**8.7. Radioiodine**

Radioiodine is one of the first line therapy for the Graves' disease. Among different isotopes of radioiodine, I131 is the agent of choice. I131 is a β-emitter isotope. After oral administration, I131is completely absorbed and rapidly concentrated in thyroid follicular cells. β- particles, which are emitted by I131, destroy the thyroid follicular cells that results in reduced thyroid hormone synthesis. Initially destruction of thyroid follicular cells results in release of preformed hormones that can precipitate the thyortoxic crisis. Weeks to months are required for control of thyrotoxicosis. Long term effects of radioiodine include atrophy and fibrosis, and a chromic inflammatory response resembling Hashimoto's thyroiditis.

Thyroid Hormone Excess: Graves' Disease 175

of the thyroid gland is removed, with only subcentimeter fragment are left around recurrent laryngeal nerve and parathyroid glands. Subtotal thyroidectomy was the procedure of choice in past, but it is associated with higher recurrence rate. Now-a-days near total thyroidectomy is used most often. Near total thyroidectomy is associated with more chance of permanent

Complications of thyroid surgery depends on the skill and experience of operating surgeon. In specialized hands, complication rate is as low as 2%, whereas complication rate increases up to 10-15% in non specialized centers. Post Operative bleeding is the most serious complication. It can be fatal by producing asphyxia, if it is not evacuated immediately. Other complications like thyroid storm, injury to recurrent laryngeal nerve and hypoparathyroidism are specific to thyroid surgery. Thyroid storm is rare now-a-days. Injury to recurrent laryngeal nerve causes dysphonia, that usually improves with time, but that may leave the patient slightly hoarse. Hypoparathyroidism can be transient or permanent. Transient hypoparathyroidism is due to removal of the some parathyroid and impairment of blood supply to parathyroid glands, whereas permanent hypoparathyroidism is due to inadvertent removal of all 4 glands. Transient hypoparathyroidism usually occur on day 1-7 postoperatively. Severe symptomatic hypoparathyroidism should be treated by intravenous calcium gluconate. Oral calcium (upto 3 gm/day) is sufficient for milder cases. Immediate postoperative hypocalcemia is due to hungry bone syndrome. Recurrence of hyperthyroidism and permanent hypothyroidism are inversely related and depends on the amount of thyroid tissue left. In case of recurrence,

hypothyroidism but less chance of recurrence than subtotal thyroidectomy.

radioiodine should be used as treatment, as second surgery is technically difficult.

Preoperative use of thionamides is associated with lesser morbidity and mortality. Preoperative thionamides are recommended to achieve euthyroidism and to deplete. The hormone store. Preoperative use of inorganic iodine decreases the gland size and vcascularity. In case of emergency surgery oral cholecystographic agents are the fastest way to obtain euthyroidism. The goal of preoperative management is to maintain euthyroid states by thionamides and then to induce involution of the gland by the inorganic iodine. β

Choice of therapy depends on the patient preference, personal experience of the treating doctor and availability of the treatment options. All the three treatment options (antithyroid drugs, radioiodine, surgery) can be used as first line therapy. In most of the Europe, antithyroid drugs are the preferred treatment whereas in USA, radioiodine is the preferred treatment. Primary choice of treatment in children and young adults upto 18 years of age is antithyroid drugs, although radioiodine is not associated with any adverse events. Pregnancy should be delayed for 6-12 months after radioiodine treatment. Presence of severe ophthalmopathy is a contraindication for radioiodine treatment. Surgery is the preferred treatment for patients with large goiter, especially if compressive symptoms are

present, endemic goiter with multiple cold nodules, and suspected malignancy.

*Preoperative preparation* 

*Choice of therapy* 

blockers can be used in preoperative preparation.

Radioiodine is given as single oral dose. Three outcomes of radioiodine treatment are possible- patients become euthyroid or remain thyrotoxic or become permanently hypothyroid. Dose of radioiodine depends on the size of gland, the uptake of I131 and its subsequent rate of release. Dose of radioiodine ranges from 80-200 Ci/gm of thyroid tissues. A total dose of 20 mCi achieves thyroid ablation in almost all patients and results in permanent hypothyroidisms in 75-90% of patients. 51 The incidence of post radioiodine hypothyroidism in first year is 25% and steadily increases thereafter at a rate of 5% per year. When required, the second dose of radioiodine should be given at least 6 months after the first dose. Failure of radioiodine treatment is more common in patients with large goiter, rapid iodine turnover and adjunctive antithyroid drugs too soon after radioiodine. Prior use of antithyorid drugs decreases the risk of thyrotoxic crisis. Chance of worsening ophthalmopathy can also be reduced by antithyroid drugs. Antithyroid drugs should be stopped 3 to 8 days prior to radioiodine treatment and should be restarted after 7 days when required. Propylthiouracil may cause radio-resistance, but it not a major concern. Short term side effects of radioiodine include transient exacerbation of thyrotoxicosis in the first few months, transient worsening of ophthalompathy, acute radiation thyroids in the first week. Radiation thyroidits may lead to transient worsening of thyrotoxicosis and ophthalmopathy. Presence of mild to moderate ophthalmopathy is not a contraindication for radioiodine treatment. Concomitant use of oral glucocorticoids, decreases the risk of worsening ophthalmopathy. Long term side effect of radioiodine is permanent hypothyroidism. Initially there was a concern regarding possible carcinogenic effect and risk of genetic damage after radioiodine treatment. But now it is proven that there is no association between radioiodine treatment and thyroid carcinoma, leukemia, solid tumors and genetic damage.52 Thyroid cancer is associated with low dose of I131 rather than higher dose of I131 in children. 53 Some centers uses radioiodine even in children of 10 years of age or younger, but still there is no consensus regarding use of radioiodine for persons younger than 16 to 18 years.

#### **8.8. Surgery**

Surgery is a form of ablative therapy. Enough thyroid tissue is removed by surgery to reduce the synthesis of thyroid hormones and prevent recurrence. Two type of thyoid surgery are used for Graves' disease. In subtotal thyroidectomy, bulk of the thyroid gland is removed and only about 2 gm (0.5%) of thyroid tissue is left in both lobes. In near total thyroidectomy, most of the thyroid gland is removed, with only subcentimeter fragment are left around recurrent laryngeal nerve and parathyroid glands. Subtotal thyroidectomy was the procedure of choice in past, but it is associated with higher recurrence rate. Now-a-days near total thyroidectomy is used most often. Near total thyroidectomy is associated with more chance of permanent hypothyroidism but less chance of recurrence than subtotal thyroidectomy.

Complications of thyroid surgery depends on the skill and experience of operating surgeon. In specialized hands, complication rate is as low as 2%, whereas complication rate increases up to 10-15% in non specialized centers. Post Operative bleeding is the most serious complication. It can be fatal by producing asphyxia, if it is not evacuated immediately. Other complications like thyroid storm, injury to recurrent laryngeal nerve and hypoparathyroidism are specific to thyroid surgery. Thyroid storm is rare now-a-days. Injury to recurrent laryngeal nerve causes dysphonia, that usually improves with time, but that may leave the patient slightly hoarse. Hypoparathyroidism can be transient or permanent. Transient hypoparathyroidism is due to removal of the some parathyroid and impairment of blood supply to parathyroid glands, whereas permanent hypoparathyroidism is due to inadvertent removal of all 4 glands. Transient hypoparathyroidism usually occur on day 1-7 postoperatively. Severe symptomatic hypoparathyroidism should be treated by intravenous calcium gluconate. Oral calcium (upto 3 gm/day) is sufficient for milder cases. Immediate postoperative hypocalcemia is due to hungry bone syndrome. Recurrence of hyperthyroidism and permanent hypothyroidism are inversely related and depends on the amount of thyroid tissue left. In case of recurrence, radioiodine should be used as treatment, as second surgery is technically difficult.

#### *Preoperative preparation*

174 Thyroid Hormone

**8.7. Radioiodine** 

**8.8. Surgery** 

Radioiodine is one of the first line therapy for the Graves' disease. Among different isotopes of radioiodine, I131 is the agent of choice. I131 is a β-emitter isotope. After oral administration, I131is completely absorbed and rapidly concentrated in thyroid follicular cells. β- particles, which are emitted by I131, destroy the thyroid follicular cells that results in reduced thyroid hormone synthesis. Initially destruction of thyroid follicular cells results in release of preformed hormones that can precipitate the thyortoxic crisis. Weeks to months are required for control of thyrotoxicosis. Long term effects of radioiodine include atrophy and fibrosis,

Radioiodine is given as single oral dose. Three outcomes of radioiodine treatment are possible- patients become euthyroid or remain thyrotoxic or become permanently hypothyroid. Dose of radioiodine depends on the size of gland, the uptake of I131 and its subsequent rate of release. Dose of radioiodine ranges from 80-200 Ci/gm of thyroid tissues. A total dose of 20 mCi achieves thyroid ablation in almost all patients and results in permanent hypothyroidisms in 75-90% of patients. 51 The incidence of post radioiodine hypothyroidism in first year is 25% and steadily increases thereafter at a rate of 5% per year. When required, the second dose of radioiodine should be given at least 6 months after the first dose. Failure of radioiodine treatment is more common in patients with large goiter, rapid iodine turnover and adjunctive antithyroid drugs too soon after radioiodine. Prior use of antithyorid drugs decreases the risk of thyrotoxic crisis. Chance of worsening ophthalmopathy can also be reduced by antithyroid drugs. Antithyroid drugs should be stopped 3 to 8 days prior to radioiodine treatment and should be restarted after 7 days when required. Propylthiouracil may cause radio-resistance, but it not a major concern. Short term side effects of radioiodine include transient exacerbation of thyrotoxicosis in the first few months, transient worsening of ophthalompathy, acute radiation thyroids in the first week. Radiation thyroidits may lead to transient worsening of thyrotoxicosis and ophthalmopathy. Presence of mild to moderate ophthalmopathy is not a contraindication for radioiodine treatment. Concomitant use of oral glucocorticoids, decreases the risk of worsening ophthalmopathy. Long term side effect of radioiodine is permanent hypothyroidism. Initially there was a concern regarding possible carcinogenic effect and risk of genetic damage after radioiodine treatment. But now it is proven that there is no association between radioiodine treatment and thyroid carcinoma, leukemia, solid tumors and genetic damage.52 Thyroid cancer is associated with low dose of I131 rather than higher dose of I131 in children. 53 Some centers uses radioiodine even in children of 10 years of age or younger, but still there is no

and a chromic inflammatory response resembling Hashimoto's thyroiditis.

consensus regarding use of radioiodine for persons younger than 16 to 18 years.

Surgery is a form of ablative therapy. Enough thyroid tissue is removed by surgery to reduce the synthesis of thyroid hormones and prevent recurrence. Two type of thyoid surgery are used for Graves' disease. In subtotal thyroidectomy, bulk of the thyroid gland is removed and only about 2 gm (0.5%) of thyroid tissue is left in both lobes. In near total thyroidectomy, most Preoperative use of thionamides is associated with lesser morbidity and mortality. Preoperative thionamides are recommended to achieve euthyroidism and to deplete. The hormone store. Preoperative use of inorganic iodine decreases the gland size and vcascularity. In case of emergency surgery oral cholecystographic agents are the fastest way to obtain euthyroidism. The goal of preoperative management is to maintain euthyroid states by thionamides and then to induce involution of the gland by the inorganic iodine. β blockers can be used in preoperative preparation.

#### *Choice of therapy*

Choice of therapy depends on the patient preference, personal experience of the treating doctor and availability of the treatment options. All the three treatment options (antithyroid drugs, radioiodine, surgery) can be used as first line therapy. In most of the Europe, antithyroid drugs are the preferred treatment whereas in USA, radioiodine is the preferred treatment. Primary choice of treatment in children and young adults upto 18 years of age is antithyroid drugs, although radioiodine is not associated with any adverse events. Pregnancy should be delayed for 6-12 months after radioiodine treatment. Presence of severe ophthalmopathy is a contraindication for radioiodine treatment. Surgery is the preferred treatment for patients with large goiter, especially if compressive symptoms are present, endemic goiter with multiple cold nodules, and suspected malignancy.

### *Thyroid ophthalmopathy*

Mild to moderate ophthalmopathy does not require any specific treatment. General measures include control of thyrotoxicosis, smoking cessation, dark glasses with side frame for photophobia and sensitivity to air, artificial tear (1% methyl cellulose) or eye ointment for eye discomfort and dry eye, eye patches or taping during sleep for lagophthalmos, elevation of the head end for periorbital edema, prism for correction of mild diplopia.

Thyroid Hormone Excess: Graves' Disease 177

trauma, thyroid surgery, radioiodine, diabetic ketoacidosis, stroke etc. It can present with fever, tachycardia, arrhythmias, profuse sweating, diarrhea and vomiting, confusion, delirium, seizures, jaundice, coma, congestive heart failure, hypotension. Thyroid storm is

Treatment of thyroid storm requires strict monitoring and proper care. Precipitating factors should be identified and treated. Supportive treatment include cooling blankets and drugs like acetaminophen, chlorpromazine or meperidine for hyperthermia, oxygen inhalation, intravenous fluids. Antithyroid drug of choice is prophylthiouracil but carbimazole can also be used. Prophylthiouracil 600 mg is given as loading dose by mouth or nasogastric tube or per rectum followed by 200-300 mg every 6-8 hourly. One hour after the first dose of propylthiouracil, stable iodide is given in the form of SSKI (3 drops twice daily) or Lugol's iodine (10 drops twice daily). Propranolol should also be given in a dose of 40-80 mg orally every 6 hours or 2 mg intravenously every 4 hours. If β blockers are contraindicated, calcium channel blockers like diltiazem can be used to control tachycardia. Large dose of dexamethasone (8 mg) by oral or intravenous route should be given to block the release of

associated with very high mortality rate (upto 30%, even with treatment).

hormone from gland and peripheral conversion of T4 to T3.

*Department of Endocrinology and Metabolism, Institute of Medical Sciences,* 

reference to temporal trends. *Metabolism* 1972; 21:197-204.

[1] Graves RJ: Newly observed affection of the thyroid. *London Med Surg J* 1835; 7:515-523. [2] Parry CH: *Collections from the Unpublished Medical Writings of the Late Caleb Hillier Parry*.

[3] von Basedow KA: Exophthalmos durch hypertrophie des zellgewebes in der Augenhole.

[4] Laurberg P, Pedersen KM, Vestergaard H, et al: High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs. high incidence of Graves' disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland. *J Intern Med* 1991; 229:415-420. [5] Furszyfer J, Kurland LT, McConahey WM, et al: Epidemiologic aspects of Hashimoto's thyroiditis and Graves' disease in Rochester Minnesota (1935–1967), with special

[6] Aghini-Lombardi F, Antonangeli L, Martino E, et al: The spectrum of thyroid disorders in an iodine-deficient community: the Pescopagano survey. *J Clin Endocrinol Metab* 1999;

**Author details** 

Manuj Sharma

**9. References** 

84:561-566

N.K. Agrawal and Ved Prakash

*Banaras Hindu University, Varanasi, India* 

London, Underwood, 1825.

*Wochenschr Ges Heilk Berl* 1840; 6:197.

*Department of Medicine, Gandhi Medical College, Bhopal* 

Other patients with more severe signs and symptoms affecting daily lives to a significant extent may benefit from immunosuppressive therapy in active disease or surgical decompression in case of inactive disease. Severe ophthalmopathy with optic neuropathy and corneal ulcer is an emergency.

### *Glucocorticoids*

Oral glucocorticoids is initiated at a relatively high dose, such as 40-80 mg of prednisolone per day. After 2-4 weeks, the daily dose is tapered by 2.5-10 mg every 2-4 weeks. Improvement in soft tissue inflammation begins within 1-2 days. Intravenous methylprednisolone pulse therapy is more effective and better tolerated than oral prednisolone.54 500 mg of methylprednisolone per week for 6 weeks followed by 250 mg of methylprednisolone per week for 6 weeks is most commonly used regimen. Cyclosporine can also be used either as a single therapy or in combination with oral prednisolone. Combination therapy of cyclosporine with prednisolone is more effective than either drug alone.55

#### *Orbital Radiotherapy*

Orbital radiotherapy is well tolerated and provide benefit in approximately two third of patients. This treatment is steroid sparing rather than steroid replacing therapy.

#### *Other immunomodulatory therapy*

Rituximab, azathioprine, cyclophosphamide, ciamexon, pentoxifylline and intravenous immunoglobulins have some benefit and are currently under trial.

#### *Orbital decompression*

Indications for orbital decompression include optic neuropathy, severe proptosis, vision threatening ocular exposure, debilitating retrobulbar and periorbital pain and intolerable corticosteroid side effects. Transantral orbital decompression with removal of a portion of medial wall and the orbital floor is most commonly used procedure. Upto 5 mm reduction in proptosis can be achieved by orbital decompression. Orbital decompression can cause onset or worsening of diplopia.

#### *Thyroid storm*

Thyroid storm or thyrotoxic crisis is a life threatening exacerbation of hyperthyroidism. Most of the cases of thyroid storm are associated with Graves' disease, but it can also occur with toxic multinodular goitre. Precipitating factor for thyroid storm include infection, trauma, thyroid surgery, radioiodine, diabetic ketoacidosis, stroke etc. It can present with fever, tachycardia, arrhythmias, profuse sweating, diarrhea and vomiting, confusion, delirium, seizures, jaundice, coma, congestive heart failure, hypotension. Thyroid storm is associated with very high mortality rate (upto 30%, even with treatment).

Treatment of thyroid storm requires strict monitoring and proper care. Precipitating factors should be identified and treated. Supportive treatment include cooling blankets and drugs like acetaminophen, chlorpromazine or meperidine for hyperthermia, oxygen inhalation, intravenous fluids. Antithyroid drug of choice is prophylthiouracil but carbimazole can also be used. Prophylthiouracil 600 mg is given as loading dose by mouth or nasogastric tube or per rectum followed by 200-300 mg every 6-8 hourly. One hour after the first dose of propylthiouracil, stable iodide is given in the form of SSKI (3 drops twice daily) or Lugol's iodine (10 drops twice daily). Propranolol should also be given in a dose of 40-80 mg orally every 6 hours or 2 mg intravenously every 4 hours. If β blockers are contraindicated, calcium channel blockers like diltiazem can be used to control tachycardia. Large dose of dexamethasone (8 mg) by oral or intravenous route should be given to block the release of hormone from gland and peripheral conversion of T4 to T3.
