**6. Diagnosis**

In HPT, anamnesis and physical examination are of fundamental importance for accurate diagnosis.

Hypercalcemia is the main consequence of the primary HPT. In most cases, the disease is asymptomatic, occupying more than 80% of cases [21, 26, 31]. This condition was introduced after the 1970s, when routine laboratory tests began to be performed in asymptomatic patients [32]. However, they can develop symptoms that usually begin when calcium levels exceed 12 mg/dL and include manifestations in several systems. Neurological disorders manifest with changes in the level of consciousness, confusion, or lack of concentration. Gastrointestinal manifestations, such as nausea, epigastric pain due to peptic disease, or even pancreatitis, can be found. Nephrolithiasis can occur, mainly of repetition, polydipsia or polyuria. Bone pain and pathological fractures are also reported, in addition to brown tumors in the bone skeleton. Cardiovascular manifestations and heart rhythm disorders are also associated with hypercalcemia [33]. We can measure ionized serum calcium or total calcium. The total calcium measurement needs to be adjusted, because much of it is bonded with serum albumin. The formula can be shown in the following: corrected calcium = measured total serum calcium in mg/dL + 0.8 × (4.0 − patient's serum albumin concentration in g/dL) [21]. Vitamin D participates actively in the diagnosis of primary HPT. The Institute of Medicine (IOM) affirms an evidence that the disease is more active when the vitamin D levels are below normal [21, 34]. A variant of primary HPT is the normocalcemic HPT, when presents with levels of PTH above normal and normal levels of serum calcium. The evolution of these cases can be stable, without clinical complications or laboratory alterations, increase the serum calcium concentration, or cause bone, kidney, or cardiovascular impairments [35].

Secondary HPT caused by CKD normally courses with normal or low levels of serum calcium. Thus, the history of CKD, especially dialysis, is fundamental for the diagnostic interpretation. The symptoms are due to bone disease with bone pain that can be of different intensities and pathological fractures with difficulty in movement. The pruritus also is most frequent, especially when the phosphate levels are above the normal.

Laboratory assessment of HPT is essential for diagnosis. Serum measurements of PTH, total serum calcium, ionized fraction of calcium, phosphorus, vitamin D, and alkaline phosphatase should be ordered. PTH will always be increased but to varying degrees. In primary HPT, PTH normally increases from two to four times normal, but it can reach much higher values depending on the severity of the disease. Consequently, serum calcium also rises. Phosphorus levels are normal or low and alkaline phosphatase rises [33]. Very high levels of PTH and calcium raise the hypothesis of parathyroid carcinoma and require a different approach. In secondary HPT there is a high elevation of PTH, commonly reaching the values of 10–20 times higher than normal or above in several cases. Calcium is usually in the normal range or at reduced levels, with hyperphosphatemia occurring in some cases. Due to decreased vitamin D activation in the kidney, there is a decrease in serum calcium due to low intestinal absorption.

In tertiary HPT, the parathyroid glands become autonomous in the production of PTH, despite the improvement in renal function, observed mainly in post-kidney transplant patients [36]. There is not a sufficient decrease in PTH, which remains in the range of 5–10 times greater than normal. Vitamin D levels also tend to normalize, since the absence of kidney damage in the post-transplant patient normalizes the conversion of vitamin D into its active form (calcitriol) and also normalizes the intestinal absorption of calcium. Thus, the mechanisms lead to increased serum calcium concentration [36, 37].

Complementary imaging exams are of great value in therapeutic planning, especially when the surgical approach is programmed [38].

Cervical ultrasonography has an important value, i.e., in trying to locate the enlarged parathyroid glands, although there is difficulty due to the overlying position of the thyroid gland and the fact that it is operator dependent. Also, we need to study the thyroid anatomy and the possibility of thyroid nodules that can be approached at the same time, if surgery is performed [39, 40].

Computed tomography, as well as magnetic resonance imaging of the neck, can also help in locating the altered glands, especially if they are much larger than normal. One of the main exams is parathyroid scintigraphy, as it can functionally reveal parathyroid glands with increased activity through the uptake of 99Tc-sestamibi (MIBI) [38, 39]. Even more sensitive and specific than scintigraphy is SPECT/CT with MIBI. This examination has the same physiological foundations as flat scintigraphy; however its fusion with the computed tomography image allows for a much more precise location of the affected parathyroid glands.

Another resource is 4D computed tomography. The mechanism of realization of this exam is based on the arterial supply and venous drainage of the analyzed structure. It helps to differentiate a parathyroid gland from a lymph node or any other structure present in the neck or mediastinal region [38, 40, 41].

#### **7. Treatment**

The treatment for HPT may be with clinical management or surgery. However, there are other previous forms of disease control, mainly in primary asymptomatic HPT and secondary HPT in early stages. In asymptomatic cases of primary HPT, clinical follow-up without surgical treatment can be performed in most cases. However, in symptomatic cases with evidence of bone and kidney disease, surgical treatment is preferred [27, 31, 32, 42]. Treatment with bisphosphonates and calcimimetics, such as cinacalcete, is applied in cases of severe hypercalcemia and difficulty in performing surgical treatment in a timely manner [43, 44]. Therapeutic doubt arises in asymptomatic cases, in which initial surgical treatment is often not

**77**

**Table 1.**

1. Serum calcium

4. Age <50 years

values

*Parathyroid Glands and Hyperparathyroidism: A General Overview*

indicated. According to the Fourth International Workshop, held in Italy in 2013 [21], surgical indications in asymptomatic patients are reserved for the situations

The surgery performed on primary HPT is, in most cases, resection of the parathyroid affected by the adenoma (85% of cases). The use of intraoperative rapid PTH allows less chance of persistent disease (as in multiple adenomas) or future recurrences [26, 45–47]. In cases of parathyroid hyperplasia in primary HPT, as in multiple endocrine neoplasia, the surgical approach is the subject of much discussion. The possibility of subtotal/partial parathyroidectomy or total parathyroidectomy with autograft of fragments of parathyroid tissue in muscle tissue (forearm, presternal, or deltoid musculature) is described [25, 48]. Although rare, being responsible for less than 1% of cases of primary HPT, parathyroid carcinoma, when clinically suspected, should be treated with special care. Cases of severe hypercalcemia (greater than 14 mg/dL) and high levels of PTH (15–20 times higher than normal) should have parathyroid carcinoma as a diagnostic hypothesis. The recommended treatment is resection of the tumor en bloc with wide safety margins. The complete surgery includes partial thyroidectomy ipsilateral to the affected parathyroid, lymphadenectomy of the central compartment, and thymectomy [49]. In secondary HPT, initial clinical treatment is focused on the control of calcemia and phosphatemia and reduction of factors that stimulate PTH overproduction, as well as avoiding exposure to aluminum. Administration of vitamin D and calcium carbonate is used to try to correct serum calcium levels. Surgical treatment is usually indicated when intact PTH levels exceed 800 pg./mL, or when persistent symptoms such as bone fractures, pain refractory bone, intractable pruritus, brown tumor, and ectopic calcification. The pathology is systemic, and hyperplasia of all parathyroid glands occurs through feedback mechanisms. Therefore, the surgery to be performed can be the total parathyroidectomy with autograft of fragments of parathyroid tissue in the muscle tissue (forearm, presternal, or deltoid musculature) in order to avoid persistent hypoparathyroidism, or subtotal parathyroidectomy, with maintenance of parathyroid tissues to avoid persistent hypoparathyroidism [50–52]. The clinical management of secondary HPT is increasingly available, with acceptable responses, especially in patients who are not candidates for surgical treatment. Calcimimetics, such as cinacalcet, have acceptable results in reducing serum PTH and, mainly, improving the quality of life of chronic renal patients. Tolerability is reasonable, with some side effects, such as nausea, vomiting,

and hypocalcemia, which may suspend treatment in some cases [53].

Serum calcium 1.0 mg/dL (0.25 mmol/L) greater than the upper limit of normal

B. Calciuria 24 h > 400 mg/d (>10 mmol/dL) and increased risk of calculosis by

C. Presence of nephrolithiasis or nephrocalcinosis by X-ray, ultrasound, or CT

2. Imaging findings A. Bone mineral density: T-score < −2.5 in the lumbar spine, hip, femur, or distal

B. Vertebral fracture on X-ray, CT, MRI, or bone densitometry

**Indication of parathyroidectomy in asymptomatic primary HPT**

third of the radius

biochemical analysis

3. Renal factors A. Creatinine clearance < 60 cc/min

*Indication of parathyroidectomy in asymptomatic primary HPT [21].*

*DOI: http://dx.doi.org/10.5772/intechopen.92785*

illustrated in **Table 1**.

*Mineral Deficiencies - Electrolyte Disturbances, Genes, Diet and Disease Interface*

due to low intestinal absorption.

calcium concentration [36, 37].

Laboratory assessment of HPT is essential for diagnosis. Serum measurements of PTH, total serum calcium, ionized fraction of calcium, phosphorus, vitamin D, and alkaline phosphatase should be ordered. PTH will always be increased but to varying degrees. In primary HPT, PTH normally increases from two to four times normal, but it can reach much higher values depending on the severity of the disease. Consequently, serum calcium also rises. Phosphorus levels are normal or low and alkaline phosphatase rises [33]. Very high levels of PTH and calcium raise the hypothesis of parathyroid carcinoma and require a different approach. In secondary HPT there is a high elevation of PTH, commonly reaching the values of 10–20 times higher than normal or above in several cases. Calcium is usually in the normal range or at reduced levels, with hyperphosphatemia occurring in some cases. Due to decreased vitamin D activation in the kidney, there is a decrease in serum calcium

In tertiary HPT, the parathyroid glands become autonomous in the production of PTH, despite the improvement in renal function, observed mainly in post-kidney transplant patients [36]. There is not a sufficient decrease in PTH, which remains in the range of 5–10 times greater than normal. Vitamin D levels also tend to normalize, since the absence of kidney damage in the post-transplant patient normalizes the conversion of vitamin D into its active form (calcitriol) and also normalizes the intestinal absorption of calcium. Thus, the mechanisms lead to increased serum

Complementary imaging exams are of great value in therapeutic planning,

Cervical ultrasonography has an important value, i.e., in trying to locate the enlarged parathyroid glands, although there is difficulty due to the overlying position of the thyroid gland and the fact that it is operator dependent. Also, we need to study the thyroid anatomy and the possibility of thyroid nodules that can be

Computed tomography, as well as magnetic resonance imaging of the neck, can also help in locating the altered glands, especially if they are much larger than normal. One of the main exams is parathyroid scintigraphy, as it can functionally reveal parathyroid glands with increased activity through the uptake of 99Tc-sestamibi (MIBI) [38, 39]. Even more sensitive and specific than scintigraphy is SPECT/CT with MIBI. This examination has the same physiological foundations as flat scintigraphy; however its fusion with the computed tomography image allows for a much

Another resource is 4D computed tomography. The mechanism of realization of this exam is based on the arterial supply and venous drainage of the analyzed structure. It helps to differentiate a parathyroid gland from a lymph node or any

The treatment for HPT may be with clinical management or surgery. However, there are other previous forms of disease control, mainly in primary asymptomatic HPT and secondary HPT in early stages. In asymptomatic cases of primary HPT, clinical follow-up without surgical treatment can be performed in most cases. However, in symptomatic cases with evidence of bone and kidney disease, surgical treatment is preferred [27, 31, 32, 42]. Treatment with bisphosphonates and calcimimetics, such as cinacalcete, is applied in cases of severe hypercalcemia and difficulty in performing surgical treatment in a timely manner [43, 44]. Therapeutic doubt arises in asymptomatic cases, in which initial surgical treatment is often not

especially when the surgical approach is programmed [38].

approached at the same time, if surgery is performed [39, 40].

more precise location of the affected parathyroid glands.

other structure present in the neck or mediastinal region [38, 40, 41].

**76**

**7. Treatment**

indicated. According to the Fourth International Workshop, held in Italy in 2013 [21], surgical indications in asymptomatic patients are reserved for the situations illustrated in **Table 1**.

The surgery performed on primary HPT is, in most cases, resection of the parathyroid affected by the adenoma (85% of cases). The use of intraoperative rapid PTH allows less chance of persistent disease (as in multiple adenomas) or future recurrences [26, 45–47]. In cases of parathyroid hyperplasia in primary HPT, as in multiple endocrine neoplasia, the surgical approach is the subject of much discussion. The possibility of subtotal/partial parathyroidectomy or total parathyroidectomy with autograft of fragments of parathyroid tissue in muscle tissue (forearm, presternal, or deltoid musculature) is described [25, 48]. Although rare, being responsible for less than 1% of cases of primary HPT, parathyroid carcinoma, when clinically suspected, should be treated with special care. Cases of severe hypercalcemia (greater than 14 mg/dL) and high levels of PTH (15–20 times higher than normal) should have parathyroid carcinoma as a diagnostic hypothesis. The recommended treatment is resection of the tumor en bloc with wide safety margins. The complete surgery includes partial thyroidectomy ipsilateral to the affected parathyroid, lymphadenectomy of the central compartment, and thymectomy [49].

In secondary HPT, initial clinical treatment is focused on the control of calcemia and phosphatemia and reduction of factors that stimulate PTH overproduction, as well as avoiding exposure to aluminum. Administration of vitamin D and calcium carbonate is used to try to correct serum calcium levels. Surgical treatment is usually indicated when intact PTH levels exceed 800 pg./mL, or when persistent symptoms such as bone fractures, pain refractory bone, intractable pruritus, brown tumor, and ectopic calcification. The pathology is systemic, and hyperplasia of all parathyroid glands occurs through feedback mechanisms. Therefore, the surgery to be performed can be the total parathyroidectomy with autograft of fragments of parathyroid tissue in the muscle tissue (forearm, presternal, or deltoid musculature) in order to avoid persistent hypoparathyroidism, or subtotal parathyroidectomy, with maintenance of parathyroid tissues to avoid persistent hypoparathyroidism [50–52]. The clinical management of secondary HPT is increasingly available, with acceptable responses, especially in patients who are not candidates for surgical treatment. Calcimimetics, such as cinacalcet, have acceptable results in reducing serum PTH and, mainly, improving the quality of life of chronic renal patients. Tolerability is reasonable, with some side effects, such as nausea, vomiting, and hypocalcemia, which may suspend treatment in some cases [53].


#### **Table 1.**

*Indication of parathyroidectomy in asymptomatic primary HPT [21].*

Tertiary HPT occurs in autonomy of parathyroid glands resulting from continuous stimulation of PTH secretion, a consequence of secondary HPT. These cases are better demonstrated after kidney transplantation, when PTH levels are kept high even after treating the cause of secondary HPT, the renal disease. Surgical treatment is indicated due to persistent hypercalcemia, in addition to symptoms that may be associated, such as bone pain, pathological fractures, and intractable pruritus. The surgical approach, as in secondary HPT, can be total parathyroidectomy with autograft of parathyroid fragments in muscle tissue, or subtotal parathyroidectomy [36, 54]. The measurement of intraoperative rapid PTH in cases of secondary and tertiary HPT during surgical treatment is the subject of much current discussion, although it is increasingly accepted in order to avoid new approaches due to recurrent or persistent disease [36, 51, 55, 56].
