcinoma. Single adenoma accounts for about 81-96% of hyperparathyroidism, depending on the series. Multigland hyperplasia accounts for 4-14%, double adenomas 2-11%, and parathyroid carcinoma <1%.1,2,4 Traditional bilateral neck exploration remains the standard of care for parathyroid carcinoma1 so the focus of this chapter on minimally invasive techniques will be on benign disease.


Table 1. Causes of Primary Hyperparathyroidism

#### **4. Traditional bilateral neck exploration**

Traditional bilateral neck exploration (BNE) was the primary approach used by parathyroid surgeons until this past decade when minimally invasive techniques became more prevalent. Even as recently as 1998 nearly ¾ of parathyroid surgeons were still performing bilateral cervical exploration as the primary surgical technique.3 In the absence of other significant contraindications, all patients with diagnosed primary hyperparathyroidism, tertiary hyperparathyroidism, or select cases of secondary hyperparathyroidisim are candidates for this operation, and no preoperative localization studies are required, as all glands should be visualized intraoperatively. 1,2,5

BNE requires general anesthesia, typically with endotracheal intubation and often with a nerve integrity monitoring tube. A midline, transverse 3-5 cm cervical incision is made and carried through platysma, subplatysmal flaps elevated, the strap muscles divided in midline, and dissection and exploration continued until all parathyroid glands are visualized. This typically entails anteromedial retraction of the thyroid lobe to reveal the parathyroids posteriorly. Care is taken to safeguard the recurrent laryngeal nerve. Glands that are abnormal in appearance are resected. Those that are questionable may be biopsied and sent for frozen section pathology to guide decision of whether or not to resect. If all glands appear abnormal as is the case with multi-gland hyperplasia, the surgeon may perform a subtotal or total resection with autotransplantation. A subtotal resection, also

result of their longer migration. These sites include the thyrothymic tissue, thyroid, thymus, anterior mediastinum, and within the carotid sheath. Understanding of this anatomic variability is important in interpreting preoperative imaging and directing

Overproduction of parathyroid hormone (PTH) is the defining feature of hyperparathyroidism. Hyperparathyroidism may be caused by a single parathyroid adenoma, multi-gland hyperplasia, double adenomas, or parathyroid carcinoma. Single adenoma accounts for about 81-96% of hyperparathyroidism, depending on the series. Multigland hyperplasia accounts for 4-14%, double adenomas 2-11%, and parathyroid carcinoma <1%.1,2,4 Traditional bilateral neck exploration remains the standard of care for parathyroid carcinoma1 so the focus of this chapter on minimally invasive techniques will be

Single adenoma 81-96%

Double adenoma 2-11%

Carcinoma <1%

Traditional bilateral neck exploration (BNE) was the primary approach used by parathyroid surgeons until this past decade when minimally invasive techniques became more prevalent. Even as recently as 1998 nearly ¾ of parathyroid surgeons were still performing bilateral cervical exploration as the primary surgical technique.3 In the absence of other significant contraindications, all patients with diagnosed primary hyperparathyroidism, tertiary hyperparathyroidism, or select cases of secondary hyperparathyroidisim are candidates for this operation, and no preoperative localization studies are required, as all

BNE requires general anesthesia, typically with endotracheal intubation and often with a nerve integrity monitoring tube. A midline, transverse 3-5 cm cervical incision is made and carried through platysma, subplatysmal flaps elevated, the strap muscles divided in midline, and dissection and exploration continued until all parathyroid glands are visualized. This typically entails anteromedial retraction of the thyroid lobe to reveal the parathyroids posteriorly. Care is taken to safeguard the recurrent laryngeal nerve. Glands that are abnormal in appearance are resected. Those that are questionable may be biopsied and sent for frozen section pathology to guide decision of whether or not to resect. If all glands appear abnormal as is the case with multi-gland hyperplasia, the surgeon may perform a subtotal or total resection with autotransplantation. A subtotal resection, also

Multi gland hyperplasia 4-14%

Table 1. Causes of Primary Hyperparathyroidism

**4. Traditional bilateral neck exploration** 

glands should be visualized intraoperatively. 1,2,5

operative exploration.1-3

**3. Pathophysiology** 

on benign disease.

known as a 3.5 gland resection is accomplished by resecting 3 abnormal glands, and approximately ½ of the most normal-appearing gland, leaving approximately 50 mg of parathyroid tissue. This approach removes the majority, but not all of the PTH secreting tissue in an attempt to allow the patient to become normocalcemic without needing chronic vitamin D and calcium supplementation. A total resection with autotransplantation involves resecting all found glands and then implanting small sections of the gland into a distant site; typically 12-24 sites within the subcutaneous tissue or the brachioradialis of the nondominant forearm. Again, this maintains functioning parathyroid tissue to reduce the risk of lifetime supplementation and permits titration of hormone level by future selective removal of auto-transplanted parathyroid tissue. 1,2,5

Intraoperative PTH monitoring is frequently used to determine completeness of resection of abnormal tissue. If PTH does not drop to <50% of the pre-operative level, then the exploration is continued in the neck and mediastinum to look for ectopic tissue. If all ectopic sites have been explored and the Miami criterion has not been met, the operation is concluded and further work-up postoperatively with imaging must be done.1-3,6,7

Cure rates have been reported at >95% with a single operation, and complications at <4%. 1,2,5 Complications include recurrent laryngeal nerve (RLN) paresis, persistent hypocalcemia, and hematoma. Postoperatively patients are admitted at least overnight, and postoperative calcium levels are followed to screen for hypocalcemia. Patients are typically placed on vitamin D and calcium postoperatively and go home on this supplementation.1

Despite the decrease in its incidence (10% of endocrine surgeons surveyed in 2008 used BNE as their primary technique, as opposed to 74% in 19983), bilateral exploration is still the preferred primary technique in cases of MEN, non-MEN familial isolated hyperparathyroidism (both of which carry an increased risk of multi-gland disease), and non-localizing pre-op imaging.2 Additionally, a minimally invasive technique failure may need to be converted to a bilateral neck exploration to achieve a cure.

#### **5. Minimally invasive techniques**

The term "minimally invasive" is applied to several different techniques. These techniques share the objectives of reduced dissection, operative time, and duration of hospitalization as well as an improvements in patient comfort and cosmesis through smaller or more discretely located incisions. Technological advancements in imaging, laboratory, and operative techniques have made these approaches possible. These adjuncts will be discussed, followed by an explanation of the techniques themselves.

#### **6. Preoperative localization studies**

#### **6.1 Parathyroid scintigraphy**

This imaging technique uses a radiotracer (usually 99mTc-sestamibi) injected intravenously to locate the parathyroid glands. 99mTc-sestamibi preferentially distributes to cells with high concentrations of mitochondria, resulting in greater concentration in cells of thyroid, heart, liver, salivary gland, and parathyroid tissue. Parathyroid glands that are hyperplastic or adenomatous tend to concentrate sestamibi to levels significant for detection, while normal

Minimally-Invasive Parathyroid Surgery 139

Radiotracer imaging and ultrasound alone show similar sensitivities. Sensitivity for sestamibi scanning has been reported in the range of 68-95% for single adenomas, with one meta-analysis putting it at 88%. Sensitivity is far less for multi-gland disease and has been reported at 44% for hyperplasia and 30% for double parathyroid adenomas.1-4,6,8,10 Sensitivity of ultrasound alone has been reported at 72-89% for patients with single adenomas. Again, sensitivity drops for multi-gland disease and has been reported at 16% for

Ultrasonography and Radio-guided imaging complement each other and increase diagnostic accuracy when used together. The surgeon may use both the functional information from scintigraphy along with the anatomic information from ultrasound. Additionally, ectopic glands that are missed by ultrasonography may be detected with scintigraphy, while ultrasonography may detect thyroid abnormalities helping to interpret scintigraphy findings. Combining these techniques results in a sensitivity of 74- 95% for single gland disease. However, the sensitivity for double adenomas is 60%, and multi-gland disease is only accurately predicted 30% of the time by these techniques. When the two imaging studies are concordant (which occurs in 50-60% of cases) the sensitivity is in the range of 94-99%.1,3 In fact, some surgeons suggest that intraoperative PTH monitoring not be used in cases of concordant ultrasound and sestamibi scan, and simply terminate the procedure after excising the gland indicated on the imaging studies. Combined ultrasonography and sestamibi is the preferred imaging method of most

Computed tomography [CT] and magnetic resonance imaging [MRI] scans may provide additional anatomical information, but are not first-line studies. CT offers the advantage of scanning the entire neck and mediastinum to help with localization of ectopic glands. Sensitivity of CT scanning alone ranges from 46-87%. When combined with ultrasonography, it results in only slightly increased sensitivity compared with ultrasonography alone. CT tends to be used only in patients undergoing reoperation or in patients with an ectopic gland

CT can also be combined with SPECT to give images that contain a combination of anatomic and functional information. This allows better localization and sensitivities ranging from 88- 93%. Benefits may be greater in the subset of patients with multi-gland disease or goiter, but

MRI has sensitivities rivaling other modalities, but its high cost and other options for

The serum half-life of parathyroid hormone (PTH) is 3-5 minutes. This short turn-over time along with the availability of rapid assays that take from 8-20 minutes for results allow the

**6.3 Combined scintigraphy and ultrasonography** 

parathyroid surgeons.1

detected on sestamibi.1,3-5,8

such combination scans require further investigation. 3

**7.1 Intraoperative parathyroid hormone monitoring** 

imaging have limited its use to select cases. 1,3-5,8

**7. Introperative adjunctive techniques** 

**6.4 Other imaging techniques** 

parathyroid hyperplasia and 35% in double adenomas. 1-4,6,8,10

glands are not typically seen. This is likely due to increased mitochondria as well as increased blood flow to these glands. Due to their anatomic relationship and shared affinity for the radiotracer, signal from the thyroid and parathyroids may overlap, obscuring the definition of an abnormal parathyroid gland. Fortunately, the retention of the radiotracer over time is greater in parathyroid than thyroid tissue. Combining early and delayed (2-3 hours) imaging permits better identification of abnormal parathyroid tissue. Additionally, an abnormal signal contour or a signal clearly separate from the thyroid bed raises suspicion of abnormal parathyroid tissue on either early or late images.3,8 Sestamibi scanning may be done with planar imaging, or with 3-dimensional imaging using singlephoton emission computed tomography (SPECT). SPECT has been reported to allow better differentiation of parathyroid tissue from the thyroid gland, and thus better detection and localization.1-3

This technology does have limitations, however. Uptake and retention of the radiotracer by abnormal parathyroid tissue may be variable. If washout from an adenoma is rapid, no discrete signal will be seen on the delayed images, despite the presence of a diseased gland (false negative). False negatives are also more commonly seen in patients with multi-gland disease, such as double adenomas or multi-gland hyperplasia. Additionally, multiple factors may cause false positive results, such as adenomas of thyroid origin, lymph nodes, or multinodular goiter, all of which have affinity for 99mTc-sestamibi and can be located in the same region as an abnormal gland.2,3Arguably, the greatest utility of sestamibi scanning is in the identification of ectopically located parathyroid tissue.

#### **6.2 Ultrasonography**

This relatively low-cost modality has the advantages of the absence of radiation and providing anatomic information in the area of intended surgery. Moreover, ultrasonography enables excellent visualization of the thyroid gland and can diagnose concurrent thyroid disease, limiting re-operation rates. Normal parathyroid glands are typically not seen on ultrasound due to their small size and location. Adenomatous glands tend to appear homogenous on ultrasound and are usually hypoechoic to the thyroid gland signal. The use of Doppler imaging can provide information regarding parathyroid galnd vascularity and can identify an artery feeding an adenomatous gland, which greatly increases the accuracy of diagnosis.3

Shortcomings of ultrasound include poor sensitivity for some ectopic glands such as retrotracheal or mediastinal glands. Glands in these locations are shadowed by the tracheal air column and bones of the sternum and clavicle, respectively. Large adenomas may also complicate diagnosis, because their imaging characteristics may be atypical. They can appear heterogeneous and/or hyperechoic to thyroid tissue. Disease of the thyroid such as mulitinodular goiter or posterior thyroid nodules may also increase the difficulty of detection of parathyroid adenomas. Enlarged lymph nodes associated with anthracotic pigment, thyroiditis and malignant thyroid disease can also confound parathyroid localization. However, as previously mentioned, even a study that fails to reveal a parathyroid adenoma may be useful by identifying thyroid disease in a patient that is being considered for surgery for hyperparathyroidism. Incidence of concurrent thyroid disease has been reported as high as 51% in patients being considered for parathyroid surgery, and the incidence of thyroid malignancy as 2-6%.2,3

glands are not typically seen. This is likely due to increased mitochondria as well as increased blood flow to these glands. Due to their anatomic relationship and shared affinity for the radiotracer, signal from the thyroid and parathyroids may overlap, obscuring the definition of an abnormal parathyroid gland. Fortunately, the retention of the radiotracer over time is greater in parathyroid than thyroid tissue. Combining early and delayed (2-3 hours) imaging permits better identification of abnormal parathyroid tissue. Additionally, an abnormal signal contour or a signal clearly separate from the thyroid bed raises suspicion of abnormal parathyroid tissue on either early or late images.3,8 Sestamibi scanning may be done with planar imaging, or with 3-dimensional imaging using singlephoton emission computed tomography (SPECT). SPECT has been reported to allow better differentiation of parathyroid tissue from the thyroid gland, and thus better

This technology does have limitations, however. Uptake and retention of the radiotracer by abnormal parathyroid tissue may be variable. If washout from an adenoma is rapid, no discrete signal will be seen on the delayed images, despite the presence of a diseased gland (false negative). False negatives are also more commonly seen in patients with multi-gland disease, such as double adenomas or multi-gland hyperplasia. Additionally, multiple factors may cause false positive results, such as adenomas of thyroid origin, lymph nodes, or multinodular goiter, all of which have affinity for 99mTc-sestamibi and can be located in the same region as an abnormal gland.2,3Arguably, the greatest utility of sestamibi scanning is in

This relatively low-cost modality has the advantages of the absence of radiation and providing anatomic information in the area of intended surgery. Moreover, ultrasonography enables excellent visualization of the thyroid gland and can diagnose concurrent thyroid disease, limiting re-operation rates. Normal parathyroid glands are typically not seen on ultrasound due to their small size and location. Adenomatous glands tend to appear homogenous on ultrasound and are usually hypoechoic to the thyroid gland signal. The use of Doppler imaging can provide information regarding parathyroid galnd vascularity and can identify an artery feeding an adenomatous gland,

Shortcomings of ultrasound include poor sensitivity for some ectopic glands such as retrotracheal or mediastinal glands. Glands in these locations are shadowed by the tracheal air column and bones of the sternum and clavicle, respectively. Large adenomas may also complicate diagnosis, because their imaging characteristics may be atypical. They can appear heterogeneous and/or hyperechoic to thyroid tissue. Disease of the thyroid such as mulitinodular goiter or posterior thyroid nodules may also increase the difficulty of detection of parathyroid adenomas. Enlarged lymph nodes associated with anthracotic pigment, thyroiditis and malignant thyroid disease can also confound parathyroid localization. However, as previously mentioned, even a study that fails to reveal a parathyroid adenoma may be useful by identifying thyroid disease in a patient that is being considered for surgery for hyperparathyroidism. Incidence of concurrent thyroid disease has been reported as high as 51% in patients being considered for parathyroid surgery, and

detection and localization.1-3

**6.2 Ultrasonography** 

the identification of ectopically located parathyroid tissue.

which greatly increases the accuracy of diagnosis.3

the incidence of thyroid malignancy as 2-6%.2,3

#### **6.3 Combined scintigraphy and ultrasonography**

Radiotracer imaging and ultrasound alone show similar sensitivities. Sensitivity for sestamibi scanning has been reported in the range of 68-95% for single adenomas, with one meta-analysis putting it at 88%. Sensitivity is far less for multi-gland disease and has been reported at 44% for hyperplasia and 30% for double parathyroid adenomas.1-4,6,8,10 Sensitivity of ultrasound alone has been reported at 72-89% for patients with single adenomas. Again, sensitivity drops for multi-gland disease and has been reported at 16% for parathyroid hyperplasia and 35% in double adenomas. 1-4,6,8,10

Ultrasonography and Radio-guided imaging complement each other and increase diagnostic accuracy when used together. The surgeon may use both the functional information from scintigraphy along with the anatomic information from ultrasound. Additionally, ectopic glands that are missed by ultrasonography may be detected with scintigraphy, while ultrasonography may detect thyroid abnormalities helping to interpret scintigraphy findings. Combining these techniques results in a sensitivity of 74- 95% for single gland disease. However, the sensitivity for double adenomas is 60%, and multi-gland disease is only accurately predicted 30% of the time by these techniques. When the two imaging studies are concordant (which occurs in 50-60% of cases) the sensitivity is in the range of 94-99%.1,3 In fact, some surgeons suggest that intraoperative PTH monitoring not be used in cases of concordant ultrasound and sestamibi scan, and simply terminate the procedure after excising the gland indicated on the imaging studies. Combined ultrasonography and sestamibi is the preferred imaging method of most parathyroid surgeons.1

#### **6.4 Other imaging techniques**

Computed tomography [CT] and magnetic resonance imaging [MRI] scans may provide additional anatomical information, but are not first-line studies. CT offers the advantage of scanning the entire neck and mediastinum to help with localization of ectopic glands. Sensitivity of CT scanning alone ranges from 46-87%. When combined with ultrasonography, it results in only slightly increased sensitivity compared with ultrasonography alone. CT tends to be used only in patients undergoing reoperation or in patients with an ectopic gland detected on sestamibi.1,3-5,8

CT can also be combined with SPECT to give images that contain a combination of anatomic and functional information. This allows better localization and sensitivities ranging from 88- 93%. Benefits may be greater in the subset of patients with multi-gland disease or goiter, but such combination scans require further investigation. 3

MRI has sensitivities rivaling other modalities, but its high cost and other options for imaging have limited its use to select cases. 1,3-5,8

#### **7. Introperative adjunctive techniques**

#### **7.1 Intraoperative parathyroid hormone monitoring**

The serum half-life of parathyroid hormone (PTH) is 3-5 minutes. This short turn-over time along with the availability of rapid assays that take from 8-20 minutes for results allow the

Minimally-Invasive Parathyroid Surgery 141

cases can be performed on an outpatient basis. Postoperative calcium levels do not typically have to be checked because the remaining parathyroid glands remain undisturbed. For this same reason, patients do not typically require postoperative supplementation with calcium and vitamin D. Hungry bone syndrome may still occur, however, and inpatient hospitalization and calcium testing should be performed when the concern of postoperative

Fig. 1. An example of a 2 cm incision possible with minimally invasive techniques.


Benefits of this approach over bilateral neck exploration include shorter operative time, shorter hospitalization, and the avoidance of general anesthesia.1,2,5 These factors contribute to a decreased overall cost of the procedure. One surgeon compared 613 BNE operations to 1037 focused parathyroidectomies under local and regional anesthesia, and found the average cost savings in his institution to be \$1471 per case.5 Additionally, cosmesis is typically improved with this technique due to a smaller incision.1,2,5,11 One disadvantage of



Table 2. Contraindications to Focused Exploration Techniques for Parathyroidectomy




hypocalcemia is high.1,2,5

operative team to monitor and predict the success of surgery based on the amount of circulating PTH. Typically, pre-operative and pre-incision blood samples are taken for baseline measurements. After excision of all of the suspected diseased tissue, samples are usually sent at 0, 5, and 10 minutes. The criteria used for a successful operation at most centers is a drop of the PTH level to 50% or less of the pre-incision level. If this occurs at 5 or 10 minutes, the operation is deemed complete. If it does not occur, further cervical exploration is performed to identify additional parathyroid tissue that may be causing the patient's hyperparathyroidism, and the suspicion for multi-gland disease increases. If the 50% criterion is met, surgical success rates (as measured by postoperative normocalcemia) are in the range of 97-98%. This technique may be used in both minimally invasive and bilateral neck exploration techniques. Additionally, rapid PTH assay may be performed on excised tissue, allowing rapid identification of parathyroid tissue if there is any doubt.1,2,4-7

#### **7.2 Gamma probe**

The radioactivity of 99mTc-sestamibi may also be detected by a hand-held probe. This adjunctive technology can help direct dissection as well as provide information regarding completeness of excision. This will be further discussed in the section regarding radioguided parathyroid surgery.

#### **8. Minimally invasive operative techniques**

#### **8.1 Focused parathyroidectomy**

Focused parathyroid surgery is possible and effective because of the availability of preoperative localization studies and the fact that about 75-90% of hyperparathyroidism is due to single adenomas. These factors allow for limited dissection in the area of the diseased gland, decreasing the invasiveness of bilateral neck dissection.

Candidates for this surgery are patients who meet the guidelines for surgical treatment of hyperparathyroidism, have positive pre-operative localization imaging, and do not have a condition that would predispose them to multi-gland disease, such as MEN or non-MEN familial isolated hyperparathyroidism. Patients with such conditions or non-localizing preoperative imaging should undergo traditional or minimally invasive bilateral neck exploration instead.1,2

This technique involves making a small (2-4 cm) transverse incision in a skin crease in the midline or on the side indicated by pre-operative imaging. The incision is carried down to the strap muscles, which are dissected and lateralized. The thyroid is mobilized and retracted medially for access. Directed dissection based on preoperative imaging allows identification of the offending gland, while care is taken not to injure the recurrent laryngeal nerve. Since the other parathyroid glands are not visualized in this technique, intraoperative parathyroid hormone monitoring is employed to determine completeness of the operation. If the 50% criterion is not met, explorative dissection to visualize the other glands is employed.1,2,5,6,11

Given the limited amount of dissection, this procedure may be performed under sedation with local and regional anesthesia instead of general anesthesia.1,2 This helps reduce the risk of anesthesia in these cases. Whether general or local anesthesia is used, the majority of

operative team to monitor and predict the success of surgery based on the amount of circulating PTH. Typically, pre-operative and pre-incision blood samples are taken for baseline measurements. After excision of all of the suspected diseased tissue, samples are usually sent at 0, 5, and 10 minutes. The criteria used for a successful operation at most centers is a drop of the PTH level to 50% or less of the pre-incision level. If this occurs at 5 or 10 minutes, the operation is deemed complete. If it does not occur, further cervical exploration is performed to identify additional parathyroid tissue that may be causing the patient's hyperparathyroidism, and the suspicion for multi-gland disease increases. If the 50% criterion is met, surgical success rates (as measured by postoperative normocalcemia) are in the range of 97-98%. This technique may be used in both minimally invasive and bilateral neck exploration techniques. Additionally, rapid PTH assay may be performed on excised tissue, allowing rapid identification of parathyroid tissue if there is any doubt.1,2,4-7

The radioactivity of 99mTc-sestamibi may also be detected by a hand-held probe. This adjunctive technology can help direct dissection as well as provide information regarding completeness of excision. This will be further discussed in the section regarding radio-

Focused parathyroid surgery is possible and effective because of the availability of preoperative localization studies and the fact that about 75-90% of hyperparathyroidism is due to single adenomas. These factors allow for limited dissection in the area of the diseased

Candidates for this surgery are patients who meet the guidelines for surgical treatment of hyperparathyroidism, have positive pre-operative localization imaging, and do not have a condition that would predispose them to multi-gland disease, such as MEN or non-MEN familial isolated hyperparathyroidism. Patients with such conditions or non-localizing preoperative imaging should undergo traditional or minimally invasive bilateral neck

This technique involves making a small (2-4 cm) transverse incision in a skin crease in the midline or on the side indicated by pre-operative imaging. The incision is carried down to the strap muscles, which are dissected and lateralized. The thyroid is mobilized and retracted medially for access. Directed dissection based on preoperative imaging allows identification of the offending gland, while care is taken not to injure the recurrent laryngeal nerve. Since the other parathyroid glands are not visualized in this technique, intraoperative parathyroid hormone monitoring is employed to determine completeness of the operation. If the 50% criterion is not met, explorative dissection to visualize the other glands is

Given the limited amount of dissection, this procedure may be performed under sedation with local and regional anesthesia instead of general anesthesia.1,2 This helps reduce the risk of anesthesia in these cases. Whether general or local anesthesia is used, the majority of

**7.2 Gamma probe** 

guided parathyroid surgery.

exploration instead.1,2

employed.1,2,5,6,11

**8.1 Focused parathyroidectomy** 

**8. Minimally invasive operative techniques** 

gland, decreasing the invasiveness of bilateral neck dissection.

cases can be performed on an outpatient basis. Postoperative calcium levels do not typically have to be checked because the remaining parathyroid glands remain undisturbed. For this same reason, patients do not typically require postoperative supplementation with calcium and vitamin D. Hungry bone syndrome may still occur, however, and inpatient hospitalization and calcium testing should be performed when the concern of postoperative hypocalcemia is high.1,2,5

Fig. 1. An example of a 2 cm incision possible with minimally invasive techniques.


Benefits of this approach over bilateral neck exploration include shorter operative time, shorter hospitalization, and the avoidance of general anesthesia.1,2,5 These factors contribute to a decreased overall cost of the procedure. One surgeon compared 613 BNE operations to 1037 focused parathyroidectomies under local and regional anesthesia, and found the average cost savings in his institution to be \$1471 per case.5 Additionally, cosmesis is typically improved with this technique due to a smaller incision.1,2,5,11 One disadvantage of

Minimally-Invasive Parathyroid Surgery 143

enlarged non-dormant. By protocol, all glands that are non-dormant are removed with more than 1 gland removed in 24.7% of cases.12 Norman employs neither frozen section analysis nor intra-operative PTH assay, and operative times average 22.3 minutes per case. One, three and ten year cure rates for radioguided minimally invasive bilateral neck

exploration exceed 99% in this case series.

Fig. 2. A gamma probe inserted into the incision to guide dissection.

pole of the thyroid, access to the superior poles is limited.2

Endoscopic parathyroidectomy attempts to take the techniques developed for minimally invasive laparoscopic surgeries and apply them to the neck. This technique was first reported by Gagner in 1996 for a bilateral cervical exploration.13 It uses several very small incisions (about 5mm) as ports for an endoscope and endoscopic instruments. Generally, a 5mm trocar is inserted superior to the sternal notch in the midline of the neck through which a 30o endoscope is placed. Three additional ports are placed, two in the right neck and one in the left. Working space is created by insufflation of CO2. The strap muscles are divided at the raphe, and the thyroid is mobilized antero-medially to reveal the parathyroid glands for resection.1,2,9,13 Other techniques include approaches from the lateral neck, anterior chest wall, and axilla. Some of these techniques change the trocar sites to improve cosmesis. Others, such as the lateral approach, attempt to improve access to superior glands—although the technique described by Gagner provides excellent access to the lower

**8.3 Endoscopic parathyroidectomy** 

this technique is the failure to visualize all parathyroids resulting in the potential risk of missing an abnormal gland which may occur in 10-25% of cases. However, the use of IPM helps to decrease this risk.

Outcomes using this technique are generally comparable to the traditional approach, with relatively high cure (95-99%) and low complication (1-4%) rates. Many studies have confirmed that this is a viable alternative to the traditional bilateral neck exploration.1,2,5,11

#### **8.2 Radio-guided surgery**

99mTc-sestamibi radioactivity can be detected by a handheld gamma probe which can be used intraoperatively to help locate the hyperfunctioning parathyroid tissue. This technique involves intravenous injection of the radiotracer 2 hours prior to surgery. In the operating room, the gamma probe can be used to determine on which side of the neck to place the incision. As in focused parathyroidectomy, efforts are made to keep the incision as short as possible (2-4 cm) without limiting the exposure. After the skin and platysma are incised, the probe can be inserted into the wound and the dissection directed in the area of highest radioactivity. Dissection is continued until the hyperfunctioning parathyroid gland is encountered and excised.2,4,8 The excised tissue can be placed directly against the probe to measure its radioactivity relative to a background level that is found by placing the probe over the thyroid isthmus. If the ex-vivo count of the excised tissue is >20% of the background radiation at the thyroid isthmus, it is strong evidence that the excised tissue is indeed parathyroid adenoma. Hyperplastic parathyroid glands tend to exhibit <16% of background radiation, and normal parathyroids, fat, and lymph nodes are usually around 2%.4,8 Much like the focused parathyroidectomy technique previously described, this technique benefits from the ability to use local and regional anesthesia with sedation. Also, it too is often used in conjunction with IPM.

Like the focused parathyroidectomy technique, this approach benefits from a small incision, limited dissection, and potential for avoidance of general anesthesia and inpatient hospitalization. Use of the gamma probe was found to have a 93-94% sensitivity and 88% positive predictive value in localization of a parathyroid adenoma.2,4,8 However, failure of localization does occur, and conversion rates to convential bilateral exploration have been found to be 10% inpatients with single adenomas, and 50% for multi-gland disease and hyperplasia, though similar rates have been observed in focused parathyroidectomy.2,5 Additionally, logistical concerns over timing of surgery and equipment may be seen as a disadvantage of this technique.

Radio-guided minimally invasive bilateral neck exploration has been advocated by high volume thyroid centers as yielding optimal cure rates while decreasing costs. Norman et al have noted that even highly selected unilateral explorations in patients with a clearly positive, "in focus" sestamibi scan with a solitary localization of radioactivity clearly distinct from a normal thyroid gland can still fail to achieve cure in up to 6% of cases. Following a planar sestamibi scan performed two hours before surgery, through a 2.5 cm incision under general laryngeal masked anesthesia, Norman identifies each of the four parathyroid glands and determines its metabolic activity by removing a portion of the gland and measuring the contained gamma radioactivity against a standard curve of hormone production. This permits classification of each gland as normal (dormant), adenoma, hyperplastic or clinically

this technique is the failure to visualize all parathyroids resulting in the potential risk of missing an abnormal gland which may occur in 10-25% of cases. However, the use of IPM

Outcomes using this technique are generally comparable to the traditional approach, with relatively high cure (95-99%) and low complication (1-4%) rates. Many studies have confirmed that this is a viable alternative to the traditional bilateral neck exploration.1,2,5,11

99mTc-sestamibi radioactivity can be detected by a handheld gamma probe which can be used intraoperatively to help locate the hyperfunctioning parathyroid tissue. This technique involves intravenous injection of the radiotracer 2 hours prior to surgery. In the operating room, the gamma probe can be used to determine on which side of the neck to place the incision. As in focused parathyroidectomy, efforts are made to keep the incision as short as possible (2-4 cm) without limiting the exposure. After the skin and platysma are incised, the probe can be inserted into the wound and the dissection directed in the area of highest radioactivity. Dissection is continued until the hyperfunctioning parathyroid gland is encountered and excised.2,4,8 The excised tissue can be placed directly against the probe to measure its radioactivity relative to a background level that is found by placing the probe over the thyroid isthmus. If the ex-vivo count of the excised tissue is >20% of the background radiation at the thyroid isthmus, it is strong evidence that the excised tissue is indeed parathyroid adenoma. Hyperplastic parathyroid glands tend to exhibit <16% of background radiation, and normal parathyroids, fat, and lymph nodes are usually around 2%.4,8 Much like the focused parathyroidectomy technique previously described, this technique benefits from the ability to use local and regional anesthesia with sedation. Also,

Like the focused parathyroidectomy technique, this approach benefits from a small incision, limited dissection, and potential for avoidance of general anesthesia and inpatient hospitalization. Use of the gamma probe was found to have a 93-94% sensitivity and 88% positive predictive value in localization of a parathyroid adenoma.2,4,8 However, failure of localization does occur, and conversion rates to convential bilateral exploration have been found to be 10% inpatients with single adenomas, and 50% for multi-gland disease and hyperplasia, though similar rates have been observed in focused parathyroidectomy.2,5 Additionally, logistical concerns over timing of surgery and equipment may be seen as a

Radio-guided minimally invasive bilateral neck exploration has been advocated by high volume thyroid centers as yielding optimal cure rates while decreasing costs. Norman et al have noted that even highly selected unilateral explorations in patients with a clearly positive, "in focus" sestamibi scan with a solitary localization of radioactivity clearly distinct from a normal thyroid gland can still fail to achieve cure in up to 6% of cases. Following a planar sestamibi scan performed two hours before surgery, through a 2.5 cm incision under general laryngeal masked anesthesia, Norman identifies each of the four parathyroid glands and determines its metabolic activity by removing a portion of the gland and measuring the contained gamma radioactivity against a standard curve of hormone production. This permits classification of each gland as normal (dormant), adenoma, hyperplastic or clinically

helps to decrease this risk.

**8.2 Radio-guided surgery** 

it too is often used in conjunction with IPM.

disadvantage of this technique.

enlarged non-dormant. By protocol, all glands that are non-dormant are removed with more than 1 gland removed in 24.7% of cases.12 Norman employs neither frozen section analysis nor intra-operative PTH assay, and operative times average 22.3 minutes per case. One, three and ten year cure rates for radioguided minimally invasive bilateral neck exploration exceed 99% in this case series.

Fig. 2. A gamma probe inserted into the incision to guide dissection.

#### **8.3 Endoscopic parathyroidectomy**

Endoscopic parathyroidectomy attempts to take the techniques developed for minimally invasive laparoscopic surgeries and apply them to the neck. This technique was first reported by Gagner in 1996 for a bilateral cervical exploration.13 It uses several very small incisions (about 5mm) as ports for an endoscope and endoscopic instruments. Generally, a 5mm trocar is inserted superior to the sternal notch in the midline of the neck through which a 30o endoscope is placed. Three additional ports are placed, two in the right neck and one in the left. Working space is created by insufflation of CO2. The strap muscles are divided at the raphe, and the thyroid is mobilized antero-medially to reveal the parathyroid glands for resection.1,2,9,13 Other techniques include approaches from the lateral neck, anterior chest wall, and axilla. Some of these techniques change the trocar sites to improve cosmesis. Others, such as the lateral approach, attempt to improve access to superior glands—although the technique described by Gagner provides excellent access to the lower pole of the thyroid, access to the superior poles is limited.2

Minimally-Invasive Parathyroid Surgery 145

Minimally Invasive Video-Assisted Parathyroidectomy (MIVAP) was first described by Miccoli in 1998. 14 It is considered a gasless endoscopic technique, and, as with focused parathyroidecotmy, relies on preoperative localization studies and IPM. Like the focused technique, MIVAP is not an option for patients with multi-gland disease, conditions predisposing to multi-gland disease, parathyroid carcinoma, or failed preoperative localization. Additionally, patients with large goiters are not candidates for this approach.2,15 A 15-20mm incision is made in the midline, and the strap muscles are divided in at the raphe. Blunt dissection on the side of the neck as indicated by localization studies, and the strap muscles are retracted laterally from the thyroid using direct visualization. Then, a 5mm 30o endoscope is inserted into the wound. Working space is created by use of external retractors, so insufflation of CO2 is not necessary. Specialized 2mm endoscopic instruments are used to complete the dissection of the parathyroid adenoma and excise it from the surrounding tissue. If the adenoma is not found, or if PTH levels do not drop appropriately,

the procedure is converted to a conventional bilateral neck exploration.1,2, 14, 15

**9. Conclusion** 

satisfaction.

**10. References** 

The absence of insufflation in this technique avoids many of the complications of the total endoscopic approach. Also, operative times tend to be shorter than total endoscopic procedures. Miccoli reported an average operative time of 36.2 minutes in a series of 370 operations, and an average time of 25.7 minutes for the last 100 in that series.15 This procedure also affords the surgeon tactile assessment of the surgical bed, which is not available with total endoscopic approaches. However, the disadvantages of a long learning curve and specialized equipment remain. Also, 2 assistants are required for this technique.1,2 Cure rates with MIVAP are comparable to the other procedures described and have been reported at 96-100%. Complication rates are also comparable to the other approaches.1,2, 15

Although first performed nearly 100 years ago, parathyroid surgery has undergone rapid evolution over the past few decades. Advances in imaging, laboratory assay, and operative technique have made new methods possible. The varied minimally invasive techniques described in this chapter are all capable of producing satisfactory outcomes, and many offer significant advantages over traditional bilateral cervical exploration. Nonetheless, cure rates approaching 100% can only be achieved through evaluation of all four glands16. Parathyroid surgeons must be well versed in both traditional and minimally invasive techniques. As cure rates are high among all techniques listed, future refinement and innovation are likely to be directed at reducing complications, lowering overall cost, and improving patient

[1] M. Augustine, P. Bravo, M. Zeiger. Surgical Treatment of Primary Hyperparathyroidism.

[2] John I. Lew, Carmen C. Solorzano. Surgical Management of Primary

Hyperparathyroidism: State of the Art. Surgical Clinics of North America. Volume

Endocrine Practice. Volume 17. Supplement 1 / March-April 2011.

89. Issue 5. October 2009: Pages 1205-1225.

**8.4 Minimally invasive video-assisted parathyroidectomy** 

These endoscopic approaches provide the benefit of improved cosmesis by reducing the incisions on the neck to small port sites, which in some cases are covered by clothing. Additionally, focused parathyroidectomy and bilateral cervical exploration both may be carried out with this technique. One important advantage of this method is the ability to visualize and dissect in the mediastinum if ectopic glands are suspected. Some have argued that the magnification of the endoscope allows better visualization of the recurrent laryngeal nerve, while others state that visualization of the never is poorer due to less exposure.1,2,9,13

Fig. 3. View of a parathyroid adenoma through an endoscope.

A major disadvantage of this method is the steep learning curve for the surgical team to become proficient with the technique. Dedicated equipment must be purchased and maintained. Most endoscopic approaches to parathyroid surgery tend to have longer overall operative time, particularly in the early part of the learning curve. Some complications specific to this technique include subcutaneous emphysema, hypercapnia, respiratory acidosis, tachycardia, and air embolism.1,2,9,13 These may be reduced by lower-pressure insufflation used in some approaches.9 Also, the surgeon loses the tactile assessment that is possible in an open approach, and violation of the parathyroid capsule may be more likely when removing an adenoma from a small port.2 Despite these disadvantages, cure rates with this technique are comparable to the previous techniques listed.1,2,9

These endoscopic approaches provide the benefit of improved cosmesis by reducing the incisions on the neck to small port sites, which in some cases are covered by clothing. Additionally, focused parathyroidectomy and bilateral cervical exploration both may be carried out with this technique. One important advantage of this method is the ability to visualize and dissect in the mediastinum if ectopic glands are suspected. Some have argued that the magnification of the endoscope allows better visualization of the recurrent laryngeal nerve, while others state that visualization of the never is poorer due to less exposure.1,2,9,13

Fig. 3. View of a parathyroid adenoma through an endoscope.

with this technique are comparable to the previous techniques listed.1,2,9

A major disadvantage of this method is the steep learning curve for the surgical team to become proficient with the technique. Dedicated equipment must be purchased and maintained. Most endoscopic approaches to parathyroid surgery tend to have longer overall operative time, particularly in the early part of the learning curve. Some complications specific to this technique include subcutaneous emphysema, hypercapnia, respiratory acidosis, tachycardia, and air embolism.1,2,9,13 These may be reduced by lower-pressure insufflation used in some approaches.9 Also, the surgeon loses the tactile assessment that is possible in an open approach, and violation of the parathyroid capsule may be more likely when removing an adenoma from a small port.2 Despite these disadvantages, cure rates

#### **8.4 Minimally invasive video-assisted parathyroidectomy**

Minimally Invasive Video-Assisted Parathyroidectomy (MIVAP) was first described by Miccoli in 1998. 14 It is considered a gasless endoscopic technique, and, as with focused parathyroidecotmy, relies on preoperative localization studies and IPM. Like the focused technique, MIVAP is not an option for patients with multi-gland disease, conditions predisposing to multi-gland disease, parathyroid carcinoma, or failed preoperative localization. Additionally, patients with large goiters are not candidates for this approach.2,15

A 15-20mm incision is made in the midline, and the strap muscles are divided in at the raphe. Blunt dissection on the side of the neck as indicated by localization studies, and the strap muscles are retracted laterally from the thyroid using direct visualization. Then, a 5mm 30o endoscope is inserted into the wound. Working space is created by use of external retractors, so insufflation of CO2 is not necessary. Specialized 2mm endoscopic instruments are used to complete the dissection of the parathyroid adenoma and excise it from the surrounding tissue. If the adenoma is not found, or if PTH levels do not drop appropriately, the procedure is converted to a conventional bilateral neck exploration.1,2, 14, 15

The absence of insufflation in this technique avoids many of the complications of the total endoscopic approach. Also, operative times tend to be shorter than total endoscopic procedures. Miccoli reported an average operative time of 36.2 minutes in a series of 370 operations, and an average time of 25.7 minutes for the last 100 in that series.15 This procedure also affords the surgeon tactile assessment of the surgical bed, which is not available with total endoscopic approaches. However, the disadvantages of a long learning curve and specialized equipment remain. Also, 2 assistants are required for this technique.1,2

Cure rates with MIVAP are comparable to the other procedures described and have been reported at 96-100%. Complication rates are also comparable to the other approaches.1,2, 15

#### **9. Conclusion**

Although first performed nearly 100 years ago, parathyroid surgery has undergone rapid evolution over the past few decades. Advances in imaging, laboratory assay, and operative technique have made new methods possible. The varied minimally invasive techniques described in this chapter are all capable of producing satisfactory outcomes, and many offer significant advantages over traditional bilateral cervical exploration. Nonetheless, cure rates approaching 100% can only be achieved through evaluation of all four glands16. Parathyroid surgeons must be well versed in both traditional and minimally invasive techniques. As cure rates are high among all techniques listed, future refinement and innovation are likely to be directed at reducing complications, lowering overall cost, and improving patient satisfaction.

#### **10. References**


**11**

*India* 

**Management of Primary Hyperparathyroidism:** 

*Department of Surgical Disciplines, MOSC Medical College, Kolenchery, Cochin* 

Over the years the disease known as primary hyperparathyroidism has undergone a dramatic change in the clinical spectrum ranging from a symptomatic disease to an asymptomatic disease. In spite of the current understanding of the disease perspective, the

The standard treatment advocated and practiced for years could be considered as a source control operation involving routine bilateral exploration of the neck with an attempt to identify and eliminate the offending gland or glands. These surgeries were elaborate, time consuming and the success rates depended on the experience of the surgeon. Of late, certain novel and more patient-friendly techniques such as minimally invasive surgery and targeted selective gland excision are being performed with reportedly excellent

This chapter reviews and discusses the surgical aspects of parathyroid surgery including the evolution of surgery from the 'conventional bilateral cervical exploration' to recent advances such as 'minimally invasive surgery' and 'focused parathyroidectomy'. The clinical features of primary hyperparathyroidism and indications for parathyroidectomy are also described,

A good surgeon should also be an excellent anatomist. The ultimate triumph of the surgical management of primary hyperparathyroidism is often based on the surgeon's knowledge of the normal anatomical relationships and more so about the important embryologic

Practically everyone has at least four parathyroid glands, but their number can vary between 2 to 6. [Figure 1]. Thus in about 80% of cases there are symmetrically four (2 on either side) and in 5-13% of the cases they may be supernumerary (Hooghe et al., 1992). For example, in an autopsy study of 503 cases, in 84% there were four glands, 3% of the cases had only three glands, and in 13% there were supernumerary glands. The supernumerary

gland was often a fifth gland tucked away in the thymus (Akerström et al., 1984).

followed by a review of surgical techniques currently being practiced.

**2.1 The surgical anatomy of the parathyroid glands** 

variations of the parathyroid anatomy.

**1. Introduction** 

outcomes.

**2. Anatomy** 

mainstay of treatment is still surgical.

**'Past, Present and Future'** 

Sanoop K. Zachariah


### **Management of Primary Hyperparathyroidism: 'Past, Present and Future'**

Sanoop K. Zachariah

*Department of Surgical Disciplines, MOSC Medical College, Kolenchery, Cochin India* 

#### **1. Introduction**

146 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

[3] N. Johnson, S. Carty, M. Tublin. Parathyroid Imaging. Radiol Clin N Am. Volume 49.

[4] H. Chen, E. Mack, J.R. Sterling. A Comprehensive Evaluation of Perioperative Adjuncts

[5] R. Udelsman, Z. Lin, P. Donovan. The Superiority of Minimally Invasive

Hyperparathyroidism. Ann Surg. Volume 253. Issue 3. March 2011: 585-591. [6] H. Takami, Y. Ikeda, N. Wada Surgical management of primary hyperparathyroidixsm.

[7] D. Canerio-Pla. Contemporary and Practical Uses of Intraoperative Parathryoid Hormone Monitoring. Endocrine Practice. Vol 17. Suppl 1. March/April 2011: 44-53. [8] Y. Ikeda, J. Takayama, H. Takami. Minimally Invasive Radioguided Parathyroidectomy

[9] Y. Ikeda, H. Takami, G. Tajima, Y. Sasaki, J. Takayama, H. Kurihara, M. Niimi. Section 1.

[10] M. Weiss, R. Schmid, M. Hacker, T. Pfluger. Hyperparathryoidism: How to Optimize

[12] Norman J, Politz D. Measuring individual parathyroid gland hormone production in

[14] P. Micoli, C. Bendinelli, E. Vignali, S. Mazzeo, G. Matteo Cecchini, L. Pinchera, C.

[15] P. Miccoli, P. Berti, G. Materazzi, M. Massi, A. Picone, M. Minuto. Results of Video-

[16] Norman J. Controversies in Parathyroid Sugery: The Quest of a "mini" unilateral

operation seems to have gone too far. J Surg Oncol. 2011. In press.

During Minimally Invasive Parathyroidectomy. Ann Surg September2005: 242(3):

Parathyroidectomy Based on 1650 Consecutive Patients With Primary

Biomedicine & Pharmacotherapy. Volume 54. Supplement 1. June 2000: Pages 17s-20s

for Hyperparathyroidism. Annals of Nuclear Medicine. Volume 24. Number 4.

Parathyroid: Total Endoscopic Parathyroidectomy. Biomed Pharmacotherapy.

Parathyroid Imaging by Means of Tc-99m Sesta-MIBI Scintigraphy and Ultrasound? The Endocrinologist. Volume 17. Number 1. February 2007: 50-56. [11] Y. Ikeda, H. Takami, G. Tajima, Y, Sasaki, J. Takayama, H. Kurihara, M. Niimi. Section

1: Parathyroid: Direct Mini-Incision Parathyroidectomy. Biomed Pharmacotherapy.

real time during radio guided parathyroidectomy. Experience in over 8,000 operations. Minerva Endocrinology. Volume 33, Issue 3. September 2008: 147-157. [13] M. Gagner. Endoscopic subtotal parathyroidectomy in patients with primary

Marcocci. Endoscopic Parathyroidectomy: Report of an Initial Experience. Surgery.

assisted Parathyroidectomy: Single Institution's Six-year Expierence. World J Surg.

Issue 3. May 2011: 489-509.

March 2010: 233-240.

Volume 56. Supplement 1. 2002: 22s-25s.

Volume 56. Suplement 1. 2002: 14s-17s.

hyperparathyroidism. Br J Surg. 83. 1996: 875 [letter].

Volume 124. Issue 6. December 1998: 1077-1080.

Volume 28. Number 12. December 2004: 1216-1218.

375–383.

Over the years the disease known as primary hyperparathyroidism has undergone a dramatic change in the clinical spectrum ranging from a symptomatic disease to an asymptomatic disease. In spite of the current understanding of the disease perspective, the mainstay of treatment is still surgical.

The standard treatment advocated and practiced for years could be considered as a source control operation involving routine bilateral exploration of the neck with an attempt to identify and eliminate the offending gland or glands. These surgeries were elaborate, time consuming and the success rates depended on the experience of the surgeon. Of late, certain novel and more patient-friendly techniques such as minimally invasive surgery and targeted selective gland excision are being performed with reportedly excellent outcomes.

This chapter reviews and discusses the surgical aspects of parathyroid surgery including the evolution of surgery from the 'conventional bilateral cervical exploration' to recent advances such as 'minimally invasive surgery' and 'focused parathyroidectomy'. The clinical features of primary hyperparathyroidism and indications for parathyroidectomy are also described, followed by a review of surgical techniques currently being practiced.

#### **2. Anatomy**

#### **2.1 The surgical anatomy of the parathyroid glands**

A good surgeon should also be an excellent anatomist. The ultimate triumph of the surgical management of primary hyperparathyroidism is often based on the surgeon's knowledge of the normal anatomical relationships and more so about the important embryologic variations of the parathyroid anatomy.

Practically everyone has at least four parathyroid glands, but their number can vary between 2 to 6. [Figure 1]. Thus in about 80% of cases there are symmetrically four (2 on either side) and in 5-13% of the cases they may be supernumerary (Hooghe et al., 1992). For example, in an autopsy study of 503 cases, in 84% there were four glands, 3% of the cases had only three glands, and in 13% there were supernumerary glands. The supernumerary gland was often a fifth gland tucked away in the thymus (Akerström et al., 1984).

Management of Primary Hyperparathyroidism: 'Past, Present and Future' 149

About 15-19 % of the glands can be found in ectopic locations and distant from the thyroid lobes, mostly posterior alongside the esophagus, in the upper anterior mediastinum encapsulated in the thymus, and within the carotid sheath or even rarely (0.5-4%) embedded within the thyroid itself. (Wang, 1981; Feliciano, 1992). The ectopic or aberrant locations of the parathyroid gland are related to discrepancies during

In 80% of cases parathyroids are normal in position, symmetrical and paired.

 Supernumerary glands may be commonly found within thymus ("*para-thymus"*). Collateral blood supply from tracheal vessels is protective to the parathyroids.

Although functionally independent, the development of thyroid, parathyroid and the thymus are closely related to one another. The parathyroid glands develop from the cranial portions of the third and fourth pharyngeal (branchial) pouches on either side of the embryo and are therefore designated as *parathyroid glands III* and *parathyroid glands IV* respectively. Since these pouches are bilateral they should normally yield four

The **parathyroid III (the future inferior parathyroids**) and the thymus arise from the third branchial pouch from its dorsal and ventral wings respectively [figure2]. The downward descent of the thymus pulls the parathyroid III along with it. But parathyroids usually halt at the dorsal surface and outside the fibrous capsule of the thyroid gland while the thymus descends further beyond. This embryonic descent therefore places the parathyroid IIIs inferior to the parathyroid IVs in the neck, thereby designating them as inferior and superior parathyroids respectively. Discrepancies in this course of normal descent can cause the parathyroid IIIs to be situated at levels higher up in the neck (sometimes referred to as

The **parathyroid IV glands (the future superior parathyroids**) and the ultimobranchial bodies are derived from the fourth pharyngeal pouch and migrate together. The superior parathyroid glands travel with the ultimobranchial bodies and consequently migrate a shorter distance than the inferior glands. They therefore remain in contact with the posterior part of the middle third of the thyroid lobes and are in a comparatively more constant

 The superior parathyroid glands are typically located about 1 cm superior to the intersection of the inferior thyroid artery and the recurrent laryngeal nerve.[ along the

embryological development and descent.

About 20% of the parathyroids are ectopic.

65mg is the upper normal weight limit for a single gland.

Intra-thyroidal location of the parathyroid is rare.

**2.2 Applied surgical embryology of the parathyroids** 

 The superior parathyroids are more constant in location. The inferior parathyroids are more prone to become ectopic.

posterior border of the thyroid].

**Key points-1**

parathyroid glands.

'*undescended parathymus'*).

position in the neck.

**Key points-2** 

The parathyroid glands are oval shaped, well encapsulated and smooth, often the size of a split pea, and yellow, pink or tan in colour weighing around 20-40 mg each. Normal parathyroid glands measure approximately 6 mm in length, 3–4 mm in transverse diameter, and 1–2 mm in anteroposterior diameter. In addition to the yellowish tinge, these small glands are often camouflaged by a covering of fat making it difficult to identify them during surgery and may be confused with surrounding fat. The parathyroid gland usually weighs around 29.5 mg ± 17.8 (mean ± standard deviation), with a reported upper limit of 65 mg (Dufour & Wilkerson, 1983). However, the weight of the normal parathyroid glands removed at surgery in patients with primary hyperparathyroidism may be greater than that reported in autopsy studies (Yao et al., 2004).

Fig. 1. The normal location of paired parathyroids and a supernumerary fifth gland within the thymus.

The inferior parathyroid gland derives its blood supply from the inferior thyroid artery. In about 10% of patients, the inferior thyroid artery may be absent, in which case the superior thyroid artery supplies the inferior parathyroids (Delattre et al, 1982). The superior parathyroid gland is also usually supplied by the inferior thyroid artery or from an anatomizing artery joining the superior and inferior parathyroid arteries. In about 20-45% of cases, the superior parathyroid glands receive their blood supply from a posterior branch of the superior thyroid artery (Bonjer & Bruining, 1997; Nobori et al., 1994). There often exists a good collateral arterial supply from the tracheal vessels and therefore adequate parathyroid function persists even if all four major thyroid arteries are ligated.

About 15-19 % of the glands can be found in ectopic locations and distant from the thyroid lobes, mostly posterior alongside the esophagus, in the upper anterior mediastinum encapsulated in the thymus, and within the carotid sheath or even rarely (0.5-4%) embedded within the thyroid itself. (Wang, 1981; Feliciano, 1992). The ectopic or aberrant locations of the parathyroid gland are related to discrepancies during embryological development and descent.

#### **Key points-1**

148 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

The parathyroid glands are oval shaped, well encapsulated and smooth, often the size of a split pea, and yellow, pink or tan in colour weighing around 20-40 mg each. Normal parathyroid glands measure approximately 6 mm in length, 3–4 mm in transverse diameter, and 1–2 mm in anteroposterior diameter. In addition to the yellowish tinge, these small glands are often camouflaged by a covering of fat making it difficult to identify them during surgery and may be confused with surrounding fat. The parathyroid gland usually weighs around 29.5 mg ± 17.8 (mean ± standard deviation), with a reported upper limit of 65 mg (Dufour & Wilkerson, 1983). However, the weight of the normal parathyroid glands removed at surgery in patients with primary hyperparathyroidism may be greater than that

Fig. 1. The normal location of paired parathyroids and a supernumerary fifth gland within

The inferior parathyroid gland derives its blood supply from the inferior thyroid artery. In about 10% of patients, the inferior thyroid artery may be absent, in which case the superior thyroid artery supplies the inferior parathyroids (Delattre et al, 1982). The superior parathyroid gland is also usually supplied by the inferior thyroid artery or from an anatomizing artery joining the superior and inferior parathyroid arteries. In about 20-45% of cases, the superior parathyroid glands receive their blood supply from a posterior branch of the superior thyroid artery (Bonjer & Bruining, 1997; Nobori et al., 1994). There often exists a good collateral arterial supply from the tracheal vessels and therefore adequate parathyroid

function persists even if all four major thyroid arteries are ligated.

reported in autopsy studies (Yao et al., 2004).

the thymus.


#### **2.2 Applied surgical embryology of the parathyroids**

Although functionally independent, the development of thyroid, parathyroid and the thymus are closely related to one another. The parathyroid glands develop from the cranial portions of the third and fourth pharyngeal (branchial) pouches on either side of the embryo and are therefore designated as *parathyroid glands III* and *parathyroid glands IV* respectively. Since these pouches are bilateral they should normally yield four parathyroid glands.

The **parathyroid III (the future inferior parathyroids**) and the thymus arise from the third branchial pouch from its dorsal and ventral wings respectively [figure2]. The downward descent of the thymus pulls the parathyroid III along with it. But parathyroids usually halt at the dorsal surface and outside the fibrous capsule of the thyroid gland while the thymus descends further beyond. This embryonic descent therefore places the parathyroid IIIs inferior to the parathyroid IVs in the neck, thereby designating them as inferior and superior parathyroids respectively. Discrepancies in this course of normal descent can cause the parathyroid IIIs to be situated at levels higher up in the neck (sometimes referred to as '*undescended parathymus'*).

The **parathyroid IV glands (the future superior parathyroids**) and the ultimobranchial bodies are derived from the fourth pharyngeal pouch and migrate together. The superior parathyroid glands travel with the ultimobranchial bodies and consequently migrate a shorter distance than the inferior glands. They therefore remain in contact with the posterior part of the middle third of the thyroid lobes and are in a comparatively more constant position in the neck.

#### **Key points-2**


Management of Primary Hyperparathyroidism: 'Past, Present and Future' 151

**TYPE CAUSE TREATMENT** 

Surgery: open /minimal

Parathyroidectomy

medical management

Total parathyroidectomy with auto transplantation,

parathyroidectomy

access

Primarily

subtotal

Unregulated overproduction of parathyroid hormone resulting in abnormal calcium homeostasis, due to adenoma, hyperplasia or carcinoma, familial syndromes(MEN 1 or MEN 2a), familial isolated hyperparathyroidism

Excessive production of parathyroid hormone secondary to a chronic

Autonomous hypersecretion of parathyroid hormone causing hyperalcaemia often seen in chronic secondary hyperparathyroidism (prolonged compensatory stimulation) and often after renal transplantation.

abnormal stimulus such as chronic renal failure and vitamin D deficiency.

There is a wide variation in the incidence of PHPT geographically. This variation is most markedly seen in between the western world and developing countries. It is a common endocrine disease in countries where hyperalcaemia is detected at an early stage due to routine biochemical screening (Bilezikian et al, 2002*)*. The exact incidence of PHPT is difficult to define since many patients remain asymptomatic and the reported incidence varies according to the population studied. In the United States, the incidence of primary hyperparathyroidism is 2 to 3 per 1000 women and approximately 1 per 1000 men. The incidence increases to 2% after the age of 55 years. It is more commonly seen in postmenopausal woman older than 50 years. With the advent of multichannel biochemical screening in the 1970s, the incidence of PHPT increased around the world especially in western countries and this brought to light the existence of the entity referred to as

The exact cause of primary hyperparathyroidism is not clear and may possibly due to an underlying primary pathology of the parathyroid gland itself.The pathogenesis of PHPT may be sporadic or familial. Normally the parathyroid glands are composed of chief cells, oxyphil cells, and transitional oxyphil cells mixed with adipose tissue. Chief cells secrete parathyroid

The pathological lesions responsible for PHPT include **solitary adenomas** (>80%); **double adenomas** (2–3%) **multigland hyperplasia** (15%) and **carcinoma** (1-2%).**(Kaplan et al,1992)**

hormone. Sporadic PHPT involves abnormal tissue in the parathyroid gland [figure 3].

(FIHPT) etc.

Table 1. The spectrum of hyperparathyroidism

**Primary HPT** 

**Secondary HPT** 

**Tertiary HPT** 

**3.2 Incidence** 

'asymptomatic PHPT'.

**3.3 Etiopathogenesis** 

 The inferior glands are commonly found near the lower pole of the thyroid more often in an anterior plane.

Fig. 2. The developing branchial complex demonstrating the parathyroid III (P3) and thymus (T) budding from the third branchial pouch on the dorsal and ventral aspects respectively. Pathways of parathyroids III (P3) and IV (P4) denoted by arrows.

#### **3. Primary hyperparathyroidism**

Primary hyperparathyroidism (PHPT) is a hypercalcaemic state caused by excessive unregulated production of parathyroid hormone, resulting in defective calcium homeostasis. The secretion of parathyroid hormone is regulated directly by the plasma concentration of ionized calcium. The exact cause of spontaneous hyperfuctioning of the parathyroids is unknown and it is often recognized due to peripheral or systemic effects of the excess hormone.

PHPT can be regarded as a relatively recent disease owing to the fact that the parathyroid glands were the last major organ to be recognized in humans. (Elaraj & Clark, 2008). Ivar Sandström, a Swedish medical student, in 1879 was the first to describe the parathyroid glands. (Eknoyan, 1995)

#### **3.1 The spectrum of parathyroid disease**

Parathyroid disease usually manifests in three forms namely **primary, secondary** and **tertiary** hyperparathyroidism. **Primary hyperparathyroidism (PHPT)** is a relatively common endocrine disorder and is the commonest reason for surgical exploration. The other two forms are consequences of other disease processes.


Table 1. The spectrum of hyperparathyroidism

#### **3.2 Incidence**

150 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

The inferior glands are commonly found near the lower pole of the thyroid more often

Fig. 2. The developing branchial complex demonstrating the parathyroid III (P3) and thymus (T) budding from the third branchial pouch on the dorsal and ventral aspects respectively. Pathways of parathyroids III (P3) and IV (P4) denoted by arrows.

Primary hyperparathyroidism (PHPT) is a hypercalcaemic state caused by excessive unregulated production of parathyroid hormone, resulting in defective calcium homeostasis. The secretion of parathyroid hormone is regulated directly by the plasma concentration of ionized calcium. The exact cause of spontaneous hyperfuctioning of the parathyroids is unknown and it is often recognized due to peripheral or systemic effects of

PHPT can be regarded as a relatively recent disease owing to the fact that the parathyroid glands were the last major organ to be recognized in humans. (Elaraj & Clark, 2008). Ivar Sandström, a Swedish medical student, in 1879 was the first to describe the parathyroid

Parathyroid disease usually manifests in three forms namely **primary, secondary** and **tertiary** hyperparathyroidism. **Primary hyperparathyroidism (PHPT)** is a relatively common endocrine disorder and is the commonest reason for surgical exploration. The

in an anterior plane.

**3. Primary hyperparathyroidism** 

**3.1 The spectrum of parathyroid disease** 

other two forms are consequences of other disease processes.

the excess hormone.

glands. (Eknoyan, 1995)

There is a wide variation in the incidence of PHPT geographically. This variation is most markedly seen in between the western world and developing countries. It is a common endocrine disease in countries where hyperalcaemia is detected at an early stage due to routine biochemical screening (Bilezikian et al, 2002*)*. The exact incidence of PHPT is difficult to define since many patients remain asymptomatic and the reported incidence varies according to the population studied. In the United States, the incidence of primary hyperparathyroidism is 2 to 3 per 1000 women and approximately 1 per 1000 men. The incidence increases to 2% after the age of 55 years. It is more commonly seen in postmenopausal woman older than 50 years. With the advent of multichannel biochemical screening in the 1970s, the incidence of PHPT increased around the world especially in western countries and this brought to light the existence of the entity referred to as 'asymptomatic PHPT'.

#### **3.3 Etiopathogenesis**

The exact cause of primary hyperparathyroidism is not clear and may possibly due to an underlying primary pathology of the parathyroid gland itself.The pathogenesis of PHPT may be sporadic or familial. Normally the parathyroid glands are composed of chief cells, oxyphil cells, and transitional oxyphil cells mixed with adipose tissue. Chief cells secrete parathyroid hormone. Sporadic PHPT involves abnormal tissue in the parathyroid gland [figure 3].

The pathological lesions responsible for PHPT include **solitary adenomas** (>80%); **double adenomas** (2–3%) **multigland hyperplasia** (15%) and **carcinoma** (1-2%).**(Kaplan et al,1992)**

Management of Primary Hyperparathyroidism: 'Past, Present and Future' 153

Asymptomatic PHPT (APHPT) is the commonest form of the disease and therefore the most common clinical presentation of primary hyperparathyroidism is asymptomatic hyperalcaemia and this accounts for 75% to 80% of cases. However it should be understood that absence of any of the obvious classical clinical presentations is what is commonly referred to as asymptomatic disease. In such patients the symptoms are mild and nonspecific, often underestimated. But studies have shown that the so called asymptomatic patients will often have symptoms or metabolic complications when carefully evaluated with standardized health questionnaires. (Burney et al., 1999; Talpos et al., 2000). Patients may have weakness, fatigue, mild depression, anorexia, and often increased absence from work. These patients have mild and sometimes only intermittent hypercalcemia. In most of these cases, the mean serum calcium concentration is less than 1.0 mg/dL (0.25 mmol/L). Truly asymptomatic PHPT is therefore rare, occurring in only 2% to 5% of patients. (Chan et al, 1995; Clark et al, 1991) The importance of APHPT is that the surgical management of asymptomatic patients has been controversial and this very aspect has encouraged the

This was the original form of the disease and is still at large in developing countries. The signs and symptoms of hyperparathyroidism largely reflect the effects of hypercalcemia and

Classical symptoms of PHPT popularly summed up as "*bones, stones, abdominal groans and psychic moans"* are hardly ever encountered today. (Silverberg et al, 1999) This may be true in the western world. Conversely, in developing countries classic and severe forms of the disease are still the presenting features and asymptomatic PHPT is probably a rarity. Some

Bone related problems were the first to call attention to the disease and include manifestations of selective cortical bone loss. The high incidence of bone disease in patients with PHPT in developing countries has been attributed to associated vitamin D and dietary calcium deficiency (Harinarayan, 1995). The various classical clinical features are summed up in [Table 2]. Cardiovascular manifestations include hypertension, bradycardia, shortened QT interval, and left ventricular hypertrophy. It should be remembered that the symptoms

In developing countries the scenario and spectrum of the disease are therefore different. In a systematic review of data of 858 patients with PHPT, from India, showed that majority of the patients (71.5%) were less than 40 yrs of age, (whereas patients from developed nations are diagnosed in the fifth and sixth decades) (Pradeep et al, 2011). Interestingly, 5 to 33% had a clinically palpable parathyroid gland. Also, the incidence of parathyroid carcinoma causing PHPT in the various series has been 2.6 to 6%, which is higher than in developing countries. Moreover in India, asymptomatic presentation is virtually unheard of. The symptomatic disease is identified much later after a series of management for fractures and renal stones. Another study also showed similar results, where in, 67% had bone disease, 48% had fractures, 21% had stone disease, 23% had psychiatric symptoms and 15% had

**3.5.1 Asymptomatic PHPT** 

formulation of treatment guidelines.

may involve multiple organ systems (Taniegra, 2004).

of the classical radiological findings are shown in figure 4.

may not be proportional to magnitude of hypercalcaemia.

peptic ulcer disease (Bhansali et al, 2005).

**3.5.2 Symptomatic PHPT** 

Inherited disorders include familial hyperparathyroidism, multiple endocrine neoplasia syndrome (MEN type 1 and 2A), and hyperparathyroidism-jaw tumor syndrome and these account for roughly about 10% of PHPT. Other suggested causes include over expression of PRAD1 oncogene and also low dose irradiation to the neck during childhood.

#### **3.4 Double parathyroid adenomas -"fact or fiction"?**

Double parathyroid adenomas account for only a small percentage of the lesions associated with PHPT. Controversy still exists as to whether double adenomas are a distinct entity or part of four gland hyperplasia presenting metasynchronously. There is no reliable method to accurately distinguish adenoma from hyperplasia. Some authors feel that the most reliable clinical criteria to document double adenomas, is the absence of recurrent hyperparathyroidism on follow up of at least 5 years following selective gland excision (Baloch & LiVolsi., 2001). Meanwhile some others have authoritatively documented the existence of double adenoma as a separate entity and are not simply missed cases of four-gland hyperplasia. (Abboud et al., 2005). Neonatal convulsions as the initial presentation of maternal PHPT due to double parathyroid adenomas has also been described (Zachariah & Thomas, 2010).

Fig. 3. Photomicrograph of a solitary parathyroid adenoma showing hypercellular parathyroid tissue, absence of fat cells and surrounding capsule (Haematoxylin & Eosin \*40)

#### **3.5 Clinical features**

It is now well known or well phrased that *"The clinical presentation of PHPT has changed from a symptomatic to an asymptomatic disease"*. Patients with severe symptoms have become exceedingly rare. To make the discussion simpler, PHPT can be broadly classified into two types-namely symptomatic and asymptomatic PHPT, a view also supported by a National Institutes of Health consensus panel. (Bilezikian et al., 2002*;* Kearns & Thompson, 2002)

Clinical features are associated to the direct and indirect effects of excess parathyroid hormone on the skeleton, kidneys, and intestine may include bone resorption of calcium and phosphorus, enhanced intestinal absorption of calcium, renal tubular reabsorption of calcium, and hypercalciuria

#### **3.5.1 Asymptomatic PHPT**

152 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Inherited disorders include familial hyperparathyroidism, multiple endocrine neoplasia syndrome (MEN type 1 and 2A), and hyperparathyroidism-jaw tumor syndrome and these account for roughly about 10% of PHPT. Other suggested causes include over expression of

Double parathyroid adenomas account for only a small percentage of the lesions associated with PHPT. Controversy still exists as to whether double adenomas are a distinct entity or part of four gland hyperplasia presenting metasynchronously. There is no reliable method to accurately distinguish adenoma from hyperplasia. Some authors feel that the most reliable clinical criteria to document double adenomas, is the absence of recurrent hyperparathyroidism on follow up of at least 5 years following selective gland excision (Baloch & LiVolsi., 2001). Meanwhile some others have authoritatively documented the existence of double adenoma as a separate entity and are not simply missed cases of four-gland hyperplasia. (Abboud et al., 2005). Neonatal convulsions as the initial presentation of maternal PHPT due to double

PRAD1 oncogene and also low dose irradiation to the neck during childhood.

parathyroid adenomas has also been described (Zachariah & Thomas, 2010).

Fig. 3. Photomicrograph of a solitary parathyroid adenoma showing hypercellular

**3.5 Clinical features** 

calcium, and hypercalciuria

parathyroid tissue, absence of fat cells and surrounding capsule (Haematoxylin & Eosin \*40)

It is now well known or well phrased that *"The clinical presentation of PHPT has changed from a symptomatic to an asymptomatic disease"*. Patients with severe symptoms have become exceedingly rare. To make the discussion simpler, PHPT can be broadly classified into two types-namely symptomatic and asymptomatic PHPT, a view also supported by a National Institutes of Health consensus panel. (Bilezikian et al., 2002*;* Kearns & Thompson, 2002)

Clinical features are associated to the direct and indirect effects of excess parathyroid hormone on the skeleton, kidneys, and intestine may include bone resorption of calcium and phosphorus, enhanced intestinal absorption of calcium, renal tubular reabsorption of

**3.4 Double parathyroid adenomas -"fact or fiction"?** 

Asymptomatic PHPT (APHPT) is the commonest form of the disease and therefore the most common clinical presentation of primary hyperparathyroidism is asymptomatic hyperalcaemia and this accounts for 75% to 80% of cases. However it should be understood that absence of any of the obvious classical clinical presentations is what is commonly referred to as asymptomatic disease. In such patients the symptoms are mild and nonspecific, often underestimated. But studies have shown that the so called asymptomatic patients will often have symptoms or metabolic complications when carefully evaluated with standardized health questionnaires. (Burney et al., 1999; Talpos et al., 2000). Patients may have weakness, fatigue, mild depression, anorexia, and often increased absence from work. These patients have mild and sometimes only intermittent hypercalcemia. In most of these cases, the mean serum calcium concentration is less than 1.0 mg/dL (0.25 mmol/L). Truly asymptomatic PHPT is therefore rare, occurring in only 2% to 5% of patients. (Chan et al, 1995; Clark et al, 1991) The importance of APHPT is that the surgical management of asymptomatic patients has been controversial and this very aspect has encouraged the formulation of treatment guidelines.

#### **3.5.2 Symptomatic PHPT**

This was the original form of the disease and is still at large in developing countries. The signs and symptoms of hyperparathyroidism largely reflect the effects of hypercalcemia and may involve multiple organ systems (Taniegra, 2004).

Classical symptoms of PHPT popularly summed up as "*bones, stones, abdominal groans and psychic moans"* are hardly ever encountered today. (Silverberg et al, 1999) This may be true in the western world. Conversely, in developing countries classic and severe forms of the disease are still the presenting features and asymptomatic PHPT is probably a rarity. Some of the classical radiological findings are shown in figure 4.

Bone related problems were the first to call attention to the disease and include manifestations of selective cortical bone loss. The high incidence of bone disease in patients with PHPT in developing countries has been attributed to associated vitamin D and dietary calcium deficiency (Harinarayan, 1995). The various classical clinical features are summed up in [Table 2]. Cardiovascular manifestations include hypertension, bradycardia, shortened QT interval, and left ventricular hypertrophy. It should be remembered that the symptoms may not be proportional to magnitude of hypercalcaemia.

In developing countries the scenario and spectrum of the disease are therefore different. In a systematic review of data of 858 patients with PHPT, from India, showed that majority of the patients (71.5%) were less than 40 yrs of age, (whereas patients from developed nations are diagnosed in the fifth and sixth decades) (Pradeep et al, 2011). Interestingly, 5 to 33% had a clinically palpable parathyroid gland. Also, the incidence of parathyroid carcinoma causing PHPT in the various series has been 2.6 to 6%, which is higher than in developing countries. Moreover in India, asymptomatic presentation is virtually unheard of. The symptomatic disease is identified much later after a series of management for fractures and renal stones. Another study also showed similar results, where in, 67% had bone disease, 48% had fractures, 21% had stone disease, 23% had psychiatric symptoms and 15% had peptic ulcer disease (Bhansali et al, 2005).

Management of Primary Hyperparathyroidism: 'Past, Present and Future' 155

The association between pancreatitis and hyperparathyroidism was first reported in 1940 by Smith and Cooke. (Bess et al, 1980). The commonest manifestation of pancreatic disease with PHPT is the history of recurrent upper abdominal pain. A high concentration of serum calcium may responsible for the increased incidence of gall stone disease in PHPT and this is

The diagnosis of PHPT is based on the documentation of elevated serum calcium in combination with elevated serum parathyroid hormone (PHT) levels. The initial finding of an elevated serum calcium (ionized fraction) level should always raise the suspicion of PHPT and in such cases hypercalceamia should be confirmed by a repeat test. In such cases, other causes of hypercalcaemia should be excluded (history of vitamin D intake, thiazide diuretics and family history of hypercalcemia). Elevated parathyroid hormone levels in the presence of persistent hypercalcemia confirms the diagnosis of primary hyperparathyroidism. Inorder to eliminate the variations that can occur with respect to time, blood volume, and dietary intake the PTH and serum calcium levels should be measured

The first generation parathyroid hormone assays is becoming obsolete. Second-generation parathyroid hormone assays (known as 'intact'), and third-generation parathyroid hormone

The concentration of serum phosphate varies between 2.5 and 4.5 mg/100ml. About half the patients with PHPT have hypo-phosphataemia provided they do not have significant renal impairment. Also, 10-40% of patients have elevated levels of serum alkaline phospatase and almost all these patients have significant bone invovelment. Imaging studies have no role in

Recently a new clinical phenotype of PHPT has been identified known as **normocalcemic PHPT. Eucalcemic primary hyperparathyroidism** may represent the earliest manifestation of primary hyperparathyroidism. As for now more information is needed on this entity to

**Surgery provides the only available cure for primary hyperparathyroidism**. Although operative management is clearly indicated for all patients with symptomatic PHPT (classic symptoms or complications of PHPT), the role of surgery for asymptomatic PHPT is still

There is no doubt patients with **symptomatic PHPT** should undergo surgery as there is enough evidence of symptomatic improvement and reversal of the effects of PHPT (such as

the diagnosis of primary hyperparathyroidism and are mainly used for localization.

consider its routine evaluation in PHPT (Peacock et al, 2005; Lowe et al, 2007).

**5.1 Decision making: "Current indications and guidelines"** 

seen especially in developing countries

**4.1 Laboratory diagnosis** 

simultaneously.

controversial.

**4.2 Additional investigations** 

**5. The surgical management of PHPT** 

**4. Making the diagnosis of primary hyperparathyroidism** 

assays (known as 'whole or bio-intact') are becoming more popular.

Fig. 4. SYMPTOMATIC PHPT: (A) Xray of the hands showing subperiosteal bone resorption over the middle phalanges (white arrows). (B) Showing *"salt and pepper"* appearance of the skull. (C) Showing a dental cystic lesion over the mandible.


Table 2. Clincal features of classical disease

The association between pancreatitis and hyperparathyroidism was first reported in 1940 by Smith and Cooke. (Bess et al, 1980). The commonest manifestation of pancreatic disease with PHPT is the history of recurrent upper abdominal pain. A high concentration of serum calcium may responsible for the increased incidence of gall stone disease in PHPT and this is seen especially in developing countries

#### **4. Making the diagnosis of primary hyperparathyroidism**

#### **4.1 Laboratory diagnosis**

154 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Fig. 4. SYMPTOMATIC PHPT: (A) Xray of the hands showing subperiosteal bone resorption over the middle phalanges (white arrows). (B) Showing *"salt and pepper"* appearance of the

**INVOLVED FEATURES** 

(rare: 3-5%) Hypercalciuria

Acute Pancreatitis Cholelithiasis (25-30%)

Depression; Poor Libido;

cysts

Bone & Joint Pain;

Osteoclastic Bone Resorption,Pseudo-gout; Chondrocalcinosis;Brown tumour, Bone

Nephrolithiasis (35-50%); Nephrocalcinosis

Cramps;Constipation;Acid Peptic Disease;

Polyuria; Haematuria; Graveluria; Recurrent urinary tract infections

Anorexia;Vomiting;Abdominal

Memory Loss,Lack of concentration

skull. (C) Showing a dental cystic lesion over the mandible.

Muscular

Manifestations

**SYMPTOMATOLOGY ORGAN SYSTEM** 

**Bones** Skeletal And Neuro-

**Abdominal Groans** Gastro-Intestinal

Table 2. Clincal features of classical disease

**Psychic Moans** Psychological

**Stones** Renal

The diagnosis of PHPT is based on the documentation of elevated serum calcium in combination with elevated serum parathyroid hormone (PHT) levels. The initial finding of an elevated serum calcium (ionized fraction) level should always raise the suspicion of PHPT and in such cases hypercalceamia should be confirmed by a repeat test. In such cases, other causes of hypercalcaemia should be excluded (history of vitamin D intake, thiazide diuretics and family history of hypercalcemia). Elevated parathyroid hormone levels in the presence of persistent hypercalcemia confirms the diagnosis of primary hyperparathyroidism. Inorder to eliminate the variations that can occur with respect to time, blood volume, and dietary intake the PTH and serum calcium levels should be measured simultaneously.

The first generation parathyroid hormone assays is becoming obsolete. Second-generation parathyroid hormone assays (known as 'intact'), and third-generation parathyroid hormone assays (known as 'whole or bio-intact') are becoming more popular.

#### **4.2 Additional investigations**

The concentration of serum phosphate varies between 2.5 and 4.5 mg/100ml. About half the patients with PHPT have hypo-phosphataemia provided they do not have significant renal impairment. Also, 10-40% of patients have elevated levels of serum alkaline phospatase and almost all these patients have significant bone invovelment. Imaging studies have no role in the diagnosis of primary hyperparathyroidism and are mainly used for localization.

Recently a new clinical phenotype of PHPT has been identified known as **normocalcemic PHPT. Eucalcemic primary hyperparathyroidism** may represent the earliest manifestation of primary hyperparathyroidism. As for now more information is needed on this entity to consider its routine evaluation in PHPT (Peacock et al, 2005; Lowe et al, 2007).

#### **5. The surgical management of PHPT**

**Surgery provides the only available cure for primary hyperparathyroidism**. Although operative management is clearly indicated for all patients with symptomatic PHPT (classic symptoms or complications of PHPT), the role of surgery for asymptomatic PHPT is still controversial.

#### **5.1 Decision making: "Current indications and guidelines"**

There is no doubt patients with **symptomatic PHPT** should undergo surgery as there is enough evidence of symptomatic improvement and reversal of the effects of PHPT (such as

Management of Primary Hyperparathyroidism: 'Past, Present and Future' 157

The argument was that, in the hands of an experienced parathyroid surgeon, 95%to 97% of the cases could be resolved by a single neck exploration. Thus, in the past, the only indication for preoperative localization was re-exploration following an unsuccessful parathyroidectomy. The various modalities for preoperative location are listed in table.

Cheap & non invasive, no radiation, can localize upto 80%

Thin-section contrast-enhanced CT is reported to have a

The 'trend setter' and breakthrough investigation. "The preoperative localization investigation of choice in

are less likely to be cured.( Allendorf et al,2003) Combined with single photon-emission computed tomography (SPECT) can localize 90% of adenomas

including ectopics.( Ho Shon et al,2001)

The interest in preoperative localization techniques is being given even more importance now, as more and more minimal access techniques are being developed for parathyroidectomy. Therefore it would be logical if the offending gland could be accurately localized as a part of preoperative planning. Preoperative localization would be advantageous for a single gland disease, but its utility in multi-gland disease is questionable. At present no single method of parathyroid localization matches to the unguided neck exploration by an experienced surgeon.

positive sestamibi does not improve surgical outcome Negative sestamibi scan is a predictor of those patients that

Ultrasound scan (USG) and Technetium (Tc 99m) sestamibi scanning are combined, localization of a parathyroid adenoma is accurate in over 95% of cases (Miura et al,2002) Allows preoperative skin marking of the parathyroid

Not very useful for ectopic parathyroids

USG guided FNAC can help confirm an adenoma

**MODALITY COMMENTS** 

of adenomas.

preoperatively

Expensive.

Expensive.

position.

parathyroid disease"

Reported accuracy 75%-80%

Useful for localizing ectopic glands

sensitivity ranging from 46% to 87%.

Useful for localizing ectopic glands Sensitivity of MRI is about 65% to 80%

**IMAGING** 

Ultrasonography

Magnetic Resonsce Imaging (T2- Weighted MRI)

Tc99m Sestamibi

Combined USG + Tc99m Sestamibi

Table 4. Techniques of preoperative localization.

Scanning

Scanning

(USG)

Computed Tomography Scan(CT)

improvement in bone density, reduction in fractures, reduced frequency of kidney stones, and improvements in some neurocognitive elements and sense of well being).

Controversy still exists as whether patients with **asymptomatic PHPT** should undergo surgery. Data increasingly appears to support parathyroidectomy in all patients with PHPT because it is associated with a quantifiable improvement in health related quality of life**. (**Sheldon et al, 2002**)**.

However, among the so called 'asymptomatic patients' only about 2-5% are truly asymptomatic. Inorder to address this issue and set down guidelines, three conferences have been held on the management of asymptomatic PHPT during the past 18 years. The most recent conference (the third) was held in 2008 from which summary of guidelines are available for reference. Important aspects based on the current guidelines for surgical intervention and for medical surveillance, for patients with asymptomatic hyperparathyroidism are listed in table 3. (Bilezikian et al, 2009). As for now the surgical treatment should definitely be based on these guidelines.


Table 3. Current guidelines for surgical management of asymptomatic PHPT

#### **5.2 Pre-operative localization: "Chasing the target"**

Once we have confirmed the diagnosis of primary hyperparathyroidism from the laboratory and clinical information, the next and one of the most important step is to identify the source of the disease process.

In the past the only way of identifying an abnormal gland was at the time of bilateral neck exploration and the best tool available was an experienced surgeon!! This is aptly reflected in the words of Doppmann *"in my opinion, the only localizing study indicated in a patient with untreated hyperparathyroidism is to localize an experienced parathyroid surgeon."(*Doppmann, 1986).

improvement in bone density, reduction in fractures, reduced frequency of kidney stones,

Controversy still exists as whether patients with **asymptomatic PHPT** should undergo surgery. Data increasingly appears to support parathyroidectomy in all patients with PHPT because it is associated with a quantifiable improvement in health related quality of life**.** 

However, among the so called 'asymptomatic patients' only about 2-5% are truly asymptomatic. Inorder to address this issue and set down guidelines, three conferences have been held on the management of asymptomatic PHPT during the past 18 years. The most recent conference (the third) was held in 2008 from which summary of guidelines are available for reference. Important aspects based on the current guidelines for surgical intervention and for medical surveillance, for patients with asymptomatic hyperparathyroidism are listed in table 3. (Bilezikian et al, 2009). As for now the surgical

FACTOR CRITERIA

Serum Calcium >1 mg/dl Above Normal Upper Limit Of Normal

(BMD) T-Score<-2.5 At Lumbar Spine, Hip, Or Forearm

without surgery)

Monitor:

Once we have confirmed the diagnosis of primary hyperparathyroidism from the laboratory and clinical information, the next and one of the most important step is to identify the

In the past the only way of identifying an abnormal gland was at the time of bilateral neck exploration and the best tool available was an experienced surgeon!! This is aptly reflected in the words of Doppmann *"in my opinion, the only localizing study indicated in a patient with untreated hyperparathyroidism is to localize an experienced parathyroid surgeon."(*Doppmann,

Table 3. Current guidelines for surgical management of asymptomatic PHPT

24 hr Urine Calcium Not Indicated (Hypercalciuria By Itself Is Not

Considered An Indication For Surgery)

serum calcium levels biannually Serum creatinine levels-annually BMD 1-2 years at three sites

Medical surveillance (Can be safely managed

Asymptomatic No Kidney Stones, Nephrocalcinosis, Fractures, Or Other Symptoms

and improvements in some neurocognitive elements and sense of well being).

treatment should definitely be based on these guidelines.

Age <50 years

Creatinine Clearance <60 ml/Min

Asymptomatic PHPT who

**5.2 Pre-operative localization: "Chasing the target"** 

do not meet above criteria(1,2,3,4,5,6)

source of the disease process.

1986).

Bone Mineral Density

**(**Sheldon et al, 2002**)**.

The argument was that, in the hands of an experienced parathyroid surgeon, 95%to 97% of the cases could be resolved by a single neck exploration. Thus, in the past, the only indication for preoperative localization was re-exploration following an unsuccessful parathyroidectomy. The various modalities for preoperative location are listed in table.


Table 4. Techniques of preoperative localization.

The interest in preoperative localization techniques is being given even more importance now, as more and more minimal access techniques are being developed for parathyroidectomy. Therefore it would be logical if the offending gland could be accurately localized as a part of preoperative planning. Preoperative localization would be advantageous for a single gland disease, but its utility in multi-gland disease is questionable. At present no single method of parathyroid localization matches to the unguided neck exploration by an experienced surgeon.

Management of Primary Hyperparathyroidism: 'Past, Present and Future' 159

equally high cure rates with lower complication rates (Udelsman R, 2002; Bergenfelz et al.,

An average Kochers collar incision was usually about 8-10cm long. With time surgeons learned to perform the conventional bilateral exploration utilizing smaller incisions of about 4.1 cm **(**Brunaud et al, 2003**).** The point at which the procedure becomes a minimal-access operation probably is best defined by the length of the incision. It has been suggested that the procedure can be referred to as MAP when the inscion length is less than 2.5cm for a

Fig. 5. Schematic representation comparing length of incisions of conventional (A) and

**5.4 Types of minimal access surgeries for parathyroid -"An overview of assortments"** 

The feasibility of unilateral neck exploration is based on the fact that that 85-90% of patients have single gland disease which could be preoperatively accurately localized by 99mTc sestamibi scanning and/or ultrasound. Therefore such patients require excision of only one gland to achieve a cure. The unilateral approach to the solitary parathyroid adenoma was

A meta-analysis of 99mTc sestamibi scanning has revealed a sensitivity and specificity of 90.7% and 98.8% respectively suggesting that the majority of patients may be suitable for unilateral exploration (Denham & Norman, 1998). A prospective randomized trial compared unilateral versus bilateral neck exploration in 91 patients. There was no statistically significant difference in the incidence of multiglandular disease, costs, or cure rate (95.1% vs. 97.5%) between unilateral versus bilateral exploration. However patients who underwent unilateral neck exploration had a lower incidence of biochemical and early severe symptomatic hypocalcaemia compared to patients who underwent bilateral

2002; Goldstein et al., 2000).

patient with BMI of less than 30.

minimally invasive parathyroidectomy (B).

**5.4.1 Unilateral neck exploration (UNE)** 

exploration (Bergenfelz et al, 2002).

advocated by Wang and later refined by Tibblin et al.

#### **Key points-3**


#### **5.3 Parathyroidectomy: "The dawn of a new concept"**

Felix Mandl performed the first successful parathyroidectomy in Vienna in 1925. (Mandl, 1925). Thereafter and for a considerably long time the standard accepted procedure was wide exposure, for bilateral neck exploration and evaluation of all the four parathyroids.

The surgical treatment for PHPT has undergone a dramatic change in the last decade owing to the development of better localization techniques. The standard treatment advocated and practiced for years could be considered as a source control operation involving routine bilateral exploration of the neck with an attempt to identify and eliminate the offending gland or glands. These surgeries were elaborate, time consuming and the success rates depended on the experience of the surgeon. When performed by experienced surgeons, cure rates with parathyroidectomy are 95% to 98%, and complication rates are 1% to 2%. (Schell & Dudley, 2003; Clark, 1997) Of late, certain novel and more patient -friendly techniques such as minimally invasive surgery and targeted selective gland excision are being performed with reportedly excellent outcomes.

The present era of 'minimal access surgery' has made considerable progress in the field of parathyroid surgery too. The recent trend is to develop procedures that require significantly smaller incisions for performing the same procedure. The routinely performed parathyroid exploration which made use of the large Kocher cervicotomy can be now be conveniently referred to as the, 'conventional' or 'standard parathyroidectomy'. Any other surgical method or access entailing a smaller incision could therefore be referred to as minimal access parathyroidectomy **(MAP)** or minimally invasive parathyroidectomy **(MIP).**

The protocol of bilateral neck exploration was challenged initially in the 1980s, when a unilateral approach was advocated in an attempt to avoid the need for contralateral exploration and its associated risks (Wang, 1985; Tibblin, et al., 1982; Russell et al., 1990).

There was a dramatic change in concept following the introduction of Tc99m-sestamibi parathyroid scanning especially with reports such as simultaneous sestamibi and ultrasound of the neck could localize an enlarged parathyroid gland with almost 95% accuracy. The rationale was that if the abnormal parathyroids could be localized accurately then they could be appropriately targeted and removed through very small incisions, thereby offering the proclaimed advantageous of minimally invasive surgery in a general perspective. This thought paved the way for developing minimal-access parathyroid surgeries.

Many studies have shown that minimally invasive parathyroidectomy offers advantages like reduced hospital costs, shorter hospital stays, a lower incidence of hypocalcemia, and

Preoperative localization studies help plan the operative approach in patients who have

 Imaging studies are mainly used for localization and they have no role in the diagnosis. A single site positive imaging result does not rule out the possibility of multiglandular

Tc-99m sestamibi-SPECT scanning has been shown to be the best imaging modality to

Felix Mandl performed the first successful parathyroidectomy in Vienna in 1925. (Mandl, 1925). Thereafter and for a considerably long time the standard accepted procedure was wide exposure, for bilateral neck exploration and evaluation of all the four parathyroids.

The surgical treatment for PHPT has undergone a dramatic change in the last decade owing to the development of better localization techniques. The standard treatment advocated and practiced for years could be considered as a source control operation involving routine bilateral exploration of the neck with an attempt to identify and eliminate the offending gland or glands. These surgeries were elaborate, time consuming and the success rates depended on the experience of the surgeon. When performed by experienced surgeons, cure rates with parathyroidectomy are 95% to 98%, and complication rates are 1% to 2%. (Schell & Dudley, 2003; Clark, 1997) Of late, certain novel and more patient -friendly techniques such as minimally invasive surgery and targeted selective gland excision are being

The present era of 'minimal access surgery' has made considerable progress in the field of parathyroid surgery too. The recent trend is to develop procedures that require significantly smaller incisions for performing the same procedure. The routinely performed parathyroid exploration which made use of the large Kocher cervicotomy can be now be conveniently referred to as the, 'conventional' or 'standard parathyroidectomy'. Any other surgical method or access entailing a smaller incision could therefore be referred to as minimal

The protocol of bilateral neck exploration was challenged initially in the 1980s, when a unilateral approach was advocated in an attempt to avoid the need for contralateral exploration and its associated risks (Wang, 1985; Tibblin, et al., 1982; Russell et al., 1990).

There was a dramatic change in concept following the introduction of Tc99m-sestamibi parathyroid scanning especially with reports such as simultaneous sestamibi and ultrasound of the neck could localize an enlarged parathyroid gland with almost 95% accuracy. The rationale was that if the abnormal parathyroids could be localized accurately then they could be appropriately targeted and removed through very small incisions, thereby offering the proclaimed advantageous of minimally invasive surgery in a general perspective. This thought paved the way for developing minimal-access

Many studies have shown that minimally invasive parathyroidectomy offers advantages like reduced hospital costs, shorter hospital stays, a lower incidence of hypocalcemia, and

access parathyroidectomy **(MAP)** or minimally invasive parathyroidectomy **(MIP).**

biochemically confirmed diagnosis of primary hyperparathyroidism.

**Key points-3** 

disease.

localize parathyroid adenomas.

performed with reportedly excellent outcomes.

parathyroid surgeries.

**5.3 Parathyroidectomy: "The dawn of a new concept"** 

equally high cure rates with lower complication rates (Udelsman R, 2002; Bergenfelz et al., 2002; Goldstein et al., 2000).

An average Kochers collar incision was usually about 8-10cm long. With time surgeons learned to perform the conventional bilateral exploration utilizing smaller incisions of about 4.1 cm **(**Brunaud et al, 2003**).** The point at which the procedure becomes a minimal-access operation probably is best defined by the length of the incision. It has been suggested that the procedure can be referred to as MAP when the inscion length is less than 2.5cm for a patient with BMI of less than 30.

Fig. 5. Schematic representation comparing length of incisions of conventional (A) and minimally invasive parathyroidectomy (B).

#### **5.4 Types of minimal access surgeries for parathyroid -"An overview of assortments"**

#### **5.4.1 Unilateral neck exploration (UNE)**

The feasibility of unilateral neck exploration is based on the fact that that 85-90% of patients have single gland disease which could be preoperatively accurately localized by 99mTc sestamibi scanning and/or ultrasound. Therefore such patients require excision of only one gland to achieve a cure. The unilateral approach to the solitary parathyroid adenoma was advocated by Wang and later refined by Tibblin et al.

A meta-analysis of 99mTc sestamibi scanning has revealed a sensitivity and specificity of 90.7% and 98.8% respectively suggesting that the majority of patients may be suitable for unilateral exploration (Denham & Norman, 1998). A prospective randomized trial compared unilateral versus bilateral neck exploration in 91 patients. There was no statistically significant difference in the incidence of multiglandular disease, costs, or cure rate (95.1% vs. 97.5%) between unilateral versus bilateral exploration. However patients who underwent unilateral neck exploration had a lower incidence of biochemical and early severe symptomatic hypocalcaemia compared to patients who underwent bilateral exploration (Bergenfelz et al, 2002).

Management of Primary Hyperparathyroidism: 'Past, Present and Future' 161

Minimally invasive endoscopic parathyroidectomy **(MIEP)** is now regarded as a feasible surgical procedure. Early work on endoscopic approach to parathyroid disease was first

The neck is obviously a small area, and therefore the major technical challenge of an endoscopic approach to parathyroidectomy was creation of enough working space to obtain

Enthusiasts have tried and tested various approaches including a three-port lateral approach along the anterior border of the sternomastoid muscle (Henry et al,1999) to a midline suprasternal port and two lateral ports on the same or opposite sides of the neck, in front or behind the sternomastoid muscle (Gauger et al, 1999). Irrespective of the port placement, the technique is essentially an endoscopic lateral approach. [Figure 7& 8] An axillary approach has also been described, inserting three trocars through the axilla. This

Fig. 7. Port positions in endoscopic parathyroidectomy using central access technique

**5.4.4 Minimally invasive videoscopically assisted parathyroidectomy (MIVAP)** 

Miccoli P et al developed and described this gaseless procedure in 1998. The localized adenoma is approached via a 1.5 cm suprasternal incision, through which 5 mm endoscope

**5.4.3 Endoscopic parathyroidectomy / Minimally invasive endoscopic** 

**parathyroidectomy (MIEP)** 

described by Gagner. (Gagner, 1996)

adequate exposure and freedom of movement.

completely avoids any scars in the neck or anterior chest.

In another series of 184 patients who underwent scan-directed UNE, long term cure rates of 98.4% were reported (Sidhu et al, 2003)

Fig. 6. Chart showing types of minimal access procedures for parathyroidectomy

#### **5.4.2 Focused parathyoidectomy (FNE)**

Also known as focused neck exploration(FNE). FNE can be performed as a day-case surgery and either under general anesthesia, cervical block, local anesthesia and sedation (Agarwal et al, 2002). Following 150 MIPs, 74 patients were discharged the same day and a further 70 were discharged the following day (within 23 h) (Mihai et al, 2007).

The technique usually makes use of a small (2cm) lateral incision to enter the space between the lateral border of the strap muscles and sternomastoid and thereby reach the lateral border of the thyroid gland and gain direct access to the parathyroid bearing areas. An FNE can be performed in as little as 12 minutes (Delbridge, 2003) and is achieved fully maintaining the principles, established with conventional parathyroid surgery.

Similar conclusions were drawn from a retrospective study comparing 255 focused lateral approaches to 401 bilateral neck explorations ,where there was no significant difference in surgical success (99% versus 97%) or complication rates (1.2% versus 3%). However a favorable reduction in the operating time from 2.4 hours to 1.3 hours for MIP was demonstrated.

As with FNE the obvious advantages are that these explorations are suitable for those patients who may otherwise be high risk candidates for general anesthesia.

In another series of 184 patients who underwent scan-directed UNE, long term cure rates of

Fig. 6. Chart showing types of minimal access procedures for parathyroidectomy

were discharged the following day (within 23 h) (Mihai et al, 2007).

maintaining the principles, established with conventional parathyroid surgery.

patients who may otherwise be high risk candidates for general anesthesia.

Also known as focused neck exploration(FNE). FNE can be performed as a day-case surgery and either under general anesthesia, cervical block, local anesthesia and sedation (Agarwal et al, 2002). Following 150 MIPs, 74 patients were discharged the same day and a further 70

The technique usually makes use of a small (2cm) lateral incision to enter the space between the lateral border of the strap muscles and sternomastoid and thereby reach the lateral border of the thyroid gland and gain direct access to the parathyroid bearing areas. An FNE can be performed in as little as 12 minutes (Delbridge, 2003) and is achieved fully

Similar conclusions were drawn from a retrospective study comparing 255 focused lateral approaches to 401 bilateral neck explorations ,where there was no significant difference in surgical success (99% versus 97%) or complication rates (1.2% versus 3%). However a favorable reduction in the operating time from 2.4 hours to 1.3 hours for MIP was

As with FNE the obvious advantages are that these explorations are suitable for those

98.4% were reported (Sidhu et al, 2003)

**5.4.2 Focused parathyoidectomy (FNE)** 

demonstrated.

#### **5.4.3 Endoscopic parathyroidectomy / Minimally invasive endoscopic parathyroidectomy (MIEP)**

Minimally invasive endoscopic parathyroidectomy **(MIEP)** is now regarded as a feasible surgical procedure. Early work on endoscopic approach to parathyroid disease was first described by Gagner. (Gagner, 1996)

The neck is obviously a small area, and therefore the major technical challenge of an endoscopic approach to parathyroidectomy was creation of enough working space to obtain adequate exposure and freedom of movement.

Enthusiasts have tried and tested various approaches including a three-port lateral approach along the anterior border of the sternomastoid muscle (Henry et al,1999) to a midline suprasternal port and two lateral ports on the same or opposite sides of the neck, in front or behind the sternomastoid muscle (Gauger et al, 1999). Irrespective of the port placement, the technique is essentially an endoscopic lateral approach. [Figure 7& 8] An axillary approach has also been described, inserting three trocars through the axilla. This completely avoids any scars in the neck or anterior chest.

#### **5.4.4 Minimally invasive videoscopically assisted parathyroidectomy (MIVAP)**

Miccoli P et al developed and described this gaseless procedure in 1998. The localized adenoma is approached via a 1.5 cm suprasternal incision, through which 5 mm endoscope

Management of Primary Hyperparathyroidism: 'Past, Present and Future' 163

50% of its preoperative (baseline ) value, within 10 to 15 minutes. Studies have reported that a 50% reduction from pre-excision PTH values within 5-10 minutes of adenoma excision can accurately predict post-operative normocalcaemia. (Inabnet et al, 1999)**.** In other words, a decrease of more than 50% from the baseline value at 5–10 minutes after resection is suggestive of a single gland disease (solitary adenoma). However, if such a drop does not occur, then the possibility of multi gland disease is likely, and a conversion to bilateral neck

**OUTCOMES COMMENTS** 

hypoparathyroidism <1%

et al 2011)

scars

neck & torso

Hospital stay Shorter hospital stay < 23 hrs

exploration is not routinely necessary, in all patients.

Table 5. Overview of outcomes in minimal access parathyroidectomy

Cure rates Similar cure rates between MAP and conventional parathyroidectomy 95%-100%

Similar complication rates between minmal access

Recurrent laryngeal nerve injury and transient

Post operative haemorrhage (0.2%–0.5%)

The disadvantages described include its cost,and interaction with anesthetic drug propofol (which should be stopped 5-10 minutes before blood sampling). The full potential of IOPTH needs further study. The role of intra-operative radioguided technique is controversial. Some are of the opinion that radioguided techniques rarely provide any additional information over the sestamibi scan itself and should not be routinely used during parathyroid

All patients may not be candidates for directed or targeted minimal access approaches. Patients with mutigland disease, MEN-related hyperplasia, and renal disease may not be suitable candidates for MAP. Whether the long term outcomes of MAP will be comparable to the best results obtainable with a conventional bilateral exploration remains to be proven.

Since majority of the patients have only a single-gland disease, bilateral neck

The term MAP/MIP should be reserved for parathyroidectomies performed through

Definitive evidence of smaller scars

parathyroidectomy and conventional parathyroidectomy(Starker

Some opine that centrally placed scars appear better than lateral

Axillary approach avoids unsightly scars in visible areas of the

Day case surgery especially if performed under local anaesthesia

Concern of central scar more prone to keloid formation

exploration should be considered.

Complications

Cosmesis

operations.

**KEY POINTS-4** 

inscions less than 2.5 cm.

is inserted, dissection is carried out with 2 mm spatulas and forceps. The rest of the operation follows the standard principles of open parathyroid surgery, with recurrent laryngeal nerve (RLN) identification and ligation of the parathyroid vascular pedicle MIVAP offers advantages over the endoscopic approach, with the preservation of tactile contact and a considerably smaller insicon.

#### **5.4.5 Minimally invasive radio-guided parathyroidectomy (MIRP) – (***gamma probe assisted parathyroidectomy)*

A hand held gamma probe is used to determine the position of the incision and guide the dissection (20 mCi of Technetium 99msestamibi is injected intravenously, two to four hours prior to the surgery) the principle is similar that of sentinel lymph node biopsy.

Fig. 8. Schematic representation of endoscopic parathyroidectomy: lateral access technique

With the continued improvements in parathyroid imaging techniques, minimally invasive parathyroidectomy is rapidly becoming the procedure of choice in patients with PHPT.

#### **5.4.6 Intra-operative PTH (IOPTH) measurement**

IOPTH measurements were first introduced in 1990, and represent an alternative to fourgland visualization. (Irvin GL., 1999) This is regarded as an important advancement in the development of unilateral surgery, replacing the need for visualisation of all glands, and has been referred to as biochemical "frozen section". During surgery, blood is drawn for PTH assays before (baseline) and after the excision of a hyperfunctioning gland. The removal of the diseased hyperfunctioning parathyroid tissue is predicted by a fall of PTH by more than

is inserted, dissection is carried out with 2 mm spatulas and forceps. The rest of the operation follows the standard principles of open parathyroid surgery, with recurrent laryngeal nerve (RLN) identification and ligation of the parathyroid vascular pedicle MIVAP offers advantages over the endoscopic approach, with the preservation of tactile

**5.4.5 Minimally invasive radio-guided parathyroidectomy (MIRP) – (***gamma probe* 

prior to the surgery) the principle is similar that of sentinel lymph node biopsy.

A hand held gamma probe is used to determine the position of the incision and guide the dissection (20 mCi of Technetium 99msestamibi is injected intravenously, two to four hours

Fig. 8. Schematic representation of endoscopic parathyroidectomy: lateral access technique

**5.4.6 Intra-operative PTH (IOPTH) measurement** 

With the continued improvements in parathyroid imaging techniques, minimally invasive parathyroidectomy is rapidly becoming the procedure of choice in patients with PHPT.

IOPTH measurements were first introduced in 1990, and represent an alternative to fourgland visualization. (Irvin GL., 1999) This is regarded as an important advancement in the development of unilateral surgery, replacing the need for visualisation of all glands, and has been referred to as biochemical "frozen section". During surgery, blood is drawn for PTH assays before (baseline) and after the excision of a hyperfunctioning gland. The removal of the diseased hyperfunctioning parathyroid tissue is predicted by a fall of PTH by more than

contact and a considerably smaller insicon.

*assisted parathyroidectomy)*

50% of its preoperative (baseline ) value, within 10 to 15 minutes. Studies have reported that a 50% reduction from pre-excision PTH values within 5-10 minutes of adenoma excision can accurately predict post-operative normocalcaemia. (Inabnet et al, 1999)**.** In other words, a decrease of more than 50% from the baseline value at 5–10 minutes after resection is suggestive of a single gland disease (solitary adenoma). However, if such a drop does not occur, then the possibility of multi gland disease is likely, and a conversion to bilateral neck exploration should be considered.


Table 5. Overview of outcomes in minimal access parathyroidectomy

The disadvantages described include its cost,and interaction with anesthetic drug propofol (which should be stopped 5-10 minutes before blood sampling). The full potential of IOPTH needs further study. The role of intra-operative radioguided technique is controversial. Some are of the opinion that radioguided techniques rarely provide any additional information over the sestamibi scan itself and should not be routinely used during parathyroid operations.

All patients may not be candidates for directed or targeted minimal access approaches. Patients with mutigland disease, MEN-related hyperplasia, and renal disease may not be suitable candidates for MAP. Whether the long term outcomes of MAP will be comparable to the best results obtainable with a conventional bilateral exploration remains to be proven.

#### **KEY POINTS-4**


Management of Primary Hyperparathyroidism: 'Past, Present and Future' 165

might create some amount of confusion. The normal parathyroids are soft and can be present in different shapes and may be sometimes very much flattened like a disc by the overlying fascial layer. Once the fascia is teased away the glands will appear to be more globular. The gland will also have a network of fine capillaries on the surface [figure 10] and a biopsy might cause it to bleed (in contrast to fat). Lymph nodes and thyroid nodules may

The recurrent laryngeal nerve typically runs in the tracheo–esophageal groove with the superior parathyroids more anteriorly and inferior parathyroids more posterior in relation to this nerve. Capsular rupture of the abnormal gland should be avoided to prevent implantation of parathyroid cells in the operative site. Histological confirmation by frozen

Fig. 10. (A) Operative photograph showing the parathyroid (P) which can be differentiated from fat (F) by the presence of fine blood vessels on the surface of the gland. (B) Operative photograph depicting normal relationships between recurrent laryngeal nerve (RLN), and

Sometimes, all the parathyroid glands cannot be identified readily. A systematic search is performed; based on the knowledge of the path of descent of superior and inferior parathyroid glands. The table gives a brief description of the places to look for in such cases. The superior parathyroid glands are normaly located on the posterior aspect of the superior or middle third of the thyroid lobe in more than 90% of the cases. The location of an ectopic superior parathyroid gland may be above the upper pole of the thyroid lobe (<1%); posterior to the pharynx or esophagus, in either the neck or the superior mediastinum (1%–

The ectopic inferior parathyroid glands may be found, inferior to the lower pole of the thyroid lobe, either in the thyrothymic ligament or associated with the cervical portion of the thymus (26%); on or adjacent to the posterior aspect of the middle third of the thyroid lobe (7%); in the anterior mediastinum (4%–5%); intrathyroidal (<3%); or along the carotid sheath (<1%–2%).

**7. Ectopic parathyroids: "The hunt for the elusive parathyroids"** 

add to confusion too but these are often palpably firm.

section examination is often valuable.

superior(SP) and inferior parathyroid(IP) glands.

4%); or intrathyroidal (<3%) (Eslamy & Ziessman, 2008).


#### **6. Conventional parathyroidectomy: "Identification and dissection of the parathyroid glands"**

The three important goals in parathyroid surgery are-


The initial operative steps are similar to that for thyroidectomy. The corresponding thyroid lobe is elevated and the structures lying under this region are carefully inspected first. The normal parathyroids and the fat in this region may appear similar initially and moreover the parathyroids may be covered by a globule or layer of adipose tissue.

Fig. 9. Schematic representation of the expected anatomy during conventional parathyroidectomy. The thyroid lobe is mobilized .The recurrent laryngeal nerve(RLN) lies in the trachea-oesophageal groove. The commonest position of the superior parathyroid gland (SP) is posterior to the superior or middle third of the thyroid lobe and that of the inferior parathyroid gland(IP) is anterior, lateral, or posterior to the inferior third of the thyroid lobe with the nerve passing obliquely between them.

A small pledget can be used to tease way cobweb like fascia lying in close proximity to the posterolateral surface of the elevated thyroid lobe. This will most often bring into view the locations of the superior and inferior parathyroids. The presence of globular fat deposits

 Cure rates are equivalent to those of a bilateral neck exploration for single gland disease. Advantages include avoidance of general aneasthesa and overnight admission, good

Minimal access approach may be best suited for single adenomatous disease.

**6. Conventional parathyroidectomy: "Identification and dissection of the** 

The initial operative steps are similar to that for thyroidectomy. The corresponding thyroid lobe is elevated and the structures lying under this region are carefully inspected first. The normal parathyroids and the fat in this region may appear similar initially and moreover the

cosmesis.

**parathyroid glands"** 

Surgical expertise is still an important factor.

The three important goals in parathyroid surgery are-

1. Recognizing the normal from abnormal parathyroids. 2. Identifying and protecting recurrent laryngeal nerves. 3. Searching for parathyroids in predictable locations.

parathyroids may be covered by a globule or layer of adipose tissue.

Fig. 9. Schematic representation of the expected anatomy during conventional

thyroid lobe with the nerve passing obliquely between them.

parathyroidectomy. The thyroid lobe is mobilized .The recurrent laryngeal nerve(RLN) lies in the trachea-oesophageal groove. The commonest position of the superior parathyroid gland (SP) is posterior to the superior or middle third of the thyroid lobe and that of the inferior parathyroid gland(IP) is anterior, lateral, or posterior to the inferior third of the

A small pledget can be used to tease way cobweb like fascia lying in close proximity to the posterolateral surface of the elevated thyroid lobe. This will most often bring into view the locations of the superior and inferior parathyroids. The presence of globular fat deposits might create some amount of confusion. The normal parathyroids are soft and can be present in different shapes and may be sometimes very much flattened like a disc by the overlying fascial layer. Once the fascia is teased away the glands will appear to be more globular. The gland will also have a network of fine capillaries on the surface [figure 10] and a biopsy might cause it to bleed (in contrast to fat). Lymph nodes and thyroid nodules may add to confusion too but these are often palpably firm.

The recurrent laryngeal nerve typically runs in the tracheo–esophageal groove with the superior parathyroids more anteriorly and inferior parathyroids more posterior in relation to this nerve. Capsular rupture of the abnormal gland should be avoided to prevent implantation of parathyroid cells in the operative site. Histological confirmation by frozen section examination is often valuable.

Fig. 10. (A) Operative photograph showing the parathyroid (P) which can be differentiated from fat (F) by the presence of fine blood vessels on the surface of the gland. (B) Operative photograph depicting normal relationships between recurrent laryngeal nerve (RLN), and superior(SP) and inferior parathyroid(IP) glands.

#### **7. Ectopic parathyroids: "The hunt for the elusive parathyroids"**

Sometimes, all the parathyroid glands cannot be identified readily. A systematic search is performed; based on the knowledge of the path of descent of superior and inferior parathyroid glands. The table gives a brief description of the places to look for in such cases.

The superior parathyroid glands are normaly located on the posterior aspect of the superior or middle third of the thyroid lobe in more than 90% of the cases. The location of an ectopic superior parathyroid gland may be above the upper pole of the thyroid lobe (<1%); posterior to the pharynx or esophagus, in either the neck or the superior mediastinum (1%– 4%); or intrathyroidal (<3%) (Eslamy & Ziessman, 2008).

The ectopic inferior parathyroid glands may be found, inferior to the lower pole of the thyroid lobe, either in the thyrothymic ligament or associated with the cervical portion of the thymus (26%); on or adjacent to the posterior aspect of the middle third of the thyroid lobe (7%); in the anterior mediastinum (4%–5%); intrathyroidal (<3%); or along the carotid sheath (<1%–2%).

Management of Primary Hyperparathyroidism: 'Past, Present and Future' 167

Surgery is the only, definitive treatment for symptomatic disease. Since majority of cases of primary hyperparathyroidism, are due to a single parathyroid adenoma, selective gland excision is a better option. This should be facilitated with appropriate preoperative localization techniques such as with (Tc99m) sestamibi scanning alone or combined with other modalities wherever possible. Intra-operative parathyroid hormonal monitoring may be a useful adjunct and can predict possibility of multigland disease and the need for converting the procedure to a bilateral neck exploration. The new surgical procedures are here to stay. Minimally access parathyroid surgery is feasible and should probably be increasingly offered to select group of patients. Conversion to bilateral neck exploration

The final statement is that: "the success of both conventional and minimal access parathyroidectomy is dependent on the surgeon's hard earned experience and nothing can

Abboud, B., Sleilaty, G., Helou, E., Mansour, E., Tohme, C., Noun, R. & Sarkis, R. (2005),

Laryngoscope, 115: 1128–1131. doi: 10.1097/01.MLG.0000163745.57542.FE Agarwal G, Barraclough BH, Reeve TS & Delbridge LW.(2002). *Minimally invasive* 

Akerström G, Malmaeus J & Bergström R.(1984). *Surgical anatomy of human parathyroid* 

Allendorf J, Kim L, Chabot J, DiGiorgi M, Spanknebel K & Logerfo P. (2003).*The impact of* 

Baloch ZW & LiVolsi VA. (2001).*Double adenoma of the parathyroid gland; Does the entity exist?*

Bergenfelz A, Lindblom P, Tibblin S, et al. (2002). *Unilateral versus bilateral neck exploration for* 

Bergenfelz A, Lindblom P, Tibblin S, Westerdahl J. (2002). *Unilateral versus bilateral neck* 

Bess MA, Edis AJ, & von Heerden JA.(1980). *Hyperparathyroidism and pancreatitis. Chance or a* 

Bhansali, S. R. Masoodi, S. Reddy et al.(2005), "Primary hyperparathyroidism in north India: a description of 52 cases," Annals of Saudi Medicine, vol. 25, no. 1, 29–35,. Bilezikian JP, Khan AA, & Potts JT Jr(2009). (Third International Workshop on the

from the Third International Workshop. *J Clin Endocrinol Metab.*;94:335-339. Bilezikian JP, Potts JT, Jr, El-Hajj Fuleihan G, et al.( 2002).*Summary statement from a workshop* 

*Existence and Anatomic Distribution of Double Parathyroid Adenoma*. The

*parathyroidectomy using the ''focused'' lateral approach. II. Surgical technique.* Aust N Z J

*sestamibi scanning on the outcome of parathyroid surgery*. J Clin Endocrinol Metab;

*primary hyperparathyroidism—a prospective randomized controlled.* Ann Surg.;236:543–

*exploration for primary hyperparathyroidism: a prospective randomized controlled trial.* 

Management of Asymptomatic Primary Hyperparathyroidism). Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement

*on asymptomatic primary hyperparathyroidism: a perspective for the 21st century.* J Bone

should not be regarded as a complication.

Surg;72:147–51

88:3015–8.

551.

*glands. Surgery.*;95(1):14-21

Arch Pathol Lab Med 125:(2)178–179

*Ann Surg.* Nov;236(5):543–51.

Miner Res.;17(suppl 2):N2-N11

*causal association*? JAMA; 243: 246–7.

substitute that. "

**9. References** 


Table 7. Locations of ectopic parathyroid s

Fig. 11.

### **8. Conclusion - "The future"**

As the patients are often asymptomatic, the diagnosis of primary hyperparathyroidism is based principally on laboratory findings of elevated serum calcium and serum parathyroid hormone levels. Asymptomatic disease is the commonest form of presentation in the developed nations. Symptomatic disease is very common in developing parts of the world. Surgery is the only, definitive treatment for symptomatic disease. Since majority of cases of primary hyperparathyroidism, are due to a single parathyroid adenoma, selective gland excision is a better option. This should be facilitated with appropriate preoperative localization techniques such as with (Tc99m) sestamibi scanning alone or combined with other modalities wherever possible. Intra-operative parathyroid hormonal monitoring may be a useful adjunct and can predict possibility of multigland disease and the need for converting the procedure to a bilateral neck exploration. The new surgical procedures are here to stay. Minimally access parathyroid surgery is feasible and should probably be increasingly offered to select group of patients. Conversion to bilateral neck exploration should not be regarded as a complication.

The final statement is that: "the success of both conventional and minimal access parathyroidectomy is dependent on the surgeon's hard earned experience and nothing can substitute that. "

#### **9. References**

166 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

As the patients are often asymptomatic, the diagnosis of primary hyperparathyroidism is based principally on laboratory findings of elevated serum calcium and serum parathyroid hormone levels. Asymptomatic disease is the commonest form of presentation in the developed nations. Symptomatic disease is very common in developing parts of the world.

Superior parathyroids

Inferior parathyroids

Fig. 11.

**8. Conclusion - "The future"** 

Table 7. Locations of ectopic parathyroid s

**Gland Where to look for** 

adjacent to the superior thyroid vessels the carotid sheath or posterior to the esophagus or pharynx (retroesophageal)

the capsule of the thyroid gland

thyrothymic ligament.

anterior mediastinum

capsule of the thyroid

the thymus

carotid sheath


Management of Primary Hyperparathyroidism: 'Past, Present and Future' 169

Hooghe L, Kinnaert P & Van Geertruyden J.( 1992). *Surgical anatomy of hyperparathyroidism*.

Inabnet WB, Fulla Y, Richard B, Bonnichon P, Icard P & Chapuis Y.( 1999). *Unilateral neck* 

Kaplan EL, Yashiro T & Salti G.(1992). *Primary hyperparathyroidism in the 1990s. Choice of* 

Kearns AE & Thompson GB. (2002). *Medical and surgical management of hyperparathyroidism*

Lee F. Starker, Annabelle L. Fonseca, Tobias Carling, & Robert Udelsman,( (2011).

Lowe H, McMahon DJ, Rubin MR, Bilezikian JP & Silverberg SJ.(2007). *Normocalcemic* 

Mandl F.(1925).*Therapeutischer Versuch bei Ostitis fibrosa generalisata mittels Exstinpationeines* 

Mihai, R., Palazzo, F.F., Gleeson, F.V. & Sadler, G.P. (2007). *Minimally invasive* 

Nobori M, Saiki S, Tanaka N, Harihara Y, Shindo S & Fujimoto Y.( 1994).*Blood supply of the parathyroid gland from the superior thyroid artery.* Surgery; 115(4):417-23. Peacock M,Bilezikian JP, Klassen PS, Guo MD, Turner SA & Shoback D.( 2005). *Cinacalcet* 

Pradeep P. V., Jayashree B., Mishra A, &. Mishra S. K.."*Systematic Review of Primary* 

Russell, C.F., Laird, J.D. & Ferguson, W.R. (1990). *Scan-directed unilateral cervical exploration* 

Schell SR & Dudley NE.(2003). *Clinical outcomes and fiscal consequences of bilateral neck* 

Sheldon DG, Lee FT, Neil NJ & Ryan JA.( 2002) *Surgical treatment of hyperparathyroidism* 

Sidhu S, Neill AK, Russell CFJ. (2003). *Long-term outcome of unilateral parathyroid exploration* 

*excision of parathyroid tumours)*. Wien Klin Wochenschr 38:1343–4

*hyperparathyroidism.* J Clin Endocrinol Metab.;90:135-141

*imaging or minimally invasive techniques*. Surgery;133(1):32–9.

*improves health related quality of life.* Arch Surg;137: 1022–8.

*with primary hyperparathyroidism*. British Journal of Surgery, 94, 42-47. Miura D, Wada N, Arici C, Morita E, Duh QY & Clark OH. (2002). *Does intraoperative quick* 

*exploration under local anaesthesia: the approach of choice for asymptomatic primary* 

[published correction appears in Mayo Clin Proc. 2002;77:298]. Mayo Clin

"*Minimally Invasive Parathyroidectomy," International Journal of Endocrinology,* vol.

*primary hyperparathyroidism: further characterization of a new clinical phenotype*. J Clin

*Epithelkorperchentumours. (Therapeutic attempt for osteitis fibrosa generalisata via the* 

*parathyroidectomy without intraoperative parathyroid hormone monitoring in patients* 

*parathyroid hormone assay improve the results of parathyroidectomy?* World J Surg;

*hydrochloride maintains long-term normocalcemia in patients with primary* 

*Hyperparathyroidism in India: The Past, Present, and the Future Trends*," International Journal of Endocrinology, vol. 2011, Article ID 921814, 7 pages, 2011.

*for parathyroid adenoma: a legitimate approach?* World Journal of Surgery, 14, 406-409.

*exploration for primary idiopathic hyperparathyroidism without preoperative radionuclide* 

*for primary hyperparathyroidism due to presumed solitary adenoma*. World J Surg; 27:

Acta Chir Belg.; 92(1):1-9.

2011, doi:10.1155/2011/206502

Endocrinol Metab.;92:3001-3005

Proc.;77:87-91.

26(8):926–30.

339-342

doi:10.1155/2011/921814

*hyperparathyroidism. Surgery;* 126: 1004-1010

Irvin GL. (1999) *Presidential address: chasin' hormones*. Surgery;126(6):993–7.

*surgical procedures for this disease.* Ann Surg. Apr;215(4):300-17.


Bonjer HJ & Bruining HA. (1997) The technique of parathyroidectomy. In: Clark O, Duh Q, eds. Textbook of Endocrine Surgery. Philadelphia, Pa: WB Saunders;. Brunaud L, Zarnegar R, Wada N, Ituarte P, Clark OH & Duh QY.(2003). *Incision length for* 

Burney RE, Jones KR & Christy B(1999). *Thompson NW. Health status improvement after* 

Chan AK, Duh QY, Katz MH, Siperstein AE & Clark OH.(1995). *Clinical manifestations of* 

Clark OH, Wilkes W, Siperstein AE & Duh QY. (1991). *Diagnosis and management of* 

Delattre JF, Flament JB, Palot JP &Pluot M.(1982).*Variations in the parathyroid glands. Number,* 

Delbridge LW. (2003). *Minimally invasive parathyroidectomy: the Australian experience*. Asian J

Denham DW & Norman J.(1998). *Cost-effectiveness of pre-operative sestamibi scan for primary* 

Dufour DR & Wilkerson SY.(1983).*Factors related to parathyroid weight in normal persons*. Arch

Elaraj DM & Clark OH (2008).*Current status and treatment of primary hyperparathyroidism*.

Eslamy HK, & Ziessman H. (2008). *Parathyroid scintigraphy in patients with primary* 

Gauger PG, Reeve TS & Delbridge LW. (1999) *Endoscopically assisted, minimally invasive* 

Goldstein RE, Blevins L, Delbeke D, et al. (2000*). Effect of minimally invasive radioguided* 

Harinarayan CV, Gupta N & Kochupillal N.(1995).*Vitamin D status in primary* 

Henry JF, Defechereux T, Gramatica L & De Boissezon C. (1999). *Endoscopic* 

Ho Shon IA, Bernard EJ, Roach PJ & Delbridge LW.(2001). *The value of oblique pinhole images* 

*hyperparathyroidism in India*. Clin Endocrinol (Oxf); 43: 35 1-8.

*parathyroidectomy via a lateral neck incision*. Ann Chir;53:302–6.

Feliciano DV*. Parathyroid pathology in an intrathyroidal position*. Am J Surg; 164(5):496-500.

*hyperparathyroidism*: 99mTc sestamibi SPECT and SPECT/CT. Radiographics28:1461–

*parathyroidectomy on efficacy, length of stay, and costs in the management of primary* 

*in pre-operative localiasation with 99Tc-MIBI for primary hyperparathyroidism*. Eur J

Eknoyan G.(1995).*A history of the parathyroid glands*. Am J Kidney Dis;26(5):801–7.

Gagner M.( 1996). Endoscopic parathyroidectomy. Br J Surg;83:875.

*parathyroidectomy*. Br J Surg;86(12):1563–6.

*hyperparathyroidism*. Ann Surg.;231:732–742

*preoperative calcium levels*. Surgery ;125(6):608-14.

Clark O.( 1997). *What's new in endocrine surgery.* J Am Coll Surg;184:126–36.

Bone Miner Res; 6 Suppl 2:S135-S42; discussion S151-2.

Ann Surg.;222(3):402-12; discussion 412-4.

Surg;138:1140–3.

(Paris);119(11):633-41.

Coll Surg; 186: 293-304.

Perm J. Winter; 12(1):32-7.

Nucl Med;28:736–42.

1476.

Pathol Lab Med; 107(4): 167–172

Surg;26(2):76–81.

*standard thyroidectomy and parathyroidectomy. When is it minimally invasive?* Arch

*surgical correction of primary hyperparathyroidism in patients with high and low* 

*primary hyperparathyroidism before and after parathyroidectomy. A case-control study.*

*asymptomatic hyperparathyroidism: safety, efficacy, and deficiencies in our knowledge*. J

*situation and arterial vascularization. Anatomical study and surgical application*. J Chir

*hyperparathyroidism is dependent solely on surgeon's choice of operative procedure*. J Am


**12**

*UK* 

R. King and R.A. Ajjan

**Treatment Modalities in Thyroid Dysfunction** 

*Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics Health* 

Thyroid dysfunction is a common condition mainly affecting women, with a male to female ratio of around 1:10. An organ-specific autoimmune response is the underlying cause in the majority and susceptibility to thyroid autoimmunity is believed to be influenced by an interaction between genetic predisposition and environmental factors, in addition to

Autoimmune hyperthyroidism, or Graves' disease (GD), affects around 2% of the female population and is characterised by the presence of thyroid stimulating antibodies (TSAb), which mimic the action of thyroid stimulating hormone (TSH), resulting in uncontrolled thyroid hormone production. TSAb also contribute to extra-thyroidal manifestation of the disease, including thyroid eye disease (TED), although the exact mechanistic pathways are not entirely clear. At the other end of the spectrum, autoimmune hypothyroidism (AH) affects up to 5% of women and is characterised by the presence of thyroid peroxidase (TPO). These antibodies do not seem to have a direct functional role but are implicated in perpetuating the

In this Chapter, we discuss the various therapies used in hyper- and hypothyroidism, and

GD is by far the commonest cause of hyperthyroidism accounting for around 80% of cases (Weetman 2000). It is frequently seen in multiple family members indicating a genetic

The second commonest cause is a solitary toxic nodule or multinodular goitre accounting for 15-20% of cases (Orgiazzi & Mornex1990). Toxic multinodular goitres tend to occur insidiously in elderly patients with a longstanding nodular goitre. Toxic adenomas result from benign monoclonal proliferation producing a single autonomously functioning nodule, typically greater than 2.5cm in diameter. Goitres of any nature are more prevalent in iodine

There are other rare causes for hyperthyroidism, which should be kept in mind when

endogenous factors such as age and sex (Vanderpump 1995).

address management of special cases.

**2. Aetiology of hyperthyroidism** 

intrathyroidal inflammation and tissue destruction (Ajjan & Weetman 2008).

predisposition, commonly seen in organ-specific autoimmune conditions.

deficient areas and are more common in females (Reinwein et al 1988).

assessing the patient and these are summarised in Table 1.

**1. Introduction** 

*and Therapeutics, Faculty of Medicine and Health, University of Leeds, Leeds* 


### **Treatment Modalities in Thyroid Dysfunction**

#### R. King and R.A. Ajjan

*Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics Health and Therapeutics, Faculty of Medicine and Health, University of Leeds, Leeds UK* 

#### **1. Introduction**

170 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Sidhu, S., Neill, A.K. & Russell, C.F. (2003). *Long-term outcome of unilateral parathyroid* 

Silverberg SJ, Shane E, Jacobs TP, Siris E & Bilezikian JP (1999). *A 10-year prospective study of* 

Talpos GB, Bone HG 3rd, Kleerekoper M, et al.(2000). *Randomized trial of parathyroidectomy in* 

Tibblin S, Bondeson AG & Ljungberg O. (1982). *Unilateral parathyroidectomy in* 

Udelsman R. (2002). *Six hundred fifty-six consecutive explorations for primary* 

Wang C.(1981).*Hyperfunctioning intrathyroid parathyroid gland: a potential cause of failure in* 

Yao K, Singer FR, Roth S, Sassoon A, C Ye, & Giuliano A E.. (2004). *Weight of Normal* 

Zachariah S K & Thomas P. A. (2010) Primary hyperparathyroidism: A report of two

*Parathyroid Glands in Patients with Parathyroid Adenomas*. The Journal of Clinical

*hyperparathyroidismdue to parathyroid adenoma.* Ann Surg 195:245–52.

*36 health survey*. Surgery; 128(6):1013-20;discussion 1020-1. Taniegra ED. (2004).*Hyperparathyroidism*. Am Fam Physician.; 69:333-339.

*hyperparathyroidism*. Ann Surg.;235:665–670.

*parathyroid surgery*. J R Soc Med.;74(1):49-52.

Endocrinology & Metabolism;vol. 89 no. 7:3208-3213

unusual cases. *Indian Journal of Surgery* 72:2, 135-137

Journal of Surgery, 27, 339-342.

1249–1255.

*exploration for primary hyperparathyroidism due to presumed solitary adenoma*. World

*primary hyperparathyroidism with or without parathyroid surgery*. N Engl J Med 341:

*mild asymptomatic primary hyperparathyroidism: patient description and effects on the SF-*

Thyroid dysfunction is a common condition mainly affecting women, with a male to female ratio of around 1:10. An organ-specific autoimmune response is the underlying cause in the majority and susceptibility to thyroid autoimmunity is believed to be influenced by an interaction between genetic predisposition and environmental factors, in addition to endogenous factors such as age and sex (Vanderpump 1995).

Autoimmune hyperthyroidism, or Graves' disease (GD), affects around 2% of the female population and is characterised by the presence of thyroid stimulating antibodies (TSAb), which mimic the action of thyroid stimulating hormone (TSH), resulting in uncontrolled thyroid hormone production. TSAb also contribute to extra-thyroidal manifestation of the disease, including thyroid eye disease (TED), although the exact mechanistic pathways are not entirely clear. At the other end of the spectrum, autoimmune hypothyroidism (AH) affects up to 5% of women and is characterised by the presence of thyroid peroxidase (TPO). These antibodies do not seem to have a direct functional role but are implicated in perpetuating the intrathyroidal inflammation and tissue destruction (Ajjan & Weetman 2008).

In this Chapter, we discuss the various therapies used in hyper- and hypothyroidism, and address management of special cases.

#### **2. Aetiology of hyperthyroidism**

GD is by far the commonest cause of hyperthyroidism accounting for around 80% of cases (Weetman 2000). It is frequently seen in multiple family members indicating a genetic predisposition, commonly seen in organ-specific autoimmune conditions.

The second commonest cause is a solitary toxic nodule or multinodular goitre accounting for 15-20% of cases (Orgiazzi & Mornex1990). Toxic multinodular goitres tend to occur insidiously in elderly patients with a longstanding nodular goitre. Toxic adenomas result from benign monoclonal proliferation producing a single autonomously functioning nodule, typically greater than 2.5cm in diameter. Goitres of any nature are more prevalent in iodine deficient areas and are more common in females (Reinwein et al 1988).

There are other rare causes for hyperthyroidism, which should be kept in mind when assessing the patient and these are summarised in Table 1.

Treatment Modalities in Thyroid Dysfunction 173

confirm a diagnosis of thyrotoxicosis, but FT3 levels should be measured when TSH levels are suppressed with normal FT4 levels as roughly 5% of all cases may only have elevated

The diagnosis of GD is usually based on clinical and biochemical thyrotoxicosis in the presence of a smooth goitre with or without extrathyroidal manifestation of the disease. In some cases, the cause of hyperthyroidism is unclear and additional biochemical and/or

The presence of thyroid autoantibodies supports the diagnosis of thyroid autoimmunity. Antibodies (Ab) against TPO are frequently checked in clinical practice, although these are only detected in 80% of individuals with GD (Ajjan & Weetman 2008). Antibodies against thyroid stimulating hormone receptor (TSHR) are detected in 95-99% of patients with GD (depending on the sensitivity of the test used) and therefore these are more informative than TPO-Ab in cases of uncertain aetiology (Ajjan&Weetman 2008; Matthews & Syed 2011).

Radioisotope uptake scans using 99mtechnetium or 131iodine, will show an increase in uptake and a diffusely enlarged thyroid in GD. Toxic MNG will show multiple nodules with increased uptake. A solitary nodule with increased uptake and suppressed function in the remaining, normal tissue is seen in a toxic adenoma (Cooper 2003). All forms of thyroiditis

Nervousness, irritability, heat intolerance, palpitation >90% Weight loss, increased appetite, fatigue, loose stool >80% Eye symptoms (TED) >50% Menstrual irregularities, insomnia, polyuria >25%

tachycardia or atrial fibrillation, moist skin >90% Thrill/bruit over the thyroid >70% Eye signs (in GD), thinning of hair, hyperreflexia 50% Pretibial myxoedema and acropachy (in GD), onycholysis 5% Table 2. Main symptoms and signs in Graves' disease. TED: thyroid eye disease, GD:

There are three main treatment modalities for hyperthyroidism, which include medical therapy, radioactive iodine and surgery. In addition, supportive therapy is sometimes required to control symptoms. Treatment options for hyperthyroidism are summarised in

*Control of hyperthyroidism*. Anti thyroid drugs (ATD), known as thionamides, are commonly prescribed to control the excessive production of thyroid hormone and include carbimazole, its active metabolite methimazole and propylthiouracil (PTU). Use of these agents varies worldwide; methimazole and PTU are preferred in the USA, carbimazole is widely used

Hyperkinetic behaviour, fast speech, tachycardia, tremor, goitre,

**Symptoms Frequency** 

**Signs Frequency** 

levels of T3 (Singer et al 1995).

imaging tests may be needed.

Graves' disease.

Figure 1.

**2.2.1 Medical** 

**2.2 Management of hyperthyroidism** 

can be differentiated by low or absent uptake.


Table 1. Hyperthyroidism: aetiology and diagnosis.

#### **2.1 Diagnosis of hyperthyroidism**

Main symptoms and signs of hyperthyroidism are summarised in Table 2. Careful history and examination will typically point towards a diagnosis of hyperthyroidism and its underlying cause. Biochemical confirmation is required and enables the clinician to monitor response to treatment. Levels of thyroid stimulating hormone (TSH) are suppressed (<0.03miu/l) together with elevated levels of circulating thyroid hormones, L-thyroxine (T4) and/or L-triidothyronine (T3). Measurement of TSH and free T4 (FT4) is usually sufficient to

Clinical examination (Smooth goitre,

Clinical examination Thyroid uptake scan

Clinical examination Thyroid uptake scan

Raised TSH and thyroid

difficult cases

ESR

hormones

Pituitary imaging

Clinical assessment Absence of thyroid autoimmunity Known pregnancy Imaging of the pelvis

Clinical assessment

Clinical assessment Family history

Thyroid/pelvic uptake scan Imaging of the pelvis

extrathyroidal complications) Thyroid autoantibodies Thyroid uptake scan in

**Cause of hyperthyroidism Frequency and aetiology Diagnosis** 

15%, activating mutations in TSH receptor and Gs protein

Variable, excess ingestion of

Rare, pituitary resistance to

Main symptoms and signs of hyperthyroidism are summarised in Table 2. Careful history and examination will typically point towards a diagnosis of hyperthyroidism and its underlying cause. Biochemical confirmation is required and enables the clinician to monitor response to treatment. Levels of thyroid stimulating hormone (TSH) are suppressed (<0.03miu/l) together with elevated levels of circulating thyroid hormones, L-thyroxine (T4) and/or L-triidothyronine (T3). Measurement of TSH and free T4 (FT4) is usually sufficient to

thyroid hormones

thyroid hormones Clinical assessment

related (amiodarone)

Graves' disease 99%, thyroid stimulating

Thyroiditis 3%, autoimmune, viral or drug-

Toxic nodule or toxic multinodular goitre

Exogenous thyroid hormone administration

Thyroid hormone

resistance

Hyperemesis gravidarum

Choriocarcinoma Rare, raised hCG

Struma ovarii Rare, ectopic ovarian thyroid tissue

Table 1. Hyperthyroidism: aetiology and diagnosis.

**2.1 Diagnosis of hyperthyroidism** 

TSH-secreting tumour <1%

antibodies

confirm a diagnosis of thyrotoxicosis, but FT3 levels should be measured when TSH levels are suppressed with normal FT4 levels as roughly 5% of all cases may only have elevated levels of T3 (Singer et al 1995).

The diagnosis of GD is usually based on clinical and biochemical thyrotoxicosis in the presence of a smooth goitre with or without extrathyroidal manifestation of the disease. In some cases, the cause of hyperthyroidism is unclear and additional biochemical and/or imaging tests may be needed.

The presence of thyroid autoantibodies supports the diagnosis of thyroid autoimmunity. Antibodies (Ab) against TPO are frequently checked in clinical practice, although these are only detected in 80% of individuals with GD (Ajjan & Weetman 2008). Antibodies against thyroid stimulating hormone receptor (TSHR) are detected in 95-99% of patients with GD (depending on the sensitivity of the test used) and therefore these are more informative than TPO-Ab in cases of uncertain aetiology (Ajjan&Weetman 2008; Matthews & Syed 2011).

Radioisotope uptake scans using 99mtechnetium or 131iodine, will show an increase in uptake and a diffusely enlarged thyroid in GD. Toxic MNG will show multiple nodules with increased uptake. A solitary nodule with increased uptake and suppressed function in the remaining, normal tissue is seen in a toxic adenoma (Cooper 2003). All forms of thyroiditis can be differentiated by low or absent uptake.


Table 2. Main symptoms and signs in Graves' disease. TED: thyroid eye disease, GD: Graves' disease.

#### **2.2 Management of hyperthyroidism**

There are three main treatment modalities for hyperthyroidism, which include medical therapy, radioactive iodine and surgery. In addition, supportive therapy is sometimes required to control symptoms. Treatment options for hyperthyroidism are summarised in Figure 1.

#### **2.2.1 Medical**

*Control of hyperthyroidism*. Anti thyroid drugs (ATD), known as thionamides, are commonly prescribed to control the excessive production of thyroid hormone and include carbimazole, its active metabolite methimazole and propylthiouracil (PTU). Use of these agents varies worldwide; methimazole and PTU are preferred in the USA, carbimazole is widely used

Treatment Modalities in Thyroid Dysfunction 175

undergo remission and generally requires a more definitive treatment once the initial

**Management of hyperthyroidism**

**Medical RAI Surgery**

**Indicated for:** TMNG GD (particularly relapsed disease) **Caution:** pregnancy, TED, incontinence, breast feeding

**Indicated for:** CI to medical therapy Relapsed GD & TED Large disfiguring goitre Suspicious thyroid nodules Patient preference

bleeding

**Caution:** laryngeal nerve palsy, hypoparathyroidism

**Outcome Hypothyroidism Possible hypocalcaemia (transient or permanent)**

**Outcome Euthyroid/hypothyroid in 90% after 1st dose**

thyrotoxicosis has been controlled.

Control of symptoms Control of hyperthyroidism

**months treatment**

necessarily occur with propylthiouracil treatment.

disease, CI: contraindication.

**Thionamides:** Carbimazole, methimazole, propylthiouracil Treatment can be given as titration or block & replace **Caution:** AGRANULOCYTOSIS **Rarely:** potassium iodide, potassium perchlorate, lithium

**Outcome Remission of GD in 50% of cases after 6‐18**

Fig. 1. Summary of the management of hyperthyroidism. BB: β-blockers, CCB: calcium channel blockers, GD: Graves' disease, TMNG: toxic nodular goitre, TED: thyroid eye

Several side effects can be attributed to thionamide medication. Common adverse effects include nausea, gastrointestinal upset, headache, fever, rash, urticaria and arthralgia. Rarely, hair loss may occur as a result of carbimazole therapy, although this may also be a manifestation of thyrotoxicosis. More worrying but less frequent side effects include agranulocytosis, vasculitis, and hepatitis, with the latter being more of an issue with PTU (Cooper & Rivkees 2009). Agranulocytosis occurs in approximately 0.4-0.5% of cases. All patients are warned of this rare but serious side effect and asked to immediately report symptoms consistent with agranulocytosis such as severe sore throat, fever or mouth ulcers. Urgent full blood count is required in patients taking thionamide with such symptoms and treatment withheld until it is clear that white blood cells and neutrophil counts are normal. When such a complication develops, patients are admitted to hospital, given appropriate antibiotics and a haematology opinion is sought, particularly if they require granulocyte stimulating factor administration. Once a patient develops agranulocytosis to an antithyroid drug, it represents a contraindication to the use of other thionamides (Biswas 1991). However, in the presence of other adverse effects, swapping to another antithyroid medication is a possibility. For example, arthralgia induced by carbimazole does not

ΒB, CCB

**Caution:** asthma (BB)

**Discontinue once euthyroid**

first line in the United Kingdom and Methimazole is preferred in the rest of Europe and Asia (Weetman 2000). Methimazole or Carbimazole is often preferred to PTU as it has a longer half life and is therefore given once a day whereas PTU needs to be taken 2 or 3 times a day (Franklyn 1994). They should generally be instituted in patients with a confirmed diagnosis of hyperthyroidism, but may not be necessary if definitive treatment is planned early and hyperthyroidism is mild (Weetman 2000). Thionamides can be used in the short term to induce euthyroidism prior to more definitive treatment such as radio-iodine or surgery or in the medium term in case of GD with the aim of inducing remission. Long term treatment is reserved for patients in whom definitive treatment is relatively contraindicated, such as elderly, frail patients

T4 and T3 molecules are formed within the thyroid gland by the coupling of iodotyrosine residues, which in turn have been formed from the binding of iodine and tyrosine within thyroglobulin, an action catalysed by TPO (Cooper 2005). The thionamides act by inhibiting the formation and coupling of these iodotyrosine residues and thus reduce T4 and T3 concentrations. Propylthiouracil also has the action of inhibiting the peripheral conversion of T4 to T3.

Carbimazole is usually commenced at a dose of 20-40mg once a day, depending on the severity of thyrotoxicosis. Regular monitoring of TSH and T4 is required every 4-6 weeks and the initial dose can be titrated as the thyroid function normalises and the patient becomes euthyroid. A drop in the T4 to low-normal levels or below the normal range indicates that a reduction in dosage or addition of levothyroxine is needed. The former scenario constitutes the "titration regime", whereas the latter is known as "block and replace regime". In the titration regime, the smallest dose of anti-thyroid drug is used to maintain thyroid function within the normal range. The levels of T4 and T3 will begin to reduce within 2-4 weeks of treatment, however the TSH may remain suppressed for significantly longer and hence TSH alone should not be used to guide and monitor treatment (British Thyroid Association guidelines [BTA] 2006, Bahn 2011).

If block and replace is used, which is usually reserved to individuals with GD, the patient is maintained on a high dose of carbimazole or propylthiouracil for 4-6 weeks and when the T4 levels fall to the normal range, Levothyroxine is commenced (usually 75-150 µg daily, according to patient weight) whilst continuing with the same dose of thionamide. Regular monitoring of TSH and T4 are required initially with alterations in the dose of thyroxine guided by T4 levels. Once established on a maintenance dose and TSH and T4 levels have normalised, the doses are unlikely to vary and so less frequent testing is possible (e.g. 6 monthly). Block and replace regimes should not be used in pregnant women (detailed below).

If thionamides are used to treat Graves' disease they can usually be discontinued after a course of treatment, ranging from 6-18 months, with approximately 50% of patients remaining in remission thereafter (Hedley et al 1989, Maugendre et al 1999). In most centres, titration regime is administered for 18 months, whereas block and replace is usually given for 6 months only (Abraham et al 2005). There does not appear to be a difference in remission rates between titration and block and replace regimes (Abraham et al 2005, Reinwein at al 1993). Higher rates of relapse typically occur with severe biochemical thyrotoxicosis at diagnosis, a large goitre, extrathyroidal complications, high anti-TSHR titres and in men (Vitti et al 1997). Thyrotoxicosis caused by nodular goitres does not

first line in the United Kingdom and Methimazole is preferred in the rest of Europe and Asia (Weetman 2000). Methimazole or Carbimazole is often preferred to PTU as it has a longer half life and is therefore given once a day whereas PTU needs to be taken 2 or 3 times a day (Franklyn 1994). They should generally be instituted in patients with a confirmed diagnosis of hyperthyroidism, but may not be necessary if definitive treatment is planned early and hyperthyroidism is mild (Weetman 2000). Thionamides can be used in the short term to induce euthyroidism prior to more definitive treatment such as radio-iodine or surgery or in the medium term in case of GD with the aim of inducing remission. Long term treatment is reserved for patients in whom definitive treatment is relatively contraindicated,

T4 and T3 molecules are formed within the thyroid gland by the coupling of iodotyrosine residues, which in turn have been formed from the binding of iodine and tyrosine within thyroglobulin, an action catalysed by TPO (Cooper 2005). The thionamides act by inhibiting the formation and coupling of these iodotyrosine residues and thus reduce T4 and T3 concentrations. Propylthiouracil also has the action of inhibiting the peripheral

Carbimazole is usually commenced at a dose of 20-40mg once a day, depending on the severity of thyrotoxicosis. Regular monitoring of TSH and T4 is required every 4-6 weeks and the initial dose can be titrated as the thyroid function normalises and the patient becomes euthyroid. A drop in the T4 to low-normal levels or below the normal range indicates that a reduction in dosage or addition of levothyroxine is needed. The former scenario constitutes the "titration regime", whereas the latter is known as "block and replace regime". In the titration regime, the smallest dose of anti-thyroid drug is used to maintain thyroid function within the normal range. The levels of T4 and T3 will begin to reduce within 2-4 weeks of treatment, however the TSH may remain suppressed for significantly longer and hence TSH alone should not be used to guide and monitor treatment (British

If block and replace is used, which is usually reserved to individuals with GD, the patient is maintained on a high dose of carbimazole or propylthiouracil for 4-6 weeks and when the T4 levels fall to the normal range, Levothyroxine is commenced (usually 75-150 µg daily, according to patient weight) whilst continuing with the same dose of thionamide. Regular monitoring of TSH and T4 are required initially with alterations in the dose of thyroxine guided by T4 levels. Once established on a maintenance dose and TSH and T4 levels have normalised, the doses are unlikely to vary and so less frequent testing is possible (e.g. 6 monthly). Block and replace regimes should not be used in pregnant

If thionamides are used to treat Graves' disease they can usually be discontinued after a course of treatment, ranging from 6-18 months, with approximately 50% of patients remaining in remission thereafter (Hedley et al 1989, Maugendre et al 1999). In most centres, titration regime is administered for 18 months, whereas block and replace is usually given for 6 months only (Abraham et al 2005). There does not appear to be a difference in remission rates between titration and block and replace regimes (Abraham et al 2005, Reinwein at al 1993). Higher rates of relapse typically occur with severe biochemical thyrotoxicosis at diagnosis, a large goitre, extrathyroidal complications, high anti-TSHR titres and in men (Vitti et al 1997). Thyrotoxicosis caused by nodular goitres does not

such as elderly, frail patients

conversion of T4 to T3.

women (detailed below).

Thyroid Association guidelines [BTA] 2006, Bahn 2011).

undergo remission and generally requires a more definitive treatment once the initial thyrotoxicosis has been controlled.

Fig. 1. Summary of the management of hyperthyroidism. BB: β-blockers, CCB: calcium channel blockers, GD: Graves' disease, TMNG: toxic nodular goitre, TED: thyroid eye disease, CI: contraindication.

Several side effects can be attributed to thionamide medication. Common adverse effects include nausea, gastrointestinal upset, headache, fever, rash, urticaria and arthralgia. Rarely, hair loss may occur as a result of carbimazole therapy, although this may also be a manifestation of thyrotoxicosis. More worrying but less frequent side effects include agranulocytosis, vasculitis, and hepatitis, with the latter being more of an issue with PTU (Cooper & Rivkees 2009). Agranulocytosis occurs in approximately 0.4-0.5% of cases. All patients are warned of this rare but serious side effect and asked to immediately report symptoms consistent with agranulocytosis such as severe sore throat, fever or mouth ulcers. Urgent full blood count is required in patients taking thionamide with such symptoms and treatment withheld until it is clear that white blood cells and neutrophil counts are normal. When such a complication develops, patients are admitted to hospital, given appropriate antibiotics and a haematology opinion is sought, particularly if they require granulocyte stimulating factor administration. Once a patient develops agranulocytosis to an antithyroid drug, it represents a contraindication to the use of other thionamides (Biswas 1991). However, in the presence of other adverse effects, swapping to another antithyroid medication is a possibility. For example, arthralgia induced by carbimazole does not necessarily occur with propylthiouracil treatment.

Treatment Modalities in Thyroid Dysfunction 177

avoided in patients who are unable to comply with the safety regulations after administration. Current treatment with amiodarone (or within the preceding 12 months) is another contraindication as this reduces the uptake of RAI into the thyroid, greatly reducing its efficacy as is suspicion of thyroid malignancy. Caution is needed in patients incontinent of urine, which represents a relative contraindication and insertion of a urinary catheter or urinary pads with appropriate disposal facilities are ways to circumvent the problem (RCP 2007). Another relative contraindication is individuals with active eye disease. If RAI treatment is necessary in TED patients then concurrent oral glucocorticoids are effective in reducing development or progression of TED (Bartalena 2011). Some centres, including ours, advocate starting block and replace one week after RAI for 6 months after which antithyroid drugs can be withdrawn and levothyroxine continued. This helps in avoiding fluctuation in thyroid function, which can be

*Precautions after RAI treatment*. Most of the radioactivity is taken up by the thyroid, whilst some is excreted in urine and sweat. It is important that patients are able to comply with the necessary restrictions following RAI treatment to limit the radiation exposure of other members of the public. These include limiting close contact (less than 1m) with people, especially children under 3 years of age and pregnant women. The exact duration of the limitations will vary depending on the dose received, and can be up to 28 days (RCP 2007). Patients should be instructed to flush the toilet twice after passing urine and to wash their hands carefully. They should not share towels or face cloths and ensure that cutlery is thoroughly cleaned. Following RAI patients should be issued with a card outlining the details of their treatment and should carry this for 4 weeks or up to 6 months if they are travelling by plane as some airport security devices are able to detect levels of radioactivity

*Follow up and monitoring*. Careful follow up after RAI is essential to detect alterations in thyroid status. Patients treated with ATD and who are biochemically euthyroid prior to RAI are unlikely to require subsequent ATD unless the risk of recurrent hyperthyroidism is deemed unacceptable such as in the elderly or those with cardiovascular co-morbidity (RCP 2007). Patients should be warned that there is a risk of an increase in hyperthyroid symptoms in the first 1-2 weeks after treatment which often respond to β-blockers. Thyroid function tests (TFT's) should be performed around 6 weeks after RAI. Hypothyroidism within the first 6 months of RAI may be transient and thyroid replacement medication should only be commenced if there is a continual rise in TSH levels and falling freeT4 levels Aizawa et al 1997). If patients require re-commencement of ATD following RAI this should be gradually withdrawn over 3 to 5 months. If a patient remains euthyroid 6 weeks post RAI then further thyroid function tests should be performed at 12 weeks, 6, 9 and 12 months. In those who remain hyperthyroid 6 months post RAI, a second dose should be considered (RCP 2007). Annual TFT's are subsequently

*Patient selection*. Thyroid surgery, in various guises, has been performed since the 1860's as a treatment of goitres (Sawyers 1972). In the modern age there are a number of indications for thyroidectomy; relapse of GD following a course of ATD is one and patients who are unable to undergo RAI, i.e., pregnant women, those with small children who are unable to comply

required to monitor for late onset hypo-, or hyperthyroidism (BTA 2006).

associated with worsening of TED (Tallstedt et al 1994).

this long after RAI (RCP 2007).

**2.2.3 Surgery** 

*Supportive management.* Some patients who present with significant thyrotoxic symptoms require supportive treatment whilst awaiting normalisation of thyroid hormone levels. Typically β-adrenergic blockers such as propranolol are used until thyroid function tests improve at which point they may be withdrawn (Franklyn 1994). Caution must be used in patients with a contra-indication such as heart failure and asthma. An alternative therapy would be a non-dihydropyridine calcium channel blockers such as diltiazem or verapamil

*Other medical therapies.* Treatments such as potassium iodide, potassium perchlorate and lithium are less conventional, but possible treatment options, particularly when agranulocytosis develops secondary to antithyroid drug treatment. When given in large enough quantities, potassium iodide blocks the synthesis and release of thyroid hormones from a thyrotoxic gland and results in an accumulation of iodide within the gland. A significant reduction in thyroid hormones can be seen as quickly as 2 days following administration, and is typically reserved for preparing thyrotoxic patients, who are unable to tolerate thionamide medication, for surgery. However, this treatment can only be given for a short period of time as the patient eventually "escapes" from the inhibitory effect of iodine (Philippou 1992).

Lithium acts by inhibiting the release of T4 & T3 and is generally used in similar circumstances to potassium iodide or in combination with a thionamide in patients who have needed recurrent doses of radioiodine as it is thought to help retention of I131 (Bal et al 2002, Bogazzi et all 1999). Potassium perchlorate is generally reserved for use in type 1 amiodarone induced thyrotoxicosis and requires similar monitoring to other anti-thyroid medication, with aplastic anaemia being the most serious side effect.

#### **2.2.2 Radioactive Iodine (RAI)**

*Indications for RAI*. This can be used as a primary treatment for hyperthyroidism or as a secondary option if anti-thyroid medication has failed to control hyperthyroidism. It is common practice for patients with GD to undergo a course of anti-thyroid medication initially. If this does not achieve long term euthyroidism, due to either the relapsing nature of the condition following withdrawal of ATD or treatment difficulties, then radioactive iodine is indicated as a definitive treatment due to long term morbidity and mortality associated with uncontrolled hyperthyroidism. Severe adverse events such as agranulocytosis and hepatic dysfunction caused by thionamides are also an indication for RAI (Royal College of Physicians [RCP] 2007). It is more commonly used in North America as a primary treatment in patients with GD (Solomon et al 1990), due to poor remission rates, and other factors including age, pre-existing medical conditions such as cardiovascular disease, availability of RAI and patient preference may influence this decision. RAI is recommended in patients with hyperthyroidism due to nodular goitres as antithyroid drugs do not result in long term cure of the disease.

RAI is successful in achieving long-term euthyroidism or hypothyroidism in approximately 90% of patients after a single dose of between 400-600MBq after 1 year (Regalbuto et al 2009). A minority will require a second dose and very rarely a third treatment with RAI.

*Contraindications to RAI.* Pregnancy and breastfeeding are absolute contraindications to RAI and pregnancy should be avoided for 6 months following treatment. Iodine is concentrated in milk and is able to cross the placenta, damaging the foetal thyroid. RAI should also be

*Supportive management.* Some patients who present with significant thyrotoxic symptoms require supportive treatment whilst awaiting normalisation of thyroid hormone levels. Typically β-adrenergic blockers such as propranolol are used until thyroid function tests improve at which point they may be withdrawn (Franklyn 1994). Caution must be used in patients with a contra-indication such as heart failure and asthma. An alternative therapy would be a non-dihydropyridine calcium channel blockers such as diltiazem or verapamil *Other medical therapies.* Treatments such as potassium iodide, potassium perchlorate and lithium are less conventional, but possible treatment options, particularly when agranulocytosis develops secondary to antithyroid drug treatment. When given in large enough quantities, potassium iodide blocks the synthesis and release of thyroid hormones from a thyrotoxic gland and results in an accumulation of iodide within the gland. A significant reduction in thyroid hormones can be seen as quickly as 2 days following administration, and is typically reserved for preparing thyrotoxic patients, who are unable to tolerate thionamide medication, for surgery. However, this treatment can only be given for a short period of time as the patient eventually "escapes" from the inhibitory effect of

Lithium acts by inhibiting the release of T4 & T3 and is generally used in similar circumstances to potassium iodide or in combination with a thionamide in patients who have needed recurrent doses of radioiodine as it is thought to help retention of I131 (Bal et al 2002, Bogazzi et all 1999). Potassium perchlorate is generally reserved for use in type 1 amiodarone induced thyrotoxicosis and requires similar monitoring to other anti-thyroid

*Indications for RAI*. This can be used as a primary treatment for hyperthyroidism or as a secondary option if anti-thyroid medication has failed to control hyperthyroidism. It is common practice for patients with GD to undergo a course of anti-thyroid medication initially. If this does not achieve long term euthyroidism, due to either the relapsing nature of the condition following withdrawal of ATD or treatment difficulties, then radioactive iodine is indicated as a definitive treatment due to long term morbidity and mortality associated with uncontrolled hyperthyroidism. Severe adverse events such as agranulocytosis and hepatic dysfunction caused by thionamides are also an indication for RAI (Royal College of Physicians [RCP] 2007). It is more commonly used in North America as a primary treatment in patients with GD (Solomon et al 1990), due to poor remission rates, and other factors including age, pre-existing medical conditions such as cardiovascular disease, availability of RAI and patient preference may influence this decision. RAI is recommended in patients with hyperthyroidism due to nodular goitres as

RAI is successful in achieving long-term euthyroidism or hypothyroidism in approximately 90% of patients after a single dose of between 400-600MBq after 1 year (Regalbuto et al 2009). A minority will require a second dose and very rarely a third treatment with RAI.

*Contraindications to RAI.* Pregnancy and breastfeeding are absolute contraindications to RAI and pregnancy should be avoided for 6 months following treatment. Iodine is concentrated in milk and is able to cross the placenta, damaging the foetal thyroid. RAI should also be

medication, with aplastic anaemia being the most serious side effect.

antithyroid drugs do not result in long term cure of the disease.

iodine (Philippou 1992).

**2.2.2 Radioactive Iodine (RAI)** 

avoided in patients who are unable to comply with the safety regulations after administration. Current treatment with amiodarone (or within the preceding 12 months) is another contraindication as this reduces the uptake of RAI into the thyroid, greatly reducing its efficacy as is suspicion of thyroid malignancy. Caution is needed in patients incontinent of urine, which represents a relative contraindication and insertion of a urinary catheter or urinary pads with appropriate disposal facilities are ways to circumvent the problem (RCP 2007). Another relative contraindication is individuals with active eye disease. If RAI treatment is necessary in TED patients then concurrent oral glucocorticoids are effective in reducing development or progression of TED (Bartalena 2011). Some centres, including ours, advocate starting block and replace one week after RAI for 6 months after which antithyroid drugs can be withdrawn and levothyroxine continued. This helps in avoiding fluctuation in thyroid function, which can be associated with worsening of TED (Tallstedt et al 1994).

*Precautions after RAI treatment*. Most of the radioactivity is taken up by the thyroid, whilst some is excreted in urine and sweat. It is important that patients are able to comply with the necessary restrictions following RAI treatment to limit the radiation exposure of other members of the public. These include limiting close contact (less than 1m) with people, especially children under 3 years of age and pregnant women. The exact duration of the limitations will vary depending on the dose received, and can be up to 28 days (RCP 2007). Patients should be instructed to flush the toilet twice after passing urine and to wash their hands carefully. They should not share towels or face cloths and ensure that cutlery is thoroughly cleaned. Following RAI patients should be issued with a card outlining the details of their treatment and should carry this for 4 weeks or up to 6 months if they are travelling by plane as some airport security devices are able to detect levels of radioactivity this long after RAI (RCP 2007).

*Follow up and monitoring*. Careful follow up after RAI is essential to detect alterations in thyroid status. Patients treated with ATD and who are biochemically euthyroid prior to RAI are unlikely to require subsequent ATD unless the risk of recurrent hyperthyroidism is deemed unacceptable such as in the elderly or those with cardiovascular co-morbidity (RCP 2007). Patients should be warned that there is a risk of an increase in hyperthyroid symptoms in the first 1-2 weeks after treatment which often respond to β-blockers. Thyroid function tests (TFT's) should be performed around 6 weeks after RAI. Hypothyroidism within the first 6 months of RAI may be transient and thyroid replacement medication should only be commenced if there is a continual rise in TSH levels and falling freeT4 levels Aizawa et al 1997). If patients require re-commencement of ATD following RAI this should be gradually withdrawn over 3 to 5 months. If a patient remains euthyroid 6 weeks post RAI then further thyroid function tests should be performed at 12 weeks, 6, 9 and 12 months. In those who remain hyperthyroid 6 months post RAI, a second dose should be considered (RCP 2007). Annual TFT's are subsequently required to monitor for late onset hypo-, or hyperthyroidism (BTA 2006).

#### **2.2.3 Surgery**

*Patient selection*. Thyroid surgery, in various guises, has been performed since the 1860's as a treatment of goitres (Sawyers 1972). In the modern age there are a number of indications for thyroidectomy; relapse of GD following a course of ATD is one and patients who are unable to undergo RAI, i.e., pregnant women, those with small children who are unable to comply

Treatment Modalities in Thyroid Dysfunction 179

no response. If successful the dose of thionamide is tapered and the thyroid function tests are monitored. If there is little to no response from first line treatment for type 1 AIT, this may raise the possibility that type 2 AIT is the predominant aetiology. Type 2 AIT is more of an inflammatory response to the drug itself leading to an increase in release of thyroid hormone rather than excessive production. Main treatment involves glucocorticoids, usually prednisolone at a dose of 0.5-1.0 mg/kg/day which is tapered over several months according to response. If hyperthyroidism persists despite these measures, in both type 1 and 2 AIT, then referral for thyroidectomy should be considered as RAI is unlikely to be of benefit due to reduced uptake secondary to amiodarone therapy. In clinical practice, it may be difficult to differentiate between type 1 and type 2 AIT, and sometimes both may occur together. Therefore, a pragmatic approach is frequently adopted by treating for both types

Although thyroid storm is becoming increasingly less common due to improved diagnosis and treatment of hyperthyroidism, it remains a potentially life threatening emergency that requires urgent attention in an intensive care setting. Early supportive measures are important including fluid resuscitation, correcting electrolyte imbalances, supplemental oxygen, active cooling, and sedation if delirium is difficult to manage. Other treatments are based on clinical findings, such as broad spectrum intravenous antibiotics if infection is suspected and treating dysrhythmia or heart failure. More focused therapy includes ATD and typically PTU is preferred as it helps to lower T3 levels quicker that carbimazole due to its added effect of preventing peripheral conversion of T4 to T3 (Cooper & Rivkees 2009). PTU is given 6 hourly initially and usually oral administration is sufficient. Nasogastric tube may be required in individuals too ill to swallow and the drug can be administered intravenously if there are concerns over drug absorption. Unless contraindicated, propranolol is used to settle tachycardia and anxiety. Once ATD have been instituted, potassium iodide can be added, usually 1 hour after ATD and continued at a dose of 100 mg every 12 hours. The use of glucocorticoids is generally accepted, especially if there is a suspicion of concomitant adrenal insufficiency and may have the additional benefit of lowering T3 levels by preventing peripheral conversion of T4 to T3 (Bahn 2011). In extreme circumstances if there has not been a satisfactory response to treatment, procedures such as dialysis and plasma exchange can reduce levels of thyroid hormone, but in practice are very

FH of thyroid autoimmunity Possible Usually absent Goitre Yes No Thyroid antibodies Yes No

assessed by ultrasound Increased Decreased

Table 2. Differentiation of type1 and type 2 amiodarone-induced thyrotoxicosis (AIT). FH:

(IL-6, CRP) No Yes

**Type 1 AIT Type 2 AIT** 

of AIT simultaneously using antithyroid drugs and steroids.

rarely required (Alfadhi & Gianoukakis 2011).

family history, IL: interleukin, CRP: C-reactive protein.

Vascularity of thyroid gland

Raised inflammatory markers

**2.3.2 Thyroid storm** 

with restrictions, and those with severe ophthalmopathy can be offered surgery as are those who decline RAI. Similarly, patients who are hyperthyroid due to nodular goitre may be offered surgery as a definitive treatment due to the same reasons. Other indications include thyroid malignancy or uncertainty regarding thyroid malignancy and to alleviate compressive or respiratory symptoms due to large goitres (BTA 2006). Another indication for surgery is a cold nodule in a patient with GD, due to the relatively high risk of malignancy in such nodules (Abraham-Nordling et al 2005).

*Preparation of patient for surgery.* Euthyroid patients undergoing thyroid surgery require no special preparation prior to surgery. If they have had previous thyroid or parathyroid surgery, cervical disc operations or have a hoarse voice then direct or indirect laryngoscopy is recommended to identify previous recurrent laryngeal nerve palsy (Moorthy et al 2011). Thyrotoxic patients should be rendered euthyroid with ATD prior to surgery. Lugol's Iodine was used to be given pre-operatively, which along with reducing thyroid hormone secretion is also thought to reduce thyroid blood flow. However, this is now less common and provided the patient is euthyroid, such a treatment is not usually required (Feek et al 1980).

*Post-operative complication.* With careful pre-operative preparation and meticulous surgical technique, mortality from thyroid surgery should be <1% and similar to that of general anaesthesia alone (Weetman 2000). Complications do occur to varying degree and include thyroid storm, wound haemorrhage, hypoparathyroidism and recurrent laryngeal nerve injury. The incidence of thyroid storm as a result of thyroid surgery is now very low due to improved pre-operative treatment with ATD and post-operative management. Wound haemorrhage although rare, (occurring <1%) can be very serious and life threatening especially if there has been arterial bleeding causing tracheal compression. Any sign of wound haemorrhage causing respiratory compromise requires urgent intervention Schwartz et al 1998). The occurrence of hypoparathyroidism post-operatively can be either permanent or temporary and is rarely due to mistaken removal of all four parathyroid glands, but rather interruption to their blood supply (Pattou et al 1998). In the hands of experienced surgeons performing a total thyroidectomy, the risk is thought to be between 0- 3% (Schüssler-Fiorenza et al 2006). New techniques such as auto transplantation of parathyroid glands during surgery are effective at reducing these rates further (Testini et al 2007). Injury to the recurrent laryngeal nerve is also thought to be around 1-2% and is also higher when surgery is performed for thyroid malignancy. Some return of function to the vocal cords can be expected within the first few months and possibly up to 12 months. Beyond this time it is likely that injury will be permanent.

#### **2.3 Special cases of hyperthyroidism**

#### **2.3.1 Amiodarone induced thyrotoxicosis**

Treatment of amiodarone induced thyrotoxicosis (AIT) can be challenging, due in most part to the degree of overlap between type1 and type 2 AIT. The first step in the treatment of either case is to discontinue amiodarone if it is safe to do so, for which a cardiology opinion is usually sought. The attending physician attempt to distinguish whether the patient has type 1 or type 2 AIT (summarised in Table 2). Type 1 AIT is due to increased production of thyroid hormones, and so treatment with a thionamide should result in lowering of thyroid hormone levels. Occasionally potassium perchlorate can be added or substituted if there is no response. If successful the dose of thionamide is tapered and the thyroid function tests are monitored. If there is little to no response from first line treatment for type 1 AIT, this may raise the possibility that type 2 AIT is the predominant aetiology. Type 2 AIT is more of an inflammatory response to the drug itself leading to an increase in release of thyroid hormone rather than excessive production. Main treatment involves glucocorticoids, usually prednisolone at a dose of 0.5-1.0 mg/kg/day which is tapered over several months according to response. If hyperthyroidism persists despite these measures, in both type 1 and 2 AIT, then referral for thyroidectomy should be considered as RAI is unlikely to be of benefit due to reduced uptake secondary to amiodarone therapy. In clinical practice, it may be difficult to differentiate between type 1 and type 2 AIT, and sometimes both may occur

together. Therefore, a pragmatic approach is frequently adopted by treating for both types

of AIT simultaneously using antithyroid drugs and steroids.

#### **2.3.2 Thyroid storm**

178 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

with restrictions, and those with severe ophthalmopathy can be offered surgery as are those who decline RAI. Similarly, patients who are hyperthyroid due to nodular goitre may be offered surgery as a definitive treatment due to the same reasons. Other indications include thyroid malignancy or uncertainty regarding thyroid malignancy and to alleviate compressive or respiratory symptoms due to large goitres (BTA 2006). Another indication for surgery is a cold nodule in a patient with GD, due to the relatively high risk of

*Preparation of patient for surgery.* Euthyroid patients undergoing thyroid surgery require no special preparation prior to surgery. If they have had previous thyroid or parathyroid surgery, cervical disc operations or have a hoarse voice then direct or indirect laryngoscopy is recommended to identify previous recurrent laryngeal nerve palsy (Moorthy et al 2011). Thyrotoxic patients should be rendered euthyroid with ATD prior to surgery. Lugol's Iodine was used to be given pre-operatively, which along with reducing thyroid hormone secretion is also thought to reduce thyroid blood flow. However, this is now less common and provided

*Post-operative complication.* With careful pre-operative preparation and meticulous surgical technique, mortality from thyroid surgery should be <1% and similar to that of general anaesthesia alone (Weetman 2000). Complications do occur to varying degree and include thyroid storm, wound haemorrhage, hypoparathyroidism and recurrent laryngeal nerve injury. The incidence of thyroid storm as a result of thyroid surgery is now very low due to improved pre-operative treatment with ATD and post-operative management. Wound haemorrhage although rare, (occurring <1%) can be very serious and life threatening especially if there has been arterial bleeding causing tracheal compression. Any sign of wound haemorrhage causing respiratory compromise requires urgent intervention Schwartz et al 1998). The occurrence of hypoparathyroidism post-operatively can be either permanent or temporary and is rarely due to mistaken removal of all four parathyroid glands, but rather interruption to their blood supply (Pattou et al 1998). In the hands of experienced surgeons performing a total thyroidectomy, the risk is thought to be between 0- 3% (Schüssler-Fiorenza et al 2006). New techniques such as auto transplantation of parathyroid glands during surgery are effective at reducing these rates further (Testini et al 2007). Injury to the recurrent laryngeal nerve is also thought to be around 1-2% and is also higher when surgery is performed for thyroid malignancy. Some return of function to the vocal cords can be expected within the first few months and possibly up to 12 months.

Treatment of amiodarone induced thyrotoxicosis (AIT) can be challenging, due in most part to the degree of overlap between type1 and type 2 AIT. The first step in the treatment of either case is to discontinue amiodarone if it is safe to do so, for which a cardiology opinion is usually sought. The attending physician attempt to distinguish whether the patient has type 1 or type 2 AIT (summarised in Table 2). Type 1 AIT is due to increased production of thyroid hormones, and so treatment with a thionamide should result in lowering of thyroid hormone levels. Occasionally potassium perchlorate can be added or substituted if there is

the patient is euthyroid, such a treatment is not usually required (Feek et al 1980).

malignancy in such nodules (Abraham-Nordling et al 2005).

Beyond this time it is likely that injury will be permanent.

**2.3 Special cases of hyperthyroidism** 

**2.3.1 Amiodarone induced thyrotoxicosis** 

Although thyroid storm is becoming increasingly less common due to improved diagnosis and treatment of hyperthyroidism, it remains a potentially life threatening emergency that requires urgent attention in an intensive care setting. Early supportive measures are important including fluid resuscitation, correcting electrolyte imbalances, supplemental oxygen, active cooling, and sedation if delirium is difficult to manage. Other treatments are based on clinical findings, such as broad spectrum intravenous antibiotics if infection is suspected and treating dysrhythmia or heart failure. More focused therapy includes ATD and typically PTU is preferred as it helps to lower T3 levels quicker that carbimazole due to its added effect of preventing peripheral conversion of T4 to T3 (Cooper & Rivkees 2009). PTU is given 6 hourly initially and usually oral administration is sufficient. Nasogastric tube may be required in individuals too ill to swallow and the drug can be administered intravenously if there are concerns over drug absorption. Unless contraindicated, propranolol is used to settle tachycardia and anxiety. Once ATD have been instituted, potassium iodide can be added, usually 1 hour after ATD and continued at a dose of 100 mg every 12 hours. The use of glucocorticoids is generally accepted, especially if there is a suspicion of concomitant adrenal insufficiency and may have the additional benefit of lowering T3 levels by preventing peripheral conversion of T4 to T3 (Bahn 2011). In extreme circumstances if there has not been a satisfactory response to treatment, procedures such as dialysis and plasma exchange can reduce levels of thyroid hormone, but in practice are very rarely required (Alfadhi & Gianoukakis 2011).


Table 2. Differentiation of type1 and type 2 amiodarone-induced thyrotoxicosis (AIT). FH: family history, IL: interleukin, CRP: C-reactive protein.

Treatment Modalities in Thyroid Dysfunction 181

All euthyroid patients who have previously received treatment for hyperthyroidism should have TFT's checked in each trimester and importantly after delivery as there is an increased risk or recurrence post-partum. If surgery is required, due to allergy or adverse effect of

Subclinical hyperthyroidism is defined as a low TSH level, which is below the reference range (<0.1-0.4 mU/l), in the presence of a normal T4 and T3 concentration. It has become an increasingly problematic clinical entity following the introduction of new and more sensitive serum TSH assays. Patients usually exhibit non-specific symptoms or have no symptoms at all. There remains much debate regarding the correct management of such patients, with a lack of firm evidence to support treatment at present. The ultimate goal of treating these patients early (with the same treatment options as discussed above) is to prevent progression to overt hyperthyroidism, to reduce the risk of developing atrial fibrillation (AF) and ostoeporotic fractures and reduce mortality (Vanderpump 2011). A serum TSH level of between 0.1 and 0.4mU/l carries a very low risk of progression to overt hyperthyroidism, and so treatment need only be considered for those with a persistently suppressed TSH, especially in the presence of cardiovascular disease (Bahn 2011). Given the lack of supporting evidence advocating treatment, a pragmatic approach may be required, balancing the morbidity of hyperthyroid treatment against the risks of developing conditions such as AF, ostoeporotic

The causes of hypothyroidism can be differentiated into primary thyroid failure or secondary central hypothyroidism caused by pituitary or hypothalamus failure. In clinical practice most cases are primary in nature, due to chronic autoimmune thyroiditis, which can be goitrous (Hashimotos thyroiditis) or non-goitrous (atrophic thyroiditis). Iatrogenic hypothyroidism is usually caused secondary to treatment of hyperthyroidism. Transient hypothyroidism may be seen following a post-partum thyroiditis or viral induced sub-acute thyroiditis as the thyroid begins recovery after a destructive phase in which stored thyroid hormone is released

Symptoms of hypothyroidism are numerous and are often also found in patients who are euthyroid, whilst some hypothyroid patients will complain of no symptoms at all. Clinical signs are also very variable, but if present give a strong suspicion of the disease. However the absence of signs cannot be relied upon to exclude a diagnosis. Thyroid function testing is vital to make a diagnosis and include the measurement of TSH and T4 levels. The presence of TSH >10mU/l and free T4 levels below the normal reference range indicate overt hypothyroidism and requires treatment with thyroid replacement hormone. Subclinical hypothyroidism is classified by TSH level above the normal reference range with normal T4. The majority of patients (>95%) with hypothyroidism due to thyroid autoimmunity have detectable TPO antibodies, which aid the diagnosis and help to differentiate from other causes of low thyroid hormone levels. The main clinical symptoms and signs of

(Franklyn 1994). Causes of primary hypothyroidism are summarised in Table 3.

ATD, it is safest to be performed in the second trimester.

fractures and overt hyperthyroidism (Vanderpump 2011).

**2.3.4 Subclinical hyperthyroidism** 

**3. Aetiology of hypothyroidism** 

**3.1 Diagnosis of hypothyroidism** 

hypothyroidism are summarised in Table 4.

#### **2.3.3 Pregnancy**

Patients who are receiving treatment with ATD should receive pre-conceptual advice with a view to optimal preparation prior to pregnancy. This includes ensuring they are euthyroid prior to conception and altering medication to PTU which is felt to be superior to carbimazole during pregnancy, especially in the first trimester due to reduced incident of aplasia cutis (Bowman et al 2011). Current evidence suggests that following organogenesis, carbimazole or methimazole should be re-introduced due to a possible increased risk of hepatitis with PTU (Lazarus 2011). Those on a block and replace regime should also be swapped to PTU alone as thionamides will cross the placenta but levothyroxine will not, thus increasing the risk of foetal goitre and hypothyroidism (Weetman 2000). Pregnant patients taking ATD should have frequent TFT's throughout pregnancy (monthly) and the dose reduced to the lowest possible to maintain euthyroidism with T4 at the upper limit of the reference range (Lazarus 2011). Doses of ATD are reduced in the latter stages of pregnancy, and not infrequently stopped altogether as the condition undergoes remission. If hyperthyroidism is secondary to GD (or patient has had previous definitive treatment such as surgery or RAI) then TSH receptor antibodies should be measured as high titres can indicate intrauterine or neonatal thyrotoxicosis (Laurberg et al 1998). TSHR antibodies should not be checked in euthyroid patients previously treated with antithyroid drugs only.

Fig. 2. Management of special cases of hyperthyroidism. AIT: amiodarone induced thyrotoxicosis, GD: Graves' disease, PTU: propylthiouracil, NG: nasogastric, TFT's: thyroid function tests. ICU: intensive care unit.

Patients who are receiving treatment with ATD should receive pre-conceptual advice with a view to optimal preparation prior to pregnancy. This includes ensuring they are euthyroid prior to conception and altering medication to PTU which is felt to be superior to carbimazole during pregnancy, especially in the first trimester due to reduced incident of aplasia cutis (Bowman et al 2011). Current evidence suggests that following organogenesis, carbimazole or methimazole should be re-introduced due to a possible increased risk of hepatitis with PTU (Lazarus 2011). Those on a block and replace regime should also be swapped to PTU alone as thionamides will cross the placenta but levothyroxine will not, thus increasing the risk of foetal goitre and hypothyroidism (Weetman 2000). Pregnant patients taking ATD should have frequent TFT's throughout pregnancy (monthly) and the dose reduced to the lowest possible to maintain euthyroidism with T4 at the upper limit of the reference range (Lazarus 2011). Doses of ATD are reduced in the latter stages of pregnancy, and not infrequently stopped altogether as the condition undergoes remission. If hyperthyroidism is secondary to GD (or patient has had previous definitive treatment such as surgery or RAI) then TSH receptor antibodies should be measured as high titres can indicate intrauterine or neonatal thyrotoxicosis (Laurberg et al 1998). TSHR antibodies should not be checked in euthyroid patients previously treated with antithyroid drugs only.

**Management of special cases of hyperthyroidism**

**Avoid block & replace PTU preferred to carbimazole Use smallest possible dose of PTU Frequently monitor TFTs** (remission of GD during pregnancy is common) **Surgery is reserved for severe cases** (second trimester is safest)

Fig. 2. Management of special cases of hyperthyroidism. AIT: amiodarone induced

thyrotoxicosis, GD: Graves' disease, PTU: propylthiouracil, NG: nasogastric, TFT's: thyroid

**AIT Hyperthyroidism in pregnancy Thyroid storm**

**Transfer patient to ICU setting High dose antithyroid drugs** (PTU preferred via NG tube) **Rarely:** dialysis, plasma

exchange

Antibiotics Cooling Arrhythmias Heart failure

**Supportive therapy** Steroid cover Electrolytes/fluid Sedation as necessary

**2.3.3 Pregnancy** 

**Type 1 Type 2**

**Thionamides Glucocorticoids**

**Use both in unclear cases**

function tests. ICU: intensive care unit.

All euthyroid patients who have previously received treatment for hyperthyroidism should have TFT's checked in each trimester and importantly after delivery as there is an increased risk or recurrence post-partum. If surgery is required, due to allergy or adverse effect of ATD, it is safest to be performed in the second trimester.

#### **2.3.4 Subclinical hyperthyroidism**

Subclinical hyperthyroidism is defined as a low TSH level, which is below the reference range (<0.1-0.4 mU/l), in the presence of a normal T4 and T3 concentration. It has become an increasingly problematic clinical entity following the introduction of new and more sensitive serum TSH assays. Patients usually exhibit non-specific symptoms or have no symptoms at all. There remains much debate regarding the correct management of such patients, with a lack of firm evidence to support treatment at present. The ultimate goal of treating these patients early (with the same treatment options as discussed above) is to prevent progression to overt hyperthyroidism, to reduce the risk of developing atrial fibrillation (AF) and ostoeporotic fractures and reduce mortality (Vanderpump 2011). A serum TSH level of between 0.1 and 0.4mU/l carries a very low risk of progression to overt hyperthyroidism, and so treatment need only be considered for those with a persistently suppressed TSH, especially in the presence of cardiovascular disease (Bahn 2011). Given the lack of supporting evidence advocating treatment, a pragmatic approach may be required, balancing the morbidity of hyperthyroid treatment against the risks of developing conditions such as AF, ostoeporotic fractures and overt hyperthyroidism (Vanderpump 2011).

#### **3. Aetiology of hypothyroidism**

The causes of hypothyroidism can be differentiated into primary thyroid failure or secondary central hypothyroidism caused by pituitary or hypothalamus failure. In clinical practice most cases are primary in nature, due to chronic autoimmune thyroiditis, which can be goitrous (Hashimotos thyroiditis) or non-goitrous (atrophic thyroiditis). Iatrogenic hypothyroidism is usually caused secondary to treatment of hyperthyroidism. Transient hypothyroidism may be seen following a post-partum thyroiditis or viral induced sub-acute thyroiditis as the thyroid begins recovery after a destructive phase in which stored thyroid hormone is released (Franklyn 1994). Causes of primary hypothyroidism are summarised in Table 3.

#### **3.1 Diagnosis of hypothyroidism**

Symptoms of hypothyroidism are numerous and are often also found in patients who are euthyroid, whilst some hypothyroid patients will complain of no symptoms at all. Clinical signs are also very variable, but if present give a strong suspicion of the disease. However the absence of signs cannot be relied upon to exclude a diagnosis. Thyroid function testing is vital to make a diagnosis and include the measurement of TSH and T4 levels. The presence of TSH >10mU/l and free T4 levels below the normal reference range indicate overt hypothyroidism and requires treatment with thyroid replacement hormone. Subclinical hypothyroidism is classified by TSH level above the normal reference range with normal T4. The majority of patients (>95%) with hypothyroidism due to thyroid autoimmunity have detectable TPO antibodies, which aid the diagnosis and help to differentiate from other causes of low thyroid hormone levels. The main clinical symptoms and signs of hypothyroidism are summarised in Table 4.

Treatment Modalities in Thyroid Dysfunction 183

In non-elderly individuals with no history of cardiovascular disease, levothyroxine can be commenced at a dose of 50-100mcg daily, otherwise low doses are started initially (25 mcg evey day or every other day). It is estimated that most individuals require roughly 1.4-1.6 mcg/kg and so frequently doses will need to be titrated further, which can be done in increments of 25-50 mcg. Free T4 and TSH should be measured 8-12 weeks after commencing levothyroxine and after a change in dose. Until patients are on a stable dose of thyroxine, TSH and T4 should be checked together, after which annual check of TSH is sufficient. Controversy remains as to what value of TSH should be the target in hypothyroid patients treated with levothyroxine (Wartofsky & Dickey 2005). There does appear to be a lack of evidence supporting improved patient well being from maintaining TSH at the lower end of the reference range (BTA 2006), however many physicians continue to advocate this along with a lowering of the upper limit of the reference range for TSH to 2.5mu/L, given that >95% of euthyroid individuals have a TSH between 0.4mU/l to 2.5 mU/L (Gursoy et al 2006). A pragmatic approach which our centre follows is to aim for a TSH in the lower reference range by adjustment of levothyroxine dose if a patient remains symptomatic. The suppression of TSH is certainly not recommended due

Assuming that a patient's weight remains stable, with no alterations to their medication or change in co-morbidities, the dose of levothyroxine should in theory remain stable. There are several factors that require alterations in doses such as pregnancy, malabsorption and

Any state that produces intestinal malabsorption, such as coeliac disease, may lead to reduced uptake of thyroxine and hence a need to increase thyroxine dose. It is important to be weary of individuals who suddenly need an increase in thyroxine and who complain of gastrointestinal symptoms. Many medications can interfere with the absorption of thyroxine, such as ferrous sulphate, calcium carbonate, proton pump inhibitors, orlistat and cholestyramine (BTA 2006). Patients prescribed these medications should be advised to take them at least 2-4 hours apart from their thyroxine. In rare circumstances, TSH levels remain raised despite replacement therapy, usually due to compliance issues that the patient typically denies. Provided malabsorption is ruled out, a large dose of supervised levothyroxine replacement (1 mg/week) can be attempted, which fixes the

Weakness, lethargy, slow speech and dry/coarse skin >90% Cold intolerance, facial oedema, coarse hair >80% Weight gain, constipation, hair loss, memory problems >60% Anorexia, impaired hearing, dyspnoea, menorrhagia >30% Emotional instability, chest pain, dysphagia 10%

Dry/coarse skin, facial oedema, thick tongue >80% Bradycardia, skin pallor, slow relaxing reflexes >65% Pericardial effusion 30% Ascites, pleural effusion, carpal tunnel syndrome <10%

Table 4. Main symptoms and signs in autoimmune hypothyroidism

**Symptoms Frequency** 

**Signs Frequency** 

**3.2.1 Levothyroxine replacement** 

medication.

to fears of osteoporosis and atrial fibrillation (BTA 2006).

problem in the majority (Grebe et al 1997).

#### **3.2 Management of hypothyroidism**

Treatment of individuals with hypothyroidism is relatively easy and consists of replacement with thyroid hormones. In frank hypothyroidism the decision to start treatment is straightforward but in subclinical disease, criteria to start treatment are more complex (detailed below). Management of hypothyroidism is summarised in Figure 3.


Table 3. Causes of primary hypothyroidism.

### **Management of hypothyroidism**

Fig. 3. Management of hypothyroidism. LT4: levothyroxine, TSH: thyroid stimulating hormone, TPOAb: thyroid peroxidise antibodies, ICU: intensive care unit.

#### **3.2.1 Levothyroxine replacement**

182 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Treatment of individuals with hypothyroidism is relatively easy and consists of replacement with thyroid hormones. In frank hypothyroidism the decision to start treatment is straightforward but in subclinical disease, criteria to start treatment are more complex

Postpartum thyroiditis Autoimmune No (30% may develop

Drug induced Iatrogenic Reversible if drug

**Management of hypothyroidism**

**Subclinical hypothyroidism (TSH 4‐10 mIU/l & normal FT4)**

**LT4 therapy recommended:** Detectable TPOAb

Fig. 3. Management of hypothyroidism. LT4: levothyroxine, TSH: thyroid stimulating

hormone, TPOAb: thyroid peroxidise antibodies, ICU: intensive care unit.

Undetectable TPOAb but patient symptomatic (trial of therapy) **Observe without treatment** Negative TPOAb and asymptomatic

permanent hypothyroidism)

discontinued

**Hypothyroid coma**

**Transfer patient to ICU setting**

**No consensus regarding FT3**

**LT4 using NG tube or intravenously**

**Supportive therapy** Steroid cover Electrolytes/fluid Antibiotics Warming Respiratory support

**therapy**

(detailed below). Management of hypothyroidism is summarised in Figure 3.

Cause of hypothyroidism Aetiology Permanent? Primary Myxoedema Autoimmune Yes Hashimotos thyroiditis Autoimmune Yes Silent Thyroiditis Autoimmune No

Subacute thyroiditis Viral No Post-surgery Iatrogenic Yes Following RAI Iatrogenic Yes

Iodine deficiency or excess Reversible

**3.2 Management of hypothyroidism** 

Table 3. Causes of primary hypothyroidism.

**Frank hypothyroidism (Raised TSH, low FT4)**

**No evidence for additional benefit**

Concomitant medications (ferrous sulphate, antacids…etc…)

**Replace with LT4**

**of T3 replacement Aim to normalise TSH Dose adjustment of LT4:**

Pregnancy Weight gain/loss In non-elderly individuals with no history of cardiovascular disease, levothyroxine can be commenced at a dose of 50-100mcg daily, otherwise low doses are started initially (25 mcg evey day or every other day). It is estimated that most individuals require roughly 1.4-1.6 mcg/kg and so frequently doses will need to be titrated further, which can be done in increments of 25-50 mcg. Free T4 and TSH should be measured 8-12 weeks after commencing levothyroxine and after a change in dose. Until patients are on a stable dose of thyroxine, TSH and T4 should be checked together, after which annual check of TSH is sufficient. Controversy remains as to what value of TSH should be the target in hypothyroid patients treated with levothyroxine (Wartofsky & Dickey 2005). There does appear to be a lack of evidence supporting improved patient well being from maintaining TSH at the lower end of the reference range (BTA 2006), however many physicians continue to advocate this along with a lowering of the upper limit of the reference range for TSH to 2.5mu/L, given that >95% of euthyroid individuals have a TSH between 0.4mU/l to 2.5 mU/L (Gursoy et al 2006). A pragmatic approach which our centre follows is to aim for a TSH in the lower reference range by adjustment of levothyroxine dose if a patient remains symptomatic. The suppression of TSH is certainly not recommended due to fears of osteoporosis and atrial fibrillation (BTA 2006).

Assuming that a patient's weight remains stable, with no alterations to their medication or change in co-morbidities, the dose of levothyroxine should in theory remain stable. There are several factors that require alterations in doses such as pregnancy, malabsorption and medication.

Any state that produces intestinal malabsorption, such as coeliac disease, may lead to reduced uptake of thyroxine and hence a need to increase thyroxine dose. It is important to be weary of individuals who suddenly need an increase in thyroxine and who complain of gastrointestinal symptoms. Many medications can interfere with the absorption of thyroxine, such as ferrous sulphate, calcium carbonate, proton pump inhibitors, orlistat and cholestyramine (BTA 2006). Patients prescribed these medications should be advised to take them at least 2-4 hours apart from their thyroxine. In rare circumstances, TSH levels remain raised despite replacement therapy, usually due to compliance issues that the patient typically denies. Provided malabsorption is ruled out, a large dose of supervised levothyroxine replacement (1 mg/week) can be attempted, which fixes the problem in the majority (Grebe et al 1997).


Table 4. Main symptoms and signs in autoimmune hypothyroidism

Treatment Modalities in Thyroid Dysfunction 185

mIU/L and positive TPO antibodies as these individuals usually progress to overt hypothyroidism. In those with similar TSH levels, symptoms of hypothyroidism but negative TPOAb, a 6 months trial of replacement therapy is advocated with reassessment as to whether this therapy is needed. In asymptomatic individuals with negative TPOAb,

Thyroid dysfunction can represent a wide spectrum of disease and the consequences of under treatment are evident with the two extremes of thyroid storm and myxoedema coma. Treatment options of both hypo- and hyperthyroidism are generally well established but are not perfect and there remain several unanswered questions regarding both forms of management, such as the optimal range of TSH with thyroxine replacement, the duration of ATD for GD, and whether to treat subclinical disease. Ongoing research into such areas is likely to provide further insight into the conditions and new therapies. Even with an expansion of the evidence base, clinical experience is likely to remain an invaluable asset in many instances. Regardless of treatment, lifelong follow up is required to maintain

Abraham-Nordling M, Törring O, Hamberger B. (2005). Graves' disease: a long-term

Abraham P, Avenell A, Park CM, Watson WA, Bevan JS. (2005). A systematic review of drug therapy for Graves' hyperthyroidism. *Europ J Endocrinol* 153, 489-498 Aizawa Y, Yoshida K, Kaise N et al (1997). The development of transient hypothyroidism

Ajjan RA, Weetman AP.(2008).Techniques to quantify TSH receptor antibodies*. Nat Clin* 

Alfadhli E, Gianoukakis AG. (2011) Management of severe thyrotoxicosis when the

Association for Clinical Biochemistry and British Thyroid Association *(*2006*)* UK

Bahn RS, Burch HB, Cooper DS, Garber JR, Greenlee MC, Klein I, Laurberg P, McDougall

Bal CS, Kumar A, Pandey RM (2002). A randomized controlled trial to evaluate the

drugs, radioiodine, or surgery. *Thyroid*. 15, 1279-1286.

mechanism and prognosis. *Clin Endocrinol*. 461–5

gastrointestinal tract is compromised *Thyroid*. 21,215-20

http://www.british-thyroid-association.org/info-forpatients/Docs/TFT\_guideline\_final\_version\_July\_2006.pdf

*Pract Endocrinol Metab*.4, 461-8

Endocrinologists. *Thyroid*. 21, 593-646

12, 399–405

quality-of-life follow up of patients randomized to treatment with antithyroid

after iodine–131 in hyperthyroid patients with Graves' disease: prevalence,

Guidelines for the Use of Thyroid Function Tests*.* Available from*:* 

IR, Montori VM, Rivkees SA, Ross DS, Sosa JA, Stan MN. (2011) Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical

adjuvant effect of lithium on radioiodine treatment of hyperthyroidism. *Thyroid.* 

simple observation with repeat TFT's is probably all that is required (BTA 2006).

**4. Conclusion** 

euthyroidism.

**5. References** 

#### **3.2.2 T3 replacement therapy**

The use of tri-iodothyronine, either alone or in addition to levothyroxine remains controversial (Escobar-Morreale et al 2005). LT-3 has a much shorter half life than T4 and so repeated doses are needed throughout the day, and this can also impair measurement of free T3. Measurement of free T4 when T3 is used alone is of no benefit, and similarly to T4 treatment, the aim is for TSH within the normal range. There is currently no consistent evidence that combination therapy of T4 and T3 is superior to T4 treatment alone, and therefore this therapy is not generally advocated (BTA 2006).

#### **3.3 Special cases of hypothyroidism**

#### **3.3.1 Myxoedema coma**

Myxoedema coma is a very rare complication of untreated hypothyroidism but is associated with significant mortality. Patients with severe long standing hypothyroidism suddenly become unable to maintain homeostasis, usually due to a precipitating event such as infection, heart failure, stroke, gastrointestinal bleeding or medications (mainly sedatives and analgesics). Prompt treatment with intravenous levothyroxine is required, initially with a loading dose, followed by smaller maintenance doses which can be given orally if the patient is able. No consensus exists as to whether T3 treatment should commence at the same time, or indeed if T3 alone is all that is required (Kwaku & Burman 2007). Caution is needed in the elderly, or those with cardiovascular disease due to increased risk of myocardial infarction and tachyarrhythmia. Concurrent use of intravenous glucocorticoids are usually required during initiation of thyroxine treatment due to the potential for evoking an adrenal crisis in the first few days as the hypothalamic-pituitary-adrenal axis is usually impaired in severe hypothyroidism. Other supportive measures include blankets to warm the patients slowly, cautious use of intravenous fluid to treat hypotension and a low threshold for broad spectrum antibiotics if infection is thought to be implicated. Consideration should be given early to intubation and mechanical ventilation if deemed appropriate, especially in a comatose patient.

#### **3.3.2 Pregnancy**

During pregnancy, it is common for thyroxine requirements to increase by roughly 50%, and it is essential therefore that all pregnant ladies on thyroxine are reviewed regularly during pregnancy so that dose alteration can be made. It is recommended that TSH is maintained at the lower end of the reference range during pregnancy, with the free T4 at the upper range of normal (Lazarus 2011). It is particularly important during the first trimester, before the foetal thyroid is formed, that normal maternal levels of T4 are maintained as they play a vital role in foetal neurological development (Williams 2008). TSH and T4 should be checked pre-conceptually, at antenatal booking, within each trimester and 4-6 weeks post-partum, at which point the dose of thyroxine can usually be reduced to pre-pregnancy levels (Lazarus 2011).

#### **3.3.3 Subclinical hypothyroidism**

This relatively common clinical scenario can cause management confusion. It is recommended that replacement therapy is started in those with TSH between 4 and 10 mIU/L and positive TPO antibodies as these individuals usually progress to overt hypothyroidism. In those with similar TSH levels, symptoms of hypothyroidism but negative TPOAb, a 6 months trial of replacement therapy is advocated with reassessment as to whether this therapy is needed. In asymptomatic individuals with negative TPOAb, simple observation with repeat TFT's is probably all that is required (BTA 2006).

#### **4. Conclusion**

184 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

The use of tri-iodothyronine, either alone or in addition to levothyroxine remains controversial (Escobar-Morreale et al 2005). LT-3 has a much shorter half life than T4 and so repeated doses are needed throughout the day, and this can also impair measurement of free T3. Measurement of free T4 when T3 is used alone is of no benefit, and similarly to T4 treatment, the aim is for TSH within the normal range. There is currently no consistent evidence that combination therapy of T4 and T3 is superior to T4 treatment alone, and

Myxoedema coma is a very rare complication of untreated hypothyroidism but is associated with significant mortality. Patients with severe long standing hypothyroidism suddenly become unable to maintain homeostasis, usually due to a precipitating event such as infection, heart failure, stroke, gastrointestinal bleeding or medications (mainly sedatives and analgesics). Prompt treatment with intravenous levothyroxine is required, initially with a loading dose, followed by smaller maintenance doses which can be given orally if the patient is able. No consensus exists as to whether T3 treatment should commence at the same time, or indeed if T3 alone is all that is required (Kwaku & Burman 2007). Caution is needed in the elderly, or those with cardiovascular disease due to increased risk of myocardial infarction and tachyarrhythmia. Concurrent use of intravenous glucocorticoids are usually required during initiation of thyroxine treatment due to the potential for evoking an adrenal crisis in the first few days as the hypothalamic-pituitary-adrenal axis is usually impaired in severe hypothyroidism. Other supportive measures include blankets to warm the patients slowly, cautious use of intravenous fluid to treat hypotension and a low threshold for broad spectrum antibiotics if infection is thought to be implicated. Consideration should be given early to intubation and mechanical ventilation if deemed

During pregnancy, it is common for thyroxine requirements to increase by roughly 50%, and it is essential therefore that all pregnant ladies on thyroxine are reviewed regularly during pregnancy so that dose alteration can be made. It is recommended that TSH is maintained at the lower end of the reference range during pregnancy, with the free T4 at the upper range of normal (Lazarus 2011). It is particularly important during the first trimester, before the foetal thyroid is formed, that normal maternal levels of T4 are maintained as they play a vital role in foetal neurological development (Williams 2008). TSH and T4 should be checked pre-conceptually, at antenatal booking, within each trimester and 4-6 weeks post-partum, at which point the dose of thyroxine can usually be

This relatively common clinical scenario can cause management confusion. It is recommended that replacement therapy is started in those with TSH between 4 and 10

**3.2.2 T3 replacement therapy** 

**3.3 Special cases of hypothyroidism** 

appropriate, especially in a comatose patient.

reduced to pre-pregnancy levels (Lazarus 2011).

**3.3.3 Subclinical hypothyroidism** 

**3.3.1 Myxoedema coma** 

**3.3.2 Pregnancy** 

therefore this therapy is not generally advocated (BTA 2006).

Thyroid dysfunction can represent a wide spectrum of disease and the consequences of under treatment are evident with the two extremes of thyroid storm and myxoedema coma. Treatment options of both hypo- and hyperthyroidism are generally well established but are not perfect and there remain several unanswered questions regarding both forms of management, such as the optimal range of TSH with thyroxine replacement, the duration of ATD for GD, and whether to treat subclinical disease. Ongoing research into such areas is likely to provide further insight into the conditions and new therapies. Even with an expansion of the evidence base, clinical experience is likely to remain an invaluable asset in many instances. Regardless of treatment, lifelong follow up is required to maintain euthyroidism.

#### **5. References**


Treatment Modalities in Thyroid Dysfunction 187

Moorthy R, Balfour A, Jeannon JP, Simo R. (2011) Recurrent laryngeal nerve palsy in

Orgiazzi J, Mornex R: Hyperthyroidism. In: Greer M ed. *The thyroid gland*. New York:

Pattou F, Combemale F, Fabre S, et al. (1998) Hypocalcemia following thyroid surgery:

Philippou G, Koutras DA, Piperingos G, Souvatzoglou A, Moulopoulos SD (1992). The

Royal College of Physicians. (2007). Radioiodine in the management of benign thyroid

Regalbuto C, Marturano I, Condorelli A, Latina A, Pezzino V (2009) Radiometabolic

Reinwein D, Benker G, Konig MP, et al. (1984). The different types of hyperthyroidism in

Reinwein D, Benker G, Lazarus JH, Alexander WD (1993). A prospective randomized trial

Sawyers JL, Martin CE, Byrd BF Jr, Rosenfeld L.(1972). Thyroidectomy for

Schüssler-Fiorenza CM, Bruns CM,Chen H. (2006). The Surgical Management of Graves'

Schwartz AE, Clark O, Ituarte P, LoGerfo P. (1998). Therapeutic controversy. Thyroid

Singer PA, Cooper DS, Levy EG, et al. (1995). Treatment guidelines for patients with

Solomon B, Glinoer D, Lagasse R, Wartofsky L. (1990). Current trends in the management

Tallstedt L, Lundell G, Blomgren H et al. (1994). Does early administration of thyroxine

Testini M, Gurrado A, Lissidini G, Nacchiero M. (2007). Hypoparathyroidism after total

Vanderpump MPJ, Tunbridge WMG, French JM. (1995). The incidence of thyroid

Vanderpump MP (2011). Should we treat mild subclinical/mild hyperthyroidism? No

reduce the development of Graves' ophthalmopathy after radioiodine treatment?

disorders in the community; a twenty-year follow up of the Whickham survey.

Incidence and prediction of outcome. *World J Surg* . 22, 718–724.

21

*London*

200.

1516-

Raven Press 442, 1990.

*Clin Endocrinol.* 36, 573-578

year follow-up*. J Endocrinol Invest.* 32, 134–138

hyperthyroidism. *Ann Surg*. 175, 939-947

*Eur J Endocrinol,* 130, 494–7.

*Clin Endocrinol.* 43, 55-68

.*Eur J Intern Med*. 22, 330-3

thyroidectomy. *Minerva Chin.* 62, 409-15

Disease*. Journal of Surgical Research*. 133, 207-214

surgery: The choice. *J Clin Endocrinol Metab*. 83, 1097–1105.

hyperthyroidism and hypothyroidism. *JAMA*. 273, 808-812

of Graves' disease*. J Clin Endocrinol Metab*. 70, 1518-1524

benign thyroid disease: can surgery make a difference?.*Eur Arch Otorhinolaryngol*.

effect of iodide on serum thyroid hormone levels in normal persons, in hyperthyroid patients, and in hypothyroid patients on thyroxine replacement.

disease. Clinical guidelines Report of a Working Party. *Royal College of Physicians*,

treatment of hyperthyroidism with a calculated dose of 131-iodine: results of one-

Europe. Results of a prospective survey of 924 patients. *J Endocrinol Invest.* 11,193-

of antithyroid drug dose in Graves' disease therapy. *J Clin Endocrinol Metab.* 76,


Bartalena L. (2011). The dilemma of how to manage Graves' disease in patients with

Biswas N, Ahn Y-H, Goldman JM, Schwartz JM. (1991) Case report: Aplastic anemia

Bogazzi F, Bartalena L, Brogioni S et a (1999*)*. Comparison of radioiodine with radioiodine

Bowan P, Osborne NJ, Sturley R, Vaidya B. (2011) Carbimazole embryopathy:

Cooper DS, Rivkees SA. (2009). Putting propylthiouracil in perspective. *J Clin Endocrinol*

Costagliola S, Morgenthaler NG, Hoermann R, et al (1999). Second generation assay for

Escobar-Morreale HF, Botella-Carretero JI, Gómez-Bueno M, Galán JM, Barrios V, Sancho

Feek CM, Sawers JSA, Irvine WJ, Beckett GJ, Ratcliffe WA, Toft AD. (1980). Combination

Gurosy A, Ozduman Cin M, Kamel N, Gullu S. (2006) Which thyroid-stimulating

Hedley AJ, Young RE, Jones SJ, Alexander WD, Bewsher PD (1989). Antithyroid drugs in

Laurberg P, Nygaard B, Glinoer D, Grussendorf M, Orgiazzi, J (1998). Guidelines for TSH-

Lazarus JH. (2011). Thyroid function in pregnancy. *British Medical Bulletin*. 97, 137-148. Matthews DC, Syed AA (2011) The role of TSH receptor antibodies in the management of

Maugendre D, Gatel A, Campion L, et al (1999). Antithyroid drugs and Graves' disease --

Kwaku MP, Burman KD. (2007) Myxedema coma. *J Intensive Care Med*. 22, 224-31

Franklyn JA (1994). The management of hyperthyroidism. *N Engl J Med.* 330, 1731-173 Grebe SK, Cooke RR, Ford HC, et al.(1997) Treatment of hypothyroidism with once

plus lithium in the treatment of Graves' hyperthyroidism *J Clin Endocrinol Metab.* 

implications for the choice of antithyroid drugs ion pregnancy. *Q J Med.* [Epub

thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves'

J. (2005). Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine

of potassium iodide and propranolol in preparation of patients with Graves'

hormone level should be sought in hypothyroid patients under L-thyroxine

the treatment of hyperthyroidism of Graves' disease: long-term follow-up of 434

receptor antibody measurements in pregnancy; results of an evidence-based symposium organized by the European Thyroid Association. *Eur J Endocrinol.* 

prospective randomised assessment of long-term treatment. *Clin Endocrinol*. 50,

associated orbitopathy*. J Clinb Endocinol Metab*. 96, 592-599.

84, 499–503

ahead of print]

*Metab*. 94, 1881-2.

Cooper DS. (2003). Hyperthyroidism. *Lancet.* 362, 459-468

disease*. J Clin Endocrinol Metab*. 84, 90-97

alone. *Ann Intern Med*. 15, 412-24

Cooper DS. (2005). Antithyroid drugs. *N Engl J Med.* 352, 905-917

disease for thyroid surgery. *N Engl J Med* .302, 883-885

weekly thyroxine*. J Clin Endocrinol Meta.* 82*,*870*–*5

replacement therapy?. *Int J Clin Pract*.60, 655-9

patients. *Clin Endocrinol*. 31, 209-218

Graves' disease..*Eur J Intern Med*. 22, 213-6

139: 584-590

127-132

associated with antithyroid drugs. *Am J Med Sci*. 301, 190-194.


**13**

*Turkey* 

**New Technologies in Thyroid Surgery** 

One of the earliest references to a successful surgical attempt for the treatment of goitre can be found in the medical writings of the Moorish physician Ali Ibn Abbas. In 952 A.D., he recorded his experience with the removal of a large goitre under opium sedation using simple ligatures and hot cautery irons as the patient sat with a bag around his neck to catch the blood. The first accounts of thyroid surgery for the treatment of goiters were given by Roger Frugardi in 1170. In response to failure of medical treatment, two setons were inserted at right angles into the goiter and tightened twice daily until the goiter separated. The open wound was treated with caustic powder and left to heal. The first successful typical partial thyroidectomy was performed by the French Surgeon, Pierre Joseph Desault, in 1791 during the French Revolution. Dupuytren followed in 1808 with the first total

Despite these limited descriptions of early successes, the surgical approach to goitre remained shrouded in misunderstanding and superstition. Thyroid surgery in the 19th century carried a mortality of around 40% even in the most skilled surgical hands, mainly due to haemorrhage and infection. The French Academy of Medicine actually banned thyroid surgery in 1850 and German authorities called for restrictions on such 'foolhardy performances'. Leading surgeons avoided thyroid surgery if at all possible, and would only intervene in cases of respiratory obstruction. Samuel Gross wrote in 1848: "Can the thyroid gland when in the state of enlargement be removed…? If a surgeon should be so foolhardy as to undertake it. .every step he takes will be environed with difficulty, every stroke of his knife will be followed by a torrent of blood and lucky it would be for him if his victim lives long enough to enable him to finish his horrid butchery. No honest and sensible surgeon

Early surgical approaches for treatment of thyroid disorders were associated with high rates of mortality and morbidity due to hemorrhage, asphyxia, air embolism, and infection. Surgical approach to thyroid disease was seen as the last resort. It was not until the late 1800s after the advent of ether as anesthesia, antiseptic technique, and effective artery forceps that allowed Theodor Kocher to perfect the technique for thyroidectomy. Kocher used the technique of precise ligation of the arterial blood supply to perform an unhurried, meticulous dissection of the thyroid gland, decreasing the morbidity and mortality

Advancements could only take place in the field of thyroid surgery with the introduction of improved anaesthesia, antiseptic techniques, and improved ways of controlling

thyroidectomy, but the patient died 36 hours after the operation.

associated with thyroid surgery to less than 1% ( Giddings,1998).

**1. Introduction** 

would ever engage in it."

 *Ankara University, Faculty of Medicine Department of Surgery* 

Bahri Çakabay and Ali Çaparlar

Vitti P, Rago T, Chiovato L, et al (1997). Clinical features of patients with Graves' disease undergoing remission after antithyroid drug treatment. *Thyroid*. 7, 369-75

Weetman AP (2000). Graves' disease. *N Engl J Med.* 343, 1236-1248


### **New Technologies in Thyroid Surgery**

Bahri Çakabay and Ali Çaparlar

 *Ankara University, Faculty of Medicine Department of Surgery Turkey* 

#### **1. Introduction**

188 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Vitti P, Rago T, Chiovato L, et al (1997). Clinical features of patients with Graves' disease undergoing remission after antithyroid drug treatment. *Thyroid*. 7, 369-75

Wartofsky L, Dickey RA (2005). The evidence for a narrower thyrotropin reference range

Williams GR. (2008) Neurodevelopmental and neurophysiological actions of thyroid

Weetman AP (2000). Graves' disease. *N Engl J Med.* 343, 1236-1248

is compelling*. J Clin Endocrinol Metab*. 90, 5483–8.

hormone. *J Neuroendocrinol*. 20, 784-194.

One of the earliest references to a successful surgical attempt for the treatment of goitre can be found in the medical writings of the Moorish physician Ali Ibn Abbas. In 952 A.D., he recorded his experience with the removal of a large goitre under opium sedation using simple ligatures and hot cautery irons as the patient sat with a bag around his neck to catch the blood. The first accounts of thyroid surgery for the treatment of goiters were given by Roger Frugardi in 1170. In response to failure of medical treatment, two setons were inserted at right angles into the goiter and tightened twice daily until the goiter separated. The open wound was treated with caustic powder and left to heal. The first successful typical partial thyroidectomy was performed by the French Surgeon, Pierre Joseph Desault, in 1791 during the French Revolution. Dupuytren followed in 1808 with the first total thyroidectomy, but the patient died 36 hours after the operation.

Despite these limited descriptions of early successes, the surgical approach to goitre remained shrouded in misunderstanding and superstition. Thyroid surgery in the 19th century carried a mortality of around 40% even in the most skilled surgical hands, mainly due to haemorrhage and infection. The French Academy of Medicine actually banned thyroid surgery in 1850 and German authorities called for restrictions on such 'foolhardy performances'. Leading surgeons avoided thyroid surgery if at all possible, and would only intervene in cases of respiratory obstruction. Samuel Gross wrote in 1848: "Can the thyroid gland when in the state of enlargement be removed…? If a surgeon should be so foolhardy as to undertake it. .every step he takes will be environed with difficulty, every stroke of his knife will be followed by a torrent of blood and lucky it would be for him if his victim lives long enough to enable him to finish his horrid butchery. No honest and sensible surgeon would ever engage in it."

Early surgical approaches for treatment of thyroid disorders were associated with high rates of mortality and morbidity due to hemorrhage, asphyxia, air embolism, and infection. Surgical approach to thyroid disease was seen as the last resort. It was not until the late 1800s after the advent of ether as anesthesia, antiseptic technique, and effective artery forceps that allowed Theodor Kocher to perfect the technique for thyroidectomy. Kocher used the technique of precise ligation of the arterial blood supply to perform an unhurried, meticulous dissection of the thyroid gland, decreasing the morbidity and mortality associated with thyroid surgery to less than 1% ( Giddings,1998).

Advancements could only take place in the field of thyroid surgery with the introduction of improved anaesthesia, antiseptic techniques, and improved ways of controlling

New Technologies in Thyroid Sugery 191

extensively. Two of the most commonly used techniques for hemostasis are suture ligation and electrocoagulation. The disadvantage of suture ligation and electrocoagulation techniques is the prolonged operating time. Recently, a number of innovative methods of hemostasis in thyroid surgery have been tested, with promising results. New techniques developed over the past decade include hemostatic clipping, laser, LigaSure diathermy (ValleyLab, CO, USA) (or the LigaSure vessel sealing system), and ultrasonic instrumentation. Clips work for large vessels and are subject to dislodgment; whereas staples are wasted and costly for multiple single-vessel applications. Lasers are hindered by the risk of injury to many vital structures (such as the recurrent nerves) in the operative field, and bipolar electrocautery does not give the surgeon the freedom of applicability at

There have been significant advances in vessel sealing systems for the occlusion of blood vessels during general and gynecological surgical procedures. Two such devices are now commonly used in thyroid surgery: a bipolar energy sealing system and ultrasonic coagulation ( Rahbari et al., 2011).Thyroid surgery is the most common endocrine surgical operation. Like all surgical procedures, the basic tenant of good exposure and hemostasis

LigaSure (ValleyLab, CO, USA) is a bipolar diathermy system that seals vessels with reduced thermal spread. The device has been used successfully in abdominal surgery and has been introduced as a new method for hemostasis during thyroidectomy. The LigaSure diathermy system enables simultaneous selective sealing and division of a vessel without dispersion of the electric power, and with less heat production. The device is used in abdominal surgery and has proved suitable for use in thyroid surgery(Çakabay et al., 2009). Any new surgical technology or operating technique should yield similar or improved patient outcomes and similar or lower rates of complications, compared with conventional methods. LigaSure, allowing vessel sealing and division with no dispersion of the electric power and with little or no heat production, has been widely used in diverse fields of surgery for its efficiency and safety. However, in thyroid surgery,where a considerable amount of minute vessels must be divided and hence microsurgical techniques required, LigaSure is also preferred for its further efficiency by shortening the

Various specialties have reported shorter operating times with LigaSure (Lee et al., 2003,Levy et al., 2003,Jayne et al., 2002). However, in the literature, the postoperative outcome of thyroidectomy with LigaSure is controversial. Some studies (Petrakis et al., 2004) reported fewer complications and shorter operating times in the LigaSure , while others (Kiriakopoulos et al., 2004) did not observe a reduction in operating time for patients who underwent total or near-total thyroidectomy with LigaSure. According to two studies (Kirdak et al., 2005,Shen et al., 2005) the operating time was reduced substantially and the reduction in operating time in the LigaSure group was most probably a reflection of changes in operating technique (Shen et al., 2005).They reported that this change in technique facilitates dissection of the thyroid lobes and helps to reduce operating time and results ina decreased requirement for lateral skin etraction;the reduction in incision length in the

different angles ( Kennedy et al., 1998).

apply to thyroid surgery.

duration of the operation.

**2.1 LigaSure** 

haemorrhage during surgery. The first thyroidectomy under ether anaesthesia took place in St Petersburg in 1849; the second half of the 19th century saw the introduction of Lister's antiseptic techniques through Europe, and the development of haemostatic forceps by such figures as Spencer Wells in London led to much better haemostasis than could be achieved by crude ligatures and cautery.

The most notable thyroid surgeons were Emil Theodor Kocher (1841–1917) and C.A. Theodor Billroth (1829–1894), who performed thousands of operations with increasingly successful results. However, as more patients survived thyroid operations, new problems and issues became apparent. After total thyroidectomy, patients became myxedematous with cretinous features. Myxedema effectively treated in 1891 by George Murray and Edward Fox. In 1909, Kocher was awarded the Nobel Prize for medicine in recognition "for his works on the physiology, pathology, and surgery of the thyroid gland."

 The thyroid gland is removed traditionally through a small curvilinear incision approximately 3 cm above the sternal notch. While these original incisions allow for optimal exposure and successful removal of the diseased organ, they tend to subject the patients to lengthy hospital stays,significant postoperative pain, and in some cases, cosmetically undesirable results.

By the end of the twentieth century, laparoscopy was already accepted worldwide for a large number of operations in general surgery. By minimizing the size of the skin incisions while still permitting superior visualization of the operative field, laparoscopy was proven for certain operations to lessen postoperative pain, improve cosmesis, and shorten postoperative hospital stays.

As minimally invasive surgery became more popular,surgeons realized some true limitations. Sensory information is limited due to lack of tactile feedback and restriction to a two-dimensional (2D) image. In addition, compared to the human hand in an open case,laparoscopic instruments have restricted degrees of freedom mainly due to the lack of a wrist-like joint in the instrument tip and the lack of maneuverability due to a fixed axis point at the trocar ( Hansen et al., 1997).

The advent of robot-assisted laparoscopic surgery seems to deal with many of the recognized limitations of hand-held laparoscopic surgery. In general, robots reduce the natural tremor of the human hand, reestablish comfortable ergonomics, reducing stress and surgeon fatigue, and,in certain cases, reestablish the three-dimensional (3D) view of the surgical field. In addition, surgical robots have the potential to be more precise and permit greater accuracy when it comes to suturing tasks and careful perivascular dissections. (Jacob et al., 2005)

#### **2. Surgical instrumants for improved hemostasis**

Thyroid surgery involves meticulous devascularization of the thyroid gland, which has one of the richest blood supplies of all organs, with numerous blood vessels and plexuses enteringits parenchyma. Therefore, hemostasis is of paramount importance when dividing the various vessels before excising the gland(Çakabay et al., 2009).

Although nearly a century has passed since Halstead and Kocher first described thyroidectomy, it has changed little until recently, and is a procedure that is performed

haemorrhage during surgery. The first thyroidectomy under ether anaesthesia took place in St Petersburg in 1849; the second half of the 19th century saw the introduction of Lister's antiseptic techniques through Europe, and the development of haemostatic forceps by such figures as Spencer Wells in London led to much better haemostasis than could be achieved

The most notable thyroid surgeons were Emil Theodor Kocher (1841–1917) and C.A. Theodor Billroth (1829–1894), who performed thousands of operations with increasingly successful results. However, as more patients survived thyroid operations, new problems and issues became apparent. After total thyroidectomy, patients became myxedematous with cretinous features. Myxedema effectively treated in 1891 by George Murray and Edward Fox. In 1909, Kocher was awarded the Nobel Prize for medicine in recognition "for

 The thyroid gland is removed traditionally through a small curvilinear incision approximately 3 cm above the sternal notch. While these original incisions allow for optimal exposure and successful removal of the diseased organ, they tend to subject the patients to lengthy hospital stays,significant postoperative pain, and in some cases, cosmetically

By the end of the twentieth century, laparoscopy was already accepted worldwide for a large number of operations in general surgery. By minimizing the size of the skin incisions while still permitting superior visualization of the operative field, laparoscopy was proven for certain operations to lessen postoperative pain, improve cosmesis, and shorten

As minimally invasive surgery became more popular,surgeons realized some true limitations. Sensory information is limited due to lack of tactile feedback and restriction to a two-dimensional (2D) image. In addition, compared to the human hand in an open case,laparoscopic instruments have restricted degrees of freedom mainly due to the lack of a wrist-like joint in the instrument tip and the lack of maneuverability due to a fixed axis

The advent of robot-assisted laparoscopic surgery seems to deal with many of the recognized limitations of hand-held laparoscopic surgery. In general, robots reduce the natural tremor of the human hand, reestablish comfortable ergonomics, reducing stress and surgeon fatigue, and,in certain cases, reestablish the three-dimensional (3D) view of the surgical field. In addition, surgical robots have the potential to be more precise and permit greater accuracy when it comes to suturing tasks and careful perivascular dissections. (Jacob

Thyroid surgery involves meticulous devascularization of the thyroid gland, which has one of the richest blood supplies of all organs, with numerous blood vessels and plexuses enteringits parenchyma. Therefore, hemostasis is of paramount importance when dividing

Although nearly a century has passed since Halstead and Kocher first described thyroidectomy, it has changed little until recently, and is a procedure that is performed

his works on the physiology, pathology, and surgery of the thyroid gland."

by crude ligatures and cautery.

undesirable results.

et al., 2005)

postoperative hospital stays.

point at the trocar ( Hansen et al., 1997).

**2. Surgical instrumants for improved hemostasis** 

the various vessels before excising the gland(Çakabay et al., 2009).

extensively. Two of the most commonly used techniques for hemostasis are suture ligation and electrocoagulation. The disadvantage of suture ligation and electrocoagulation techniques is the prolonged operating time. Recently, a number of innovative methods of hemostasis in thyroid surgery have been tested, with promising results. New techniques

developed over the past decade include hemostatic clipping, laser, LigaSure diathermy (ValleyLab, CO, USA) (or the LigaSure vessel sealing system), and ultrasonic instrumentation. Clips work for large vessels and are subject to dislodgment; whereas staples are wasted and costly for multiple single-vessel applications. Lasers are hindered by the risk of injury to many vital structures (such as the recurrent nerves) in the operative field, and bipolar electrocautery does not give the surgeon the freedom of applicability at different angles ( Kennedy et al., 1998).

There have been significant advances in vessel sealing systems for the occlusion of blood vessels during general and gynecological surgical procedures. Two such devices are now commonly used in thyroid surgery: a bipolar energy sealing system and ultrasonic coagulation ( Rahbari et al., 2011).Thyroid surgery is the most common endocrine surgical operation. Like all surgical procedures, the basic tenant of good exposure and hemostasis apply to thyroid surgery.

#### **2.1 LigaSure**

LigaSure (ValleyLab, CO, USA) is a bipolar diathermy system that seals vessels with reduced thermal spread. The device has been used successfully in abdominal surgery and has been introduced as a new method for hemostasis during thyroidectomy. The LigaSure diathermy system enables simultaneous selective sealing and division of a vessel without dispersion of the electric power, and with less heat production. The device is used in abdominal surgery and has proved suitable for use in thyroid surgery(Çakabay et al., 2009).

Any new surgical technology or operating technique should yield similar or improved patient outcomes and similar or lower rates of complications, compared with conventional methods. LigaSure, allowing vessel sealing and division with no dispersion of the electric power and with little or no heat production, has been widely used in diverse fields of surgery for its efficiency and safety. However, in thyroid surgery,where a considerable amount of minute vessels must be divided and hence microsurgical techniques required, LigaSure is also preferred for its further efficiency by shortening the duration of the operation.

Various specialties have reported shorter operating times with LigaSure (Lee et al., 2003,Levy et al., 2003,Jayne et al., 2002). However, in the literature, the postoperative outcome of thyroidectomy with LigaSure is controversial. Some studies (Petrakis et al., 2004) reported fewer complications and shorter operating times in the LigaSure , while others (Kiriakopoulos et al., 2004) did not observe a reduction in operating time for patients who underwent total or near-total thyroidectomy with LigaSure. According to two studies (Kirdak et al., 2005,Shen et al., 2005) the operating time was reduced substantially and the reduction in operating time in the LigaSure group was most probably a reflection of changes in operating technique (Shen et al., 2005).They reported that this change in technique facilitates dissection of the thyroid lobes and helps to reduce operating time and results ina decreased requirement for lateral skin etraction;the reduction in incision length in the

New Technologies in Thyroid Sugery 193

harmonic scalpel versus conventional techniques. The characteristics of these studies summarized in Table1. The majority of these studies compared operative time, hospitalization time, drain use, incision size, postoperative pain, cosmetic results, cost analysis, and RLNP and other postoperative complications. The main advantage of using the harmonic scalpel in thyroid surgery is the reduction in operative time. Studies showed that the use of a harmonic scalpel significantly decreased the operative time (Yildirim et al.,

Some studies shown that no difference (Siperstein et al., 2002) was observed between the two techniques (harmonic scalpel and conventional techniques ) regarding the amount of blood loss,others (Miccoli et al., 2006,Kilic et al., 2007, Yildirim et al., 2008) have shown that drainage volume is significantly lower in patients treatment with a harmonic scalpel

Despite the safety demonstrated by harmonic scalpel in several studies, specific training and experience in the use of the device are necessary because the active blade in inexperienced hands can easily injure surrounding vital structures. Approximately 10 h of experience are required (Voutilainen et al., 2000).The majority of transient and permanent complications occurred in the period of early training. Hypocalcemia and nerve palsy rates will decrease in

> **Number of patients (HS/CSL)**

**Summary of studies** 

Hospitalization time, postoperative drainage, and intraoperative bleeding

Operative time was shorter in the HS

The incision length was shorter and the operating time was reduced in the HS compared to CSL group. Bleeding was negligible and complications

Operative time was shorter in the HS

The operative time was shorter in the HS group than in the CSL group. Hospitalization was similar between groups, but the global cost per patient was significantly less in the HS group. Postoperative complications were

were similar between groups.

group than in the CSL group.

group than in the CSL group. Thyroid size tended to be larger in the HS group than in the CSL group.

The two groups were similar

regarding blood loss.

similar between groups.

were few.

2008, Voutilainen et al., 2000).

 **References Year Type of** 

<sup>1</sup>Voutilainen

<sup>3</sup>Siperstein

compared to those treated with conventional techniques.

time as our experience with the harmonic scalpel technique increases.

**study** 

et al., 2000 Prospective 19/17

2 Shemen 2002 Retrospective 105/20

et al., 2002 Retrospective 86/85

4 Ortega et al., 2004 Prospective 100/100

LigaSure group is probably a result of this decreased need for lateral retraction.The reduced operating time may result in decreased postoperative pain. The cause of postoperative pain is hyperextension of the neck (Defechereux et al., 2003); therefore, the pain can be reduced if the operating time is minimized. We found (Çakabay et al., 2009) that the use of the LigaSure significantly reduced the operating time for both total and one side total+other side subtotal thyroidectomy. The reduction in operating time was greatest in the total+subtotal thyroidectomy group. This is probably the result of faster but equally safe dissection of the thyroid gland compared with the conventional clampand-tie technique. In our experience, thyroid surgery using LigaSure does not require a significant learning period.

The major complications of thyroidectomy are laryngeal nerve injury and hypocalcemia. The reported permanent RLN palsy rate is 0%-14%. The use of LigaSure did not increase the RLN palsy risk(Çakabay2 et al., 009). Iatrogenic injury to the parathyroid glands resulting in hypocalcemia can occur from direct damage through inappropriate manipulation of surgery.

The cost of the LigaSure device is an important issue. According to some studies (Kirdak et al., 2005) the use of LigaSure is more expensive than the other conventional techniques. They reported that a cost-benefit analysis of this instrument may be helpful when choosing one of these techniques over the other. However, as the LigaSure device is produced to be disposable, the costeffectivenessof LigaSure can be increased by using one device for several patients. The reuse of LigaSure hand pieces decreases its cost of purchase (Dilek et al., 2005). İn our exprience,we found that the additional cost of using LigaSure was \$95 per operation, and our observations indicate that the same device will provide safe hemostasis for no more than 10 patients .

#### **2.2 Harmonic scalpel**

New techniques, such as hemostatic clipping, monopolar/bipolar diathermy, and laser and ultrasonic instrumentation, have been developed over the past decade. Of these, the harmonic scalpel is the most frequently used. The harmonic scalpel uses high-frequency mechanical energy to cut and coagulate tissues at the same time ,and it is widely used in otorhinolaryngological, cardiac, gastrointestinal, vascular, hemorrhoid, laparoscopic, obstetric, and gynecological surgery. The main advantages of ultrasonic coagulating /dissecting systems compared with a standard electrosurgical device are represented by minimal lateral thermal tissue damage (the harmonic scalpel causes lateral thermal injury 1-3 mm wide, approximately half that caused by bipolar systems),less smoke formation, no neuromuscular stimulation, and no electrical energy to or through the patient (Roye et al., 2000). Since its introduction, the harmonic scalpel has also gained popularity in thyroid and neck surgery. The proposed advantages of the harmonic scalpel include less lateral thermal tissue damage with no electrical energy transferred to the patient, as in electrocautery. In addition, the harmonic scalpel has some advantages over conventional techniques, particularly in terms of operative time, intraoperative bleeding, and hospitalization time.

The harmonic scalpel is a new surgical device for thyroid surgery and, to the best of our knowledge, studies in the English-language literature have been undertaken to compare

LigaSure group is probably a result of this decreased need for lateral retraction.The reduced operating time may result in decreased postoperative pain. The cause of postoperative pain is hyperextension of the neck (Defechereux et al., 2003); therefore, the pain can be reduced if the operating time is minimized. We found (Çakabay et al., 2009) that the use of the LigaSure significantly reduced the operating time for both total and one side total+other side subtotal thyroidectomy. The reduction in operating time was greatest in the total+subtotal thyroidectomy group. This is probably the result of faster but equally safe dissection of the thyroid gland compared with the conventional clampand-tie technique. In our experience, thyroid surgery using LigaSure does not require a

The major complications of thyroidectomy are laryngeal nerve injury and hypocalcemia. The reported permanent RLN palsy rate is 0%-14%. The use of LigaSure did not increase the RLN palsy risk(Çakabay2 et al., 009). Iatrogenic injury to the parathyroid glands resulting in hypocalcemia can occur from direct damage through inappropriate

The cost of the LigaSure device is an important issue. According to some studies (Kirdak et al., 2005) the use of LigaSure is more expensive than the other conventional techniques. They reported that a cost-benefit analysis of this instrument may be helpful when choosing one of these techniques over the other. However, as the LigaSure device is produced to be disposable, the costeffectivenessof LigaSure can be increased by using one device for several patients. The reuse of LigaSure hand pieces decreases its cost of purchase (Dilek et al., 2005). İn our exprience,we found that the additional cost of using LigaSure was \$95 per operation, and our observations indicate that the same device will provide safe hemostasis for no more

New techniques, such as hemostatic clipping, monopolar/bipolar diathermy, and laser and ultrasonic instrumentation, have been developed over the past decade. Of these, the harmonic scalpel is the most frequently used. The harmonic scalpel uses high-frequency mechanical energy to cut and coagulate tissues at the same time ,and it is widely used in otorhinolaryngological, cardiac, gastrointestinal, vascular, hemorrhoid, laparoscopic, obstetric, and gynecological surgery. The main advantages of ultrasonic coagulating /dissecting systems compared with a standard electrosurgical device are represented by minimal lateral thermal tissue damage (the harmonic scalpel causes lateral thermal injury 1-3 mm wide, approximately half that caused by bipolar systems),less smoke formation, no neuromuscular stimulation, and no electrical energy to or through the patient (Roye et al., 2000). Since its introduction, the harmonic scalpel has also gained popularity in thyroid and neck surgery. The proposed advantages of the harmonic scalpel include less lateral thermal tissue damage with no electrical energy transferred to the patient, as in electrocautery. In addition, the harmonic scalpel has some advantages over conventional techniques, particularly in terms of operative time, intraoperative bleeding, and

The harmonic scalpel is a new surgical device for thyroid surgery and, to the best of our knowledge, studies in the English-language literature have been undertaken to compare

significant learning period.

manipulation of surgery.

than 10 patients .

**2.2 Harmonic scalpel** 

hospitalization time.

harmonic scalpel versus conventional techniques. The characteristics of these studies summarized in Table1. The majority of these studies compared operative time, hospitalization time, drain use, incision size, postoperative pain, cosmetic results, cost analysis, and RLNP and other postoperative complications. The main advantage of using the harmonic scalpel in thyroid surgery is the reduction in operative time. Studies showed that the use of a harmonic scalpel significantly decreased the operative time (Yildirim et al., 2008, Voutilainen et al., 2000).

Some studies shown that no difference (Siperstein et al., 2002) was observed between the two techniques (harmonic scalpel and conventional techniques ) regarding the amount of blood loss,others (Miccoli et al., 2006,Kilic et al., 2007, Yildirim et al., 2008) have shown that drainage volume is significantly lower in patients treatment with a harmonic scalpel compared to those treated with conventional techniques.

Despite the safety demonstrated by harmonic scalpel in several studies, specific training and experience in the use of the device are necessary because the active blade in inexperienced hands can easily injure surrounding vital structures. Approximately 10 h of experience are required (Voutilainen et al., 2000).The majority of transient and permanent complications occurred in the period of early training. Hypocalcemia and nerve palsy rates will decrease in time as our experience with the harmonic scalpel technique increases.


New Technologies in Thyroid Sugery 195

**Number of patients (HS/CSL)**

Table 1. A summary of studies on the use of harmonic scalpel(HS) versus conventional

Neck surgey is one of the newest and most interesting applications of minimally invasive surgery.Several approaches have ben proposed in the application of endoscopic thyroidectomy. The primary aim of all these different approaches has been to improve the cosmetic results of conventional surgery. Endoscopic thyroidectomy has been divided into two types, videoassisted and total endoscopic. Others classified it as with CO2

Minimally invasive video-assisted thyroidectomy (MIVAT) is characterized by a single access of 1.5 cm in the middle area of the neck, approximately 1-2 cm above the sternal notch; the midline is incised, and a blunt dissection is carried out with tiny spatulas to separate the strap muscles from the underlying thyroid lobe. From this point on the procedure is performed endoscopically on a gasless basis with an external retraction. An laparoscope of 5 mm, 30 degrees, is used. After the insertion of laparoscope through the skin incision, the lobe was completely dissected from the strap muscles with 2-mm-diameter laparoscopic instruments and other instruments regularly used. The optical magnification allows an excellent vision of both the external branch of the superior laryngeal nerve and the recurrent nerve, which are prepared together with the upper parathyroid gland. The vessels are ligated between clips or with the harmonic scalpel until the lobe, completely freed, can be extracted by gently pulling it out through the skin incision.The isthmus is then dissected from the trachea and divided. After checking the recurrent laryngeal nerve once again, the lobe is finally removed (Miccoli et al., 2001). In this technique, no subplatysmal flaps are raised and no muscules are divided, resulting in reduced tissue edema when compared with conventional surgery.I nitial experiences published on MIVAT underlined the advantages of

**Summary of studies** 

The operative time was shorter in the HS group than in the CSL group. The rate of postoperative complications and hospitalization time were similar

between groups.

The two groups were similar regarding hospitalization time and operative cost. Operative time decreased significantly in the HS group compared to the CSL group.

Use of the HS in thyroid surgery decreased operative time, mean blood loss, drain usage, number of ligatures, and amount of bleeding, and did not increase postoperative complications.

 **References Year Type of** 

<sup>14</sup> Manouras

suture ligation(CSL)

insufflation or gasless.

**3. Endoscopic techniques** 

13 Yildirim et al., 2008 Prospective 50/54

et al., 2008 Prospective 144/90

15 Sebaq et al., 2009 Prospective 50/50

**study** 


**Number of patients (HS/CSL)**

**Summary of studies** 

Operative time and number of ligatures were significantly reduced in the HS group compared to the CSL group. Drainage and postoperative pain were similar between groups. No

episode of persistent RLNP or hypoparathyroidism occurred in

No significant difference was observed in terms of postoperative

hypoparathyroidism, or RLNP, although use of the HS significantly

Use of the HS decreased operative time, but increased the cost of

Use of the HS in thyroid surgery resulted in decreased operative time, number of ligatures, total drain time, average incision length, and number of blood-soaked gauzes; it also produced better cosmetic results, but did not increase postoperative

Operative time was significantly shorter in the HS group than in the

Operative time and total operating room occupation time were

higher in the HS group.

operative time.

The two groups were similar

significantly shorter in the HS group than in the CSL group. The cost of the disposable materials was significantly

regarding operative time and incision size. This was the first reported series in which HS usage did not reduce

blood loss, temporary

decreased operative time.

Postoperative pain, operative time, drainage volume, and transient hypocalcemia decreased significantly in the HS group compared to the CSL

either group.

group.

surgery.

complications.

CSL group.

 **References Year Type of** 

5 Cordon et al., 2005 Prospective 30/30

6 Miccoli et al., 2006 Prospective 50/50

et al., 2006 Prospective 150/150

et al., 2007 Prospective 107/88

9 Kilic et al., 2007 Prospective 40/40

et al., 2008 Prospective 27/24

et al., 2008 Prospective 100/100

12 Leonard et al., 2008 Prospective 21/31

<sup>7</sup>Karvounaris

<sup>8</sup>Koutsoumanis

<sup>10</sup> Hallgrimsson

<sup>11</sup> Lombardi

**study** 


Table 1. A summary of studies on the use of harmonic scalpel(HS) versus conventional suture ligation(CSL)

#### **3. Endoscopic techniques**

Neck surgey is one of the newest and most interesting applications of minimally invasive surgery.Several approaches have ben proposed in the application of endoscopic thyroidectomy. The primary aim of all these different approaches has been to improve the cosmetic results of conventional surgery. Endoscopic thyroidectomy has been divided into two types, videoassisted and total endoscopic. Others classified it as with CO2 insufflation or gasless.

Minimally invasive video-assisted thyroidectomy (MIVAT) is characterized by a single access of 1.5 cm in the middle area of the neck, approximately 1-2 cm above the sternal notch; the midline is incised, and a blunt dissection is carried out with tiny spatulas to separate the strap muscles from the underlying thyroid lobe. From this point on the procedure is performed endoscopically on a gasless basis with an external retraction. An laparoscope of 5 mm, 30 degrees, is used. After the insertion of laparoscope through the skin incision, the lobe was completely dissected from the strap muscles with 2-mm-diameter laparoscopic instruments and other instruments regularly used. The optical magnification allows an excellent vision of both the external branch of the superior laryngeal nerve and the recurrent nerve, which are prepared together with the upper parathyroid gland. The vessels are ligated between clips or with the harmonic scalpel until the lobe, completely freed, can be extracted by gently pulling it out through the skin incision.The isthmus is then dissected from the trachea and divided. After checking the recurrent laryngeal nerve once again, the lobe is finally removed (Miccoli et al., 2001). In this technique, no subplatysmal flaps are raised and no muscules are divided, resulting in reduced tissue edema when compared with conventional surgery.I nitial experiences published on MIVAT underlined the advantages of

New Technologies in Thyroid Sugery 197

requires to work in a small space, significantly limiting the type of equipment that can be used. In spite of its deficiencies and unanswered questions especially about cost efectiveness, robotic technology seems to overcome the limitations of conventional

The Da Vinci Surgical System consists of a ''surgeon console'' and a ''surgical arm cart.''. The surgical arm cart holds the robotic instruments and the endoscopic camera. The endoscope for the Da Vinci system is a specially designed 12 mm dual-camera endoscope that is capable of sending a 3D image to a specialized viewing screen in the console called the InSite Vision System. By looking into this 3D-image system, which eliminates all extraperipheral images other than those on the screen, the surgeon immerses himself in the operative field. The camera and instruments are both controlled by maneuvering the joysticks on the console. To alternate the digital handle's control back and forth between control of the camera and control of the instruments, the surgeon taps a foot pedal at the base of the console. At the current time there are 18 different robotic instruments in the Da

Once immersed in the Da Vinci's virtual field, the surgeon inserts his fingers into the handles, sits in an ergonomically correct position, and then maneuvers the endowrist instruments with up to 7 degrees freedom: yaw (side-to-side), pitch (up/down), insertion (in andout), grip, and three additional degrees of freedom provided by the second joint in the instrument tip. In effect, maneuvering the Da Vinci instruments is like miniaturizing your hands and wrists and placing them into cavities they normally could never fit into, thus permitting the performance of delicate, precise dissection and suturing in the smallest

Once the system was on the market, Intuitive continued perfecting it, and the second generation—the da Vinci S—was released in 2006 (Figure 1). The latest version, the da Vinci Si became available in April 2009 with improved full HD camera system, advanced ergonomic

Fig. 1. Master controllers and the patient side manipulators of the new Da Vinci Si surgical

system. (Photo: Intuitive Surgical Inc.)

features, and most importantly, the possibility to use two consoles for assisted surgery.

Vinci system, which are appropriately called ''endowrist instruments.''

cavity—all through small skin incisions (Jacob BP& Gagner M,2004).

laparoscopic technology in thyroid surgery.

the procedure in terms of a better cosmetic result and less postoperative pain when compared with conventional surgery.

Endoscopic lateral cervical approach used for hemithyroidectomy, two 2-5 mm trocars an done 10-mm trocar are inserted along the anterior border of the sternocleidomastoid muscle on the ipsilateral side and using endoscopic instruments specially designed fort his procedure. An additional advantage of this technique over endoscopically assisted midline technique was that no additional assistants were requred to hold retractors(Palazzo et al., 2006).

Total endoscopic thyroidectomy is a more sophisticated variation of minimally invasive thyroid. Using special instrument and technique, part or all of the thyroid gland can be removed through small puncture site, avoiding any incision on the neck whatsoever . Various approaches have been devised and improved further to fulfill this goal, mainly including the cervical approach, anterior chest approach, axillary and breast approach. However, none of these approaches is exclusively advantageous and universally accepted. (Irawati, 2010). The cervical approach and anterior chest approach are minimally invasive, but not cosmetically excellent. The axillary and breast approaches have maximized cosmesis, but meanwhile cause much invasiveness. Furthermore, the axillary approaches is not suitable for bilateral manipulation and even more technically challenging with abnormal anatomic vision. Therefore, an axillary-bilateral-breast approach (ABBA) has been developed, which is actually a combination of the procedure. Bilateral-axillary-breast approach (BABA) was introduced later and was claimed be easily applied for thyroid cancer as well. Whereas applicability of the endoscopic-assisted approach is limited by the size of the gland, the investigators noted that this constraint does not exist for BABA, as even large glands are easily retrieved through the axillary port (Becker et al., 2008). This technique now is even improved by using Da Vinci robotic system (Eun Lee et al., 2009). The endowrist function of the instrument is beneficial in doing complex tasks in difficult areas with limited access.

Disadvatages of endoscopic thyroidectomy include the requirement for additional equipment, namely high-resolution endoscopes and monitors for video-assisted techniques and insufflation units for purely endoscopic approaches. In addition,there is a distinct learning curve, which is more pronounced with purely endoscopic approaches.While videoassisted techniques clearly result in limited surgical dissection, purely endoscopic approaches, by virtue of their remote approaches, result in an equivalent amount of dissection. Because of this, most description include the routine use of drains, which may increase the lenght of hospitalization (Becker 2008).The increased chest-wall dissection can result in hypoesthesia in this area, and cases of pneumothorax have been described (Choe et al., 2007).Operative time for endoscopic approaches may be up to %30 longer than they are for traditional approaches (Terris et al.,2007).

#### **4. Robotic surgery**

Robots have been in the operating room for approximately 15 years now, but their use in assisting laparoscopic endocrine surgery is very new. With the refinement of the technology, easier set up, better image quality, and smaller robotic systems, there has been an interest in using the robot for more general surgical laparoscopic procedures as well as for thyroid surgery. Thyroid surgery procedures are excellent targets for robotic instrumentation when compared with the conventional endoscopic techniques, since it

the procedure in terms of a better cosmetic result and less postoperative pain when

Endoscopic lateral cervical approach used for hemithyroidectomy, two 2-5 mm trocars an done 10-mm trocar are inserted along the anterior border of the sternocleidomastoid muscle on the ipsilateral side and using endoscopic instruments specially designed fort his procedure. An additional advantage of this technique over endoscopically assisted midline technique was

Total endoscopic thyroidectomy is a more sophisticated variation of minimally invasive thyroid. Using special instrument and technique, part or all of the thyroid gland can be removed through small puncture site, avoiding any incision on the neck whatsoever . Various approaches have been devised and improved further to fulfill this goal, mainly including the cervical approach, anterior chest approach, axillary and breast approach. However, none of these approaches is exclusively advantageous and universally accepted. (Irawati, 2010). The cervical approach and anterior chest approach are minimally invasive, but not cosmetically excellent. The axillary and breast approaches have maximized cosmesis, but meanwhile cause much invasiveness. Furthermore, the axillary approaches is not suitable for bilateral manipulation and even more technically challenging with abnormal anatomic vision. Therefore, an axillary-bilateral-breast approach (ABBA) has been developed, which is actually a combination of the procedure. Bilateral-axillary-breast approach (BABA) was introduced later and was claimed be easily applied for thyroid cancer as well. Whereas applicability of the endoscopic-assisted approach is limited by the size of the gland, the investigators noted that this constraint does not exist for BABA, as even large glands are easily retrieved through the axillary port (Becker et al., 2008). This technique now is even improved by using Da Vinci robotic system (Eun Lee et al., 2009). The endowrist function of the instrument is beneficial in

Disadvatages of endoscopic thyroidectomy include the requirement for additional equipment, namely high-resolution endoscopes and monitors for video-assisted techniques and insufflation units for purely endoscopic approaches. In addition,there is a distinct learning curve, which is more pronounced with purely endoscopic approaches.While videoassisted techniques clearly result in limited surgical dissection, purely endoscopic approaches, by virtue of their remote approaches, result in an equivalent amount of dissection. Because of this, most description include the routine use of drains, which may increase the lenght of hospitalization (Becker 2008).The increased chest-wall dissection can result in hypoesthesia in this area, and cases of pneumothorax have been described (Choe et al., 2007).Operative time for endoscopic approaches may be up to %30 longer than they are

Robots have been in the operating room for approximately 15 years now, but their use in assisting laparoscopic endocrine surgery is very new. With the refinement of the technology, easier set up, better image quality, and smaller robotic systems, there has been an interest in using the robot for more general surgical laparoscopic procedures as well as for thyroid surgery. Thyroid surgery procedures are excellent targets for robotic instrumentation when compared with the conventional endoscopic techniques, since it

that no additional assistants were requred to hold retractors(Palazzo et al., 2006).

doing complex tasks in difficult areas with limited access.

for traditional approaches (Terris et al.,2007).

**4. Robotic surgery** 

compared with conventional surgery.

requires to work in a small space, significantly limiting the type of equipment that can be used. In spite of its deficiencies and unanswered questions especially about cost efectiveness, robotic technology seems to overcome the limitations of conventional laparoscopic technology in thyroid surgery.

The Da Vinci Surgical System consists of a ''surgeon console'' and a ''surgical arm cart.''. The surgical arm cart holds the robotic instruments and the endoscopic camera. The endoscope for the Da Vinci system is a specially designed 12 mm dual-camera endoscope that is capable of sending a 3D image to a specialized viewing screen in the console called the InSite Vision System. By looking into this 3D-image system, which eliminates all extraperipheral images other than those on the screen, the surgeon immerses himself in the operative field. The camera and instruments are both controlled by maneuvering the joysticks on the console. To alternate the digital handle's control back and forth between control of the camera and control of the instruments, the surgeon taps a foot pedal at the base of the console. At the current time there are 18 different robotic instruments in the Da Vinci system, which are appropriately called ''endowrist instruments.''

Once immersed in the Da Vinci's virtual field, the surgeon inserts his fingers into the handles, sits in an ergonomically correct position, and then maneuvers the endowrist instruments with up to 7 degrees freedom: yaw (side-to-side), pitch (up/down), insertion (in andout), grip, and three additional degrees of freedom provided by the second joint in the instrument tip. In effect, maneuvering the Da Vinci instruments is like miniaturizing your hands and wrists and placing them into cavities they normally could never fit into, thus permitting the performance of delicate, precise dissection and suturing in the smallest cavity—all through small skin incisions (Jacob BP& Gagner M,2004).

Once the system was on the market, Intuitive continued perfecting it, and the second generation—the da Vinci S—was released in 2006 (Figure 1). The latest version, the da Vinci Si became available in April 2009 with improved full HD camera system, advanced ergonomic features, and most importantly, the possibility to use two consoles for assisted surgery.

Fig. 1. Master controllers and the patient side manipulators of the new Da Vinci Si surgical system. (Photo: Intuitive Surgical Inc.)

New Technologies in Thyroid Sugery 199

the preservation of the parathyroid and recurrent laryngeal nerves. The robot arm can be driven in multi-angular motions with seven degrees freedom. This enables safe and complete central compartment node dissection in the deep and narrow operation space (Jacob et al., 2003). The hand-tremor filtration, the fine motion scaling, the negative motion reversal of the robot system (providing minute and precise manipulations of tissue), and the ergonomically designed console means that surgeons experience less fatigue (Gutt et al.,

Despite these various advantages of the Da Vinci surgical robot system, it may prove cost inhibitive when factors such as general cost, fees of disposables, and maintenance are taken into consideration. Additionally, the large room space it requires may be another factor

The early surgical outcomes of robot-assisted endoscopic thyroidectomies were compared with the data for conventional open thyroidectomies. As described earlier, this transaxillary approach is a more time-consuming procedure than conventional open thyroidectomy. However,with accumulation of experience, the actual operation time is decreasing. The patients in the robotic group were highly selected for several reasons such as the expected risk group and the expensive operation fee, and the difference in operation method was expected. However, there was little difference in the retrieved lymph node numbers, postoperative hospital stays, and pain between the two groups. Moreover, the postoperative complications in the robotic group were somewhat fewer than in the conventional open

Although robot-assisted endoscopic thyroid surgery showed cosmetic and various technical advantages for surgeons, the major concerns when a new treatment technique for malignant tumors is considered should be the safety and radicalness of the operation to prevent local recurrence and distant metastasis. The relative oncologic safety of endoscopic versus robotassisted endoscopic thyroid surgery has not yet been established due to the newness of this technology. To prevent cancer cell dissemination and to minimize the possibility of local recurrence during endoscopic thyroidectomy, the safety of the operational methods and the degree of surgical skill are important. If the safety and radicalness of robotic thyroid surgery as a treatment for papillary thyroid microcarcinoma can be established by the performance of complete thyroidectomies with secure lymphadenectomies, then the application boundaries

and development area of this technique can be gradually extended (Kang et al., 2009).

axillo-breast approach.*World J Surg*. 2007 Mar;31(3):601-6

thyroidectomy.*Surgery*. 2005 Mar;137(3):337-41.

Ballantyne GH.(2007). Telerobotic gastrointestinal surgery: phase2 safety and efficacy. *Surg* 

Choe JH, Kim SW, Chung KW,at al.(2007). Endoscopic thyroidectomy using a new bilateral

Cordón C, Fajardo R, Ramírez J, Herrera MF. (2005). A randomized, prospective, paralel

Cakabay B, Sevinç MM, Gömceli I,et al. (2009).LigaSure versus clamp-and-tie in

group study comparing the Harmonic Scalpel to electrocautery in

thyroidectomy: a single-center experience. Adv Ther. 2009 Nov;26(11):1035-41.

thatlimits its widespread use in thyroid surgery (Link et al., 2006).

2004, Savitt et al., 2005, Link et al., 2006).

thyroidectomy group.

**5. References** 

*Endosc.*2007,21:1054–1062

Epub 2009 Dec 18

The Zeus Robotic Surgical System also has two components: the surgeon console and the robotic instrument arms connected by a computer interface that can filter tremor and adjust the movement and rotational scale of the instruments. Unlike the Da Vinci system, the Zeus robotic arms are not on a cart, but instead can be attached directly to the operating room table. A second difference between the Zeus and the Da Vinci is that the Zeus uses a oiceactivated camera control system called the AESOP Robotic Endoscope Positioner. Instead of requiring a special 12 mm endoscope as with the Da Vinci, the Zeus allows the use of routine 5 or 10 mm endoscopes with the AESOP arm. With this system the surgeon can continuously maneuver the camera's position with simple voice commands like ''camera in, camera out.'' The third difference between the two robotic surgery systems is that currently the Zeus system uses robotic laparoscopic instruments that mimic the hand-held laparoscopic instruments, thus lacking the additional degrees of freedom that you would get with an ''endorist'' instrument tip designed to mimic the human hand. Like standard laparoscopic instruments, these current Zeus instruments have only 5 degrees of freedom.

As the robotic technology is advancing rapidly, the Zeus is already in its third phase of design and is now available with instruments called ''Microwrist technology.'' These new instruments, like the Da Vinci, have tips that offer a second joint mimicking the movements of the human wrist. Because this technology has just become available, there are no studies or published results demonstrating their efficiency, but the ability to perform wrist-like articulations inside the abdomen through small skin incisions is obviously promising.

The Zeus robot proved to be a solid platform to test and experiment different telesurgical scenarios. Between 1994 and 2003 the French Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD) (Strasbourg, France) and Computer Motion Inc. Worked together in several experiments to learn about the feasibility of long distance telesurgery and effects of latency, signal quality degradation (Fig. 2).

Fig. 2. The Zeus robot during the first intercontinental surgery, the colecystectomy was performed on the patient in Strasbourg from New York. (Photo: IRCAD)

Each robotic system has been used for a large number of different surgical procedures. The Da Vinci surgical robot system provides a three dimensional field of view and a more accurate sense of perspective (Ballantyne et al., 2007, Hartmann et al., 2008,Jacobsen et al., 2004).Moreover, because this system can magnify target structures, it more easily enables

The Zeus Robotic Surgical System also has two components: the surgeon console and the robotic instrument arms connected by a computer interface that can filter tremor and adjust the movement and rotational scale of the instruments. Unlike the Da Vinci system, the Zeus robotic arms are not on a cart, but instead can be attached directly to the operating room table. A second difference between the Zeus and the Da Vinci is that the Zeus uses a oiceactivated camera control system called the AESOP Robotic Endoscope Positioner. Instead of requiring a special 12 mm endoscope as with the Da Vinci, the Zeus allows the use of routine 5 or 10 mm endoscopes with the AESOP arm. With this system the surgeon can continuously maneuver the camera's position with simple voice commands like ''camera in, camera out.'' The third difference between the two robotic surgery systems is that currently the Zeus system uses robotic laparoscopic instruments that mimic the hand-held laparoscopic instruments, thus lacking the additional degrees of freedom that you would get with an ''endorist'' instrument tip designed to mimic the human hand. Like standard laparoscopic instruments, these current

As the robotic technology is advancing rapidly, the Zeus is already in its third phase of design and is now available with instruments called ''Microwrist technology.'' These new instruments, like the Da Vinci, have tips that offer a second joint mimicking the movements of the human wrist. Because this technology has just become available, there are no studies or published results demonstrating their efficiency, but the ability to perform wrist-like articulations inside the abdomen through small skin incisions is obviously promising.

The Zeus robot proved to be a solid platform to test and experiment different telesurgical scenarios. Between 1994 and 2003 the French Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD) (Strasbourg, France) and Computer Motion Inc. Worked together in several experiments to learn about the feasibility of long distance telesurgery

Fig. 2. The Zeus robot during the first intercontinental surgery, the colecystectomy was

Each robotic system has been used for a large number of different surgical procedures. The Da Vinci surgical robot system provides a three dimensional field of view and a more accurate sense of perspective (Ballantyne et al., 2007, Hartmann et al., 2008,Jacobsen et al., 2004).Moreover, because this system can magnify target structures, it more easily enables

performed on the patient in Strasbourg from New York. (Photo: IRCAD)

Zeus instruments have only 5 degrees of freedom.

and effects of latency, signal quality degradation (Fig. 2).

the preservation of the parathyroid and recurrent laryngeal nerves. The robot arm can be driven in multi-angular motions with seven degrees freedom. This enables safe and complete central compartment node dissection in the deep and narrow operation space (Jacob et al., 2003). The hand-tremor filtration, the fine motion scaling, the negative motion reversal of the robot system (providing minute and precise manipulations of tissue), and the ergonomically designed console means that surgeons experience less fatigue (Gutt et al., 2004, Savitt et al., 2005, Link et al., 2006).

Despite these various advantages of the Da Vinci surgical robot system, it may prove cost inhibitive when factors such as general cost, fees of disposables, and maintenance are taken into consideration. Additionally, the large room space it requires may be another factor thatlimits its widespread use in thyroid surgery (Link et al., 2006).

The early surgical outcomes of robot-assisted endoscopic thyroidectomies were compared with the data for conventional open thyroidectomies. As described earlier, this transaxillary approach is a more time-consuming procedure than conventional open thyroidectomy. However,with accumulation of experience, the actual operation time is decreasing. The patients in the robotic group were highly selected for several reasons such as the expected risk group and the expensive operation fee, and the difference in operation method was expected. However, there was little difference in the retrieved lymph node numbers, postoperative hospital stays, and pain between the two groups. Moreover, the postoperative complications in the robotic group were somewhat fewer than in the conventional open thyroidectomy group.

Although robot-assisted endoscopic thyroid surgery showed cosmetic and various technical advantages for surgeons, the major concerns when a new treatment technique for malignant tumors is considered should be the safety and radicalness of the operation to prevent local recurrence and distant metastasis. The relative oncologic safety of endoscopic versus robotassisted endoscopic thyroid surgery has not yet been established due to the newness of this technology. To prevent cancer cell dissemination and to minimize the possibility of local recurrence during endoscopic thyroidectomy, the safety of the operational methods and the degree of surgical skill are important. If the safety and radicalness of robotic thyroid surgery as a treatment for papillary thyroid microcarcinoma can be established by the performance of complete thyroidectomies with secure lymphadenectomies, then the application boundaries and development area of this technique can be gradually extended (Kang et al., 2009).

#### **5. References**


New Technologies in Thyroid Sugery 201

Lee WJ, Chen TC, Lai IR, et al.(2003). Randomized clinical trial of LigaSure versus

Levy B, Emery L.(2003). Randomized trial of suture versus electrosurgical bipolar vessel

Leonard DS, Timon C.(2008).Prospective trial of the ultrasonic dissector in thyroid surgery.

Link RE, Bhayani SB, Kavoussi LR.(2006). A prospective comparison of robotic and

Lombardi CP, Raffaelli M, Cicchetti A,et al.(2008). The use of "harmonic scalpel" versus

Manouras A, Markogiannakis H, Koutras AS, et al. (2008).Thyroid surgery: comparison

Miccoli P, Berti P, Raffaelli M, et al.(2001). Comparison between minimally invasive video-

Miccoli P, Berti P, Dionigi GL, et al. (2006). Randomized Controlled Trial of Harmonic Scalpel Use During Thyroidectomy *Arch Otolaryngol Head Neck Surg.* 2006;132:1069-1073 Ortega J, Sala C, Flor B, Lledo S. (2004). Efficacy and cost-effectiveness of the UltraCision

Palazzo FF, Sebag F, Henry JF. (2006).Endocrine surgical technique: endoscopic

Petrakis IE, Kogerakis NE, Lasithiotakis KG,et al. (2004). LigaSure versus clamp-and-tie thyroidectomy for benign nodulardisease. *Head Neck*. 2004;26:903-909. Rahbari R, Mathur A, Kitano M et al.(2011). Prospective Randomized Trial of Ligasure

Roye GD, Monchik JM, Amaral JF. (2000). Endoscopic adrenalectomy using ultrasonic

Savitt MA, Gao G, Furnary AP, Swanson J, Gately HL, Handy JR. (2005) Application of

Sebag F, Fortanier C, Ippolito G, et al.(2009). Harmonic scalpel in multinodular goiter

Shemen L.(2002). Thyroidectomy using the harmonic scalpel: analysis of 105 consecutive

Shen WT, Baumbusch MA, Kebebew E, Duh QY. (2005).Use of the electrothermal vessel

cutting and coagulating. *Surg Technol Int*. 2000;IX:129-138.

mediastinum. *Ann Thorac Surg* 2005, 79:450–455

cases. *Otolaryngol Head Neck Surg*.2002;127:234-238

"knot tying" for conventional "open" thyroidectomy: results of a prospective randomized study. *Langenbecks Arch Surg.* 2008 Sep;393(5):627-31. Epub 2008 Jul 15.

between the electrothermal bipolar vessel sealing system, harmonic scalpel, and

assisted thyroidectomy and conventional thyroidectomy: a prospective

harmonic scalpel in thyroid surgery: an analysis of 200 cases in a randomized trial.

thyroidectomy via the lateral approach.Surg Endosc. 2006 Feb;20(2):339-42. Epub

Versus Harmonic Hemostasis Technique in Thyroidectomy. *Ann Surg Oncol* (2011)

robotic-assisted techniques to the surgical evaluation and treatment of the anterior

surgery: impact on surgery and cost analysis. *J Laparoendosc Adv Surg Tech A*. 2009

sealing systemversus standard vessel ligation in thyroidectomy. *Asian J Surg*.

sealing in vaginal hysterectomy. *Obstet Gynecol*. 2003;102:147-151.

laparoscopic pyeloplasty. *Ann Surg* 2006,243:486–491

classic suture ligation.*Am J Surg*. 2008 Jan;195(1):48-52

randomized study. *Surgery*. 2001 Dec;130(6):1039-43

*J Laparoendosc Adv Surg Tech A*. 2004 Feb;14(1):9-12

2003;90:1493-1496.

2005 Dec 9.

18:1023–1027

Apr;19(2):171-4.

2005;28:86-89.

*Head Neck*. 2008 Jul;30(7):904-8.

conventional surgery for extended gastric cancer resection.*Br J Surg*.


Defechereux T, Rinken F, Maweja S, et al.(2003). Evaluation of the ultrasonic dissector in thyroid surgery. A prospective randomisedstudy. *Acta Chir Belg*. 2003;103;274-227. Dilek ON, Yilmaz S, Degirmenci B, et al. (2005).The use of a vessel sealing system in thyroid

Eun Lee K, Rao J, Kyu Youn Y, et al.(2009). Endoscpic Thyroidectomy with the da-Vinci

Gutt CN, Oniu T, Mehrabi A, Kashfi A, Schemmer P, Bu¨chler MW.(2004). Robot-ssisted

Hallgrimsson P, Lovén L, Westerdahl J, Bergenfelz A.(2008). Use of the harmonic scalpel

Hansen P, Bax T, Swanstrom L.(1997). Laparoscopic adrenalectomy: history, indications,

Hartmann J, Jacobi CA, Menenakos C, Ismail M, Braumann C.(2008).Surgical treatment of

robotic system: a prospective study. *J Gastrointest Surg* 2008 .12:504–509 Irawati N.(2010).Endoscopic right lobectomy axillary-breast approach: a report of two cases.

Jacobsen G, Elli F, Horgan S.(2004). Robotic surgery update. *Surg Endosc* 18:1186–1191 Jacob BP, Gagner M.(2003). Robotics and general surgery. *Surg Clin North* Am 83:1405–1419 Jacob BP&Gagner M. (2004). Robotic Endocrine Surgery,In:*Endocrine Surgery*, Arthur E.

Cataloging-in-Publication Data, ISBN: 0-8247-4297-4,Canada

Giddings AE.(1998). The history of thyroidectomy. *J R Soc Med*.1998;91 Suppl 33:3–6.

*Langenbecks Arch Surg*. 2008 Sep;393(5):675-80. Epub 2008 Aug 2.

Robot System Unsing the BABA Technique- Our Initial Experience. *Surg Laparosc,* 

versus conventional haemostatic techniques in patients with Grave disease undergoing total thyroidectomy: a prospective randomised controlled trial.

and current techniques for a minimally invasive approach to adrenal pathology.

gastroesophageal reflux disease and upside-down stomach using the Da Vinci

Schwartz,Demetrius Persemlidis, Michel Gagner ,pp.(11-16), Library of Congress

experience with the first 100 patients. *Surg Endosc*. 2009 Nov;23(11):2399-406. Epub

harmonic scalpel with conventional knot tying in thyroidectomy.*Adv Ther*. 2007

Jayne DG, Botterill I, Ambrose NS, et al. (2002).Randomized clinical trial of Ligasure versus conventional diathermy for day-case haemorrhoidectomy. *Br J Surg*.2002;89:428-432. Kang SW, Jeong JJ, Yun JS, et al.(2009). Robot-assisted endoscopic surgery for thyroid cancer:

Karvounaris DC, Antonopoulos V, Psarras K, Sakadamis A .(2006).Efficacy and safety of ultrasonically activated shears in thyroid surgery.*Head Neck*.2006;28;1028-1031 Kennedy JS, Stranahan PL, Taylor KD, Chandler JG. (1998).High-burst-strength, feedbackcontrolled bipolar vessel sealing. *Surg Endosc.* 1998;12:876-878. Kilic M, Keskek M, Ertan T, et al. (2007). A prospective randomized trial comparing the

Kirdak T, Korun N, Ozguc H.(2005). Use of LigaSure inthyroidectomy procedures: results of

Kiriakopoulos A, Dimitrios T, Dimitrios L. (2004). Use ofa diathermy system in thyroid

Koutsomanis K,Koutras AS,Drimousis PG,et al.(2007). The use of aharmonic scalpel in

a prospectivecomparative study. *World J Surg*. 2005;29:771-774.

thyroid surgery:report of a 3-year experience.*Am J Surg.*2007;193

surgery. *Acta Chir Belg.*2005;105:369-372.

*Endosc & Percutan Tech* 2009; 19 (3): e71-5

*Endoscopy* 1997; 29:309–314.

2009 Mar 5.

May-Jun;24(3):632-8.

surgery. *Arch Surg*.2004;139:997-1000.

abdominal surgery. *Br J Surg .*2004,91:1390–1397

*Int J Otolaryngol.* 2010;2010:958764. Epub 2010 Dec 28.


**14**

*USA* 

**Management of Primary Hyperparathyroidism** 

Primary hyperparathyroidism (PHPT) is caused by overproduction of parathyroid hormone (PTH) by at least 1 autonomously functioning parathyroid gland. Such overproduction results in increased blood calcium levels because of increased renal absorption, increased vitamin D synthesis (and calcium absorption in the gastrointestinal tract), and increased bone resorption. (Felger, Johnson) PHPT is caused by a single parathyroid adenoma 80% to 85% of the time. (Pyrah) Less frequently, it is caused by multiple adenomas or multigland hyperplasia (MGH). Intraoperatively, MGH may be difficult to differentiate from an adenoma, because hyperplasia may occasionally be asymmetric. (Kaplan) PHPT is generally a benign disease, but parathyroid carcinoma accounts for 0.5% of cases. The majority of PHPT cases are sporadic, but PHPT may also be associated with familial syndromes, including familial PHPT and multiple endocrine

Most normal parathyroid glands (parathyroids for short) weigh between 35 and 50 mg, are under 5 mm in diameter, and are yellowish-brown. (Pyrah, Johnson) The upper parathyroids develop embryologically from the fourth branchial pouches. They descend with the thyroid into the neck and tend to have a fairly consistent location in the posterior portion of the middle third of the thyroid, just above the intersection of the inferior thyroid artery and recurrent laryngeal nerve. (Pyrah) Ectopic superior parathyroids may be found in the tracheoesophageal groove; in the retropharyngeal or retroesophageal space; posterior mediastinum; in the carotid sheath; or within the thyroid itself (intrathyroidal). (Johnson) Inferior parathyroids derive from the third branchial pouch, descend with the thymus, and are typically found on the posterior portion of the lower pole of the thyroid. However, *ectopic* inferior parathyroids may be submandibular, intrathymic, or intrathyroidal, or may be found in the thyrothymic ligament or anterior mediastinum. (Pyrah) Supernumerary parathyroids are found in 13% of cases;

PHPT commonly affects individuals between the ages of 30 and 60 years—and women by a 3 to-1 ratio. (Kaplan) In outpatients, it is the most frequent cause of hypercalcemia. It is typically identified as hypercalcemia on routine laboratory evaluation in a seemingly asymptomatic individual. Symptoms may include weakness, easy fatigability, muscle aches, weight loss,

**1. Introduction** 

**2. Embryology** 

**3. Diagnosis** 

neoplasia type I and IIA. (Johnson)

fewer than 4 of them are found in about 3% of cases. (Johnson)

Jessica Rose and Marlon A. Guerrero

*Department of Surgery, University of Arizona, Tucson, Arizona* 


### **Management of Primary Hyperparathyroidism**

Jessica Rose and Marlon A. Guerrero

*Department of Surgery, University of Arizona, Tucson, Arizona USA* 

#### **1. Introduction**

202 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Siperstein AE, Berber E, Morkoyun E. (2002). The Use of the Harmonic Scalpel vs

Terris DJ, Chin E. (2006). Clinical implementation of endoscopic thyroidectomy in selected

Voutilainen PE, Haglund CH. (2000). Ultrasonically activated shears in thyroidectomies: a

Yildirim O, Umit T, Ebru M, et al. (2008). Ultrasonic harmonic scalpel in total

*Surg.* 2002;137:137-142.

patients. *Laryngoscope*. 2006 Oct;116(10):1745-8

randomized trial. *Ann Surg.* 2000;231:322-328.

thyroidectomies. *Adv Ther*. 2008 Mar;25(3):260-5.

Conventional Knot Tying for Vessel Ligation in Thyroid Surgery *Arch* 

Primary hyperparathyroidism (PHPT) is caused by overproduction of parathyroid hormone (PTH) by at least 1 autonomously functioning parathyroid gland. Such overproduction results in increased blood calcium levels because of increased renal absorption, increased vitamin D synthesis (and calcium absorption in the gastrointestinal tract), and increased bone resorption. (Felger, Johnson) PHPT is caused by a single parathyroid adenoma 80% to 85% of the time. (Pyrah) Less frequently, it is caused by multiple adenomas or multigland hyperplasia (MGH). Intraoperatively, MGH may be difficult to differentiate from an adenoma, because hyperplasia may occasionally be asymmetric. (Kaplan) PHPT is generally a benign disease, but parathyroid carcinoma accounts for 0.5% of cases. The majority of PHPT cases are sporadic, but PHPT may also be associated with familial syndromes, including familial PHPT and multiple endocrine neoplasia type I and IIA. (Johnson)

#### **2. Embryology**

Most normal parathyroid glands (parathyroids for short) weigh between 35 and 50 mg, are under 5 mm in diameter, and are yellowish-brown. (Pyrah, Johnson) The upper parathyroids develop embryologically from the fourth branchial pouches. They descend with the thyroid into the neck and tend to have a fairly consistent location in the posterior portion of the middle third of the thyroid, just above the intersection of the inferior thyroid artery and recurrent laryngeal nerve. (Pyrah) Ectopic superior parathyroids may be found in the tracheoesophageal groove; in the retropharyngeal or retroesophageal space; posterior mediastinum; in the carotid sheath; or within the thyroid itself (intrathyroidal). (Johnson) Inferior parathyroids derive from the third branchial pouch, descend with the thymus, and are typically found on the posterior portion of the lower pole of the thyroid. However, *ectopic* inferior parathyroids may be submandibular, intrathymic, or intrathyroidal, or may be found in the thyrothymic ligament or anterior mediastinum. (Pyrah) Supernumerary parathyroids are found in 13% of cases; fewer than 4 of them are found in about 3% of cases. (Johnson)

#### **3. Diagnosis**

PHPT commonly affects individuals between the ages of 30 and 60 years—and women by a 3 to-1 ratio. (Kaplan) In outpatients, it is the most frequent cause of hypercalcemia. It is typically identified as hypercalcemia on routine laboratory evaluation in a seemingly asymptomatic individual. Symptoms may include weakness, easy fatigability, muscle aches, weight loss,

Management of Primary Hyperparathyroidism 205

An operation can be helpful in patients with PHPT in order to restore their calcium balance and euparathyroid state. Postoperatively, most symptoms resolve, especially osteitis fibrosa.

Preoperatively, all patients should begin, or continue, treatment for any concomitant diseases, such as angina, hypertension, and diabetes. They should be adequately hydrated, especially if they have significant hypercalcemia. In addition, their calcium level and renal function should be evaluated. It is also a good idea to assess bone mineral density, which gives an idea of the chronicity of a given patient's PHPT and the potential need for

In patients with confirmed PHPT who can tolerate surgery, symptoms are one of the main indications. (Kaplan, Bilezikian) Those with renal involvement benefit from a parathyroidectomy, in order to reduce the risk of nephrolithiasis and to help improve renal function. Those with pancreatitis should be offered a parathyroidectomy; without one, the risk of disease recurrence and of significant complications is significant. Those with osteitis fibrosa and osteoporosis also benefit from a parathyroidectomy, which improves cortical and trabecular bone symptoms, though not always bone mineral density. A parathyroidectomy also decreases the risk of a pathologic fracture and lessens muscle

Reviewing the records of their own patients and other studies, Kaplan et al. found that 100% of patients with osteitis and pancreatitis saw improvement after a parathyroidectomy. And about 90% of patients with nephrolithiasis saw improvement, although renal function improved only variably (in 0% to 43% of patients). Other symptoms of PHPT also improved only variably, specifically peptic ulcers, hypertension, neuropsychiatric symptoms, and

> Renal involvement Pancreatitis Osteitis fibrosa Osteoporosis Bone Fracture Muscle weakness Fatigue Hypercalcemic crisis

In most asymptomatic patients, if they are not treated surgically, PHPT will eventually progress; in many of them, bone mineral density (BMD) will decrease. Such patients are also potentially at risk for cardiovascular and neurocognitive problems, and they have lower

weakness and fatigue. In addition, it helps avoid a hypercalcemic crisis. (Davies)

**4. Surgical indications** 

**4.1 Symptomatic PHPT** 

constipation. (Kaplan)

**4.2 Asymptomatic PHPT** 

antiresorptive therapy postoperatively. (Davies)

Table 2. Indications for surgery: *symptomatic* PHPT

quality of life scores and more psychological symptoms. (Bilezikian)

(Kaplan)

irritability, depression, constipation, epigastric pain, nausea, vomiting, polyuria, renal colic, arthralgias, bony aches, pruritus, and paresthesias. Less common are the supposedly classic symptoms known by this rhyming mnemonic: stones, bones, groans, and psychic overtones (for renal calculi, osteoporosis, abdominal pain, and neuropsychiatric symptoms). If left untreated, patients with PHPT are at risk for hypertension, peptic ulcers, pancreatitis, nephrolithiasis, gout, and pathologic fractures. Patients typically present in one of three groups: those with osteitis fibrosa, those with nephrolithiasis, and those who are asymptomatic and whose disease is incidentally found. Those with osteitis fibrosa tend to have more symptoms and higher concentrations of PTH. (Mallette)

Most cases of PHPT are diagnosed incidentally, when hypercalcemia is identified on routine blood work. Hypercalcemia with an elevated PTH level confirms the diagnosis of PHPT. Some patients have a PTH level within the normal range, but the level is inappropriately high relative to the serum calcium level. (Mallette) In patients with symptoms suggestive of PHPT, the serum calcium level (corrected for albumin) should be checked and compared with the specific laboratory reference range. (Chan, Kaplan, Glendenning) The ionized calcium level may also be obtained, because that level is not affected by binding globulins, transfusions, venous stasis, or gadolinium. (Glendenning)

If the serum or ionized calcium level is elevated, other causes must be considered, such as milk-alkali syndrome, malignancy, sarcoidosis, hyperthyroidism, hypervitaminosis D, and many primary bone disorders. (Keating) In addition, the PTH level (via second- or thirdgeneration assays) should be measured. (Chan AK, Bilezikian) In young patients and in patients of any age who have family members with hypercalcemia, the urinary calcium level should also be obtained, in order to evaluate for familial hypocalciuric hypercalcemia (FHH). (Kaplan) A Ca/Cr ratio of less than 0.01 is diagnostic of FHH; a ratio of more than 0.02 confirms PHPT. (Glendenning) Other laboratory abnormalities associated with PHPT include hypophosphatemia, hyperchloremic acidosis, hypomagnesemia, elevated alkaline phosphatase levels, and increased urinary calcium excretion. Moreover, 25-hydroxy vitamin D levels should be checked, in order to identify coexisting vitamin D deficiency. (Mallette)


Table 1. Symptoms of PHPT

### **4. Surgical indications**

204 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

irritability, depression, constipation, epigastric pain, nausea, vomiting, polyuria, renal colic, arthralgias, bony aches, pruritus, and paresthesias. Less common are the supposedly classic symptoms known by this rhyming mnemonic: stones, bones, groans, and psychic overtones (for renal calculi, osteoporosis, abdominal pain, and neuropsychiatric symptoms). If left untreated, patients with PHPT are at risk for hypertension, peptic ulcers, pancreatitis, nephrolithiasis, gout, and pathologic fractures. Patients typically present in one of three groups: those with osteitis fibrosa, those with nephrolithiasis, and those who are asymptomatic and whose disease is incidentally found. Those with osteitis fibrosa tend to

Most cases of PHPT are diagnosed incidentally, when hypercalcemia is identified on routine blood work. Hypercalcemia with an elevated PTH level confirms the diagnosis of PHPT. Some patients have a PTH level within the normal range, but the level is inappropriately high relative to the serum calcium level. (Mallette) In patients with symptoms suggestive of PHPT, the serum calcium level (corrected for albumin) should be checked and compared with the specific laboratory reference range. (Chan, Kaplan, Glendenning) The ionized calcium level may also be obtained, because that level is not affected by binding globulins,

If the serum or ionized calcium level is elevated, other causes must be considered, such as milk-alkali syndrome, malignancy, sarcoidosis, hyperthyroidism, hypervitaminosis D, and many primary bone disorders. (Keating) In addition, the PTH level (via second- or thirdgeneration assays) should be measured. (Chan AK, Bilezikian) In young patients and in patients of any age who have family members with hypercalcemia, the urinary calcium level should also be obtained, in order to evaluate for familial hypocalciuric hypercalcemia (FHH). (Kaplan) A Ca/Cr ratio of less than 0.01 is diagnostic of FHH; a ratio of more than 0.02 confirms PHPT. (Glendenning) Other laboratory abnormalities associated with PHPT include hypophosphatemia, hyperchloremic acidosis, hypomagnesemia, elevated alkaline phosphatase levels, and increased urinary calcium excretion. Moreover, 25-hydroxy vitamin D levels should be checked, in order to identify coexisting vitamin D deficiency. (Mallette)

Classic symptoms Associated symptoms Associated conditions

Weakness Easy fatigability Muscle aches Weight loss Irritability Depression Constipation Epigastric pain Nausea Vomiting Polyuria Renal colic Arthralgias Bony aches Pruritus Paresthesias

Hypertension Peptic ulcers Pancreatitis Nephrolithiasis Gout Pathologic fractures Osteitis fibrosa

have more symptoms and higher concentrations of PTH. (Mallette)

transfusions, venous stasis, or gadolinium. (Glendenning)

Renal calculi Osteoporosis Abdominal pain Neuropsychiatric symptoms

Table 1. Symptoms of PHPT

An operation can be helpful in patients with PHPT in order to restore their calcium balance and euparathyroid state. Postoperatively, most symptoms resolve, especially osteitis fibrosa. (Kaplan)

Preoperatively, all patients should begin, or continue, treatment for any concomitant diseases, such as angina, hypertension, and diabetes. They should be adequately hydrated, especially if they have significant hypercalcemia. In addition, their calcium level and renal function should be evaluated. It is also a good idea to assess bone mineral density, which gives an idea of the chronicity of a given patient's PHPT and the potential need for antiresorptive therapy postoperatively. (Davies)

#### **4.1 Symptomatic PHPT**

In patients with confirmed PHPT who can tolerate surgery, symptoms are one of the main indications. (Kaplan, Bilezikian) Those with renal involvement benefit from a parathyroidectomy, in order to reduce the risk of nephrolithiasis and to help improve renal function. Those with pancreatitis should be offered a parathyroidectomy; without one, the risk of disease recurrence and of significant complications is significant. Those with osteitis fibrosa and osteoporosis also benefit from a parathyroidectomy, which improves cortical and trabecular bone symptoms, though not always bone mineral density. A parathyroidectomy also decreases the risk of a pathologic fracture and lessens muscle weakness and fatigue. In addition, it helps avoid a hypercalcemic crisis. (Davies)

Reviewing the records of their own patients and other studies, Kaplan et al. found that 100% of patients with osteitis and pancreatitis saw improvement after a parathyroidectomy. And about 90% of patients with nephrolithiasis saw improvement, although renal function improved only variably (in 0% to 43% of patients). Other symptoms of PHPT also improved only variably, specifically peptic ulcers, hypertension, neuropsychiatric symptoms, and constipation. (Kaplan)

> Renal involvement Pancreatitis Osteitis fibrosa Osteoporosis Bone Fracture Muscle weakness Fatigue Hypercalcemic crisis

Table 2. Indications for surgery: *symptomatic* PHPT

#### **4.2 Asymptomatic PHPT**

In most asymptomatic patients, if they are not treated surgically, PHPT will eventually progress; in many of them, bone mineral density (BMD) will decrease. Such patients are also potentially at risk for cardiovascular and neurocognitive problems, and they have lower quality of life scores and more psychological symptoms. (Bilezikian)

Management of Primary Hyperparathyroidism 207

A sestamibi scan is a scintigraphic study; sestamibi was first noted to be taken up by the parathyroids when the study was used to evaluate cardiac perfusion. Since then, it has been thought to be a valuable tool for preoperative evaluation of the parathyroids. It uses technetium-99m hexakis-methoxyisobutyl isonitrile as the radionucleotide. The technetium is taken up by both the thyroid and parathyroids, so iodine (I123) is used for thyroid subtraction. Initially, the study was performed with thallium technetium; however, sestamibi has a higher affinity for abnormal parathyroids. A sestamibi scan result is deemed positive if it pinpoints a "hot focus" on the initial and/or the delayed image of the

One group noted that the accuracy of the sestamibi scan is 80% and the positive predictive value is 89%. (Shaha) Its sensitivity for identifying solitary adenomas ranges from 68% to 95%. (Johnson) However, it is able to identify only 30% of patients with double adenomas. As a single modality, it has a higher sensitivity than other imaging modalities for identifying solitary adenomas. However, false-positives may be due to thyroid nodules, lymph nodes,

Using the sestamibi scan to preoperatively locate abnormal parathyroids is thought to improve the cure rate of PHPT, decrease operative time, and allow the possibility of a minimally invasive parathyroidectomy; however, such speculation is not always supported in the literature. Patients with negative sestamibi scan results are more likely to have lower operative cure rates (92%) than those whose scans showed a distinct adenoma (99%). (Allendorf) The scan result is more likely to be positive for adenomas in the face of higher calcium and PTH levels, higher oxyphil concentration, and vitamin D deficiency. Patients who are taking a calcium channel blocker are more likely to have a negative sestamibi scan result. Radiotracer retention is necessary in order for the sestamibi scan result to be positive; therefore, patients with high levels of P-glycoprotein (a multidrug resistance protein) are

Pros Cons

An US study performed with a high-frequency transducer is used to comprehensively evaluate the neck from the hyoid bone to the thoracic inlet. The thyroid is imaged as well, looking for nodules or intrathyroidal parathyroids. Doppler is added to image the vascular structures and to visualize vessels supplying adenomas. In obese patients, graded

US has a sensitivity for finding solitary adenomas of 72% to 89%. On US, adenomas appear homogenous and hypoechoic. They are most frequently seen if they are at least 10 mm.

False-positives due to thyroid nodules, lymph nodes, and brown adipose False-negatives in patients on calcium channel blockers, high P-glycoprotein,

and drug resistance genes

**5.1 Sestamibi scans** 

and brown adipose. (Mihai)

likely to have a negative result. (Mihai)

Highest sensitivity as single modality Positive results suggestive of higher cure Visualization of one focus allows facilitates minimally invasive parathyroidectomy

Table 4. Pros and Cons of Sestamibi Scans

compression can be used to assist in visualization. (Johnson)

**5.2 Ultrasound (US) scans** 

parathyroids (but not on the thyroid scan). (Shaha)

Asymptomatic PHPT should be treated surgically if the patient meets the criteria set by the Task Force on Primary Hyperparathyroidism of the American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons (AACE/AAES). The criteria are as follows: patient age under 50 years, serum calcium level more than 1 mg/dL above the upper limit of normal, creatinine clearance less than 30% below age-matched norms, decreased BMD (T or Z score under -2.5), and difficulty with medical follow-up. (Felger, Bilezikian, Kukora)

In the past, hypercalciuria (excretion of more than 400 mg/day of calcium) was an indication for surgery--even in the absence of renal stones; it is no longer an indication, according to a summary statement from the Third International Workshop on Asymptomatic PHPT. (Bilezikian)

Most asymptomatic patients have improved symptoms postoperatively. (Felger) The reason is probably that many patients with hyperparathyroidism suffer preoperatively from weakness, easy fatigability, depression, neurocognitive dysfunction, and increased sleep requirements; still, it is impossible to predict which patients will benefit from surgery. (Bilezikian) Surgeons adhering to the National Institutes of Health (NIH) surgical indications criteria have noticed a cure rate of 95% to 98%, with a risk of complications of only 1% to 2%. (Sosa, Kukora) Some groups feel that the criteria for a parathyroidectomy are too limited, and that more patients would benefit from it. (Sywak)

> Patient age < 50 years Serum calcium level > 1 mg/dL above the upper limit of normal Creatinine clearance < 30% below age-matched norms Decreased BMD (T or Z score under -2.5) Difficulty with medical follow-up

Table 3. Indications for surgery: *asymptomatic* PHPT

#### **5. Preoperative imaging**

The choice of preoperative imaging for patients with PHPT is often controversial. Without imaging, in the hands of an experienced surgeon, a patient undergoing a bilateral neck exploration for PHPT typically has a cure rate of 95% to 98%. (Shaha) But given the ability to perform minimally invasive surgery, preoperative imaging is gaining importance. (Shaha, Johnson) Such imaging can lead to the discovery of ectopic parathyroids and other pathology (such as other cervical masses). (Lumachi)

Imaging is most valuable for patients who require a reoperation for persistent or recurrent PHPT. Other populations who particularly benefit from preoperative localization via imaging include asymptomatic patients who previously underwent related neck surgery (such as a thyroidectomy or neck dissection); patients with difficult anatomic issues (such as those who are obese with a short neck); and patients at high operative risk. (Shaha)

Currently, sestamibi and ultrasound studies are the most common preoperative imaging modalities, but other imaging modalities are being more readily utilized.

#### **5.1 Sestamibi scans**

206 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Asymptomatic PHPT should be treated surgically if the patient meets the criteria set by the Task Force on Primary Hyperparathyroidism of the American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons (AACE/AAES). The criteria are as follows: patient age under 50 years, serum calcium level more than 1 mg/dL above the upper limit of normal, creatinine clearance less than 30% below age-matched norms, decreased BMD (T or Z score under -2.5), and difficulty with medical follow-up.

In the past, hypercalciuria (excretion of more than 400 mg/day of calcium) was an indication for surgery--even in the absence of renal stones; it is no longer an indication, according to a summary statement from the Third International Workshop on

Most asymptomatic patients have improved symptoms postoperatively. (Felger) The reason is probably that many patients with hyperparathyroidism suffer preoperatively from weakness, easy fatigability, depression, neurocognitive dysfunction, and increased sleep requirements; still, it is impossible to predict which patients will benefit from surgery. (Bilezikian) Surgeons adhering to the National Institutes of Health (NIH) surgical indications criteria have noticed a cure rate of 95% to 98%, with a risk of complications of only 1% to 2%. (Sosa, Kukora) Some groups feel that the criteria for a parathyroidectomy are

> Patient age < 50 years Serum calcium level > 1 mg/dL above the upper limit of normal Creatinine clearance < 30% below age-matched norms Decreased BMD (T or Z score under -2.5) Difficulty with medical follow-up

The choice of preoperative imaging for patients with PHPT is often controversial. Without imaging, in the hands of an experienced surgeon, a patient undergoing a bilateral neck exploration for PHPT typically has a cure rate of 95% to 98%. (Shaha) But given the ability to perform minimally invasive surgery, preoperative imaging is gaining importance. (Shaha, Johnson) Such imaging can lead to the discovery of ectopic parathyroids and other

Imaging is most valuable for patients who require a reoperation for persistent or recurrent PHPT. Other populations who particularly benefit from preoperative localization via imaging include asymptomatic patients who previously underwent related neck surgery (such as a thyroidectomy or neck dissection); patients with difficult anatomic issues (such as

Currently, sestamibi and ultrasound studies are the most common preoperative imaging

those who are obese with a short neck); and patients at high operative risk. (Shaha)

modalities, but other imaging modalities are being more readily utilized.

too limited, and that more patients would benefit from it. (Sywak)

Table 3. Indications for surgery: *asymptomatic* PHPT

pathology (such as other cervical masses). (Lumachi)

**5. Preoperative imaging** 

(Felger, Bilezikian, Kukora)

Asymptomatic PHPT. (Bilezikian)

A sestamibi scan is a scintigraphic study; sestamibi was first noted to be taken up by the parathyroids when the study was used to evaluate cardiac perfusion. Since then, it has been thought to be a valuable tool for preoperative evaluation of the parathyroids. It uses technetium-99m hexakis-methoxyisobutyl isonitrile as the radionucleotide. The technetium is taken up by both the thyroid and parathyroids, so iodine (I123) is used for thyroid subtraction. Initially, the study was performed with thallium technetium; however, sestamibi has a higher affinity for abnormal parathyroids. A sestamibi scan result is deemed positive if it pinpoints a "hot focus" on the initial and/or the delayed image of the parathyroids (but not on the thyroid scan). (Shaha)

One group noted that the accuracy of the sestamibi scan is 80% and the positive predictive value is 89%. (Shaha) Its sensitivity for identifying solitary adenomas ranges from 68% to 95%. (Johnson) However, it is able to identify only 30% of patients with double adenomas. As a single modality, it has a higher sensitivity than other imaging modalities for identifying solitary adenomas. However, false-positives may be due to thyroid nodules, lymph nodes, and brown adipose. (Mihai)

Using the sestamibi scan to preoperatively locate abnormal parathyroids is thought to improve the cure rate of PHPT, decrease operative time, and allow the possibility of a minimally invasive parathyroidectomy; however, such speculation is not always supported in the literature. Patients with negative sestamibi scan results are more likely to have lower operative cure rates (92%) than those whose scans showed a distinct adenoma (99%). (Allendorf) The scan result is more likely to be positive for adenomas in the face of higher calcium and PTH levels, higher oxyphil concentration, and vitamin D deficiency. Patients who are taking a calcium channel blocker are more likely to have a negative sestamibi scan result. Radiotracer retention is necessary in order for the sestamibi scan result to be positive; therefore, patients with high levels of P-glycoprotein (a multidrug resistance protein) are likely to have a negative result. (Mihai)


Table 4. Pros and Cons of Sestamibi Scans

#### **5.2 Ultrasound (US) scans**

An US study performed with a high-frequency transducer is used to comprehensively evaluate the neck from the hyoid bone to the thoracic inlet. The thyroid is imaged as well, looking for nodules or intrathyroidal parathyroids. Doppler is added to image the vascular structures and to visualize vessels supplying adenomas. In obese patients, graded compression can be used to assist in visualization. (Johnson)

US has a sensitivity for finding solitary adenomas of 72% to 89%. On US, adenomas appear homogenous and hypoechoic. They are most frequently seen if they are at least 10 mm.

Management of Primary Hyperparathyroidism 209

A newer form of PET called [18F]-2-fluorodeoxyglucose (FDG)-PET can be helpful with parathyroid imaging. FDG-PET uses a methionine-labeled radiotracer that has good specificity for hyperfunctioning parathyroid tissue. It is helpful in patients who have had a negative result on localization imaging studies or who need a reoperation. Its sensitivity is

MRI can be used in a similar manner to CT to diagnose the cause of PHPT. (Johnson) It has not been used frequently or studied extensively in patients with PHPT, but its sensitivity ranges from 71% to 100%. MRI may be especially useful if paired with a sestamibi scan or with a methoxyisobutylisonitrile (MIBI) scan for enhanced accuracy, though no protocols

Image Modality Sensitivity

Sestamibi 68-95% US 72-89% CT 76-83% PET 86% MRI 70-100%

Combined Sestamibi and US 95% Combined CT and Sestamibi 100% Combined PET and CT 92%

As minimally invasive procedures become more popular, the need becomes greater to provide minimally invasive parathyroidectomies. With a minimally invasive parathyroidectomy, as previously mentioned, preoperative imaging is necessary in order to determine which gland needs to be removed. Additionally, intraoperative adjuncts (described below) are frequently used in order to decrease operative time and increase

Intraoperative PTH (IOPTH) monitoring was developed to help guide the extent of surgical exploration and parathyroid resection. The most common reason for a failed initial operation is missed multigland disease. (Irvin, 1994) IOPTH monitoring is based on the assumption that removing the hyperfunctioning gland will cause the PTH level to fall appropriately. (Vignali) The half-life of PTH ranges from 3 to 4 minutes and can be measured easily with a quick immunoradiometric assay or with a two-site antibody

**5.4 Positron emission tomography (PET)** 

**5.5 Magnetic resonance imaging (MRI)** 

Table 6. Sensitivities of Imaging Modalities

**6. Adjuncts in parathyroid surgery** 

**6.1 Intraoperative PTH monitoring** 

immunochemiluminometric assay. (Irvin, 1994)

operative success.

86%, but increases to 92% when coupled with CT. (Mihai)

have yet been developed for such combinations. (Mihai)

Sometimes the blood supply of the adenoma can be visualized with Doppler: frequently a rim of vascularity at the periphery of the gland is seen. Normal parathyroids are small (about 5 mm) and are rarely seen on ultrasound. It can be difficult to diagnose hyperplasia with US, since the parathyroids are not markedly enlarged. Retrotracheal and mediastinal ectopic parathyroids are not well visualized on US. (Johnson)

Another difficulty is differentiating cervical lymph nodes from parathyroids; the two can be mistaken for each other. Nodes typically have a fatty hilum and are supplied by small hilar vessels. Thyroid nodules, especially those posteriorly located, can also be difficult to differentiate from parathyroids. Thyroid nodules do not typically display a vascular pattern. Intrathyroid parathyroids are also difficult to discern from thyroid nodules. (Johnson) Diagnostic fine-needle aspiration of thyroid nodules helps differentiate parathyroids from other cervical nodules. (Dimashkieh)

Individually, sestamibi and US studies have limited accuracy, but the use of both imaging modalities increases the ability to successfully identify a single adenoma: the reported combined sensitivity is 95%. (Lumachi, 2000) When the results of both the sestamibi and US studies are concordant, the accuracy for identifying a single adenoma can be as high as 98%. (Haciyanli)


Table 5. Pros and Cons of US Scans

#### **5.3 Computed tomography (CT)**

CT of the neck and mediastinum is very good for recognizing enlarged glands, with sensitivity from 76% to 83%. Despite its accuracy, CT is infrequently used because of the associated radiation exposure and the need to give intravenous (IV) contrast. However, it can help predict four-gland hyperplasia (necessitating bilateral neck exploration) more frequently than other imaging modalities. It has also been shown to pick up some parathyroid adenomas previously missed on ultrasound scans. (Lumachi, 2004)

CT is efficacious when combined with sestamibi scans: their combined sensitivity nears 100%. (Lumachi, 2004)

SPECT/CT is an emerging technology that allows better definition of scintigraphic images; its sensitivity for defining parathyroid lesions preoperatively is close to 88%. (Neumann) (SPECT stands for single-photon- emission CT.) It is most beneficial when patients have had a prior operation and when anatomic details matched with functional information from sestamibi scans are required. It is also very useful for identifying ectopic parathyroids. (Krauz)

A new method, called 4D-CT, uses CT anatomic images combined with functional images. Its purported sensitivity is 88%, higher than the individual sensitivities of sestamibi and US scans. 4D-CT is very beneficial for identifying multigland disease. (Mihai)

Sometimes the blood supply of the adenoma can be visualized with Doppler: frequently a rim of vascularity at the periphery of the gland is seen. Normal parathyroids are small (about 5 mm) and are rarely seen on ultrasound. It can be difficult to diagnose hyperplasia with US, since the parathyroids are not markedly enlarged. Retrotracheal and mediastinal

Another difficulty is differentiating cervical lymph nodes from parathyroids; the two can be mistaken for each other. Nodes typically have a fatty hilum and are supplied by small hilar vessels. Thyroid nodules, especially those posteriorly located, can also be difficult to differentiate from parathyroids. Thyroid nodules do not typically display a vascular pattern. Intrathyroid parathyroids are also difficult to discern from thyroid nodules. (Johnson) Diagnostic fine-needle aspiration of thyroid nodules helps differentiate parathyroids from

Individually, sestamibi and US studies have limited accuracy, but the use of both imaging modalities increases the ability to successfully identify a single adenoma: the reported combined sensitivity is 95%. (Lumachi, 2000) When the results of both the sestamibi and US studies are concordant, the accuracy for identifying a single adenoma can be as high as

Pros Cons

disease

CT of the neck and mediastinum is very good for recognizing enlarged glands, with sensitivity from 76% to 83%. Despite its accuracy, CT is infrequently used because of the associated radiation exposure and the need to give intravenous (IV) contrast. However, it can help predict four-gland hyperplasia (necessitating bilateral neck exploration) more frequently than other imaging modalities. It has also been shown to pick up some

CT is efficacious when combined with sestamibi scans: their combined sensitivity nears

SPECT/CT is an emerging technology that allows better definition of scintigraphic images; its sensitivity for defining parathyroid lesions preoperatively is close to 88%. (Neumann) (SPECT stands for single-photon- emission CT.) It is most beneficial when patients have had a prior operation and when anatomic details matched with functional information from sestamibi

A new method, called 4D-CT, uses CT anatomic images combined with functional images. Its purported sensitivity is 88%, higher than the individual sensitivities of sestamibi and US

parathyroid adenomas previously missed on ultrasound scans. (Lumachi, 2004)

scans are required. It is also very useful for identifying ectopic parathyroids. (Krauz)

scans. 4D-CT is very beneficial for identifying multigland disease. (Mihai)

Difficulty visualizing normal glands Mistaking of thyroid nodules and lymph

Difficulty in identifying multigland

nodes for adenomas

ectopic parathyroids are not well visualized on US. (Johnson)

other cervical nodules. (Dimashkieh)

Anatomic study

Intraoperative use

Table 5. Pros and Cons of US Scans

**5.3 Computed tomography (CT)** 

disease

100%. (Lumachi, 2004)

Identifies concomitant thyroid

98%. (Haciyanli)

#### **5.4 Positron emission tomography (PET)**

A newer form of PET called [18F]-2-fluorodeoxyglucose (FDG)-PET can be helpful with parathyroid imaging. FDG-PET uses a methionine-labeled radiotracer that has good specificity for hyperfunctioning parathyroid tissue. It is helpful in patients who have had a negative result on localization imaging studies or who need a reoperation. Its sensitivity is 86%, but increases to 92% when coupled with CT. (Mihai)

#### **5.5 Magnetic resonance imaging (MRI)**

MRI can be used in a similar manner to CT to diagnose the cause of PHPT. (Johnson) It has not been used frequently or studied extensively in patients with PHPT, but its sensitivity ranges from 71% to 100%. MRI may be especially useful if paired with a sestamibi scan or with a methoxyisobutylisonitrile (MIBI) scan for enhanced accuracy, though no protocols have yet been developed for such combinations. (Mihai)


Table 6. Sensitivities of Imaging Modalities

#### **6. Adjuncts in parathyroid surgery**

As minimally invasive procedures become more popular, the need becomes greater to provide minimally invasive parathyroidectomies. With a minimally invasive parathyroidectomy, as previously mentioned, preoperative imaging is necessary in order to determine which gland needs to be removed. Additionally, intraoperative adjuncts (described below) are frequently used in order to decrease operative time and increase operative success.

#### **6.1 Intraoperative PTH monitoring**

Intraoperative PTH (IOPTH) monitoring was developed to help guide the extent of surgical exploration and parathyroid resection. The most common reason for a failed initial operation is missed multigland disease. (Irvin, 1994) IOPTH monitoring is based on the assumption that removing the hyperfunctioning gland will cause the PTH level to fall appropriately. (Vignali) The half-life of PTH ranges from 3 to 4 minutes and can be measured easily with a quick immunoradiometric assay or with a two-site antibody immunochemiluminometric assay. (Irvin, 1994)

Management of Primary Hyperparathyroidism 211

Intraoperative frozen sections for PHPT are helpful in many situations. Parathyroids can be difficult to grossly differentiate from other tissues, such as fat, thymus, thyroid, and lymph nodes. Despite advances in preoperative imaging studies, their accuracy remains limited; sampling parathyroids intraoperatively, before excision, may be necessary to look for hypercellularity. (Osamura) Frozen section analysis allows for rapid confirmation of the tissue, and especially for differentiation between parathyroid and non-parathyroid tissue. Like any other test, frozen sections have limitations. During the freezing process, the tissue can be damaged and distorted, leading to a delay in diagnosis (while awaiting final pathology results) or to an error in diagnosis. In small glands, the sample may not be large enough for an adequate diagnosis (although this is not an issue with enlarged, abnormal glands). It can be very difficult to differentiate thyroid nodules from intrathyroidal parathyroids. (Westra) With the advent of minimally invasive parathyroidectomies, frozen

At some institutions, instead of frozen section analysis, scrape cytology is performed to assess the parathyroids intraoperatively. Scrape cytology requires few instruments and little equipment, which makes it a more economical test. One study reported its sensitivity to be 86%. Its main drawback is that, in very small glands, obtaining an adequate sample may be more difficult. Occasionally, the sample is misinterpreted as thyroid tissue. Still, if frozen

An alternative to frozen section analysis for intraoperative identification of parathyroids is needle aspiration with rapid PTH analysis. This method is more cost-effective than frozen section analysis because it allows for intraoperative identification without the need for pathologic evaluation. It uses the same technique as IOPTH monitoring, but requires much less tissue for diagnosis. Some groups advocate this method for intraoperative confirmation of PHPT, while others use it to confirm that the removed tissue is parathyroid tissue. Some have raised the concern that this method can damage normal parathyroids, yet no evidence of this effect exists. Needle aspiration for PTH can also be used preoperatively by percutaneously aspirating a presumed parathyroid under imaging guidance, in order to

The technique for needle aspiration involves a 25-gauge needle on a 3-cc syringe filled with 1.0 mL normal saline solution. The PTH level is determined by the dual-antibody immunoassay for intact PTH. The PTH value of the thyroid is used as a control. Aspiration of parathyroids have reportedly produced a value greater than 1600 pg/mL; the average PTH of the thyroid is 87 pg/mL. (Chan RK) Some clinicians, while advocating similar methods of obtaining tissue, have shown that more needle passes (20 instead of 10) and a larger biopsy size (1.0-mm3) increase accuracy. The method can be performed in vivo or ex vivo. Its sensitivity for

When this method is performed preoperatively, either a CT or ultrasound scan is obtained to identify cervical masses in patients with PHPT or in patients who have recurrent PHPT

sections are no longer used to assess non-affected glands. (Osamura)

sections are not available, scrape cytology can be very helpful. (Rohaizak)

confirm that a visualized neck nodule is a parathyroid. (Chan RK)

identifying parathyroid tissue is 99%, using 1,000 pg/mL as the cutoff. (Conrad)

**6.3.2 Needle aspiration and PTH analysis** 

**6.3 Intraoperative assessment 6.3.1 Frozen section analysis** 

The Miami group was the first to describe IOPTH monitoring in conjunction with a minimally invasive parathyroidectomy. The PTH is measured twice before the parathyroid is resected (preincision and preexcision). The higher value of the two is used. Once the parathyroid is removed, the PTH is measured again at 5 and 10 minutes. PTH levels are drawn either from a peripheral vein or from an internal jugular vein. Additional intervals are also measured if deemed necessary by the operating surgeon. (Boggs) A successful resection is defined as a 50% drop in PTH from baseline at 10 minutes after parathyroid removal. (Boggs, Vignali, Irvin, 1994) A fall in PTH < 50% indicates inadequate resection and necessitates further exploration. (Boggs) The success of minimally invasive parathyroidectomies and IOPTH monitoring is now reported as 98%, a rate equivalent to the standard bilateral neck exploration. (Vignali) However, IOPTH also results in a falsepositive rate of 3% to 24% (the rate is lower with adenomas and higher with multigland disease), leading to failed operations. (Yang)

IOPTH monitoring is an important adjunct to surgery, especially with negative or discordant results of preoperative imaging studies. (Gawande) It can guide the operation and minimize unnecessary bilateral neck dissections. It is also beneficial in reoperative parathyroidectomies, when it is necessary to find the source of disease. Higher success rates (from 76% to 94%) have been noted for reoperative parathyroidectomies that incorporate IOPTH monitoring. (Irvin, 1999)

#### **6.2 Gamma probes**

Minimally invasive radio-guided surgery is now performed for patients with PHPT. The technique involves preoperative IV injection of 37MBq of MIBI). (Rubello) Then the 11-mm gamma probe is used to scan the patient's neck, near the site of the presumed adenoma, in order to obtain a preoperative background gamma count. After the surgical field is exposed, the radioactivity of the parathyroid adenoma, thyroid, and surrounding area are all remeasured. An adenoma is defined as an ex-vivo parathyroid with at least 20% of the background radioactivity. The empty parathyroid bed is also checked for radioactivity, and any remaining tissue should only have up to 3% of the radioactivity of the adenoma. (Rubello, Howe) Some clinicians opt to perform *intraoperative* PTH measurements as well, to enhance their accuracy. (Rubello)

One of the benefits of using the gamma probe is that it assists in localizing ectopic adenomas and those located deep in the neck. It allows re-checking not only of the operative field for radioactivity after removal of the presumed source but also of the removed tissue, in order to be certain that the hyperactive adenoma has been removed. (Rubello) Technically, the gamma probe is also helpful with a very small incision, which makes visualization of glands much more difficult than in a traditional bilateral neck exploration. It is also helpful for reoperations, because scar tissue makes finding the adenoma of interest much more difficult. (Jaskowiak) Some clinicians find that the gamma probe is also more cost-effective in that it decreases the number of frozen sections. (Jaskowiak) However, most agree that it is possible to miss multigland disease with this technique. (Rubello) About 2% to 3% of patients require conversion to a bilateral neck exploration, most frequently because intraoperative PTH levels failed to decrease. (Rubello, Jaskowiak)

#### **6.3 Intraoperative assessment**

210 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

The Miami group was the first to describe IOPTH monitoring in conjunction with a minimally invasive parathyroidectomy. The PTH is measured twice before the parathyroid is resected (preincision and preexcision). The higher value of the two is used. Once the parathyroid is removed, the PTH is measured again at 5 and 10 minutes. PTH levels are drawn either from a peripheral vein or from an internal jugular vein. Additional intervals are also measured if deemed necessary by the operating surgeon. (Boggs) A successful resection is defined as a 50% drop in PTH from baseline at 10 minutes after parathyroid removal. (Boggs, Vignali, Irvin, 1994) A fall in PTH < 50% indicates inadequate resection and necessitates further exploration. (Boggs) The success of minimally invasive parathyroidectomies and IOPTH monitoring is now reported as 98%, a rate equivalent to the standard bilateral neck exploration. (Vignali) However, IOPTH also results in a falsepositive rate of 3% to 24% (the rate is lower with adenomas and higher with multigland

IOPTH monitoring is an important adjunct to surgery, especially with negative or discordant results of preoperative imaging studies. (Gawande) It can guide the operation and minimize unnecessary bilateral neck dissections. It is also beneficial in reoperative parathyroidectomies, when it is necessary to find the source of disease. Higher success rates (from 76% to 94%) have been noted for reoperative parathyroidectomies that incorporate

Minimally invasive radio-guided surgery is now performed for patients with PHPT. The technique involves preoperative IV injection of 37MBq of MIBI). (Rubello) Then the 11-mm gamma probe is used to scan the patient's neck, near the site of the presumed adenoma, in order to obtain a preoperative background gamma count. After the surgical field is exposed, the radioactivity of the parathyroid adenoma, thyroid, and surrounding area are all remeasured. An adenoma is defined as an ex-vivo parathyroid with at least 20% of the background radioactivity. The empty parathyroid bed is also checked for radioactivity, and any remaining tissue should only have up to 3% of the radioactivity of the adenoma. (Rubello, Howe) Some clinicians opt to perform *intraoperative* PTH measurements as well, to

One of the benefits of using the gamma probe is that it assists in localizing ectopic adenomas and those located deep in the neck. It allows re-checking not only of the operative field for radioactivity after removal of the presumed source but also of the removed tissue, in order to be certain that the hyperactive adenoma has been removed. (Rubello) Technically, the gamma probe is also helpful with a very small incision, which makes visualization of glands much more difficult than in a traditional bilateral neck exploration. It is also helpful for reoperations, because scar tissue makes finding the adenoma of interest much more difficult. (Jaskowiak) Some clinicians find that the gamma probe is also more cost-effective in that it decreases the number of frozen sections. (Jaskowiak) However, most agree that it is possible to miss multigland disease with this technique. (Rubello) About 2% to 3% of patients require conversion to a bilateral neck exploration, most frequently because intraoperative PTH

disease), leading to failed operations. (Yang)

IOPTH monitoring. (Irvin, 1999)

enhance their accuracy. (Rubello)

levels failed to decrease. (Rubello, Jaskowiak)

**6.2 Gamma probes** 

#### **6.3.1 Frozen section analysis**

Intraoperative frozen sections for PHPT are helpful in many situations. Parathyroids can be difficult to grossly differentiate from other tissues, such as fat, thymus, thyroid, and lymph nodes. Despite advances in preoperative imaging studies, their accuracy remains limited; sampling parathyroids intraoperatively, before excision, may be necessary to look for hypercellularity. (Osamura) Frozen section analysis allows for rapid confirmation of the tissue, and especially for differentiation between parathyroid and non-parathyroid tissue. Like any other test, frozen sections have limitations. During the freezing process, the tissue can be damaged and distorted, leading to a delay in diagnosis (while awaiting final pathology results) or to an error in diagnosis. In small glands, the sample may not be large enough for an adequate diagnosis (although this is not an issue with enlarged, abnormal glands). It can be very difficult to differentiate thyroid nodules from intrathyroidal parathyroids. (Westra) With the advent of minimally invasive parathyroidectomies, frozen sections are no longer used to assess non-affected glands. (Osamura)

At some institutions, instead of frozen section analysis, scrape cytology is performed to assess the parathyroids intraoperatively. Scrape cytology requires few instruments and little equipment, which makes it a more economical test. One study reported its sensitivity to be 86%. Its main drawback is that, in very small glands, obtaining an adequate sample may be more difficult. Occasionally, the sample is misinterpreted as thyroid tissue. Still, if frozen sections are not available, scrape cytology can be very helpful. (Rohaizak)

#### **6.3.2 Needle aspiration and PTH analysis**

An alternative to frozen section analysis for intraoperative identification of parathyroids is needle aspiration with rapid PTH analysis. This method is more cost-effective than frozen section analysis because it allows for intraoperative identification without the need for pathologic evaluation. It uses the same technique as IOPTH monitoring, but requires much less tissue for diagnosis. Some groups advocate this method for intraoperative confirmation of PHPT, while others use it to confirm that the removed tissue is parathyroid tissue. Some have raised the concern that this method can damage normal parathyroids, yet no evidence of this effect exists. Needle aspiration for PTH can also be used preoperatively by percutaneously aspirating a presumed parathyroid under imaging guidance, in order to confirm that a visualized neck nodule is a parathyroid. (Chan RK)

The technique for needle aspiration involves a 25-gauge needle on a 3-cc syringe filled with 1.0 mL normal saline solution. The PTH level is determined by the dual-antibody immunoassay for intact PTH. The PTH value of the thyroid is used as a control. Aspiration of parathyroids have reportedly produced a value greater than 1600 pg/mL; the average PTH of the thyroid is 87 pg/mL. (Chan RK) Some clinicians, while advocating similar methods of obtaining tissue, have shown that more needle passes (20 instead of 10) and a larger biopsy size (1.0-mm3) increase accuracy. The method can be performed in vivo or ex vivo. Its sensitivity for identifying parathyroid tissue is 99%, using 1,000 pg/mL as the cutoff. (Conrad)

When this method is performed preoperatively, either a CT or ultrasound scan is obtained to identify cervical masses in patients with PHPT or in patients who have recurrent PHPT

Management of Primary Hyperparathyroidism 213

neck explorations. The Michigan group reported no incidence of recurrent disease after

This type of neck exploration uses multiple small incisions to insert endoscopic instruments and a camera.(Lorenz) It has several advantages. First, it is a minimally invasive method that can treat multigland disease. Second, it magnifies all of the anatomy, making a nerve injury less likely. Third, it allows exploration of the mediastinum, if needed, for ectopic glands. (Gagner) Its downsides are that the surgeon is unable to use tactile sensation and

An endoscopic parathyroidectomy can be performed in several different ways. Gagner et al. devised a method with CO2 insufflation. They use a 2-cm suprasternal incision for a 5-mm trocar, and then place 2 to 3 needle trocars and one more 5-mm trocar on the medial aspect of the ipsilateral sternocleidomastoid muscle. The camera goes in the 5-mm trocars; the rest are working trocars. The area is insufflated to 15 mm Hg. Endoscopic scissors and dissectors are used to dissect out the borders of the thyroid and trachea. Clips are used to ligate vessels. The specimen is retrieved through an incision of 2 to 3 cm at the maxillary angle. Single adenomas as well as multigland disease can be effectively treated with this method. Yeung et al. place an 11-mm trocar above the suprasternal notch. The platysma is incised, and CO2 is insufflated to 6 to 8 mm Hg. Then a 5-mm trocar is placed near the lower edge of the sternocleidomastoid muscle, 2 cm above the incision on the opposite side of the lesion. A second 5-mm trocar is placed 2 to 3 cm lateral to the midline incision. One additional trocar, if needed, is occasionally placed. Endoscopic scissors are used to create a plane between the sternocleidomastoid and the strap muscles. The carotid sheath and thyroid lobe are exposed, and the fascia of the thyroid is incised, to mobilize the thyroid anteromedially after dividing the middle thyroid vein. Any abnormal parathyroids are identified and resected, then

An endoscopic video-assisted parathyroidectomy is also possible. Miccoli et al. described a procedure using only CO2 during the initial dissection, in order to avoid hypercarbia and subcutaneous emphysema. They make a 1.5-cm incision 1 cm above the sternal notch and incise the linea alba to insert a 12-mm trocar toward the side of the adenoma. The area is insufflated to 12 mm Hg, in order to dissect the strap muscles away. Then the CO2 is turned off, and the space is maintained with retraction. A 5-mm camera is inserted in the same incision, as are skin retractors (one lifting the thyroid up and the other retracting laterally). The thyrotracheal groove is exposed, and the 2-mm instruments are inserted through a

Robot-assisted parathyroidectomy was first used to assist with removing mediastinal parathyroids. (Harvey) The daVinci system has now been used for robotic transaxillary parathyroid surgery. A daVinci-assisted parathyroidectomy and an open operation have equivalent cure and complication rates. However, the advantages of a daVinci-assisted parathyroidectomy include cosmesis (it avoids neck scars), reduced operating times, shorter hospital stays, and decreased analgesia requirement. The robotic endoscope has

small lateral incision. The parathyroid of interest is identified and resected.

that the patient is prone to hypercarbia and subcutaneous emphysema. (Naitoh)

unilateral neck explorations and a follow-up of 4 years. (Lucas)

**7.1.3 Endoscopic parathyroidectomy** 

removed through the 11-mm port.

**7.1.4 DaVinci-assisted parathyroidectomy** 

after an initial operation. Any level of PTH is considered a positive result, because no other tissue should contain PTH. Percutaneous aspiration can be performed safely with minimal associated complications. Although this method allows for accurate identification of parathyroid tissue, the false-negative rate is 13% (likely depending on the needle aspiration technique). (Sacks)

#### **7. Operative techniques**

#### **7.1 Minimally invasive parathyroidectomy (MIP)**

With technical advances in imaging and surgical adjuncts, PHPT is now commonly treated with a minimally invasive parathyroidectomy. Most clinicians agree that candidates for a minimally invasive parathyroidectomy need to have two concordant preoperative imaging studies (typically, sestamibi and ultrasound scans). The operation is usually performed with one of the aforementioned surgical adjuncts, which allow for a more focused operation, a smaller and more cosmetic incision, less operative risk, and outpatient surgery or the use of local anesthesia. Most patients have single-gland disease, so a minimally invasive approach seems preferable. (Lorenz)

#### **7.1.1 Focused parathyroidectomy**

A focused parathyroidectomy entails a targeted exploration, directed by the results of preoperative imaging, at the site of the suspected adenoma. All patients undergoing a focused parathyroidectomy were thought to possibly have single-gland disease, per preoperative imaging. The operation can be performed with IOPTH monitoring or the gamma probe. A 2-cm transverse incision is made over the site of the suspected adenoma, at the medial border of the ipsilateral sternocleidomastoid muscle. The sternocleidomastoid muscle and carotid artery are retracted laterally, and the thyroid is retracted anteromedially. If the adenoma is identified, it is circumferentially dissected. If the adenoma is not identified, the ipsilateral neck should be explored; conversion to a traditional bilateral exploration may be necessary. Although focused parathyroidectomy allows for a smaller cosmetic incision, the downside is that conversion to a bilateral neck exploration may require a second incision. (Lorenz)

#### **7.1.2 Unilateral neck exploration**

In a unilateral neck exploration, the incision is half the length of the traditional Kocher incision. The skin and subcutaneous layers are divided down through the platysma, and the subplatysmal flaps are raised. The median raphe of the strap muscles is divided; the ipsilateral strap muscles are retracted laterally; and the thyroid lobe is rotated anteromedially. Once the adenoma is identified, it is circumferentially dissected and resected. Both parathyroids on the ipsilateral side should be visualized: one normal and one abnormal gland should be visualized. However, if both those glands appear normal, or if an abnormal adenoma is not localized, the contralateral side must be explored. (Lorenz)

A unilateral exploration may be performed under local anesthesia. Frequently, this operation is coupled with intraoperative adjuncts to help guide the extent of resection. (Lorenz) Most groups report similar rates of disease recurrence after unilateral and bilateral

after an initial operation. Any level of PTH is considered a positive result, because no other tissue should contain PTH. Percutaneous aspiration can be performed safely with minimal associated complications. Although this method allows for accurate identification of parathyroid tissue, the false-negative rate is 13% (likely depending on the needle aspiration

With technical advances in imaging and surgical adjuncts, PHPT is now commonly treated with a minimally invasive parathyroidectomy. Most clinicians agree that candidates for a minimally invasive parathyroidectomy need to have two concordant preoperative imaging studies (typically, sestamibi and ultrasound scans). The operation is usually performed with one of the aforementioned surgical adjuncts, which allow for a more focused operation, a smaller and more cosmetic incision, less operative risk, and outpatient surgery or the use of local anesthesia. Most patients have single-gland disease, so a minimally invasive approach

A focused parathyroidectomy entails a targeted exploration, directed by the results of preoperative imaging, at the site of the suspected adenoma. All patients undergoing a focused parathyroidectomy were thought to possibly have single-gland disease, per preoperative imaging. The operation can be performed with IOPTH monitoring or the gamma probe. A 2-cm transverse incision is made over the site of the suspected adenoma, at the medial border of the ipsilateral sternocleidomastoid muscle. The sternocleidomastoid muscle and carotid artery are retracted laterally, and the thyroid is retracted anteromedially. If the adenoma is identified, it is circumferentially dissected. If the adenoma is not identified, the ipsilateral neck should be explored; conversion to a traditional bilateral exploration may be necessary. Although focused parathyroidectomy allows for a smaller cosmetic incision, the downside is that conversion to a bilateral neck exploration may

In a unilateral neck exploration, the incision is half the length of the traditional Kocher incision. The skin and subcutaneous layers are divided down through the platysma, and the subplatysmal flaps are raised. The median raphe of the strap muscles is divided; the ipsilateral strap muscles are retracted laterally; and the thyroid lobe is rotated anteromedially. Once the adenoma is identified, it is circumferentially dissected and resected. Both parathyroids on the ipsilateral side should be visualized: one normal and one abnormal gland should be visualized. However, if both those glands appear normal, or if an

abnormal adenoma is not localized, the contralateral side must be explored. (Lorenz)

A unilateral exploration may be performed under local anesthesia. Frequently, this operation is coupled with intraoperative adjuncts to help guide the extent of resection. (Lorenz) Most groups report similar rates of disease recurrence after unilateral and bilateral

technique). (Sacks)

**7. Operative techniques** 

seems preferable. (Lorenz)

**7.1.1 Focused parathyroidectomy** 

require a second incision. (Lorenz)

**7.1.2 Unilateral neck exploration** 

**7.1 Minimally invasive parathyroidectomy (MIP)** 

neck explorations. The Michigan group reported no incidence of recurrent disease after unilateral neck explorations and a follow-up of 4 years. (Lucas)

#### **7.1.3 Endoscopic parathyroidectomy**

This type of neck exploration uses multiple small incisions to insert endoscopic instruments and a camera.(Lorenz) It has several advantages. First, it is a minimally invasive method that can treat multigland disease. Second, it magnifies all of the anatomy, making a nerve injury less likely. Third, it allows exploration of the mediastinum, if needed, for ectopic glands. (Gagner) Its downsides are that the surgeon is unable to use tactile sensation and that the patient is prone to hypercarbia and subcutaneous emphysema. (Naitoh)

An endoscopic parathyroidectomy can be performed in several different ways. Gagner et al. devised a method with CO2 insufflation. They use a 2-cm suprasternal incision for a 5-mm trocar, and then place 2 to 3 needle trocars and one more 5-mm trocar on the medial aspect of the ipsilateral sternocleidomastoid muscle. The camera goes in the 5-mm trocars; the rest are working trocars. The area is insufflated to 15 mm Hg. Endoscopic scissors and dissectors are used to dissect out the borders of the thyroid and trachea. Clips are used to ligate vessels. The specimen is retrieved through an incision of 2 to 3 cm at the maxillary angle. Single adenomas as well as multigland disease can be effectively treated with this method.

Yeung et al. place an 11-mm trocar above the suprasternal notch. The platysma is incised, and CO2 is insufflated to 6 to 8 mm Hg. Then a 5-mm trocar is placed near the lower edge of the sternocleidomastoid muscle, 2 cm above the incision on the opposite side of the lesion. A second 5-mm trocar is placed 2 to 3 cm lateral to the midline incision. One additional trocar, if needed, is occasionally placed. Endoscopic scissors are used to create a plane between the sternocleidomastoid and the strap muscles. The carotid sheath and thyroid lobe are exposed, and the fascia of the thyroid is incised, to mobilize the thyroid anteromedially after dividing the middle thyroid vein. Any abnormal parathyroids are identified and resected, then removed through the 11-mm port.

An endoscopic video-assisted parathyroidectomy is also possible. Miccoli et al. described a procedure using only CO2 during the initial dissection, in order to avoid hypercarbia and subcutaneous emphysema. They make a 1.5-cm incision 1 cm above the sternal notch and incise the linea alba to insert a 12-mm trocar toward the side of the adenoma. The area is insufflated to 12 mm Hg, in order to dissect the strap muscles away. Then the CO2 is turned off, and the space is maintained with retraction. A 5-mm camera is inserted in the same incision, as are skin retractors (one lifting the thyroid up and the other retracting laterally). The thyrotracheal groove is exposed, and the 2-mm instruments are inserted through a small lateral incision. The parathyroid of interest is identified and resected.

#### **7.1.4 DaVinci-assisted parathyroidectomy**

Robot-assisted parathyroidectomy was first used to assist with removing mediastinal parathyroids. (Harvey) The daVinci system has now been used for robotic transaxillary parathyroid surgery. A daVinci-assisted parathyroidectomy and an open operation have equivalent cure and complication rates. However, the advantages of a daVinci-assisted parathyroidectomy include cosmesis (it avoids neck scars), reduced operating times, shorter hospital stays, and decreased analgesia requirement. The robotic endoscope has

Management of Primary Hyperparathyroidism 215

mediastinum. (Pyrah) At this point, if the adenoma is still not localized, an ipsilateral thyroidectomy is performed. The success rate of a bilateral neck exploration is 95% when

A bilateral neck exploration should be performed when the results of preoperative localizing imaging studies are equivocal or discordant. (Lumachi, 2000) It is also recommended for patients with familial PHPT; patients with multiple endocrine neoplasia syndrome type I and IIA; and patients who may have a carcinoma. In addition, it should be performed when a thyroid resection is planned concomitantly. Obese patients may be more likely to require a bilateral neck exploration, because their body habitus may preclude a

A minimally invasive parathyroidectomy is becoming more common in patients with single-gland disease. However, in some patients, it may be necessary to convert from a minimally invasive parathyroidectomy to a bilateral neck exploration. The most common reason for conversion is failure to appropriately identify a single abnormal gland. Conversion is also recommended when surgical adjuncts fail to indicate success (for example, the operation is unsuccessful when IOPTH monitoring shows a drop of < 50% in the PTH). Note that, if a unilateral neck exploration finds two normal or two abnormal

> *For Initial Surgery*  Equivocal or discordant preoperative imaging results Familial PHPT Multiple endocrine neoplasia syndrome type I and IIA Carcinoma Concomitant thyroid resection Obesity *For Conversion from Minimally Invasive Surgery*  Failure to identify a single abnormal gland Multiple abnormal glands Failure of adjuncts to indicate success

All operations on the parathyroids have potential complications, regardless of the surgical approach. Of most concern to patients is the risk of RLN injury leading to vocal cord paralysis on the side of the injury. The risk of RLN injury is about 1% in the hands of experienced surgeons. Rarely, both RLNs may be injured, resulting in airway obstruction, stridor, and the need for a tracheostomy. The superior laryngeal nerve can also be injured,

which leaves patients hoarse and unable to change the pitch of their voice. (Fewins)

**7.2.3 Indications for conversion from a minimally invasive parathyroidectomy** 

glands, it, too, should be converted to a bilateral neck exploration. (Moalem)

performed by an experienced endocrine surgeon. (Low)

minimally invasive procedure. (Grant)

Table 7. Indications for Bilateral Neck Exploration

**8. Complications**

**7.2.2 Indications** 

magnification, enabling better visualization than traditional endoscopic procedures. Though robotic instrumentation allows more flexible motion than traditional endoscopic instruments, it is still more restricted than open surgery. Other limitations include difficulties with depth perception, less tactile feedback, and dependence on multiple assistants. (Tolley)

For a daVinci-assisted parathyroidectomy, the patient is positioned supine, with the neck extended and the shoulder bolstere. The initial incision is made below the ipsilateral clavicle to expose the sternoclavicular junction, long enough for a 12-mm trocar. Dissection continues cranially until exposure of the internal jugular vein, carotid artery, and omohyoid and sternohyoid muscles. A retractor is used to retract the strap muscles. At this point, the posterolateral border of the thyroid is exposed. The other three trocars are then inserted at the anterior axillary line. The camera is placed through the infraclavicular trocar. The daVinci instruments are placed through the axillary incisions (5-mm trocars). Then, the inferior thyroid pole, recurrent laryngeal nerve (RLN), and vascular pedicle of the parathyroid gland are exposed. A nerve stimulator may be used to continually identify the RLN. A harmonic scalpel is used to dissect the pathologic parathyroid free. Hemostasis is obtained, the trocars are removed, and the wounds are closed. (Tolley)

#### **7.2 Conventional bilateral neck exploration**

#### **7.2.1 Surgical approach**

A traditional bilateral neck exploration is performed through a transverse cervical incision (Kocher), about 2 cm above the sternal notch and just below the cricoid cartilage. The dissection is carried through the subcutaneous tissue and platysma down to the strap muscles, which are opened in the midline and retracted laterally. A self-retaining retractor is placed to assist with exposure. The strap muscles are separated from the thyroid. The right lobe of the thyroid is dissected bluntly and retracted medially, enabling the surgeon to look for the course of the recurrent laryngeal nerve. The middle thyroid vein is identified and ligated. The thyroid gland is rotated anteromedially, and the recurrent laryngeal nerve is identified near the middle thyroid artery. The superior parathyroid is found by slowly dissecting the loose tissue attaching the superior pole of the thyroid. The inferior gland is found in the same manner near the inferior thyroid artery. The procedure is repeated on the left side. All four glands are accessible through this incision and all four glands are viewed. (Johnson)

Once all four glands are identified, the extent of resection must be decided. If a single adenoma is found, it is removed. Two glands are removed if a double adenoma is visually confirmed. If all four glands are enlarged, indicating multigland hyperplasia, then a 3.5 gland resection is performed. All four glands can be biopsied to accurately distinguish single-gland from multigland disease. (Lorenz)

If the parathyroids are not found in their usual location, it is necessary to explore the common locations of ectopic glands. Ectopic *superior* glands may be found in the tracheoesophageal groove; in the retropharyngeal or retroesophageal space; posterior mediastinum; in the carotid sheath; or within the thyroid itself (intrathyroidal). (Johnson) Ectopic *inferior* parathyroids are typically on the posterior portion of the lower pole of the thyroid, but may be submandibular, intrathymic, or intrathyroidal, or may be found in the thyrothymic ligament or anterior mediastinum. (Pyrah) At this point, if the adenoma is still not localized, an ipsilateral thyroidectomy is performed. The success rate of a bilateral neck exploration is 95% when performed by an experienced endocrine surgeon. (Low)

#### **7.2.2 Indications**

214 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

magnification, enabling better visualization than traditional endoscopic procedures. Though robotic instrumentation allows more flexible motion than traditional endoscopic instruments, it is still more restricted than open surgery. Other limitations include difficulties with depth perception, less tactile feedback, and dependence on multiple

For a daVinci-assisted parathyroidectomy, the patient is positioned supine, with the neck extended and the shoulder bolstere. The initial incision is made below the ipsilateral clavicle to expose the sternoclavicular junction, long enough for a 12-mm trocar. Dissection continues cranially until exposure of the internal jugular vein, carotid artery, and omohyoid and sternohyoid muscles. A retractor is used to retract the strap muscles. At this point, the posterolateral border of the thyroid is exposed. The other three trocars are then inserted at the anterior axillary line. The camera is placed through the infraclavicular trocar. The daVinci instruments are placed through the axillary incisions (5-mm trocars). Then, the inferior thyroid pole, recurrent laryngeal nerve (RLN), and vascular pedicle of the parathyroid gland are exposed. A nerve stimulator may be used to continually identify the RLN. A harmonic scalpel is used to dissect the pathologic parathyroid free. Hemostasis is

A traditional bilateral neck exploration is performed through a transverse cervical incision (Kocher), about 2 cm above the sternal notch and just below the cricoid cartilage. The dissection is carried through the subcutaneous tissue and platysma down to the strap muscles, which are opened in the midline and retracted laterally. A self-retaining retractor is placed to assist with exposure. The strap muscles are separated from the thyroid. The right lobe of the thyroid is dissected bluntly and retracted medially, enabling the surgeon to look for the course of the recurrent laryngeal nerve. The middle thyroid vein is identified and ligated. The thyroid gland is rotated anteromedially, and the recurrent laryngeal nerve is identified near the middle thyroid artery. The superior parathyroid is found by slowly dissecting the loose tissue attaching the superior pole of the thyroid. The inferior gland is found in the same manner near the inferior thyroid artery. The procedure is repeated on the left side. All four glands are accessible through this incision and all four

Once all four glands are identified, the extent of resection must be decided. If a single adenoma is found, it is removed. Two glands are removed if a double adenoma is visually confirmed. If all four glands are enlarged, indicating multigland hyperplasia, then a 3.5 gland resection is performed. All four glands can be biopsied to accurately distinguish

If the parathyroids are not found in their usual location, it is necessary to explore the common locations of ectopic glands. Ectopic *superior* glands may be found in the tracheoesophageal groove; in the retropharyngeal or retroesophageal space; posterior mediastinum; in the carotid sheath; or within the thyroid itself (intrathyroidal). (Johnson) Ectopic *inferior* parathyroids are typically on the posterior portion of the lower pole of the thyroid, but may be submandibular, intrathymic, or intrathyroidal, or may be found in the thyrothymic ligament or anterior

obtained, the trocars are removed, and the wounds are closed. (Tolley)

**7.2 Conventional bilateral neck exploration** 

**7.2.1 Surgical approach** 

glands are viewed. (Johnson)

single-gland from multigland disease. (Lorenz)

assistants. (Tolley)

A bilateral neck exploration should be performed when the results of preoperative localizing imaging studies are equivocal or discordant. (Lumachi, 2000) It is also recommended for patients with familial PHPT; patients with multiple endocrine neoplasia syndrome type I and IIA; and patients who may have a carcinoma. In addition, it should be performed when a thyroid resection is planned concomitantly. Obese patients may be more likely to require a bilateral neck exploration, because their body habitus may preclude a minimally invasive procedure. (Grant)

#### **7.2.3 Indications for conversion from a minimally invasive parathyroidectomy**

A minimally invasive parathyroidectomy is becoming more common in patients with single-gland disease. However, in some patients, it may be necessary to convert from a minimally invasive parathyroidectomy to a bilateral neck exploration. The most common reason for conversion is failure to appropriately identify a single abnormal gland. Conversion is also recommended when surgical adjuncts fail to indicate success (for example, the operation is unsuccessful when IOPTH monitoring shows a drop of < 50% in the PTH). Note that, if a unilateral neck exploration finds two normal or two abnormal glands, it, too, should be converted to a bilateral neck exploration. (Moalem)

Table 7. Indications for Bilateral Neck Exploration

#### **8. Complications**

All operations on the parathyroids have potential complications, regardless of the surgical approach. Of most concern to patients is the risk of RLN injury leading to vocal cord paralysis on the side of the injury. The risk of RLN injury is about 1% in the hands of experienced surgeons. Rarely, both RLNs may be injured, resulting in airway obstruction, stridor, and the need for a tracheostomy. The superior laryngeal nerve can also be injured, which leaves patients hoarse and unable to change the pitch of their voice. (Fewins)

Management of Primary Hyperparathyroidism 217

Allendorf J, Kim L, Chabot J, DiGiorgi M, Spanknebel K, Logerfo P. The impact of Sestamibi

Bergenfelz A, Kannigiesser V, Zielke A, Neis C, Rothmund M. Conventional bilateral

local anesthesia for primary hyperparathyroidism. BJS, 2005; 92: 190-197. Bilezikian JP, Khan AA, Potts JT. Guidelines for the management of asymptomatic primary

Boggs JE, Irvin GL, Molinari AS, Deriso GT. Intraoperative parathyroid hormone monitoring as an adjunct to parathyroidectomy. Surgery, 1996; 120: 954-958.. Chan AK, Duh QY, Katz, MH, Siperstein AE, Clark OH. Clinical manifestations of primary

Chan RK, Ibrahim SI, Pil P, Tanasijevic M. Validation of a method to replace frozen section

Conrad DN, Olson JE, Hartwig HM, Mack E, Chen H. A prospective evaluation of novel

Davies M, Fraser WD, Hosking DJ. Management of primary hyperparathyroidism. Clinical

Dimashkieh H, Krishnamurthy S. Ultrasound guided fine needle aspiration biopsy of

Felger EA, Kandil E. Primary hyperparathyroidism. Otolaryngol Clin N Am 43 (2010) 417–

Fewins J, Simpson CB, Miller FR. Complications of thyroid and parathyroid surgery.

Gagner M. Endoscopic subtotal parathyroidectomy in patients with primary

Gawande AA, Monchik JM, Abbruzzese TA, Iannuccilli JD, Ibrahim SI, Moore FD.

Glendenning P. Diagnosis of primary hyperparathyroidism: controversies, practical issues and the need for Australian guidelines. Intern Med J 2003; 33: 598–603. Grant CS, Thompson G, Farley D, van Heerden J. Primary hyperparathyroidism surgical

Haber RS, Kim CK, and Inabnet WB. Ultrasonography for preoperative localization of

Reassessment of parathyroid hormone monitoring during parathyroidectomy for primary hyperparathyroidism after 2 preoperative studies. Arch Surg. 2006; 141:

management since the introduction of minimally invasive parathyroidectomy.

enlarged parathyroid glands in primary hyperparathyroidism: comparison with 99m technetium sestamibi scintigraphy. Clinical Endocrinology, 2002; 57: 241-249. Haciyanli M, Lal G, Morita E, Duh QY, Kebebew E, Clark OH. Accuracy of preoperative

localization studies and intraoperative parathyroid hormone assay in patients with

Clin Endocrinol Metab, 2009; 94: 335-339.

parathyroid aspirates. Arch Surg. 2005; 140: 371-373.

parathyroid glands and lesions. Cytojournal. 2006; 3: 6.

hormone assay. Journal of Surgical Research, 2006; 133: 38-41.

Ann. Surg., 1995; 222: 402-414.

Endocrinology, 2002; 57: 145-155.

Arch Surg. 2005; 140: 472-479.

Otolaryngol Clin N Am., 2003; 36: 189-206.

hyperparathyroidism. Br J Surg., 1996; 83: 875.

scanning on the outcome of parathyroid surgery. J Clin Endocrinol Metab, 2003; 88:

cervical exploration versus open minimally invasive parathyroidectomy under

hyperparathyroidism: Summary statement from the third international workshop. J

hyperparathyroidism before and after parathyroidectomy: A case-control study.

during parathyroid exploration by using the rapid parathyroid hormone assay on

methods to intraoperatively distinguish parathyroid tissue using a parathyroid

**11. References** 

3015-3018.

432.

381-384.

Another common risk is postoperative hypocalcemia, which occurs temporarily in 5% of patients (because of bone hunger or inadequate PTH secretion from the remaining parathyroids as a result of prolonged suppression). In 1% of patients, hypocalcemia is permanent, as a consequence of inadvertent injury to the remaining parathyroid(s). (Inabnet) Hypocalcemia typically involves perioral numbness or digit tingling and paresthesias, but can progress to tetany or stridor. Treatment requires calcium, and often vitamin D, supplementation. (Fewins)

Other, more rare complications include cervical hematomas, injury to the carotid artery, dysphagia, deep vein thrombosis, wound infection, and pneumothorax. (Low, Fewins) Hematomas are usually secondary to inadequate hemostasis. (Fewins) Symptoms can include pain, dysphagia, and respiratory distress. Such patients need to emergently undergo reexploration; however, the hematoma needs to be evacuated at the bedside if the patient is in respiratory distress. (Fewins) Complications specific to endoscopic parathyroidectomies include hypercarbia and extended subcutaneous emphysema. (Lorenz)

If the patient has significant comorbidities before surgery, the risks of anesthesia can also cause complications, including aspiration pneumonia, respiratory failure, cardiac events, and even death. (Low) It is important to note that, in the hands of experienced endocrine surgeons at high-volume parathyroidectomy centers, postoperative complication rates decrease. (Stavrakis)

Table 8. Surgical Complications

### **9. Summary**

PHPT is a common disease that is effectively treated by surgery. The many surgical options range from a minimally invasive parathyroidectomy to a bilateral neck exploration. Regardless of the surgical approach, the likelihood of success is highest with an experienced endocrine surgeon at a high-volume center. To reduce the chance of operative failure, knowledge of the anatomy and embryology of the parathyroids is paramount.

#### **10. Acknowledgement**

We would like to acknowledge and thank Mary Knatterud for her assistance in editing this chapter.

#### **11. References**

216 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Another common risk is postoperative hypocalcemia, which occurs temporarily in 5% of patients (because of bone hunger or inadequate PTH secretion from the remaining parathyroids as a result of prolonged suppression). In 1% of patients, hypocalcemia is permanent, as a consequence of inadvertent injury to the remaining parathyroid(s). (Inabnet) Hypocalcemia typically involves perioral numbness or digit tingling and paresthesias, but can progress to tetany or stridor. Treatment requires calcium, and often

Other, more rare complications include cervical hematomas, injury to the carotid artery, dysphagia, deep vein thrombosis, wound infection, and pneumothorax. (Low, Fewins) Hematomas are usually secondary to inadequate hemostasis. (Fewins) Symptoms can include pain, dysphagia, and respiratory distress. Such patients need to emergently undergo reexploration; however, the hematoma needs to be evacuated at the bedside if the patient is in respiratory distress. (Fewins) Complications specific to endoscopic parathyroidectomies

If the patient has significant comorbidities before surgery, the risks of anesthesia can also cause complications, including aspiration pneumonia, respiratory failure, cardiac events, and even death. (Low) It is important to note that, in the hands of experienced endocrine surgeons at high-volume parathyroidectomy centers, postoperative complication rates

> *Common*  Hypocalcemia Injury to the recurrent or superior laryngeal nerve *Rare*  Cervical hematomas Injury to the carotid artery Dysphagia Deep vein thrombosis Wound infection Pneumothorax

PHPT is a common disease that is effectively treated by surgery. The many surgical options range from a minimally invasive parathyroidectomy to a bilateral neck exploration. Regardless of the surgical approach, the likelihood of success is highest with an experienced endocrine surgeon at a high-volume center. To reduce the chance of operative failure,

We would like to acknowledge and thank Mary Knatterud for her assistance in editing this

knowledge of the anatomy and embryology of the parathyroids is paramount.

include hypercarbia and extended subcutaneous emphysema. (Lorenz)

vitamin D, supplementation. (Fewins)

decrease. (Stavrakis)

Table 8. Surgical Complications

**10. Acknowledgement** 

**9. Summary** 

chapter.


Management of Primary Hyperparathyroidism 219

Mallette LE, Bilezikian JP, Heath DA, Aurbach GD. Primary hyperparathyroidism: Clinical

Miccoli P, Bendinelli C, Conte C, Pinchera A, Marcocci C. Endoscopic parathyroidectomy by a gasless approach. J Laparoendosc Adv Surg Tech A., 1998; 8: 189-194. Mihai R, Simon D, Hellman P. Imaging for primary hyperparathyroidism—an evidence-

Moalem J, Guerrero M, Kebebew E. Bilateral exploration in primary hyperparathyroidism— When is it selected and how is it performed? World J Surg, 2009; 33:2282–2291. Naitoh T, Gagner M, Garcia-Ruiz A, Heniford BT. Endoscopic endocrine surgery in the

Neumann, DR. Obuchowski NA. DiFilippo FP. Pre-operative 123I/99mTc-Sestamibi

Osamura RY, Hunt JL. Current practices in performing frozen sections for thyroid and

Pyrah LN, Hodgkinson A, Anderson CK. Critical Review: Primary hyperparathyroidism.

Rohaizak M, Munchar MJJ, Meah FA, Jasmi AY. Prospective study comparing scrape

Rubello D, Piotto A, Muzzio PC, Shapiro B, Pelizzo MR. Role of gamma probes in

Saaristo RA, Salmi JJO, Koobi T, Turjanmaa V, Sand JA, Nordback IH. Intraoperative

Shaha AR, Sarkar S, Strashun A, Yeh S. Sestamibi scan for preoperative localization in

Smit PC, Rinkes IHMB, van Dalen A, van Vroonhoven TJVMV. Direct, minimally invasive

Sosa JA, Powe NR, Levine MA, Udelsman R, Zeiger MA. Profile of a clinical practice:

Stavrakis AI, Ituarte PHG, Ko CY, Yeh MW. Surgeon volume as a predictor of outcomes in inpatient and outpatient endocrine surgery. Surgery 2007; 142: 887-99. Sywak MS, Knowlton ST, Pasieka JL, Parsons LL, Jones J. Do the National Institutes of

primary hyperparathyroidism. Head Neck , 1997; 19: 87–91.

neck exploration? Ann. Surg., 2000; 231: 559-565.

neck: An initial report of endoscopic subtotal parathyroidectomy. Surg Endosc,

subtraction SPECT and SPECT/CT in primary hyperparathyroidism. Nucl Med

cytology and frozen section in the intraoperative identification of parathyroid

performing minimally invasive parathyroidectomy in patients with primary hyperparathyroidism: optimization of preoperative and intraoperative procedures.

localization of parathyroid glands with gamma counter probe in primary hyperparathyroidism: A prospective study. J Am Coll Surg, 2002; 195: 19–22. Sacks BA, Pallotta JA, Cole A, Hurwitz J. Diagnosis of parathyroid adenomas: efficacy of

measuring parathormone levels in needle aspirates of cervical masses. AJR, 1994;

adenomectomy for primary hyperparathyroidism: An alternative to conventional

Thresholds for surgery and surgical outcomes for patients with primary hyperparathyroidism: A National survey of endocrine surgeons. J Clin Endocrinol

Health consensus guidelines for parathyroidectomy predict symptom severity and

and biochemical features. Medicine, 1974; 53: 127-146.

1998; 12: 202–205.

2008; 49:2012–2017.

163: 1223-1226.

Metab, 1998; 83: 2658-2665.

Brit J Surg, 1966; 53: 245-316.

tissue. Asian J Surg, 2005; 28: 82–5.

based analysis. Langenbeck's Arch Surg, 2009; 394:765–784.

parathyroid surgery. Virchow Arch, 2008; 453: 443-440.

European Journal of Endocrinology, 2003; 149: 7-15.

primary hyperparathyroidism and double adenoma. J Am Coll Surg. 2003; 197: 739- 46.


Inabnet WB, Fulla Y, Richard B, Bonnichon P, Icard P, Chapuis Y. Unilateral neck

Irvin GL, Deriso GT. A new, practical intraoperative parathyroid hormone assay. Am J

Irvin GL. Molinari AS, Figuroa C, Carniero DM. Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg. 1999; 229: 874-879. Jaskowiak NT, Sugg SL, Helke J, Koka MR, Kaplan EL. Pitfalls of intraoperative quick

Johnson, NA. Tublin ME, Ogilvie JB. Parathyroid imaging: Technique and role in the

Kaplan EL, Yahiro T, Salti G. Primary Hyperparathyroidism in the 1990s: Choice of surgical

Keating FR. Diagnosis of primary hyperparathyroidism: Clinical and laboratory diagnosis.

Kern KA, Shawker TH, Doppman JL, Miller DL, Marx SJ, Spiegel AM, Aurbach GD, Norton

Kukora JS, Zeiger MA. The American Association of Clinical Endocrinologists and The

Lorenz K, Nguyen-Thanh P, Dralle H. Unilateral open and minimally invasive procedures

Low RA, Katz AD. Parathyroidectomy via bilateral cervical exploration: a retrospective

Lucas RJ, Welsh RJ, Glocer JL. Unilateral neck exploration for primary hyperparathyroidism.

Lumachi F, Zucchetta P, Marzola MC, Boccagni P, Angelini F, Bui F, D'Amico DF, Favia G.

Lumachi F, Tregnaghi A, Zucchetta P, Marzola MC, Cecchin D, Marchesi P, Fallo F, Bui F.

primary hyperparathyroidism. Endocrine Practice, 2005; 11: 49-54.

primary hyperparathyroidism. Surgery, 1999; 126: 1004-10.

primary hyperparathyroidism. Arch Surg. 2002; 137: 659-669.

procedures for this disease. Ann. Surg., 1992; 300-317.

hyperparathyroidism. World J Surg, 2006; 30: 76–83.

review of 866 cases. Head Neck, 1998; 20: 583-587.

46.

1715.

Surg., 1994; 168: 466-468.

JAMA, 1961; 178: 547-555.

Arch Surg, 2000; 385:106–117.

Arch Surg., 1990; 125: 982-985.

2000; 143: 755-760.

primary hyperparathyroidism and double adenoma. J Am Coll Surg. 2003; 197: 739-

exploration under local anesthesia: the approach of choice for asymptomatic

parathyroid hormone monitoring and gamma probe localization in surgery for

preoperative evaluation of primary hyperparathyroidism. AJR, 2007; 188: 1706-

JA. The use of high-resolution ultrasound to locate parathyroid tumors during reoperations for primary hyperparathyroidism. World J. Surg., 1987; 11: 579-585. Krausz Y, Bettman L, Guralnik L, Yosilevsky G, Keidar Z, Bar-Shalom R, Even-Sapir E,

Chisin R, Isreal O. Technetium-99m-MIBI SPECT/CT in primary

American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism: AACE/AAES task force on

for primary hyperparathyroidism: a review of selective approaches. Langenbeck's

Advantages of combined techneticum-99m-sestamibi scintigraphy and highresolution ultrasonography in parathyroid localization: comparative study in 91 patients with primary hyperparathyroidism. European Journal of Endocrinology,

Technetium-99m sestamibi scintigraphy and helical CT together in patients with primary hyperparathyroidism: a prospective clinical study. BJR, 2004; 77: 100-103.


**15**

*1,3Brazil 2USA* 

**Synthetic and Plant Derived**

Suzana T. Cunha Lima1, Travis L. Merrigan2 and Edson D. Rodrigues3

Nuclear receptors (NRs) are transcription factors that regulate gene expression in response to small signaling molecules. The NR family includes receptors for thyroid hormone (TH) (Yen, 2001), retinoids, vitamin D, steroid hormones, fatty acids, bile acids and cholesterol derivatives, a variety of xenobiotics and other ligands. Additionally, other members are called orphans and could either bind to ligands that have not yet been identified or

Since NR play important roles in development and disease, they are important candidates for pharmaceuticals. This family of proteins can be modulated by natural and synthetic ligands and are therefore promising targets for drug discovery. The natural ligands may include different kinds of plant molecules or even a combination of compounds present in

Ligands that target NRs include TH, glucocorticoids, estrogens for hormone replacement therapy (HRT), the diabetes drug thiazolidinedione, synthetic retinoids, and many others. Though the list of possible targets is extensive, it is restricted by the fact that NR ligands have both beneficial and deleterious effects. For instance, TH improves overall lipid balance and promotes weight loss by increasing metabolism, but causes tachycardia that can be severe enough to lead to heart failure, muscle wasting and osteoporosis (Felig & Baxter, 1995; Braverman et al. 2000). Likewise, estrogen use in HRT alleviates symptoms of hot flashes and reverses bone loss, but increases the risk of breast and uterine cancers, and

Thyroid hormone signals are transduced by two related thyroid receptor subtypes, TR α and

stroke (Gustafsson, 1998; McKenna & O´Mally, 2000; McDonnel & Norris, 2002).

TR β (Figure 01.) which are encoded by different genes (Gauthier et al., 1999).

modulate gene expression in a ligand independent fashion (Webb et al., 2002).

**1. Introduction** 

raw extracts of medicinal plants.

**1.1 Compounds that bind NR** 

**1.2 Thyroid hormone receptor (TR) isoforms** 

**Thyroid Hormone Analogs** 

*1Federal University of Bahia 2Community Colleges of Spokane 3Centro Universitário Estácio da Bahia* 

surgical outcome in patients with primary hyperparathyroidism? Surgery, 2002; 132: 1013-1020.


### **Synthetic and Plant Derived Thyroid Hormone Analogs**

Suzana T. Cunha Lima1, Travis L. Merrigan2 and Edson D. Rodrigues3 *1Federal University of Bahia 2Community Colleges of Spokane 3Centro Universitário Estácio da Bahia 1,3Brazil 2USA* 

#### **1. Introduction**

220 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Vignali E, Picone A, Materazzi G, Steffe S, Berti P, Cianferotti L, Ambrogini E, Miccoli P,

consecutive cases. European Journal of Endocrinology, 2002; 146: 783-788. Westra WH, Pritchett DD, Udelsman R. Intraoperative confirmation of parathyroid tissue

Yang GP, Levine S, Weigel RJ. A spike in parathyroid hormone during neck exploration

Yeung GHC, Ng JWT. The technique of endoscopic exploration for parathyroid adenoma of

Zollinger RM, Zollinger RM. Parathyroidectomy. In Zollinger RM, Zollinger RM. Zollinger's

Atlas of Surgical Operations. 8th ed. Colombia: McGraw-Hill; 2003.

The American Journal of Surgical Pathology, 1998; 22: 538-544.

the neck. Aust. N.Z. J. Surg., 1998; 68: 147-150.

132: 1013-1020.

949.

surgical outcome in patients with primary hyperparathyroidism? Surgery, 2002;

Pinchera A, Marcocci A. A quick intraoperative parathyroid hormone assay in the surgical management of patients with primary hyperparathyroidism: a study of 206

during Parathyroid Exploration: A Retrospective Evaluation of the Frozen Section.

may cause a false-negative intraoperative assay result. Arch Surg. 2001; 136: 945-

Nuclear receptors (NRs) are transcription factors that regulate gene expression in response to small signaling molecules. The NR family includes receptors for thyroid hormone (TH) (Yen, 2001), retinoids, vitamin D, steroid hormones, fatty acids, bile acids and cholesterol derivatives, a variety of xenobiotics and other ligands. Additionally, other members are called orphans and could either bind to ligands that have not yet been identified or modulate gene expression in a ligand independent fashion (Webb et al., 2002).

Since NR play important roles in development and disease, they are important candidates for pharmaceuticals. This family of proteins can be modulated by natural and synthetic ligands and are therefore promising targets for drug discovery. The natural ligands may include different kinds of plant molecules or even a combination of compounds present in raw extracts of medicinal plants.

#### **1.1 Compounds that bind NR**

Ligands that target NRs include TH, glucocorticoids, estrogens for hormone replacement therapy (HRT), the diabetes drug thiazolidinedione, synthetic retinoids, and many others. Though the list of possible targets is extensive, it is restricted by the fact that NR ligands have both beneficial and deleterious effects. For instance, TH improves overall lipid balance and promotes weight loss by increasing metabolism, but causes tachycardia that can be severe enough to lead to heart failure, muscle wasting and osteoporosis (Felig & Baxter, 1995; Braverman et al. 2000). Likewise, estrogen use in HRT alleviates symptoms of hot flashes and reverses bone loss, but increases the risk of breast and uterine cancers, and stroke (Gustafsson, 1998; McKenna & O´Mally, 2000; McDonnel & Norris, 2002).

#### **1.2 Thyroid hormone receptor (TR) isoforms**

Thyroid hormone signals are transduced by two related thyroid receptor subtypes, TR α and TR β (Figure 01.) which are encoded by different genes (Gauthier et al., 1999).

Synthetic and Plant Derived Thyroid Hormone Analogs 223

TR antagonists would be useful for short-term relief from the symptoms of hyperthyroidism, and might even be used on a long term basis. The first generation of T3 antagonists, which include DIBRT, HY-4, and GC-14, used the "extension hypothesis" as a general guideline in hormone antagonist design (Baxter et al., 2002; Yashihara et al., 2001; Chiellini et al., 2002). This extension in the ligand structure blocks normal receptor function

**Thyroid hormone receptor antagonist DIBRT**

Although the "extension hypothesis" is applicable to the design of nuclear receptor antagonists, the nature of chemical groups that convert agonist ligands to antagonists will likely depend on specific interactions between residues of the receptor and the ligand extension, to help stabilize the antagonist conformation. Following the first designed TR antagonists it was reported the design and synthesis of a novel series of compounds sharing the GC-1 halogen-free thyronine scaffold (second generation). One of them (NH-3) is a T3 antagonist with improved TR binding affinity and potency that allow for further characterization of its observed activity. One mechanism for antagonism appears to be the ability of NH-3 to block TR-coactivator interactions (Ngoc-Ha et al., 2002). NH-3 (Figure 04.) is the first T3 antagonist to exhibit potent antagonism in vivo and therefore may prove to be a generally useful tool for studying the effects of TR inactivation in a variety of animal models. Until now, such studies have been done primarily using TR-knockout mice because a pharmacological tool for inducing TR inactivation has not been available. TR inactivation was limited under previous ligands because they have only a modest affinity and potency for the thyroid hormone receptor (TR), which limits studies of their actions. T3 antagonists such as NH-3 may be useful therapeutic agents in the treatment of hyperthyroidism and

Although modern research on drug discovery involves the design of hormone analogs based on the structure of the receptor, natural ligands can also be found in nature. Estrogen analogs are most common and have been discovered in a variety of plants. Ginsenosides (Figure 05.)

by occupying the pocket region where the hormone normally binds.

Fig. 3. Chemical structure of thyroid hormone receptor antagonist DIBRT.

**2. TR antagonists** 

**2.1 First generation of synthetic ligands** 

**2.2 Novel series of antagonist compounds** 

other metabolic disorders.

**3.1 Estrogen analogs** 

**3. Plant ligands of nuclear receptors** 

Fig. 1. Chemical structures of thyroid hormones thyroxine (α) and triiodothyronine (β).

Studies of TR isoform-specific knockout mice and patients with resistance to thyroid hormone syndrome suggest that TR α mediates the effects of thyroid hormone on heart rate, whereas analogs that exclusively stimulate TR beta might have desirable effects without causing cardiac distress. Indeed, animal studies using thyroid receptor agonists with modest TR beta selectivity have validated this hypothesis (Taylor et al. 1997; Baxter et al., 2001; Grover et al., 2003). However, structure-based approaches to develop ligands with further improvements in isoform specificity are limited by the fact that the LBDs of TR alfa and TR beta are ~75% identical in amino acid sequence, and that the internal hydrophobic cavities that hold the hormone, called the pocket of the receptor, differ by just one amino acid (Ser-277 in TR alfa versus Asn-331 in TR beta). Therefore, it would be interesting to develop selective TR agonists that increase metabolism and improve lipid balance, but do not cause side effects on the heart. The first compound to show this property was GC-1 (Figure 02), an analog of T3 (Chiellini et al., 2002).

**GC-1**

Fig. 2. Chemical structure of the β-specific thyroid hormone receptor agonist GC1.

#### **2. TR antagonists**

222 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

**Thyroxine Triiodothyronine**

Studies of TR isoform-specific knockout mice and patients with resistance to thyroid hormone syndrome suggest that TR α mediates the effects of thyroid hormone on heart rate, whereas analogs that exclusively stimulate TR beta might have desirable effects without causing cardiac distress. Indeed, animal studies using thyroid receptor agonists with modest TR beta selectivity have validated this hypothesis (Taylor et al. 1997; Baxter et al., 2001; Grover et al., 2003). However, structure-based approaches to develop ligands with further improvements in isoform specificity are limited by the fact that the LBDs of TR alfa and TR beta are ~75% identical in amino acid sequence, and that the internal hydrophobic cavities that hold the hormone, called the pocket of the receptor, differ by just one amino acid (Ser-277 in TR alfa versus Asn-331 in TR beta). Therefore, it would be interesting to develop selective TR agonists that increase metabolism and improve lipid balance, but do not cause side effects on the heart. The first compound to show this property was GC-1 (Figure 02), an

Fig. 1. Chemical structures of thyroid hormones thyroxine (α) and triiodothyronine (β).

**GC-1** Fig. 2. Chemical structure of the β-specific thyroid hormone receptor agonist GC1.

analog of T3 (Chiellini et al., 2002).

#### **2.1 First generation of synthetic ligands**

TR antagonists would be useful for short-term relief from the symptoms of hyperthyroidism, and might even be used on a long term basis. The first generation of T3 antagonists, which include DIBRT, HY-4, and GC-14, used the "extension hypothesis" as a general guideline in hormone antagonist design (Baxter et al., 2002; Yashihara et al., 2001; Chiellini et al., 2002). This extension in the ligand structure blocks normal receptor function by occupying the pocket region where the hormone normally binds.

**Thyroid hormone receptor antagonist DIBRT**

Fig. 3. Chemical structure of thyroid hormone receptor antagonist DIBRT.

#### **2.2 Novel series of antagonist compounds**

Although the "extension hypothesis" is applicable to the design of nuclear receptor antagonists, the nature of chemical groups that convert agonist ligands to antagonists will likely depend on specific interactions between residues of the receptor and the ligand extension, to help stabilize the antagonist conformation. Following the first designed TR antagonists it was reported the design and synthesis of a novel series of compounds sharing the GC-1 halogen-free thyronine scaffold (second generation). One of them (NH-3) is a T3 antagonist with improved TR binding affinity and potency that allow for further characterization of its observed activity. One mechanism for antagonism appears to be the ability of NH-3 to block TR-coactivator interactions (Ngoc-Ha et al., 2002). NH-3 (Figure 04.) is the first T3 antagonist to exhibit potent antagonism in vivo and therefore may prove to be a generally useful tool for studying the effects of TR inactivation in a variety of animal models. Until now, such studies have been done primarily using TR-knockout mice because a pharmacological tool for inducing TR inactivation has not been available. TR inactivation was limited under previous ligands because they have only a modest affinity and potency for the thyroid hormone receptor (TR), which limits studies of their actions. T3 antagonists such as NH-3 may be useful therapeutic agents in the treatment of hyperthyroidism and other metabolic disorders.

#### **3. Plant ligands of nuclear receptors**

#### **3.1 Estrogen analogs**

Although modern research on drug discovery involves the design of hormone analogs based on the structure of the receptor, natural ligands can also be found in nature. Estrogen analogs are most common and have been discovered in a variety of plants. Ginsenosides (Figure 05.)

Synthetic and Plant Derived Thyroid Hormone Analogs 225

Recently, *Tephrosia candida* (native to the tropical foothills of the Himalayas in India and introduced in South America) was reported to contain estrogenically active chemical constituents, which acted by binding to estrogen receptor ERα. Results were interpreted via virtual docking of isolated compounds to an ERα crystal structure (Hegazy et al., 2011). Also sesame ligands, from *Sesamum indicum* (flowering plant, native to Africa and widely naturalized in tropical regions around the world), and their metabolites have been evaluated for estrogenic activities (Pianjing et al., 2011). Two of them, enterodiol (Figure 06.) and enterolactone, have been indicated to have estrogenic/antiestrogenic properties on human

**Enterodiol**

As compared to estrogen analogs, androgen-like compounds in the flora are less frequently referred in scientific literature. But a few chemicals have shown androgen-like activity. Andrographolide (Figure 07.), an herbal medicine, inhibits interleukin-6 expression and suppresses prostate cancer cell growth (Chun et al., 2010). According to the author, this phytochemical could be developed as a therapeutic agent to treat both androgen-stimulated and castration-resistant prostate cancer. Another compound, Isoangustone A, present in hexane/ethanol extract of *Glycyrrhiza uralensis*, induces apoptosis in DU145 human prostate cancer (Seon et al., 2010). This species, also known as Chinese liquorice, is a flowering plant

Some studies have specifically demonstrated that consuming one or more portions of broccoli per week can reduce the incidence of prostate cancer, and also induce the progression from localized to aggressive forms of prostate cancer (Trakka, et al. 2008). The reduction in risk may be modulated by glutathione S-transferase mu 1 (GSTM1) genotype, with individuals who possess at least one GSTM1 allele (i.e. approximately 50% of the population) gaining more benefit than those who have a homozygous deletion of GSTM1,

breast cancer cells.

Fig. 6. Chemical structure of an enterodiol

**3.2.1 Androgen ligands in the diet** 

according to the author.

native to Asia, which is used in traditional Chinese medicine.

**3.2 Androgen analogs** 

for instance, found in *Ginko biloba*, have demonstrated pharmacological effects on the central nervous, cardiovascular, and endocrine systems. Although no direct interaction of the compound with estrogen receptor seems to be necessary for estrogenic action, the author classified this plant ligand as a novel class of potent phytoestrogen (Chan et al., 2002).

Fig. 4. Chemical structure of the thyroid hormone receptor antagonist NH-3 (Lim et al. 2002), designed by the extension hypothesis from GC-1 compound.

Fig. 5. Chemical structure of a ginsenoside.

for instance, found in *Ginko biloba*, have demonstrated pharmacological effects on the central nervous, cardiovascular, and endocrine systems. Although no direct interaction of the compound with estrogen receptor seems to be necessary for estrogenic action, the author

classified this plant ligand as a novel class of potent phytoestrogen (Chan et al., 2002).

**NH-3** Fig. 4. Chemical structure of the thyroid hormone receptor antagonist NH-3 (Lim et al.

**Ginsenoside**

Fig. 5. Chemical structure of a ginsenoside.

2002), designed by the extension hypothesis from GC-1 compound.

Recently, *Tephrosia candida* (native to the tropical foothills of the Himalayas in India and introduced in South America) was reported to contain estrogenically active chemical constituents, which acted by binding to estrogen receptor ERα. Results were interpreted via virtual docking of isolated compounds to an ERα crystal structure (Hegazy et al., 2011). Also sesame ligands, from *Sesamum indicum* (flowering plant, native to Africa and widely naturalized in tropical regions around the world), and their metabolites have been evaluated for estrogenic activities (Pianjing et al., 2011). Two of them, enterodiol (Figure 06.) and enterolactone, have been indicated to have estrogenic/antiestrogenic properties on human breast cancer cells.

#### **Enterodiol**

Fig. 6. Chemical structure of an enterodiol

#### **3.2 Androgen analogs**

As compared to estrogen analogs, androgen-like compounds in the flora are less frequently referred in scientific literature. But a few chemicals have shown androgen-like activity. Andrographolide (Figure 07.), an herbal medicine, inhibits interleukin-6 expression and suppresses prostate cancer cell growth (Chun et al., 2010). According to the author, this phytochemical could be developed as a therapeutic agent to treat both androgen-stimulated and castration-resistant prostate cancer. Another compound, Isoangustone A, present in hexane/ethanol extract of *Glycyrrhiza uralensis*, induces apoptosis in DU145 human prostate cancer (Seon et al., 2010). This species, also known as Chinese liquorice, is a flowering plant native to Asia, which is used in traditional Chinese medicine.

#### **3.2.1 Androgen ligands in the diet**

Some studies have specifically demonstrated that consuming one or more portions of broccoli per week can reduce the incidence of prostate cancer, and also induce the progression from localized to aggressive forms of prostate cancer (Trakka, et al. 2008). The reduction in risk may be modulated by glutathione S-transferase mu 1 (GSTM1) genotype, with individuals who possess at least one GSTM1 allele (i.e. approximately 50% of the population) gaining more benefit than those who have a homozygous deletion of GSTM1, according to the author.

Synthetic and Plant Derived Thyroid Hormone Analogs 227

compounds that may be associated with this effect are, according to the author, isoflavones, lignans and 2-hydroxyestrogens. Although anti-carcinogenic response was linked to those molecules, it was not explained how they may affect metabolism in humans or their physiological mechanism of action. Another compound, indole-3 carbinol, the most studied component of cruciferous vegetables, has been demonstrated to have chemopreventive activity in several different animal models of carcinogenesis, including mammary gland, but in another hand, the same compound has also been reported to exhibit adverse promoting effects, including liver and thyroid gland

**Genistein**

It seems to have a cross talk between the thyroid hormone receptor and the estrogen receptor. Our recent results (Cunha Lima et al, not published) have shown that ligands originally referred for thyroid diseases have activated estrogen receptor in transient transfection assays. This could explain why phytoestrogens have caused responses in thyroid cancer and thyroid hormone analogs have also effect in breast cancer, for

Considering medications used for thyroid hormone replacement, as sodic levothyroxine, aT4 analog, the side effects referred (Cunha Lima , 2008) may include headache, chest pain, rapid or irregular heartbeat, shortness of breath, trembling, sweating, diarrhea and weight loss. The most severe responses are those related to the heart, which can lead to serious cardiopathies and are due to the α isoform of the receptor, as cited previously. A single base difference in the pocket of the protein can lead to these harmful responses. This means that we have a two step work on the search for new agonists and antagonists: they should mimesis the response caused by the thyroid hormone (or antagonize it, depending on the disease) and second, they should have a β specificity to avoid

In the other hand, some compounds that modulate TR may not be specific for this receptor, as it is very common with estrogen ligands. Since women hormone analogs may interfere with the function of the thyroid, as referred before with some flavonoids, they may have beneficial effects in cases of thyroid cancer. Nevertheless those compounds may influence thyroid actions at the cellular level and could cause side effects harmful for

tumorigenesis (Murilo & Mehta, 2001).

Fig. 8. Chemical structure of a Genistein.

**3.4 Toxicity of thyroid hormone analogs** 

tachycardia and more serious heart problems.

example.

healthy individuals.

**Andrographolide**

Fig. 7. Chemical structure of an andrographolide.

From these studies, we can conclude that diet has a significant influence on the activity of the androgen receptors and possibly other types of nuclear receptor. If so, a wide range of diseases may be avoided by increasing intake of food that contains hormone analogs or other nuclear receptor modulators.

#### **3.3 Plant thyroid hormone analogs**

Concerning the thyroid hormone receptor, we find even fewer studies about thyroid hormone (T3 and T4) analogs in plants. In a work about patients where thyroid have been removed partially or totally due to thyroid cancer, the plant *R. rosea* was seen as a viable alternative treatment for the symptoms of short-term hypothyroidism in patients who require hormone withdrawal (Zubeldia et al., 2010). Some compounds of natural origin have also shown to affect the thyroid hormone feedback system by interfering with different components of this homeostatically regulated system: biosynthesis, secretion and metabolism, transport, distribution, and action of thyroid hormones, including the feedback mechanism.

Genistein (Figure 07.) and daidzein, the major components of soy, influence thyroid hormone synthesis by inhibition of the iodide oxidizing enzyme thyroperoxidase. This interferes with thyroid hormone transport proteins and 5′-deiodinase type I activities in peripheral tissues, leading to altered thyroid hormone action at the cellular level. Synthetic flavonoids, such as F21388, which is structurally similar to thyroxine, cross the placenta and also reach the fetal brain of animal models (Hamann et al. 2008).

The cruciferous family was also referred when we consider thyroid modulators in plant. In a study that examined the effects of both soy-foods and specific phytoestrogenic molecules on the development of thyroid cancer in humans it was demonstrated that intake of plants from that family decreases the risk of this kind of cancer (Horn-Ross et al., 2002). The

**Andrographolide**

From these studies, we can conclude that diet has a significant influence on the activity of the androgen receptors and possibly other types of nuclear receptor. If so, a wide range of diseases may be avoided by increasing intake of food that contains hormone analogs or

Concerning the thyroid hormone receptor, we find even fewer studies about thyroid hormone (T3 and T4) analogs in plants. In a work about patients where thyroid have been removed partially or totally due to thyroid cancer, the plant *R. rosea* was seen as a viable alternative treatment for the symptoms of short-term hypothyroidism in patients who require hormone withdrawal (Zubeldia et al., 2010). Some compounds of natural origin have also shown to affect the thyroid hormone feedback system by interfering with different components of this homeostatically regulated system: biosynthesis, secretion and metabolism, transport, distribution, and action of thyroid hormones, including the

Genistein (Figure 07.) and daidzein, the major components of soy, influence thyroid hormone synthesis by inhibition of the iodide oxidizing enzyme thyroperoxidase. This interferes with thyroid hormone transport proteins and 5′-deiodinase type I activities in peripheral tissues, leading to altered thyroid hormone action at the cellular level. Synthetic flavonoids, such as F21388, which is structurally similar to thyroxine, cross the placenta and

The cruciferous family was also referred when we consider thyroid modulators in plant. In a study that examined the effects of both soy-foods and specific phytoestrogenic molecules on the development of thyroid cancer in humans it was demonstrated that intake of plants from that family decreases the risk of this kind of cancer (Horn-Ross et al., 2002). The

also reach the fetal brain of animal models (Hamann et al. 2008).

Fig. 7. Chemical structure of an andrographolide.

other nuclear receptor modulators.

**3.3 Plant thyroid hormone analogs** 

feedback mechanism.

compounds that may be associated with this effect are, according to the author, isoflavones, lignans and 2-hydroxyestrogens. Although anti-carcinogenic response was linked to those molecules, it was not explained how they may affect metabolism in humans or their physiological mechanism of action. Another compound, indole-3 carbinol, the most studied component of cruciferous vegetables, has been demonstrated to have chemopreventive activity in several different animal models of carcinogenesis, including mammary gland, but in another hand, the same compound has also been reported to exhibit adverse promoting effects, including liver and thyroid gland tumorigenesis (Murilo & Mehta, 2001).

**Genistein**

Fig. 8. Chemical structure of a Genistein.

It seems to have a cross talk between the thyroid hormone receptor and the estrogen receptor. Our recent results (Cunha Lima et al, not published) have shown that ligands originally referred for thyroid diseases have activated estrogen receptor in transient transfection assays. This could explain why phytoestrogens have caused responses in thyroid cancer and thyroid hormone analogs have also effect in breast cancer, for example.

#### **3.4 Toxicity of thyroid hormone analogs**

Considering medications used for thyroid hormone replacement, as sodic levothyroxine, aT4 analog, the side effects referred (Cunha Lima , 2008) may include headache, chest pain, rapid or irregular heartbeat, shortness of breath, trembling, sweating, diarrhea and weight loss. The most severe responses are those related to the heart, which can lead to serious cardiopathies and are due to the α isoform of the receptor, as cited previously. A single base difference in the pocket of the protein can lead to these harmful responses. This means that we have a two step work on the search for new agonists and antagonists: they should mimesis the response caused by the thyroid hormone (or antagonize it, depending on the disease) and second, they should have a β specificity to avoid tachycardia and more serious heart problems.

In the other hand, some compounds that modulate TR may not be specific for this receptor, as it is very common with estrogen ligands. Since women hormone analogs may interfere with the function of the thyroid, as referred before with some flavonoids, they may have beneficial effects in cases of thyroid cancer. Nevertheless those compounds may influence thyroid actions at the cellular level and could cause side effects harmful for healthy individuals.

Synthetic and Plant Derived Thyroid Hormone Analogs 229

of DM2. Ahmed et al. (2005) demonstrated that the extract from this plant also has

Among the plants used for obesity control, with probable effect on the metabolism, *Borreria verticillata* (carqueija or vassorinha-de-botão) was the species with the highest number of references in our survey. This plant, also used for the treatment of diabetes type 2, is found across Brazil. Phytochemical studies have demonstrated the presence of alcaloids and iridoids (Vieira et al., 1999) associated with their antipyretic and analgesic properties, although no active principle linked to obesity was confirmed. The leaves of *Bauhinia forficata*, *Costus spiralis* and *Theobroma cacao*, were used as teas in combination with the commercial medical prescriptions sibutramine (an oral anorexiant used for weight control) and niphedipine (a dihydropyridine calcium channel blocker used for high blood pressure) indicated by the physicians from the Diabetes Ambulatory of the Federal University of Bahia Hospital (HUPES). The teas of *Tragia volubilis* leaves and the seeds of *Ocimum* 

The problems related to the thyroid attended at the Hospital of Federal University of Bahia include throat itch, tachycardia, arm pain, chokings, dizziness and fainting. The most extreme side effects symptoms are associated with the T4 hormone replacement for patients whose thyroid was partially or completely removed. The doses used vary from 50 to 200mcg/day of sodic levotiroxine. In addition to the plants cited for treatment of thyroid problems, watercress (*Nasturtium officinale* R.Br.) and spring-green (*Brassica oleraceae* L.) were eaten as iodine source. Although the majority of the patients did not tell their doctors they were using those teas, there are no reported adverse side effects due to the combination of the plant products and the medications indicated, nor any reference in the literature about

Ethnobotanical surveys are good source of information for drug candidates and offer a less expensive way of finding hormone analogs than the design of synthetic compounds. The cited information represents an important source of regional knowledge on plants with pharmacological potential and presents 31 candidates (Table 1) that might contain triiodothyronine (T3) and thyroxin (T4) analogs, including agonists, antagonists and other compounds able to modulate thyroid receptor that may act against metabolic disorders.

Brazil has more than 55.000 species of cataloged plants (Simões & Schenkel, 2002), a significant portion of which has some phytotherapic activity known by the local population. However, the number of patents on plant-based pharmaceuticals is very small. In particular, the capital of Bahia has numerous plants used by inhabitants to treat diseases and this use is part of the local culture, based in the Candomblé (religion of African origin which uses many plants in rituals and treatments). Traditionally, information about medicinal plants is shared orally. Therefore, it is necessary to scientifically systematize and analyze this phytotherapic knowledge so that those species can be identified and their pharmacological

Table 2 lists the species referred in this survey that had their active principles identified and/or properties confirmed, and the bibliographic references where the data was obtained. These works include results from clinical and experimental studies aiming the confirmation

hypoglycemic activity and improves general clinical conditions.

*gratissimum* were also used in combination with niphedipine and aspirin.

harmful effect of such interaction.

properties tested.

of therapeutic properties.

#### **3.5 Ethnobotanical search for TR plant ligands**

Since thyroid hormone analogs have much fewer discovered natural ligands, and most of those nuclear receptor ligands are found from plant sources, ethnobotanical surveys can be a good strategy to discover hormone analogs in nature. This approach has an increased probability of success in locations with higher biodiversity; because they contain a privileged number of candidate species. Along with botanical diversity, ethnobotanical surveys are likely to succeed where the population has an in depth knowledge of medicinal plants and systematically uses those plants to treat a range of metabolic disorders.

In a recent work (Cunha Lima et al., 2008) we investigated the medicinal flora used for the treatment of metabolic disorders in Salvador, Bahia, in Northeastern Brazil. The city has hot, tropical weather, with average daily highs reaching 170C in the winter and 380C in the summer. Northeastern Brazil is the economically poorest region of the country, 60% of the active population has an income under \$100 per month, (Brazilian Institute of Statistics and Geography, 2003) and many residents depend on medicinal plants to treat multiple ailments and diseases.

The referred study analyzed the knowledge of the urban population of Bahia city on the use of potentially therapeutic plants for the treatment of Diabetes mellitus type 2 (DM2), thyroid diseases, obesity and cardiopathies. Questionnaires were applied to traditional healers as well as to patients of the thyroid disease and diabetes ambulatory in the Hospital from Federal University of Bahia (UFBA). Thirty-one cited species were collected, taxonomically classified, and stored in Alexandre Leal Costa Herbarium (ALCB) from UFBA. Leaves were most commonly used in preparations (87%), followed by the whole plant (10%), and fruits and seeds (3%). The majority of the preparation (88%) required decoction (boiling the plant tea for at least 5 minutes); the rest includes infusion (liquid preparation without boiling) and ingestion of the fresh plant. Among the plant parts used the leaves were more frequent (87%), followed by the whole plant (10%), seeds and fruits (3%). The families Asteraceae (17%), Lamiaceae (15%) and Myrtaceae (12%) were the most cited among plants referred.

This survey identified botanical families frequently cited in other surveys of medicinal plant use in Brazil. In two studies conducted in the state of Rio de Janeiro, one in Rio city (Azevedo & Silva) and one in the reservation of Mangaratiba (Medeiros et al., 2005), the Asteraceae and Lamiaceae family of plants were the most frequently cited, the same happening in Conceição Açú-MT (Pasa et al., 2005). Species from the Asteraceae family were also the most frequently noted for medicinal use in a survey done in Ingaí-MG (Botrel et al., 2006) and by a "quilombola"(community of people descended from former Brazilian slaves), among the plants with possible action in the central nervous system (Rodrigues & Carlini, 2004). These data suggest that the Asteraceae and Lamiaceae family have excellent pharmacological potential on different kinds of diseases and they are currently being investigate in many clinical studies.

In the survey performed by our group in Salvador (Cunha Lima, 2008), the plant most used for the treatment of DM2 belongs to the genus Bauhinia (pata-de-vaca). The most commonly cited species in this work, *B. forficate*, has the flavonoid Kaempferitrina, Kaempferol-3-O-α-Diraminoside and the steroid Sitosterol as the hypoglycemic active principle (da Silva & Cechinel Filho, 2002). *Terminalia catappa* was the second most cited species for the treatment

Since thyroid hormone analogs have much fewer discovered natural ligands, and most of those nuclear receptor ligands are found from plant sources, ethnobotanical surveys can be a good strategy to discover hormone analogs in nature. This approach has an increased probability of success in locations with higher biodiversity; because they contain a privileged number of candidate species. Along with botanical diversity, ethnobotanical surveys are likely to succeed where the population has an in depth knowledge of medicinal

In a recent work (Cunha Lima et al., 2008) we investigated the medicinal flora used for the treatment of metabolic disorders in Salvador, Bahia, in Northeastern Brazil. The city has hot, tropical weather, with average daily highs reaching 170C in the winter and 380C in the summer. Northeastern Brazil is the economically poorest region of the country, 60% of the active population has an income under \$100 per month, (Brazilian Institute of Statistics and Geography, 2003) and many residents depend on medicinal plants to treat multiple

The referred study analyzed the knowledge of the urban population of Bahia city on the use of potentially therapeutic plants for the treatment of Diabetes mellitus type 2 (DM2), thyroid diseases, obesity and cardiopathies. Questionnaires were applied to traditional healers as well as to patients of the thyroid disease and diabetes ambulatory in the Hospital from Federal University of Bahia (UFBA). Thirty-one cited species were collected, taxonomically classified, and stored in Alexandre Leal Costa Herbarium (ALCB) from UFBA. Leaves were most commonly used in preparations (87%), followed by the whole plant (10%), and fruits and seeds (3%). The majority of the preparation (88%) required decoction (boiling the plant tea for at least 5 minutes); the rest includes infusion (liquid preparation without boiling) and ingestion of the fresh plant. Among the plant parts used the leaves were more frequent (87%), followed by the whole plant (10%), seeds and fruits (3%). The families Asteraceae (17%), Lamiaceae (15%) and Myrtaceae (12%)

This survey identified botanical families frequently cited in other surveys of medicinal plant use in Brazil. In two studies conducted in the state of Rio de Janeiro, one in Rio city (Azevedo & Silva) and one in the reservation of Mangaratiba (Medeiros et al., 2005), the Asteraceae and Lamiaceae family of plants were the most frequently cited, the same happening in Conceição Açú-MT (Pasa et al., 2005). Species from the Asteraceae family were also the most frequently noted for medicinal use in a survey done in Ingaí-MG (Botrel et al., 2006) and by a "quilombola"(community of people descended from former Brazilian slaves), among the plants with possible action in the central nervous system (Rodrigues & Carlini, 2004). These data suggest that the Asteraceae and Lamiaceae family have excellent pharmacological potential on different kinds of diseases and they are currently being

In the survey performed by our group in Salvador (Cunha Lima, 2008), the plant most used for the treatment of DM2 belongs to the genus Bauhinia (pata-de-vaca). The most commonly cited species in this work, *B. forficate*, has the flavonoid Kaempferitrina, Kaempferol-3-O-α-Diraminoside and the steroid Sitosterol as the hypoglycemic active principle (da Silva & Cechinel Filho, 2002). *Terminalia catappa* was the second most cited species for the treatment

plants and systematically uses those plants to treat a range of metabolic disorders.

**3.5 Ethnobotanical search for TR plant ligands** 

ailments and diseases.

were the most cited among plants referred.

investigate in many clinical studies.

of DM2. Ahmed et al. (2005) demonstrated that the extract from this plant also has hypoglycemic activity and improves general clinical conditions.

Among the plants used for obesity control, with probable effect on the metabolism, *Borreria verticillata* (carqueija or vassorinha-de-botão) was the species with the highest number of references in our survey. This plant, also used for the treatment of diabetes type 2, is found across Brazil. Phytochemical studies have demonstrated the presence of alcaloids and iridoids (Vieira et al., 1999) associated with their antipyretic and analgesic properties, although no active principle linked to obesity was confirmed. The leaves of *Bauhinia forficata*, *Costus spiralis* and *Theobroma cacao*, were used as teas in combination with the commercial medical prescriptions sibutramine (an oral anorexiant used for weight control) and niphedipine (a dihydropyridine calcium channel blocker used for high blood pressure) indicated by the physicians from the Diabetes Ambulatory of the Federal University of Bahia Hospital (HUPES). The teas of *Tragia volubilis* leaves and the seeds of *Ocimum gratissimum* were also used in combination with niphedipine and aspirin.

The problems related to the thyroid attended at the Hospital of Federal University of Bahia include throat itch, tachycardia, arm pain, chokings, dizziness and fainting. The most extreme side effects symptoms are associated with the T4 hormone replacement for patients whose thyroid was partially or completely removed. The doses used vary from 50 to 200mcg/day of sodic levotiroxine. In addition to the plants cited for treatment of thyroid problems, watercress (*Nasturtium officinale* R.Br.) and spring-green (*Brassica oleraceae* L.) were eaten as iodine source. Although the majority of the patients did not tell their doctors they were using those teas, there are no reported adverse side effects due to the combination of the plant products and the medications indicated, nor any reference in the literature about harmful effect of such interaction.

Ethnobotanical surveys are good source of information for drug candidates and offer a less expensive way of finding hormone analogs than the design of synthetic compounds. The cited information represents an important source of regional knowledge on plants with pharmacological potential and presents 31 candidates (Table 1) that might contain triiodothyronine (T3) and thyroxin (T4) analogs, including agonists, antagonists and other compounds able to modulate thyroid receptor that may act against metabolic disorders.

Brazil has more than 55.000 species of cataloged plants (Simões & Schenkel, 2002), a significant portion of which has some phytotherapic activity known by the local population. However, the number of patents on plant-based pharmaceuticals is very small. In particular, the capital of Bahia has numerous plants used by inhabitants to treat diseases and this use is part of the local culture, based in the Candomblé (religion of African origin which uses many plants in rituals and treatments). Traditionally, information about medicinal plants is shared orally. Therefore, it is necessary to scientifically systematize and analyze this phytotherapic knowledge so that those species can be identified and their pharmacological properties tested.

Table 2 lists the species referred in this survey that had their active principles identified and/or properties confirmed, and the bibliographic references where the data was obtained. These works include results from clinical and experimental studies aiming the confirmation of therapeutic properties.

Synthetic and Plant Derived Thyroid Hormone Analogs 231

**Species Properties associated to the referred use Reference** 

da Silva & Cechinel

Ahmed et al (2005)

Filho (2002)

Nagappa et al

Ibanez et al (2000)

Prakash et al (2007); Negrelle (2007)

Parry (1986); Sundararajan et al

Ren et al (2003)

Carvalho (2005)

Bialy et al (2005)

(2004)

(1991)

Mentreddy (2007); Teixeira et al (2004); Schossler et al

Colker et al (1999)

Mendonça et al

Gazola et al (2004)

(2006)

(2003)

The flavonoids Kaempferitrin and Kaempferol-3- *O*--Diraminoside and the steroid Sitosterol found in the extract own hypoglycemic properties.

Leaf extract prepared in different ways produced antidiabetic response with 1/5 of the lethal dose revealed by the lipid, creatine and urea profile as also serum alkaline phosphatase. The same dose caused anti-diabetic effects with fruit extracts.

The anti-oxidants impair the mechanism of oxidation that occurs in cancer, heart disease ,

Intense anti-oxidant activity due to the phenolic composition. The essential oil extracted from the leaf causes depression of the CNS in rats.

Deposits of opaline silica in the leaves and extracts of the whole plant obtained with n- hexane demonstrated significant anti-cancer activity.

Flavonoids found in this plant are active against different kinds of cancer including thyroid

Graviola, a Brazilian fruit from the plant *Annona muricata* demonstrated anti-diabetic effect greater

The plant has kinase protein inhibitors that act creating obesity resistance and increasing insulin

The species presents anti-diabetic action in clinical and animal studies. Stem extracts stimulate the development of cells positive for insulin in the

The combination of *C. aurantium* extract, caffeine and Saint John´s Herb (*Hypericum perforatum)* is

dependent decrease in artery pressure in rats and

The aqueous extract of leaves from this plant, associated to the ones from *Melissa officinalis* and *Cymbopogon citratus* caused significant reduction in cardiac rhythm in rats, without changing the

safe and effective for weight lost and improvement of lipid levels in obese adults.

The hidroalcoolic extract induces a dose-

than the medication Clorpropamide, oral hypoglycemic from the sulphonilurea class.

atherosclerosis and aging.

cancers.

production.

dogs.

pancreatic epithelial duct.

contractile strength.

*Bauhinia forficata*

*Terminalia catappa*

*Rosmarinus officinalis* 

*Cymbopogon citratus* 

*Bidens pilosa* 

*Lippia alba* 

*Annona muricata* 

*Annona montana* 

*Syzygium cumini* 

*Citrus aurantium* 

*Alpinia nutans* 

*Lippia alba* 


Table 1. Medicinal plants candidates for thyroid hormone analogs according to ethnobotanical research in Salvador-Bahia, Brazil (Cunha Lima, 2008).

**Vernacular Name ALCB Family Species** 

1. aroeira 76103 Anacardiaceae *Schinus terebinthifolius* Raddi

2. graviola 76101 Annonaceae *Annona muricata* L. 3. jaca-de-pobre 76154 Annonaceae *Annona montana* Macfad 4. carrapixo-de-agulha 76135 Asteraceae *Bidens bipinnata* L. 5. carrapixo-preto 76111 Asteraceae *Bidens pilosa* L. 6. chapéu-de-couro 76138 Asteraceae *Zinnia elegans* Jacq. 7. urucum 76100 Bixaceae *Bixa orellana* L. 8. cactus 78152 Cactaceae *Cereus sp.* L.

9. pata-de-vaca 76159 Caesalpiniaceae *Bauhinia forficata* Link 10. amendoeira 76096 Combretaceae *Terminalia catappa* L.

14. alecrim ou alecrim-do-

23. capim- cidreira ou capim-

25. carqueija ou vassourinha-

11. cana-de-macaco 76122 Costaceae *Costus spiralis* (Jacq,) Roscoe 12. mamona 76141 Euphorbiaceae *Ricinus communis* (L.) Müll. Arg. 13. urtiga 76108 Euphorbiaceae *Tragia volubilis* (L.) Müll. Arg.

reino 76128 Lamiaceae *Rosmarinus officinalis* L.

16. quiôiô 76112 Lamiaceae *Ocimum gratissimum* L.

19. Murici 78150 Malpighiaceae *Byrsonima sericea* DC.

22. pitangueira 76163 Myrtaceae *Eugenia uniflora* L.

24. roma 76162 Punicaceae *Punica granatum* L.

26. laranjeira 76097 Rutaceae *Citrus aurantium* L. 27. vassourinha 76114 Scrophulariacea *Scoparia dulcis* L. 28. cacau 78148 Sterculiaceae *Theobroma cacao* L. 29. erva cidreira 76105 Verbenaceae *Lippia alba* N.E.Brown

31. levante 76123 Zingiberaceae *Alpinia nutans* Roscoe Table 1. Medicinal plants candidates for thyroid hormone analogs according to

30. melissa 76120 Verbenaceae *Lippia alba* L..

ethnobotanical research in Salvador-Bahia, Brazil (Cunha Lima, 2008).

15. hortelã-grosso 76110 Lamiaceae *Plectranthus amboinicus* (Lour.)

17. canela 76099 Lauraceae *Cinnamomum zeylanicum* Breyn 18. erva-de-passarinho 76107 Loranthaceae *Struthanthus flexicaulis* Mart.

20. barbatimão 76158 Leguminosae *Abarema cochliocarpum* (Gomez)

21. jamelão 76156 Myrtaceae *Syzygium cumini* (L.) Skeels

santo 75150 Poaceae *Cymbopogon citratus* Stapf.

de-botão 76132 Rubiaceae *Borreria verticillata* (l.) G.Mey

Spreng

Barnbey


Synthetic and Plant Derived Thyroid Hormone Analogs 233

molecules in the flora that can modulate TR and may be used in the treatment of diseases

Ahmed, S.M., Vrushabendra, B.M., Dhanapal, P.G. & Chandrashekara, V.M. (2005). Anti-

Azevedo, S.K.S. & Silva, I.M. (2006). Plantas medicinais e de uso religioso comercializadas

Baxter, J. D., Dillmann, W. H., West, B. L., Huber, R., Furlow, J. D., Fletterick, R. J., Webb, P.,

Baxter, J.D., Goede, P., Apriletti, J.W., West, B.L. & Feng, W. (2002). Structure-Based Design

Botrel, R. T., Rodrigues, L. A., Gomes, L. J., Carvalho, D.A., & Fontes, M.A.L. (2006). Uso da

Bialy, L., Waldmann, H., Chemie, A. (2005). Review. Inhibitors of protein tyrosine

Braverman, E., Utiger, R.D. (2000). *Ingbar, S.H. & Werner, S.C. The Thyroid: A Fundamental and* 

Carvalho, A.C.B., Diniz, M.F.F.M., Mukherjee, R. (2005). Hypoglycemic activity studies of

Chan, R.Y., Chen , W.F., Dong, A., Guo, D. & Wong, M.S. (2002). Estrogen-like activity of

*Endocrinology & Metabolism,* Vol. 87, No. 8, pp. 3691-3695. ISSN: 1945-7197. Chiellini, G., Nguyen, N. H., Apriletti, J.W., Baxter, J.D. & Scanlan, T.S. (2002). Synthesis and

Chiellini, G., Nguyen, N., Apriletti, J. W., Baxter, J.D., Scanlan, T. S., Laudet V. &

Chun , J.Y. , Tummala , R., Nadiminty, N., Lou, W., Liu, C., Yang, J., Evans, C.P., Zhou, Q. &

Colker, C.M., Kalman, D.S., Torina, G.C., Perlis, T., Street, C. (1999). Effects of *Citrus* 

*Botanica Brasílica*, Vol. 20, No. 1, pp. 143-156. ISSN: 0102-3306.

*Brasileira de Farmácia,* Vol. 86, No. 1, pp.11-16. ISSN: 2176-0667.

Diabetic activity of *Terminalia catappa* Linn. Leaf extracts in alloxan-induced diabetic rats. *Iranian Journal of Pharmacology & Therapeutics*, Vol. 4, No. 1, pp. 36-39.

em mercados e feiras livres no Rio de Janeiro, RJ, Brasil. *Acta Botanica Brasílica*, Vol.

Apriletti, J. W. & Scanlan, T. S. (2001). Selective modulation of thyroid hormone receptor action. *Journal of Steroid Biochemistry and Molecular Biology,* Vol. 76, No.1-5,

and Synthesis of a Thyroid Hormone Receptor (TR) Antagonist. *Endocrinology*, Vol.

vegetação nativa pela população local no município de Ingaí, MG, Brasil. *Acta* 

phosphatases: Next-generation drugs? *Angewandte Chemie International Edition*, Vol.

*Clinical Text* (9th Edition), Lippincott Williams & Wilkins, Philadelphia. ISBN-10:

some plants used in diabetes treatment in Brazilian traditional medicine. *Revista* 

ginsenoside Rg1 derived from *Panax notoginseng*. *The Journal of Clinical* 

biological activity of novel thyroid hormone analogues: 5'-aryl substituted GC-1 derivatives. *Bioorganic & Medicinal Chemistry Letters,* Vol. 10, No. 2, pp. 333-346.

Gronemeyer, H. (2002). *The Nuclear Receptor Facts Book. Factsbook Series*, 1st ed.,

Gao, A.C. (2010). Andrographolide, an herbal medicine, inhibits interleukin-6 expression and suppresses prostate cancer cell growth. *Genes Cancer*. Vol. 1, No. 8,

*aurantium* extract, caffeine, and St. John's Wort on body fat loss, lipid levels, and

related to thyroid malfunction.

ISSN: 1735-2657.

0781750474.

ISSN: 0960-894X.

pp. 868-876. ISSN: 1947-6019.

20, No. 1, pp.185-194. ISSN 0102-3306.

143, No. 2, pp. 517-524. ISSN: 1945-7170.

44, No. 25, pp. 3814-3839. ISSN: 1521-3773.

Academic Press, London. ISBN 10: 0124377356.

pp. 31–42. ISSN: 0960-0760.

**5. References** 


Table 2. Plant species referred in the survey that have their therapeutic properties confirmed or active principles isolated according to scientific publications.

#### **4. Conclusion**

Studying medicinal plants can be a less expensive way of finding treatments for hundreds of diseases. This can be an important factor in areas where a great part of the population lacks financial conditions of buying allopathic medication and, in the other hand, have a big incidence of metabolic disorders.

The search for hormone analogs in medicinal plants is extremely promising. Over 100 existing nuclear receptors have been identified, not counting the orphan NRs that lack known ligands. Since those transcription factors modulate almost all genetic activity and human physiology, they are important targets for drug discovery. Besides the ligands, usually hormones, other molecules can also modulate nuclear receptors, including cofactors (co-activators and co-repressors), responsive elements, and other ligands (not exclusively the hormone that naturally binds this receptor). According to that, the molecules found in plants do not have to be only analogs of hormones, but also compounds similar to all other complementary modulators of NRs.

Countries with higher biodiversity are good targets for discovery of plant molecules that can control the activity of thyroid receptor. Unfortunately there is not enough scientific knowledge about their medicinal plants or about patent procedures that would guarantee intellectual property of discoveries made by local scientists. In addition to that, the forests are being devastated very fast before important plant compounds can be found. Therefore, additional research needs to be done to identify new ligands and other molecules in the flora that can modulate TR and may be used in the treatment of diseases related to thyroid malfunction.

#### **5. References**

232 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

**Species Properties associated to the referred use Reference** 

Pepato et al (2002); da Silva & Cechinel

Filho (2002)

Consolini et al

Sudheesh (2005)

Latha & Pari (2004)

(1999)

The rats treated with decoction of the plant leaves demonstrated significant reduction in serum and urine glucose. The results obtained with the purified extracts confirmed the therapeutic use for

treatment of diabetes in clinical studies.

increased renal blood flow.

significant increase.

oxygen radicals in rats.

or active principles isolated according to scientific publications.

The empiric use of this plant is due to the hypotensive effect, mediated by vessel dilatation and weak diuretic effect that may be related to

Flavonoid rich fractions obtained from fruit extracts demonstrated antiperoxidative effect. Malondialdehyde, hydroperoxide, and conjugated dienes were significantly decreased in the liver, while enzymatic activity of catalase, superoxide dismutase and glutathione reductase have shown

Plant extracts were effective on decreasing hyperglycemia and the susceptibility to free

Table 2. Plant species referred in the survey that have their therapeutic properties confirmed

Studying medicinal plants can be a less expensive way of finding treatments for hundreds of diseases. This can be an important factor in areas where a great part of the population lacks financial conditions of buying allopathic medication and, in the other hand, have a big

The search for hormone analogs in medicinal plants is extremely promising. Over 100 existing nuclear receptors have been identified, not counting the orphan NRs that lack known ligands. Since those transcription factors modulate almost all genetic activity and human physiology, they are important targets for drug discovery. Besides the ligands, usually hormones, other molecules can also modulate nuclear receptors, including cofactors (co-activators and co-repressors), responsive elements, and other ligands (not exclusively the hormone that naturally binds this receptor). According to that, the molecules found in plants do not have to be only analogs of hormones, but also compounds similar to all other

Countries with higher biodiversity are good targets for discovery of plant molecules that can control the activity of thyroid receptor. Unfortunately there is not enough scientific knowledge about their medicinal plants or about patent procedures that would guarantee intellectual property of discoveries made by local scientists. In addition to that, the forests are being devastated very fast before important plant compounds can be found. Therefore, additional research needs to be done to identify new ligands and other

*Bauhinia forficata* 

*Eugenia uniflora* 

*Punica granatum* 

*Scoparia dulcis* 

**4. Conclusion** 

incidence of metabolic disorders.

complementary modulators of NRs.


Synthetic and Plant Derived Thyroid Hormone Analogs 235

Lim ,W., Nguyen, N., Ha, Y. Y., Scanlan, T. S. & Furlow, J. D. (2002). A Thyroid Hormone

McDonnell, D.P. & Norris, J.D. (2002). Connections and regulation of the human estrogen receptor, *Science*, Vol. 296, No. 5573, pp. 1642–1644. ISSN: 1095-9203. McKenna, N.J. & O'Malley, B.W. (2000). An issue of tissues: divining the split personalities

Medeiros, M.F.T., Fonseca, V.S. & Andreata, R.H.P. (2004). Plantas medicinais e seus usos

Mendonça, V.L.M., Oliveira, C.L.A., Craveiro, A.A., Rao, V.S., Fonteles, M.C. (1991).

Mentreddy, S.R. (2007). Medicinal plant species with potential antidiabetic properties. *Journal of the Science of Food and Agriculture*, Vol. 87, No. 5, pp.743-750. ISSN: 1097-0010. Murillo, G. & Mehta, R.G. (2001). Cruciferous Vegetable and Cancer Prevention. *Nutrition* 

Nagappa, A.N. , Thakurdesai, P.A. , Rao, N.V. & Singh, J. (2003). Antidiabetic activity of

Negrelle, R.R.B. & Gomes, E.C. (2007). *Cymbopogon citrates* (DC.) Stapf.: chemical

Ngoc-Ha, N., Apriletti, J.W., Cunha Lima, S.T., Webb, P., Baxter, J.D. & Scanlan, T. S. (2002).

Parry, D.W., O'neill C. H., Hodson, M.J. (1986). Opaline silica deposits in the leaves of *Bidens* 

Pasa, M.C., Soares, J.J. & Germano, G.N. (2005). Estudo etnobotânico na comunidade de Conceição-Açú. *Acta Botanica Brasílica*, Vol. 19, No. 2, pp. 195-207. ISSN: 0102-3306. Pepato, M.T., Keller, E.H., Baviera, A.M., Kettelhut, I.C., Vendramini, R.C., Brunetti, I.L. (2002).

*Journal of Ethnopharmacology*, Vol. 81, No. 2, pp. 191-197. ISSN: 0378-8741. Pianjing , P., Thiantanawat, A., Rangkadilok, N., Watcharasit, P., Mahidol, C.& Satayavivad

Prakash, D., Suri, S., Upadhyay, G. & Singh, B.N. (2007). Total phenol, antioxidant and free

Ren, W., Qiao, Z., Wang, H., Zhu, L., Zhang, L. (2003). Flavonoids: Promising anticancer agents. *Medicinal Research Reviews,* Vol. 23, No. 4, pp. 519-534. ISSN: 0198-6325.

*Sciences and Nutrition*, Vol. 58, No. 1, pp. 18-28. ISSN: 0963-7486.

*Instituto Oswaldo Cruz*, Vol. 86, No. 2, pp. 93-97. ISSN: 0074-0276.

*Chemistry,* Vol. 277, No. 38, pp. 35664–35670. ISSN: 1083-351X.

*Brasílica*, Vol. 18, No. 2, pp. 391-399. ISSN: 0102-3306.

*and Cancer,* Vol. 41 (1-2), pp. 17-28. ISSN: 0163-5581.

586. ISSN: 1678-4510.

ISSN: 1546-170X.

ISSN: 0378-8741.

No. 1, pp. 80-92. ISSN: 1516-0572.

3310-3320. ISSN: 0022-2623.

pp. 641-647. ISSN: 1095-8290.

212-221. ISSN: 0021-8561.

diabetes. *Brazilian Journal of Medical and Biological Research*, Vol. 37, No. 4, pp. 577-

Antagonist That Inhibits Thyroid Hormone Action *in Vivo. Journal of Biological* 

of selective estrogen receptor modulators. *Nature Medicine,* Vol. 6, pp. 960–962.

pelos sitiantes da reserva do Rio das Pedras, Mangaratiba, RJ, Brasil. *Acta Botanica* 

Pharmacological and toxicological evaluation of *Alpinia speciosa*. *Memórias do* 

*Terminalia catappa* Linn fruits. *Journal of Ethnopharmacology*, Vol. 88, No. 1, pp. 45-50.

composition and biological activities. *Revista Brasileira de Plantas Medicinais*, Vol. 9,

Rational Design and Synthesis of a Novel Thyroid Hormone Antagonist That Blocks Coactivator Recruitment. *Journal of Medicinal Chemistry,* Vol. 45, No. 15, pp.

*pilosa* L. and their possible significance in cancer. *Annals of Botany*, Vol. 58, No. 5,

Anti-diabetic activity of *Bauhinia forficata* decoction in streptozotocin-diabetic rats.

J. (2011). Estrogenic activities of sesame lignans and their metabolites on human breast cancer cells. *The Journal of Agricultural and Food Chemistry*, Vol. 12, No. 1, pp.

radical scavenging activities of some medicinal plants. *International Journal of Food* 

mood states in overweight healthy adults. *Current Therapeutic Research*, Vol. 60, No. 3, pp.145-153. ISSN: 0011-393X.


Consolini, A.E., Baldini, O.A., Amat, A.G. (1999). Pharmacological basis for the empirical

Cunha Lima, S.T., Rodrigues, E.D., Melo, T., Nascimento, A.F. Guedes, M.L.S., Cruz, T.,

*Brasileira de Plantas Medicinais,* Vol. 10, No. 4, pp. 83-89. ISSN: 1516-0572. da Silva, K.L. & Cechinel Filho, V. (2002). Plants of the genus Bauhinia: chemical composition and pharmacological potential. *Química Nova*, Vol. 25, No. 3, pp. 449-454. Felig, P.F. & Baxter J.D. (1995). *The thyroid: physiology, thyrotoxicosis, hypothyroidism, and the* 

Gauthier, K., Chassande, O., Plateroti., M., Roux, J.P., Legrand, C., Pain, B., Rousset, B.,

Grover, G. J., Mellström, K., Ye, L., Malm, J., Li, Y. L., Bladh, L. G., Sleph, P. G., Smith, M. A.,

Gustafsson, J.A. (1998). Therapeutic potential of selective estrogen receptor modulators. *Current Opinion in Chemical Biology*, Vol. 2, No. 4, pp. 508–511. ISSN: 1367-5931. Hamann, I., Seidlova-Wuttke, D., Wuttke, W. & Köhrle, J. (2008). Environment and

Hegazy, M.E., Mohamed, A.E., El-Halawany, A.M., Djemgou, P.C., Shahat, A.A. & Paré ,

Ibañez , E., Cifuentes, A., Crego, A.L., Señoráns, F.J., Cavero, S. & Reglero, G. (2000).

*Journal of Natural Products*, Vol. 74, No. 5, pp 937–942. ISSN: 0163-3864. Horn-Ross, P.L., Hoggatt, K.J. & Lee, M.M. (2002). Phytoestrogens and Thyroid Cancer Risk:

*Ethnopharmacology*, Vol. 66, No. 1, pp.33-39. ISSN: 0378-8741.

3, pp.145-153. ISSN: 0011-393X.

York. ISBN: 0070204489 / 0-07-020448-9.

Vol. 100, No. 17, pp. 10067–10072. ISSN: 0027-8424.

*Prevention,* Vol. 11, pp.42-49. ISSN: 1055-9965.

pp. 116-122. ISSN: 0003-4266.

1096-1186.

mood states in overweight healthy adults. *Current Therapeutic Research*, Vol. 60, No.

use of *Eugenia uniflora* L. (Myrtaceae) as antihypertensive. *Journal of* 

Alves, C., Meyer, R., & Toralles, M.B (2008). Levantamento da flora medicinal usada no tratamento de doenças metabólicas em Salvador, BA- Brasil. *Revista* 

*painful thyroid*. Frohman (Eds.), *Endocrinology and Metabolism*, McGraw-Hill, New

Weiss, R., Trouillas, J., Samarut, J. (1999). Different functions for the thyroid hormone receptors TRα and TRβ in the control of thyroid hormone production and post-natal development. *EMBO Journal*, Vol. 18, No. 3, 623 – 631. ISSN: 0261-4189. Gazola, R., Machado, D., Ruggiero, C., Singi, G., Macedo Alexandre, M. (2004). *Lippia alba*,

*Melissa officinalis* and *Cymbopogon citratus*: effects of the aqueous extracts on the isolated hearts of rats. *Pharmacological Research*, Vol. 50, No. 5, pp. 477-480. ISSN:

George, R. & Vennström, B., Mookhtiar, K., Horvath, R., Speelman, J., Egan, D. & Baxter, J.D. (2003). Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. *Proceedings of the National Academy of Science of the United States of America*,

endocrinology: The case of thyroidology. *Annales d'Endocrinologie*, Vol. 69, No. 2,

P.W. (2011). Estrogenic Activity of Chemical Constituents from *Tephrosia candida*.

The San Francisco Bay Area Thyroid Cancer Study. *Cancer Epidemiology Biomarkers* 

Combined use of supercritical fluid extraction, micellar electrokinetic chromatography, and reverse phase high performance liquid chromatography for the analysis of antioxidants from rosemary (*Rosmarinus officinalis* L.). *Journal of Agricultural and Food Chemistry*, Vol. 48, No. 9, pp. 4060-4065. ISSN: 0021-8561. Latha, M. and PARI, L. (2004). Effect of an aqueous extract of *Scoparia dulcis* on blood

glucose, plasma insulin and some polyol pathway enzymes in experimental rat

diabetes. *Brazilian Journal of Medical and Biological Research*, Vol. 37, No. 4, pp. 577- 586. ISSN: 1678-4510.


**Part 3** 

**to Thyroid Diseases** 

**Psychiatric Disturbances Associated** 


## **Part 3**

### **Psychiatric Disturbances Associated to Thyroid Diseases**

236 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Rodrigues, E. & Carlini, E.A (2004). Plants used by a Quilombola group in Brazil with

Schossler, D.R.C., Mazzanti, C.M., da Luz, S.C.A, Filappi, A., Prestes, D., da Silveira, A.F.,

Seon , M.R., Lim , S.S., Choi, H.J., Park, S.Y., Cho, H.J., Kim, J.K., Kim, J., Kwon, D.Y. & Park,

Simões, C. M. O. & Schenkel, E. P. (2002). A pesquisa e a produção brasileira de medicamentos

Taylor, A. H., Stephan, Z. F., Steele, R. E. & Wong, N. C. (1997). Beneficial Effects of a Novel

Teixeira, C.C., Weinert, L.S., Barbosa, D.C., Ricken, C., Esteves, J.F. & Fuchs F.D. (2004).

Traka, M., Gasper, A.V., Melchini, A., Bacon, J.R., Needs, P.W., Frost, V., Chantry, A., Jones,

Pathways in the Prostate. *PLoS One*, Vol. 3, No. 7, pp. 1-14. ISSN: 1932-6203. Vieira, I. J. C. , Mathias, L., Braz-Filho, R. & Schripsema, J.. (1999). .Iridoids from Borreria verticillata*.Organic Letters*, Vol.1, No.8, pp.1169-71. ISSN: 1523-7052. Webb, P., Nguyen , N.H., Chiellini , G., Yoshihara, H.A., Cunha Lima, S.T., Apriletti, J.W.,

Yen, P.M. (2001). Physiological and molecular basis of thyroid hormone action. *Physiological* 

Yoshihara, H.A., Apriletti, J.W., Baxter, J.D. & Scanlan, T.S. (2001). A designed antagonist of

Zubeldia, J.M., Nabi, H.A., Jiménez, D.R.M, & Genovese, J. (2010). Exploring new

*and Molecular Biology,* Vol. 83, No. 1–5, pp. 59–73. ISSN: 0960-0760.

*Reviews*, Vol. 81, No. 3, pp. 1097–1142. ISSN: 0031-9333.

*Food,* Vol. 13, No. 6, pp. 1287-1292. ISSN: 1096-620X.

*Revista Brasileira de Farmacognosia.* Vol. 2. No.1, PP. 35-40. ISSN 0102-695X. Sudheesh, S., Vijayalakshmi, N.R. (2005). Flavonoids from *Punica granatum* - potential antiperoxidative agents. *Fitoterapia*, Vol. 76, No. 2, pp.181-186. ISSN: 0367-326X. Sundararajan, P., Dey, A., Smith, A., Doss, A.G., Rajappan, M. & Natarajan, S. (2006). Studies

*Health Sciences*, Vol. 6, No. 1, pp. 27-30. ISSN: 1680-6905.

748- 53. ISSN: 0951-418X.

Vol. 41, No. 4, pp. 236-239. ISSN: 1413-9596.

54, No. 9, pp. 1329-39. ISSN: 1613-4133.

pp. 542–547. ISSN: 0026-895X.

No. 12, pp. 3019-3020. ISSN: 0149-5992.

21, pp. 2821-2825. ISSN: 0960-894X.

potential central nervous system effects. *Phytotherapy Research*, Vol. 18, No. 9, pp.

Cecim, M. (2004). Syzygium cumini and the regeneration of insulin positive cells from the pancreatic duct. *Brazilian Journal of Veterinary Research and Animal Science*,

J.H. (2010). Isoangustone A present in hexane/ethanol extract of *Glycyrrhiza uralensis* induces apoptosis in DU145 human prostate cancer cells via the activation of DR4 and intrinsic apoptosis pathway. *Molecular Nutrition & Food Research,* Vol.

a partir de plantas medicinais: a necessária interação da indústria com a academia.

of anticancer and antipyretic activity of *Bidens pilosa* whole plant (2006). *African* 

Thyromimetic on Lipoprotein Metabolism. *Molecular Pharmacology,* Vol. 52, No. 3,

*Syzygium cumini* (L.) Skeels in the treatment of type 2 diabetes: results of a randomized, double-blind, double-dummy, controlled trial. *Diabetes Care*, Vol. 27,

A.M.E., Ortori, C.A., Barrett, D.A., Ball, R.Y., Mills, R.D., Mithen, R.F. (2008). Broccoli Consumption Interacts with GSTM1 to Perturb Oncogenic Signalling

Ribeiro, R.C., Marimuthu, A., West, B.L., Goede, P., Mellstrom, K., Nilsson, S., Kushner, P.J., Fletterick, R.J., Scanlan, T.S. & Baxter, J.D. (2002). Design of thyroid hormone receptor antagonists from first principles. *Journal of Steroid Biochemistry* 

the thyroid hormone receptor. *Bioorganic & Medicinal Chemistry Letters,* Vol. 11, No.

applications for *Rhodiola rosea*: can we improve the quality of life of patients with short-term hypothyroidism induced by hormone withdrawal? *Journal of Medicinal* 

**16**

*Spain* 

**Thyroid and Parathyroid Diseases and** 

*4Center for Biomedical Research in Mental Health Network (CIBERSAM)* 

*1Miguel Servet University Hospital (Department of Surgery)* 

*3Clínico University Hospital (Department of Psychiatry)* 

A. Lobo-Escolar1,2, A. Campayo2,3,4, C.H. Gómez-Biel3 and A. Lobo2,3,4

Different factors have stimulated the interest on the relationships between psychiatric conditions and endocrine disturbances in general and thyroid disease in particular (Lishman, 1998). Historically, several authors have speculated about the role of hormones and endocrine disorders in relation to psychiatric conditions, and important attention has been devoted to the role of hormones in relation to control and feedback processes in neural structures (Carroll et al. 1981). Psychiatric syndromes have consistently been described or documented in endocrine diseases (Lishman, 1998; Kathol, 2002) and may pose a real clinical challenge for psychiatrists working in general hospitals (liaison or psychosomatic psychiatrists), but the evidence in the literature to support his or her intervention is limited, according to modern criteria. The purpose of this chapter is primarily to review available data in relation to the characteristics and frequency of specific psychiatric syndromes in primary thyroid and parathyroid disturbances; issues of diagnosis and differential diagnosis; mechanisms of production of psychiatric symptomatology; and treatment issues, including response of psychiatric syndromes to treatment of the endocrinopathy and to

The most severe psychiatric syndromes in endocrine diseases are not as frequent as in the past, due to improvements in diagnosis and treatment of the hormonal disorders (Kathol, 2002). Still, a high prevalence of psychiatric disturbances has been reported in most endocrine conditions, including thyroid and parathyroid diseases. Depression and anxiety together with cognitive disorders are the most common presentations (Table 1). As expected, lifetime prevalence is even higher in several reports (Eiber et al. 1997). Cognitive impairment is rather frequent in conditions such as hyperparathyroidism, particularly among the elderly, and dementia can also be found; delirium, but also psychosis in clear consciousness, including paranoid psychosis and mania may be seen in severe endocrine

**1. Introduction** 

psychotropic medication.

**2. General clinical and epidemiological aspects** 

**Psychiatric Disturbance** 

*Institute of Health "Carlos III", Madrid* 

*2The University of Zaragoza* 

### **Thyroid and Parathyroid Diseases and Psychiatric Disturbance**

A. Lobo-Escolar1,2, A. Campayo2,3,4, C.H. Gómez-Biel3 and A. Lobo2,3,4 *1Miguel Servet University Hospital (Department of Surgery) 2The University of Zaragoza 3Clínico University Hospital (Department of Psychiatry) 4Center for Biomedical Research in Mental Health Network (CIBERSAM) Institute of Health "Carlos III", Madrid Spain* 

#### **1. Introduction**

Different factors have stimulated the interest on the relationships between psychiatric conditions and endocrine disturbances in general and thyroid disease in particular (Lishman, 1998). Historically, several authors have speculated about the role of hormones and endocrine disorders in relation to psychiatric conditions, and important attention has been devoted to the role of hormones in relation to control and feedback processes in neural structures (Carroll et al. 1981). Psychiatric syndromes have consistently been described or documented in endocrine diseases (Lishman, 1998; Kathol, 2002) and may pose a real clinical challenge for psychiatrists working in general hospitals (liaison or psychosomatic psychiatrists), but the evidence in the literature to support his or her intervention is limited, according to modern criteria. The purpose of this chapter is primarily to review available data in relation to the characteristics and frequency of specific psychiatric syndromes in primary thyroid and parathyroid disturbances; issues of diagnosis and differential diagnosis; mechanisms of production of psychiatric symptomatology; and treatment issues, including response of psychiatric syndromes to treatment of the endocrinopathy and to psychotropic medication.

#### **2. General clinical and epidemiological aspects**

The most severe psychiatric syndromes in endocrine diseases are not as frequent as in the past, due to improvements in diagnosis and treatment of the hormonal disorders (Kathol, 2002). Still, a high prevalence of psychiatric disturbances has been reported in most endocrine conditions, including thyroid and parathyroid diseases. Depression and anxiety together with cognitive disorders are the most common presentations (Table 1). As expected, lifetime prevalence is even higher in several reports (Eiber et al. 1997). Cognitive impairment is rather frequent in conditions such as hyperparathyroidism, particularly among the elderly, and dementia can also be found; delirium, but also psychosis in clear consciousness, including paranoid psychosis and mania may be seen in severe endocrine

Thyroid and Parathyroid Diseases and Psychiatric Disturbance 241

patients, the prevalence of disorder at the time of admission (first three days) was significantly higher than in all the comparison groups (Table 2). Similarly, according to standardized criteria, the severity of disorder was significantly higher in the endocrine inpatients (68% had "moderate" or "severe" syndromes) than in the control groups (26,6%,

Prevalence of any Disorder Comments

Admission Discharge Severity of psychiatric

disorders is

Correlations

significantly higher in endocrine in-patients (++); and decreases significantly at discharge (+++)

biochemical variables (any)/ Irrtability, Psychastenia.

16% and 40%, respectively).

 I.M. in-patients (n=30) I.M out-patients (n=100) Endocrine out-patients

Controls

(n=100)

All patients (n=100) 91% 54%

Hyperthyroidism 100% 86%

Prevalence and correlation with biochemical variables.\*

+ Significance p< 0,05; ++ p<0,01; +++ p<0,001. \* Pérez-Echeverría, 1985; Lobo et al., 1988.

severity and/or special characteristics.

53,3% 38% 70%

Table 2. Psychiatric disorders in endocrine in-patients and in hyperthyroidism in- patients.

This epidemiological documentation may be important to identify the individuals at risk for specific psychiatric syndromes in liaison programs with endocrine departments; or to search for the syndromes when the psychiatrist consults in specific endocrine patients such as the individuals with thyroid or parathyroid conditions. Screening instruments such as the Hospital Anxiety and Depression Scale (HADS) (Lloyd et al., 2000) or the General Health Questionnaire-28 Items (Lobo et al., 1988) are considered to be appropriate in endocrine patients. The sections dedicated to specific endocrine diseases suggest when the search may be mandatory, such as in cases of hyperthyroidism, where anxiety, but also depressive syndromes may be severe or in cases of cognitive deficits in hypothyroid disease. Table 1 also summarizes the authors' judgement about the clinical relevance (+ to +++) of the psychiatric syndromes in these specific endocrine conditions, according to their frequency,

Non-biological hypotheses have been formulated to explain depressive or anxiety syndromes when there is considerable stress and psychosocial difficulties associated with conditions such as hyperthyroidism. However, the authors suggest that the "organic", endocrine origin of the psychiatric syndromes in these patients is most important. The following data support this contention: studies documenting a higher prevalence of psychiatric disturbance than in comparable general population samples (Mayou et al., 1991) and, in particular, in medical samples of comparable severity of the medical disorder (Pérez-Echeverría, 1985); both clinical practice and studies documenting that the prevalence of psychiatric disorder and/or its severity decreases after successful treatment of the endocrine condition (Pérez-Echeverría, 1985). Although some reports are discrepant (Joborn et al., 1988), special support comes from studies documenting statistically significant correlations

diseases. Methodological issues limit the value of the available data: case studies and case reports abound in this literature, research diagnostic criteria have rarely been used and comparison between studies is difficult due to wide differences in the samples selected and methods used. However, standardized research interviews were used in some studies reviewed here and standardized instruments in most. The emerging general picture suggests the clinical relevance of the documented psychopathology, including the depressive and anxiety syndromes, which may be very severe in diseases such as hyperthyroidism (Table 2).


DAT: Dementia, Alzheimer Type.

+/+++: Clinical relevance.

Brown et al., 1987; Bunevicius et al.; Casella et al., 2008; Eiber et al., 1997; Espiritu et al., 2010; Joborn et al., 1986; Kathol & Delahunt, 1986; Mooradian, 2008; Pérez- Echeverria, 1985; Velasco et al., 1999; Solin et al., 2009

Table 1. Psychiatric syndromes in thyroid and parathyroid disorders: prevalence and clinical relevance.

It was in this context that we completed a study in 100 consecutive patients admitted to the Endocrine Unit in our University hospital (Pérez-Echeverría, 1985; Lobo et al., 1988). Patients hospitalized in the Internal Medicine ward were used as a comparison group, as well as outpatient groups of both the internal medicine and the endocrine Departments. Standardized instruments, including the Clinical Interview Schedule (CIS) and the General Health Questionnaire-28 items (GHQ-28), were used throughout the study. In support of the relevance of psychiatric syndromes in these patients and specifically in hyperthyroid

diseases. Methodological issues limit the value of the available data: case studies and case reports abound in this literature, research diagnostic criteria have rarely been used and comparison between studies is difficult due to wide differences in the samples selected and methods used. However, standardized research interviews were used in some studies reviewed here and standardized instruments in most. The emerging general picture suggests the clinical relevance of the documented psychopathology, including the depressive and anxiety syndromes, which may be very severe in diseases such as

Hyperthyroidism Hypothyroidism Hyperpara-

30%-70% ++ ++

+++

Cretinism

 Slowing/Lethargy Mania (Treatment

induced)

Brown et al., 1987; Bunevicius et al.; Casella et al., 2008; Eiber et al., 1997; Espiritu et al., 2010; Joborn et al., 1986; Kathol & Delahunt, 1986; Mooradian, 2008; Pérez- Echeverria, 1985; Velasco et al., 1999; Solin

Table 1. Psychiatric syndromes in thyroid and parathyroid disorders: prevalence and clinical

It was in this context that we completed a study in 100 consecutive patients admitted to the Endocrine Unit in our University hospital (Pérez-Echeverría, 1985; Lobo et al., 1988). Patients hospitalized in the Internal Medicine ward were used as a comparison group, as well as outpatient groups of both the internal medicine and the endocrine Departments. Standardized instruments, including the Clinical Interview Schedule (CIS) and the General Health Questionnaire-28 items (GHQ-28), were used throughout the study. In support of the relevance of psychiatric syndromes in these patients and specifically in hyperthyroid

DAT? ++ + +/-

hyperthyroidism" + +

Any Disorder 53%-100% 23%-66%

Delirium + + ++

thyroidism

++

 Fatigue Violent behaviour?

16%-36% <sup>+</sup>

2%-5% ++

3%-12% <sup>+</sup>

 Social withdrawl "Neurotic" behaviour

Hypoparathyroidism

hyperthyroidism (Table 2).

Depression ++

cognition ++

DAT: Dementia, Alzheimer Type. +/+++: Clinical relevance.

Dementia Risk Factor

 Overactivity Irritability Organic

> personality in the elderly

Impaired

Others

et al., 2009

relevance.

Apathy "Apathetic

patients, the prevalence of disorder at the time of admission (first three days) was significantly higher than in all the comparison groups (Table 2). Similarly, according to standardized criteria, the severity of disorder was significantly higher in the endocrine inpatients (68% had "moderate" or "severe" syndromes) than in the control groups (26,6%, 16% and 40%, respectively).


+ Significance p< 0,05; ++ p<0,01; +++ p<0,001.

\* Pérez-Echeverría, 1985; Lobo et al., 1988.

Table 2. Psychiatric disorders in endocrine in-patients and in hyperthyroidism in- patients. Prevalence and correlation with biochemical variables.\*

This epidemiological documentation may be important to identify the individuals at risk for specific psychiatric syndromes in liaison programs with endocrine departments; or to search for the syndromes when the psychiatrist consults in specific endocrine patients such as the individuals with thyroid or parathyroid conditions. Screening instruments such as the Hospital Anxiety and Depression Scale (HADS) (Lloyd et al., 2000) or the General Health Questionnaire-28 Items (Lobo et al., 1988) are considered to be appropriate in endocrine patients. The sections dedicated to specific endocrine diseases suggest when the search may be mandatory, such as in cases of hyperthyroidism, where anxiety, but also depressive syndromes may be severe or in cases of cognitive deficits in hypothyroid disease. Table 1 also summarizes the authors' judgement about the clinical relevance (+ to +++) of the psychiatric syndromes in these specific endocrine conditions, according to their frequency, severity and/or special characteristics.

Non-biological hypotheses have been formulated to explain depressive or anxiety syndromes when there is considerable stress and psychosocial difficulties associated with conditions such as hyperthyroidism. However, the authors suggest that the "organic", endocrine origin of the psychiatric syndromes in these patients is most important. The following data support this contention: studies documenting a higher prevalence of psychiatric disturbance than in comparable general population samples (Mayou et al., 1991) and, in particular, in medical samples of comparable severity of the medical disorder (Pérez-Echeverría, 1985); both clinical practice and studies documenting that the prevalence of psychiatric disorder and/or its severity decreases after successful treatment of the endocrine condition (Pérez-Echeverría, 1985). Although some reports are discrepant (Joborn et al., 1988), special support comes from studies documenting statistically significant correlations

Thyroid and Parathyroid Diseases and Psychiatric Disturbance 243

treatment. Well-controlled studies are lacking, but syndrome specific medication is usually recommended, as well as supportive psychotherapy and, recently, cognitive-behavioural psychotherapy in cases of abnormal illness behaviour. Relevant clinical factors, and exceptions to these general norms will now be discussed for the specific endocrine diseases.

**Treat if psychiatric** 

or extreme severity

**persist after adequate** 

**syndromes** 

**endocrine treatment\*** 

**Endocrinophaty Psychiatric syndromes** 

the older population were considered to be a research priority.

Lobo et al., 2007.

patients.

Hyperthyroidism Anxiety (Depression) >4 weeks

Hypothyroidism Depression/ Anxiety >4 weeks

Hyperparathyroidism >4 weeks

Table 4. Treatment of psychiatric syndromes with psychotropic medications in endocrine

**3. Thyroid disease and the "clustering" of somatic and psychiatric morbidity**  In relation to epidemiology, we have recently studied the role of thyroid disease in the clustering of somatic and psychiatric morbidity in the elderly population. Pioneer studies by authors such as Eastwood and Trevelyan found that psychiatric and somatic illnesses tend to "cluster" in a limited group of individuals in the general population. The first author speculated about vulnerability to illness, and research in this area was considered "the main task for epidemiology in the field of psychosomatic medicine". Since then, a considerable number of studies have approached this subject, and some authors argued that the association between somatic and psychiatric morbidity is well established. However, previous research was conducted primarily in clinical samples, and not in representative, general population samples (Scott et al., 2007). Furthermore, Eastwood's statement (Eastwood, 1989) suggesting that the association of general psychiatric and somatic morbidity has not been convincingly shown in the elderly population is still valid. Given the relationships between comorbidity and frailty described in the elderly, as well as the negative consequences (Slaets, 2006), studies in

The study we conducted was part of the ZARADEMP Project, an epidemiological enquiry to document in the elderly community the prevalence, incidence and risk factors of dementia, depression and psychiatric morbidity, as well as their association with somatic morbidity (Lobo et al., 2005). The main objective in this specific study was to try to confirm in the elderly population the tendency of general psychiatric morbidity to cluster with general

Hypoparathyroidism Depression ?

\*Treatment should also be recommended when syndromes are very severe or life threatening.

between severity of psychiatric symptoms/syndromes and hormonal levels or biological parameters (Table 2) (Pérez-Echeverría, 1985; Lobo et al., 1988; Linder et al., 1988).

In relation to diagnosis the dictum of experienced, anonymous liaison psychiatrists seem to be quite appropriate here: "In the general hospital, every psychiatric symptom is "organic"…unless you can document otherwise". In taking the history of rather atypical psychiatric presentations, the clinical psychiatrist should include questions related to the thyroid or parathyroid disorder, particularly when there are signs and /or symptoms suggesting the endocrine abnormality (table 3). If the suggestions are well founded, he or she should also perform at least focal physical examinations to document the presence or absence of endocrine signs. In these cases, but not routinely, he or she should also indicate tests of endocrine function.


Table 3. Somatic symptoms and signs suggesting a thyroid disease.

According to the International Classification of Diseases (10th edition or ICD-10), the diagnosis of an "organic" psychiatric syndrome of thyroid or parathyroid origin in a given patient should be considered when the presenting syndrome is known to be associated with the specific endocrine disease, and is supported by the absence of suggestive evidence of an alternative cause of the mental syndrome. Specifically, the "organic" psychiatric syndrome in cases of thyroid or parathyroid disease is supported when: a) the psychiatric symptoms, the course of illness and/or the age of presentation are atypical for a primary psychiatric disorder; b) there is no family or personal history of the psychiatric condition; c) no precipitating stress is known; d) there is a temporal relationship between the onset of the psychiatric and the endocrine symptoms. The challenge for the consulting psychiatrist is to make explicit the diagnosis of the endocrine origin of the psychiatric syndrome early in the procedure, before his or her diagnosis is confirmed after observing that the syndrome disappears following the removal or improvement of the underlying endocrine disorder.

Most psychiatric syndromes in endocrine patients resolve with standard treatment of the endocrine disease, and this applies to thyroid and parathyroid disorders. However, when symptoms are particularly severe or life-threatening; or when they last longer than reasonably expected (table 4), good clinical sense suggests the importance of psychiatric

between severity of psychiatric symptoms/syndromes and hormonal levels or biological

In relation to diagnosis the dictum of experienced, anonymous liaison psychiatrists seem to be quite appropriate here: "In the general hospital, every psychiatric symptom is "organic"…unless you can document otherwise". In taking the history of rather atypical psychiatric presentations, the clinical psychiatrist should include questions related to the thyroid or parathyroid disorder, particularly when there are signs and /or symptoms suggesting the endocrine abnormality (table 3). If the suggestions are well founded, he or she should also perform at least focal physical examinations to document the presence or absence of endocrine signs. In these cases, but not routinely, he or she should also indicate

**Endocrinopathy Symptoms Signs** 

Exophthalmos Tachycardia

Tremor

Goiter

Myxedema

Hypertension

Chvostek´s sign Trousseau´s sign

Arrytmia (in elderly)

Slow relaxing reflexes

Choreiform movements

Diaphoresis Heat intolerance Oligomenorrhea

Menorrhagia

Muscular weakness

According to the International Classification of Diseases (10th edition or ICD-10), the diagnosis of an "organic" psychiatric syndrome of thyroid or parathyroid origin in a given patient should be considered when the presenting syndrome is known to be associated with the specific endocrine disease, and is supported by the absence of suggestive evidence of an alternative cause of the mental syndrome. Specifically, the "organic" psychiatric syndrome in cases of thyroid or parathyroid disease is supported when: a) the psychiatric symptoms, the course of illness and/or the age of presentation are atypical for a primary psychiatric disorder; b) there is no family or personal history of the psychiatric condition; c) no precipitating stress is known; d) there is a temporal relationship between the onset of the psychiatric and the endocrine symptoms. The challenge for the consulting psychiatrist is to make explicit the diagnosis of the endocrine origin of the psychiatric syndrome early in the procedure, before his or her diagnosis is confirmed after observing that the syndrome disappears following the removal or improvement of the underlying endocrine disorder.

Most psychiatric syndromes in endocrine patients resolve with standard treatment of the endocrine disease, and this applies to thyroid and parathyroid disorders. However, when symptoms are particularly severe or life-threatening; or when they last longer than reasonably expected (table 4), good clinical sense suggests the importance of psychiatric

Nausea

(proximal) Abdominal pain

Paresthesias

Table 3. Somatic symptoms and signs suggesting a thyroid disease.

Hypothyroidism Cold intolerance

Hypoparathyroidism Muscle spams

parameters (Table 2) (Pérez-Echeverría, 1985; Lobo et al., 1988; Linder et al., 1988).

tests of endocrine function.

Hyperthyroidism

Hyperparathyroidism

treatment. Well-controlled studies are lacking, but syndrome specific medication is usually recommended, as well as supportive psychotherapy and, recently, cognitive-behavioural psychotherapy in cases of abnormal illness behaviour. Relevant clinical factors, and exceptions to these general norms will now be discussed for the specific endocrine diseases.


\*Treatment should also be recommended when syndromes are very severe or life threatening. Lobo et al., 2007.

Table 4. Treatment of psychiatric syndromes with psychotropic medications in endocrine patients.

#### **3. Thyroid disease and the "clustering" of somatic and psychiatric morbidity**

In relation to epidemiology, we have recently studied the role of thyroid disease in the clustering of somatic and psychiatric morbidity in the elderly population. Pioneer studies by authors such as Eastwood and Trevelyan found that psychiatric and somatic illnesses tend to "cluster" in a limited group of individuals in the general population. The first author speculated about vulnerability to illness, and research in this area was considered "the main task for epidemiology in the field of psychosomatic medicine". Since then, a considerable number of studies have approached this subject, and some authors argued that the association between somatic and psychiatric morbidity is well established. However, previous research was conducted primarily in clinical samples, and not in representative, general population samples (Scott et al., 2007). Furthermore, Eastwood's statement (Eastwood, 1989) suggesting that the association of general psychiatric and somatic morbidity has not been convincingly shown in the elderly population is still valid. Given the relationships between comorbidity and frailty described in the elderly, as well as the negative consequences (Slaets, 2006), studies in the older population were considered to be a research priority.

The study we conducted was part of the ZARADEMP Project, an epidemiological enquiry to document in the elderly community the prevalence, incidence and risk factors of dementia, depression and psychiatric morbidity, as well as their association with somatic morbidity (Lobo et al., 2005). The main objective in this specific study was to try to confirm in the elderly population the tendency of general psychiatric morbidity to cluster with general

Thyroid and Parathyroid Diseases and Psychiatric Disturbance 245

(*n*=1088) 29 2,7 1.8 – 3,8

(*n*=1702) 66 3,9 3.0 – 4,9

(*n*=1097) 34 3,1 2.2 – 4,3

**≥85 years** 21 2,3 1,4 – 3,5

The relevant results for this chapter may be summarized as follows. As expected, the prevalence of somatic disease tended to increase with age in most categories (Table 4). However, it decreased after the age of 84 in several categories, including thyroid disease. General comorbidity clustered in 19.9% of the elderly when hypertension was removed from the somatic conditions category, 33.5% of the sample remaining free of both somatic and psychiatric illness. General comorbidity was associated with age, female sex and limited education, but did not increase systematically with age. The frequency of psychiatric illness was higher among the somatic cases than among non-cases, and the frequency of somatic morbidity among the psychiatric cases was higher than among noncases. This association between somatic and psychiatric morbidity remained statistically significant after controlling for age, sex and education (OR= 1.61, IC 1.38-1.88). Most somatic categories were associated with psychiatric illness but, adjusting for demographic variables and individual somatic illnesses, the association remained statistically significant only for cerebro-vascular accidents, CVA's (OR= 1,47, CI 1,09-1,98) and thyroid

**Thyroid disease** 46 2,1 1,5 – 2,8

**Thyroid disease Cases (***n***) Prevalence (%) 95% CI**

Table 6. Prevalence of thyroid disease in patients with or without psychiatric morbidity in

This was the first study documenting in the (predominantly) elderly population that there is a positive and statistically significant association of general somatic and general psychiatric morbidity. Furthermore, in support of the initial hypothesis our results suggest that thyroid

Table 5. Prevalence of thyroid disease in community-dwelling individuals aged ≥ 55 years

**55 – 64 years** 

**65 – 74 years** 

**75 – 84 years** 

(distribution by age group).

disease OR= 1,67, CI 1,10-2,54).

community-dwelling individuals aged ≥ 55 years.

disease may have more weight in this association.

**Cases (***n***) Prevalence (%) 95% CI** 

**Without psychiatric morbidity (***n***=2211) Cases (***n***) Prevalence (%) 95% CI** 

**Psychiatric morbidity (***n***=2592)**

104 4.0 3,3 – 4,8

somatic morbidity. In view of the considerable prevalence of thyroid disease in the elderly and the documented association between thyroid disturbances and psychopathology, we also set as an objective to study the role of thyroid disease in the clustering.

The site of the study was Zaragoza, a capital concentrating 622,371 inhabitants (fifth city in Spain) or 51% the population of the historical kingdom of Aragón. The objectives and general methodology of the ZARADEMP Project have been previously described (Lobo et al., 2005). It is a longitudinal, epidemiological study with four waves*,* and Wave I (*ZARADEMP I*) was relevant for this report (Figure 1). It was the baseline, cross-sectional study, intended to document the prevalence and distribution of somatic and psychiatric morbidity and of comorbidity. Participating individuals have been followed up in Waves II, III and IV (or *ZARADEMP II, III* and *IV*) to eventually study the influence of hypothesized risk factors for incident cases.

#### Fig. 1.

A stratified, random sample of 4,803 individuals aged 55 and over was selected for the baseline study. The elderly were assessed with standardized, Spanish versions of instruments, including the Geriatric Mental State (GMS)-AGECAT (Lobo et al, 2005). The GMS is a semistructured standardized clinical interview used for assessing the mental state of elderly people. A computerized diagnostic program, *AGECAT* is available to be applied to it. This interview is also a syndrome case finding instrument, the *GMS-B* threshold scores discriminating between "non-cases", "subcases" and "cases". We also used the *History and Aetiology Schedule (HAS)*, a standardized method of collecting history and etiology data from an informant, or directly from the respondent when he or she was judged to be reliable. Psychiatric cases were diagnosed according to GMS-AGECAT criteria, and somatic morbidity, and specifically thyroid disease was documented with the EURODEM Risk Factors Questionnaire.

somatic morbidity. In view of the considerable prevalence of thyroid disease in the elderly and the documented association between thyroid disturbances and psychopathology, we

The site of the study was Zaragoza, a capital concentrating 622,371 inhabitants (fifth city in Spain) or 51% the population of the historical kingdom of Aragón. The objectives and general methodology of the ZARADEMP Project have been previously described (Lobo et al., 2005). It is a longitudinal, epidemiological study with four waves*,* and Wave I (*ZARADEMP I*) was relevant for this report (Figure 1). It was the baseline, cross-sectional study, intended to document the prevalence and distribution of somatic and psychiatric morbidity and of comorbidity. Participating individuals have been followed up in Waves II, III and IV (or *ZARADEMP II, III* and *IV*) to eventually study the influence of

ZARADEMP Project

Design

**Background Study** *" ZARAGOZA Study"1990*

> **ZARADEMP II n = 4,061 Fase I: "Lay Interviewers" Fase II: Specialists Fase III: Hospital**

A stratified, random sample of 4,803 individuals aged 55 and over was selected for the baseline study. The elderly were assessed with standardized, Spanish versions of instruments, including the Geriatric Mental State (GMS)-AGECAT (Lobo et al, 2005). The GMS is a semistructured standardized clinical interview used for assessing the mental state of elderly people. A computerized diagnostic program, *AGECAT* is available to be applied to it. This interview is also a syndrome case finding instrument, the *GMS-B* threshold scores discriminating between "non-cases", "subcases" and "cases". We also used the *History and Aetiology Schedule (HAS)*, a standardized method of collecting history and etiology data from an informant, or directly from the respondent when he or she was judged to be reliable. Psychiatric cases were diagnosed according to GMS-AGECAT criteria, and somatic morbidity, and specifically thyroid disease was documented with the

**ZARADEMP III n = 3,160 Fase I: "Lay Interviewers" Fase II: Specialists Fase III: Hospital** 

> ZARADEMP IV Year 2011.....

Incidence Life-time risk

also set as an objective to study the role of thyroid disease in the clustering.

hypothesized risk factors for incident cases.

**ZARADEMP I n = 4,803 Fase I: "Lay Interviewers" Fase II: Specialists**

Prevalence

EURODEM Risk Factors Questionnaire.

Fig. 1.


Table 5. Prevalence of thyroid disease in community-dwelling individuals aged ≥ 55 years (distribution by age group).

The relevant results for this chapter may be summarized as follows. As expected, the prevalence of somatic disease tended to increase with age in most categories (Table 4). However, it decreased after the age of 84 in several categories, including thyroid disease. General comorbidity clustered in 19.9% of the elderly when hypertension was removed from the somatic conditions category, 33.5% of the sample remaining free of both somatic and psychiatric illness. General comorbidity was associated with age, female sex and limited education, but did not increase systematically with age. The frequency of psychiatric illness was higher among the somatic cases than among non-cases, and the frequency of somatic morbidity among the psychiatric cases was higher than among noncases. This association between somatic and psychiatric morbidity remained statistically significant after controlling for age, sex and education (OR= 1.61, IC 1.38-1.88). Most somatic categories were associated with psychiatric illness but, adjusting for demographic variables and individual somatic illnesses, the association remained statistically significant only for cerebro-vascular accidents, CVA's (OR= 1,47, CI 1,09-1,98) and thyroid disease OR= 1,67, CI 1,10-2,54).


Table 6. Prevalence of thyroid disease in patients with or without psychiatric morbidity in community-dwelling individuals aged ≥ 55 years.

This was the first study documenting in the (predominantly) elderly population that there is a positive and statistically significant association of general somatic and general psychiatric morbidity. Furthermore, in support of the initial hypothesis our results suggest that thyroid disease may have more weight in this association.

Thyroid and Parathyroid Diseases and Psychiatric Disturbance 247

The possibility that subclinical hyperthyroidism in the elderly increases the risk of Alzheimer´s disease has been suggested (Kalmijn, 2001) and we are now involved in a large longitudinal study to assess specific risks of dementia, including thyroid disease, in a 15-

The initial symptoms in hyperthyroidism may be quite similar to anxiety disorders, but the described, unusual symptoms of anxiety may alert the clinicians (Kathol et al., 1986 ). Other symptoms that should alert the physicians are the preference for cold and intolerance to heat, or loss of weight coupled with increased appetite. A careful medical history and examination are mandatory in such cases and the laboratory test would usually give unequivocal answers to the diagnostic difficulties. An accelerated pulse during sleep or cognitive difficulties are also considered to suggest the diagnosis of hyperthyroidism in such cases (Hall et al., 1979; Mackenzie,1988). To help in the differential diagnosis some specific scales have been developed (Iacovides et al, 2000). Transient thyroid hormone elevations, usually mild, may occur in approximately 10% of psychiatric inpatients, but should not be diagnosed of hyperthyroidism. Thyroid abnormalities have also been documented in some studies in primary affective disorders (Oomen et al., 1996). However, later studies did not replicate the findings (Engum et al., 2002) and the possibility of factors of confusion such as the use of psychotropic medication has been considered. Other clinical situations may mimic the thyroid condition before the laboratory results are available, such as abuse of stimulants or drug intoxications. However, the nervousness and emotional lability in hyperthyroid patients

Subclinical hyperthyroidism has also stirred interest in recent studies. The clinical interest derives from the fact that it has been associated with cognitive deterioration and dementia in the elderly (Kalmijn,2000;Ceresini,2009), both in cross-sectional and longitudinal studies. While the clinical and epidemiological studies reviewed support the association of hyperthyroid function with psychopathological disturbance, the causal mechanisms are not clear (Bunevicius et al., 2006). One study suggested that the active thyroid hormone (T3) influenced mental performance in healthy subjects (Kathmann et al., 1994). The individuals overestimated time intervals and increased their word fluency, but no other cognitive problems were detected. Pérez-Echeverría (1985) and Lobo et al (1988) documented direct, convincing correlations between abnormal levels of thyroid hormones and psychopathology. The abnormal psychological phenomenon seemed to be directly related to the endocrine disturbance, since non-endocrine medical patients in the same ward, and with similar levels of illness severity had lower levels of psychopathology. Furthermore, in support of the direct effect of thyroid hormones elevation on the psychopathology, anxiety, depression and related phenomenon improved with "treatment as usual", when hormonal

In general, there is a good resolution of anxiety and depression with antithyroid treatment alone, unless there is previous psychiatric history (Kathol et al., 1986). Beta-blockers such as propanolol are also considered to be effective in cases of anxiety (Trzepacz et al, 1988). However, recovery may be slow and reduced psychological well-being has been reported in a considerable proportion of "remitted" hyperthyroidism (Pérez-Echeverría, 1985). Bunevicius also reported persistent mood and anxiety symptoms in treated hyperthyroidism (Bunevicius et al., 2005). Psychosis may occur or be exacerbated by antithyroid medication. Low potency

year follow-up study ingrained in the ZARADEMP project. (Lobo, 2005).

may be wrongly diagnosed as alcohol abuse or abstinence.

levels returned to normal, at the time of hospital discharge.

#### **4. Hyperthyroidism**

Hyperthyroidism is usually accompanied by physiological symptoms such as sweating, heat intolerance and muscle weakness. However, also common symptoms such as nervousness, fatigue or weight lost may be confounded for primary psychiatric symptoms. Graves´ disease, an autosomal disorder, is the most frequent cause of hyperthyroidism or thyrotoxicosis. While proponents of psychosomatic theories suggested in the last century that an important etiological factor for hyperthyroidism was the presence of psychological conflicts, there is very slight evidence to support the theory. Clinicians in Europe, certainly do not support this conjecture, as shown in the E.C.L.W. study (Huyse et al, 2000). No cases of this endocrine condition were referred for psychiatric consult among 15,000 medical inpatients seen in psychosomatic psychiatry services because of psychopathological reasons (Lobo et al , 1992). However, there is some evidence to support the idea that stress can precipitate the hyperthyroidism (Santos et al, 2002) or complicate the clinical course (Fukao et al , 2003 ).

The study by Pérez- Echeverría was one of the early investigations reporting the prevalence of psychiatric disturbance among hyperthyroid patients. Only few more studies have reported prevalence data since then. (Trzepacz et al., 1988; Bunevicius et al., 2005). The study by Stern conducted in members of a patients` foundation documented, as expected, that anxiety (72%) and irritability (78%) were the commonest symptoms (Stern et al., 1996).

Psychological disturbance of some degree is universal in Graves` disease (Pérez-Echeverría et al., 1986; Stern et al., 1996), and may delay the diagnosis of the hormonal disorder. Anxiety is most frequently reported, but also depressive syndromes. Rather unusual symptoms may accompany these psychopathological syndromes such as overactivity and restlessness or hyperacuity of perception and increased reaction to noise stimulus. It is the unusual presentation of anxiety (or depression) that may help the physician to differentiate the endocrine disorder from primary affective disturbance. Emotional lability may also be apparent, and both anxiety and irritability may be quite severe and stimulate relatively understandable behavior such as impatience and intolerance of frustration. While depression is not so common, it may be quite prominent and be accompanied by weakness, fatigue and other somatic symptoms. Psychomotor retardation is rare, the exception being the subgroup of elderly patients. "Apathetic hyperthyroidism" has been described in this age group (Mooradian & Arshg, 2008), and some of these cases may progress to stupor and coma.

Classical studies suggested that up to 20% of Graves` disease patients might have some kind of psychosis. However, as discussed by Lishman , there was probably a selection bias (Lishman, 1998). Delirium-type, acute organic syndromes are now rare because of advances in medical treatment. However, delirium in such cases may be a medical emergency. Affective psychoses have been described (Brownlie et al., 2000; Marian et al, 2009), but also schizophrenia-type psychoses, most commonly with paranoid ideation. Organic personality disorder has been described, particularly among the apathetic elderly. Distraibility and over-arousal have also been reported, sometimes leading to persistent cognitive impairment, which may continue even after the patient is euthyroid (Stern et al, 1996). Specific cognitive difficulties in hyperthyroid patient have been described, such as deterioration of memory, concentration or visuomotor speed (MacCrimmon et al., 1979; Álvarez et al., 1983).

Hyperthyroidism is usually accompanied by physiological symptoms such as sweating, heat intolerance and muscle weakness. However, also common symptoms such as nervousness, fatigue or weight lost may be confounded for primary psychiatric symptoms. Graves´ disease, an autosomal disorder, is the most frequent cause of hyperthyroidism or thyrotoxicosis. While proponents of psychosomatic theories suggested in the last century that an important etiological factor for hyperthyroidism was the presence of psychological conflicts, there is very slight evidence to support the theory. Clinicians in Europe, certainly do not support this conjecture, as shown in the E.C.L.W. study (Huyse et al, 2000). No cases of this endocrine condition were referred for psychiatric consult among 15,000 medical inpatients seen in psychosomatic psychiatry services because of psychopathological reasons (Lobo et al , 1992). However, there is some evidence to support the idea that stress can precipitate the hyperthyroidism (Santos et al, 2002) or

The study by Pérez- Echeverría was one of the early investigations reporting the prevalence of psychiatric disturbance among hyperthyroid patients. Only few more studies have reported prevalence data since then. (Trzepacz et al., 1988; Bunevicius et al., 2005). The study by Stern conducted in members of a patients` foundation documented, as expected, that anxiety (72%) and irritability (78%) were the commonest symptoms (Stern et al., 1996). Psychological disturbance of some degree is universal in Graves` disease (Pérez-Echeverría et al., 1986; Stern et al., 1996), and may delay the diagnosis of the hormonal disorder. Anxiety is most frequently reported, but also depressive syndromes. Rather unusual symptoms may accompany these psychopathological syndromes such as overactivity and restlessness or hyperacuity of perception and increased reaction to noise stimulus. It is the unusual presentation of anxiety (or depression) that may help the physician to differentiate the endocrine disorder from primary affective disturbance. Emotional lability may also be apparent, and both anxiety and irritability may be quite severe and stimulate relatively understandable behavior such as impatience and intolerance of frustration. While depression is not so common, it may be quite prominent and be accompanied by weakness, fatigue and other somatic symptoms. Psychomotor retardation is rare, the exception being the subgroup of elderly patients. "Apathetic hyperthyroidism" has been described in this age group (Mooradian & Arshg, 2008), and

Classical studies suggested that up to 20% of Graves` disease patients might have some kind of psychosis. However, as discussed by Lishman , there was probably a selection bias (Lishman, 1998). Delirium-type, acute organic syndromes are now rare because of advances in medical treatment. However, delirium in such cases may be a medical emergency. Affective psychoses have been described (Brownlie et al., 2000; Marian et al, 2009), but also schizophrenia-type psychoses, most commonly with paranoid ideation. Organic personality disorder has been described, particularly among the apathetic elderly. Distraibility and over-arousal have also been reported, sometimes leading to persistent cognitive impairment, which may continue even after the patient is euthyroid (Stern et al, 1996). Specific cognitive difficulties in hyperthyroid patient have been described, such as deterioration of memory,

concentration or visuomotor speed (MacCrimmon et al., 1979; Álvarez et al., 1983).

**4. Hyperthyroidism** 

complicate the clinical course (Fukao et al , 2003 ).

some of these cases may progress to stupor and coma.

The possibility that subclinical hyperthyroidism in the elderly increases the risk of Alzheimer´s disease has been suggested (Kalmijn, 2001) and we are now involved in a large longitudinal study to assess specific risks of dementia, including thyroid disease, in a 15 year follow-up study ingrained in the ZARADEMP project. (Lobo, 2005).

The initial symptoms in hyperthyroidism may be quite similar to anxiety disorders, but the described, unusual symptoms of anxiety may alert the clinicians (Kathol et al., 1986 ). Other symptoms that should alert the physicians are the preference for cold and intolerance to heat, or loss of weight coupled with increased appetite. A careful medical history and examination are mandatory in such cases and the laboratory test would usually give unequivocal answers to the diagnostic difficulties. An accelerated pulse during sleep or cognitive difficulties are also considered to suggest the diagnosis of hyperthyroidism in such cases (Hall et al., 1979; Mackenzie,1988). To help in the differential diagnosis some specific scales have been developed (Iacovides et al, 2000). Transient thyroid hormone elevations, usually mild, may occur in approximately 10% of psychiatric inpatients, but should not be diagnosed of hyperthyroidism. Thyroid abnormalities have also been documented in some studies in primary affective disorders (Oomen et al., 1996). However, later studies did not replicate the findings (Engum et al., 2002) and the possibility of factors of confusion such as the use of psychotropic medication has been considered. Other clinical situations may mimic the thyroid condition before the laboratory results are available, such as abuse of stimulants or drug intoxications. However, the nervousness and emotional lability in hyperthyroid patients may be wrongly diagnosed as alcohol abuse or abstinence.

Subclinical hyperthyroidism has also stirred interest in recent studies. The clinical interest derives from the fact that it has been associated with cognitive deterioration and dementia in the elderly (Kalmijn,2000;Ceresini,2009), both in cross-sectional and longitudinal studies.

While the clinical and epidemiological studies reviewed support the association of hyperthyroid function with psychopathological disturbance, the causal mechanisms are not clear (Bunevicius et al., 2006). One study suggested that the active thyroid hormone (T3) influenced mental performance in healthy subjects (Kathmann et al., 1994). The individuals overestimated time intervals and increased their word fluency, but no other cognitive problems were detected. Pérez-Echeverría (1985) and Lobo et al (1988) documented direct, convincing correlations between abnormal levels of thyroid hormones and psychopathology. The abnormal psychological phenomenon seemed to be directly related to the endocrine disturbance, since non-endocrine medical patients in the same ward, and with similar levels of illness severity had lower levels of psychopathology. Furthermore, in support of the direct effect of thyroid hormones elevation on the psychopathology, anxiety, depression and related phenomenon improved with "treatment as usual", when hormonal levels returned to normal, at the time of hospital discharge.

In general, there is a good resolution of anxiety and depression with antithyroid treatment alone, unless there is previous psychiatric history (Kathol et al., 1986). Beta-blockers such as propanolol are also considered to be effective in cases of anxiety (Trzepacz et al, 1988). However, recovery may be slow and reduced psychological well-being has been reported in a considerable proportion of "remitted" hyperthyroidism (Pérez-Echeverría, 1985). Bunevicius also reported persistent mood and anxiety symptoms in treated hyperthyroidism (Bunevicius et al., 2005). Psychosis may occur or be exacerbated by antithyroid medication. Low potency

Thyroid and Parathyroid Diseases and Psychiatric Disturbance 249

the elderly. Treatment of depression in such cases is recommended (Carvalho et al., 2009), but may be frustrating (Hendrick et al., 1998). It has been suggested that subclinical hypothyroidism is rather common in the general population, particularly in the adult and elderly women, but may go undetected and untreated. Screening tests of hormonal levels

Delirium has been observed in approximately 10% of severe cases of hypothyroidism, and organic delusional syndromes have been documented in some case reports. "Mixedema madness", a psychosis in untreated cases of hypothyroidism was described before the standard use of thyroid function tests (Kudrjavcev, 1978), but is quite rare now. Some authors have called "Hashimoto`s encephalopathy" the clinical picture of delirium with focal neurological signs and seizures. It has been considered to be associated with high levels of serum antithyroid antibodies, but the psychopathological symptoms probably

Longstanding hypothyroidism may end up in a marked dementia syndrome. Before, cognitive disturbance may be apparent (Samuels et al, 2008). Memory deterioration is common, but may be accompanied by impairment of other cognitive functions. While some cognitive difficulties may be associated with the depressive syndromes, some authors have reported independent, cognitive difficulties (Burmeister et al.,2001). Mild hypothyroidism has also been associated with mild cognitive difficulties (Bunevicius et al, 1999; Miller et al, 2007). While most cases of cognitive disturbance improve with hormonal treatment, some studies reported negative results (Walsh et al., 2003). Hypothyroidism used to be considered one example of reversible dementia with appropriate hormonal treatment (Cummings et al., 1980). However, most authors doubt about its effectiveness in well established cases of

Present knowledge about the effects of thyroid hormones in the central nervous system suggests the critical influence in brain development, and probably a direct role in adult brain homeostasis. Multiple isolated effects have been described, including a modulation of noradrenergic, serotonergic, and dopaminergic receptor function, and an influence on second messenger, calcium homeostasis, axonal transport mechanisms, and morphology. However, both the biochemical mechanisms and the physiological relevance are poorly understood.

Even minor changes in thyroid hormone may induce important affective changes (Bauer et al., 1990). However, the connections between this hormone and primary affective disorder remain controversial .Some authors conclude that depressed patients are basically euthyroid (Baumgartner, 1993). Thyroid autoimmunity has been reported in bipolar disorder (Kupka et al., 2002) but the finding needs replication. Special consideration merit the cases of hypothyroidism seen in 10% of patients treated with lithium. Disregulation in the hypothalamic-pituitary-thyroid axis is commonly linked to primary affective disorders (Hendrick, 1998; Engum et al., 2002). Close to 50% of depressive patients with major depression have a positive, blunted TSH response to TRH. While these findings support the connection between thyroid disorder and primary affective disorder (Stipcevic et al., 2008), other authors conclude that depressed patients are basically euthyroid (Baumgartner et al.,

The neuropsychiatric symptoms of hypothyroidism maybe the first to recover, probably in few days, with adequate hormonal replacement. Slow correction is usually recommended,

1993). New studies are considered to be needed to clarify this relationship.

overlap with delirium of different etiologies (Schiess & Pardo, 2008).

dementia (Clarnette & Patterson, 1994; Lobo et al., 2010).

may be crucial in doubtful cases.

neuroleptics such as haloperidol and perphenazine have been reported, including symptoms resembling thyroid storm and malignant neuroleptic syndrome. There is a limited clinical experience with the new generation of neuroleptics. Finally, treatment of depression is recommended if psychopathological symptoms are severe or persistent.

#### **5. Hypothyroidism**

Classical symptoms of hypothyroidism include fatigue and weakness, somnolence, weight gain, constipation and cold intolerance. However, other common symptoms may suggest primary psychiatric disease and include lethargy, progressive slowing, diminished initiative and impaired concentration and memory. (Kornstein et al., 2000).

Congenital hypothyroidism is also well known, and usually occurs as the consequence of thyroid dysgenesis, and more rarely as the result of inherited defects in the synthesis of thyroid hormone. The cretinism syndrome emerges if hypothyroidism is untreated. This syndrome is characterized by mental retardation, aside from the classical somatic and neurological signs. Screening programs for hypothyroidism at birth are now mandatory to prevent this severe condition. (American Academy of Pediatrics, 2006), since early treatment should lead to normal intellectual development. The most frequent cause of adult hypothyroidism is Hashimoto´s thyroiditis or autoimmune thyroiditis. Treatment of Grave´s disease with radioactive iodine may also lead to hypothyroidism, but an important iatrogenic cause in psychiatric patients is the side effect of lithium, particularly in vulnerable individuals such as women or rapid cyclers.

There are no good prevalence studies of psychiatric disturbance in hypothyroid patients, but the main psychiatric syndromes have been described in case reports and/or clinical samples. Depression and, to a lesser extent anxiety (Sait Gönen et al., 2004), occur rather frequently, even with moderate hormonal deficits, and could be observed as early as few weeks after the onset of the condition. Previous history of affective disorder is considered to increase the risk. The depressive syndromes may mimic primary affective disorder, particularly in old women, and may need the checking of hormonal levels for the differential diagnosis. The initial symptoms of hypothyroidism mimic the somatic symptoms of depression, and may include low energy, fatigue, apathy, low appetite and sleep disturbance. Marked irritability and labiliy of mood may alert to the presence of atypical syndromes, suggesting an organic condition. Thyroid replacement is required in such cases and is usually effective, although depression persists in a proportion of patients

A special emphasis should be placed in subclinical hypothyroidism. In this controversial condition, which is sometimes classified as grade 2 and grade 3 hypothyroidism, there may be minimal clinical, traditional symptoms, and thyroid levels may be normal, but with increased TSH. The relevance of subclinical hypothyroidism is derived from the fact that depression is common and may severely affect quality of life. (Haggerty et al., 1993; Dermatini et al., 2010). In the study by Chueire et al. (2003), using standardized instruments and psychiatric diagnostic citeria, they found depression among 49% of subclinical hypothyroid, elderly patients. The same authors have recently reported that depression in such patients is more frequent than among patients with overt hyperthyroidism (Chueire et al., 2007). Furthermore, they conclude that subclinical hypothyroidism increases more than four times the risk of depression, and highlight the relevance of thyroid screening tests in

neuroleptics such as haloperidol and perphenazine have been reported, including symptoms resembling thyroid storm and malignant neuroleptic syndrome. There is a limited clinical experience with the new generation of neuroleptics. Finally, treatment of depression is

Classical symptoms of hypothyroidism include fatigue and weakness, somnolence, weight gain, constipation and cold intolerance. However, other common symptoms may suggest primary psychiatric disease and include lethargy, progressive slowing, diminished initiative

Congenital hypothyroidism is also well known, and usually occurs as the consequence of thyroid dysgenesis, and more rarely as the result of inherited defects in the synthesis of thyroid hormone. The cretinism syndrome emerges if hypothyroidism is untreated. This syndrome is characterized by mental retardation, aside from the classical somatic and neurological signs. Screening programs for hypothyroidism at birth are now mandatory to prevent this severe condition. (American Academy of Pediatrics, 2006), since early treatment should lead to normal intellectual development. The most frequent cause of adult hypothyroidism is Hashimoto´s thyroiditis or autoimmune thyroiditis. Treatment of Grave´s disease with radioactive iodine may also lead to hypothyroidism, but an important iatrogenic cause in psychiatric patients is the side effect of lithium, particularly in vulnerable

There are no good prevalence studies of psychiatric disturbance in hypothyroid patients, but the main psychiatric syndromes have been described in case reports and/or clinical samples. Depression and, to a lesser extent anxiety (Sait Gönen et al., 2004), occur rather frequently, even with moderate hormonal deficits, and could be observed as early as few weeks after the onset of the condition. Previous history of affective disorder is considered to increase the risk. The depressive syndromes may mimic primary affective disorder, particularly in old women, and may need the checking of hormonal levels for the differential diagnosis. The initial symptoms of hypothyroidism mimic the somatic symptoms of depression, and may include low energy, fatigue, apathy, low appetite and sleep disturbance. Marked irritability and labiliy of mood may alert to the presence of atypical syndromes, suggesting an organic condition. Thyroid replacement is required in such cases and is usually effective, although depression persists in a proportion of patients A special emphasis should be placed in subclinical hypothyroidism. In this controversial condition, which is sometimes classified as grade 2 and grade 3 hypothyroidism, there may be minimal clinical, traditional symptoms, and thyroid levels may be normal, but with increased TSH. The relevance of subclinical hypothyroidism is derived from the fact that depression is common and may severely affect quality of life. (Haggerty et al., 1993; Dermatini et al., 2010). In the study by Chueire et al. (2003), using standardized instruments and psychiatric diagnostic citeria, they found depression among 49% of subclinical hypothyroid, elderly patients. The same authors have recently reported that depression in such patients is more frequent than among patients with overt hyperthyroidism (Chueire et al., 2007). Furthermore, they conclude that subclinical hypothyroidism increases more than four times the risk of depression, and highlight the relevance of thyroid screening tests in

recommended if psychopathological symptoms are severe or persistent.

and impaired concentration and memory. (Kornstein et al., 2000).

individuals such as women or rapid cyclers.

**5. Hypothyroidism** 

the elderly. Treatment of depression in such cases is recommended (Carvalho et al., 2009), but may be frustrating (Hendrick et al., 1998). It has been suggested that subclinical hypothyroidism is rather common in the general population, particularly in the adult and elderly women, but may go undetected and untreated. Screening tests of hormonal levels may be crucial in doubtful cases.

Delirium has been observed in approximately 10% of severe cases of hypothyroidism, and organic delusional syndromes have been documented in some case reports. "Mixedema madness", a psychosis in untreated cases of hypothyroidism was described before the standard use of thyroid function tests (Kudrjavcev, 1978), but is quite rare now. Some authors have called "Hashimoto`s encephalopathy" the clinical picture of delirium with focal neurological signs and seizures. It has been considered to be associated with high levels of serum antithyroid antibodies, but the psychopathological symptoms probably overlap with delirium of different etiologies (Schiess & Pardo, 2008).

Longstanding hypothyroidism may end up in a marked dementia syndrome. Before, cognitive disturbance may be apparent (Samuels et al, 2008). Memory deterioration is common, but may be accompanied by impairment of other cognitive functions. While some cognitive difficulties may be associated with the depressive syndromes, some authors have reported independent, cognitive difficulties (Burmeister et al.,2001). Mild hypothyroidism has also been associated with mild cognitive difficulties (Bunevicius et al, 1999; Miller et al, 2007). While most cases of cognitive disturbance improve with hormonal treatment, some studies reported negative results (Walsh et al., 2003). Hypothyroidism used to be considered one example of reversible dementia with appropriate hormonal treatment (Cummings et al., 1980). However, most authors doubt about its effectiveness in well established cases of dementia (Clarnette & Patterson, 1994; Lobo et al., 2010).

Present knowledge about the effects of thyroid hormones in the central nervous system suggests the critical influence in brain development, and probably a direct role in adult brain homeostasis. Multiple isolated effects have been described, including a modulation of noradrenergic, serotonergic, and dopaminergic receptor function, and an influence on second messenger, calcium homeostasis, axonal transport mechanisms, and morphology. However, both the biochemical mechanisms and the physiological relevance are poorly understood.

Even minor changes in thyroid hormone may induce important affective changes (Bauer et al., 1990). However, the connections between this hormone and primary affective disorder remain controversial .Some authors conclude that depressed patients are basically euthyroid (Baumgartner, 1993). Thyroid autoimmunity has been reported in bipolar disorder (Kupka et al., 2002) but the finding needs replication. Special consideration merit the cases of hypothyroidism seen in 10% of patients treated with lithium. Disregulation in the hypothalamic-pituitary-thyroid axis is commonly linked to primary affective disorders (Hendrick, 1998; Engum et al., 2002). Close to 50% of depressive patients with major depression have a positive, blunted TSH response to TRH. While these findings support the connection between thyroid disorder and primary affective disorder (Stipcevic et al., 2008), other authors conclude that depressed patients are basically euthyroid (Baumgartner et al., 1993). New studies are considered to be needed to clarify this relationship.

The neuropsychiatric symptoms of hypothyroidism maybe the first to recover, probably in few days, with adequate hormonal replacement. Slow correction is usually recommended,

Thyroid and Parathyroid Diseases and Psychiatric Disturbance 251

1986). Psychosis has rarely been described, but Joborn et al reported paranoid ideas and hallucinations in their study and Bresler et al (2000) reported violent behavior, included attempted mass murder in a case of paranoid ideation in clear consciousness. More chronic cases, aside from cognitive disorder, have been associated with personality changes leading

The pathogenesis of psychiatric syndromes in hyperparathyroidism may be explained by the hipercalcemia itself, since similar symptoms have been reported in different etiologies. The calcium ions are considered to be crucial in normal neurotransmission. High calcium levels have been associated with abnormal CSF concentrations of monoamine metabolites, such as 5-hydroxy-indoleacetic acid (5-HIAA) found in primary hyperparathyroid patients. Calcium levels correlated with depressive symptoms and returned to normal after parathyroid surgery (Joborn et al 1988). Affective symptoms in primary hyperparathyroidism have also been reported to correlate with abnormal levels of both cortisol and melatonin, which improve after successful surgery (Linder et al 1988). Nevertheless, other studies did not find a correlation of psychopathology and calcium levels. (Joborn et al 1988; White et al., 1996). The influence of hypomagnesemia and hypophosphoremia, as well as the parathormone itself and vitamin B have also been hypothesized to influence the pathogenesis of

Most studies suggest that psychiatric symptoms in hyperparathyroidism significantly improve or disappear after successful surgical treatment, unless the endocrine disorder is chronic. (Roman and Sosa 2007, Casella et al., 2008, Espiritu, 2010). Joborn reported that improvement may be observed in few days, and the same authors have shown that approximately half the patients significantly improved in a follow-up period of several years (Joborn et al., 1988). Wilheim et al 2004 observed that both depression and quality of life improved in a similar proportion of patients. However, Chiang (Chiang et al .,2005), did not find significant differences in neuropsychological performance between patients undergoing parathyroidectomy and the controls. On the basis of significant improvement in depressive symptoms and quality of life in patients with mild hypercalcemia, parathyroidectomy has been suggested in the management of asymptomatic hyperparathyroidism (Wilheim et al., 2004). However, in view of rather conflicting results, we have previously recommended a conservative treatment in asymptomatic cases or cases

Hypoparathyroidism can occur as a primary form with inadequate parathyroid hormone secretion, but the commonest cause is the removal of, or interference with blood supply in the parathyroid gland during neck surgery. The affected patients present with hypocalcemia,

Muscle cramps and paresthesias are typical symptoms, but facial grimacing and seizures may occur, suggesting a neuro-psychiatric condition. In a classical study, Denko & Kaelbing (1962) and similarly other authors (Velasco et al., 1999), reported a high frequency of cognitive disorder, but a considerable proportion of patients had psychotic symptoms, including hallucinations and catatonic stupor. However, the systematic study of psychiatric symptoms in hyperparathyroid patients is sparse. Reviews of this subject have concluded

to withdrawn behavior and seclusion.

psychiatric symptoms in hyperparathyroidism.

with mild symptoms (Lobo et al.,1992).

which causes neuromuscular irritability.

**7. Hypoparathyroidism** 

particularly in the elderly, because the risk of cardiac or psychiatric dysfunction. Short periods of mania or hypomania may occur during the treatment, but will typically subside during the replacement. Moderate doses of neuroleptics are usually well tolerated in cases of psychosis, but these cases may not recover totally.

#### **6. Hyperparathyroidism**

Primary hyperparathyroidism is often caused by parathyroid adenomas (Bresler et al., 2002). It is characterized by the presence of elevated parathyroid hormone, elevated calcium and hypophosphatemia. Hyperparathyroidism may lead to renal calculus and bone disease. Classical symptoms of hypercalcemia, such as anorexia, lethargy or fatigue, may be attributed to primary psychiatric disease. The symptoms may be insidious, but gradually increase and may lead to coma. The early recognition of hyperparathyroidism is now more common, due to the use of routine biochemical screening.

The prevalence of hyperparathyroidism is considered to be around 0.1%, and increases both in women and with age. Radiation of head and neck may produce this condition, but is also a known consequence of lithium therapy in psychiatric patients (Kingsbury & Salzman, 1993). The common use of lithium in long term treatment of affective disorders should alert physicians about side effects, since hyperparathyroidism symptoms may be confounded for affective psychopathology. The determination of serum calcium levels may be considered in the protocol of atypical psychiatric presentations of cognitive difficulties or affective symptoms, particularly depression. Calcium levels may also be monitored in patients in lithium treatment, since hypercalcemia as a secondary affect has been reported and may be confounded with the relapse of affective symptoms (Pieri-Balandraud et al., 2001).The EEG is an important diagnostic tool in such cases, since the slow activity accompanied by frontal delta paroxysms are quite suggestive of hypercalcemia.

Lithium is considered to alter the feedback inhibition, and the set point of the parathyroid gland. It also stimulates hormone secretion. The lower incidence of stones in lithium-induced hypercalcemia, contrary to what is observed in primary hyperparathyroidism, has been considered to be the effect of interference of lithium in cAMP production (Kingsburg et al 1993). Hypercalcemia should be considered in the differential diagnosis of bipolar, lithiumtreated patients with unusual psychopathological symptoms and/or resistance to treatment. Mild calcium elevations may be managed medically. However, cessation of lithium frequently does not correct the hyperparathyrodism and the parathyroidectomy may be necessary.

Psychopathological symptoms are considered to be quite common in hyperparathyroidism (Brown et al 1987). However, most studies are derived from case reports or were completed in short samples and standardized methods of assessment were rarely used (White et al 1996). Depressive and anxiety syndromes have been most frequently described (Joborn et al., 1986; Birder, 1988). Nevertheless, the preponderance of symptoms such as apathy, fatigue, irritability or neuro-vegetative symptoms should alert the physician. Cognitive symptoms of depression are usually not as severe as in primary affective disorder, the exception being the elderly patients (Linder et al 1988). Overt delirium has frequently been observed when hypercalcemia is high (above 16 mg/dl), and coma has been reported with serum levels above 19 mg/dl (Petersen 1968). In the elderly, cognitive disorders and eventually dementing syndromes may occur if the endocrine disorder persists (Joborn et al.,

particularly in the elderly, because the risk of cardiac or psychiatric dysfunction. Short periods of mania or hypomania may occur during the treatment, but will typically subside during the replacement. Moderate doses of neuroleptics are usually well tolerated in cases

Primary hyperparathyroidism is often caused by parathyroid adenomas (Bresler et al., 2002). It is characterized by the presence of elevated parathyroid hormone, elevated calcium and hypophosphatemia. Hyperparathyroidism may lead to renal calculus and bone disease. Classical symptoms of hypercalcemia, such as anorexia, lethargy or fatigue, may be attributed to primary psychiatric disease. The symptoms may be insidious, but gradually increase and may lead to coma. The early recognition of hyperparathyroidism is now more

The prevalence of hyperparathyroidism is considered to be around 0.1%, and increases both in women and with age. Radiation of head and neck may produce this condition, but is also a known consequence of lithium therapy in psychiatric patients (Kingsbury & Salzman, 1993). The common use of lithium in long term treatment of affective disorders should alert physicians about side effects, since hyperparathyroidism symptoms may be confounded for affective psychopathology. The determination of serum calcium levels may be considered in the protocol of atypical psychiatric presentations of cognitive difficulties or affective symptoms, particularly depression. Calcium levels may also be monitored in patients in lithium treatment, since hypercalcemia as a secondary affect has been reported and may be confounded with the relapse of affective symptoms (Pieri-Balandraud et al., 2001).The EEG is an important diagnostic tool in such cases, since the slow activity accompanied by frontal

Lithium is considered to alter the feedback inhibition, and the set point of the parathyroid gland. It also stimulates hormone secretion. The lower incidence of stones in lithium-induced hypercalcemia, contrary to what is observed in primary hyperparathyroidism, has been considered to be the effect of interference of lithium in cAMP production (Kingsburg et al 1993). Hypercalcemia should be considered in the differential diagnosis of bipolar, lithiumtreated patients with unusual psychopathological symptoms and/or resistance to treatment. Mild calcium elevations may be managed medically. However, cessation of lithium frequently does not correct the hyperparathyrodism and the parathyroidectomy may be necessary.

Psychopathological symptoms are considered to be quite common in hyperparathyroidism (Brown et al 1987). However, most studies are derived from case reports or were completed in short samples and standardized methods of assessment were rarely used (White et al 1996). Depressive and anxiety syndromes have been most frequently described (Joborn et al., 1986; Birder, 1988). Nevertheless, the preponderance of symptoms such as apathy, fatigue, irritability or neuro-vegetative symptoms should alert the physician. Cognitive symptoms of depression are usually not as severe as in primary affective disorder, the exception being the elderly patients (Linder et al 1988). Overt delirium has frequently been observed when hypercalcemia is high (above 16 mg/dl), and coma has been reported with serum levels above 19 mg/dl (Petersen 1968). In the elderly, cognitive disorders and eventually dementing syndromes may occur if the endocrine disorder persists (Joborn et al.,

of psychosis, but these cases may not recover totally.

common, due to the use of routine biochemical screening.

delta paroxysms are quite suggestive of hypercalcemia.

**6. Hyperparathyroidism** 

1986). Psychosis has rarely been described, but Joborn et al reported paranoid ideas and hallucinations in their study and Bresler et al (2000) reported violent behavior, included attempted mass murder in a case of paranoid ideation in clear consciousness. More chronic cases, aside from cognitive disorder, have been associated with personality changes leading to withdrawn behavior and seclusion.

The pathogenesis of psychiatric syndromes in hyperparathyroidism may be explained by the hipercalcemia itself, since similar symptoms have been reported in different etiologies. The calcium ions are considered to be crucial in normal neurotransmission. High calcium levels have been associated with abnormal CSF concentrations of monoamine metabolites, such as 5-hydroxy-indoleacetic acid (5-HIAA) found in primary hyperparathyroid patients. Calcium levels correlated with depressive symptoms and returned to normal after parathyroid surgery (Joborn et al 1988). Affective symptoms in primary hyperparathyroidism have also been reported to correlate with abnormal levels of both cortisol and melatonin, which improve after successful surgery (Linder et al 1988). Nevertheless, other studies did not find a correlation of psychopathology and calcium levels. (Joborn et al 1988; White et al., 1996). The influence of hypomagnesemia and hypophosphoremia, as well as the parathormone itself and vitamin B have also been hypothesized to influence the pathogenesis of psychiatric symptoms in hyperparathyroidism.

Most studies suggest that psychiatric symptoms in hyperparathyroidism significantly improve or disappear after successful surgical treatment, unless the endocrine disorder is chronic. (Roman and Sosa 2007, Casella et al., 2008, Espiritu, 2010). Joborn reported that improvement may be observed in few days, and the same authors have shown that approximately half the patients significantly improved in a follow-up period of several years (Joborn et al., 1988). Wilheim et al 2004 observed that both depression and quality of life improved in a similar proportion of patients. However, Chiang (Chiang et al .,2005), did not find significant differences in neuropsychological performance between patients undergoing parathyroidectomy and the controls. On the basis of significant improvement in depressive symptoms and quality of life in patients with mild hypercalcemia, parathyroidectomy has been suggested in the management of asymptomatic hyperparathyroidism (Wilheim et al., 2004). However, in view of rather conflicting results, we have previously recommended a conservative treatment in asymptomatic cases or cases with mild symptoms (Lobo et al.,1992).

#### **7. Hypoparathyroidism**

Hypoparathyroidism can occur as a primary form with inadequate parathyroid hormone secretion, but the commonest cause is the removal of, or interference with blood supply in the parathyroid gland during neck surgery. The affected patients present with hypocalcemia, which causes neuromuscular irritability.

Muscle cramps and paresthesias are typical symptoms, but facial grimacing and seizures may occur, suggesting a neuro-psychiatric condition. In a classical study, Denko & Kaelbing (1962) and similarly other authors (Velasco et al., 1999), reported a high frequency of cognitive disorder, but a considerable proportion of patients had psychotic symptoms, including hallucinations and catatonic stupor. However, the systematic study of psychiatric symptoms in hyperparathyroid patients is sparse. Reviews of this subject have concluded

Thyroid and Parathyroid Diseases and Psychiatric Disturbance 253

frequent as in the past, due to improvements in diagnosis and treatment of the hormonal disorders, but still, a high prevalence of psychiatric disturbances has been reported in both thyroid and parathyroid diseases. Depression and anxiety together with cognitive disorders are the most common presentations. Cognitive impairment is frequent among the elderly, and dementia can also be found; delirium, but also psychosis in clear consciousness, including paranoid psychosis and mania may be seen in severe endocrinopaties. Methodological issues limit the value of the available data. However, standardized research interviews were used in some studies reviewed here and standardized instruments in most. The emerging general picture suggests the clinical relevance of the documented psychopathology, which may be very severe in some cases. The authors review their contribution in two relevant, epidemiological type of studies. In the first one, neat correlations were documented between hormonal disturbances and psychopathology in patients hospitalized because of hyperthyroid conditions. In the second study, during the ZARADEMP project, the clustering of somatic and psychiatric morbidity was documented in a large, community sample of individuals aged 55 years or more, and thyroid disease was

 94-1562, 97-1321E, 98-0103, 01-0255, 03-0815, G03/128 from the Fondo de Investiugación Sanitaria, and the Spanish Ministry of Health, Instituto de Salud Carlos III. Madrid

Alvarez Ma, Gomez A, Alavez E, et al: Attention disturbance in Grave´s disease.

American Academy of Pediatrics, Section on Endocrinology an Committee on Genetics:

Bauer, M.S. and Whybrow, P.C. (1990). Rapid cycling bipolar affective disorder. II.

Baumgartner, A. (1993). Thyroid hormones and depressive disorders--critical overview and

Bresler, S.A., Logan, W.S. and Washington, D. (2000). Hyperparathyroidism and psychosis:

Brown, G.G., Preisman, R.C. and Kleerekoper, M. (1987). Neurobehavioral symptoms in

Brownlie, BE., Rae, AM., Walshe, JW.,et al: Psychoses association-thytoxicosis-"thytotoxic

perspectives. Part 1: Clinical aspects. *Nervenarzt.* 64, 1-10.

possible prelude to murder. *J Forensic Sci.* 45, 728-730.

parathyroidectomy. *Henry Ford Hosp Med J.* 35, 211-215.

Update of newborn screening and therapy for congenital hytpothyroidism.

Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary

mild primary hyperparathyroidism: related to hypercalcemia but not improved by

psychosis": a report of with statistical analysis of incidence. Eur J End 142:438-

considered to have specific weight in this association.

CIBERSAM PI10/01132 from the Instituto de Salud Carlos III

Psychoneuroendocrinology 8:451-454,1983

study. *Arch Gen Psychiatry.* 47, 435-440.

Pediatrics 117:2290-2303,2006

**9. Acknowledgements** 

**Supported by Grants:** 

Spain.

**10. References** 

444,2000

that approximately half the cases due to surgery had psychopathological symptoms, and the frequency might be even higher in idiopathic cases (Lishman 1998). Delirium has been commonly reported in the post-surgery period, as might be expected in relation to abrupt biochemical disturbances.

In non-acute idiopathic hypoparathyroidism, emotional lability and anxious syndromes have been described, and also depressive syndromes. Cognitive difficulties and even dementia syndromes have also been reported in these patients. The emotional lability may coincide with fluctuating, neurotic kind of minor symptoms and behavior. Irritability, nervousness and socially inadequate behavior are among the symptoms most often described. On the contrary the reviews suggest that psychotic syndromes in clear conscientious are uncommon. Chronic cases of hypoparathyroidism may eventually lead to neurological and cognitive deficits. They are considered to be related to intracranial calcification, and in such cases they are irreversible (Kowdley et al., 1999).

Hypoparathyroidism is also frequent in the velocardiofacial syndrome (22q.11.2 deletion syndrome), in wich attentional and behavioral disorders are common among children, and schizophreniform and bipolar disorders are common in adults. (Jolin et al., 2009). In the pathogenesis of this condition, the hypocalcemia itself is considered to be the main agent. Patients with calcium levels in the lower limit of normal may be relatively asymptomatic ("partial parathyroid insufficiency"), but psychopathological symptoms such as depression and anxiety may appear episodically, precipitated by calcium deprivation. In an early study, Fourman et al (1967) reported the efficacy of calcium versus placebo in a double blind clinical trial to improve the psychopathological symptoms.

An important issue, similarly to other endocrine disorders, is the failure to detect and diagnose this condition. This is particularly relevant in cases of anxiety resistant to treatment. Since anxiety can provoke hyperventilation, tetany in hypoparathyroid patients may be precipitated (Fourman et al., 1967). In doubtful cases, calcium and phosphorus levels should be monitored, especially in patients operated in the neck. The presenting signs of hypoparathyroidism may be an epileptic crisis or an abnormal EEG.

Psychiatric syndromes in non-chronic hypoparathyroidism patients are treatable with calcium supplements and vitamin D. (Velasco et al., 1999). Depressive and anxiety syndromes have a good response, unless they are severe. The benzodiazepines are considered to be effective in cases of anxiety. Improvement in cognitive syndromes has also been reported in a considerable proportion of patients, the exception being the severe cases and the dementia syndromes. There is some report about the susceptibility of these patients to the parkinsonian side effects of neuroleptics. However, Pratty et al (1986) did not confirm this unwanted side effect.

#### **8. Conclusions**

This chapter reviews available data in relation to the characteristics and frequency of psychiatric syndromes in primary thyroid and parathyroid disturbances, including the contributions of the authors. It also reviews issues of diagnosis and differential diagnosis; mechanisms of production of psychiatric symptomatology; and treatment issues, including response of psychiatric syndromes to treatment of the endocrinopathy and to psychotropic medication. The most severe psychiatric syndromes in endocrine diseases are not as frequent as in the past, due to improvements in diagnosis and treatment of the hormonal disorders, but still, a high prevalence of psychiatric disturbances has been reported in both thyroid and parathyroid diseases. Depression and anxiety together with cognitive disorders are the most common presentations. Cognitive impairment is frequent among the elderly, and dementia can also be found; delirium, but also psychosis in clear consciousness, including paranoid psychosis and mania may be seen in severe endocrinopaties. Methodological issues limit the value of the available data. However, standardized research interviews were used in some studies reviewed here and standardized instruments in most. The emerging general picture suggests the clinical relevance of the documented psychopathology, which may be very severe in some cases. The authors review their contribution in two relevant, epidemiological type of studies. In the first one, neat correlations were documented between hormonal disturbances and psychopathology in patients hospitalized because of hyperthyroid conditions. In the second study, during the ZARADEMP project, the clustering of somatic and psychiatric morbidity was documented in a large, community sample of individuals aged 55 years or more, and thyroid disease was considered to have specific weight in this association.

#### **9. Acknowledgements**

#### **Supported by Grants:**

252 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

that approximately half the cases due to surgery had psychopathological symptoms, and the frequency might be even higher in idiopathic cases (Lishman 1998). Delirium has been commonly reported in the post-surgery period, as might be expected in relation to abrupt

In non-acute idiopathic hypoparathyroidism, emotional lability and anxious syndromes have been described, and also depressive syndromes. Cognitive difficulties and even dementia syndromes have also been reported in these patients. The emotional lability may coincide with fluctuating, neurotic kind of minor symptoms and behavior. Irritability, nervousness and socially inadequate behavior are among the symptoms most often described. On the contrary the reviews suggest that psychotic syndromes in clear conscientious are uncommon. Chronic cases of hypoparathyroidism may eventually lead to neurological and cognitive deficits. They are considered to be related to intracranial

Hypoparathyroidism is also frequent in the velocardiofacial syndrome (22q.11.2 deletion syndrome), in wich attentional and behavioral disorders are common among children, and schizophreniform and bipolar disorders are common in adults. (Jolin et al., 2009). In the pathogenesis of this condition, the hypocalcemia itself is considered to be the main agent. Patients with calcium levels in the lower limit of normal may be relatively asymptomatic ("partial parathyroid insufficiency"), but psychopathological symptoms such as depression and anxiety may appear episodically, precipitated by calcium deprivation. In an early study, Fourman et al (1967) reported the efficacy of calcium versus placebo in a double blind

An important issue, similarly to other endocrine disorders, is the failure to detect and diagnose this condition. This is particularly relevant in cases of anxiety resistant to treatment. Since anxiety can provoke hyperventilation, tetany in hypoparathyroid patients may be precipitated (Fourman et al., 1967). In doubtful cases, calcium and phosphorus levels should be monitored, especially in patients operated in the neck. The presenting signs of

Psychiatric syndromes in non-chronic hypoparathyroidism patients are treatable with calcium supplements and vitamin D. (Velasco et al., 1999). Depressive and anxiety syndromes have a good response, unless they are severe. The benzodiazepines are considered to be effective in cases of anxiety. Improvement in cognitive syndromes has also been reported in a considerable proportion of patients, the exception being the severe cases and the dementia syndromes. There is some report about the susceptibility of these patients to the parkinsonian side effects of neuroleptics. However, Pratty et al (1986) did not confirm

This chapter reviews available data in relation to the characteristics and frequency of psychiatric syndromes in primary thyroid and parathyroid disturbances, including the contributions of the authors. It also reviews issues of diagnosis and differential diagnosis; mechanisms of production of psychiatric symptomatology; and treatment issues, including response of psychiatric syndromes to treatment of the endocrinopathy and to psychotropic medication. The most severe psychiatric syndromes in endocrine diseases are not as

calcification, and in such cases they are irreversible (Kowdley et al., 1999).

clinical trial to improve the psychopathological symptoms.

hypoparathyroidism may be an epileptic crisis or an abnormal EEG.

biochemical disturbances.

this unwanted side effect.

**8. Conclusions** 


#### **10. References**


Thyroid and Parathyroid Diseases and Psychiatric Disturbance 255

Espiritu RP, Kearns AE, Vickers KS, Grant C, Ryu E, Wermers RA. Depression in Primary

Fourman, P., Rawnsley, K., Davis, R.H., Jones, K.H. and Morgan, D.B. (1967). Effect of

Fukao A, Takamatsu J, Murakami Y, Sakane S, Miyauchi A, Kuma K, et al.(2003) The

Haggerty JJ, Jr., Stern RA, Mason GA, Beckwith J, Morey CE, Prange AJ, Jr. Subclinical

Hall RC, Gruzenski WP, Popkin MK. Differential diagnosis of somatopsychic disorders.

Hendrick V, Altshuler L, Whybrow P. Psychoneuroendocrinology of mood disorders. The

Huyse FJ, Herzog T, Lobo A, Malt UF, Opmeer BC, Stein B, Creed F, Crespo MD, Cardoso

Iacovides A, Fountoulakis KN, Grammaticos P, Ierodiakonou C. Difference in symptom

Joborn, C., Hetta, J., Palmer, M., Akerstrom, G. and Ljunghall, S. (1986). Psychiatric

Joborn, C., Hetta, J., Rastad, J., Agren, H., Akerstrom, G. and Ljunghall, S. (1988). Psychiatric

Jolin, E. M., R. A. Weller and E. B. Weller. 2009. "Psychosis in children with velocardiofacial syndrome (22q11.2 deletion syndrome)." Curr Psychiatry Rep 11(2):99-105. Kalmijn, S., Mehta, K.M., Pols, H.A., Hofman, A., Drexhage, H.A. and Breteler, M.M. (2000).

Kathmann N, Kuisle U, Bommer M, Naber D, Muller OA, Engel RR. Effects of elevated

Kathol R.G. (2002). Endocrine Disorders. In *The American Psychiatric Publishing textbook of* 

Rundell, 2nd edn, pp. 563-567. Washington, DC: American Psychiatric Pub. Kathol, R.G. and Delahunt, J.W. (1986). The relationship of anxiety and depression to

Sep 14.

915.

92.

77-87.

28.

May;58(5):550-5.

Mar;150(3):508-10.

Psychosomatics1979 Jun;20(6):381-5, 8-9.

*Acta Psychiatrica Scandinavica* 2000; 101(5): 360-366.

hyperparathyroidism. *Biol Psychiatry.* 23, 149-158.

*Endocrinol (Oxf).* 53, 733-737.

Neuropsychobiology1994;29(3):136-42.

hyperthyroidism. Int J Psychiatry Med2000;30(1):71-81.

Hyperparathyroidism: Prevalence and Benefit of Surgery. J Clin Endocrinol Metab

calcium on mental symptoms in partial parathyroid insufficiency. *Lancet.* 2, 914-

relationship of psychological factors to the prognosis of hyperthyroidism in antithyroid drug-treated patients with Graves' disease. Clin Endocrinol (Oxf)2003

hypothyroidism: a modifiable risk factor for depression? Am J Psychiatry1993

hypothalamic-pituitary-thyroid axis. Psychiatr Clin North Am1998 Jun;21(2):277-

G, Guimaraes-Lopes R, Mayou R, van Moffaert M, Rigatelli M, Sakkas P, Tienari P. European Consultation Liaison Psychiatric Services: the ECLW collaborative study.

profile between generalized anxiety disorder and anxiety secondary to

symptomatology in patients with primary hyperparathyroidism. *Ups J Med Sci.* 91,

symptoms and cerebrospinal fluid monoamine metabolites in primary

Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study. *Clin* 

triiodothyronine on cognitive performance and mood in healthy subjects.

*consultation-liaison psychiatry psychiatry in the medically ill,* ed., M.G. Wise and J.R.

symptoms of hyperthyroidism using operational criteria. *Gen Hosp Psychiatry.* 8, 23-


Bunevicius R, Prange AJ, Jr. Psychiatric manifestations of Graves' hyperthyroidism: pathophysiology and treatment options. CNS Drugs2006;20(11):897-909. Burmeister LA, Ganguli M, Dodge HH, Toczek T, DeKosky ST, Nebes RD. Hypothyroidism

Carroll, B.J., Feinberg, M., Greden, J.F., Tarika, J., Albala, A.A., Haskett, R.F., James, N.M.,

Carvalho GA, Bahls SC, Boeving A, Graf H. Effects of selective serotonin reuptake inhibitors

Casella C, Pata G, Di Betta E, Nascimbeni R. [Neurological and psychiatric disorders in

Ceresini G, Lauretani F, Maggio M, Ceda GP, Morganti S, Usberti E, et al. Thyroid function

Chiang, C. Y., D. G. Andrewes, D. Anderson, M. Devere, I. Schweitzer and J. D. Zajac. 2005.

Chueire VB, Romaldini JH, Ward LS. Subclinical hypothyroidism increases the risk for depression in the elderly. Arch Gerontol Geriatr. 2007 Jan-Feb;44 (1):21-8. Chueire VB, Silva ET, Perotta E, Romaldini JH, Ward LS. High serum TSH levels are

Clarnette RM, Patterson CJ. Hypothyroidism: does treatment cure dementia? J Geriatr

Cummings, J., D. F. Benson and S. LoVerme, Jr. 1980. "Reversible dementia. Illustrative

Demartini, B., Masu, A., Scarone, S., Pontiroli, AE., & Gambini, O. Prevalence of depression

Denko, J. D. and R. Kaelbling. 1962. "The psychiatric aspects of hypoparathyroidism." Acta

Eastwood R. Relationship between physical and psychological morbidity. In: Williams P,

Eiber, R., Berlin, I., Grimaldi, A. and Bisserbe, J.C. (1997). Insulin-dependent diabetes and

Engum, A., Bjoro, T., Mykletun, A. and Dahl, A.A. (2002). An association between

Invecchiare in Chianti study. J Am Geriatr Soc2009 Jan;57(1):89-93.

Dec;11(12):1177-85.

62(1):99-104.

Jun;36(3):281-8.

82.

357.

clinical utility. *Arch Gen Psychiatry.* 38, 15-22.

thyroid function. Thyroid2009 Jul;19(7):691-7.

May-Jun;79(3):157-61; discussion 61-3.

Psychiatry Neurol1994 Jan-Mar;7(1):23-7.

Psychiatr Scand Suppl 38(164):1-70.

London: Routledge, 1989. pp.210-21

*Psychiatr Scand.* 106, 27-34.

cases, definition, and review." JAMA 243(23):2434-2439.

and cognition: preliminary evidence for a specific defect in memory. Thyroid2001

Kronfol, Z., Lohr, N., Steiner, M., de Vigne, J.P. and Young, E. (1981). A specific laboratory test for the diagnosis of melancholia. Standardization, validation, and

on thyroid function in depressed patients with primary hypothyroidism or normal

primary hyperparathyroidism: the role of parathyroidectomy]. Ann Ital Chir2008

abnormalities and cognitive impairment in elderly people: results of the

"A controlled, prospective study of neuropsychological outcomes post parathyroidectomy in primary hyperparathyroid patients." Clin Endocrinol (Oxf)

associated with depression in the elderly. Arch Gerontol Geriatr. 2003 May-

in patients affected by subclinical hypothyroidism. Panminerva Med Dec;52(4):277-

Wilkinson G, Rawnsley, K. editors The scope of epidemiological psuchiatry.

psychiatric pathology: general clinical and epidemiologic review. *Encephale.* 23, 351-

depression, anxiety and thyroid function--a clinical fact or an artefact? *Acta* 


Thyroid and Parathyroid Diseases and Psychiatric Disturbance 257

MacCrimmon DJ, Wallace JE, Goldberg WM, et al: Emotional disturbance and cognitive

Mackenzie AH. Differential diagnosis of rheumatoid arthritis. Am J Med1988 Oct

Marian G, Nica EA, Ionescu BE, Ghinea D. Hyperthyroidism--cause of depression and

Mayou, R., Peveler, R., Davies, B., Mann, J. and Fairburn, C. (1991). Psychiatric morbidity in young adults with insulin-dependent diabetes mellitus. *Psychol Med.* 21, 639-645. Miller KJ, Parsons TD, Whybrow PC, Van Herle K, Rasgon N, Van Herle A, et al.(2007)

Miller KJ, Parsons TD, Whybrow PC, van Herle K, Rasgon N, van Herle A, et al. Memory

Mooradian AD. Asymptomatic hyperthyroidism in older adults: is it a distinct clinical and

Oomen, H.A., Schipperijn, A.J. and Drexhage, H.A. (1996). The prevalence of affective

Pérez-Echeverría, M.J. (1985). Correlaciones entre trastornos endocrinológicos, niveles

Petersen, P. (1968). Psychiatric disorders in primary hyperparathyroidism. *J Clin Endocrinol* 

Pieri-Balandraud N, Hugueny P, Henry JF, Tournebise H, Dupont C. [Hyperparathyroidism induced by lithium. A new case]. Rev Med Interne2001 May;22(5):460-4 Pratty, J.S. , Ananth, J. and O'Brien, J.E. (1986). Relationship between dystonia and serum

Roman S, Sosa JA. Psychiatric and cognitive aspects of primary hyperparathyroidism. Curr

Sait Gönen M, Kisakol G, Savas Cilli A, Dikbas O, Gungor K, Inal A, et al. Assessment of anxiety in subclinical thyroid disorders. Endocr J2004 Jun;51(3):311-5. Samuels MH. Cognitive function in untreated hypothyroidism and hyperthyroidism. Curr

Santos AM, Nobre EL, Garcia e acosta:Graves´s disease and stress.ActaMed Port 15:423-

Schiess N, Pardo CA: Hashimoto´s encephalopathy. Ann New York academy Science

Scott KM, Bruffaerts R, Tsang A, Ormel J, Alonso J, Angermeyer MC, et al.(2007)

World Mental Health Surveys. J Affect Disord2007 Nov;103(1-3):113-20. Slaets JP. Vulnerability in the elderly: frailty. Med Clin North Am2006 Jul;90(4):593-601. Stern RA, Robinson B, Thorner AR, et al: A survery study of neuropsychiatric complaints in patients with Grave´s disease. J Neupsychiatry Clin Neurosci 8:181,1996 Stipcevic T, Pivac N, Kozaric-Kovacic D, Muck-Seler D. Thyroid activity in patients with

Depression-anxiety relationships with chronic physical conditions: results from the

abnormal thyroid function tests. *Clin Endocrinol (Oxf).* 45, 215-223.

Verbal memory retrieval deficits associated with untreated hypothyroidism. J

improvement with treatment of hypothyroidism. Int J Neurosci2006

disorder and in particular of a rapid cycling of bipolar disorder in patients with

hormonales en sangre, variables de personalidad y alteraciones psicopatológicas.

deficits in hyperthyroidism. Psychosom Med 41:331-340, 1979

psychosis: a case report. J Med Life2009 Oct-Dec;2(4):440-2.

Neuropsychiatry Clin Neurosci2007 Spring;19(2):132-6.

laboratory entity? Drugs Aging2008;25(5):371-80.

*Doctoral Thesis,* Universidad de Zaragoza.

calcium levels. *J Clin Psychiatry.* 47, 418-419.

Opin Endocrinol Diabetes Obes2008 Oct;15(5):429-33.

major depression. Coll Antropol2008 Sep;32(3):973-6.

14;85(4A):2-11.

Aug;116(8):895-906.

*Metab.* 28, 1491-1495.

427,2002

1142:254-265, 2008.

Opin Oncol2007 Jan;19(1):1-5.


Kathol, R.G., Turner, R. and Delahunt, J. (1986). Depression and anxiety associated with hyperthyroidism: response to antithyroid therapy. *Psychosomatics* 27, 501-505. Kingsbury SJ, Salzman C. Lithium's role in hyperparathyroidism and hypercalcemia. Hosp

Kowdley, K. V., B. M. Coull and E. S. Orwoll. 1999. "Cognitive impairment and intracranial calcification in chronic hypoparathyroidism." Am J Med Sci 317(5):273-277. Kornstein SG, Sholar EF, Gardner DG: Endocrine disorders, in Psychiatric Care of the

Kupka, R.W., Nolen, W.A., Post, R.M., McElroy, S.L., Altshuler, L.L., Denicoff, K.D.,

Lishman´s, W.A. (2009). Endocrine diseases and metabolic disorders. In Organic Psychiatry,

Lishman, W.A. (1998). Endocrine Diseases and Metabolic Disorders. In *Organic psychiatry the* 

Lloyd, C.E., Dyer, P.H. and Barnett, A.H. (2000). Prevalence of symptoms of depression and

Lobo, A, Campos R, Marcos G, García-Campayo J, Campayo A, Lopez-Antón R & Pérez-

Lobo, A., Saz, P., Marcos G, Dia JL, De-la-Camara, C., & Ventura T. Prevalence of dementia

Lobo, A., Saz, P. Marcos, C. Día, JL. De la Cámara, C. Ventura, T. (2005). The ZARADEMP

Lobo, A, Huyse, F., Herzog, T., Malt, V.F. and E.C.L.W. (1992). Profiles of psychiatric and

Lobo, A., Perez-Echeverria, M.J., Jimenez-Aznarez, A. and Sancho, M.A. (1988). Emotional

Lobo-Escolar A, Saz P, Marcos G, Quintanilla MA, Campayo A, Lobo A. Somatic and

Lobo A, Saz P, Quintanilla MA. Dementia. In: Levenson JL, editor. Textbook of Psychosomatic Medicine. Washington: American Psychiatric Press (2010, in press)

Health Questionnaire (GHQ-28). *Br J Psychiatry.* 152, 807-812.

ZARADEMP Project. J Psychosom Res2008 Oct;65(4):347-55.

lack of association with lithium exposure. *Biol Psychiatry.* 51, 305-311. Kudrjavcev T. Neurologic complications of thyroid dysfunction. Adv Neurol1978;19:619-36. Linder, J., Brimar, K., Granberg, P.O., Wetterberg, L. and Werner, S. (1988). Characteristic

primary hyperparathyroidism. *Acta Psychiatr Scand.* 78, 32-40.

anxiety in a diabetes clinic population. *Diabet Med.* 17, 198-202.

patients in Spain. Eur J Psychiat 2007; 21(1): 71-8.

Project. Acta Psychiatr Scand2007 Oct;116(4):299-307.

Medical Patient, 2nd Edition. Edited by Stoudemire A, Fogel BS, Grennberg D. New

Frye.M.A.,Keck, P.E. Jr, Leverich, G.S., Rush, A.J., Suppes, T., Pollio, C. and Drexhage, H.A. (2002). High rate of autoimmune thyroiditis in bipolar disorder:

changes in psychiatric symptoms, cortisol and melatonin but not prolactin in

*psychological consequences of cerebral disorder* , 3rd edn, pp. 507-69. Oxford: Blackwell

Echeverría MJ.(2007). Somatic and psychiatric co-morbidity in Primary Care

in a southern European population in two different time periods: the ZARADEMP

Project on the Incidence, Prevalence and Risk Factors of Dementia (and Depression) in the Elderly Community: ll. Methods an First Results. Eur J Psychiatry 2005;19-40-

physical co-morbidity. Paper read before the E.C.L.W. Health Service Study

disturbances in endocrine patients. Validity of the scaled version of the General

psychiatric comorbidity in the general elderly population: results from the

Community Psychiatry1993 Nov;44(11):1047-8.

York, Oxford University Press,2000, pp 801-819

4th edn. Wiley-Blackwell.

Conference: Amsterdam

Science.

54


**17**

*Chile* 

**Depressive Disorders and Thyroid Function** 

A. Verónica Araya1, Teresa Massardo2, Jenny Fiedler3, Luis Risco4,

*5Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile* 

The complex relationship of thyroid hormones (TH) with brain function is known since a century. The TH mediate important effects on central nervous system (CNS) during development and throughout life (Bauer et al., 2002a; Smith et al., 2002). Is well known that hyper and hypothyroidism are frequently associated with subtle behavioral and psychiatric symptoms. By the other side, patients with mood disorders show alterations in thyroidstimulating hormone (TSH) release under thyrotropin-releasing hormone (TRH) stimulation although, circulating TH: triiodothyronine (T3) and thyroxine (T4) are usually in the normal range (Linkowski et al., 1981; Loosen, 1985; Larsen et al., 2004; Risco et al., 2003). Animal studies have provided considerable data on the reciprocal interactions between TH and neurotransmitter systems related with the pathogenesis of mood disorders (Bauer et al., 2002a). These studies provide the basis for several hypotheses, which propose that the modulatory effects of TH on mood are mediated by their actions on different neurotransmitter as norepinephrine and serotonin (Belmaker&Agam, 1998). There is also experimental evidence that some antidepressant drugs have some effects on brain TH concentration and T3 generation through a modulatory effect on deiodinases. Many trials have demonstrated that under certain conditions the use of TH can enhance or accelerate the

Considering that major depression is currently viewed as a serious public health problem with significant social and economic consequences, we found interesting to review how thyroid function and brain could interact in depressive disorders and how some new aspects as evaluation of some polymorphism of deiodinases and neuroimaging, can help in

Thyroid hormones participate in the normal neurological development increasing the rate of neuronal proliferation in the cerebellum, acting as the "time clock" to end neuronal

therapeutic effects of antidepressants (Kirkegaard & Faber, 1998).

identifying depressive subjects susceptible to be treat with TH.

**2. Thyroid hormones and brain** 

**1. Introduction** 

*1Endocrinology Section, Clinical Hospital of the University of Chile 2Nuclear Medicine Section, Clinical Hospital of the University of Chile 3Faculty of Chemical and Pharmaceutical Sciences, University of Chile 4Psychiatric Clinic of the Clinical Hospital of the University of Chile* 

Juan C. Quintana5 and Claudio Liberman1


### **Depressive Disorders and Thyroid Function**

A. Verónica Araya1, Teresa Massardo2, Jenny Fiedler3, Luis Risco4,

Juan C. Quintana5 and Claudio Liberman1 *1Endocrinology Section, Clinical Hospital of the University of Chile 2Nuclear Medicine Section, Clinical Hospital of the University of Chile 3Faculty of Chemical and Pharmaceutical Sciences, University of Chile 4Psychiatric Clinic of the Clinical Hospital of the University of Chile 5Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile Chile* 

#### **1. Introduction**

258 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Trzepacz, P.T., McCue, M., Klein, I., Levey, G.S. and Greenhouse, J. (1988). A psychiatric and

Velasco PJ, Manshadi M, Breen K, Lippmann S. Psychiatric aspects of parathyroid disease.

Walsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, et al. Combined

White, R.E., Pickering, A. and Spathis, G.S. (1996). Mood disorder and chronic

Wilhelm SM, Lee J, Prinz RA. Major depression due to primary hyperparathyroidism: a frequent and correctable disorder. Am Surg2004 Feb;70(2):175-9; discussion 9-80.

*Psychiatry.* 10, 49-55.

Oct;88(10):4543-50.

Psychosomatics1999 Nov-Dec;40(6):486-90.

hypercalcemia. *J Psychosom Res.* 41, 343-347.

neuropsychological study of patients with untreated Graves' disease. *Gen Hosp* 

thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab2003

> The complex relationship of thyroid hormones (TH) with brain function is known since a century. The TH mediate important effects on central nervous system (CNS) during development and throughout life (Bauer et al., 2002a; Smith et al., 2002). Is well known that hyper and hypothyroidism are frequently associated with subtle behavioral and psychiatric symptoms. By the other side, patients with mood disorders show alterations in thyroidstimulating hormone (TSH) release under thyrotropin-releasing hormone (TRH) stimulation although, circulating TH: triiodothyronine (T3) and thyroxine (T4) are usually in the normal range (Linkowski et al., 1981; Loosen, 1985; Larsen et al., 2004; Risco et al., 2003). Animal studies have provided considerable data on the reciprocal interactions between TH and neurotransmitter systems related with the pathogenesis of mood disorders (Bauer et al., 2002a). These studies provide the basis for several hypotheses, which propose that the modulatory effects of TH on mood are mediated by their actions on different neurotransmitter as norepinephrine and serotonin (Belmaker&Agam, 1998). There is also experimental evidence that some antidepressant drugs have some effects on brain TH concentration and T3 generation through a modulatory effect on deiodinases. Many trials have demonstrated that under certain conditions the use of TH can enhance or accelerate the therapeutic effects of antidepressants (Kirkegaard & Faber, 1998).

> Considering that major depression is currently viewed as a serious public health problem with significant social and economic consequences, we found interesting to review how thyroid function and brain could interact in depressive disorders and how some new aspects as evaluation of some polymorphism of deiodinases and neuroimaging, can help in identifying depressive subjects susceptible to be treat with TH.

#### **2. Thyroid hormones and brain**

Thyroid hormones participate in the normal neurological development increasing the rate of neuronal proliferation in the cerebellum, acting as the "time clock" to end neuronal

Depressive Disorders and Thyroid Function 261

is tissue dependent; in the brain, the main isoforms of TRs are: TRα1, TRα2, TRβ1 and TRβ2. TRα1 and α2 accounting for most of TRs in the organ, whereas TRβ1 and β2 are detected in only a few areas as retina, cochlea, anterior pituitary and hypothalamus. In mice in which TR or TR were inactivated, different phenotypes are observed indicating that TRs isoforms mediate specific functions but also, they can substitute each other to mediate some actions of T3 (Jones et al., 2007; Forrest et al., 1996a; Forrest et al., 1996b; Wikström et al.,

Some studies have reported, in propylthiouracyl-induced hypothyroidal adult rats, a decreased expression of TRα1 and TRβ in the hippocampus, associated with an increase in -amyloid peptides in the same area. Hypoactivity of the thyroid signaling in the hippocampus could induce modifications in the amiloydogenic pathway and this could be related with a greater vulnerability of developing Alzheimer disease in hypothyroidal

**2.1 T3 generation in the central nervous system: The importance of deiodinases** 

indicating mechanisms for an efficient transformation into biological active hormone.

Although both forms of TH (T4, T3) are present in the circulating blood, some studies have demonstrated that T4 is transported into the brain much more efficiently than T3 (Hagen & Solberg, 1974). In contrast to peripheral tissue, in the brain T4 and T3 are in equimolar range

TH production is regulated by the HPT axis, while its biological activity is mainly regulated by three selenodeiodinasas coded by different genes (D1, D2, D3). Deiodinases act at prereceptor level influencing both, extracellular and intracellular TH levels and its action. Whether it activates or inactivates it, will depend on the level where deiodination occurs (5 or 5` position on the iodothyronine molecule). In the periphery, in the kidney and liver, D1 isoform is responsible for the production of most of the circulating T3

In the CNS, the most important isoforms are D2 and D3. In the brain, T3 is produced locally by the action of D2 which is also expressed in pituitary, thyroid, brown adipose tissue, skeletal muscle, and aortic smooth muscle cell, in humans. D2 activity varies extensively in different brain regions, with the highest levels found in cortical areas and lesser activity in the midbrain, pons, hypothalamus and brainstem (Bianco et al., 2002; Gouveia et al., 2005; Zavacki et al., 2005). It has been described in adult rats, that approximately 80% of T3 bound to nuclear receptors is produced locally by D2 activity (Crantz et al., 1982). Moreover, inactivation of TH is mainly carried out by D3 as well as glucoronosyltransferase and sulfotransferases. D3 is highly expressed within the CNS, with low peripheral expression. D3 degrades T4 to rT3 and T3 to 3,3′-diiodothyronine (T2) therefore preventing or finishing actions of T3. Thus, combined actions of D2 and D3 can locally increase or decrease thyroid hormone signaling in a tissue -and a temporal- fashion, and more importantly in a way independent of thyroid hormone plasma levels. In addition, increasing evidences pointed out that deiodinase expression can be modulated by a wide variety of endogenous signaling molecules, suggesting a local modulation of T3 production in the brain (Gereben et al., 2008a, Gereben et al., 2008b). D2 enzymatic activity is increased also in hypothyroidism and

decreased in hyperthyroidism (Kirkegaard & Faber, 1998).

1998; Fraichard et al., 1997; Göthe et al., 1999).

subjects (Ghenimi et al., 2010).

(Bianco et al., 2002).

proliferation, differentiation and also stimulating the development of neuronal processes, axons and dendrites. As well TH mediate effects on CNS occur throughout life (Bauer et al., 2002a; Smith et al., 2002). Different studies have demonstrated the presence of thyroid receptors in rat CNS with a particular distribution during development and adulthood (Bradley et al., 1992; Bradley et al., 1989). Thus, TH regulate the expression of genes implicated in myelination, neuronal and glial cell differentiation (Bernal, 2005; Bernal & Nunez, 1995) and neuronal viability and function (Smith et al., 2002). These hormones are able to modify cell morphology by acting on cytoskeleton machinery required for neuronal migration and outgrowth (Aniello et al., 1991; Morte et al., 2010). Additionally, TH are present in noradrenergic nuclei of CNS (Rozanov & Dratman, 1996) probably acting as neuromodulator or co-neurotransmitter (Dratman & Gordon, 1996). In line with this, TH increase β-adrenergic receptors levels (Ghosh & Das, 2007; Whybrow & Prange, 1981) and improve both cholinergic (Smith et al., 2002) and serotonin neurotransmission in animals (Bauer et al., 2002a). The effect of TH on serotonin (5 HT) has been explained by a desensitization of 5HT1A autoreceptor in the raphe nuclei which probably results in enhancement of firing and release of serotonin from raphe neurons (Heal & Smith, 1988). Furthermore, these hormones can stimulate the expression of neuronal growth factor (NGF) suggesting certain trophic actions on CNS (Walker et al., 1979; Walker et al., 1981).

In mice models, maternal hypo and hyperthyroidism cause some malformation and developmental defects in the cerebellar and cerebral cortex of their newborns. Concomitantly, there is some degeneration, deformation and severe growth retardation in neurons of these regions in both groups (El-Bakry et al., 2010). Therefore, TH play an important role in brain development, neuronal migration and axonal projection to target cells. *In vitro* and *in vivo* studies have shown that TH exert a non genomic action over the actin citoskeleton development in astrocytes and neurons. The lack of TH impaire cell growth, granule cells migration and explain those defects in the hypothyroid brain (Farwell et al., 2006; Leonard&Farwell, 1997; Farwell&Dubord, 1996).

Moreover, both acute and chronic Thyroxine treatment in rats increases the cognitive function, probably through an enhancement in cholinergic neurotransmission (Smith et al., 2002).

In humans, TH deficiency during the fetal and postnatal periods may cause irreversible mental retardation, neurological and behavioral deficits, and long lasting, irreversible motor dysfunctions. In adulthood, hypothyroidism may also determine profound behavioral consequences such as depressive symptoms, impaired memory, impairment in learning, verbal fluency, and spatial tasks (Miller et al., 2007; Samuels et al., 2007). Probably these alterations are due to neurotransmission impairment in brain areas related to learning and memory, such as hippocampus. Thus, the reduction of TH levels in CNS, can promote an altered neurotransmission activity contributing to some mood disorders like major depression.

The biologically active thyroid hormone T3 exerts its effects by interacting with their specific nuclear thyroid receptors (TRs) that are positively regulated by its own ligand, acting as transcription factors. TRs are encoded for two different genes: TR located on chromosome 3, encodes three isoforms: 1, 2 and 3, and TR located on chromosome 17, encodes the isoforms α1, α2 and α3. TR1 is expressed early in the embryonic development and TR is expressed at later stages of development. By the other hand, the expression of these isoforms

proliferation, differentiation and also stimulating the development of neuronal processes, axons and dendrites. As well TH mediate effects on CNS occur throughout life (Bauer et al., 2002a; Smith et al., 2002). Different studies have demonstrated the presence of thyroid receptors in rat CNS with a particular distribution during development and adulthood (Bradley et al., 1992; Bradley et al., 1989). Thus, TH regulate the expression of genes implicated in myelination, neuronal and glial cell differentiation (Bernal, 2005; Bernal & Nunez, 1995) and neuronal viability and function (Smith et al., 2002). These hormones are able to modify cell morphology by acting on cytoskeleton machinery required for neuronal migration and outgrowth (Aniello et al., 1991; Morte et al., 2010). Additionally, TH are present in noradrenergic nuclei of CNS (Rozanov & Dratman, 1996) probably acting as neuromodulator or co-neurotransmitter (Dratman & Gordon, 1996). In line with this, TH increase β-adrenergic receptors levels (Ghosh & Das, 2007; Whybrow & Prange, 1981) and improve both cholinergic (Smith et al., 2002) and serotonin neurotransmission in animals (Bauer et al., 2002a). The effect of TH on serotonin (5 HT) has been explained by a desensitization of 5HT1A autoreceptor in the raphe nuclei which probably results in enhancement of firing and release of serotonin from raphe neurons (Heal & Smith, 1988). Furthermore, these hormones can stimulate the expression of neuronal growth factor (NGF)

suggesting certain trophic actions on CNS (Walker et al., 1979; Walker et al., 1981).

et al., 2006; Leonard&Farwell, 1997; Farwell&Dubord, 1996).

al., 2002).

In mice models, maternal hypo and hyperthyroidism cause some malformation and developmental defects in the cerebellar and cerebral cortex of their newborns. Concomitantly, there is some degeneration, deformation and severe growth retardation in neurons of these regions in both groups (El-Bakry et al., 2010). Therefore, TH play an important role in brain development, neuronal migration and axonal projection to target cells. *In vitro* and *in vivo* studies have shown that TH exert a non genomic action over the actin citoskeleton development in astrocytes and neurons. The lack of TH impaire cell growth, granule cells migration and explain those defects in the hypothyroid brain (Farwell

Moreover, both acute and chronic Thyroxine treatment in rats increases the cognitive function, probably through an enhancement in cholinergic neurotransmission (Smith et

In humans, TH deficiency during the fetal and postnatal periods may cause irreversible mental retardation, neurological and behavioral deficits, and long lasting, irreversible motor dysfunctions. In adulthood, hypothyroidism may also determine profound behavioral consequences such as depressive symptoms, impaired memory, impairment in learning, verbal fluency, and spatial tasks (Miller et al., 2007; Samuels et al., 2007). Probably these alterations are due to neurotransmission impairment in brain areas related to learning and memory, such as hippocampus. Thus, the reduction of TH levels in CNS, can promote an altered neurotransmission activity contributing to some mood disorders like major depression. The biologically active thyroid hormone T3 exerts its effects by interacting with their specific nuclear thyroid receptors (TRs) that are positively regulated by its own ligand, acting as transcription factors. TRs are encoded for two different genes: TR located on chromosome 3, encodes three isoforms: 1, 2 and 3, and TR located on chromosome 17, encodes the isoforms α1, α2 and α3. TR1 is expressed early in the embryonic development and TR is expressed at later stages of development. By the other hand, the expression of these isoforms is tissue dependent; in the brain, the main isoforms of TRs are: TRα1, TRα2, TRβ1 and TRβ2. TRα1 and α2 accounting for most of TRs in the organ, whereas TRβ1 and β2 are detected in only a few areas as retina, cochlea, anterior pituitary and hypothalamus. In mice in which TR or TR were inactivated, different phenotypes are observed indicating that TRs isoforms mediate specific functions but also, they can substitute each other to mediate some actions of T3 (Jones et al., 2007; Forrest et al., 1996a; Forrest et al., 1996b; Wikström et al., 1998; Fraichard et al., 1997; Göthe et al., 1999).

Some studies have reported, in propylthiouracyl-induced hypothyroidal adult rats, a decreased expression of TRα1 and TRβ in the hippocampus, associated with an increase in -amyloid peptides in the same area. Hypoactivity of the thyroid signaling in the hippocampus could induce modifications in the amiloydogenic pathway and this could be related with a greater vulnerability of developing Alzheimer disease in hypothyroidal subjects (Ghenimi et al., 2010).

#### **2.1 T3 generation in the central nervous system: The importance of deiodinases**

Although both forms of TH (T4, T3) are present in the circulating blood, some studies have demonstrated that T4 is transported into the brain much more efficiently than T3 (Hagen & Solberg, 1974). In contrast to peripheral tissue, in the brain T4 and T3 are in equimolar range indicating mechanisms for an efficient transformation into biological active hormone.

TH production is regulated by the HPT axis, while its biological activity is mainly regulated by three selenodeiodinasas coded by different genes (D1, D2, D3). Deiodinases act at prereceptor level influencing both, extracellular and intracellular TH levels and its action. Whether it activates or inactivates it, will depend on the level where deiodination occurs (5 or 5` position on the iodothyronine molecule). In the periphery, in the kidney and liver, D1 isoform is responsible for the production of most of the circulating T3 (Bianco et al., 2002).

In the CNS, the most important isoforms are D2 and D3. In the brain, T3 is produced locally by the action of D2 which is also expressed in pituitary, thyroid, brown adipose tissue, skeletal muscle, and aortic smooth muscle cell, in humans. D2 activity varies extensively in different brain regions, with the highest levels found in cortical areas and lesser activity in the midbrain, pons, hypothalamus and brainstem (Bianco et al., 2002; Gouveia et al., 2005; Zavacki et al., 2005). It has been described in adult rats, that approximately 80% of T3 bound to nuclear receptors is produced locally by D2 activity (Crantz et al., 1982). Moreover, inactivation of TH is mainly carried out by D3 as well as glucoronosyltransferase and sulfotransferases. D3 is highly expressed within the CNS, with low peripheral expression. D3 degrades T4 to rT3 and T3 to 3,3′-diiodothyronine (T2) therefore preventing or finishing actions of T3. Thus, combined actions of D2 and D3 can locally increase or decrease thyroid hormone signaling in a tissue -and a temporal- fashion, and more importantly in a way independent of thyroid hormone plasma levels. In addition, increasing evidences pointed out that deiodinase expression can be modulated by a wide variety of endogenous signaling molecules, suggesting a local modulation of T3 production in the brain (Gereben et al., 2008a, Gereben et al., 2008b). D2 enzymatic activity is increased also in hypothyroidism and decreased in hyperthyroidism (Kirkegaard & Faber, 1998).

Depressive Disorders and Thyroid Function 263

(Forman-Hoffman & Philibert, 2006; Stipcević et al., 2008) and other studies showed TSH

In reference to T3 levels, results are more conclusive, showing a trend to decrease in the presence of depression, as well as an association with high risk of long term relapse. In addition there seems to be a more pronounced T3 decrease in direct relation with the severity of depression (Stipcević et al, 2008; Saxena et al., 2000). Reported T4 levels in depression are also contradictory, since there is evidence showing a rise as well as a decrease of T4 during depressive episodes. (Saxena et al., 2000; Kirkegaard&Faber, 1998). In a study, with more than 6,000 subjects, it was shown that a low TSH and a high T4 levels were associated with depression specially in young men but, in women only a higher T4 levels correlated with current depression syndrome (Forman-Hoffman&Philibert, 2006). It is possible that these findings could be explained by a diversity of factors, such as differences in phenotypes of depressive patients, severity and duration of the disease, difficulties in isolating drugs effects in TH levels (antidepressants and mood stabilizers) and probably,

Overt thyroid disease is infrequent among depressive patients. Nevertheless, many authors have seen that a subgroup of depressive patients manifest a subclinical hypothyroidism and this might be a negative prognostic factor (Fountoulakis et al., 2006). On the other side, some antidepressants as lithium inhibits TH secretion and could increase antithyroid antibodies, promoting hypothyroidism in susceptible subjects (Emerson et al., 1972; Myers et al., 1985). There is still no hypothesis that can satisfactory integrate these data. Interactions between TH and neurotransmitters, gene expression and neurohormonal receptors are not clear yet. For instance, 5 HT seems to inhibit TRH secretion and somatostatin TSH secretion (Kirkegaard&Faber, 1998); both of them are reduced in cerebro spinal fluid (CSF) in patients with psychiatric illness and affective disorders (Gerner&Yamada, 1982, Roy-Birne et al., 1983; Rubinow et al., 1983). Otherwise, T3 influx to intracellular level in the brain is determined by many factors, including T3 and T4 circulating levels, protein transporters,

About a 25% of major depressed patients show a reduction in TSH release under TRH stimulation (Loosen 1985, Risco et al, 2003). It has been proposed that in them exist a blunted response due to the raise of circulating cortisol, associated to hypothalamicpituitary-adrenal axis hyperactivity. This response has also been observed in bipolar disorders (Linkowsky et al., 1981). On the other hand, in rapid cycling depressives, TSH hypersecretion is observed in response to TRH (20% of basal TSH levels above the normal

Nevertheless, as we mentioned before, the mechanism by which TH affect the adult brain is not completely clear, because the complex interactions between neurotransmitters and thyroid. One hypothesis is that TH modulate the number of post-synaptic β-adrenergic receptors in the cerebral cortex and cerebellum This could be relevant considering the influence of catecholamines deficit, mainly norepinephrine as a cause of depression (Atterwill et al., 1984). Another possible mechanism is the modulation of 5 HT and its receptors. It has been suggested that TH inhibit the impulse rate of neurons present at the raphe and reducing the release of 5HT. T3 administration to mice attenuates the function of 5HT1A and 5HT1B receptors, increasing the cortical and hippocampus synthesis and

elevation in bipolar depression (Brouwer et al., 2005; Saxena et al., 2000).

gender and other differences.

and deiodinase activity.

range) (Szabadi, 1991, Larsen et al., 2004).

#### **2.2 Association between deionidase polymorphisms and thyroid hormone metabolism**

Genetic variations in deionidade genes may impact significantly thyroid function and TH levels in euthyroid subjects (Hansen et al., 2007; Peeters et al., 2007; Peeters et al., 2006; Peeters et al., 2003). The effect of two polymorphisms in D1 gene, D1-rs11206244 (D1-C785T) and D1-rs12095080 (D1-A1814G) on thyroid hormone metabolism has been evaluated in randomly selected subjects (Peeters et al., 2003). The allele T of D1-rs11206244 was associated with high levels of rT3 and high rT3/T4 ratio and a low T3/rT3 in plasma; whereas the G allele of D1-A1814G was associated with a high T3/rT3 (de Jong et al., 2007; Peeters et al., 2003). These results suggest a lower activity in T carriers of rs11206244 than G carriers (Peeters et al., 2003).

Of special interest is the common polymorphism in humans: D2 rs225014 (D2-Thr92Ala), characterized by a threonine (Thr) change to alanine (Ala) at codon 92 (D2 Thr92Ala). It is associated with insulin resistance in different populations, suggesting that D2-generated T3 in skeletal muscle plays a role in insulin sensitivity (Mentuccia et al., 2002, Canani et al., 2005). The minor allele (G) is associated with a low D2 activity in thyroid samples obtained from patients (Canani et al., 2005). In accordance, G allele seems to predict the need for higher T4 intake in thyroidectomized patients (Torlontano et al., 2008). Nonetheless, it has been observed that GG subjects show a delayed serum T3 rise in response to TRH-mediated TSH secretion consistent with decreased D2 activity (Butler et al., 2010). Some studies have described a naturally occurring polymorphism located in 5'-untranslated region of the D2 gene (Coppotelli et al., 2006). In healthy blood donors, the minor allele of this polymorphism (D2- ORFa-Asp variant, rs12885300) is associated with an increase in circulating T3/T4 ratio but not with plasma T3 and TSH levels, suggesting an increased D2 gene expression (Peeters et al., 2005). In agreement, i*n vitro* studies suggested that D2-rs1288530 polymorphism leads to higher activity of D2 at the pituitary level (Coppotelli et al., 2006). In a long case-control Chinese study, the haplotypes ORFa-3Asp-92Ala and ORFa-3Gly-92Ala indicated higher susceptibility for bipolar disorders, while ORFa-3Asp-92Thr probably played a protective role (He et al., 2009). According to this evidence, it is feasible that variants of D2 gene can produce "brain hypothyroidism" limiting T3 action on CNS affecting brain neurotransmission.

#### **3. Thyroid and depression**

The similarity and overlapping between symptoms of depression and thyroid disorders has been the theoretical base for the hypothesis regarding a possible relationship between both entities. As we mention above, hypothyroidism could induce cognitive dysfunction and depressive symptoms besides psychological distress in a very similar way to primary depression (Constant et al., 2005; Bould et al., 2011; Mowla et al., 2011). Likewise, TH effect as augmentation therapy in refractory depression, and thyroid disorders as risk factors for rapidcycling in bipolar disorder sustain a possible association between both types of diseases.

The involvement of HPT axis in the pathogenesis of depression is supported by multiple data. There are few studies that show normal range TH levels during a depressive episode; however most of them demonstrate diverse changes in different hormones associated with this axis. Concerning TSH levels, data are contradictory, some authors have reported a decrease in basal TSH values as well as in those observed in response to exogenous TRH

Genetic variations in deionidade genes may impact significantly thyroid function and TH levels in euthyroid subjects (Hansen et al., 2007; Peeters et al., 2007; Peeters et al., 2006; Peeters et al., 2003). The effect of two polymorphisms in D1 gene, D1-rs11206244 (D1-C785T) and D1-rs12095080 (D1-A1814G) on thyroid hormone metabolism has been evaluated in randomly selected subjects (Peeters et al., 2003). The allele T of D1-rs11206244 was associated with high levels of rT3 and high rT3/T4 ratio and a low T3/rT3 in plasma; whereas the G allele of D1-A1814G was associated with a high T3/rT3 (de Jong et al., 2007; Peeters et al., 2003). These results suggest a lower activity in T carriers of rs11206244 than G

Of special interest is the common polymorphism in humans: D2 rs225014 (D2-Thr92Ala), characterized by a threonine (Thr) change to alanine (Ala) at codon 92 (D2 Thr92Ala). It is associated with insulin resistance in different populations, suggesting that D2-generated T3 in skeletal muscle plays a role in insulin sensitivity (Mentuccia et al., 2002, Canani et al., 2005). The minor allele (G) is associated with a low D2 activity in thyroid samples obtained from patients (Canani et al., 2005). In accordance, G allele seems to predict the need for higher T4 intake in thyroidectomized patients (Torlontano et al., 2008). Nonetheless, it has been observed that GG subjects show a delayed serum T3 rise in response to TRH-mediated TSH secretion consistent with decreased D2 activity (Butler et al., 2010). Some studies have described a naturally occurring polymorphism located in 5'-untranslated region of the D2 gene (Coppotelli et al., 2006). In healthy blood donors, the minor allele of this polymorphism (D2- ORFa-Asp variant, rs12885300) is associated with an increase in circulating T3/T4 ratio but not with plasma T3 and TSH levels, suggesting an increased D2 gene expression (Peeters et al., 2005). In agreement, i*n vitro* studies suggested that D2-rs1288530 polymorphism leads to higher activity of D2 at the pituitary level (Coppotelli et al., 2006). In a long case-control Chinese study, the haplotypes ORFa-3Asp-92Ala and ORFa-3Gly-92Ala indicated higher susceptibility for bipolar disorders, while ORFa-3Asp-92Thr probably played a protective role (He et al., 2009). According to this evidence, it is feasible that variants of D2 gene can produce

"brain hypothyroidism" limiting T3 action on CNS affecting brain neurotransmission.

The similarity and overlapping between symptoms of depression and thyroid disorders has been the theoretical base for the hypothesis regarding a possible relationship between both entities. As we mention above, hypothyroidism could induce cognitive dysfunction and depressive symptoms besides psychological distress in a very similar way to primary depression (Constant et al., 2005; Bould et al., 2011; Mowla et al., 2011). Likewise, TH effect as augmentation therapy in refractory depression, and thyroid disorders as risk factors for rapidcycling in bipolar disorder sustain a possible association between both types of diseases.

The involvement of HPT axis in the pathogenesis of depression is supported by multiple data. There are few studies that show normal range TH levels during a depressive episode; however most of them demonstrate diverse changes in different hormones associated with this axis. Concerning TSH levels, data are contradictory, some authors have reported a decrease in basal TSH values as well as in those observed in response to exogenous TRH

**2.2 Association between deionidase polymorphisms and thyroid hormone** 

**metabolism**

carriers (Peeters et al., 2003).

**3. Thyroid and depression** 

(Forman-Hoffman & Philibert, 2006; Stipcević et al., 2008) and other studies showed TSH elevation in bipolar depression (Brouwer et al., 2005; Saxena et al., 2000).

In reference to T3 levels, results are more conclusive, showing a trend to decrease in the presence of depression, as well as an association with high risk of long term relapse. In addition there seems to be a more pronounced T3 decrease in direct relation with the severity of depression (Stipcević et al, 2008; Saxena et al., 2000). Reported T4 levels in depression are also contradictory, since there is evidence showing a rise as well as a decrease of T4 during depressive episodes. (Saxena et al., 2000; Kirkegaard&Faber, 1998). In a study, with more than 6,000 subjects, it was shown that a low TSH and a high T4 levels were associated with depression specially in young men but, in women only a higher T4 levels correlated with current depression syndrome (Forman-Hoffman&Philibert, 2006). It is possible that these findings could be explained by a diversity of factors, such as differences in phenotypes of depressive patients, severity and duration of the disease, difficulties in isolating drugs effects in TH levels (antidepressants and mood stabilizers) and probably, gender and other differences.

Overt thyroid disease is infrequent among depressive patients. Nevertheless, many authors have seen that a subgroup of depressive patients manifest a subclinical hypothyroidism and this might be a negative prognostic factor (Fountoulakis et al., 2006). On the other side, some antidepressants as lithium inhibits TH secretion and could increase antithyroid antibodies, promoting hypothyroidism in susceptible subjects (Emerson et al., 1972; Myers et al., 1985).

There is still no hypothesis that can satisfactory integrate these data. Interactions between TH and neurotransmitters, gene expression and neurohormonal receptors are not clear yet. For instance, 5 HT seems to inhibit TRH secretion and somatostatin TSH secretion (Kirkegaard&Faber, 1998); both of them are reduced in cerebro spinal fluid (CSF) in patients with psychiatric illness and affective disorders (Gerner&Yamada, 1982, Roy-Birne et al., 1983; Rubinow et al., 1983). Otherwise, T3 influx to intracellular level in the brain is determined by many factors, including T3 and T4 circulating levels, protein transporters, and deiodinase activity.

About a 25% of major depressed patients show a reduction in TSH release under TRH stimulation (Loosen 1985, Risco et al, 2003). It has been proposed that in them exist a blunted response due to the raise of circulating cortisol, associated to hypothalamicpituitary-adrenal axis hyperactivity. This response has also been observed in bipolar disorders (Linkowsky et al., 1981). On the other hand, in rapid cycling depressives, TSH hypersecretion is observed in response to TRH (20% of basal TSH levels above the normal range) (Szabadi, 1991, Larsen et al., 2004).

Nevertheless, as we mentioned before, the mechanism by which TH affect the adult brain is not completely clear, because the complex interactions between neurotransmitters and thyroid. One hypothesis is that TH modulate the number of post-synaptic β-adrenergic receptors in the cerebral cortex and cerebellum This could be relevant considering the influence of catecholamines deficit, mainly norepinephrine as a cause of depression (Atterwill et al., 1984). Another possible mechanism is the modulation of 5 HT and its receptors. It has been suggested that TH inhibit the impulse rate of neurons present at the raphe and reducing the release of 5HT. T3 administration to mice attenuates the function of 5HT1A and 5HT1B receptors, increasing the cortical and hippocampus synthesis and

Depressive Disorders and Thyroid Function 265

Several studies using thyroid hormones in the management of patients with mood disorders have been reported since the early seventies. TH have been used in euthyroid depressed patients to enhance the effects of antidepressants. In patients receiving electroconvulsive therapy, those treated with T3 required less sessions and presented less memory loss compared with placebo treated group (Stern et al., 1991). T3 has been employed in initial combination therapy, and T3 or T4 in refractary depression or non responder patients.

T3 in doses of 20 to 50 g is able to enhance the effect of tricyclic antidepressants and shorten the depression period but, many studies have not demonstrated differences in the number of patients recovered (Prange et al., 1969; Wilson et al., 1970; Coppen et al., 1972; Wheatley, 1972). A meta-analysis showed that when T3 was used in refractary depression in addition to tricyclic antidepressant therapy, patients treated with it were twice as likely to respond as controls, decreasing depression severity scores (Aronson et al., 1996). However, samples size were small and deserve more evidence. Other studies, using T3 augmentation to SSRI-resistant depression, observed an improvement in mood scores (Agid&Lerer, 2003, Iosifescu et al., 2005, Abraham et al., 2006). Some authors found that patients who responded to T3 had higher serum TSH levels than non-responders and T3 appears to be less effective in men than in women (Agid&Lerer, 2003). Other authors reported that patients with atypical depression experienced significantly greater clinical improvement in final HAM-D with higher rates of treatment response and remission compared to subjects with non-atypical major depressive disorder (Iosifescu et al., 2005). All those cases were treated mainly with fluoxetine in a daily

L-thyroxine (T4) added to antidepressants has been used less frequently than T3. Some authors have suggested that T4 augmentation is less effective than T3 (Joffe&Singer, 1990) and that supra physiological doses (250-600 ug/day) are needed, as has been demonstrated in patients with resistant major depression or refractary uni and bipolar disorders (Baumgartner et al., 1994, Bauer et al., 1998, 2002). These results support the theory of a reduced deiodination of T4 compatible with an inhibition of the D2 or a stimulation of the

Nevertheless, the addition of T4 (100 ug /day during 4 weeks) to serotoninergic antidepressants obtained remission in 11 of 12 female patients with a resistant depressive episode but, these results did not show association with T3, T4 or TSH levels (Łojko &

To date, the use of TH in mood disorders is controversial and the rationale for this therapy is still not completely clear. Main limitations of the studies are: small number of cases, lack of a placebo group, heterogeneity in diagnosis criteria, differences in observational period and in antidepressant therapy. For example, lithium has a known inhibitory effect on TH secretion; fluoxetine has a stimulatory effect over D2 as well as desipramine and both of

In this line, we evaluated a group of euthyroidal adult female patients with major depression according to DSM IV-R criteria. All of them were free of antidepressants for at least for 6 month. We studied the effect of adding T3 in a dose of 50 ug per day (n=11) or placebo (n=10), to the standard antidepressant therapy with fluoxetine during 8 weeks. At the end of the observational period final HAM-D scores were similar in both groups. (See **Table 1**). Patients in T3 group showed significant T4, T3 and TSH changes; but they remain

**4. Use of thyroid hormone in depression** 

dose of 20 to 40 mg/ and 25-50 g of T3, with few side effects.

D3 in brain tissues resulting in reduced local T3 concentration.

Rybakowski, 2007).

them could induce deficit of T4.

turnover of 5-HT. Administration of T3 plus electroconvulsive shock markedly potentiated its actions on 5-HT2-mediated responses. (Heal&Smith, 1988). These findings provide evidences for possible antidepressant effects of T3 and/or potentiating therapy by TH. This issue is relevant in patients suffering depressive disorders, related with reduction in mono amine neurotransmission such as serotonin (reviewed in Belmaker&Agam 2008).

A positive correlation between serotonin levels and circulating T3 has been described in humans. Indirect evidences showed that brain serotonin is increased in hyperthyroidism and decreased in hypothyroidism (Singhal et al., 1975). In the last situation, this is reversed with TH replacement (Bauer et al., 2002b, Strawn et al., 2004). In depressed subjects, the decrease in serotoninergic tone could be related to lower brain T3 levels, perhaps due to a reduction of deiodinases activity. Furthermore, an imbalance in T3 conversion could account for depressive disorder and/or clinical outcome to antidepressants therapy. It has been suggested that in depression, T3 may favor the release of cortical 5-HT and thus synergize the response to antidepressants. Administration of desipramine a selective serotonergic reuptake inhibitor (SSRI) in rats, induces an increase of D2 activity and T3 concentration in cortical tissue. Interestingly, T4 concentrations were significantly lowered after administration of the antidepressant but, serum T3 levels were significantly reduced only after toxic dosis of desipramine. Other commonly used SSRI, fluoxetine also decreases D3 activity (Eravci et al., 2000). Based on these data, one might suggest that depression occurs by the inhibition of D2, determining decreased T3 levels and secondarily, reduced levels of brain 5HT.

The efficacy of T3 as a supplement of sertraline therapy, another SSRI, was studied recently in relation D1 polymorphism (Cooper-Kazaz et al., 2009). Patients carrying the T allele of D1-rs11206244 showed a significant response to 8 week of antidepressant treatment in comparison with non-carriers of the allele. Additionally, there was no effect of T allele on sertraline response, suggesting that the polymorphism is not associated to antidepressant effect (Cooper-Kazaz et al., 2009). As we mentioned, the T allele of D1-rs11206244 showed lower T3 and higher rT3 than non-T carriers (de Jong et al., 2007; Peeters et al., 2003). Thus, it seems that patients genetically characterized by poor conversion of T4 to T3, are better responders to T3-antidepressant co-treatment (Cooper-Kazaz et al., 2007; 2008). Another study evaluated whether baseline thyroid function and D2 rs225014 (D2-Thr92Ala) predict response to paroxetine. It showed that high TSH levels predict the response, and heterozygous patients showed lower TSH levels than the wild-type allele (A) (Brouwer et al., 2006). However, up to date there is no study evaluating the influence of T3 and D2 polymorphisms on antidepressant response.

Based on these observations, we evaluated the presence of D2 polymorphism related with a lower activity of the enzyme: D2-Thr92Ala (T/C). The polymorphism was analyzed in 61 euthyroid patients with depression and 48 subjects of a population sample using the PCR-RFLP method. Clinical response to fluoxetine was evaluated before and after 8 weeks of treatment, using Hamilton Scale for Depression (HAM-D). We found that the CC genotype of Thr92Ala polymorphism was more frequent in depressed subjects and in non-responders patients (unpublished data). We concluded that Thr92Ala polymorphism of D2 gene could be considered a predictive marker of clinical response to fluoxetine, and hence of pharmacological therapy, but more studies are needed to confirm this preliminary results.

The presence of these polymorphisms could influence basal activity of type 2 deiodinase, and therefore of T3 bioavailability in the brain.

turnover of 5-HT. Administration of T3 plus electroconvulsive shock markedly potentiated its actions on 5-HT2-mediated responses. (Heal&Smith, 1988). These findings provide evidences for possible antidepressant effects of T3 and/or potentiating therapy by TH. This issue is relevant in patients suffering depressive disorders, related with reduction in mono

A positive correlation between serotonin levels and circulating T3 has been described in humans. Indirect evidences showed that brain serotonin is increased in hyperthyroidism and decreased in hypothyroidism (Singhal et al., 1975). In the last situation, this is reversed with TH replacement (Bauer et al., 2002b, Strawn et al., 2004). In depressed subjects, the decrease in serotoninergic tone could be related to lower brain T3 levels, perhaps due to a reduction of deiodinases activity. Furthermore, an imbalance in T3 conversion could account for depressive disorder and/or clinical outcome to antidepressants therapy. It has been suggested that in depression, T3 may favor the release of cortical 5-HT and thus synergize the response to antidepressants. Administration of desipramine a selective serotonergic reuptake inhibitor (SSRI) in rats, induces an increase of D2 activity and T3 concentration in cortical tissue. Interestingly, T4 concentrations were significantly lowered after administration of the antidepressant but, serum T3 levels were significantly reduced only after toxic dosis of desipramine. Other commonly used SSRI, fluoxetine also decreases D3 activity (Eravci et al., 2000). Based on these data, one might suggest that depression occurs by the inhibition of D2,

The efficacy of T3 as a supplement of sertraline therapy, another SSRI, was studied recently in relation D1 polymorphism (Cooper-Kazaz et al., 2009). Patients carrying the T allele of D1-rs11206244 showed a significant response to 8 week of antidepressant treatment in comparison with non-carriers of the allele. Additionally, there was no effect of T allele on sertraline response, suggesting that the polymorphism is not associated to antidepressant effect (Cooper-Kazaz et al., 2009). As we mentioned, the T allele of D1-rs11206244 showed lower T3 and higher rT3 than non-T carriers (de Jong et al., 2007; Peeters et al., 2003). Thus, it seems that patients genetically characterized by poor conversion of T4 to T3, are better responders to T3-antidepressant co-treatment (Cooper-Kazaz et al., 2007; 2008). Another study evaluated whether baseline thyroid function and D2 rs225014 (D2-Thr92Ala) predict response to paroxetine. It showed that high TSH levels predict the response, and heterozygous patients showed lower TSH levels than the wild-type allele (A) (Brouwer et al., 2006). However, up to date there is no study evaluating the influence of T3 and D2

Based on these observations, we evaluated the presence of D2 polymorphism related with a lower activity of the enzyme: D2-Thr92Ala (T/C). The polymorphism was analyzed in 61 euthyroid patients with depression and 48 subjects of a population sample using the PCR-RFLP method. Clinical response to fluoxetine was evaluated before and after 8 weeks of treatment, using Hamilton Scale for Depression (HAM-D). We found that the CC genotype of Thr92Ala polymorphism was more frequent in depressed subjects and in non-responders patients (unpublished data). We concluded that Thr92Ala polymorphism of D2 gene could be considered a predictive marker of clinical response to fluoxetine, and hence of pharmacological therapy, but more studies are needed to confirm this preliminary results. The presence of these polymorphisms could influence basal activity of type 2 deiodinase,

amine neurotransmission such as serotonin (reviewed in Belmaker&Agam 2008).

determining decreased T3 levels and secondarily, reduced levels of brain 5HT.

polymorphisms on antidepressant response.

and therefore of T3 bioavailability in the brain.

#### **4. Use of thyroid hormone in depression**

Several studies using thyroid hormones in the management of patients with mood disorders have been reported since the early seventies. TH have been used in euthyroid depressed patients to enhance the effects of antidepressants. In patients receiving electroconvulsive therapy, those treated with T3 required less sessions and presented less memory loss compared with placebo treated group (Stern et al., 1991). T3 has been employed in initial combination therapy, and T3 or T4 in refractary depression or non responder patients.

T3 in doses of 20 to 50 g is able to enhance the effect of tricyclic antidepressants and shorten the depression period but, many studies have not demonstrated differences in the number of patients recovered (Prange et al., 1969; Wilson et al., 1970; Coppen et al., 1972; Wheatley, 1972). A meta-analysis showed that when T3 was used in refractary depression in addition to tricyclic antidepressant therapy, patients treated with it were twice as likely to respond as controls, decreasing depression severity scores (Aronson et al., 1996). However, samples size were small and deserve more evidence. Other studies, using T3 augmentation to SSRI-resistant depression, observed an improvement in mood scores (Agid&Lerer, 2003, Iosifescu et al., 2005, Abraham et al., 2006). Some authors found that patients who responded to T3 had higher serum TSH levels than non-responders and T3 appears to be less effective in men than in women (Agid&Lerer, 2003). Other authors reported that patients with atypical depression experienced significantly greater clinical improvement in final HAM-D with higher rates of treatment response and remission compared to subjects with non-atypical major depressive disorder (Iosifescu et al., 2005). All those cases were treated mainly with fluoxetine in a daily dose of 20 to 40 mg/ and 25-50 g of T3, with few side effects.

L-thyroxine (T4) added to antidepressants has been used less frequently than T3. Some authors have suggested that T4 augmentation is less effective than T3 (Joffe&Singer, 1990) and that supra physiological doses (250-600 ug/day) are needed, as has been demonstrated in patients with resistant major depression or refractary uni and bipolar disorders (Baumgartner et al., 1994, Bauer et al., 1998, 2002). These results support the theory of a reduced deiodination of T4 compatible with an inhibition of the D2 or a stimulation of the D3 in brain tissues resulting in reduced local T3 concentration.

Nevertheless, the addition of T4 (100 ug /day during 4 weeks) to serotoninergic antidepressants obtained remission in 11 of 12 female patients with a resistant depressive episode but, these results did not show association with T3, T4 or TSH levels (Łojko & Rybakowski, 2007).

To date, the use of TH in mood disorders is controversial and the rationale for this therapy is still not completely clear. Main limitations of the studies are: small number of cases, lack of a placebo group, heterogeneity in diagnosis criteria, differences in observational period and in antidepressant therapy. For example, lithium has a known inhibitory effect on TH secretion; fluoxetine has a stimulatory effect over D2 as well as desipramine and both of them could induce deficit of T4.

In this line, we evaluated a group of euthyroidal adult female patients with major depression according to DSM IV-R criteria. All of them were free of antidepressants for at least for 6 month. We studied the effect of adding T3 in a dose of 50 ug per day (n=11) or placebo (n=10), to the standard antidepressant therapy with fluoxetine during 8 weeks. At the end of the observational period final HAM-D scores were similar in both groups. (See **Table 1**). Patients in T3 group showed significant T4, T3 and TSH changes; but they remain

Depressive Disorders and Thyroid Function 267

Single-photon tomography (SPECT), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are able to capture physiological events linked to underlying neuronal activity. They have been employed to image and quantify brain perfusion, flow and metabolism in several conditions as well as the radionuclide techniques have been used to map neurotransmissors, receptors, drug actions and many metabolic pathways. Functional imaging in mood disorders may show abnormalities at different brain levels that could normalize with therapy. Several serotonin and adrenergic markers have also been employed to study negative emotional stimuli response in mood disorders. For instance: thalamic activity was increased by reboxetine, whereas citalopram primarily affected ventrolateral prefrontal regions. It would be interesting to have a method able to predict therapy responses to either noradrenergic or serotoninergic antidepressants (Carey et al., 2004; Navarro et al., 2004; Zobel et al., 2005; Kohn et al., 2007; MacQueen, 2009; Brühl et al., 2011). It is also known that even mild hypothyroidism may produce changes in brain regions modulating attention, motor speed, memory and visual-spatial processing. In severe hypothyroidism induced by thyroidectomy in cancer patients, it have been reported a clear parietal and partial occipital lobe hypoperfusion, measured with SPECT; the abnormalities improved after reaching normal thyroid function, in some subjects. However, fluorodeoxyglucose (FDG) and oxygen-15-labeled water studies, in similar patients, showed lower global brain glucose metabolism and flow. Hypothyroidal patients were also significantly more depressed, anxious and psychomotor slowered than euthyroidal subjects

Brain metabolism and flow are usually decreased in major depression and bipolar disease being metabolism inversely associated with the severity of depression. Changes are variable and as we mentioned earlier, could reverse with adequate therapy. Subgenual prefrontal cortex presents abnormal blood flow and metabolism in the depressed state. Prefrontal cortex and limbic structures are involved in emotion regulation and amygdale is involved in emotional memory formation (Buchsbaum et al., 1997; Kennedy et al., 2007; Chen et al., 2011). In major depression patients, glucose metabolism in orbitofrontal and inferior frontal cortex correlates with therapy response; responders have a significant decrease in the orbitofrontal and ventrolateral regions compared with non-responders, implicating ventral prefrontal subcortical circuits in response to specific therapy with SSRI. In major depression and bipolar patients, FDG has shown an inverse correlation between brain metabolism and

Cerebral fMRI has been reported to be helpful in major depression intending to predict therapy response using brain activation. Morphometric studies have evaluated hippocampus volume association with response to treatment. Patients who remit have larger pretreatment hippocampus volumes bilaterally compared with those who do not remit. There are similar preliminary findings for the anterior cingulate cortex. A recent work demonstrated a significantly thinner posterior cingulate cortex in non-remitters than in remitters, and also significant decrease in perfusion in frontal lobes and anterior cingulate cortex in non-remitters

There are reports with increased perfusion in anterior cingulate and prefrontal medial cortex when using SSRI or amesergide. Responders and non-responders to cognitive behavior therapy versus antidepressive pharmacotherapy and deep brain stimulation could also be

circulating TSH (Brody et al., 1999; Marangell et al., 1997; Milak et al., 2005).

compared with healthy controls, at baseline (MacQueen, 2009; Järnum et al., 2011).

**5. Hypothyroidism, depression and brain imaging** 

(Nagamachi et al., 2004; Constant et al., 2001).

clinically euthyroid during the whole treatment period. Their body mass index , heart rate and other clinical parameters did not change. The placebo group showed a non significant increase of THS at the end of the observation time (See **Figure 1**, unpublished results).


Table 1. Age and Hamilton score (HAM-D) with 21 items, in the groups with T3 addition or placebo. Both initial and 2 months means±SD were similar (using non paired t student test). The difference between initial and 2 month was highly significant in both groups (using paired t tests).

Fig. 1. TSH changes after addition of T3 or placebo in both groups. Measurements of TSH are shown at baseline, 1 month and 2 months using similar SSRI therapy. T3 hormone induced significant decreased TSH levels. No significant change was observed in placebo group.

Summarizing, our results suggest that TH addition to SSRI therapy in euthyroid depressed patients is safe and has not deleterious clinical effects in spite of TSH changes during treatment. Although, we could not demonstrated in this particular group, a significant antidepressant effect.

clinically euthyroid during the whole treatment period. Their body mass index , heart rate and other clinical parameters did not change. The placebo group showed a non significant increase of THS at the end of the observation time (See **Figure 1**, unpublished results).

**T3 Group Placebo p**

**HAM-D** 24±4 8±4 26±6 7±4 <0.0001 ns

Table 1. Age and Hamilton score (HAM-D) with 21 items, in the groups with T3 addition or placebo. Both initial and 2 months means±SD were similar (using non paired t student test). The difference between initial and 2 month was highly significant in both groups (using

Fig. 1. TSH changes after addition of T3 or placebo in both groups. Measurements of TSH are shown at baseline, 1 month and 2 months using similar SSRI therapy. T3 hormone induced significant decreased TSH levels. No significant change was observed in placebo group.

**T3 Group Placebo**

Summarizing, our results suggest that TH addition to SSRI therapy in euthyroid depressed patients is safe and has not deleterious clinical effects in spite of TSH changes during treatment. Although, we could not demonstrated in this particular group, a significant

Initial 2m Initial 2m Initial vs 2m Groups

**Age** (y.o.) 40±12 36±10 ns

paired t tests).

antidepressant effect.

#### **5. Hypothyroidism, depression and brain imaging**

Single-photon tomography (SPECT), positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are able to capture physiological events linked to underlying neuronal activity. They have been employed to image and quantify brain perfusion, flow and metabolism in several conditions as well as the radionuclide techniques have been used to map neurotransmissors, receptors, drug actions and many metabolic pathways. Functional imaging in mood disorders may show abnormalities at different brain levels that could normalize with therapy. Several serotonin and adrenergic markers have also been employed to study negative emotional stimuli response in mood disorders. For instance: thalamic activity was increased by reboxetine, whereas citalopram primarily affected ventrolateral prefrontal regions. It would be interesting to have a method able to predict therapy responses to either noradrenergic or serotoninergic antidepressants (Carey et al., 2004; Navarro et al., 2004; Zobel et al., 2005; Kohn et al., 2007; MacQueen, 2009; Brühl et al., 2011).

It is also known that even mild hypothyroidism may produce changes in brain regions modulating attention, motor speed, memory and visual-spatial processing. In severe hypothyroidism induced by thyroidectomy in cancer patients, it have been reported a clear parietal and partial occipital lobe hypoperfusion, measured with SPECT; the abnormalities improved after reaching normal thyroid function, in some subjects. However, fluorodeoxyglucose (FDG) and oxygen-15-labeled water studies, in similar patients, showed lower global brain glucose metabolism and flow. Hypothyroidal patients were also significantly more depressed, anxious and psychomotor slowered than euthyroidal subjects (Nagamachi et al., 2004; Constant et al., 2001).

Brain metabolism and flow are usually decreased in major depression and bipolar disease being metabolism inversely associated with the severity of depression. Changes are variable and as we mentioned earlier, could reverse with adequate therapy. Subgenual prefrontal cortex presents abnormal blood flow and metabolism in the depressed state. Prefrontal cortex and limbic structures are involved in emotion regulation and amygdale is involved in emotional memory formation (Buchsbaum et al., 1997; Kennedy et al., 2007; Chen et al., 2011). In major depression patients, glucose metabolism in orbitofrontal and inferior frontal cortex correlates with therapy response; responders have a significant decrease in the orbitofrontal and ventrolateral regions compared with non-responders, implicating ventral prefrontal subcortical circuits in response to specific therapy with SSRI. In major depression and bipolar patients, FDG has shown an inverse correlation between brain metabolism and circulating TSH (Brody et al., 1999; Marangell et al., 1997; Milak et al., 2005).

Cerebral fMRI has been reported to be helpful in major depression intending to predict therapy response using brain activation. Morphometric studies have evaluated hippocampus volume association with response to treatment. Patients who remit have larger pretreatment hippocampus volumes bilaterally compared with those who do not remit. There are similar preliminary findings for the anterior cingulate cortex. A recent work demonstrated a significantly thinner posterior cingulate cortex in non-remitters than in remitters, and also significant decrease in perfusion in frontal lobes and anterior cingulate cortex in non-remitters compared with healthy controls, at baseline (MacQueen, 2009; Järnum et al., 2011).

There are reports with increased perfusion in anterior cingulate and prefrontal medial cortex when using SSRI or amesergide. Responders and non-responders to cognitive behavior therapy versus antidepressive pharmacotherapy and deep brain stimulation could also be

Depressive Disorders and Thyroid Function 269

As we mentioned before, a half of the women in our group received T3 in addition of SSRI and the other half a placebo instead of T3. Our results showed no evidence that adding T3 to SSRI therapy in unipolar major depression females produces significant change in regional cerebral blood flow at neocortical level (See Figure 3). Only a small difference was found at deep structure level that could imply diverse brain mechanism involved [data not published].

These findings are in agreement with other reports showing relative normalization of perfusion and metabolism that were abnormally increased at baseline in patients with mood disorders. Some of these regional metabolism changes are correlated with emotional behavior. The amygdala and limbic structures have been associated with face recognition and emotional processing. It is well known that there is increased perfusion and metabolism in specific brain areas, reflecting molecular abnormalities in neurotransmitter systems. The development of new molecular imaging methods could help in the individualization of

Fig. 3. Absence of regional cerebral blood flow change after SSRI therapy in T3 group, using Statistical Parametric Analysis (SPM8) with significant level <0.001; uncorrected p value.

Depressive and thyroid disorders are important public health problems. There is strong experimental evidence showing thyroid involvement on early stages of CNS development and on metabolic function of the mature brain. It is also accepted that overt hyper or hypothyroidism are not found frequently among mood disorders patients except in those with bipolar disorders, indicating that in most cases the underlying abnormality is at cellular or molecular levels. Although there is a prolific literature on the relationship between thyroid function and depressive disorders, clear results in humans on the role of TH in antidepressant therapy are still lacking. There are no randomized controlled trials, and the number of patients included in existing studies is too small. On the other hand,

antidepressant therapies (Chen et al., 2011).

**6. Conclusions** 

differentiated using brain perfusion SPECT or glucose metabolism with PET (Vlassenko et al., 2004; Kennedy et al., 2007; Richieri et al., 2011).

Another work with fMRI demonstrated also that successful paroxetine treatment decreases amygdala activation, presumably by improved frontolimbic control, in line with SSRI, induced increased functional connectivity between pregenual anterior cingulated cortex, prefrontal cortex, and amygdala. Changes in amygdala activation when processing negative faces expressions might serve as an indicator for improved frontolimbic control required for clinical response (Ruhé, 2011).

We recently studied a group of major depression middle age patients using brain perfusion SPECT, all in their first episode of major depression and /or without any specific therapy for at least six months. Their initial HAM-D scores corresponded to 24±4.8; all of them received standard SSRI therapy. Ninety-three percent were responders at 2 months (HAM-D decrease >50%) and 59% were remitters (HAM-D score ≤5). There was association of decreased perfusion in diverse brain areas with HAM-D changes in the whole group using Statistical Parametric Analysis (SPM) as covariate (See Figure 2). We did not observe significant neocortical perfusion change after 2 months of standard dose of fluoxetine therapy. However, there was a bilateral decrease in parahippocampal gyrus, thalamus and striatum as well as in anterior cingulate gyrus (Brodmann 32 area) after SSRI therapy. No significant difference was observed between remitters and non-remitters.

Fig. 2. In the whole group, SPM8 analysis demonstrated association between decreased perfusion and HAM-D scores considered as a covariate, at baseline and after 2 months of therapy (non corrected p <0.001): -at left: in amygdala, anterior cingulate, globus pallidum, putamen and Brodmann area 9 (mid frontal gyrus) -bilaterally: both hyppocampal gyrus, mid and superior temporal and insulas and cerebellar hemispheres -at right: in central and supramarginal gyrus

differentiated using brain perfusion SPECT or glucose metabolism with PET (Vlassenko et

Another work with fMRI demonstrated also that successful paroxetine treatment decreases amygdala activation, presumably by improved frontolimbic control, in line with SSRI, induced increased functional connectivity between pregenual anterior cingulated cortex, prefrontal cortex, and amygdala. Changes in amygdala activation when processing negative faces expressions might serve as an indicator for improved frontolimbic control required for

We recently studied a group of major depression middle age patients using brain perfusion SPECT, all in their first episode of major depression and /or without any specific therapy for at least six months. Their initial HAM-D scores corresponded to 24±4.8; all of them received standard SSRI therapy. Ninety-three percent were responders at 2 months (HAM-D decrease >50%) and 59% were remitters (HAM-D score ≤5). There was association of decreased perfusion in diverse brain areas with HAM-D changes in the whole group using Statistical Parametric Analysis (SPM) as covariate (See Figure 2). We did not observe significant neocortical perfusion change after 2 months of standard dose of fluoxetine therapy. However, there was a bilateral decrease in parahippocampal gyrus, thalamus and striatum as well as in anterior cingulate gyrus (Brodmann 32 area) after SSRI therapy. No

significant difference was observed between remitters and non-remitters.

Fig. 2. In the whole group, SPM8 analysis demonstrated association between decreased perfusion and HAM-D scores considered as a covariate, at baseline and after 2 months of therapy (non corrected p <0.001): -at left: in amygdala, anterior cingulate, globus pallidum, putamen and Brodmann area 9 (mid frontal gyrus) -bilaterally: both hyppocampal gyrus, mid and superior temporal and insulas and cerebellar hemispheres -at right: in central and

al., 2004; Kennedy et al., 2007; Richieri et al., 2011).

clinical response (Ruhé, 2011).

supramarginal gyrus

As we mentioned before, a half of the women in our group received T3 in addition of SSRI and the other half a placebo instead of T3. Our results showed no evidence that adding T3 to SSRI therapy in unipolar major depression females produces significant change in regional cerebral blood flow at neocortical level (See Figure 3). Only a small difference was found at deep structure level that could imply diverse brain mechanism involved [data not published].

These findings are in agreement with other reports showing relative normalization of perfusion and metabolism that were abnormally increased at baseline in patients with mood disorders. Some of these regional metabolism changes are correlated with emotional behavior. The amygdala and limbic structures have been associated with face recognition and emotional processing. It is well known that there is increased perfusion and metabolism in specific brain areas, reflecting molecular abnormalities in neurotransmitter systems. The development of new molecular imaging methods could help in the individualization of antidepressant therapies (Chen et al., 2011).

Fig. 3. Absence of regional cerebral blood flow change after SSRI therapy in T3 group, using Statistical Parametric Analysis (SPM8) with significant level <0.001; uncorrected p value.

#### **6. Conclusions**

Depressive and thyroid disorders are important public health problems. There is strong experimental evidence showing thyroid involvement on early stages of CNS development and on metabolic function of the mature brain. It is also accepted that overt hyper or hypothyroidism are not found frequently among mood disorders patients except in those with bipolar disorders, indicating that in most cases the underlying abnormality is at cellular or molecular levels. Although there is a prolific literature on the relationship between thyroid function and depressive disorders, clear results in humans on the role of TH in antidepressant therapy are still lacking. There are no randomized controlled trials, and the number of patients included in existing studies is too small. On the other hand,

Depressive Disorders and Thyroid Function 271

Baumgartner, A.; Bauer, M. & Hellweg, R. (1994). Treatment of intractable non-rapid cycling

Belmaker, RH. & Agam, G. (2008). Mechanisms of Disease: Major Depressive Disorder. *New* 

Bernal, J. & Nunez, J. (1995). Thyroid hormones and brain development. *European Journal of* 

Bernal, J. (2005). Thyroid hormones and brain development. *Vitamines and Hormones*, Vol. 71,

Bianco, A.C.; Salvatore, D.; Gereben, B.; Berry, M.J. & Larsen, P.R. (2002). Biochemistry,

Bradley, D.J.; Towle, H.C. & Young, W.S., 3rd. (1992). Spatial and temporal expression of

Bradley, D.J.; Young, W.S. 3rd & Weinberger, C. (1989). Differential expression of alpha and

Brody, A.L., Saxena,S., Silverman, D.H., Alborzian, S., Fairbanks, L.A., Phelps, M.E., Huang,

Brouwer, J.P., Appelhof, B.C., Hoogendijk, W.J., Huyser, J., Endert, E., Zuketto, C., Schene,

Brouwer, J.P.; Appelhof, B.C.; Peeters, R.P.; Hoogendijk, W.J.; Huyser, J.; Schene, A.H.;

Brühl, A.B., Jäncke, L., Herwig, U. (2011). Differential modulation of emotion processing brain

*Research*, (October 1999), Vol 91, N°.3 91, pp.127-139.

*Endocrinology,* Vol.152, N°2, (February 2005) pp.185-191.

*(Berlin)*, (August 2011), Vol. 216. N°3, pp.389-399.

cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. *Endocrine Reviews*, Vol.23, No. 1 (February 2002), pp. 38-89. Bould, H., Panicker, V., Kessler, D., Durant, C., Lewis, G., Dayan, C., Evans, J. (2011).

Investigation of thyroid dysfunction in general practice is more likely in patients with high psychological morbidity. *Family Practice* (September 2011) [Epub ahead of print]

alpha- and beta-thyroid hormone receptor mRNAs, including the beta 2-subtype, in the developing mammalian nervous system. *Journal of Neurosciences*, Vol.12, No.6

beta thyroid hormone receptor genes in rat brain and pituitary. *Proceedings of National Academy of Sciences U S A*, Vol.86, No.18 (September 1989), pp. 7250-7254. Breteler, M.M., (2007). The association of polymorphisms in the type 1 and 2 deiodinase

genes with circulating thyroid hormone parameters and atrophy of the medial temporal lobe. *Journal of Clinical Endocrinology and Metabolism*, Vol.92, N°2,

S.C., Wu, H.M., Maidment, K., Baxter, L.R. Jr. (1999). Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine. *Psychiatry* 

A.H., Tijssen. J.G., Van Dyck, R., Wiersinga, W.M., Fliers, E. Thyroid and adrenal axis in major depression: a controlled study in outpatients. *European Journal of* 

Tijssen, J.G.; Van Dyck, R.; Visser, T.J.; Wiersinga, W.M. & Fliers, E. (2006). Thyrotropin, but not a polymorphism in type II deiodinase, predicts response to paroxetine in major depression. *European Journal of Endocrinology*, Vol.154, No.6

regions by noradrenergic and serotonergic antidepressants. *Psychopharmacology* 

*Neuropsychopharmacology*, Vol.10, No.3 (May 1994), pp. 183–189.

*Endocrinology*, Vol.133, No.4 (October 1995), pp. 390-398.

*England Journal of Medicine*, Vol.358, No.1 (January 2008), pp. 55-68.

1998), pp. 444-455.

pp. 95-122.

(June 1992), pp. 2288-2302.

(February 2007), pp.636-640.

(June 2006), pp. 819-825.

Thyroxine in the maintenance treatment of prophylaxis-resistant affective disorders. *Neuropsychopharmacology*, Vol.27, No.4 (October 2002), pp. 620–628. Bauer, M.; Hellweg, R.; Gräf, KJ. & Baumgartner, A. (1998). Treatment of refractory

depression with high-dose thyroxine. *Neuropsychopharmacology*, Vol.18, No.6 (June

bipolar affective disorder with high-dose thyroxine: An open trial.

more research is needed in order to define the importance of genetic variants in deiodinases and the role of neuroimaging into the complex interactions between HPT function and mood disorders and in clinical response to treatments.

Therefore, considering the available evidence and our own experience, we can recommend this strategy only as an alternative treatment in major depression patients who have failed to respond to other measures.

#### **7. Acknowledgments**

The work described in this chapter was partially financed by the grant "Líneas de Investigación Prioritarias" #240/07 HCUCH from the Clinical Hospital of the University of Chile, Santiago, Chile.

The authors thank Dr. Rodrigo Jaimovich (Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile) who processed and analyzed all SPECT data; Dr. Tamara Galleguillos (Psychiatric Clinic of the Clinical Hospital of the University of Chile ) by her collaboration in patient´s recruitment, selection and follow up; Mr. Egardo Caamaño for his technical laboratory support and Ms. Clara Menares who performed the molecular biology studies.

#### **8. References**


more research is needed in order to define the importance of genetic variants in deiodinases and the role of neuroimaging into the complex interactions between HPT function and

Therefore, considering the available evidence and our own experience, we can recommend this strategy only as an alternative treatment in major depression patients who have failed

The work described in this chapter was partially financed by the grant "Líneas de Investigación Prioritarias" #240/07 HCUCH from the Clinical Hospital of the University of

The authors thank Dr. Rodrigo Jaimovich (Department of Radiology, School of Medicine, Pontificia Universidad Católica de Chile) who processed and analyzed all SPECT data; Dr. Tamara Galleguillos (Psychiatric Clinic of the Clinical Hospital of the University of Chile ) by her collaboration in patient´s recruitment, selection and follow up; Mr. Egardo Caamaño for his technical laboratory support and Ms. Clara Menares who performed the molecular

Abraham, G.; Milev, R. & Stuart Lawson, J. (2006). T3 augmentation of SSRI resistant depression. *Journal of Affective Disorders*, Vol.91, No.2-3 (April 2006), pp. 211–215. Agid, O. & Lerer, B. (2003). Algorithm-based treatment of major depression in an outpatient

Altshuler, L.L.; Bauer, M.; Frye, M.A.; Gitlin, M.J.; Mintz, J., Szuba, M.P., Leight, K.L. &

Aniello, F.; Couchie, D.; Bridoux, A.M.; Gripois, D. & Nunez, J. (1991). Splicing of juvenile

Atterwill, C.K, Bunn S.J., Atkinson, D.J., Smith, S.L., Heal. D.J. Effects of thyroid status on

Bauer, M.; Berghöfer, A.; Bschor, T.; Baumgartner, A.; Kiesslinger, U.; Hellweg, R.; Adli, M.;

*Journal of Psychiatry*, Vol.158, No.10 (October 2001), pp. 1617-1622.

*National Academic of Sciences*, Vol. 88, No.9 (May 1991), pp. 4035-4039. Aronson, R.; Offman, HJ.; Joffe, RT. & Naylor, CD. (1996). Triiodothyronine augmentation in

rat brain. *Journal of Neural Transmission*, Vol. 59, N°1, (1984), pp.43-55. Bauer, M., Heinz, A., Whybrow, P.C. (2002a). Thyroid hormones, serotonin and mood: of

*Psychiatry*, Vol. 53, No.9 (September 1996), pp. 842-848.

clinic: clinical correlates of response to a specific serotonin reuptake inhibitor and to triiodothyronine augmentation. *International Journal of Neuropsychopharmacology*,

Whybrow, P.C. (2001). Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. *American* 

and adult tau mRNA variants is regulated by thyroid hormone. *Proceedings of* 

the treatment of refractory depression. A meta-analysis. *Archives General of* 

presynaptic alpha 2-adrenoceptor function and beta-adrenoceptor binding in the

synergy and significance in the adult brain. *Molecular Psychiatry*, Vol.7, N° 2,(2002a)

Baethge, C. & Müller-Oerlinghausen, B. (2002b). Supraphysiological doses of L-

mood disorders and in clinical response to treatments.

Vol.6, No.1 (March 2003), pp.41-49.

to respond to other measures.

**7. Acknowledgments** 

Chile, Santiago, Chile.

biology studies.

**8. References** 

pp.140-156.

Thyroxine in the maintenance treatment of prophylaxis-resistant affective disorders. *Neuropsychopharmacology*, Vol.27, No.4 (October 2002), pp. 620–628.


Depressive Disorders and Thyroid Function 273

Coppen, A.; Whyborw, PC.; Noguera, R.; Maggs, R. & Prange, Jr AJ. (1972). The comparative

Coppotelli, G., Summers, A., Chidakel, A., Ross, J.M., Celi, F.S. (2006). Functional

Crantz, F.R., Silva, J.E., Larsen, P.R. (1982). An analysis of the sources and quantity of 3,5,3'-

Dratman, M.B. & Gordon, J.T. (1996). Thyroid hormones as neurotransmitters. *Thyroid*,

Dussault, JH. & Ruel, J. (1987). Thyroid hormones and brain development. *Annual Review of* 

El-Bakry, A.M., El-Gareib, A.W., Ahmed, R.G. (2010). Comparative study of the effects of

Emerson, CH.; Dyson, WL. & Utiger, RD. (1973). Serum thyrotropin and thyroxine

*Endocrinology and Metabolism*, Vol. 36, No.2 (February 1972), pp. 338–346. Eravci, M., Pinna, G., Meinhold, H., Baumgartner, A. (2000). Effects of pharmacological and

Farwell, A.P., Dubord, S.A. (1996) Thyroid hormone regulates neurite outgrowth and neuronal migration onto laminin. *Thyroid,* Vol.6, (Suppl 1) (1996) pp.S-6 Farwell, AP.; Dubord-Tomasetti, SA.; Pietrzykowski, AZ. & Leonard, JL. (2006). Dynamic

Forman-Hoffman, V., Philibert, R.A. (2006). Lower TSH and higher T4 levels are associated

Forrest, D.; Erway, LC.; Ng, L.; Altschuler, R. & Curran, T. (1996a). Thyroid hormone

Forrest, D.; Hanebuth, E.; Smeyne, RJ.; Everds, N.; Stewart, CL.; Wehner, JM. & Curran, T.

*EMBO Journal*, Vol.15, No.12 (June 1996), pp. 3006–3015.

experimentally induced hypothyroidism and hyperthyroidism in some brain regions in albino rats. *Journal of Developmental Neuroscience*, Vol.28, No.5 (August

concentrations in patients receiving lithium carbonate. *Journal of Clinical* 

nonpharmacological treatments on thyroid hormone metabolism and concentrations in rat brain. *Endocrinology,* Vol.141, N° 3, (March 2000) pp.1027-1040.

nongenomic actions of thyroid hormone in the developing rat brain. *Endocrinology*,

with current depressive syndrome in young adults. *Acta Psychiatrica Scandinava*,

receptor beta is essential for development of auditory function. *Nature Genetics,*

(1996b). Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function. *The*

cerebellum. *Endocrinology*, Vol.110, N°2, (February 1982) pp.367-375. de Jong, F.J., Peeters, R.P., den Heijer, T., van der Deure, W.M., Hofman, A., Uitterlinden,

*Metabolism*, Vol.92,No 2 (February 2007), pp. 636-640.

*Physiology*, Vol.49, No. 3 (March 1987), pp. 321-334.

Vol.6; N°6 (December 1996) pp.639-647.

Vol.147, No.5 (May 2006), pp. 2567–2574.

Vol. 114, N°2, (August 2006) pp.132-139

Vol.13, No.3 (July 1996), pp. 354–357.

1972), pp. 234–241.

2010), pp. 371–389.

2006),Vol.16, N°7, pp. 625-632.

antidepressant value of L-tryptophan and imipramine with and without attempted potentiation by liothyronine. *Archives of General Psychiatry*, Vol. 26, No.3 (March

characterization of the 258 A/G (D2-ORFa-Gly3Asp) human type-2 deiodinase polymorphism: a naturally occurring variant increases the enzymatic activity by removing a putative repressor site in the 5' UTR of the gene. *Thyroid*, (July

triiodothyronine specifically bound to nuclear receptors in rat cerebral cortex and

A.G., Visser, T.J., T.J. & Breteler M.M. (2007). The association of polimorphisms in the type 1 and 2 deidinase genes with circulating thyroid hormone parameters and atrophy of the medial temporal lobe. *Journal of Clinical Endocrinology and* 


Buchsbaum, M.S., Wu, J., Siegel, B.V., Hackett, E., Trenary, M., Abel, L., Reynolds, C. (1997).

Butler, P.W.; Smith, S.M.; Linderman, J.D.; Brychta, R.J.; Alberobello, A.T.; Dubaz, O.M.;

Campos-Barros, A., Meinhold, H., Kohler, R., Muller, F., Eravci, M., Baumgartner, A., (1995).

Carey, P.D., Warwick, J., Niehaus, D.J., van der Linden, G., van Heerden, B.B., Harvey, B.H.,

Chen, Q., Liu, W., Li, H., Zhang, H., Tian, M. (2011). Molecular imaging in patients with

Constant, E.L., Adam, S., Seron, X., Bruyer, R., Seghers, A., Daumerie, C. (2005). Anxiety and

Constant, E.L., de Volder, A.G., Ivanoiu, A., Bol, A., Labar, D., Seghers, A., Cosnard, G.,

*Endocrinology and Metabolism*, Vol 86, N° 8, (August 2001), pp.3864-3870. Cooper-Kazaz, R., Apter, J.T., Cohen, R., Karagichev, L., Muhammed-Moussa, S., Grupper,

Cooper-Kazaz, R., van der Deure, W.M., Medici, M., Visser, T.J., Alkelai, A., Glaser, B.,

Cooper-Kazaz, R.Lerer, B. (2008). Efficacy and safety of triiodothyronine supplementation in

*Biological Psychiatry*, Vol. 41, N°1. (January 1997), pp.15-22.

*and Metabolism,* Vol.90, N°6, (June 2005). pp.3472-3478.

*Molecular Imaging*, Vol. 38, N°7, (July 2011), pp. 1367-1380

(December 2010), pp. 1407-1412.

*Psychiatry,* (October 2004) 14;4:30.

pp.535–544.

(June 2007), pp. 679-688.

Vol.116, N°1-2, pp.113-116.

2008), pp. 685-699.

Effect of sertraline on regional metabolic rate in patients with affective disorder.

Luzon, J.A.; Skarulis, M.C.; Cochran, C.S.; Wesley, R.A.; Pucino, F. & Celi, F.S. (2010). The Thr92Ala 5' type 2 deiodinase gene polymorphism is associated with a delayed triiodothyronine secretion in response to the thyrotropin-releasing hormone-stimulation test: a pharmacogenomic study. *Thyroid*, Vol.20, No.12

The effects of desipramine on thyroid hormone concentrations in rat brain. *Naunyn Schmiedebergs Archives of Pharmacology,* Vol.351, N°5, (May 1995), pp.469-474. Canani, L.H., Capp, C., Dora, J.M., Meyer, E.L., Wagner, M.S., Harney, J.W., Larsen, P.R.,

Gross, J.L., Bianco, A.C., Maia, A.L., (2005). The type 2 deiodinase A/G (Thr92Ala) polymorphism is associated with decreased enzyme velocity and increased insulin resistance in patients with type 2 diabetes mellitus. *Journal of Clinical Endocrinology*

Seedat, S., Stein, D.J. (2004). Single photon emission computed tomography (SPECT) of anxiety disorders before and after treatment with citalopram. *BMC*

mood disorders: a review of PET findings. *European Journal of Nuclear Medicine and* 

depression, attention, and executive functions in hypothyroidism, *Journal of the International Neuropsychological Society,* (2005), Vol.11, N°5, (September 2005),

Melin, J., Daumerie, C. (2001). Cerebral blood flow and glucose metabolism in hypothyroidism: a positron emission tomography study. *Journal of Clinical* 

D., Drori, T., Newman, M.E., Sackeim, H.A., Glaser, B., Lerer, B.(2007). Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial. *Archives of General Psychiatry*, Vol.64, N°6,

Peeters, R.P., Lerer, B. (2009). Preliminary evidence that a functional polymorphism in type 1 deiodinase is associated with enhanced potentiation of the antidepressant effect of sertraline by triiodothyronine. *Journal of Affective Disorders,* (July 2009),

patients with major depressive disorder treated with specific serotonin reuptake inhibitors. *International Journal of Neuropsychopharmacology*, Vol.11, N°5, (August


Depressive Disorders and Thyroid Function 275

Iosifescu, DV.; Nierenberg, AA.; Mischoulon, D.; Perlis, RH.; Papakostas, GI.; Ryan, JL.;

Joffe, RT. & Singer, W. (1990). A comparison of triiodotironine and thyroxine in the

Jones, I.; Ng, L., Liu, H. & Forrest, D. (2007). An intron control region differentially regulates

Kirkegaard, C., Faber, J. (1998). The role of thyroid hormones in depression. *European Journal* 

Kohn, Y., Freedman, N., Lester, H., Krausz, Y., Chisin, R., Lerer, B., Bonne, O. (2007). 99mTc-

Larsen, JK.; Faber, J.; Christensen, EM.; Bendsen, BB.; Solstad, K.; Gjerris, A. & Siersbaek-

Leonard, JL. & Farwell, AP. (1997). Thyroid hormone-regulated actin polymerization in

Lifschytz, T., Segman, R., Shalom, G., Lerer, B., Gur, E., Golzer, T., Newman, M.E. (2006).

Linkowski, P.; Brauman, H. & Mendlewicz, J. (1981). Thyrotrophin response to

Łojko, D. Rybakowski, JK. (2007). L-thyroxine augmentation of serotonergic antidepressants

Loosen, PT. (1985). The TRH-induced TSH response in psychiatric patients: a possible neuroendocrine marker. *Psychoneuroendocrinology*, Vol.10, No.3, pp. 237–260. MacQueen, G.M. (2009) Magnetic resonance imaging and prediction of outcome in patients

Marangell, L.B., Ketter, T.A., George. M.S., Pazzaglia, P.J., Callahan, A.M., Parekh, P.,

0447.2011.01766.x. [Epub ahead of print]

*Psychiatry*, Vol.164, N°5. (May 2007), pp.778–788

N°8, (August 2007) pp. 1273-1278

(August 2004), pp. 917–924.

*of Endocrinology,* (January1998), Vol.138, N°1, pp.1-9.

brain. *Thyroid*, Vol.7, No.1 (February 1997), pp. 147–151.

*Affective Disorders*, Vol. 3, No.1 (March 1981), pp. 9–16.

No. 1-3 (November 2007), pp. 253-256.

(September 2009) pp.343-349.

*Current Drug Targets*, Vol.7, N°2, (February 2006), pp. 203-210.

1990), pp. 241-251.

Alpert, JE. & Fava, M. (2005). An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder. *Journal of Clinical Psychiatry*, Vol.66, No.8 (August 2005), pp. 1038-1042. Järnum, H., Eskildsen, S.F., Steffensen, E.G., Lundbye-Christensen, S., Simonsen, C.W.,

Thomsen, I.S., Fründ, E.T., Théberge, J., Larsson, E.M. (2011). Longitudinal MRI study of cortical thickness, perfusion, and metabolite levels in major depressive disorder. *Acta Psychiatrica Scandinavica,* (September 2011)16. doi: 10.1111/j.1600-

potentiation of tricyclic antidepressants. *Psychiatry Research*, Vol.32, No.3 (June

expression of thyroid hormone receptor beta2 in the cochlea, pituitary, and cone photoreceptors. *Molecular Endocrinology*, Vol.21, No.5 (May 2007), pp. 1108–1119. Kennedy, S.H., Konarski, J.Z., Segal, Z.V., Lau, M.A., Bieling, P.J., McIntyre, R.S., Mayberg,

H.S. (2007). Differences in brain glucose metabolism between responders to CBT and Venlafaxine in a 16-week randomized controlled trial. *American Journal of* 

HMPAO SPECT study of cerebral perfusion after treatment with medication and electroconvulsive therapy in major depression. *Journal of Nuclear Medicine*, Vol. 48,

Nielsen, K. (2004). Relationship between mood and TSH response to TRH stimulation in bipolar affective disorder. *Psychoneuroendocrinology*, Vol.29, No.7

Basic mechanisms of augmentation of antidepressant effects with thyroid hormone.

thyrotrophin-releasing hormone in unipolar and bipolar affective illness. *Journal of* 

in female patients with refractory depression. *Journal of Affective Disorders*, Vol. 103,

with major depressive disorder. *Journal of Psychiatry & Neurosciences*, Vol. 34, N°5,

Andreason, P.J., Horwitz, B., Herscovitch, P. & Post, R.M. (1997) Inverse


Fountoulakis, K., Kantartzis, S., Siamouli, M., Panagiotidis, P., Kaprinis, S., Iacovides, A.,

Fraichard, A.; Chassande, O.; Plateroti, M. Roux, JP.; Trouillas, J.; Dehay, C.; Legrand, C.;

Gereben, B., Zavacki, A.M., Ribich, S., Kim, B.W., Huang, S.A., Simonides, W.S., Zeold, A.,

Gereben B, Zeöld A, Dentice M, Salvatore D, Bianco AC. (2008b). Activation and inactivation

Gerner, RH. & Yamada, T. (1982). Altered neuropeptide concentrations in cerebrospinal

Ghenimi, N.; Alfos, S.; Redonnet, A.; Higueret, P.; Pallet, V. & Enderlin, V. (2010). Adult-

Ghosh, M. , Das, S. (2007). Increased beta(2)-adrenergic receptor activity by thyroid

Gouveia, C.H., Christoffolete, M.A., Zaitune, C.R., Dora, J.M., Harney, J.W., Maia, A.L.,

Hansen, P.S., van der Deure, W.M., Peeters, R.P., Iachine, I., Fenger, M., Sorensen, T.I.,

He, B.; Li, J.; Wang, G.; Ju, W.; Lu, Y.; Shi, Y.; He, L. & Zhong, N. (2009). Association of

Heal, D.J., Smith, S.L. (1988). The effects of acute and repeated administration of T3 to mice

*Clinical Endocrinology (Oxf),* Vol.66, N°6, (June 2007), pp. 827-832.

*Psychiatry*, Vol. 33, No.6 (August 2009), pp. 986-990.

*and Molecular Life Sciences,* Vol. 65, N°4, (February 2008), pp.570-590.

*Genes & Development* , Vol.13, No.10 (May 1999), pp. 1329–1341.

*of Biological Psychiatry*, Vol.7, N°3, (2006), pp.131-137.

(July 1997), pp. 4412–4420.

No.8 (August 2010), pp. 951–959.

pp.1398-1410.

1988), pp.1239-1248.

Kaprinis, G. (2006). Peripheral thyroid dysfunction in depression. *The World Journal* 

Gauthier, K.; Kedinger, M.; Malaval, L.; Rousset, B. & Samarut, J. (1997). The T3R alpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production. *The EMBO Journal*, Vol.16, No.14

Bianco, A.C., (2008a). Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. *Endocrinology Review* Vol.29, N° 7, (December 2008) pp. 898-938.

of thyroid hormone by deiodinases: local action with general consequences. *Cellular* 

fluid of psychiatric patients. *Brain Research*, Vol.238, No.1 (April 1982), pp. 298–302.

onset hypothyroidism induces the amyloidogenic pathway of amyloid precursor protein processing in the rat hippocampus. *Journal of Neuroendocrinology*, Vol.22,

hormone possibly leads to differentiation and maturation of astrocytes in culture. *Cellular and Molecular Neurobiology*, Vol.27, N°8, (December 2007), pp.1007-1021. Göthe, S.; Wang, Z.; Ng, L.; Kindblom, JM.; Barros, AC.; Ohlsson, C.; Vennström, B. &

Forrest, D. (1999). Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation.

Bianco, A.C. (2005). Type 2 iodothyronine selenodeiodinase is expressed throughout the mouse skeleton and in the MC3T3-E1 mouse osteoblastic cell line during differentiation. *Endocrinology*, Vol.146, N°.1, (January 2005), pp. 195-200. Hagen, G.A.Solberg, L.A., Jr. (1974). Brain and cerebrospinal fluid permeability to

intravenous thyroid hormones. *Endocrinology*, Vol. 95, N°.5, (November 1974),

Kyvik, K.O., Visser, T.J., Hegedus, L. (2007). The impact of a TSH receptor gene polymorphism on thyroid-related phenotypes in a healthy Danish twin population.

genetic polymorphisms in the type II deiodinase gene with bipolar disorder in a subset of Chinese population. *Progress in Neuropsychopharmacology & Biological* 

on 5-HT1 and 5-HT2 function in the brain and its influence on the actions of repeated electroconvulsive shock. *Neuropharmacology*, Vol.27, N°.12, (December


Depressive Disorders and Thyroid Function 277

Peeters, R.P., van Toor, H., Klootwijk, W., de Rijke, Y.B., Kuiper, G.G., Uitterlinden, A.G.,

Richieri, R., Boyer. L., Farisse, J., Colavolpe, C., Mundler, O., Lancon, C., Guedj, E. (2011).

Risco, L., González, M., Garay, J., Arancibia, P., Nuñez, A., Hasler, G., Galleguillos, T. (2003).

Roy-Byrne, P.; Post, RM.; Rubinow, DR.; Linnoila, M.; Savard, R. & Davis, D. (1983). CSF

Rubinow, DR.; Gold, PW.; Post, RM.; Ballenger, JC.; Cowdry, R.; Bollinger, J. & Reichlin, S.

Ruhé, H.G., Booij, J., Veltman, D.J., Michel, M.C., Schene, A. (2011). Successful

study. *Journal of Clinical Psychiatry*, (August 2011), [Epub ahead of print] Samuels, M.H., Schuff, K.G., Carlson, N.E., Carello, P., Janowsky, J.S. (2007). Health status,

*of Clinical Endocrinology and Metabolism,* Vol. 92, N°7, (2007), pp.2545-2551. Saxena, J., Singh, P.N., Srivastava, U., Siddiqui, A.Q. (2000). A study of thyroid hormones

Singhal, R.L., Rastogi, R.B., Hrdina P.D. (1975) Brain biogenic amines and altered thyroid function. *Life Sciences,*Vol. 17, N°11, (December 1975),pp. 1617-1626. Smith, J.W., Evans, A.T., Costall, B., Smythe, J.W. (2002). Thyroid hormones, brain function

Stern, RA.; Nevels, CT.; Shelhorse, ME.; Prohaska, ML.; Mason, GA. & Prange Jr, AJ. (1991).

*Neuroscience,* Vol. 74, N°3 (October, 1996), pp. 897-915.

655-662.

No.4 (October 1969), pp. 457–469.

(September 2011), pp.1715-1722.

No.4 (April 1983), pp. 377–386.

(July 2000) pp.243-246.

(January 2002), pp.45-60.

(September 1991), pp. 623–627.

N°.4, (2003), pp. 320-328.

deiodinases. *European Journal of Endocrinology* Vol.155, N°5, (November 2006), pp.

Visser, T.J. (2003). Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. *Journal of Clinical Endocrinology and Metabolism*, Vol. 88, N°6, (June 2003), pp. 2880-2888. Prange Jr, AJ.; Wilson, IC.; Rabon, AM. & Lipton, MA. (1969). Enhancement of imipramine

antidepressant activity by thyroid hormone. *American Journal of Psychiatry*, Vol.126,

Predictive value of brain perfusion SPECT for rTMS response in pharmacoresistant depression. *European Journal of Nuclear Medicine and Molecular Imaging,* Vol. 38, N°9,

Evaluación funcional del eje hipotálamo-hipófisis-tiroides en episodio depresivo mayor único: ¿desregulación a nivel central?. *Revista de Neuro-Psiquiatría*, Vol.66,

5HIAA and personal and family history of suicide in affectively ill patients: a negative study. *Psychiatry Research*, Vol.10, No.4 (December 1983), pp. 263-274. Rozanov, C.B.Dratman, M.B., (1996). Immunohistochemical mapping of brain

triiodothyronine reveals prominent localization in central noradrenergic systems.

(1983). CSF somatostatin in affective illness. *Archives of General Psychiatry*, Vol.40,

pharmacologic treatment of major depressive disorder attenuates amygdala activation to negative facial expressions: a functional magnetic resonance imaging

mood, and cognition in experimentally induced subclinical hypothyroidism. *Journal* 

(T3, T4 & TSH) in patients of depression. *Indian Journal of Psychiatry,* Vol. 42, N°3,

and cognition: a brief review. *Neurosciences and Biobehavioral Reviews,* Vol. 26, N°1,

Antidepressant and memory effects of combined thyroid hormone treatment and electroconvulsive therapy: Preliminary findings. *Biological Psychiatry*, Vol. 30, No.6

relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders. *American Journal of Psychiatry*, Vol.154, N°2, (February 1997), pp.224-230,


Mentuccia, D., Proietti-Pannunzi, L., Tanner, K., Bacci, V., Pollin, T.I., Poehlman, E.T.,

Milak, M.S., Parsey, R.V., Keilp, J., Oquendo, M.A., Malone, K.M., Mann, J.J. (2005).

Morte, B., Diez, D., Auso, E., Belinchon, M.M., Gil-Ibanez, P., Grijota-Martinez, C., Navarro,

Mowla, A., Kalantarhormozi, M.R., Khazraee, S. (2011) Clinical characteristics of patients

study. *Journal of Psychiatric Practice,* (January 2011), Vol 17, N°1, pp.67–71. Myers, DH.; Carter, RA.; Burns, BH.; Armond, A.; Hussain, SB. & Chengapa, VK. (1985). A

Nagamachi, S., Jinnouchi, S., Nishii, R., Ishida, Y., Fujita, S., Futami, S., Kodama, T., Tamura,

*Annals of Nuclear Medicine,* Vol.18, N°6, (September 2004), pp. 469-77. Navarro, V., Gasto, C., Lomena, F., Mateos, J.J., Portella, M.J., Massana, G., Bernardo, M.,

study *Journal of Clinical Psychiatry,* Vol. 65, N°5, (May 2004), pp. 656-661. Peeters, R.P., van den Beld, A.W., Attalki, H., Toor, H., de Rijke, Y.B., Kuiper, G.G.,

Peeters, R.P., van der Deure, W.M., van den Beld, A.W., van Toor, H., Lamberts, S.W.,

Clinical Endocrinology (Oxf), Vol. 66, N°6, (June 2007), pp. 808-815. Peeters, R.P., van der Deure, W.M., Visser, T.J. (2006). Genetic variation in thyroid hormone

pp.224-230,

(March 2002), pp. 880-883.

*Neurosciences*, Vol.19, N°2, (2007), pp. 132-136.

151,N°2, (February 2010), pp. 810-820.

Vol. 289, N°1, (July 2005), pp.E75-81.

1985), pp. 55–61.

relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders. *American Journal of Psychiatry*, Vol.154, N°2, (February 1997),

Shuldiner, A.R., Celi, F.S. (2002). Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor. *Diabetes*, Vol.51, N°3,

Neuroanatomic correlates of psychopathologic components of major depressive disorder. *Archives of General Psychiatry*, Vol. 62, N°4, (April 2005), pp. 397-408, Miller, K.J., Parsons, T.D., Whybrow, P.C., Van Herle, K., Rasgon, N., Van Herle, A.,

Martinez, D., Silverman, D.H., Bauer, M. (2007). Verbal memory retrieval deficits associated with untreated hypothyroidism. *Journal of Neuropsychiatry and Clinical* 

D., de Escobar, G.M., Berbel, P., Bernal, J. (2010). Thyroid hormone regulation of gene expression in the developing rat fetal cerebral cortex: prominent role of the Ca2+/calmodulin-dependent protein kinase IV pathway. *Endocrinology*, Vol.

with major depressive disorder with and without hypothyroidism: A comparative

prospective study of the effects of lithium on thyroid function and on the prevalence of antithyroid antibodies. *Psychological Medicine*, Vol. 15, No.1 (February

S., Kawai, K. (2004). Cerebral blood flow abnormalities induced by transient hypothyroidism after thyroidectomy-analysis by tc-99m-HMPAO and SPM96.

Marcos, T. (2004). Frontal cerebral perfusion after antidepressant drug treatment versus ECT in elderly patients with major depression: a 12-month follow-up control

Lamberts, S.W., Janssen, J.A., Uitterlinden, A.G., Visser, T.J. (2005). A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. *American Journal of Physiology, Endocrinology and Metabolism*,

Janssen, J.A., Uitterlinden, A.G., Visser, T.J. (2007). The Asp727Glu polymorphism in the TSH receptor is associated with insulin resistance in healthy elderly men.

pathway genes; polymorphisms in the TSH receptor and the iodothyronine

deiodinases. *European Journal of Endocrinology* Vol.155, N°5, (November 2006), pp. 655-662.


**18**

**Psychosocial Factors in Patients** 

In the contemporary, or in endocrinological literature, there is still increasing interest in psychological or psychosocial aspects of thyreopathy (thyroid disease). Unfortunately, this theme is rather marginalized in the Czech Republic therefore we have begun to be interested in this topic (Janečková, 2007a, 2008a; Mandincová 2008a, 2008b, 2009a, 2009b, 2011a, 2011b). We have delivered an overview of the research findings in journal Czechoslovak Psychology (Janečková, 2007b) and at conferences (Janečková, 2007c, 2008c). It is possible to trace down

One part of the research aimed at the role of stress in pathogenesis of thyreopathies, within their process and prognosis, some of them also included research of modifying stress

Although a lot of studies stated connection between stress and autoimmune disease, most of evidence is indirect and a mechanism, which the autoimmune disease is influenced by, is not fully recognised. Just the relation between Graves' disease origination and higher levels of stress is considered to be the best indirect proof of the thyroid autoimmune disease, though it is still the subject of discussions. Most of contemporary studies support hypothesis that stress effects origination and clinical course of Graves' disease. Stress influences immune system directly or indirectly through nervous and endocrine system. These immune modulators can lead to a development of autoimmune illness in genetically predisposed individuals (Mizokami et al. 2004; comp. Schreiber, 1985). Depression can be applied as an intervening variable between life stress and an outbreak of autoimmune disease, because evidence it modifies immune response is available

Anciently it was observed that hyperthyroidism was preceded by presence of life stresses. Even the latest study confirms the effect of stress on Graves' disease development. Patients with Graves' disease were researched exclusively. An exception is a research comprising also patients with non-autoimmune hyperthyroidism (Matos-Santos et al., 2001), which results can show the fact that stress contributes to origination of nonautoimmune hyperthyroidism, but less than with autoimmune Graves' disease. Recent

four main lines of the research abroad (see chap. 1.1 – 1.4).

factors, but their importance has not been fully appreciated.

**1.1 Researches concerning stress** 

(Harris, Creed, Brugha, 1992).

**1. Introduction** 

**with Thyroid Disease** 

Petra Mandincová

*Czech Republic* 

*Tomas Bata University in Zlin* 


### **Psychosocial Factors in Patients with Thyroid Disease**

Petra Mandincová

*Tomas Bata University in Zlin Czech Republic* 

#### **1. Introduction**

278 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

Stipcević T, Pivac N, Kozarić-Kovacić D, Mück-Seler D. (2008) Thyroid activity in patients

Strawn, JR.; Ekhator, NN.; D'Souza, BB. & Geracioti Jr, TD. (2004). Pituitary-thyroid state

Szabadi, E. (1991). Thyroid dysfunction and affective illness. *British Medical Journal*, Vol.302,

Torlontano, M., Durante, C., Torrente, I., Crocetti, U., Augello, G., Ronga, G., Montesano, T.,

Vlassenko, A., Sheline, Y.I., Fischer, K., Mintun, M.A. (2004). Cerebral perfusion response to

Walker, P., Weichsel, M.E., Jr., Fisher, D.A., Guo, S.M. (1979). Thyroxine increases nerve

Walker, P., Weil, M.L., Weichsel, M.E., Jr., Fisher, D.A. (1981). Effect of thyroxine on nerve

Wheatley, D. (1972). Potentiation of amitriptyline by thyroid hormone. *Archives of General* 

Whybrow, P.C.Prange, A.J., Jr. (1981). A hypothesis of thyroid-catecholamine-receptor

Wikström, L.; Johansson, C.; Saltó, C.; Barlow, C.; Campos Barros, A.; Baas, F.; Forrest, D.;

Wilson, IC.; Prange Jr, AJ.; McClane, TK.; Rabon, AM. & Lipton, MA. (1970). Thyroid

Zavacki, A.M., Ying, H., Christoffolete, M.A., Aerts, G., So, E., Harney, J.W., Cheng, S.Y.,

Zobel, A., Joe, A., Freymann, N., Clusmann, H., Schramm, J., Reinhardt, M., Biersack, H.J,

*Journal of Medicine*, Vol. 282, No.19 (May 1970), pp. 1063–1067.

*Research,* Vol. 139, N 3, (August 2005), pp. 165-179.

*Psychiatry*, Vol. 26, No.3 (March 1972), pp. 229–233.

*Neuropsychobiology*, Vol.49, No.2, pp. 84–87.

No. 6782 (April 1991), pp. 923–924.

N°3, (March 2008) pp. 910-913.

1979), pp.427-429.

(April 1981), pp. 1777-1787.

N°1, (1981), pp. 106-113.

(January 1998), pp. 455–461.

(March 2005)pp. 1568-1575.

973-976.

with major depression. *Collegium Antropologicum*, Vol. 32,No3 (September 2008),pp.

correlates with central dopaminergic and serotonergic activity in healthy humans.

Travascio, L., Verrienti, A., Bruno, R., Santini, S., D'Arcangelo, P., Dallapiccola, B., Filetti, S., Trischitta, V. (2008). Type 2 deiodinase polymorphism (threonine 92 alanine) predicts L-thyroxine dose to achieve target thyrotropin levels in thyroidectomized patients. *Journal of Clinical Endocrinology and Metabolism*, Vol. 93,

successful treatment of depression with different serotoninergic agents. *Journal of Neuropsychiatry and Clinical Neurosciences*, Vol.16, N° 3, (Summer 2004), pp. 360-363.

growth factor concentration in adult mouse brain. *Science*, Vol. 204, N°4391, (April

growth factor concentration in neonatal mouse brain. *Life Sciences*,Vol 28, N°15-16

interaction. Its relevance to affective illness. *Archives of General Psychiatry,* Vol. 38,

Thorén, P. & Vennström, B. (1998). Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. *The EMBO Journal*, Vol.17, No.2

hormone enhancement of imipramine in nonretarded depressions. *New England* 

Larsen, P.R., Bianco, A.C., (2005). Type 1 iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse. *Endocrinology,* Vol.146, N°3,

Maier, W., Broich, K. (2005). Changes in regional cerebral blood flow by therapeutic vagus nerve stimulation in depression: An exploratory approach *Psychiatry*

In the contemporary, or in endocrinological literature, there is still increasing interest in psychological or psychosocial aspects of thyreopathy (thyroid disease). Unfortunately, this theme is rather marginalized in the Czech Republic therefore we have begun to be interested in this topic (Janečková, 2007a, 2008a; Mandincová 2008a, 2008b, 2009a, 2009b, 2011a, 2011b).

We have delivered an overview of the research findings in journal Czechoslovak Psychology (Janečková, 2007b) and at conferences (Janečková, 2007c, 2008c). It is possible to trace down four main lines of the research abroad (see chap. 1.1 – 1.4).

#### **1.1 Researches concerning stress**

One part of the research aimed at the role of stress in pathogenesis of thyreopathies, within their process and prognosis, some of them also included research of modifying stress factors, but their importance has not been fully appreciated.

Although a lot of studies stated connection between stress and autoimmune disease, most of evidence is indirect and a mechanism, which the autoimmune disease is influenced by, is not fully recognised. Just the relation between Graves' disease origination and higher levels of stress is considered to be the best indirect proof of the thyroid autoimmune disease, though it is still the subject of discussions. Most of contemporary studies support hypothesis that stress effects origination and clinical course of Graves' disease. Stress influences immune system directly or indirectly through nervous and endocrine system. These immune modulators can lead to a development of autoimmune illness in genetically predisposed individuals (Mizokami et al. 2004; comp. Schreiber, 1985). Depression can be applied as an intervening variable between life stress and an outbreak of autoimmune disease, because evidence it modifies immune response is available (Harris, Creed, Brugha, 1992).

Anciently it was observed that hyperthyroidism was preceded by presence of life stresses. Even the latest study confirms the effect of stress on Graves' disease development. Patients with Graves' disease were researched exclusively. An exception is a research comprising also patients with non-autoimmune hyperthyroidism (Matos-Santos et al., 2001), which results can show the fact that stress contributes to origination of nonautoimmune hyperthyroidism, but less than with autoimmune Graves' disease. Recent

Psychosocial Factors in Patients with Thyroid Disease 281

Newly, works calling for usage of psychological means in the treatment of thyreopathies occasionally appear. Available resources discuss these issues, especially with hyperthyroidism treatment. Monographs provide only general recommendations concerning suitability of psychotherapy (e.g. Baštecký et al., 1993; Kaplan et al., 1994; Markalous & Gregorová, 2007). A few works confirm successful treatment of patients with hyperthyroidism with a combination of conventional medicine and psychological means (Fukao et al., 2000, as cited in Fukao et al., 2003; Zeng et al., 2003; comp. Brown et al., 2010). In a British study Lincoln et al. (2000) realised that patients with hyperthyroidism do not have enough knowledge concerning this disease. Likewise, treated patients with hypothyroidism were not satisfied with insufficient or misleading information that was provided by the doctors on the disease and its treatment (Mc Millan et al., 2004). Air et al. (2006, 2007) state that it is not possible to rely on the Internet as a tool of patients' education, because the information concerning thyroid carcinoma on the web sites was quite often incomplete and outdated. Roberts et al. (2008) surveyed which information would be necessary for the patients with the carcinoma. Sawka et al. (2011) have developed a computerized educational tool (called a decision aid) to inform patients about available treatment options and have been utilized in oncologic decision-making. Huang et al. (2004) rightfully assume that a big potential is hidden in nurses' care (comp. Filická & Hadačová,

We are informed on a range of organisations that help patients in thyroid disease or they associate them, and on a big amount of information materials for these patients (more detailed Janečková, 2008b; Mandincová, 2010). On the other hand, a lot of Czech patients have very little quality information and educational materials on the disease and its consequences, diagnostics and treatment. More or less, there is only one web site created by a female patient after a thyroid operation (available at www.stitnazlaza.estranky.cz dated 04/09/2011). As well as, special organisations supporting or associating patients, selfsupporting groups are still missing. Practically, the situation in the Czech Republic has not

We suppose if the mental disorder was not diagnosed in the patient with thyreopathy, the role of psychological and psychosocial means and psychotherapy itself has not been fully appreciated in their treatment (comp. Sinclair, 2006). Austrian researchers (König et al., 2007), among others, point out the importance of psychological and psychosocial methods introduction into the healthcare system with these patients. Ponto and Kahaly (2010) recommend psychosomatic treatment also in the ills with orbitopathy, as well as Hirsch et

The recent studies especially deal with examining health status and/or quality of life that

Measuring quality of life has become a key part in the evaluation of the disease impact and treatment or intervention effect (Razvi, McMillan, Weaver, 2005). Residual symptoms can often persist with the patient even after adequate treatment. Psychiatric symptoms usually

**1.3 Psychological means usage with treatment of thyroid disease** 

2006; Olosová & Filická, 2006).

change within the last two years.

al. (2009) and Lee et al. (2010) in patients with carcinoma.

**1.4 Researches concerning quality of life and perception of health status** 

often include examining of mental condition and cognitive functioning.

studies looked into life events and observed more negative life events in patients with Graves' disease compared to a control group (Kung, 1995; Lee et al., 2003; Matos-Santos et al., 2001; Radosavljević et al., 1996; Sonino, et al., 1993; Winsa et al., 1991; Yoshiuchi et al., 1998a, 1998b). Some earlier studies rejected the relation between stressful events and hyperthyroidism origination. However, they had considerable methodological problems to which can be attributed the fact that a consistent coherence was not found. Most probably, a difference in Martin-du Pan's research was not proved due to the same reasons (1998, as cited in Mizokami et al., 2004), because he arguably created a control group. Some studies (Kung, 1995; Winsa et al., 1991; Yoshiuchi et al., 1998b) integrated modifying factors into the research – evaluation of coping and social support. Furthermore, Kung (1995) and Yoshiuchi et al. (1998b) realized that life events occur rarely and they cannot reflect total stress that an individual experiences and the source of distress can also be hassles or daily stresses and minor events.

Much less prospective studies dealing with the effect of stress on hyperthyroidism course were carried out, yet they denote that more important life events and daily hassles can be of a negative effect on Graves' disease course (Ferguson-Rayport, 1956, as cited in Whybrow, 1991; Fukao et al., 2003; Hobbs, 1992; Yoshiuchi et al., 1998a). Already Schreiber (1985) speaks about the fact as a psychological stress, difficult task from an environment and individual's reaction to it can exacerbate calmed hyperthyroidism, and even hypothyroidism.

It is difficult to evaluate stress influence on origination and course of another autoimmune disease – Hashimoto's thyroidism, because it is quite often developed inconspicuously, the stress influence could have been overlooked (Mizokami et al., 2004).

#### **1.2 Researches concerning personality**

Another group of surveys researched a personality of a sick. The research into a personality was very popular with researchers (Ham, Alexander and others), especially in 50s and 60s of 20th century, when specific personality traits predisposing to hyperthyroidism were sought. Later studies proved neither typical personality, nor found a specific conflict in childhood (in Whybrow, 1991; Rodewig, 1993; Kaplan, Sadock, Grebb, 1994). Robbins and Vinson (1960) also regard the result of their study as an evidence of the fact that the personality role was overestimated in hyperthyroidism. At present, these issues are getting into the background compared to other research topics.

Influence of the thyroid disease on a personality and relation between personality traits and thyreopathy is realised in a quite difficult way. It is difficult to make a decision what the cause and consequence is. Harineková (1976) describes specific personality characteristics in girls with eufunctional goitre. Similarly, Ma, Luo and Zeng (2002) found some personality characteristics in adult patients different from the control group. Jenšovský et al. (2000, 2002) did not prove changes of personality traits in individuals with subclinical hypothyroidism during T4 treatment in the Czech study. Caparevic et al. (2005) examined patients with nodular goitre with whom the occurrence of mental disorders was reduced after an operation. Yang and Zang (2001) indicate that the choice of coping strategy is influenced by the personality in the patients with Graves' disease. Fukao et al. (2003) carried out a prospective research in Japan and they realised that some personality traits worsen the prognosis of treated Graves' disease.

studies looked into life events and observed more negative life events in patients with Graves' disease compared to a control group (Kung, 1995; Lee et al., 2003; Matos-Santos et al., 2001; Radosavljević et al., 1996; Sonino, et al., 1993; Winsa et al., 1991; Yoshiuchi et al., 1998a, 1998b). Some earlier studies rejected the relation between stressful events and hyperthyroidism origination. However, they had considerable methodological problems to which can be attributed the fact that a consistent coherence was not found. Most probably, a difference in Martin-du Pan's research was not proved due to the same reasons (1998, as cited in Mizokami et al., 2004), because he arguably created a control group. Some studies (Kung, 1995; Winsa et al., 1991; Yoshiuchi et al., 1998b) integrated modifying factors into the research – evaluation of coping and social support. Furthermore, Kung (1995) and Yoshiuchi et al. (1998b) realized that life events occur rarely and they cannot reflect total stress that an individual experiences and the source of

Much less prospective studies dealing with the effect of stress on hyperthyroidism course were carried out, yet they denote that more important life events and daily hassles can be of a negative effect on Graves' disease course (Ferguson-Rayport, 1956, as cited in Whybrow, 1991; Fukao et al., 2003; Hobbs, 1992; Yoshiuchi et al., 1998a). Already Schreiber (1985) speaks about the fact as a psychological stress, difficult task from an environment and individual's reaction to it can exacerbate calmed hyperthyroidism, and even

It is difficult to evaluate stress influence on origination and course of another autoimmune disease – Hashimoto's thyroidism, because it is quite often developed inconspicuously, the

Another group of surveys researched a personality of a sick. The research into a personality was very popular with researchers (Ham, Alexander and others), especially in 50s and 60s of 20th century, when specific personality traits predisposing to hyperthyroidism were sought. Later studies proved neither typical personality, nor found a specific conflict in childhood (in Whybrow, 1991; Rodewig, 1993; Kaplan, Sadock, Grebb, 1994). Robbins and Vinson (1960) also regard the result of their study as an evidence of the fact that the personality role was overestimated in hyperthyroidism. At present, these issues are getting into the

Influence of the thyroid disease on a personality and relation between personality traits and thyreopathy is realised in a quite difficult way. It is difficult to make a decision what the cause and consequence is. Harineková (1976) describes specific personality characteristics in girls with eufunctional goitre. Similarly, Ma, Luo and Zeng (2002) found some personality characteristics in adult patients different from the control group. Jenšovský et al. (2000, 2002) did not prove changes of personality traits in individuals with subclinical hypothyroidism during T4 treatment in the Czech study. Caparevic et al. (2005) examined patients with nodular goitre with whom the occurrence of mental disorders was reduced after an operation. Yang and Zang (2001) indicate that the choice of coping strategy is influenced by the personality in the patients with Graves' disease. Fukao et al. (2003) carried out a prospective research in Japan and they realised that some personality traits worsen the

distress can also be hassles or daily stresses and minor events.

stress influence could have been overlooked (Mizokami et al., 2004).

**1.2 Researches concerning personality** 

background compared to other research topics.

prognosis of treated Graves' disease.

hypothyroidism.

#### **1.3 Psychological means usage with treatment of thyroid disease**

Newly, works calling for usage of psychological means in the treatment of thyreopathies occasionally appear. Available resources discuss these issues, especially with hyperthyroidism treatment. Monographs provide only general recommendations concerning suitability of psychotherapy (e.g. Baštecký et al., 1993; Kaplan et al., 1994; Markalous & Gregorová, 2007). A few works confirm successful treatment of patients with hyperthyroidism with a combination of conventional medicine and psychological means (Fukao et al., 2000, as cited in Fukao et al., 2003; Zeng et al., 2003; comp. Brown et al., 2010).

In a British study Lincoln et al. (2000) realised that patients with hyperthyroidism do not have enough knowledge concerning this disease. Likewise, treated patients with hypothyroidism were not satisfied with insufficient or misleading information that was provided by the doctors on the disease and its treatment (Mc Millan et al., 2004). Air et al. (2006, 2007) state that it is not possible to rely on the Internet as a tool of patients' education, because the information concerning thyroid carcinoma on the web sites was quite often incomplete and outdated. Roberts et al. (2008) surveyed which information would be necessary for the patients with the carcinoma. Sawka et al. (2011) have developed a computerized educational tool (called a decision aid) to inform patients about available treatment options and have been utilized in oncologic decision-making. Huang et al. (2004) rightfully assume that a big potential is hidden in nurses' care (comp. Filická & Hadačová, 2006; Olosová & Filická, 2006).

We are informed on a range of organisations that help patients in thyroid disease or they associate them, and on a big amount of information materials for these patients (more detailed Janečková, 2008b; Mandincová, 2010). On the other hand, a lot of Czech patients have very little quality information and educational materials on the disease and its consequences, diagnostics and treatment. More or less, there is only one web site created by a female patient after a thyroid operation (available at www.stitnazlaza.estranky.cz dated 04/09/2011). As well as, special organisations supporting or associating patients, selfsupporting groups are still missing. Practically, the situation in the Czech Republic has not change within the last two years.

We suppose if the mental disorder was not diagnosed in the patient with thyreopathy, the role of psychological and psychosocial means and psychotherapy itself has not been fully appreciated in their treatment (comp. Sinclair, 2006). Austrian researchers (König et al., 2007), among others, point out the importance of psychological and psychosocial methods introduction into the healthcare system with these patients. Ponto and Kahaly (2010) recommend psychosomatic treatment also in the ills with orbitopathy, as well as Hirsch et al. (2009) and Lee et al. (2010) in patients with carcinoma.

#### **1.4 Researches concerning quality of life and perception of health status**

The recent studies especially deal with examining health status and/or quality of life that often include examining of mental condition and cognitive functioning.

Measuring quality of life has become a key part in the evaluation of the disease impact and treatment or intervention effect (Razvi, McMillan, Weaver, 2005). Residual symptoms can often persist with the patient even after adequate treatment. Psychiatric symptoms usually

Psychosocial Factors in Patients with Thyroid Disease 283

type of thyroid disease therefore they are not applicable across different thyreopathies. For a long time there has not been created a questionnaire that would cover all the relevant aspects of thyreopathies in longitudinal studies, when there can happen changes of hormonal status based on the character of the disease or treatment. (Razvi, Mc Millan, Weaver, 2005; Watt et al., 2006). According to available data we were the first who tried to create such method (Janečková 2001, 2006). Currently ThyPRO is being developed with promising psychometric characteristics focused on patients with any benign thyroid

There are studies which prove that despite the treatment of hypothyroidism with hormone T4 substitution, a lot of patients quote more or less vague complaints and feel worsened quality of life (Mc Millan et al., 2004, 2005, 2008; Saravanan et al., 2002; Wekking et al., 2005). Researches of alternative therapy – treatment with hormone T4 and T3 combined substitution have been carried out. Based on Grozinsky-Glasberg et al.'s (2006) metaanalysis and Ma et al.'s (2009) systematic review it can be summed up that combined T4 and T3 treatment does not improve well-being, cognitive function, or health status compared with T4 itself. This is proved with works by Appelhof et al., 2005; Clyde et al., 2003; Joffe et al., 2004; Meng et al., 2004; Nygaard et al., 2009; Regalbuto et al., 2007; Saravanan et al., 2005; Sawka et al., 2003; Siegmund et al., 2004; Valizadeh et al., 2009; Walsh et al., 2003 and others. Whereas first works signalled differences in favour of combined T4 and T3 (Bunevičius et

Hormonal therapy is considered as a very successful for reduction of morbidity and mortality. On the other hand, there are also real deficiencies that we have to be aware of – it is always dealt with imitation of normal hormone secretion. Additionally, it is difficult to quantify the effect of hormones on the level of tissues. Being aware of hormonal therapy deficiencies we can avoid incorrect marking of patients' complaints. In fact, it is probable that deficiencies of biological therapy partially participate in the complaints. On the contrary, it is important to strive for this treatment further improvement, because we contribute to creation a "chronic endocrine patient" (Kaplan, Sarne, Schneider, 2003; Lamberts, Romijn, Wiersinga, 2003; Romijn, Smit, Lamberts, 2003). There are several proofs that patients do not follow sufficient treatment that can be indicative of their dissatisfaction with the treatment (McMillan et al., 2004). There are a lot of organisations abroad associating patients with thyroid disease, especially those dissatisfied patients create a big stress on professional public, they have reservations about the diagnostics and therapy (they criticise laboratory testing as a diagnostic criteria, or they prefer dried pork thyroid to synthetic

A study realising that in patients with Graves' disease persists worsen health status in some aspects even after reaching the euthyreosis has been carried out (Elberling et al., 2004). Abraham–Nordling et al. (2005) have concluded similar results, but they have not found dependence of the health status on the way of therapy (surgical, drug, radioiodine). According to Watt et al. (2005) specialists and patients' opinions on the most important

disorders (Watt et al., 2009).

**1.4.1 Researches in hypothyroidism** 

al., 1999, 2002; Bunevičius & Prange, 2000).

hormone substitution).

**1.4.2 Researches in hyperthyroidism** 

subside with a suitable treatment nevertheless long-lasting disorders can contain a degree of disease process irreversibility and provoke highly individual affective response according to psychological losses and gains of individual patients. The quality of life can be seriously endangered even in case that the patient should be well (at least from the hormonal viewpoint). Therefore the contradiction in health perception among the patients, their partners and doctors is often emphasized in the quality of life research. The emphasis is often placed on laboratory measurements 'hard' data, but 'soft' data gained with reliable methods for quality of life evaluation are underestimated (Sonino, Fava, 1998). To assess seriousness of the disease and response to treatment it is necessary, except for biochemical test, to observe the symptoms, health status and quality of life with the help of suitable methods. The relation between physiological and clinical evaluation and consequences that are given by the patient is in fact moderate and rather changeable (Razvi, McMillan, Weaver, 2005). The results of many studies dealing with the health status measurement, alternatively quality of life, often signal their independence on the thyroid functioning (Biondi et al., 2000; Elberling et al., 2004; Wekking et al, 2005). Also König et al. (2007) realised that the evaluation of subjective and objective health status in the ills with thyroid have considerably differed, before the treatment and even after it.

The patients with non-treated thyreopathy independently of the type of disease suffer from a whole range of symptoms and their health status, alternatively quality of life, is considerably disrupted in most aspects. Moreover, it shows that this disruption persists in many patients for a long time, even if they are treated. Substantial part of patients with thyreopathy experience limitations in their common activities, they feel worsen health status and disruption of social and emotional areas. Cognitive ailments and tiredness are also frequent. Cosmetic problems are also usual. Long-term consequences of the treated by thyreopathies are very frequent. Approximately 1/2 of patients have stated total deterioration of the health status, alternatively quality of life, limitation in usual activities, as well as social and emotional problems. Two thirds feel tiredness and approximately one third is anxious, they have cognitive and sexual problems. Moreover, the patients with earlier hyperthyroidism very often suffer from classic symptoms of hypothyroidism and, vice versa, symptoms of hyperthyroidism persist approximately in one third. Patients with eufunctional goitre have been examined the least, there does not exist a study which would indicate that such patients suffer from cognitive ailments (Watt et al., 2006).

But insufficient defining the sample of patients (i.e. type of thyreopathy) and confusion or incorrect usage of basic notions is quite typical for current studies dealing with patients in thyreopathy. Only a few studies research patients' quality of life in the true sense of the word (Abraham-Nordling, 2005; Dow, Ferrell, Anello, 1997; Huang et al., 2004; McMillan et al., 2004, 2005; Terwee 1998, 1999, 2002). A lot of works confuse the evaluation of the quality of life for the measurement of symptoms non/presence, health status, psychical status, eventually mental well-being are often incorrectly described as the quality of life. People, whose health is bad, do not have to necessarily feel worsen quality of life. Incorrect understanding of the notions leads to the fact that the results of these studies can be incorrect or misleading, because a method for evaluation of one variable is used for measurement of something else. Moreover, available specific tools lack convincing data on validity, the exceptions are GO-QOL, ThyDQoL and ThyTSQ, which are of good psychometric characteristics. A disadvantage of the tools is that they only focus on a specific

subside with a suitable treatment nevertheless long-lasting disorders can contain a degree of disease process irreversibility and provoke highly individual affective response according to psychological losses and gains of individual patients. The quality of life can be seriously endangered even in case that the patient should be well (at least from the hormonal viewpoint). Therefore the contradiction in health perception among the patients, their partners and doctors is often emphasized in the quality of life research. The emphasis is often placed on laboratory measurements 'hard' data, but 'soft' data gained with reliable methods for quality of life evaluation are underestimated (Sonino, Fava, 1998). To assess seriousness of the disease and response to treatment it is necessary, except for biochemical test, to observe the symptoms, health status and quality of life with the help of suitable methods. The relation between physiological and clinical evaluation and consequences that are given by the patient is in fact moderate and rather changeable (Razvi, McMillan, Weaver, 2005). The results of many studies dealing with the health status measurement, alternatively quality of life, often signal their independence on the thyroid functioning (Biondi et al., 2000; Elberling et al., 2004; Wekking et al, 2005). Also König et al. (2007) realised that the evaluation of subjective and objective health status in the ills with thyroid

The patients with non-treated thyreopathy independently of the type of disease suffer from a whole range of symptoms and their health status, alternatively quality of life, is considerably disrupted in most aspects. Moreover, it shows that this disruption persists in many patients for a long time, even if they are treated. Substantial part of patients with thyreopathy experience limitations in their common activities, they feel worsen health status and disruption of social and emotional areas. Cognitive ailments and tiredness are also frequent. Cosmetic problems are also usual. Long-term consequences of the treated by thyreopathies are very frequent. Approximately 1/2 of patients have stated total deterioration of the health status, alternatively quality of life, limitation in usual activities, as well as social and emotional problems. Two thirds feel tiredness and approximately one third is anxious, they have cognitive and sexual problems. Moreover, the patients with earlier hyperthyroidism very often suffer from classic symptoms of hypothyroidism and, vice versa, symptoms of hyperthyroidism persist approximately in one third. Patients with eufunctional goitre have been examined the least, there does not exist a study which would

But insufficient defining the sample of patients (i.e. type of thyreopathy) and confusion or incorrect usage of basic notions is quite typical for current studies dealing with patients in thyreopathy. Only a few studies research patients' quality of life in the true sense of the word (Abraham-Nordling, 2005; Dow, Ferrell, Anello, 1997; Huang et al., 2004; McMillan et al., 2004, 2005; Terwee 1998, 1999, 2002). A lot of works confuse the evaluation of the quality of life for the measurement of symptoms non/presence, health status, psychical status, eventually mental well-being are often incorrectly described as the quality of life. People, whose health is bad, do not have to necessarily feel worsen quality of life. Incorrect understanding of the notions leads to the fact that the results of these studies can be incorrect or misleading, because a method for evaluation of one variable is used for measurement of something else. Moreover, available specific tools lack convincing data on validity, the exceptions are GO-QOL, ThyDQoL and ThyTSQ, which are of good psychometric characteristics. A disadvantage of the tools is that they only focus on a specific

have considerably differed, before the treatment and even after it.

indicate that such patients suffer from cognitive ailments (Watt et al., 2006).

type of thyroid disease therefore they are not applicable across different thyreopathies. For a long time there has not been created a questionnaire that would cover all the relevant aspects of thyreopathies in longitudinal studies, when there can happen changes of hormonal status based on the character of the disease or treatment. (Razvi, Mc Millan, Weaver, 2005; Watt et al., 2006). According to available data we were the first who tried to create such method (Janečková 2001, 2006). Currently ThyPRO is being developed with promising psychometric characteristics focused on patients with any benign thyroid disorders (Watt et al., 2009).

#### **1.4.1 Researches in hypothyroidism**

There are studies which prove that despite the treatment of hypothyroidism with hormone T4 substitution, a lot of patients quote more or less vague complaints and feel worsened quality of life (Mc Millan et al., 2004, 2005, 2008; Saravanan et al., 2002; Wekking et al., 2005).

Researches of alternative therapy – treatment with hormone T4 and T3 combined substitution have been carried out. Based on Grozinsky-Glasberg et al.'s (2006) metaanalysis and Ma et al.'s (2009) systematic review it can be summed up that combined T4 and T3 treatment does not improve well-being, cognitive function, or health status compared with T4 itself. This is proved with works by Appelhof et al., 2005; Clyde et al., 2003; Joffe et al., 2004; Meng et al., 2004; Nygaard et al., 2009; Regalbuto et al., 2007; Saravanan et al., 2005; Sawka et al., 2003; Siegmund et al., 2004; Valizadeh et al., 2009; Walsh et al., 2003 and others. Whereas first works signalled differences in favour of combined T4 and T3 (Bunevičius et al., 1999, 2002; Bunevičius & Prange, 2000).

Hormonal therapy is considered as a very successful for reduction of morbidity and mortality. On the other hand, there are also real deficiencies that we have to be aware of – it is always dealt with imitation of normal hormone secretion. Additionally, it is difficult to quantify the effect of hormones on the level of tissues. Being aware of hormonal therapy deficiencies we can avoid incorrect marking of patients' complaints. In fact, it is probable that deficiencies of biological therapy partially participate in the complaints. On the contrary, it is important to strive for this treatment further improvement, because we contribute to creation a "chronic endocrine patient" (Kaplan, Sarne, Schneider, 2003; Lamberts, Romijn, Wiersinga, 2003; Romijn, Smit, Lamberts, 2003). There are several proofs that patients do not follow sufficient treatment that can be indicative of their dissatisfaction with the treatment (McMillan et al., 2004). There are a lot of organisations abroad associating patients with thyroid disease, especially those dissatisfied patients create a big stress on professional public, they have reservations about the diagnostics and therapy (they criticise laboratory testing as a diagnostic criteria, or they prefer dried pork thyroid to synthetic hormone substitution).

#### **1.4.2 Researches in hyperthyroidism**

A study realising that in patients with Graves' disease persists worsen health status in some aspects even after reaching the euthyreosis has been carried out (Elberling et al., 2004). Abraham–Nordling et al. (2005) have concluded similar results, but they have not found dependence of the health status on the way of therapy (surgical, drug, radioiodine). According to Watt et al. (2005) specialists and patients' opinions on the most important

Psychosocial Factors in Patients with Thyroid Disease 285

Recently, the research has especially focused on follow up of patients with differentiated thyroid cancer. Impaired health status and quality of life have been surveyed in them (Hoftijzer et al., 2008; Lee et al., 2010). Quality-of-life and health status parameters were inversely affected by duration of cure and consequently may be restored after prolonged follow-up (Giusti et al., 2011; Gómez et al., 2010; Hoftijzer et al., 2008; Malterling et al., 2010; Pelttari et al., 2009). Special attention should be paid in patients with more severe staging on diagnosis (Almeida et al., 2009; Giusti et al., 2011). An interesting qualitative study has been

In connection with laboratory diagnostics improvement the research of subclinical thyroid disorder moves forward. Some patients may suffer from clinical symptoms resembling hypothyroidism or hyperthyroidism, and others do not. There is not a consensus concerning the fact whether these diseases should be treated (Stárka, Zamrazil et al., 2005), therefore the research in health status and some aspects of quality of life are

A lot of studies observing patients with non-treated subclinical hypothyroidism proved deterioration in some aspects of the health status (Appolinario et al., 2005; Baldini et al., 1997, 2009; Monzani et al., 1993; Razvi et al., 2005). However, the results of works observing if the therapy with T4 hormone is beneficial are disputable. Some studies mention specific effects (Baldini et al., 1997, 2009; Bono et al., 2004; Jenšovský et al., 2000, 2002; Monzani et al., 1993;), other works do not prove positive changes (e.g. Parle et al., 2010). Recent study by Jorde et al. (2006) does not either demonstrate the profit of T4 treatment, but it does not find any differences among patients with subclinical hypothyroidism, concerning the health

Compared to the control group, the research results by Biondi et al. (2000) testify for deterioration of some health status aspects with non-treated patients with endogenous

Only little attention was paid to the patients with euthyroid goitre within the research of quality of life and health status. The results of the studies in non-treated and treated patients signal deteriorated health status in some aspects (Bianchi et al., 2004; Janečková, 2001, 2006;

It is supposed that just a regular monitoring of patient's euthyroid status with nodules in thyroid reduces the quality of his life; on the other hand, more significant deterioration of the quality of life would occur if the patient was not dispensarized within his course of life

The aim of our research was to map psychosocial aspects of thyroid disease (thyreopathy). We have especially focused on patients' quality of life, role of stress and coping with it, including protective factors (resilience and social support); at the same time we tried to

**1.4.4 Researches in subclinical hypothyroidism and hyperthyroidism** 

status, as well as by Vigário et al. (2009), Park et al. (2010).

carried out in this topic (Sawka et al., 2009).

becoming more important.

subclinical hyperthyroidism.

**2. Aims and background** 

König et al., 2007).

**1.4.5 Researches in euthyroid goitre** 

(Dietlein & Schicha, 2003; Vidal-Trécan et al., 2002).

aspects of the quality of life with Graves' disease are significantly different. According to the patients, it is higher tiredness, perception of heart beating and internal restlessness, according to the endocrinologists it is dealt with hand shake, increased perspiration and weight loss.

Persistence of worsened health status even after the hyperthyroidism treatment has been proved by Fahrenfort, Wilterdink and Van-der-Veen (2000). Paschke et al.'s (1990, as cited in Rodewig, 1993) study indicates that higher anxiety appears in patients with hyperthyroidism in euthyroid status.

Studies of the quality of life are also focused on the patients with orbitopathy connected with Graves' disease. Orbitopathy (even in a moderate form) significantly influences patients' quality of life (Egle et al., 1999; Kahaly et al., 2002, 2005), and this negative influence is not in accordance with usual clinical evaluation (Gerding et al., 1997) and it often persists even many years after the treatment (Terwee et al., 2002). Other surveys have been devoted to the development of specific GO-QOL method that measures psychosocial consequences of a changed look and the consequences of diplopia (double vision) and worsen sharpness in common sight functioning (Terwee et al., 1998, 1999, 2001; Wiersinga et al., 2004). An interesting qualitative study in patients with orbitopathy has been carried out (Estcourt et al., 2008).

#### **1.4.3 Researches in thyroid carcinoma**

Evaluation of the quality of life and health status is especially important in the patients with thyroid carcinoma because they can experience changes of hormone statuses within the treatment – from long-term use of supra-physiological doses of T4 hormone (subclinical hyperthyroidism) to short-term time-limited period of T4 discontinuation (hypothyroidism) that is required by the preparation for diagnostics or radioiodine therapy.

Available studies are identical that there is a significant deterioration of patient's health status with short T4 discontinuation (Botella-Carretero et al., 2003; Pacini et al., 2006; Schroeder et al., 2006; Tagay et al., 2005). Due to the fact that T4 discontinuation is of a significant effect on patient's health status, other methods or preparation for diagnostics or radioiodine therapy have been sought. Usage of rhTSH (recombinant human thyrotropin hormone) is considered as a suitable method instead of the previous one what leads to improvement of patient's compliance and maintenance of patient's common daily routine and productivity (Duntas, Biondi, 2007).

Concerning the patients undergoing long-term usage of supra-physiological doses of T4, the research findings with mentioned above methods application are inconsistent – the results of some studies signal deterioration of the health status, even if less significant than in patients after T4 discontinuation (Botella-Carretero et al., 2003, Tagay et al., 2005), other studies have not found disturbed health status (Eustatia-Rutten et al., 2006; Schroeder et al., 2006).

The first studies in general methods of quality of life have been carried out in China. Hou et al. (2001) have found out that the quality of life in patients with non-papillary carcinoma was worse in some aspects in comparison with other patients. Huang et al. (2004) have carried out measurement of patients' quality of life after removing the carcinoma surgically when the level of the result score was analogous to other chronically ill.

aspects of the quality of life with Graves' disease are significantly different. According to the patients, it is higher tiredness, perception of heart beating and internal restlessness, according to the endocrinologists it is dealt with hand shake, increased perspiration and

Persistence of worsened health status even after the hyperthyroidism treatment has been proved by Fahrenfort, Wilterdink and Van-der-Veen (2000). Paschke et al.'s (1990, as cited in Rodewig, 1993) study indicates that higher anxiety appears in patients with

Studies of the quality of life are also focused on the patients with orbitopathy connected with Graves' disease. Orbitopathy (even in a moderate form) significantly influences patients' quality of life (Egle et al., 1999; Kahaly et al., 2002, 2005), and this negative influence is not in accordance with usual clinical evaluation (Gerding et al., 1997) and it often persists even many years after the treatment (Terwee et al., 2002). Other surveys have been devoted to the development of specific GO-QOL method that measures psychosocial consequences of a changed look and the consequences of diplopia (double vision) and worsen sharpness in common sight functioning (Terwee et al., 1998, 1999, 2001; Wiersinga et al., 2004). An interesting qualitative study in patients with orbitopathy has been carried out

Evaluation of the quality of life and health status is especially important in the patients with thyroid carcinoma because they can experience changes of hormone statuses within the treatment – from long-term use of supra-physiological doses of T4 hormone (subclinical hyperthyroidism) to short-term time-limited period of T4 discontinuation (hypothyroidism)

Available studies are identical that there is a significant deterioration of patient's health status with short T4 discontinuation (Botella-Carretero et al., 2003; Pacini et al., 2006; Schroeder et al., 2006; Tagay et al., 2005). Due to the fact that T4 discontinuation is of a significant effect on patient's health status, other methods or preparation for diagnostics or radioiodine therapy have been sought. Usage of rhTSH (recombinant human thyrotropin hormone) is considered as a suitable method instead of the previous one what leads to improvement of patient's compliance and maintenance of patient's common daily routine

Concerning the patients undergoing long-term usage of supra-physiological doses of T4, the research findings with mentioned above methods application are inconsistent – the results of some studies signal deterioration of the health status, even if less significant than in patients after T4 discontinuation (Botella-Carretero et al., 2003, Tagay et al., 2005), other studies have

The first studies in general methods of quality of life have been carried out in China. Hou et al. (2001) have found out that the quality of life in patients with non-papillary carcinoma was worse in some aspects in comparison with other patients. Huang et al. (2004) have carried out measurement of patients' quality of life after removing the carcinoma surgically

not found disturbed health status (Eustatia-Rutten et al., 2006; Schroeder et al., 2006).

when the level of the result score was analogous to other chronically ill.

that is required by the preparation for diagnostics or radioiodine therapy.

weight loss.

(Estcourt et al., 2008).

hyperthyroidism in euthyroid status.

**1.4.3 Researches in thyroid carcinoma** 

and productivity (Duntas, Biondi, 2007).

Recently, the research has especially focused on follow up of patients with differentiated thyroid cancer. Impaired health status and quality of life have been surveyed in them (Hoftijzer et al., 2008; Lee et al., 2010). Quality-of-life and health status parameters were inversely affected by duration of cure and consequently may be restored after prolonged follow-up (Giusti et al., 2011; Gómez et al., 2010; Hoftijzer et al., 2008; Malterling et al., 2010; Pelttari et al., 2009). Special attention should be paid in patients with more severe staging on diagnosis (Almeida et al., 2009; Giusti et al., 2011). An interesting qualitative study has been carried out in this topic (Sawka et al., 2009).

#### **1.4.4 Researches in subclinical hypothyroidism and hyperthyroidism**

In connection with laboratory diagnostics improvement the research of subclinical thyroid disorder moves forward. Some patients may suffer from clinical symptoms resembling hypothyroidism or hyperthyroidism, and others do not. There is not a consensus concerning the fact whether these diseases should be treated (Stárka, Zamrazil et al., 2005), therefore the research in health status and some aspects of quality of life are becoming more important.

A lot of studies observing patients with non-treated subclinical hypothyroidism proved deterioration in some aspects of the health status (Appolinario et al., 2005; Baldini et al., 1997, 2009; Monzani et al., 1993; Razvi et al., 2005). However, the results of works observing if the therapy with T4 hormone is beneficial are disputable. Some studies mention specific effects (Baldini et al., 1997, 2009; Bono et al., 2004; Jenšovský et al., 2000, 2002; Monzani et al., 1993;), other works do not prove positive changes (e.g. Parle et al., 2010). Recent study by Jorde et al. (2006) does not either demonstrate the profit of T4 treatment, but it does not find any differences among patients with subclinical hypothyroidism, concerning the health status, as well as by Vigário et al. (2009), Park et al. (2010).

Compared to the control group, the research results by Biondi et al. (2000) testify for deterioration of some health status aspects with non-treated patients with endogenous subclinical hyperthyroidism.

#### **1.4.5 Researches in euthyroid goitre**

Only little attention was paid to the patients with euthyroid goitre within the research of quality of life and health status. The results of the studies in non-treated and treated patients signal deteriorated health status in some aspects (Bianchi et al., 2004; Janečková, 2001, 2006; König et al., 2007).

It is supposed that just a regular monitoring of patient's euthyroid status with nodules in thyroid reduces the quality of his life; on the other hand, more significant deterioration of the quality of life would occur if the patient was not dispensarized within his course of life (Dietlein & Schicha, 2003; Vidal-Trécan et al., 2002).

#### **2. Aims and background**

The aim of our research was to map psychosocial aspects of thyroid disease (thyreopathy). We have especially focused on patients' quality of life, role of stress and coping with it, including protective factors (resilience and social support); at the same time we tried to

Psychosocial Factors in Patients with Thyroid Disease 287

itself and in the end, the patients were given questionnaires and instructions to them. The patient was informed to fill in the questionnaire 1 or 2 days before release from hospital (even due to the fact he will probably feel himself well), what was followed, with some exceptions. Being released from hospital, the researched person handed in the filled in questionnaire in a sealed envelope. Data collection after 3 and 6 months has also been realised in the hospital in a group form. The group was always formed by patients who were operated on within ± 14 days. At first, they filled in the questionnaires, then and individual semi-structured dialogue was carried out with them. The research has been

The examined sample was created by the patients with thyroid operation carried out within the period from January 2006 to January 2007. The data were gained from 143 patients, 132 women (92.3 %) and 11 men (7.7 %). Average age of the patients was 51.9 ± 14.4 years. It was dealt with 45 patients with hyperthyroidism, 70 with nodular goitre, 17 with carcinoma (7 papillary carcinoma, 7 papillary microcarcinoma, 3 medullary carcinoma) and 11 with thyroiditis. Concerning the patients in nodular goitre, 36 of them underwent hemithyroidectomy and 34 of them total thyroidectomy. Patient's hormone level was adjusted within the hospitalisation in the way so that he would be euthyroid. Originally, according to thyroid function there were 45 patients hyperfunctional, 89 eufunctional and 9 hypofunctional. 68 patients did not take any specific medication, 39 took thyrostatics and 36 took synthetic thyroid hormones. An average length of thyreopathy from the diagnosis was 5.6 ± 8.7 years. Co-morbidity of diseases in patients with thyreopathy was also followed, when the doctor confirmed with all of them that, from an objective viewpoint, no one of them suffers from more serious disease than it corresponds to common population of the same age. We also inquired if the patient did not experience any important changes in his recent life. Persons from the control group were asked the same, because it could influence

Altogether 91.1% of addressed patients with thyreopathy took part in the research within their hospitalisation. After 3 months since surgery, 131 patients continued in the research and, after 6 months, 125 patients from the original sample (143 people). Altogether 87.4% of patients from the original sample finished the longitudinal follow up. "Wear and tear" of the sample occurred approximately in the same percentage with men and women. In general it can be said that we were successful in reaching quite a high percentage of filled in questionnaires and a small wear and tear of the sample (experimental mortality) during the longitudinal follow up. Probably due to this reason, that nearly all patients were enthusiastic about nice approach to them by the medical staff, especially by the doctor and

Selection of people into the control sample was given by respondents' availability and their willingness to participate in the research. In a maximum extent, we equalised this file with a group of patients according to criteria, such as sex, age and residence in the same region. We excluded people who were in the past, or who are currently treated with thyreopathy, or who are in medical dispensarization due to the mentioned above disease. Due to the fact that it was quite difficult to gather needed amount of healthy people, at the same time an avalanche selection, or the method of snowball, was applied (Ferjenčík,

approved by an ethics committee of the involved hospital.

for example the results in the questionnaires.

they felt gratitude for that.

**4. Samples** 

compare the results with the healthy population. It dealt with comparing the patients in thyroid disease who have undergone an operation, including their follow up after surgery.

We have looked into this topic from the viewpoint of two relatively young disciplines, namely health psychology and, at the same time, we are inspired by positive psychology. Health psychology represents one of the fastest developing spheres of present psychology; it is a relatively young discipline. Mostly there is a consensus that it is dealt with a discipline that applies psychological knowledge into the sphere of health, diseases and the healthcare system (comp. Kebza, 2005; Křivohlavý, 2009; Mohapl, 1992; Vašina, 1999). Many psychologists are aware of the necessity of a change, but not in a radical diversion from existing negative topics in psychology (basically given by the historic development), but rather in the sense of the whole picture completion with "positive" topics. It is due to the fact that absence of negative aspects is not the same as presence of the positive ones. Dissatisfaction with the existing state, newly oriented constituent psychological research, new attitudes to the representatives of different psychological disciplines have gradually flown into a bigger stream that has taken a shape and determined itself as the positive psychology (Kebza, 2005; Křivohlavý, 2010; Mareš, 2001; Seligman, 2000).

#### **3. Design of the research**

In correspondence with our research aim we have chosen non-experimental research plan (Hendl, 2006), where its core does not consist in an invasion or in a deliberate manipulation with the observed variables. Sometime such research plans are called as sample surveys. We understand our study as a descriptive research focused on exploration, description and orientation, or confirmation of carried out research, eventually prediction. We have used differentiation overview where we have compared patients in thyreopathy to health population, or patients with different types of thyreopathies among each other. We have presumed to compare health population with the ills in thyreopathy as a whole, because it is known from literature that within the course of this disease there can occur changes of hormonal status based on the disease or treatment character. We have used a development overview (a specific type of a differentiation overview) in the sense of longitudinal follow up of patients after 3 and 6 months since surgery where we try to capture a change of observed variables in time in patients with thyreopathy overall, or in the patients with different types of thyreopathies. We want to avoid frequent, quite easy process of measuring the status only before and after the change, what is rightly criticised (Břicháček, 2006), especially in measuring the quality of life (Mareš, 2005). We have also followed in our orientation research (Janečková, 2001, 2006), where we have especially focused on the thyroid disease as a mental strain (stress) and we have researched the consequences that this disease brings to the patients, its diagnostics and treatment. With respect to the research problem, the choice of a mixed research strategy has been considered as the most suitable one (quantitatively-qualitative).

The patients have almost always been asked by the doctor, who operated them on, to take part in this research. Then, the researcher conducted an interview with the patient. At first, he described him simply the aim and character of the research, then there was the dialogue itself and in the end, the patients were given questionnaires and instructions to them. The patient was informed to fill in the questionnaire 1 or 2 days before release from hospital (even due to the fact he will probably feel himself well), what was followed, with some exceptions. Being released from hospital, the researched person handed in the filled in questionnaire in a sealed envelope. Data collection after 3 and 6 months has also been realised in the hospital in a group form. The group was always formed by patients who were operated on within ± 14 days. At first, they filled in the questionnaires, then and individual semi-structured dialogue was carried out with them. The research has been approved by an ethics committee of the involved hospital.

#### **4. Samples**

286 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

compare the results with the healthy population. It dealt with comparing the patients in thyroid disease who have undergone an operation, including their follow up after

We have looked into this topic from the viewpoint of two relatively young disciplines, namely health psychology and, at the same time, we are inspired by positive psychology. Health psychology represents one of the fastest developing spheres of present psychology; it is a relatively young discipline. Mostly there is a consensus that it is dealt with a discipline that applies psychological knowledge into the sphere of health, diseases and the healthcare system (comp. Kebza, 2005; Křivohlavý, 2009; Mohapl, 1992; Vašina, 1999). Many psychologists are aware of the necessity of a change, but not in a radical diversion from existing negative topics in psychology (basically given by the historic development), but rather in the sense of the whole picture completion with "positive" topics. It is due to the fact that absence of negative aspects is not the same as presence of the positive ones. Dissatisfaction with the existing state, newly oriented constituent psychological research, new attitudes to the representatives of different psychological disciplines have gradually flown into a bigger stream that has taken a shape and determined itself as the positive psychology (Kebza, 2005; Křivohlavý, 2010; Mareš, 2001;

In correspondence with our research aim we have chosen non-experimental research plan (Hendl, 2006), where its core does not consist in an invasion or in a deliberate manipulation with the observed variables. Sometime such research plans are called as sample surveys. We understand our study as a descriptive research focused on exploration, description and orientation, or confirmation of carried out research, eventually prediction. We have used differentiation overview where we have compared patients in thyreopathy to health population, or patients with different types of thyreopathies among each other. We have presumed to compare health population with the ills in thyreopathy as a whole, because it is known from literature that within the course of this disease there can occur changes of hormonal status based on the disease or treatment character. We have used a development overview (a specific type of a differentiation overview) in the sense of longitudinal follow up of patients after 3 and 6 months since surgery where we try to capture a change of observed variables in time in patients with thyreopathy overall, or in the patients with different types of thyreopathies. We want to avoid frequent, quite easy process of measuring the status only before and after the change, what is rightly criticised (Břicháček, 2006), especially in measuring the quality of life (Mareš, 2005). We have also followed in our orientation research (Janečková, 2001, 2006), where we have especially focused on the thyroid disease as a mental strain (stress) and we have researched the consequences that this disease brings to the patients, its diagnostics and treatment. With respect to the research problem, the choice of a mixed research strategy has been considered as the most suitable

The patients have almost always been asked by the doctor, who operated them on, to take part in this research. Then, the researcher conducted an interview with the patient. At first, he described him simply the aim and character of the research, then there was the dialogue

surgery.

Seligman, 2000).

**3. Design of the research** 

one (quantitatively-qualitative).

The examined sample was created by the patients with thyroid operation carried out within the period from January 2006 to January 2007. The data were gained from 143 patients, 132 women (92.3 %) and 11 men (7.7 %). Average age of the patients was 51.9 ± 14.4 years. It was dealt with 45 patients with hyperthyroidism, 70 with nodular goitre, 17 with carcinoma (7 papillary carcinoma, 7 papillary microcarcinoma, 3 medullary carcinoma) and 11 with thyroiditis. Concerning the patients in nodular goitre, 36 of them underwent hemithyroidectomy and 34 of them total thyroidectomy. Patient's hormone level was adjusted within the hospitalisation in the way so that he would be euthyroid. Originally, according to thyroid function there were 45 patients hyperfunctional, 89 eufunctional and 9 hypofunctional. 68 patients did not take any specific medication, 39 took thyrostatics and 36 took synthetic thyroid hormones. An average length of thyreopathy from the diagnosis was 5.6 ± 8.7 years. Co-morbidity of diseases in patients with thyreopathy was also followed, when the doctor confirmed with all of them that, from an objective viewpoint, no one of them suffers from more serious disease than it corresponds to common population of the same age. We also inquired if the patient did not experience any important changes in his recent life. Persons from the control group were asked the same, because it could influence for example the results in the questionnaires.

Altogether 91.1% of addressed patients with thyreopathy took part in the research within their hospitalisation. After 3 months since surgery, 131 patients continued in the research and, after 6 months, 125 patients from the original sample (143 people). Altogether 87.4% of patients from the original sample finished the longitudinal follow up. "Wear and tear" of the sample occurred approximately in the same percentage with men and women. In general it can be said that we were successful in reaching quite a high percentage of filled in questionnaires and a small wear and tear of the sample (experimental mortality) during the longitudinal follow up. Probably due to this reason, that nearly all patients were enthusiastic about nice approach to them by the medical staff, especially by the doctor and they felt gratitude for that.

Selection of people into the control sample was given by respondents' availability and their willingness to participate in the research. In a maximum extent, we equalised this file with a group of patients according to criteria, such as sex, age and residence in the same region. We excluded people who were in the past, or who are currently treated with thyreopathy, or who are in medical dispensarization due to the mentioned above disease. Due to the fact that it was quite difficult to gather needed amount of healthy people, at the same time an avalanche selection, or the method of snowball, was applied (Ferjenčík,

Psychosocial Factors in Patients with Thyroid Disease 289

neither any total COPE score is counted from the method, nor the scales are divided into problem-focused and emotion-focused coping strategies. He rather pays attention to each scale separately and he observes what relation it is to other variables. He recommends so that each researcher would identify in their data own factors because different samples show different regularities of relations (dated 04/09/2011 available

SEIQoL is a method detecting individual quality of life, based on a interview. Altogether it requires a period of 10 to 20 minutes and it is suitable for research and clinical purposes (O'Boyle et al., 1994, as cited in Křivohlavý, 2009; O'Boyle et al., 1995). It has been used for different groups of patients even in healthy people (e.g. Buchtová, 2004; Koukola & Ondřejová, 2006; Rybářová et al., 2006; Řehulka & Řehulková, 2003). According to authors' conception, the quality of life of an individual, it depends on his own system of values that is fully respected within this method detection. The individual determines, considers and evaluates aspects of life that are essential for him in the specific situation and time (Křivohlavý, 2002). In the Czech Republic, this method was translated by Křivohlavý (2009). The result is calculation of a table (table – quality of life) and graphic presentation (line – life satisfaction). Analytic approach is necessary for the scale calculated from component areas, graphic scale requires holistic approach. Because most of the respondents wanted to fill in the form on their own, we especially built on written answers (similarly, e.g. Koukola & Ondřejová, 2006; Rybářová et al., 2006). We consider it as an advantage, because it is very difficult for a researcher not to influence a proband during the dialogue. Westerman et al. (2006) refer on the fact that it can easily happen the researcher (inadvertently) influences the interviewed and a big attention should be paid to this. Further on, they mention that, in different times, the patients indicate different key topics (reconceptualisation) and they can change the rate of importance in the same topics (recalibration), when both kinds of changes signal change of values (Schwartz & Sprangers, 1999, as cited in Westerman et al., 2006; comp. Mareš, 2005). Therefore, O'Boyle et al. (1995) recommend so that the respondents would always form new key areas in prospective studies, what we have kept. Křivohlavý

from http://www.psy.miami.edu/faculty/ccarver/sclCOPEF.html). **Schedule for the Evaluation of Individual Quality of Life = SEIQoL** 

(2002) also states that the areas can change within the course of life.

To measure anxiety we have used STAI by Spielberger (1980) that we have translated from Slovak into Czech. This widely usable method enables to distinguish anxiety as a status and anxiety as a personality trait (anxiousness). This can be an advantage in usage with a longitudinal follow up. But it can be benefited from in patients even with first questionnaires administration after operation, because some patients can experience a high level of anxiety during hospitalisation, otherwise, they do not have the tendency to react in their lives like this. No less important advantage of this questionnaire compared to other ones is that it is more suitable for patients with thyreopathy. Anxiety is more likely deduced from feelings (feelings of tension, nervousness, fear, worries vs. feelings of calm, safety, satisfaction), than from physical symptoms, these could be more likely display of thyroid disorder that anxiety. State Anxiety Scale and Trait Anxiety Scale are always formed with 20

**State-Trait Anxiety Inventory = STAI** 

items that are assessed on the scale from 1 to 4.

2010; Miovský, 2006). Finally, the control sample was formed by 137 healthy people not suffering from thyreopathy, 127 women and 10 men. Average age of the respondents was 51.5 ± 14.8 years. Altogether, the questionnaires were filled in by 86.2 % of responded healthy people.

#### **5. Methods**

While choosing the method of data collection we endeavoured so that they were relevant to the aim of the research and observed variables based on the studied literature. We chose methods with good psychometric characteristics. All the persons were administrated with 7 tested methods and a semi-structured interview was carried out.

#### **Antonovsky's Sense of Coherence Scale = SOC**

SOC (sense of coherence) questionnaire contains 29 items, the extent of scores is 29 to 230. The method is based on Antonovsky's conception of SOC resilience and was translated by Křivohlavý. Except for the total coherence (integrity) of a personality, it measures 3 dimensions of SOC – comprehensibility (C), manageability (MA) and meaningfulness (ME). Křivohlavý (1990) mentions correlation of SOC, among others with Spielberger's STAI questionnaire.

#### **Perceived Social Support Scale = PSSS**

Perceived social support scale was surveyed by means of PSSS self-assessment method by Blumental et al. (1987). It consists of 12 basic and 4 additional items by means of which a person assesses availability of social support and satisfaction with it. The questionnaire items are assessed on a 7-point scale of Likert's type, where an individual expresses the extent of his agreement or disagreement with the given statement. A total score and 3 constituent scores are inquired – social support from an important, not specified person (PSSS\_A), from family members (PSSS\_B), and from friends (PSSS\_C). Other 4 items (scales) that were added by Vašina (1999) allow to compare social support evaluation from the family, friends, co-workers and superiors.

#### **COPE inventory**

We used COPE questionnaire created by the team of Carver, Scheier and Weintraub (1989), in the Czech Republic translated by Vašina (2002), to find out coping strategies. Through 15 scales the method captures 15 groups, types of coping strategies. Each type is diagnosed with the help of 4 items on a 4-level scale from "I do not react like this" to "I react like this quite often". The authors of the method were thinking about a problem, whether the choise of specific types of reaction depends on a situation or on personal traits (similarly to Spielberger in STAI method), and with the help of a suitably chosen instruction they managed to capture dispositional and situational coping reactions (Vašina, 1999). In our study we have rather focused on general tendency of strategy selection. The questionnaire contains either, reactions that can be regarded as adaptive, effective, or maladaptive, ineffective. Each scale is unipolar, it means its missing does not mean that the present is the opposite. The method contains at least 2 pairs of opposite tendencies when it can be presupposed that a man can use wide repertoire of strategies in specific periods of life, including both opposite tendencies. Carver emphasizes that

2010; Miovský, 2006). Finally, the control sample was formed by 137 healthy people not suffering from thyreopathy, 127 women and 10 men. Average age of the respondents was 51.5 ± 14.8 years. Altogether, the questionnaires were filled in by 86.2 % of responded

While choosing the method of data collection we endeavoured so that they were relevant to the aim of the research and observed variables based on the studied literature. We chose methods with good psychometric characteristics. All the persons were administrated with 7

SOC (sense of coherence) questionnaire contains 29 items, the extent of scores is 29 to 230. The method is based on Antonovsky's conception of SOC resilience and was translated by Křivohlavý. Except for the total coherence (integrity) of a personality, it measures 3 dimensions of SOC – comprehensibility (C), manageability (MA) and meaningfulness (ME). Křivohlavý (1990) mentions correlation of SOC, among others with Spielberger's

Perceived social support scale was surveyed by means of PSSS self-assessment method by Blumental et al. (1987). It consists of 12 basic and 4 additional items by means of which a person assesses availability of social support and satisfaction with it. The questionnaire items are assessed on a 7-point scale of Likert's type, where an individual expresses the extent of his agreement or disagreement with the given statement. A total score and 3 constituent scores are inquired – social support from an important, not specified person (PSSS\_A), from family members (PSSS\_B), and from friends (PSSS\_C). Other 4 items (scales) that were added by Vašina (1999) allow to compare social support evaluation from the

We used COPE questionnaire created by the team of Carver, Scheier and Weintraub (1989), in the Czech Republic translated by Vašina (2002), to find out coping strategies. Through 15 scales the method captures 15 groups, types of coping strategies. Each type is diagnosed with the help of 4 items on a 4-level scale from "I do not react like this" to "I react like this quite often". The authors of the method were thinking about a problem, whether the choise of specific types of reaction depends on a situation or on personal traits (similarly to Spielberger in STAI method), and with the help of a suitably chosen instruction they managed to capture dispositional and situational coping reactions (Vašina, 1999). In our study we have rather focused on general tendency of strategy selection. The questionnaire contains either, reactions that can be regarded as adaptive, effective, or maladaptive, ineffective. Each scale is unipolar, it means its missing does not mean that the present is the opposite. The method contains at least 2 pairs of opposite tendencies when it can be presupposed that a man can use wide repertoire of strategies in specific periods of life, including both opposite tendencies. Carver emphasizes that

tested methods and a semi-structured interview was carried out.

**Antonovsky's Sense of Coherence Scale = SOC** 

**Perceived Social Support Scale = PSSS** 

family, friends, co-workers and superiors.

healthy people.

**5. Methods** 

STAI questionnaire.

**COPE inventory** 

neither any total COPE score is counted from the method, nor the scales are divided into problem-focused and emotion-focused coping strategies. He rather pays attention to each scale separately and he observes what relation it is to other variables. He recommends so that each researcher would identify in their data own factors because different samples show different regularities of relations (dated 04/09/2011 available from http://www.psy.miami.edu/faculty/ccarver/sclCOPEF.html).

#### **Schedule for the Evaluation of Individual Quality of Life = SEIQoL**

SEIQoL is a method detecting individual quality of life, based on a interview. Altogether it requires a period of 10 to 20 minutes and it is suitable for research and clinical purposes (O'Boyle et al., 1994, as cited in Křivohlavý, 2009; O'Boyle et al., 1995). It has been used for different groups of patients even in healthy people (e.g. Buchtová, 2004; Koukola & Ondřejová, 2006; Rybářová et al., 2006; Řehulka & Řehulková, 2003). According to authors' conception, the quality of life of an individual, it depends on his own system of values that is fully respected within this method detection. The individual determines, considers and evaluates aspects of life that are essential for him in the specific situation and time (Křivohlavý, 2002). In the Czech Republic, this method was translated by Křivohlavý (2009). The result is calculation of a table (table – quality of life) and graphic presentation (line – life satisfaction). Analytic approach is necessary for the scale calculated from component areas, graphic scale requires holistic approach. Because most of the respondents wanted to fill in the form on their own, we especially built on written answers (similarly, e.g. Koukola & Ondřejová, 2006; Rybářová et al., 2006). We consider it as an advantage, because it is very difficult for a researcher not to influence a proband during the dialogue. Westerman et al. (2006) refer on the fact that it can easily happen the researcher (inadvertently) influences the interviewed and a big attention should be paid to this. Further on, they mention that, in different times, the patients indicate different key topics (reconceptualisation) and they can change the rate of importance in the same topics (recalibration), when both kinds of changes signal change of values (Schwartz & Sprangers, 1999, as cited in Westerman et al., 2006; comp. Mareš, 2005). Therefore, O'Boyle et al. (1995) recommend so that the respondents would always form new key areas in prospective studies, what we have kept. Křivohlavý (2002) also states that the areas can change within the course of life.

#### **State-Trait Anxiety Inventory = STAI**

To measure anxiety we have used STAI by Spielberger (1980) that we have translated from Slovak into Czech. This widely usable method enables to distinguish anxiety as a status and anxiety as a personality trait (anxiousness). This can be an advantage in usage with a longitudinal follow up. But it can be benefited from in patients even with first questionnaires administration after operation, because some patients can experience a high level of anxiety during hospitalisation, otherwise, they do not have the tendency to react in their lives like this. No less important advantage of this questionnaire compared to other ones is that it is more suitable for patients with thyreopathy. Anxiety is more likely deduced from feelings (feelings of tension, nervousness, fear, worries vs. feelings of calm, safety, satisfaction), than from physical symptoms, these could be more likely display of thyroid disorder that anxiety. State Anxiety Scale and Trait Anxiety Scale are always formed with 20 items that are assessed on the scale from 1 to 4.

Psychosocial Factors in Patients with Thyroid Disease 291

physically healthier and there is a higher probability with them to stay healthy (e.g. Kebza, 2005; Kebza & Šolcová, 2008; Křivohlavý, 1990; Vašina, 1999). Moreover, a difficult life situation can result in lowering the feeling of control over the life (comp. Kebza, 2005;

H2: We suppose the ills with thyreopathy will use rather non-effective coping strategies compared to the control group. The problems of coping strategies with thyreopathies are not examined a lot, the attention was only paid to Graves' disease, and yet it is called for more research into modifying stress factors in this diagnose (e.g. Rosch, 1993). Kung's (1995) and Winsy et al.'s (1991) studies have not proved differences between the healthy and ills. On the other hand, Yoshiuchi et al. (1998b) has found out that the group of health women compared to the female patients scored higher in problem-focused coping strategy, the group of healthy men compared to the patients waited till the situation passes. Ma, Luo and Zeng (2002) have realised in ill people non-effective coping

H3: We suppose the patients with thyreopathy will show lower quality of life, less life satisfaction than the control group. Deteriorated health status and quality of life, limitations in usual activities, social and emotional troubles occur with not only untreated patients, but as well as with the half of treated patients, and with one third even anxiety and so on. (Razvi

H4: We suppose the patients with thyreopathy will experience more negative emotions (depression and anxiety) that the control group. It is known that especially anxiety and depression occur in patients with different diagnoses (e.g. Kukleta, 2001; Vymětal, 2003).

H5: We suppose the patients with thyreopathy will perceive higher social support compared to the healhy ones. With regard to the fact it is dealt with a planned operation mobilisation of patient social network and providing increased social support can be presupposed, and even from the side of medical staff. Otherwise, social support has been researched only in patients with Graves' disease, and this areas also considers it as insufficient, e.g. Rosch (1993). Differences between the ills and healthy ones have not been proved (Winsa et al, 1991; Yoshiuschi et al., 1998b). Ma, Luo and Zeng's (2002; comp. Kukleta, 2001) research was an exception, were less support was shown in patients probably due to the reason the

H6: We suppose that increase of resilience occurs in time within a half-year follow up in patients (growth of the sense for coherence and tendency to internal locus of control). The researches show that even if the sense for coherence can show itself as a stable trait, difficult life situations can change man's view of the world (Schnyder, 2000). After experiencing surgery (situation with less control) patients can gradually perceived a growth of the control

H7: We suppose that the patients with thyreopathy will begin to choose effective coping strategies in time within a half-year follow up. Even earlier experience plays a specific role in managing and choice of coping strategy (comp. Baumgartner, 2001). The patients could acquire more adaptive strategies of manageability with the help of coping with surgery and

disease is developed with insufficient social support in an easier way.

they could be stimulated to this by the contacts with doctors, and so on.

over their lives (comp. Kebza, 2005; Křivohlavý, 2002).

Křivohlavý, 2002).

strategies, compared to the healthy ones.

et al., 2005; Watt et al., 2006).

#### **Beck Depression Inventory = BDI**

Beck's questionnaire BDI for detection of depression belongs among the most frequent selfassessment methods for detection of depressive symptoms. In order to burden the patient as little as possible, we have used shortened version in our study with 13 items that is also considered as valid and reliable enough (Reynold & Gould, 1981). A person evaluates each item on four-point assessment scale from 0 to 3.

#### **Visual analogous scale Locus of Control = LOC**

To detect Rotter's (1966, e.g. as cited in Kebza & Šolcová, 2008) LOC we have used visual analogue scale. The researched person was asked a question "To what extent do you suppose your life is in your hands (you can influence it, you control its course)?". As an answer he shall illustrate graphically his position between two extremes "not at all – completely" on a line segment of 100 mm long. LOC can reach the scores from 0 to 100. The more the score is closer to 100 (vs. closer to 0), the more it approaches internal locus of control (vs. external locus of control).

#### **Semi-structured interviews**

The interview was always carried out with approximately 80% of the patients, who filled in the questionnaires, in each administration of questionnaires (i.e. at the period of hospitalisation, 3 and 6 months since surgery). At least once a dialogue was carried out with each patient (except for 4), but usually three times. Altogether more than 300 dialogues of average length of approximately 20 minutes were realised. With respect to the research extensity, the interviews were recorded in a form of detailed notes. First three pilot depth interviews helped to map important topics and based on them a structure of semi-structured interview was created.

Statistical data processing was carried out with the help of statistical programme SPSS 14.0. To assess differences between averages of two groups, T-test was used (comp. Reiterová, 2007, 2009). To observe changes in patients in time, an analysis of variance was used for repeated measurements (general linear model). To detect level of the relation (dependence) tightness between two variables we used a correlation analysis. (Hendl, 2006). We assessed data of qualitative character through content analysis (Hendl, 2009; Silverman, 2005; Miovský, 2006). χ2 test of independence was used in SEIQoL method to detect whether frequency distribution in individual areas (life goals or cues) depends on (relates to) belonging to a group (the ills x the healthy). On the other hand, assessment of changes in frequency distribution in individual areas with 3 measurements in patients in time was detected with the help of Cochran's test. With respect to the low number of people, in some areas, it was not possible to carry out statistical test in all areas and to draw attention to all substantively significant differences.

#### **6. Hypotheses and explorative questions**

Based on the studies of these issues, we define the hypotheses as follows:

H1: We suppose the patient with thyreopathy will be less resilient (they will be with less sense of coherence and with a tendency to external locus of control) that the control group. It is described in the literature that people with a high level of resilience are

Beck's questionnaire BDI for detection of depression belongs among the most frequent selfassessment methods for detection of depressive symptoms. In order to burden the patient as little as possible, we have used shortened version in our study with 13 items that is also considered as valid and reliable enough (Reynold & Gould, 1981). A person evaluates each

To detect Rotter's (1966, e.g. as cited in Kebza & Šolcová, 2008) LOC we have used visual analogue scale. The researched person was asked a question "To what extent do you suppose your life is in your hands (you can influence it, you control its course)?". As an answer he shall illustrate graphically his position between two extremes "not at all – completely" on a line segment of 100 mm long. LOC can reach the scores from 0 to 100. The more the score is closer to 100 (vs. closer to 0), the more it approaches internal locus of

The interview was always carried out with approximately 80% of the patients, who filled in the questionnaires, in each administration of questionnaires (i.e. at the period of hospitalisation, 3 and 6 months since surgery). At least once a dialogue was carried out with each patient (except for 4), but usually three times. Altogether more than 300 dialogues of average length of approximately 20 minutes were realised. With respect to the research extensity, the interviews were recorded in a form of detailed notes. First three pilot depth interviews helped to map important topics and based on them a structure of semi-structured

Statistical data processing was carried out with the help of statistical programme SPSS 14.0. To assess differences between averages of two groups, T-test was used (comp. Reiterová, 2007, 2009). To observe changes in patients in time, an analysis of variance was used for repeated measurements (general linear model). To detect level of the relation (dependence) tightness between two variables we used a correlation analysis. (Hendl, 2006). We assessed data of qualitative character through content analysis (Hendl, 2009; Silverman, 2005; Miovský, 2006). χ2 test of independence was used in SEIQoL method to detect whether frequency distribution in individual areas (life goals or cues) depends on (relates to) belonging to a group (the ills x the healthy). On the other hand, assessment of changes in frequency distribution in individual areas with 3 measurements in patients in time was detected with the help of Cochran's test. With respect to the low number of people, in some areas, it was not possible to carry out statistical test in all areas and to draw attention to all

H1: We suppose the patient with thyreopathy will be less resilient (they will be with less sense of coherence and with a tendency to external locus of control) that the control group. It is described in the literature that people with a high level of resilience are

**Beck Depression Inventory = BDI** 

control (vs. external locus of control).

substantively significant differences.

**6. Hypotheses and explorative questions** 

Based on the studies of these issues, we define the hypotheses as follows:

**Semi-structured interviews** 

interview was created.

item on four-point assessment scale from 0 to 3. **Visual analogous scale Locus of Control = LOC**  physically healthier and there is a higher probability with them to stay healthy (e.g. Kebza, 2005; Kebza & Šolcová, 2008; Křivohlavý, 1990; Vašina, 1999). Moreover, a difficult life situation can result in lowering the feeling of control over the life (comp. Kebza, 2005; Křivohlavý, 2002).

H2: We suppose the ills with thyreopathy will use rather non-effective coping strategies compared to the control group. The problems of coping strategies with thyreopathies are not examined a lot, the attention was only paid to Graves' disease, and yet it is called for more research into modifying stress factors in this diagnose (e.g. Rosch, 1993). Kung's (1995) and Winsy et al.'s (1991) studies have not proved differences between the healthy and ills. On the other hand, Yoshiuchi et al. (1998b) has found out that the group of health women compared to the female patients scored higher in problem-focused coping strategy, the group of healthy men compared to the patients waited till the situation passes. Ma, Luo and Zeng (2002) have realised in ill people non-effective coping strategies, compared to the healthy ones.

H3: We suppose the patients with thyreopathy will show lower quality of life, less life satisfaction than the control group. Deteriorated health status and quality of life, limitations in usual activities, social and emotional troubles occur with not only untreated patients, but as well as with the half of treated patients, and with one third even anxiety and so on. (Razvi et al., 2005; Watt et al., 2006).

H4: We suppose the patients with thyreopathy will experience more negative emotions (depression and anxiety) that the control group. It is known that especially anxiety and depression occur in patients with different diagnoses (e.g. Kukleta, 2001; Vymětal, 2003).

H5: We suppose the patients with thyreopathy will perceive higher social support compared to the healhy ones. With regard to the fact it is dealt with a planned operation mobilisation of patient social network and providing increased social support can be presupposed, and even from the side of medical staff. Otherwise, social support has been researched only in patients with Graves' disease, and this areas also considers it as insufficient, e.g. Rosch (1993). Differences between the ills and healthy ones have not been proved (Winsa et al, 1991; Yoshiuschi et al., 1998b). Ma, Luo and Zeng's (2002; comp. Kukleta, 2001) research was an exception, were less support was shown in patients probably due to the reason the disease is developed with insufficient social support in an easier way.

H6: We suppose that increase of resilience occurs in time within a half-year follow up in patients (growth of the sense for coherence and tendency to internal locus of control). The researches show that even if the sense for coherence can show itself as a stable trait, difficult life situations can change man's view of the world (Schnyder, 2000). After experiencing surgery (situation with less control) patients can gradually perceived a growth of the control over their lives (comp. Kebza, 2005; Křivohlavý, 2002).

H7: We suppose that the patients with thyreopathy will begin to choose effective coping strategies in time within a half-year follow up. Even earlier experience plays a specific role in managing and choice of coping strategy (comp. Baumgartner, 2001). The patients could acquire more adaptive strategies of manageability with the help of coping with surgery and they could be stimulated to this by the contacts with doctors, and so on.

Psychosocial Factors in Patients with Thyroid Disease 293

3. Statistically significant difference of averages has not been found out in patients and healthy persons in any of the coping strategies. An exception is a strategy of "planning" where it has been showed on the edge of statistical significance, respectively closely behind it, that it is used more frequently by the healthy respondents than the ills with

4. On the edge of statistical significance, respectively closely behind it, it is indicated that higher life satisfaction has been mentioned by the member of the control group that the patients. The patients have stated significantly higher quality of life (p < 0.05) than the

5. The ills have scored significantly higher (p < 0.05) in state anxiety and anxiousness than

6. Statistically significant difference in average scores of depression has not been proved

7. Significantly higher tendency (p < 0.01) to internality (internal locus of control) and, therefore, to the feeling they have the life in their hands, have had the healthy people compared to the ills. Higher variance in locus of control on the edge of statistical

**Variables Patients compared to healthy ones** 

B -family ↑ /p>0.05/

line - life satisfaction ↓ close t. ed.

trait anxiety ↑ /p>0.05/

COPE planning ↓ close t. ed.

QoL table - quality of life ↑ /p>0.05/

STAI state anxiety ↑ /p>0.05/

LOC locus of control ↓ /p>0.01/

Caption: ↑ means that patients in the given variable scored higher than healthy population

↓ means that patients in the given variable scored lower than healthy population "close t. ed." is an abbreviation for close to the edge of statistical significance Table 1. Comparison of patients with thyreopathy to healthy population

significance has been found out in the patients compared with controls.

thyreopathy.

SOC

PSSS

the healthy persons.

persons not suffering from thyreopathy.

between the patients and the control group.

ME - meaningfulness MA - manageability C - comprehensibility sense of coherence

A - significant others

C - friends perceived social

support

BDI depression

H8: We suppose there occur improvement in quality of life and life satisfaction in patients in time within a half-year follow up. Satisfaction and quality of life usually increases with decrease of health problems that we suppose after an operation (comp. Křivohlavý, 2002; Kebza, 2005; Křížová, 2005).

H9: We suppose that decrease of negative emotions (depression and anxiety) occur in patients with thyreopathy within a half-year follow up. There should be less negative emotions with presupposed improvement of the health status due to the surgery (comp. Vymětal, 2003).

H10: We suppose that decrease of perceived social support occur in patients with thyreopathy within a half-year follow up. After initial mobilisation of the social support (including medical staff) due to the surgery, there will be its decrease, when the surroundings begin to consider the patient as "healthy", "cured".

With respect to these unexplored issues we have also been interested in answers to the following explorative questions:

Q1: What are the differences in the observed variables among the patients with different thyreopathies? Insufficient defining the sample of patients (i.e. type of thyreopathy) is typical for contemporary studies dealing with patients with thyreopathy (Watt et al., 2006). We regard comparison of such type a very interesting and we have not been informed on any similar researches.

Q2: What is the composition of the key areas (life topics) in the framework of quality of life, what importance and satisfaction with individual areas patients with thyreopathy will mention within the follow up period and how it is going to be in the control group? It is necessary to await that disease, treatment effects the quality of life not only in its total height, but also concerning the composition and importance of individual areas (cues) and their satisfaction with them (Křivohlavý, 2002).

Q3: Which variable does the quality of life relate to? Connection of the quality of life with resilience and social support is described in the literature, on the contrary, stress and negative emotions should deteriorate it. (comp. Kebza, 2005; Křivohlavý, 2002, 2009).

#### **7. Results and discussion**

#### **7.1 Results comparison of patients with thyreopathy to healthy population**


H8: We suppose there occur improvement in quality of life and life satisfaction in patients in time within a half-year follow up. Satisfaction and quality of life usually increases with decrease of health problems that we suppose after an operation (comp. Křivohlavý, 2002;

H9: We suppose that decrease of negative emotions (depression and anxiety) occur in patients with thyreopathy within a half-year follow up. There should be less negative emotions with presupposed improvement of the health status due to the surgery (comp.

H10: We suppose that decrease of perceived social support occur in patients with thyreopathy within a half-year follow up. After initial mobilisation of the social support (including medical staff) due to the surgery, there will be its decrease, when the

With respect to these unexplored issues we have also been interested in answers to the

Q1: What are the differences in the observed variables among the patients with different thyreopathies? Insufficient defining the sample of patients (i.e. type of thyreopathy) is typical for contemporary studies dealing with patients with thyreopathy (Watt et al., 2006). We regard comparison of such type a very interesting and we have not been informed on

Q2: What is the composition of the key areas (life topics) in the framework of quality of life, what importance and satisfaction with individual areas patients with thyreopathy will mention within the follow up period and how it is going to be in the control group? It is necessary to await that disease, treatment effects the quality of life not only in its total height, but also concerning the composition and importance of individual areas (cues) and

Q3: Which variable does the quality of life relate to? Connection of the quality of life with resilience and social support is described in the literature, on the contrary, stress and

1. A statistically significant difference between the patients and the control group has not been proved in average scores of the total sense of coherence. An significant difference of average scores have not been proved in scores between the patients and the control group, neither in comprehensibility, nor in manageability, or in meaningfulness. Significantly higher variance (p < 0.05) has been found out in comprehensibility with a

2. Statistically significant difference has not been proved in average scores of completely perceived social support between the experimental and control groups. Statistically significant difference has not been proved between the two groups in the social support from an important, not closely specified person, neither concerning the social support from friends. It shows that the patients perceive significantly higher (p < 0.05) social

negative emotions should deteriorate it. (comp. Kebza, 2005; Křivohlavý, 2002, 2009).

**7.1 Results comparison of patients with thyreopathy to healthy population** 

surroundings begin to consider the patient as "healthy", "cured".

Kebza, 2005; Křížová, 2005).

following explorative questions:

**7. Results and discussion** 

their satisfaction with them (Křivohlavý, 2002).

healthy control group than in patients.

support from the family that in the control group.

any similar researches.

Vymětal, 2003).



 Caption: ↑ means that patients in the given variable scored higher than healthy population ↓ means that patients in the given variable scored lower than healthy population "close t. ed." is an abbreviation for close to the edge of statistical significance

Table 1. Comparison of patients with thyreopathy to healthy population

Psychosocial Factors in Patients with Thyroid Disease 295

3. A difference in averages, close to the edge of significance, appeared in patients during the follow up after the surgery, and on the edge of significance there was indicated a linear decrease in "use of emotional social support". Statistically significant difference (p < 0.01) has been found out in averages with scale of "focus on and venting of emotion" and it was dealt with a quadratic trend (p < 0.05) – within the follow up period after surgery, at first, decrease of average score in coping strategy of "focus on and venting of emotions" in patients after 3 months and, after 6 months, it increased. We have not found out any statistically significant differences in averages in other

4. Statistically significant difference in averages of the life satisfaction level in the patients has not been found out during the follow up. On the edge of statistical significance, respectively close to it there has been indicated a significant difference in averages and a significant linear decrease of quality of life (p < 0.05) has been proved in patients

5. We have proved statistically significant difference (p < 0.05) in average scores and statistically significant linear decrease (p < 0.05) of state anxiety within the follow up period. Also a statistically significant difference (p < 0.01) in averages have been realised and a significant linear decrease (p < 0.01) of anxiousness during the follow up. 6. We have not proved a statistically significant difference of depression averages in

7. A difference in average scores on the edge of statistical significance has been indicated and a statistically significant linear trend (p < 0.05) to higher internality (internal locus

Hypothesis H10 has been confirmed, hypotheses H6 and H9 have been proved partially, hypotheses H7 and H8 have not been proved (see Tab. 2). During the half-year follow up period there occurred significant decrease of anxiety in patients, an increase in comprehensibility and in the feeling of the control over the situation has been indicated on the edge of significance (comp. Kebza, 2005; Kebza & Šolcová, 2008). Our finding is in compliance with the fact that in managing a difficult situation a man at first tries to understand it (comprehensibility) (comp. Mareš, 2007, 2008, 2009; Mareš et al., 2007). A linear decrease in coping strategy of "use of emotional social support" was indicated in patients within the follow up, and a significant decrease was indicated in perceived social support from the family, apparently due to the fact the stress situation of operation passed. Total social support, support from friends and coping strategy of "focus on and venting of emotions" changed in a quadratic way – at first, there was a significant decrease after 3 months, and a slight increase after 6 months after hospitalisation. Apparently it relates to the fact, the patient can feel himself isolated during the first 3 months after the surgery. Close to the edge of statistical significance a decrease in total quality of life was indicated in patients within the follow up, that relates to original overvaluation of life satisfaction with individual areas, but at the same time it can relate to the fact what was apparent in first interviews with them– inappropriate expectations in relation to the medical intervention (they expected complete cure). It is similarly reflected

months and, after 6 months, it increased.

coping strategies within the follow up period.

of control) has been proved within the follow up period.

by Vavrda (2005), comp. Calman (1984, as cited in Křivohlavý, 2002).

within the follow up period.

patients during the follow up.

quadratic trend (p < 0.05) has been found out – during the follow up period after the surgery, at first, the decrease of perceived social support from friends occurred after 3

Hypotheses H1 to H5 have been proved only partially (see Tab. 1). The patients with thyreopathy, compared to the healthy persons, significantly perceive higher social support from the family, they are more anxious and on the edge of significance they are less satisfied with the life. Even other literature resources state that the disease causes the need for help (e.g. Baštecká, 2003; Haškovcová, 1985). Razvi, McMillan, Weaver (2005) and Watt et al. (2006) summarize similar findings of some aspects sides concerning the quality of life. The healthy persons score significantly higher in locus of control and in coping strategy of "planning" on the edge of significance that is often regarded as an effective strategy. Differences between the patients and the healthy persons have not been found out in sense of coherence and depression. A paradox finding, that total higher quality of life is in patients compared to the healthy ones, has been explained in compliance with the quantitative data from the interviews. The patients have made an impression that they rather overestimated (idealised) the satisfaction evaluation in individual areas, especially within the period of hospitalisation, but also a little bit 3 months after it. As if due to the fact they have occurred in a difficult situation and they are to cope with it, they needed to see their life more positively and not to admit dissatisfaction with individual areas of life. Results graphically illustrated on the line segment of satisfaction level have been much more credible. Because the scale of life satisfaction requires holistic approach, but analytic assessment is necessary for the scale of total quality of life calculated from individual parts (comp. Rybářová et al., 2006), it is possible that real emotional status has been reflected on the line segment of satisfaction display, whereas the total calculated quality of life reflected their wish rather than the reality. On the other hand, for example Edelmann (1997, as cited in Baštecká et al., 2003), Moons et al. (2004) have stated that the quality of life does not have to unfold from the presence of a disease, so from the health status.

#### **7.2 Follow up results of patients with thyreopathy since surgery during the period of six months**


Hypotheses H1 to H5 have been proved only partially (see Tab. 1). The patients with thyreopathy, compared to the healthy persons, significantly perceive higher social support from the family, they are more anxious and on the edge of significance they are less satisfied with the life. Even other literature resources state that the disease causes the need for help (e.g. Baštecká, 2003; Haškovcová, 1985). Razvi, McMillan, Weaver (2005) and Watt et al. (2006) summarize similar findings of some aspects sides concerning the quality of life. The healthy persons score significantly higher in locus of control and in coping strategy of "planning" on the edge of significance that is often regarded as an effective strategy. Differences between the patients and the healthy persons have not been found out in sense of coherence and depression. A paradox finding, that total higher quality of life is in patients compared to the healthy ones, has been explained in compliance with the quantitative data from the interviews. The patients have made an impression that they rather overestimated (idealised) the satisfaction evaluation in individual areas, especially within the period of hospitalisation, but also a little bit 3 months after it. As if due to the fact they have occurred in a difficult situation and they are to cope with it, they needed to see their life more positively and not to admit dissatisfaction with individual areas of life. Results graphically illustrated on the line segment of satisfaction level have been much more credible. Because the scale of life satisfaction requires holistic approach, but analytic assessment is necessary for the scale of total quality of life calculated from individual parts (comp. Rybářová et al., 2006), it is possible that real emotional status has been reflected on the line segment of satisfaction display, whereas the total calculated quality of life reflected their wish rather than the reality. On the other hand, for example Edelmann (1997, as cited in Baštecká et al., 2003), Moons et al. (2004) have stated that the quality of life does not have to unfold from the

**7.2 Follow up results of patients with thyreopathy since surgery during the period of** 

1. Statistically significant difference in average scores of the whole sense of coherence within the follow up period has not been proved. Statistically significant difference in average scores of manageability have not been proved, nor in the average scores of meaningfulness within the follow up period. The difference between the averages have been indicated on the edge of statistical significance and a significant linear growth (p < 0.05) of comprehensibility has been proved in the patients with thyroid

2. We have found out a statistically significant difference (p < 0.05) in average scores of total perceived social support within the follow up period and a significant quadratic trend has been proved (p < 0.05) – at first, more significant decrease of totally perceived social support occurs in the patients after 3 months and to its slight increase after 6 months. Statistically significant difference in averages of perceived social support from an important, not specified person has not been proved in patients within the follow up period. We have realised a statistically significant difference (p < 0.05) in average scores and a significant linear decrease (p < 0.05) of perceived social support from the family members in the patients within the follow up period. Also a statistically significant difference (p < 0.05) in averages of perceived social support from friends in patients within the follow up period a significant

presence of a disease, so from the health status.

disease during the follow up.

**six months** 

quadratic trend (p < 0.05) has been found out – during the follow up period after the surgery, at first, the decrease of perceived social support from friends occurred after 3 months and, after 6 months, it increased.


Hypothesis H10 has been confirmed, hypotheses H6 and H9 have been proved partially, hypotheses H7 and H8 have not been proved (see Tab. 2). During the half-year follow up period there occurred significant decrease of anxiety in patients, an increase in comprehensibility and in the feeling of the control over the situation has been indicated on the edge of significance (comp. Kebza, 2005; Kebza & Šolcová, 2008). Our finding is in compliance with the fact that in managing a difficult situation a man at first tries to understand it (comprehensibility) (comp. Mareš, 2007, 2008, 2009; Mareš et al., 2007). A linear decrease in coping strategy of "use of emotional social support" was indicated in patients within the follow up, and a significant decrease was indicated in perceived social support from the family, apparently due to the fact the stress situation of operation passed. Total social support, support from friends and coping strategy of "focus on and venting of emotions" changed in a quadratic way – at first, there was a significant decrease after 3 months, and a slight increase after 6 months after hospitalisation. Apparently it relates to the fact, the patient can feel himself isolated during the first 3 months after the surgery. Close to the edge of statistical significance a decrease in total quality of life was indicated in patients within the follow up, that relates to original overvaluation of life satisfaction with individual areas, but at the same time it can relate to the fact what was apparent in first interviews with them– inappropriate expectations in relation to the medical intervention (they expected complete cure). It is similarly reflected by Vavrda (2005), comp. Calman (1984, as cited in Křivohlavý, 2002).

Psychosocial Factors in Patients with Thyroid Disease 297

4. During 2nd measurement, the patients with thyroid carcinoma use coping strategy of "humour" significantly less frequently (p < 0.05) and more frequent "use of instrumental social support" was indicated on the edge of significance than in patients with nodular goitre. The patients with hyperthyroidism used significantly more often (p < 0.05) "planning" strategy during 2nd measurement and more frequent coping through "suppression of competing activities", through "restraint coping" and through "focusing on and venting of emotions" was indicated on the edge of statistical significance, compared to other patients. During 2nd measurement there were not proved any statistically significant differences of averages in other coping strategies

5. We did not find statistically significant differences of averages in any of the coping strategies in patients with different types of thyreopathies within 3rd measurement. 6. Higher variance in coping strategy of "religious coping" was indicated in patients with carcinoma, compared to other patients, on the edge of significance, within 2nd

7. Results on the edge of statistical significance (p = 0.05) within 1st measurement indicate higher life satisfaction in patients with nodular goitre compared to other patients. During 2nd and 3rd measurements, any statistically significant differences in averages of satisfaction were not found out. Statistically significant difference in averages with quality of live among the patients with different types of thyreopathies was not proved

8. Statistically significant difference in averages of anxiousness among the patients with different types of thyreopathies was not proved in any of the measurements. Higher average scores of state anxiety in patients with carcinoma were indicated on the edge of significance during 2nd and 3rd measurements compared to other ills. During 2nd measurement there was indicated difference in variances on the edge of significance,

9. Statistically significant difference in depression among patients with different types of

10. Comparing the average scores of locus of control there were not found any statistically significant differences in 1st and 3rd measurements. A higher tendency to externality (external locus of control) and the feeling they cannot influence their lives were indicated in patients with carcinoma on the edge of statistical significance during 2nd

Comparison of patients with different types of thyreopathies brought interesting results (see Tab. 3.). The patients with nodular goitre were significantly more satisfied with life at the time of surgery than other patients. The most significant difference from other types of

where the highest variance was in the results of patients with carcinoma.

thyreopathies was not proved within any measurement.

measuring compared to other patients.

among the patients with different types of thyreopathies.

measurement, and especially within 3rd measurement (p < 0.05).

thyreopathies.

in any of the measurements.

showed higher variance in social support from friends in 2nd measurement (p < 0.05) and, the patients with carcinoma especially in 3rd measurement, compared to other ills. 3. We did not prove any statistically significant differences of average scores in different coping strategies, except for 2, in 1st measurement among the patients with different types of thyreopathies. The results on the edge of statistical significance indicate that the patients with carcinoma probably coped stress more often through "positive reinterpretation and growth" within 1st measurement, and, conversely, they used less coping strategy of "humour", compared to the patients with other types of


Caption: ↑ means that the given variable was dealt with a linear increase

↓ means that the given variable was dealt with a linear decrease

depicted curve illustrates course of a quadratic trend

"ed." is an abbreviation for edge of statistical significance

"close t. ed. " is an abbreviation for close to the edge of statistical significance

Table 2. Follow up of patients with thyreopathy since surgery during the period of six months

#### **7.3 Comparison of results in patients with different types of thyreopathies**


C - comprehensibility linear ↑ ed.

B -family linear ↓ /p>0.05/ C - friends quadratic /p>0.05/ perceived social support quadratic /p>0.05/

support linear <sup>↓</sup> close t. ed.

emotions quadratic /p>0.01/

trait anxiety linear ↓ /p>0.01/

Table 2. Follow up of patients with thyreopathy since surgery during the period of six months

1. There were not found out statistically significant differences of averages among the patients with different types of thyreopathies, nor in the total sense of coherence, or in manageability or meaningfulness within any of the 3 measurements. Comparing the average scores of comprehensibility there were not found any significant differences during 1st measurement, bur with 2nd and 3rd measurements, there were indicated lower average scores of comprehensibility on the edge of statistical significance in patients

2. Statistically significant differences of averages were not proved in patients with different types of thyreopathies, neither in total perceived social support, nor in the social support from significant others, in social support from family members and from friends. Concerning the variances there was not found any statistically significant difference in the sphere of social support from friends within 1st measurement, but they

QoL table - quality of life linear <sup>↓</sup> close t. ed.

STAI state anxiety linear ↓ /p>0.05/

LOC locus of control linear ↑ ed.

**7.3 Comparison of results in patients with different types of thyreopathies** 

Caption: ↑ means that the given variable was dealt with a linear increase ↓ means that the given variable was dealt with a linear decrease

"close t. ed. " is an abbreviation for close to the edge of statistical significance

with carcinoma compared to other types of thyreopathies.

depicted curve illustrates course of a quadratic trend "ed." is an abbreviation for edge of statistical significance

SOC

PSSS

COPE

BDI depression

ME - meaningfulness MA - manageability

sense of coherence

A - significant others

use of emotional social

focus on & venting of

line - life satisfaction

**Variables Follow up of patients during 6 months (trend)** 

showed higher variance in social support from friends in 2nd measurement (p < 0.05) and, the patients with carcinoma especially in 3rd measurement, compared to other ills.


Comparison of patients with different types of thyreopathies brought interesting results (see Tab. 3.). The patients with nodular goitre were significantly more satisfied with life at the time of surgery than other patients. The most significant difference from other types of

Psychosocial Factors in Patients with Thyroid Disease 299

support from friends. Support from friends is probably related to what the patients referred to during the interviews; some of them hid till the end of observation from their family and friends that thyroid cancer had been found out with them. Tschuschke (2004) also refers on similar findings, for example a tendency to apply mechanisms of suppression and increased

**7.4 Follow up results of patients with different types of thyreopathies since surgery** 

experienced more changes in life than those with hemithyroidectomy.

internality (internal locus of control) than the original level was.

loss over the situation development (comp. Kebza, 2005; Kebza & Šolcová, 2008).

1. Statistically significant difference in average scores of life satisfaction was not proved, neither in total quality of life within the observed period, nor in patients with hyperthyroidism, or in patients with carcinoma. We found out a statistically significant difference in average scores in patients with nodular goitre and a significant linear decrease of life satisfaction was proved (always for p < 0.05) and in total quality of life (always to p < 0.01). Patients with nodular goitre, who underwent total thyroidectomy, had lower level of life satisfaction in 3rd measuring on the edge of significance compared to those who underwent hemithyroidectomy. We attribute this finding to the fact that nodular goitre recently undergoing total intervention

2. Statistically significant difference in averages of locus of control was not proved during the follow up period in patients with nodular goitre. The patients with nodular goitre, who had already undergone hemithyroidectomy, had higher tendency to internality (internal locus of control) with 3rd measurement on the edge of significance compared to those who had undergone total thyroidectomy. We attribute this finding to the fact that nodular goitre recently undergoing total intervention experienced more changes in life than those with hemithyroidectomy. Differences on the edge of significance in average scores of locus of control were indicated in patients with hyperthyroidism and carcinoma within the observed period. During operation follow up, the linear trend to higher internality (internal locus of control) was indicated on the edge of significance in patients with hyperthyroidism. During operation follow up, the quadratic trend was indicated on the edge of significance in patients with carcinoma – at first, after 3 months, there was a tendency to higher externality (external locus of control) and after 6 month, conversely, to higher

The results indicate (see Tab. 4, Fig. 1-3), that it is probable, the observed changes in time in life satisfaction rate, in total quality of life and in locus of control are effected by type of thyreopathy. Concerning nodular goitres, there occur a significant reduction in the level of life satisfaction and total quality of life during the half-year follow up; in other types of thyreopathies, significant changes of these variables do not occur in any direction. This corresponds with our finding resulting from interviews that people who had some difficulties before intervention adapt better and express higher satisfaction with their status than people who did not have any problems (most often nodular goitres). In patients with hyperthyroidism there occurs increase of internality on the edge of significance during follow up, but in the patients with carcinoma, at first a significant decrease occurs after 3 months and, after 6 months, there occurs increase to higher level that it was at the time of hospitalisation. Last-mentioned disease can be considered as the most serious from the viewpoint of control

level of anxiety in patients with carcinoma.

**during the period of six months in selected variables** 


Caption: ↑ means that patients with this diagnose scored higher in the given variable that other patients ↓ means that patients with this diagnose scored lower in the given variable that other patients " ed." is an abbreviation for edge of statistical significance

Table 3. Comparison of results in patients with different types of thyreopathies

thyreopathies is in patients with thyroid carcinoma. Only a small amount of these was in our researched file, but we will try to indicate statistically significant and marginally significant differences and trends. The biggest differences appear after 3 months since surgery when patients with carcinoma score lower in coping strategies as "humour", "suppression of competing activities" and "focus on and venting emotions", as well as in locus of control. In the period after 3 and 6 months since surgery the patients with carcinoma are more anxious compared to the others and score lower in comprehensibility. Bigger interindividual differences can be captured in carcinomas compared to the others after 3 and 6 months since surgery in coping strategy in "religious coping" and in social

religious coping ↑s2 ed. ↑s2 /p>0.05/

**Variables Nodular goitres at the time of surgery** 

planning ↑ /p>0.05/

activities ↑ ed. restraint coping ↑ ed.

emotions ↑ ed. Caption: ↑ means that patients with this diagnose scored higher in the given variable that other patients

thyreopathies is in patients with thyroid carcinoma. Only a small amount of these was in our researched file, but we will try to indicate statistically significant and marginally significant differences and trends. The biggest differences appear after 3 months since surgery when patients with carcinoma score lower in coping strategies as "humour", "suppression of competing activities" and "focus on and venting emotions", as well as in locus of control. In the period after 3 and 6 months since surgery the patients with carcinoma are more anxious compared to the others and score lower in comprehensibility. Bigger interindividual differences can be captured in carcinomas compared to the others after 3 and 6 months since surgery in coping strategy in "religious coping" and in social

↓ means that patients with this diagnose scored lower in the given variable that other patients

Table 3. Comparison of results in patients with different types of thyreopathies

**Variables Hyperthyroidism after 3 months since surgery** 

SOC C - comprehensibility ↓ ed. ↓ ed. PSSS C - friends ↑s2 /p>0.05/ ↑s2 /p>0.01/

activities ↓ ed.

support ↑ ed.

emotions ↓ ed.

humor ↓ ed. ↓ /p>0.05/

LOC locus of control ↓ ed.

STAI state anxiety ↑ ed. ↑ ed.

QoL line - life satisfaction ↑ ed.

**Carcinomas Sugery 3 months 6 months** 

**Variables** 

suppression of competing

use of instrumental social

positive reinterpretation &

suppression of competing

" ed." is an abbreviation for edge of statistical significance

focus on & venting of

focus on & venting of

growth ↑ ed.

COPE

COPE

support from friends. Support from friends is probably related to what the patients referred to during the interviews; some of them hid till the end of observation from their family and friends that thyroid cancer had been found out with them. Tschuschke (2004) also refers on similar findings, for example a tendency to apply mechanisms of suppression and increased level of anxiety in patients with carcinoma.

#### **7.4 Follow up results of patients with different types of thyreopathies since surgery during the period of six months in selected variables**


The results indicate (see Tab. 4, Fig. 1-3), that it is probable, the observed changes in time in life satisfaction rate, in total quality of life and in locus of control are effected by type of thyreopathy. Concerning nodular goitres, there occur a significant reduction in the level of life satisfaction and total quality of life during the half-year follow up; in other types of thyreopathies, significant changes of these variables do not occur in any direction. This corresponds with our finding resulting from interviews that people who had some difficulties before intervention adapt better and express higher satisfaction with their status than people who did not have any problems (most often nodular goitres). In patients with hyperthyroidism there occurs increase of internality on the edge of significance during follow up, but in the patients with carcinoma, at first a significant decrease occurs after 3 months and, after 6 months, there occurs increase to higher level that it was at the time of hospitalisation. Last-mentioned disease can be considered as the most serious from the viewpoint of control loss over the situation development (comp. Kebza, 2005; Kebza & Šolcová, 2008).

Psychosocial Factors in Patients with Thyroid Disease 301

Fig. 2. Monitoring of average scores of life satisfaction in SEIQoL (line) during the six-month

Caption: ‗‗‗‗‗‗‗‗‗‗ (double line) statistically significant trend in time \_ \_ \_ \_ \_ \_ \_ (dashed line) statistically insignificant trend in time

Caption: \_\_\_\_\_\_\_\_\_\_ (single line) trend in time on the edge of statistical significance

Fig. 3. Monitoring of average scores of LOC (locus of control) during the six-month period

\_ \_ \_ \_ \_ \_ \_ (dashed line) statistically insignificant trend in time

in patients with different types of thyreopathies

period in patients with different types of thyreopathies


Caption: ↑ means that the given variable was dealt with a linear increase

↓ means that the given variable was dealt with a linear decrease

depicted curve illustrates course of a quadratic trend

" ed." is an abbreviation for edge of statistical significance

Table 4. Follow up results of patients with different types of thyreopathies since sugery during the period of six months in selected variables

\_ \_ \_ \_ \_ \_ \_ (dashed line) statistically insignificant trend in time

Fig. 1. Monitoring of average scores of total quality of life in SEIQoL (table) during the sixmonth period in patients with different types of thyreopathies

table - quality of life linear ↓ /p>0.01/

line - life satisfaction linear ↓ /p>0.05/

LOC locus of control quadratic ed.

LOC locus of control linear ↑ ed.

Table 4. Follow up results of patients with different types of thyreopathies since sugery

Caption: ↑ means that the given variable was dealt with a linear increase ↓ means that the given variable was dealt with a linear decrease

Caption: ‗‗‗‗‗‗‗‗‗‗ (double line) statistically significant trend in time \_ \_ \_ \_ \_ \_ \_ (dashed line) statistically insignificant trend in time

month period in patients with different types of thyreopathies

Fig. 1. Monitoring of average scores of total quality of life in SEIQoL (table) during the six-

 depicted curve illustrates course of a quadratic trend " ed." is an abbreviation for edge of statistical significance

during the period of six months in selected variables

QoL

**Variables Nodular goitre follow up during 6 months (trend)** 

**Variables Carcinomas follow up during 6 months (trend)** 

**Variables Hyperthyroidism follow up during 6 months** 

**(trend)** 

Caption: ‗‗‗‗‗‗‗‗‗‗ (double line) statistically significant trend in time \_ \_ \_ \_ \_ \_ \_ (dashed line) statistically insignificant trend in time

Fig. 2. Monitoring of average scores of life satisfaction in SEIQoL (line) during the six-month period in patients with different types of thyreopathies

Caption: \_\_\_\_\_\_\_\_\_\_ (single line) trend in time on the edge of statistical significance \_ \_ \_ \_ \_ \_ \_ (dashed line) statistically insignificant trend in time

Fig. 3. Monitoring of average scores of LOC (locus of control) during the six-month period in patients with different types of thyreopathies

Psychosocial Factors in Patients with Thyroid Disease 303

can lead to awareness of the importance of faith (comp. Hodačová, 2007). In our findings there were changes in patients´ reconceptualisation (change of key topics), and recalibration (change of importance) (e.g. Schwartz & Sprangers, 1999, as cited in Westerman et al., 2006; comp. Mareš, 2005). During interviews we noted that one of our patients with carcinoma, 6 months after surgery, had so called posttraumatic growth. Higher levels of satisfaction of patients are explained by their overvaluation (idealization)

**7.5.1 Content analysis of categories (life goals or cues) reported by respondents in** 

It included mentions of family members – mostly mentioned children, mainly by patients, desire for having children, then a partner, siblings, and only patients recorded in their answers parents. Patients seem to be more aware of what would happen to their children or parents dependent on them if something happened to them. Healthy and ill people associated this category with concepts such as family relationships and satisfaction, happiness in family. They perceived the family as a place that should provide support and help with governance of love, peace, cohesiveness, harmony and understanding. They

It contained mainly answers specifying the person or persons who should be healthy – the most frequent goal was to be healthy and health of close people, a lot of responses concerned the health of loved ones (most frequently with patients), only little less his/her own health. Healthy people rather than patients stated a healthy lifestyle. Sometimes

Answers related to feelings of satisfaction, peace and happiness. Patients are featured

It included themes of work, employment, profession – his/her own work was most mentioned, and then the same number of responses focused on career and caring for family members to have a job and succeed in it. A number of formulations expressed a goal to have

Patients and healthy persons expected peace, satisfaction and financial security at work they also show the importance of interpersonal relationships in the workplace, the work to be

It contained topics related to awareness of society, nature - respondents mostly wished for world peace, the same number of responses went to topics about environment and events in

formulation in terms of: health is the most important value, appeared.

of a life situation (see also chap. 7.1 and 7.9).

recorded also a topic of raising children.

responses expressing a desire for life securities.

a job. The patients had a topic of having secured job.

society, politics. Patients recorded answers about social security.

interesting, allowing self-realization.

**Category living conditions** 

**the SEIQoL method Category family** 

**Category health** 

**Category work** 

**Category mental well-being** 

#### **7.5 Results for quality life assessment measured by SEIQoL method acquired from individual areas (life goals or cues)**


The answers of respondents in the quality of life were categorized into 11 (or 12) areas that occurred both in patients and controls. Patients put more emphasis on life securities and care for close people dependent on them. In connection with their own illness they were apparently aware of what would happen to their children or parents dependent on them if something happened to them. Respondents of all groups mentioned as the most frequent and the most important goals family and health. Findings of Buchtová (2004) and Rybářová et al. (2006) correspond. Spiritual dimension category was little recorded but the people that recorded it saw its importance right after family and health (comp. Rybářová et al., 2006). Patients frequently reported categories of good old age and mental well-being because these areas can be threaten by the disease. Also, at the time of surgery, they were least satisfied with mental well-being. Their dissatisfaction with the work within 3 and 6 months after surgery is probably due to return to work, which can be difficult. The spiritual dimension is gaining importance within 3 months after surgery which is likely due to demands for coping with surgery. Experiencing difficult situations can lead to awareness of the importance of faith (comp. Hodačová, 2007). In our findings there were changes in patients´ reconceptualisation (change of key topics), and recalibration (change of importance) (e.g. Schwartz & Sprangers, 1999, as cited in Westerman et al., 2006; comp. Mareš, 2005). During interviews we noted that one of our patients with carcinoma, 6 months after surgery, had so called posttraumatic growth. Higher levels of satisfaction of patients are explained by their overvaluation (idealization) of a life situation (see also chap. 7.1 and 7.9).

#### **7.5.1 Content analysis of categories (life goals or cues) reported by respondents in the SEIQoL method**

#### **Category family**

302 Thyroid and Parathyroid Diseases – New Insights into Some Old and Some New Issues

1. Respondents' answers regarding quality of life were divided into 11 categories (excluding a collective category: other): family, health, work, interpersonal relationships, leisure, material security, mental well-being, spiritual dimension, education, living conditions and good old age. All above mentioned categories appeared in the group of patients and in the control group. Patients with thyroid gland, when compared to healthy people, mentioned life and social security within more categories (work, mental well-being, living conditions). In category family, they reported close people, mainly those that are somehow depended on them (children, old parents). Patients, more than the controls, had more answers connected with health of close people. During follow up, patients didn´t change their understanding of content

2. Respondents of all groups most often mentioned cues: 1. family, 2. health and 3. work. Patients frequently reported life goals as good old age, or mental well-being, while the control group reported more leisure and education. During the follow up of patients with thyreopathy changes occurred in the distribution of frequencies (significant and

3. The most important cues for all respondent groups were 1. family, 2. health, 3. spiritual dimension, rarely good old age, which otherwise closely followed the spiritual dimension. It seems that during follow up of patients there was, on the edge of significance, a sign of decline for family and increase for health. Apparently there is also a change in the spiritual dimension category; its importance (with probands who

4. We have a reason to believe that the patients rather overevaluated (idealized) a situation while evaluating satisfaction for individual categories, sometimes slightly also after 3 months; therefore we cannot objectively assess the shift over time or differences between patients and control group. All observed groups assessed life conditions and material security as the least satisfactory, patients at the time of surgery recorded little satisfaction with mental well-being and after 3 to 6 month showed little satisfaction

The answers of respondents in the quality of life were categorized into 11 (or 12) areas that occurred both in patients and controls. Patients put more emphasis on life securities and care for close people dependent on them. In connection with their own illness they were apparently aware of what would happen to their children or parents dependent on them if something happened to them. Respondents of all groups mentioned as the most frequent and the most important goals family and health. Findings of Buchtová (2004) and Rybářová et al. (2006) correspond. Spiritual dimension category was little recorded but the people that recorded it saw its importance right after family and health (comp. Rybářová et al., 2006). Patients frequently reported categories of good old age and mental well-being because these areas can be threaten by the disease. Also, at the time of surgery, they were least satisfied with mental well-being. Their dissatisfaction with the work within 3 and 6 months after surgery is probably due to return to work, which can be difficult. The spiritual dimension is gaining importance within 3 months after surgery which is likely due to demands for coping with surgery. Experiencing difficult situations

the significance edge) for more than half the categories.

recorded it) is highly evaluated within 3 months after surgery.

**7.5 Results for quality life assessment measured by SEIQoL method acquired from** 

**individual areas (life goals or cues)** 

of individual categories.

with category work.

It included mentions of family members – mostly mentioned children, mainly by patients, desire for having children, then a partner, siblings, and only patients recorded in their answers parents. Patients seem to be more aware of what would happen to their children or parents dependent on them if something happened to them. Healthy and ill people associated this category with concepts such as family relationships and satisfaction, happiness in family. They perceived the family as a place that should provide support and help with governance of love, peace, cohesiveness, harmony and understanding. They recorded also a topic of raising children.

#### **Category health**

It contained mainly answers specifying the person or persons who should be healthy – the most frequent goal was to be healthy and health of close people, a lot of responses concerned the health of loved ones (most frequently with patients), only little less his/her own health. Healthy people rather than patients stated a healthy lifestyle. Sometimes formulation in terms of: health is the most important value, appeared.

#### **Category mental well-being**

Answers related to feelings of satisfaction, peace and happiness. Patients are featured responses expressing a desire for life securities.

#### **Category work**

It included themes of work, employment, profession – his/her own work was most mentioned, and then the same number of responses focused on career and caring for family members to have a job and succeed in it. A number of formulations expressed a goal to have a job. The patients had a topic of having secured job.

Patients and healthy persons expected peace, satisfaction and financial security at work they also show the importance of interpersonal relationships in the workplace, the work to be interesting, allowing self-realization.

#### **Category living conditions**

It contained topics related to awareness of society, nature - respondents mostly wished for world peace, the same number of responses went to topics about environment and events in society, politics. Patients recorded answers about social security.

Psychosocial Factors in Patients with Thyroid Disease 305

1. We identified four types of general coping strategies based on preference or rejection of some partial methods of coping, as measured using the COPE method. They were strategies that we called strategy of active, constructive coping, a passive strategy, a

For completeness, we mapped the psychosocial factors of patients with thyroid gland, depending on their economic activity. Patients with thyroid gland didn´t show any statistically significant differences in any of the examined characteristics between economically active people and pensioners. In this case an intervening variable is obviously

Whereas in old-age pensioners not suffering from thyroid disease we found significantly higher levels of anxiousness (p < 0,01) compared with healthy economically active people. Compared to old-age pensioners not suffering from thyroid disease, healthy economically active people scored significantly in sense of coherence (p < 0,05) and had more internal locus of control (p = 0,055). Higher levels of anxiousness in old-age pensioners is probably related to their age and situation, as well as feeling that their life is determined by external circumstances, which they cannot affect. Křivohlavý (2009) indicates higher anxiety

1. Many patients did not felt subjectively well, long before the correct diagnosis was established. Thyroid disease in the early days was often mistaken for mental illness – by both healthcare professionals and patients who then feared to search the doctors. 2. Patients in the time before surgery reported diverse and varying physical and mental

3. The patients considered a psychological stress as the most common reason for a disease breakout (roughly half of patients). All expected a full recovery after the surgery, which

4. At the time of surgery, patients felt social support from their families, but not at work. They rather feared situations at work, and thought they might lose their jobs. 5. The patients gave the impression of overestimating (idealizing) the situation when evaluating satisfaction for each category, especially at the time of surgery, and a little

6. Patients would need more information about the recovery, especially in the first 3 months, (primarily about the state of scars) and further prognosis for thyreopathy. 7. Satisfaction or dissatisfaction, which they expressed with their health status, related to whether and to what extent they experienced difficulties resulting from illness prior to surgery, and whether and with what effect they have been previously treated. The patients, who experienced difficulties resulting from their disease and hadn´t been

cured, were more satisfied with their health status after the surgery.

symptoms – especially tiredness, anxiety, irritability, sadness.

**7.7 Factor analysis of a questionnaire for coping strategies COPE** 

emotion-focused strategy and strategy for obtaining a distance. In many respects, our results correspond with Vašina's (2002) findings.

important– most likely it is the thyroid gland disease.

associated with a lower level of sense of coherence.

**7.9 Results from semi-structured interviews** 

is not possible.

after 3 months.

**7.8 Comparison of results of people depending on their economic activity** 

#### **Category interpersonal relationships**

It contained mainly friendly relations and relationships with people in general – in connection with this, the respondents mentioned love, understanding and harmony between people. Some of them were also aware of their own share in relationships and reported character behaviour to others (willingness to help, be polite, etc.). Several responses were related to relations with neighbours.

#### **Category education**

The answers were mainly related to respondents' own education and training, but also to education of their children.

#### **Category good old age**

It included the pursuit of contented old age, some people mentioned self-sufficiency. This category was recorded by both groups of respondents in their elderly age.

#### **Category leisure**

It contained a variety of leisure activities, rest was mentioned only exceptionally. As for activities, respondents most frequently reported sport, followed by gardening, culture, travel, household chores, but also reading, nature (including walks in the countryside) and others.

#### **Category material security**

In both groups it related to material and financial security, provisions. About 2/3 of answers were formed by subcategory finance, 1/3 was associated with housing.

#### **Category spiritual dimension**

It included topics related to faith or spiritual life. There were not only traditional religious answers (God, prayer, etc.), but also answers expressing some sort of overlap (spiritual growth, to understand the meaning of life, respect for life, look for better side of matters, etc.)

#### **7.6 Determination of proximity of relations (correlation) between the monitored variables particularly in regards to results of SEIQoL method**


Our findings regarding the relationship of other variables to measure satisfaction and overall quality of life correspond with the findings reported in several studies (e.g. Matuz, 2006) as well as in literature about health psychology (e.g. Kebza, 2005; Křivohlavý, 2009).

It contained mainly friendly relations and relationships with people in general – in connection with this, the respondents mentioned love, understanding and harmony between people. Some of them were also aware of their own share in relationships and reported character behaviour to others (willingness to help, be polite, etc.). Several

The answers were mainly related to respondents' own education and training, but also to

It included the pursuit of contented old age, some people mentioned self-sufficiency. This

It contained a variety of leisure activities, rest was mentioned only exceptionally. As for activities, respondents most frequently reported sport, followed by gardening, culture, travel, household chores, but also reading, nature (including walks in the countryside)

In both groups it related to material and financial security, provisions. About 2/3 of answers

It included topics related to faith or spiritual life. There were not only traditional religious answers (God, prayer, etc.), but also answers expressing some sort of overlap (spiritual growth, to understand the meaning of life, respect for life, look for better side of matters, etc.)

1. Patients more satisfied with life, healthy people more satisfied with life and healthy people reporting about higher quality of life were more resilient (rather with internal locus of control, with a higher sense of coherence), perceived higher social support and were less anxious and depressed. Results of all questionnaires and scales in patients were more dependent of level of life satisfaction than total quality of life consisting of

2. The results of all methods used for patients do not depend on the length of diagnosis, nor the age or marital status as in the control group, they usually only moderately correlate with recent in/experienced life changes. Educated patients and educated

Our findings regarding the relationship of other variables to measure satisfaction and overall quality of life correspond with the findings reported in several studies (e.g. Matuz, 2006) as well as in literature about health psychology (e.g. Kebza, 2005; Křivohlavý, 2009).

healthy people have a higher sense of coherence and are less anxious.

**7.6 Determination of proximity of relations (correlation) between the monitored** 

category was recorded by both groups of respondents in their elderly age.

were formed by subcategory finance, 1/3 was associated with housing.

**variables particularly in regards to results of SEIQoL method** 

**Category interpersonal relationships** 

**Category education** 

education of their children.

**Category material security** 

**Category spiritual dimension** 

different areas.

**Category good old age** 

**Category leisure** 

and others.

responses were related to relations with neighbours.

#### **7.7 Factor analysis of a questionnaire for coping strategies COPE**

1. We identified four types of general coping strategies based on preference or rejection of some partial methods of coping, as measured using the COPE method. They were strategies that we called strategy of active, constructive coping, a passive strategy, a emotion-focused strategy and strategy for obtaining a distance.

In many respects, our results correspond with Vašina's (2002) findings.

#### **7.8 Comparison of results of people depending on their economic activity**

For completeness, we mapped the psychosocial factors of patients with thyroid gland, depending on their economic activity. Patients with thyroid gland didn´t show any statistically significant differences in any of the examined characteristics between economically active people and pensioners. In this case an intervening variable is obviously important– most likely it is the thyroid gland disease.

Whereas in old-age pensioners not suffering from thyroid disease we found significantly higher levels of anxiousness (p < 0,01) compared with healthy economically active people. Compared to old-age pensioners not suffering from thyroid disease, healthy economically active people scored significantly in sense of coherence (p < 0,05) and had more internal locus of control (p = 0,055). Higher levels of anxiousness in old-age pensioners is probably related to their age and situation, as well as feeling that their life is determined by external circumstances, which they cannot affect. Křivohlavý (2009) indicates higher anxiety associated with a lower level of sense of coherence.

#### **7.9 Results from semi-structured interviews**


Psychosocial Factors in Patients with Thyroid Disease 307

Dissatisfaction or worse quality of life was recorded by patients who had an impression of being without difficulties before the surgery, and suddenly they experience some and must use hormone replacement (usually nodular goitre, rarely carcinomas). The biggest relief is experienced by patients, who had some symptoms and were not treated by other means than surgical, as manifestations of their disease didn´t last long. Patients with thyroid

Patients in our country do not have comparable information in terms of quantity and quality when compared to patients in traditionally democratic countries, and they do not have

We are aware of the limitations of our work. In particular, it would be necessary to increase the number of surveyed people. It would be necessary to include a larger number of men into the set of surveyed people (but there is low incidence of this disease with men). Members of the control group in our survey honestly declared that they are not, and were not, treated or monitored for thyroid disease. When choosing members of the control group, it would be most suitable to have each member screened for thyreopathy, which would be, on the other hand, costly. When comparing patients with healthy population it would be better to set a paired control group and adjust it according to status and demographic features. In regards to the specificity of the sample, results cannot be generalized or only with some reservations. On the other hand, it is a six-month follow up of almost the entire population of patients who underwent thyroid surgery in one of the hospitals in the Czech Republic, which is very valuable for better exploration of this issue. It would be useful to verify our results in another, similar department or collect data from more departments focusing on thyroid surgeries, in the same time. In future, it would be good to keep only the most informative methods in a battery of tests, in order not to bother the patients unnecessarily. It should be strictly monitored whether patients fill out a questionnaire at the time of hospitalization under the same conditions. As for the longitudinal follow up, it would be necessary to make more than 3 measurements in time to be able to better predict events. It would also be valuable if follow up could last longer than 6 months. Research of patients treated by means other than surgical could be very useful. We believe that it would be very desirable to continue in the research of these issues, because the current findings

give us more questions and directions of interest than "finished " and clear answers.

preoperative preparation of a patient and work with his expectations while doing it.

*Thyroid*, Vol.15 (Suppl.1), pp. S27-S28, ISSN 1050-7256

We are not aware of any similar research in the Czech Republic on this topic. The performed research is in such a stage and complexity unique even for the English literature. We believe that this issue deserves a greater attention of researchers and psychotherapists because many of the untreated and treated patients may suffer from a variety of symptoms, experience worse health status and quality of life. It would be useful to concentrate on

Abraham-Nordling et al. (2005). Graves' disease: A long term quality of life follow-up of

Air et al. (2006). Outdated and missing: A review of the quality of thyroid cancer

information on the internet. *Thyroid*, Vol.16, p. 865, ISSN 1050-7256

patients randomized to treatment with antithyroid drugs, radioiodine or surgery.

carcinoma differ from other types of thyreopathies the most.

background of patient organizations.

**9. References** 


Overall, we observed three types of attitudes to an interview. The first type of patients was willing to share their illness and their life experiences. The second type of patients was particularly willing to share their experience with thyroid disease, physical condition, the diagnosis and treatment, in other areas they were less willing to share (seems consistent with the classical biomedical model). The third type consisted of patients who were generally more reserved, and answered any type of questions briefly.

#### **8. Conclusion**

Comparisons of people with thyroid gland disease and healthy people, and longitudinal follow up of patients were carried out. In some psychosocial aspects the patients with thyreopathy differ from the general population, which does not suffer from this disease, independently of the thyreopathy type. Statistically, the patients were significantly more anxious and perceived higher social support from family when compared with the control group. The control group scored significantly higher in locus of control and on the edge of significance they felt more satisfied with life than the patients. During the six-month follow up after the surgery, some indicators of quality of life were improved. We found a statistically significant decrease in anxiety and social support. Comprehensibility and the feeling of having my life firmly in my hands increased on the edge of significance. One patient with cancer we even saw so called posttraumatic growth. Results of total quality of life calculated from individual categories cannot be evaluated fully psychometrically, since the situation was most likely overvalued (idealized) by patients mainly during hospitalization and a bit after 3 month after the surgery. Results recorded in graphics on segment line of life satisfaction were more plausible. Life satisfaction and quality of life significantly positively correlated with sense of coherence, with the locus of control and perceived social support, and significantly negatively correlated with anxiety and depression.

Division of patients by type of thyreopathy to nodular goitre (including thyroiditis), hyperthyroidism, and cancer was critical for the research. Patients with eufunctional nodular goitre in some respects also differ from healthy population. These have been studied very rarely; they are even assigned to the control group as healthy people during research on other types of thyreopathies. Patients who benefited from surgery the most were those who had some difficulties before the surgery (usually with hyperthyroidism) they better adapted to the surgery and expressed satisfaction with their condition.

8. If patients had no difficulties after the surgery, they believed that they will feel as good

9. Patients with cancer experienced disease differently than others. There were significant interindividual differences in coping with illness. 3 months after surgery, when they often responded with denial, were more dissatisfied with their condition than other patients. It was difficult for them to tell their close ones diagnosis. Compared to other patients, the topic of disease was topical even after 6 month after the surgery. In this

10. During follow up, patients reported more positive than negative consequences of surgery. As the most positive they considered improvement of health, further reevaluation of values, which could indicate the direction to posttraumatic growth (comp. Costa & Pakenham, 2011). As the most negative consequences of the surgery they

Overall, we observed three types of attitudes to an interview. The first type of patients was willing to share their illness and their life experiences. The second type of patients was particularly willing to share their experience with thyroid disease, physical condition, the diagnosis and treatment, in other areas they were less willing to share (seems consistent with the classical biomedical model). The third type consisted of patients who were

Comparisons of people with thyroid gland disease and healthy people, and longitudinal follow up of patients were carried out. In some psychosocial aspects the patients with thyreopathy differ from the general population, which does not suffer from this disease, independently of the thyreopathy type. Statistically, the patients were significantly more anxious and perceived higher social support from family when compared with the control group. The control group scored significantly higher in locus of control and on the edge of significance they felt more satisfied with life than the patients. During the six-month follow up after the surgery, some indicators of quality of life were improved. We found a statistically significant decrease in anxiety and social support. Comprehensibility and the feeling of having my life firmly in my hands increased on the edge of significance. One patient with cancer we even saw so called posttraumatic growth. Results of total quality of life calculated from individual categories cannot be evaluated fully psychometrically, since the situation was most likely overvalued (idealized) by patients mainly during hospitalization and a bit after 3 month after the surgery. Results recorded in graphics on segment line of life satisfaction were more plausible. Life satisfaction and quality of life significantly positively correlated with sense of coherence, with the locus of control and perceived social support, and significantly negatively

Division of patients by type of thyreopathy to nodular goitre (including thyroiditis), hyperthyroidism, and cancer was critical for the research. Patients with eufunctional nodular goitre in some respects also differ from healthy population. These have been studied very rarely; they are even assigned to the control group as healthy people during research on other types of thyreopathies. Patients who benefited from surgery the most were those who had some difficulties before the surgery (usually with hyperthyroidism) they better adapted to the surgery and expressed satisfaction with their condition.

in future. If they had difficulties, they hoped to feel better.

generally more reserved, and answered any type of questions briefly.

reported a scar and use of medication.

correlated with anxiety and depression.

**8. Conclusion** 

time, one patient with cancer showed so called posttraumatic growth.

Dissatisfaction or worse quality of life was recorded by patients who had an impression of being without difficulties before the surgery, and suddenly they experience some and must use hormone replacement (usually nodular goitre, rarely carcinomas). The biggest relief is experienced by patients, who had some symptoms and were not treated by other means than surgical, as manifestations of their disease didn´t last long. Patients with thyroid carcinoma differ from other types of thyreopathies the most.

Patients in our country do not have comparable information in terms of quantity and quality when compared to patients in traditionally democratic countries, and they do not have background of patient organizations.

We are aware of the limitations of our work. In particular, it would be necessary to increase the number of surveyed people. It would be necessary to include a larger number of men into the set of surveyed people (but there is low incidence of this disease with men). Members of the control group in our survey honestly declared that they are not, and were not, treated or monitored for thyroid disease. When choosing members of the control group, it would be most suitable to have each member screened for thyreopathy, which would be, on the other hand, costly. When comparing patients with healthy population it would be better to set a paired control group and adjust it according to status and demographic features. In regards to the specificity of the sample, results cannot be generalized or only with some reservations. On the other hand, it is a six-month follow up of almost the entire population of patients who underwent thyroid surgery in one of the hospitals in the Czech Republic, which is very valuable for better exploration of this issue. It would be useful to verify our results in another, similar department or collect data from more departments focusing on thyroid surgeries, in the same time. In future, it would be good to keep only the most informative methods in a battery of tests, in order not to bother the patients unnecessarily. It should be strictly monitored whether patients fill out a questionnaire at the time of hospitalization under the same conditions. As for the longitudinal follow up, it would be necessary to make more than 3 measurements in time to be able to better predict events. It would also be valuable if follow up could last longer than 6 months. Research of patients treated by means other than surgical could be very useful. We believe that it would be very desirable to continue in the research of these issues, because the current findings give us more questions and directions of interest than "finished " and clear answers.

We are not aware of any similar research in the Czech Republic on this topic. The performed research is in such a stage and complexity unique even for the English literature. We believe that this issue deserves a greater attention of researchers and psychotherapists because many of the untreated and treated patients may suffer from a variety of symptoms, experience worse health status and quality of life. It would be useful to concentrate on preoperative preparation of a patient and work with his expectations while doing it.

#### **9. References**


Psychosocial Factors in Patients with Thyroid Disease 309

Bunevičius, R., Kažanavičius, G., Žalinkevičius, R. & Prange, A. J. Jr (1999). Effects of

Bunevičius, R. & Prange, A. J. Jr (2000). Mental improvement after replacement therapy with

Caparevic, Z. V., Diligenski, V. M., Stojanovic, D. M. & Bojkovic, G. D. (2005). Psychological

Carver, Ch. S., Scheier, M. F. & Weintraub, J. K. (1989). Assesing coping strategies: A

Clyde, P. W et al. (2003). Combined levothyroxine plus liothyronine compared with

Costa, R. V. & Pakenham, K. I. (2011). Associations between benefit finding and adjustment

Dietlein, M. & Schicha, H. (2003). Lifetime follow-up care is necessary for all patients with

Dow, K. H., Ferrell, B. R. & Anello, C. (1997). Quality- of-life changes in patients with

Duntas, L. H. & Biondi, B. (2007). Short-term hypothyroidism after levothyroxine-

Egle, U. T. et al. (1999). The relevance of physical and psychosocial factors for the quality of

Estcourt, S., Vaidya, B., Quinn, A. & Shepherd, M. (2008). The impact of thyroid eye disease

Eustatia-Rutten, C. F. A. et al. (2006). Quality of life in longterm exogenous subclinical

controlled trial. *Clinical Endocrinology*, Vol.64, pp. 284-291, ISSN 0300-0664

*Advances in psychology research*, Vol.37, pp. 47-61), ISSN 1532-723X

4793

133, ISSN 1355-008X

267-283, ISSN 0022-3514

ISSN 0098-7484

ISSN 0804-4643

613-619, ISSN 1050-7256

pp.635-639, ISSN 0300-0664

1057-9249

4643

0804-4643

thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. *New England Journal of Medicine*, Vol.340, pp. 424-429, ISSN 0028-

thyroxine plus triiodothyronine: Relationship to cause of hypothyroidism. *International Journal of Neuropsychopharmacology*, Vol.3, pp. 167-174, ISSN 1461-1457 Bunevičius, R. et al. (2002). Thyroxine vs thyroxine plus triiodothyronine in treatment of

hypothyroidism after thyroidectomy for Graves' disease. *Endocrine*, Vol.18, pp. 129-

evaluation of patients with a nodular goiter before and after surgical treatment.

theoretically based approach. *Journal of Personality and Social Psychology*, Vol.56, pp.

levothyroxine alone in primary hypothyroidism. *JAMA*, Vol.290, pp. 2952-2958,

outcomes in thyroid cancer. *Psychooncology*, Mar 17. doi: 10.1002/pon.1960, ISSN

treated thyroid nodules. *European Journal of Endocrinology*, Vol.148, pp. 377-379,

thyroid cancer after withdrawal of thyroid hormone therapy. *Thyroid*, Vol.7, pp.

withdrawal in patients with differentiated thyroid cancer: clinical and quality of life consequences. *European Journal of Endocrinology*, Vol.156, pp. 13-19, ISSN 0804-

life in patients with thyroid-associated orbitopathy (TAO). *Experimental and Clinical Endocrinology and Diabetes*, Vol.107 (Suppl.5), pp. S168 - S171, ISSN 0947-7349 Elberling, T. V. et al. (2004). Impaired health-related quality of life in Graves' disease. A

prospective study. *European Journal of Endocrinology*, Vol.151, pp. 549-555, ISSN

upon patients' wellbeing: a qualitative analysis.*Clinical Endocrinology*, Vol.68, No.4,

hyperthyroidism and the effects of restoration of euthyroidism, a randomized


Air et al. (2007). Thyroid net outdated and incomplete: A review of thyroid cancer on the

Almeida, J., Vartanian, J. G. & Kowalski L. P. (2009). Clinical predictors of quality of life in

Appelhof, B. C. et al. (2005). Combined therapy with levothyroxine and liothyronine in two

Appolinario, J. C., Fontenelle, L. F., Rodrigues, A. L. C., Segenreich, D. & Fontes, R. (2005).

Baldini, M. et al. (2009). Neuropsychological functions and metabolic aspects in subclinical

Baštecká, B. et al. (2003). *Klinická psychologie v praxi*. Portál, ISBN 80-7178-735-3, Prague,

Baštecký, J., Šavlík, J. & Šimek, J. (1993). *Psychosomatická medicína*. Grada Avicenum, ISBN

Baumgartner, F. (2001). Zvládanie stresu - coping. In: *Aplikovaná sociální psychologie II.*, J.

Bianchi, G. P. et al. (2004). Health-related quality of life in patients with thyroid disorders.

Biondi, B. et al. (2000). Endogenous subclinical hyperthyroidism affects quality of life and

*Clinical Endocrinology and Metabolism*, Vol.85, pp. 4701-4705, ISSN 0021-972X Blumenthal, J. A. et al. (1987). Social support, type A behavior, and coronary artery disease.

Bono, G., Fancellu, R., Blandini, F., Santoro, G. & Mauri, M. (2004). Cognitive and affective

Botella-Carretero, J. I., Galán, J. M., Caballero, C., Sancho, J. & Escobar-Morreale, H. F.

Břicháček, V. (2006). Dlouhodobé výzkumné projekty v psychologii zdraví. In: *Psychologie* 

Buchtová, B. (2004). Kvalita života dlouhodobě nezaměstnaných. *Československá psychologie*,

patients with initial differentiated thyroid cancers. *Archives of Otolaryngology-Head* 

ratios, compared with levothyroxine monotherapy in primary hypothyroidism. *Journal of Clinical Endocrinology and Metabolism*, Vol.90, pp. 2666-2674, ISSN 0021-972X

Symptoms of depression and anxiety among patients with subclinical hypothyroidism. *Jornal Brasileiro de Psiquiatria*, Vol.54, pp. 94-97, ISSN 0047-2085 Baldini, M. et al. (1997). Psychopathological and cognitive features in subclinical

hypothyroidism. *Progress in Neuro-Psychopharmacology & Biological Psychiatry*,

hypothyroidism: The effects of L-thyroxine. *Progress in Neuro-Psychopharmacology &* 

Výrost, I. Slaměník, (Eds.), 113-128. Grada Publishing, ISBN 80-247-0042-5, Prague,

cardiac morphology and function in young and middle-aged patients. *Journal of* 

status in mild hypothyroidism and interactions with L-thyroxine treatment. *Acta* 

(2003). Quality of life and psychometric functionality in patients with differentiated thyroid carcinoma. *Endocrine-Related Cancer*, Vol.10, pp. 601–610, ISSN 1351-0088 Brown, B. T., Bonello, R., Pollard, H. & Graham, P. (2010). The influence of a

biopsychosocial-based treatment approach to primary overt hypothyroidism: a

*zdraví a kvalita života*, B. Koukola, J. Mareš, (Eds.), 116-117, MSD, ISBN 80-86633-66-

world wide web. *Thyroid*, Vol.17, pp. 259-265, ISSN 1050-7256

*and Neck Surgery*, Vol.35, pp. 342-346, ISSN 0886-4470

*Biological Psychiatry*, Vol.33, pp. 854-859, ISSN 0278-5846

*Quality of Life Research*, Vol.13, pp. 45-54, ISSN 0962-9343

*Psychosomatic Medicine*, Vol.49, pp. 331-340, ISSN 0033-3174

*Neurologica Scandinavica*, Vol.110, pp. 59-66, ISSN 0001-6314

protocol for a pilot study. *Trials*, Vol.11, No.106, ISSN 1745-6215

Vol.21, pp. 925-935, ISSN 0278-5846

80-7169-031-7, Prague, Czech Republic

Czech Republic

Czech Republic

7, Brno, Czech Republic

Vol.48, pp. 121- 135, ISSN 0009-062X


Psychosocial Factors in Patients with Thyroid Disease 311

Huang, S. M., Lee, CH. H, Chien, L. Y., Liu H. E. & Tai, Ch. J. (2004). Postoperative quality of

Janečková, P. (2001). *Problematika psychické zátěže u tyreopatie* (Dissertation), FF UP, Olomouc,

Janečková, P. (2006). Psychological distress in patients with thyroid gland disease. *Homeostasis in Health and Diseases*, Vol.44, No.1-2, pp. 83-87, ISSN 0960-7560 Janečková, P. (2007a). Psychosocial aspects of thyroid disease. Proceedings of *10th European* 

Janečková, P. (2007b). Současné výzkumy psychosociálních aspektů tyreopatie. *Československá psychologie*, Vol.51, No.6, pp. 635-654, ISSN 0009-062X Janečková, P. (2007c). Výzkum psychosociálních aspektů tyreopatie. In: *Psychologie zdraví a* 

Janečková, P. (2008a). Onemocnění štítné žlázy z psychosociálního hlediska/Zjištění o

Janečková, P. (2008b). *Psychosociální aspekty tyreopatie* (Dissertation), FSS MU, Brno, Czech

Janečková, P. (2008c). Základní poznatky z výzkumů psychosociálních aspektů onemocnění

Jenšovský, J., Špačková, N., Hejduková, B. & Růžička, E. (2000). Vliv normalizace izolovaně

Jenšovský, J., Růžička, E., Špačková, N. & Hejduková, B. (2002). Changes of event related

Jorde, R. et al. (2006). Neuropsychological function and symptoms in subjects with

Kahaly, G. J., Hardt, J., Petrak, F. & Egle, U. T. (2002). Psychosocial factors in subjects with thyroid – associated ophthalmopathy. *Thyroid*, Vol.12, s. 237-239, ISSN 1050-7256 Kahaly, G. J., Petrak, F., Hardt, J., Pitz, S. & Egle, U. T. (2005). Psychosocial morbidity of Graves' orbitopathy. *Clinical Endocrinology*, Vol.63, pp. 395-402, ISSN 0300-0664 Kaplan, H. I., Sadock & B. J., Grebb, J. A. (1994). *Synopsis of Psychiatry: Behavioral Sciences,* 

Kaplan, M. M., Sarne, D. H. & Schneider, A. B. (2003). In search of the impossible dream?

Thyroid hormone replacement therapy that treats all symptoms in all hypothyroid patients. *Journal of Clinical Endocrinology and Metabolism*, Vol.88, pp. 4540-4542, ISSN

*Endocrinology and Metabolism*, Vol.91, pp. 145-153, ISSN 0021-972X

*Clinical Psychiatry* (7th ed.). Williams & Wilkins, Baltimore, USA

(Eds.), 45-53, MSD, ISBN 978-80-7392-074-6, Brno, Czech Republic

492-499, ISSN 0309-2402

Brno, Czech Republic

Republic

0021-972X

Republic, April

017-2, ČMPS, Prague, Czech Republic, July

Vol.139, No.10, pp. 313-316, ISSN 0008-7335

*Academy of Sciences*, Vol.1032, pp. 287-88, ISSN 0077-8923

Czech Republic

life among patients with thyroid cancer. *Journal of Advanced Nursing*, Vol.47, pp.

*Congress of Psychology* (Mapping of Psychological Knowledge), ISBN 978-80-7064-

*kvalita života II.*, B. Koukola, J. Mareš, (Eds.), 36-41, MSD, ISBN 987-80-7392-009-8,

kvalitě života/. In: *Psychologie zdraví a kvalita života 2008*, B. Koukola, J. Mareš,

štítné žlázy. Proceedings of *Dokbat*, ISBN 978-80-7318-664-7, UTB, Zlín, Czech

zvýšeného TSH na neuropsychologický profil pacientů. *Časopis lékařů českých*,

potential and cognitive processes in patients with subclinical hypothyroidism after thyroxine treatment. *Endocrine regulations*, Vol.36, pp. 115-122, ISSN 1210-0668 Joffe, R. T. et al. (2004). Does substitution of T4 with T3 plus T4 for T4 replacement improve

depressive symptoms in patients with hypothyroidism? *Annals of the New York* 

subclinical hypothyroidism and the effect of thyroxine treatment. *Journal of Clinical* 


Fahrenfort, J. J., Wilterdink, A. M. & van der Veen, E. A. (2000). Long-term residual

Ferjenčík, J. (2010). *Úvod do metodologie psychologického výzkumu* (2nd ed.), Portál, ISBN 978-80-

Filická, K., Hadačová, M. (2006). Úloha sestry v terapeutickom procese endokrinných

Fukao, A. et al. (2003). The relationship of psychological factors to the prognosis of

Gerding, M. N. et al. (1997). Quality of life in patients with Graves' ophthalmopathy is

Giusti, M. et al. (2011). Five-year longitudinal evaluation of quality of life in a cohort of

Gómez, M. M. N., Gutiérrez, R. M. V., Castellanos, S. A. O., Vergara, M. P. & Pradilla, Y. K.

*Clinical Endocrinology and Metabolism*, Vol.91, pp. 2592-2599, ISSN 0021-972X Harineková, M. (1976). Struma v školskom veku a jej odraz v psychickej oblasti.

Harris, T., Creed, F. & Brugha, T. S. (1992). Stressful life events and Graves' disease. *British* 

Hendl, J. (2006). *Přehled statistických metod zpracování dat: analýza metaanalýza dat* (2nd ed.),

Hendl, J. (2009). *Kvalitativní výzkum* (2nd ed.), Portál, ISBN 978-80-7367-485-4, Prague, Czech

Hirsch, D. et al. (2009). Illness perception in patients with differentiated epithelial cell

Hobbs, J. R. (1992). Stress and Graves' disease. *Lancet*, Vol.339, pp. 427-428, ISSN 0140-6736 Hodačová, L. (2007). Posttraumatický rozvoj a změna v prožívání spirituality. In: *Kvalita* 

Hoftijzer, H. C. et al. (2008). Quality of life in cured patients with differentiated thyroid

Hou, T. et al. (2001). Quality of life of patients operated on for thyroid tumor. *Chinese Mental* 

*života u dětí a dospívajících II.*, J. Mareš et al., (Eds.), 35-47, MSD, ISBN 987-80-7392-

carcinoma. *Journal of Clinical Endocrinology and Metabolism*, Vol.93, No.1, pp. 200-

thyroid cancer. *Thyroid*, Vol.19, No.5, pp. 459-65, ISSN 1050-7256

*Československá psychologie*, Vol.20, pp. 257-258, ISSN 0009-062X

*Journal of Psychiatry*, Vol.161, pp. 535-541, ISSN 0007-1250 Haškovcová, H. (1985). *Spoutaný život*, Panorama, Prague, Czech Republic

Portál, ISBN 80-7178-820-1, Prague, Czech Republic

*Health Journal*, Vol.15, pp. 312-314, ISSN 1000-6729

Republic

009-8, Brno, Czech Republic

203, ISSN 0021-972X

*Psychoneuroendocrinology*, Vol.25, pp. 201-211, ISSN 0306-4530

*endokrinologie, výživa*, No.3, p. 145, ISSN 1211-9326

*Endocrinology*, Vol.58, pp. 550-551, ISSN 0300-0664

*Science. B.*, Vol.12, No.3, pp. 163-173, ISSN 1673-1581

*Thyroid*, Vol.6, pp. 885-889, ISSN 1050-7256

7367-815-9, Prague, Czech Republic

complaints and psychological sequelae after remission, of hyperthyroidism.

ochorení – špecifiká a význam informovanosti pacienta. *Diabetologie, metabolismus,* 

hyperthyroidism in antithyroid drug-treated patients with Graves' disease. *Clinical* 

markedly decreased: Measurement by the medical outcomes study instrument.

patients with differentiated thyroid carcinoma. *Journal of Zhejiang University.* 

R. (2010). Psychological well-being and quality of life in patients treated for thyroid cancer after surgery. *Terapia Psicológica*, Vol.28, No.1, pp. 69-84, ISSN 0716-6184 Grozinsky-Glasberg, S., Fraser, A., Nahshoni, E., Weizman, A. & Leibovici, L. (2006).

Thyroxine-triiodthyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: Meta-analysis of randomized controlled trials. *Journal of* 


Psychosocial Factors in Patients with Thyroid Disease 313

Mandincová, P. (2008b). Primární a sekundární prevence tyreopatie–pohled psychologa.

Mandincová, P. (2009a). Některé psychosociální ukazatele kvality života a ekonomická

Mandincová, P. (2009b). Klíčové oblasti kvality života u pacientů operovaných pro

Mandincová, P. (2010). Psychosociální pomoc pacientům s onemocněním štítné žlázy.

Mandincová, P. (2011a). Pohled pacientů na onemocnění štítné žlázy. Proceedings of *Konference psychologie zdraví*, ČMPS, Vernířovice, Czech Republic, May Mandincová, P. (2011b) *Psychosociální aspekty péče o nemocného: Onemocnění štítné žlázy*, Grada

Markalous, B. & Gregorová, M. (2007). *Nemoci štítné žlázy – otázky a odpovědi pro pacienty a jejich rodiny* (3rd ed.), Triton, ISBN 80-7254-961-8, Prague, Czech Republic Mareš, J. (2001). Pozitivní psychologie: důvod k zamyšlení i výzva. *Československá* 

Mareš, J. (2005). Kvalita života a její proměny v čase u téhož jedince. *Československá* 

Mareš, J. (2007). Posttraumatický rozvoj u dětí a dospívajících. In: *Kvalita života u dětí a* 

Mareš, J. (2008). Posttraumatický rozvoj: nové pohledy, nové teorie a modely. *Československá* 

Mareš, J. (2009). Posttraumatický rozvoj: výzkum, diagnostika, intervence. *Československá* 

Mareš, J., Rybářová, M. & Tůmová, Š. (2007). Posttraumatický rozvoj mediků. In: *Kvalita* 

Matos-Santos, A. et al. (2001). Relationship between the number of impact of stressful life

Matuz, T. (2006). End of life decisions and psychological aspects in amyotrophic lateral

McMillan, C. V., Bradley, C., Razvi, S. & Weaver, J. U. (2008). Evaluation of new Measures of

*International Symposium on ALS/MND*, Yokohama, Japan, November McMillan et al. (2004). Design of new questionnaires to measure quality of life and treatment satisfaction in hypothyroidism. *Thyroid*, Vol.14, pp. 916-925, ISSN 1050-7256 McMillan, C. V., Bradley, C., Razvi, S. & Weaver, J. U. (2005). Psychometric validation of

ThySRQ. *Value in Health*, Vol.11, No.2, pp. 285-294, ISSN 1098-3015

*dospívajících II.*, J. Mareš et al., (Eds.), 9-33, MSD, ISBN 978-80-7392-008-1, Brno,

*života u dětí a dospívajících II.*, J. Mareš et al., (Eds.), 225-234, MSD, ISBN 978-80-7392-

events and the onset of Graves' disease and toxic nodular goitre. *Clinical* 

sclerosis - empirical ethics and neuropsychological approaches. Proceedings of *17th* 

new measures of hypothyroid-dependent quality of life (QoL) and symptoms.

the impact of hypothyroidism on quality of life and symptoms: The ThyDQoL and

Publishing, ISBN 978-80-247-3811-6, Prague, Czech Republic

*psychologie*, Vol.45, pp. 97-117, ISSN 0009-062X

*psychologie*, Vol.49, pp. 19-33, ISSN 0009-062X

*psychologie*, Vol.52, No.6, pp. 567-583, ISSN 0009-062X

*psychologie*, Vol.53, No.3, pp. 271-290, ISSN 0009-062X

*Endocrinology*, Vol.55, pp. 15-19, ISSN 0300-0664

*Endocrine Abstracts*, Vol.9, P151, ISSN 1470-3947

UTB, Zlín, Czech Republic, November

Vernířovice, Czech Republic, May

April

May

Czech Republic

008-1, Brno, Czech Republic

Proceedings of *Integrující přístupy k prevenci a péči o zdraví*, ISBN 978-80-7318-778-1,

aktivita. Proceedings of *Dokbat*, ISBN 978-80-7318-811-5, UTB, Zlín, Czech Republic,

onemocnění štítné žlázy. Proceedings of *Konference psychologie zdraví*, ČMPS,

Proceedings of *Konference psychologie zdraví*, ČMPS, Vernířovice, Czech Republic,


Kebza, V. (2005). *Psychosociální determinanty zdraví*, Academia, ISBN 80-200-1307-5, Prague,

Kebza, V. & Šolcová, I. (2008). Hlavní koncepce psychické odolnosti. *Československá* 

König, D., Jagsch, R., Beirer, A., Kryspin-Exner, I. & Koriska, K. (2007). Patient reported

Koukola, B. & Ondřejová, E. (2006). Kvalita života vysokoškoláků zjišťovaná metodou

Křivohlavý, J. (1990). Nezdolnost v pojetí SOC. *Československá psychologie*, Vol.34, pp. 511 -

Křivohlavý, J. (2002). *Psychologie nemoci*, Grada Publishing, ISBN 80-247-0179-0, Prague,

Křivohlavý, J. (2009). *Psychologie zdraví* (2nd ed.), Portál, ISBN 978-80-7367-568-4, Prague,

Křivohlavý, J. (2010). *Pozitivní psychologie* (2nd ed.), Portál, ISBN 978-80-7367-726-8, Prague,

Křížová, E. (2005). Sociologické podmínky kvality života. In: *Kvalita života a zdraví*, J. Payne et al., (Eds.), 351-364, Triton, ISBN 80-7254-657-0, Prague, Czech Republic Kukleta, M. (2001). Psychosocial stress and health. *Homeostasis in Health and Diseases*, Vol.41,

Kung, A. W. C. (1995). Life events, daily stresses and coping in patients with Graves'

Lamberts, S. W. J., Romijn, J. A. & Wiersinga, W. M. (2003). The future endocrine patient.

Lee, I. T. et al. (2003). Relationship of stressful life events, anxiety and depression to

Lee, J. I. et al. (2010). Decreased health-related quality of life in disease-free survivors of

Lincoln, N. B. et al. (2000). Patient education in thyrotoxicosis. *Patient Education and* 

Ma, L., Luo, G. & Zeng Z. (2002). Psychological factors in patients with Graves' Disease.

Ma, C. et al. (2009). Thyroxine alone or thyroxine plus triiodothyronine replacement therapy

Malterling, R. R. et al. (2010). Differentiated thyroid cancer in a Swedish county – long-term results and quality of life. *Acta Oncologica*, Vol.49, pp. 454–459, ISSN 0284-186X Mandincová, P. (2008a). Česká studie psychosociálních aspektů onemocnění štítné žlázy.

Reflections on the future of clinical endocrinology. *European Journal of* 

hyperthyroidism in an asian population. *Hormone Research*, Vol.60, pp. 247-251,

differentiated thyroid cancer in Korea. *Health and Quality of Life Outcomes*, Vol.8,

for hypothyroidism. *Nuclear Medicine Communications*, Vol.30, No.8, pp. 586-593,

Proceedings of *XXVI. Psychologické dny*, ISBN 978-80-210-4938-3, FSS MU & ČMPS,

disease. *Clinical Endocrinology*, Vol.42, pp. 303-308, ISSN 0300-0664

*Endocrinology*, Vol.149, pp. 169-175, ISSN 0804-4643

*Counseling*, Vol.40, pp. 143-149, ISSN 0738-3991

*Chinese Mental Health Journal*, Vol.16, p. 616, ISSN 1000-6729

outcomes in treatment for thyroid diseases. Proceedings of *10th European Congress of Psychology* (Mapping of Psychological Knowledge), ISBN 978-80-7064-017-2,

SEIQoL. In: *Psychologie zdraví a kvalita života*, B. Koukola, J. Mareš, (Eds.), 149-151,

Czech Republic

517, ISSN 0009-062X

Czech Republic

Czech Republic

Czech Republic

ISSN 0301-0163

ISSN 0143-3636

No.101, ISSN 1477-7525

Brno, Czech Republic, September

*psychologie*, Vol.52, pp. 1-19, ISSN 0009-062X

MSD, ISBN 80-86633-66-7, Brno, Czech Republic

ČMPS, Prague, Czech Republic, July

No.1-2, pp.35-40, ISSN 0960-7560


Psychosocial Factors in Patients with Thyroid Disease 315

Radosavljević, V. R., Janković, S. M. & Marinković, J. M. (1996). Stressful life events in the

Razvi, S., Ingoe, L. E., McMillan, C. V. & Weaver, J. U. (2005). Health status in patients with

Razvi, S., McMillan, C. V. & Weaver, J. U. (2005). Instruments used in measuring symptoms,

Regalbuto, C. et al. (2007). Effects of either LT4 monotherapy or LT4/LT3 combined therapy

Reiterová, E. (2007). *Statistické metody v psychologickém výzkumu,* FF UP, ISBN 978-80-244-

Reiterová, E. (2009). *Základy statistiky pro studenty psychologie* (3rd ed.), FF UP, ISBN 978-80-

Reynolds, W. M. & Gould, J. W. (1981). A Psychometric Investigation of the Standard and

Robbins, L. R. & Vinson, D. B. (1960). Objective psychologic assessment of the thyrotoxic

Roberts, K. J., Lepore, S. J. & Urken, M. L. (2008). Quality of life after thyroid cancer: An

Rodewig, K. (1993). Psychosomatische Aspekte der Hyperthyreose unter besonderer

*Psychosomatik, medizinische Psychologie*, Vol.43, pp. 271-277, ISSN 0937-2032 Romijn, J. A., Smit, J. W. A. & Lamberts, S. W. J. (2003). Intrinsic imperfections of endocrine

Rosch, P. J. (1993). Stressful life events and Graves' disease. *Lancet*, Vol.342, pp. 566-567,

Rybářová, M., Mareš, J., Ježek, S. & Tůmová, Š. (2006). Kvalita života vysokoškoláků

Saravanan, P. et al. (2002). Psychological well-being in patients on 'adequate' doses of L-

Saravanan, P. et al. (2005). Partial substitution of thyroxine (T4) with tri-iodothyronine in

*Clinical Endocrinology*, Vol.57, pp. 577-585, ISSN 0300-0664

Vol.90, pp. 805-812, ISSN 0021-972X

*Clinical Endocrinology*, Vol.63, pp. 617-624, ISSN 0300-0664

701, ISSN 0804-4643

ISSN 0804-4643

ISSN 1050-7256

0804-4643

ISSN 0140-6736

Czech Republic

1678-6, Olomouc, Czech Republic

244-2316-6, Olomouc, Czech Republic

Vol.49, pp. 306-307, ISSN 0022-006X

*Endocrinology*, Vol.20, pp. 120-129, ISSN 0368-1610

*Cancer Education*, Vol.23, No.3, pp. 186-191, ISSN 0885-8195

pathogenesis of Graves' disease. *European Journal of Endocrinology*, Vol.134, pp. 699-

sub-clinical hypothyroidism. *European Journal of Endocrinology*, Vol.152, pp. 713-717,

health status and quality of life in hypothyroidism: a systematic qualitative review.

in patients totally thyroidectomized for thyroid cancer. *Thyroid*, Vol.17, pp. 323-331,

Short Form Beck Depression Inventory. *Journal of Consulting and Clinical Psychology*,

patient and the response to treatment: preliminary report. *Journal of Clinical* 

assessment of patient needs and preferences for information and support. *Journal of* 

Berücksichtigung des Morbus Basedow. Ein Überblick. *Psychotherapie,* 

replacement therapy. *European Journal of Endocrinology*, Vol.149, pp. 91-97, ISSN

zjišťována zjednodušenou metodou SEIQoL. In: *Kvalita života u dětí a dospívajících I.*, J. Mareš et al., (Eds.), 189-198, MSD, ISBN 80-86633-65-9, Brno, Czech Republic Řehulka, E., Řehulková, O. (2003). Teachers and quality of life. In: *Teachers and health 5*, E.

Řehulka, (Ed.), 177-197, Nakladatelství Pavel Křepela, ISBN 80-8669-02-5, Brno,

thyroxine: results of a large, controlled community-based questionnaire study.

patients on T4 replacement therapy. *Journal of Clinical Endocrinology and Metabolism*,


Meng,W. et al. (2004). Replacement therapy with thyroxine plus triiodothyronine (14 : 1) is

Miovský, M. (2006). *Kvalitativní výzkum a metody v psychologickém výzkumu*, Grada

Mizokami, T., Wu Li, A., El-Kaissi, S. & Wall, J. R. (2004). Stresss and thyroid autoimmunity.

Monzani, F. et al. (1993). Subclinical hypothyroidism: Neurobehavioral features and

Moons, P., Marquet, K., Budts, W. & De Geest, S. (2004). Validity, reliability and

Nygaard, B., Jensen, E. W., Kvetny, J., Jarløv, A. & Faber, J. (2009). Effect of combination

Olosová, Ľ., Filická, A. (2006). Úloha sestry v diagnotickom procese endokrinných ochorení

Pacini, F. et al. (2006). Radioiodine ablation of thyroid remnants after preparation with

Park, Y. J. et al. (2010). Subclinical hypothyroidism (SCH) is not associated with metabolic

Parle, J. et al. (2010). A randomized controlled trial of the effect of thyroxine replacement on

*Endocrinology and Metabolism*, Vol.95, No.8, pp. 3623–3632, ISSN 0021-972X Pelttari, H., Sintonen, H., Schalin-Jäntti, C. & Välimäki, M. J. (2009). Health-related quality of

*European Journal of Endocrinology*, Vol.161, pp. 895–902, ISSN 0804-4643 O'Boyle, C. A., Browne, J., Hickey, A., McGee, H. & Joyce, C. R. B. (1995). *Schedule for the* 

beneficial effect of L-thyroxine treatment. *Journal of Clinical Investigation*, Vol.71, pp.

responsiveness of the "Schedule for the Evaluation of Individual Quality of Life – Direct Weighting" (SEIQoL-DW) in congenital heart disease. *Health and Quality of* 

therapy with thyroxine (T4) and 3,5,30-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study.

*Evaluation of Individual Quality of Life (SEIQoL): a Direct Weighting procedure for Quality of Life Domains (SEIQoL-DW)* (Administration Manual), Royal College of

– špecifiká a význam informovanosti pacienta. *Diabetologie, metabolismus,* 

recombinant human thyrotropin in differentiated thyroid carcinoma: Results of an international, randomized, controlled study. *Journal of Clinical Endocrinology and* 

derangement, cognitive impairment, depression or poor quality of life (QoL) in elderly subjects. *Archives of Gerontology and Geriatrics*, Vol.50, pp. e68–e73, ISSN

cognitive function in community-living elderly subjects with subclinical hypothyroidism: The Birmingham elderly thyroid study. *Journal of Clinical* 

life in long-term follow-up of patients with cured TNM Stage I or II differentiated thyroid carcinoma. *Clinical Endocrinology*, Vol.70, No.3, pp. 493-7, ISSN 0300-0664 Ponto, K. A. & Kahaly, G. J. (2010). Quality of life in patients suffering from thyroid

orbitopathy. *Pediatric endocrinology reviews*, Vol.7 (Suppl.2), pp. 245-249, ISSN 1565-

Mohapl, P. (1992). *Úvod do psychologie nemoci a zdraví*, UP, Olomouc, Czech Republic

*and Diabetes*, Vol.112, p. S26, ISSN 0947-7349

*Thyroid*, Vol.14, pp. 1047-1055, ISSN 1050-7256

*Life Outcomes*, Vol.2, No.27, ISSN 1477-7525

*endokrinologie, výživa*, No.3, p. 147, ISSN 1211-9326

*Metabolism*, Vol.91, pp. 926-932, ISSN 0021-972X

367-371, ISSN 0021-9738

Surgeons Dublin, Ireland

0167-4943

4753

Publishing, ISBN 80-247-1362-4, Prague, Czech Republic

not superior to thyroxine alone with respect to the psychical and physical wellbeing of patients with hypothyroidism. *Experimental and Clinical Endocrinology* 


Psychosocial Factors in Patients with Thyroid Disease 317

Terwee, C. B. et al. (1999). Test-retest reliability of the GO-QOL: a disease-specific quality of

Terwee, C. B. et al. (2001). Interpretation and validity of changes in scores on the Graves'

Terwee, C. B. et al. (2002). Long-term effects of Graves' ophthalmopathy on health-related

Tschuschke, V. (2004). *Psychoonkologie: psychologické aspekty vzniku a zvládnutí rakoviny*,

Vašina, B. (2002). Osobnostní vlastnosti a copingové strategie. In: *Učitelé a zdraví 4*, E.

Valizadeh, M. et al. (2009). Efficacy of combined levothyroxine and liothyronine as

Vavrda, V. (2005). Změna kvality života: očekávání a realita. In: *Kvalita života a zdraví*, J. Payne et al., (Eds.), 176-180, Triton, ISBN 80-7254-657-0, Prague, Czech Republic Vidal-Trécan, G. M., Stahl, J. E. & Durand-Zaleski, I. (2002). Managing toxic thyroid

Vigário, P. et al. (2009). Perceived health status of women with overt and subclinical

Vymětal, J. (2003). *Lékařská psychologie* (3rd ed.). Portál, ISBN 80-7178-740-X, Prague, Czech

Walsh, J. P. et al. (2003). Combined thyroxine/liothyronine treatment does not improve well-

*Clinical Endocrinology and Metabolism*, Vol.88, pp. 4543-4550, ISSN 0021-972X Watt, T. et al. (2005). Which aspects of quality of life are relevant to patients with Graves'

Watt, T. et al. (2006). Quality of life in patients with benign thyroid disorders. A review. *European Journal of Endocrinology*, Vol.154, pp. 501-510, ISSN 0804-4643 Watt, T. et al. (2009). Establishing construct validity for the thyroid-specific patient reported

Wekking et al. (2005). Cognitive functioning and well-being in euthyroid patients on

Westerman M., Hak T., The, A. M., Groen, H. & van der Wal, G. (2006). Problems Eliciting

disease? *Thyroid*, Vol.15 (Suppl.1), p. S209, ISSN 1050-7256

*Endocrinology*, Vol.153, pp. 747-753, ISSN 0804-4643

*Quality of Life Research*, Vol.15, pp. 441-449, ISSN 0962-9343

*Epidemiology*, Vol.52, pp. 875-84, ISSN 0895-4356

4643

5800

Republic

Czech Republic

283-294, ISSN 0804-4643

pp. 483-496, ISSN 0962-9343

*Clinical Endocrinology*, Vol.54, pp. 391-398, ISSN 0300-0664

Portál, ISBN 80-7178-826-0, Prague, Czech Republic Vašina, B. (1999). *Psychologie zdraví*, FF OV, Ostrava, Czech Republic

life questionnaire for patients with Graves' ophthalmopathy. *Journal of Clinical* 

ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments.

quality of life. *European Journal of Endocrinology*, Vol.146, pp. 751-757, ISSN 0804-

Řehulka, (Ed.), 39-52, Nakladatelství Pavel Křepela, ISBN 80-902653-9-4, Brno,

compared with levothyroxine monotherapy in primary hypothyroidism: a randomized controlled trial. *Endocrine Research*, Vol.34, No.3, pp.80-89, ISSN 0743-

adenoma: a cost-effectivness analysis. *European Journal of Endocrinology*, Vol.146, pp.

hypothyroidism. *Medical Principles and Practise*, Vol.18, pp. 317–322, ISSN 1011-7571

being, quality of life, or cognitive function compared to thyroxine alone. *Journal of* 

outcome measure (ThyPRO): an initial examination. *Quality of Life Research*, Vol.18,

thyroxine replacement therapy for primary hypothyroidism. *European Journal of* 

Cues in SEIQoL-DW: Quality of Life Areas in Small-Cell Lung Cancer Patients.


Sawka, A. M. et al. (2003). Does a combination regimen of thyroxine (T4) and 3,5,3' -

Sawka, A. M. et al. (2009). The impact of thyroid cancer and post-surgical radioactive iodine

Sawka, A. M. et al. (2011). How can we meet the information needs of patients with early

Seligman, M. (2000). Positive psychology. In: *The Science of Optimism and Hope (Research* 

Schnyder, N. et al. (2000). Antonovsky's sense of coherence: Trait or state? *Psychotherapy and* 

Schreiber, V. (1985). *Stres: Patofyziologie, endokrinologie, klinika*, Avicenum, Prague, Czech

Schroeder, P. R. et al. (2006). A comparison of short-term changes in health-related quality of

Siegmund, W. et al. (2004). Replacement therapy with levothyroxine plus triiodothyronine

Sinclair, D. L. (2006). The interface of psychology and thyroid disorders. *Dissertation* 

Silverman, D. (2005). *Ako robiť kvalitatívny výskum: praktická příručka*, Ikar, ISBN 80-551-0904-

Sonino, N. & Fava, G. A. (1998). Psychological aspects of endocrine disease. *Clinical* 

Sonino, N. et al. (1993). Life events in the pathogenesis of Graves' disease. A controlled

Spielberger, C. D. (1980). *Dotazník na meranie úzkosti a úzkostlivosti STAI*. Psychodiagnostika,

Stárka, L. & Zamrazil, V. et al. (2005). *Základy klinické endokrinologie* (2nd ed.). Maxdorf, ISBN

Tagay, S. et al. (2005). Health-related quality of life, anxiety and depression in thyroid cancer

patients under short-term hypothyroidism and TSH-suppressive levothyroxine treatment. *European Journal of Endocrinology*, Vol.153, pp. 755-763, ISSN 0804-4643 Terwee, C. B., Gerding, M. N., Dekker, F. W., Prummel, M. F. & Wiersinga, W. M. (1998).

Development of a disease specific quality od life questionnaire for patients with Graves' ophtalmopathy: the GO-QOL. *British Journal of Ophthalmology*, Vol.82, pp.

study. *Acta Endocrinologica*, Vol.128, pp. 293-296, ISSN 0001-5598

*Clinical Endocrinology*, Vol.74, No.4, pp. 419-23, ISSN 0300-0664

Foundation Press, ISBN 978-1-890151-26-3, Philadelphia, USA

*Psychosomatics*, Vol.69, pp. 296-302, ISSN 0033-3190

*Endocrinology*, Vol.49, pp. 1-7, ISSN 0300-0664

80-7345-066-6, Prague, Czech Republic

4551-4555, ISSN 0021-972X

pp. 750-757, ISSN 0300-0664

6936, ISSN 0419-4217

4, Bratislava, Slovakia

Bratislava, Slovakia

773-779, ISSN 0007-1161

Republic

Vol.4, No.1, e4191, ISSN 1932-6203

triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? *Journal of Clinical Endocrinology and Metabolism*, Vol.88, pp.

treatment on the lives of thyroid cancer survivors: A qualitative study. *PLoS One*,

stage papillary thyroid cancer considering radioactive iodine remnant ablation?

*Essays in Honor of Martin E. P. Seligman)*, J. E. Gillham, (Ed.), 415-429, Templeton

life in thyroid carcinoma patients undergoing diagnostic evaluation with recombinant human thyrotropin compared with thyroid hormone withdrawal. *Journal of Clinical Endocrinology and Metabolism*, Vol.91, pp. 878-884, ISSN 0021-972X

(bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve wellbeing and cognitive performance in hypothyroidism. *Clinical Endocrinology*, Vol.60,

*Abstracts International. Section B: Physical Sciences and Engineering*, Vol.66, 12-B, p.


Whybrow, P. C. (1991). Behavioral and psychiatric aspects of thyrotoxicosis. In: *Werner and* 

Wiersinga, W. M., Prummel, M. F. & Terwee, C. B. (2004). Effects of Graves'

Winsa, B. et al. (1991). Stressful life events and Graves' disease. *Lancet*, Vol.338, pp. 1475-

Yang, H. & Zang, D. (2001). Coping style and personality of patients with Graves disease.

Yoshiuchi, K. et al. (1998a). Psychosocial factors influencing the short-term outcome of

Yoshiuchi, K. et al. (1998b). Stressful life events and smoking were associated with Graves'

Zeng, Z., Ma, L., Luo, G. & Zhou, H. (2003). Clinical study of combined psychological

*Chinese Mental Health Journal*, Vol.15, pp. 156-157, ISSN 1000-6729

(Eds.), 863-870, J. B. Lippincott Company, Philadelphia, USA

pp. 259-264, ISSN 0391-4097

1479, ISSN 0140-6736

592-596, ISSN 0033-3174

0033-3174

ISSN 1000-6729

*Ingbar's the Thyroid: a Fundamental and Clinical Text*, L. E. Braverman, R. D. Utiger,

ophthalmopathy on quality of life. *Journal of Endocrinological Investigation*, Vol.27,

antithyroid drug therapy in Graves' disease. *Psychosomatic Medicine*, Vol.60, pp.

disease in women, but not in man. *Psychosomatic Medicine*, Vol.60, pp. 182-185, ISSN

treatments on hyperthyroidism. *Chinese Mental Health Journal*, Vol.17, pp. 382-384,

### *Edited by Laura Sterian Ward*

This book was designed to meet the requirements of all who wish to acquire profound knowledge of basic, clinical, psychiatric and laboratory concepts as well as surgical techniques regarding thyroid and parathyroid glands. It was divided into three main sections: 1. Evaluating the Thyroid Gland and its Diseases includes basic and clinical information on the most novel and quivering issues in the area. 2. Psychiatric Disturbances Associated to Thyroid Diseases addresses common psychiatric disturbances commonly encountered in the clinical practice. 3. Treatment of Thyroid and Parathyroid Diseases discusses the management of thyroid and parathyroid diseases including new technologies.

Thyroid and Parathyroid Diseases - New Insights into Some Old and Some New Issues

Thyroid

and Parathyroid Diseases

New Insights into

Some Old and Some New Issues

*Edited by Laura Sterian Ward*

Photo by alex-mit / iStock