eMedicine Specialties > Endocrinology > Thyroid

Graves Disease: Treatment & Medication

Author: Sai-Ching Jim Yeung, MD, PhD, FACP, Deputy Section Chief of Emergency Care, Assistant Professor, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, University of Texas MD Anderson Cancer Center
Coauthor(s): Mouhammed Amir Habra, MD, Endocrine Fellow, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center; Alice Cua Chiu, MD, Consulting Staff, Department of Internal Medicine, Division of Endocrinology, Columbia Bayshore Medical Center
Contributor Information and Disclosures

Updated: Mar 16, 2010

Treatment

Medical Care

Treatment involves alleviation of symptoms and correction of the thyrotoxic state. Adrenergic hyperfunction is treated with beta-adrenergic blockade. Correcting the high thyroid hormone levels can be achieved with antithyroid medications that block the synthesis of thyroid hormones or by treatment with radioactive iodine.

  • The most commonly used therapy for Graves disease is radioactive iodine. Indications for radioactive iodine over antithyroid agents include a large thyroid gland, multiple symptoms of thyrotoxicosis, high levels of thyroxine, and high titers of TSI. Information and guidelines are as follows:
    • Many physicians in the United States prefer to use radioactive iodine as first-line therapy, especially in younger patients, because of the high relapse rates (>50%) associated with antithyroid therapy.
    • Radioiodine treatment can be performed in an outpatient setting.
    • The usual dose ranges from 5-15 mCi, determined either by using various formulas that take into account the estimated thyroid weight and radioiodine uptake or by using fixed dosages of iodine I 131; detailed kinetic studies of131 I are not essential and do not lead to better treatment results. A fixed dose of 7 mCi has been advocated by some researchers as the first empirical dose in the treatment of hyperthyroidism. In general, higher dosages are required for patients who have large goiters, have low radioiodine uptake, or who have been pretreated with antithyroid drugs.
    • Patients currently taking antithyroid drugs must discontinue the medication at least 2 days prior to taking the radiopharmaceutical.28 In one study, withholding antithyroid drugs for just over 2 weeks before radioiodine treatment resulted in the lowest failure rate. Pretreatment with thioanmides reduces the cure rate of radioiodine therapy in hyperthyroid diseases, although a rise in TSH due to thionamides may alleviate this problem.29
    • Thyroid function test results generally improve within 6-8 weeks of therapy, but this can be highly variable.
    • With radioactive iodine, the desired result is hypothyroidism due to destruction of the gland, which usually occurs 2-3 months after administration.
    • Following up with the patient and monitoring thyroid function monthly or as the clinical condition dictates is important.
    • When patients become hypothyroid, they require lifelong replacement with thyroid hormone.
    • The possibility exists that radioactive iodine can precipitate thyroid storm by releasing thyroid hormones. This risk is higher in elderly and debilitated patients. This problem can be addressed by pretherapy administration with antithyroidal medication such as propylthiouracil (PTU) or methimazole, but antithyroid medication also may decrease the effectiveness of radioiodine, as discussed above.
    • If thyroid function does not normalize within 6-12 months of treatment, a second course at a similar or higher dose can be given. Third courses are rarely needed.
    • Hypothyroidism may ensue in the first year in up to 90% of patients given higher doses of radioiodine. The incidence of permanent hypothyroidism is 3% per year many years after treatment.
    • Approximately one third of patients develop transient hypothyroidism. Unless a patient is highly symptomatic, thyroxine replacement may be withheld if hypothyroidism occurs within the first 2 months of therapy. If it persists for longer than 2 months, permanent hypothyroidism is likely and replacement with T4 should be initiated.
    • Radiation thyroiditis is rare, but it may occur and exacerbate thyrotoxicosis.
    • Long-term follow-up is mandatory for all patients.
    • One concern with the use of radioiodine in persons with Graves disease is its controversial potential for exacerbating existing Graves ophthalmopathy. However, the presence of ophthalmopathy should not influence the choice of therapy for hyperthyroidism. If possible in patients with mild progressive ophthalmopathy, institute a course of steroids (prednisone up to 1 mg/kg) for 2-3 months, tapering a few days before radioiodine therapy. For those with no obvious ophthalmopathy, the chances of exacerbation are much lower. In patients with severe Graves ophthalmopathy, treatment of hyperthyroidism and ophthalmopathy should proceed concurrently and independently of each other.
    • The absolute contraindication for radioiodine is pregnancy. No evidence of germ-line mutations has been demonstrated from gonadal exposure. The incidence of birth defects or abnormal pregnancies has not increased after radioiodine treatments.30 After radioiodine therapy, germinal epithelium and Leydig cell function may change marginally, which may have some clinical significance in male patients with preexisting fertility impairment.31
    • Because it is known that low-dose thyroid radiation exposure in children increases the risk of thyroid cancer later in life, larger doses of131 I are recommended for children.32 If patients are aged 6-10 years, ablative doses of131 I (100-150 mCi/g of thyroid tissue) may be used to prevent the survival of thyroid cells that may be transformed.
  • Graves ophthalmopathy
    • Graves ophthalmopathy can be divided into 2 clinical phases: the inflammatory stage and the fibrotic stage. The inflammatory stage is marked by edema and deposition of glycosaminoglycan in the extraocular muscles. This results in the clinical manifestations of orbital swelling, stare, diplopia, periorbital edema, and at times, pain. The fibrotic stage is a convalescent phase and may result in further diplopia and lid retraction. It improves spontaneously in 64% of patients.
    • Approximately 10-20% of patients have gradual progression of disease over many years, followed by clinical stability. Approximately 2-5% have progressive worsening of the disease, with visual impairment in some.
    • Correction of both hyperthyroidism and hypothyroidism is important for the ophthalmopathy. Antithyroid drugs and thyroidectomy do not influence the course of the ophthalmopathy, whereas radioiodine treatment may exacerbate preexisting ophthalmopathy but can be prevented by glucocorticoids. In the long term, thyroid ablation may be beneficial for ophthalmopathy because of the decrease in antigens shared by the thyroid and the orbit in the autoimmune reactions. In general, treatment of hyperthyroidism is associated with an improvement of ophthalmopathy, but hypothyroidism must be avoided because it worsens ophthalmopathy.
    • For mild-to-moderate ophthalmopathy, local therapeutic measures (eg, artificial tears and ointments, sunglasses, eye patches, nocturnal taping of the eyes, prisms, elevating the head at night) can control symptoms and signs.
    • If the disease is active, the mainstays of therapy are (1) high-dose glucocorticoids,33 (2) orbital radiotherapy, (3) both, or (4) orbital decompression. For severe or progressive disease, glucocorticoids at 40 mg/d (usual dose) may be tried. The drug should be continued until evidence of improvement and disease stability is observed. The dosage is then tapered over 4-12 weeks. High-dose pulse glucocorticoid therapy has also been used with good results.
    • If no response to therapy occurs in the inflammatory phase, orbital radiotherapy with or without steroids may be tried. Orbital radiotherapy does not increase the risk for radiation-induced tumors, cataract, and retinopathy, except in patients with diabetes with possible or definite retinopathy. Diuretics have a limited effect on the edema caused by venous engorgement of the orbit.
    • Gamma knife surgery has been attempted with success in a limited number of patients, but further studies are needed to validate this approach.
    • Surgical management is generally performed in the fibrotic phase, when the patient is euthyroid. See Surgical Care.
    • Novel treatments such as somatostatin analogs or intravenous immunoglobulins are under evaluation. Studies with octreotide LAR (long-acting, repeatable) show conflicting or marginal therapeutic benefit for patients with Graves ophthalmopathy.34,35,36 Infliximab, an anti-tumour necrosis factor alpha (TNF-α) antibody, has been reported to successfully treat a case of sight-threatening Graves ophthalmopathy.37 Rituximab, anti-CD20 monoclonal antibody, may transiently deplete B-lymphocytes and potentially suppress the active inflammatory phase of Graves ophthalmopathy (TAO).38 A multicentered prospective pilot study suggests that periocular injection of triamcinolone may reduce diplopia and the size of extraocular muscles in patients with Graves ophthalmopathy of recent onset. In a prospective randomized trial, pentoxifylline improved symptoms and proptosis in the inactive phase of Graves ophthalmopathy.
  • Pretibial myxedema
    • Some degree of pretibial (localized dermopathy) myxedema is observed in 5-10% of patients, with 1-2% having cosmetically significant lesions.
    • Affected patients tend to have more severe ophthalmopathy than those who are not affected.
    • It usually manifests as elevated, firm, nonpitting, localized thickening over the lateral aspect of the lower leg, with bilateral involvement. It also may involve the upper extremities.
    • Milder cases do not require therapy other than treatment of the thyrotoxicosis.
    • Therapy with topical steroids applied under an occlusive plastic dressing film (eg, Saran Wrap) for 3-10 weeks has been helpful.
    • In severe cases, pulse glucocorticoid therapy may be tried.
  • Acropachy
    • Clubbing of fingers with osteoarthropathy, including periosteal new bone formation, may occur.
    • This almost always occurs in association with ophthalmopathy and dermopathy.
    • No therapy has been proven to be effective.

Surgical Care

  • Indications and outcomes
    • Thyroidectomy is no longer the recommended first-line therapy for hyperthyroid Graves disease. However, a retrospective cohort study39 showed that one-third of all patients electing surgery as definitive management did so without a specific indication, and the patient satisfaction with the decision for surgery as definitive management of Graves disease was high. Surgery is a safe alternative therapeutic option in patients who are noncompliant with or cannot tolerate antithyroid drugs, have moderate-to-severe ophthalmopathy, have large goiters, or refuse or cannot undergo radioiodine therapy.
    • Thyroidectomy may be appropriate in the presence of a thyroid nodule that is suggestive of carcinoma.
    • In certain cases (eg, in pregnant patients with severe hyperthyroidism), thyroidectomy may be indicated because radioactive iodine and antithyroid medications may be contraindicated.
    • It generally is reserved for patients with large goiters with or without compressive symptoms.
    • It also may be indicated in patients who refuse radioiodine as definitive therapy or in those in whom the use of antithyroid drugs and/or radioiodine does not control hyperthyroidism.
    • Surgery provides rapid treatment of Graves disease and permanent cure of hyperthyroidism in most patients, and it has "negligible mortality and acceptable morbidity" by experienced surgeons.40
  • Procedures and preparations
    • Preoperative preparation to render the patient euthyroid is essential in order to prevent thyrotoxic crisis (thyroid storm). The hyperthyroid state can be rapidly corrected using a combination of iopanoic acid, dexamethasone, beta-blockers, and thionamides.41
    • This can be accomplished with the use of antithyroid drugs for approximately 6 weeks, with or without concomitant beta-blockade.
    • Most surgeons administer iodine (as Lugol solution or saturated solution of potassium iodide to provide >30 mg of iodine/d) for 10 days before surgery to decrease thyroid gland vascularity, the rate of blood flow, and intraoperative blood loss during thyroidectomy.42
    • With experienced surgeons, vocal cord paralysis due to superior or recurrent laryngeal nerve injury and hypoparathyroidism are rare adverse events, occurring in less than 1% of patients.
    • Subtotal thyroidectomy is usually used with the intention of leaving enough thyroid remnants behind to avoid hypothyroidism.
    • Importantly, keep in mind that the risk of recurrent hyperthyroidism potentially increases with larger remnant sizes. However, many studies have shown that the size of the remnant is not the only determinant of the risk of recurrence.
    • Iodine uptake and immunologic activity (eg, level of TSI) are just 2 of the other factors that influence the risk of recurrent hyperthyroidism.
    • If the goal of surgery is to avoid recurrent hyperthyroidism, near-total thyroidectomy has been advocated as the procedure of choice.
    • Regardless of the extent of surgery, all patients require long-term follow-up.
  • Ophthalmopathy
    • Near-total thyroidectomy has little, if any, effect on the course of ophthalmopathy.
    • If ophthalmopathy is severe but inactive, orbital decompression may be performed. Reducing proptosis and decompressing the optic nerve can be achieved by transantral orbital decompression.
    • The major adverse effect is postoperative diplopia, which may necessitate a second surgery on the extraocular muscles to correct the problem.
    • Rehabilitative (extraocular muscle or eyelid) surgery is often needed. Eyelid surgery (eg, severance of the Müller muscle, scleral or palatal graft insertion) can be performed to improve exposure keratitis.

Consultations

  • Consultation with an endocrinologist may be necessary for the management and regulation of thyroid hormone levels in atypical presentations, as follows:
    • Graves disease in pregnancy
    • Neonatal Graves disease management
    • Graves disease complicated by a nodular thyroid gland unresponsive to usual medical therapy or in older adults
  • Consultation with an ophthalmologist may be needed in the following situations:
    • Unilateral or bilateral proptosis
    • Workup of other etiologies for eye findings besides Graves disease
    • Follow-up of visual acuity, corneal disease prevention, and eye muscle function
  • Consultation with a dermatologist may be needed in patients with localized myxedema that is unresponsive to topical corticosteroids.

Diet

The amount of iodine in the diet can influence the hormone synthesis activity in the thyroid gland.

  • Iodine-containing food has different effects on thyroid uptake of131 I and technetium Tc 99m. Iodine-rich food decreases131 I uptake but increases99m Tc in most patients. However, the diagnostic value of a radioiodine uptake test to differentiate Graves disease and silent thyroiditis is not affected by dietary iodine intake. Iodine restriction before a radioiodine uptake test is unnecessary.
  • Dietary iodine intake may influence the remission rate after antithyroid drug therapy. This is based on the observation that the outcome of antithyroid therapy in the older literature showed lower remission rates than it did in later studies and that the average dietary iodine content has been decreasing over the years. However, a direct causal relationship has not been established by clinical trials.

Activity

Given the high-output state of the heart, strenuous exercise may be detrimental. The patient should be advised to avoid severe fatigue from exercise. Patients can use their pulse as a guide to activity.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Antithyroid agents

Thioamides function as antithyroid agents mainly by inhibiting iodide organification and coupling processes, thereby preventing synthesis of thyroid hormones. Half-life of T4 is 7 d in persons who are euthyroid and somewhat shorter in patients who are thyrotoxic. This accounts for a several-week delay in onset of clinical improvement in most patients. Agents have been reported to alter intrathyroidal immunoregulatory mechanisms. Only oral preparations are available, but they have been used as retention enemas in patients in whom oral intake is not possible or is contraindicated.

Although these agents fall under pregnancy category D, they have been used safely in many pregnant patients. Retrospective study indicates rate of major congenital malformations with PTU (3%) or methimazole (2.7%) was not significantly different from normal background rate (2-5%). Duration of treatment ranged from 0-23 wk, with doses ranging from 100-600 mg/d of PTU or 10-60 mg/d of methimazole.

Concentrations of methimazole are higher in breast milk; therefore, PTU is preferred in this patient population.

Risk of agranulocytosis is similar (0.2-0.5%) in members of this class. In general, PTU is associated with transaminase elevation in susceptible individuals, while methimazole may cause a cholestatic effect.43

The US Food and Drug Administration (FDA) has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with PTU. Of the adults, 12 deaths and 5 liver transplants occurred, and among the pediatric patients, 1 death and 6 liver transplants occurred. PTU is indicated for hyperthyroidism due to Graves disease. These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death).

PTU is considered to be a second-line drug therapy, except in patients who are allergic to or intolerant of methimazole, or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy. The FDA recommends the following criteria be considered for prescribing PTU (for more information see the FDA Safety Alert)44 :

  • Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole.
  • Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.
  • For suspected liver injury, promptly discontinue PTU therapy, evaluate the patient for evidence of liver injury, and provide supportive care.
  • PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole and no other treatment options are available.
  • Counsel patients to promptly contact their health care provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.


Propylthiouracil

Derivative of thiourea that inhibits organification of iodine by thyroid gland. Blocks oxidation of iodine in thyroid gland, thereby inhibiting thyroid hormone synthesis; inhibits T4-to-T3 conversion by blocking type I deiodinase (advantage over other agents). Usual course/duration of therapy is 1-2 y; sustained remission more likely after 1-2 y vs 3-6 mo of therapy.

Adult

Not first-line agent
Initial: 300-400 mg/d PO divided tid; not to exceed 1200 mg/d
Maintenance (patient euthyroid): 100-300 mg/d PO
If PO not possible, administer PR as retention enema with propylthiouracil dissolved in Fleet mineral oil, phospho soda, or water q6h in patients with thyroid storm (Yeung, 1995)

Pediatric

Not first-line agent
<6 years: 120-200 mg/m2/d PO divided tid initially
6-10 years: 50-150 mg/d or 5-7 mg/kg/d PO divided q6-8h
>10 years: 150-300 mg/d or 5-7 mg/kg/d PO divided q6-8h
Maintenance (patient euthyroid): 50 mg bid or 33-66% of initial dose

Has anti–vitamin K activity; may potentiate activity of oral anticoagulants; propylthiouracil pretreatment reduces the cure rate of radioiodine therapy in Graves disease (Bonnema, 2004)

Documented hypersensitivity; breastfeeding; pediatric patients (unless allergic or intolerant to methimazole and no other treatment is an option)

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Cross-sensitivity between thioamide compounds for minor reactions is low; if minor adverse effects occur (other than agranulocytosis), substitute thioamide; bleeding disorders or easy bruising; liver disease (anorexia, pruritus, RUQ pain, 3-fold elevation of transaminase levels); pregnancy; signs of infection; monitor WBC count and differential (rate of life-threatening infection related to agranulocytosis induced by antithyroid medication is 0.2-0.5%; agranulocytosis usually occurs 2-3 mo after starting therapy, unrelated to therapy dosage); pruritus to exfoliative dermatitis may result, cross-reactivity is not always seen with this adverse effect; ANCA-positive vasculitis (including vasculitic oral ulcers (Karincaoglu, 2006); ANCA-positive pyoderma gangrenosum (Gungor, 2006); although propylthiouracil is listed in pregnancy category D (below), expert opinion recommends that the drug should still be considered as the first-line agent in the treatment of Graves disease during pregnancy (Chattaway, 2007)
Risk of serious liver injury, including liver failure and death, has been reported in adults and children by the FDA (carefully consider drug therapy, and if PTU initiated, monitor for symptoms and signs of liver injury, especially during first 6 mo of therapy)


Methimazole (Tapazole)

Inhibits thyroid hormone by blocking oxidation of iodine in thyroid gland; however, not known to inhibit peripheral conversion of thyroid hormone. Considerable debate surrounds optimal dosage/duration.

Adult

30-40 mg/d PO can reduce free thyroxine concentrations to normal or subnormal within 3 mo; 10 mg/d is less effective
Maintenance strategy 1 (patient euthyroid): Titration to maintain euthyroidism after initial normalization of thyroid hormone level
Maintenance strategy 2 (patient euthyroid): 40-60 mg/d PO to suppress thyroid hormone to hypothyroid levels in all patients; thyroxine supplements administered to the 40-mg group to establish and maintain euthyroid condition; relapse rates in patients receiving 60 mg/d with thyroxine supplements were significantly lower than in patients taking low doses alone with titration regimen (initially 15 mg bid)
Support for this method has not been found in the literature since its initial report
Initial: 15 mg/d PO for mild hyperthyroidism; 30-40 mg/d for moderate-to-severe; 60 mg/d for severe
Maintenance: 5-30 mg/d PO; some data suggest single qd dose of 30 mg/d to be as effective as divided doses of 10 mg tid
Thyroid storm or thyrotoxic crisis: 60-120 mg/d divided tid

Pediatric

Average dose: 0.4-0.7 mg/kg/d PO divided tid
Maintenance: 50% initial dose; not to exceed 30 mg

Has anti–vitamin K activity and may potentiate activity of oral anticoagulants

Documented hypersensitivity; breastfeeding

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Bleeding disorders and easy bruising; liver disease (anorexia, pruritus, RUQ pain, 3-fold elevation of transaminase levels); pregnancy; signs of infection; surgery; monitor WBC count and differential; also associated with cholestasis

Beta-adrenergic blocker

Both cardioselective and noncardioselective types are important adjuncts in treating hyperthyroidism. Beta-blockade provides rapid relief of hyperadrenergic symptoms and signs of thyrotoxicosis (eg, palpitations, tremors, anxiety, heat intolerance, various eyelid signs) before any decrease in thyroid hormone levels demonstrated. Also useful in preventing episodes of hypokalemic periodic paralysis in susceptible individuals. DOC for thyroiditis, which is self-limiting. Higher-dose propranolol can inhibit peripheral T4-to-T3 conversion. Also useful in preparing thyrotoxic patients for surgery.


Propranolol (Inderal, Inderal LA)

DOC in treating cardiac arrhythmias resulting from hyperthyroidism. Controls cardiac and psychomotor manifestations within minutes.
Drug completely absorbed from GI tract; because of extensive first-pass metabolism in liver, systemic bioavailability affected by hepatic blood flow, intrinsic clearance in liver, and genetic and age differences in individuals.
Dosage prediction for IV from prior PO difficult; therefore, careful titration of IV dose necessary.

Adult

Initial: 10 mg PO qid; increase until symptoms controlled
Maintenance: 40-60 mg PO qid; 120 mg qid has been used
Rapid control of thyroid storm: 1 mg/min IV; not to exceed 10 mg, with continuous ECG monitoring; may repeat in 4-6 h
Thyroid surgery preparation: Sole or adjunctive therapy for patients undergoing subtotal thyroidectomy, 20-40 mg qid titrated to achieve pulse rate of <90 bpm administered 4 d to 2 wk preoperatively and continued for 7-10 d postoperatively

Pediatric

Neonates: 2 mg/kg/d IV divided q6h as adjunct to antithyroid medications
Adolescents: 1-3 mg/dose IV once over 10 min; alternatively, 10-40 mg PO q6h

Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase

Documented hypersensitivity; bronchial asthma or chronic obstructive pulmonary disease; cardiogenic shock; overt cardiac failure; second- and third-degree AV block; severe sinus bradycardia

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Beta-adrenergic blockade may decrease signs of acute hypoglycemia and hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; withdraw drug slowly and monitor closely; caution in bronchospastic disease, cerebrovascular insufficiency, congestive heart failure, diabetes mellitus, hepatic disease, myasthenic conditions, peripheral vascular disease, and renal disease


Atenolol (Tenormin)

Selectively blocks beta1 receptors with little or no effect on beta2 types. Useful in treating cardiac arrhythmias resulting from hyperthyroidism.

Adult

50-100 mg/d PO
0.5 mg/min IV in 2.5-mg aliquots at 10-min interval between each; not to exceed 10 mg

Pediatric

0.3-1.4 mg/kg/d PO qd; may increase by increments of 0.5 mg/kg/d q3-4d; not to exceed 2 mg/kg/d

Coadministration with aluminum salts, barbiturates, calcium salts, cholestyramine, NSAIDs, penicillins, and rifampin may decrease effects; haloperidol, hydralazine, loop diuretics, and MAOIs may increase toxicity

Documented hypersensitivity; congestive heart failure; pulmonary edema; cardiogenic shock; AV conduction abnormalities and heart block (without a pacemaker)

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may reduce symptoms of acute hypoglycemia and mask signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism and cause thyroid storm; monitor patients closely and withdraw drug slowly; during IV, carefully monitor BP, heart rate, and ECG; caution in bronchospastic disease, congestive heart failure, diabetes mellitus, patients receiving clonidine (stop atenolol several days prior to clonidine withdrawal), peripheral vascular disease, and renal disease


Metoprolol (Lopressor, Toprol XL)

Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. Useful in treating cardiac arrhythmias resulting from hyperthyroidism. During IV administration, carefully monitor BP, heart rate, and ECG.

Adult

50-450 mg PO qd, must be individualized with gradual increases at weekly intervals
2-20 mg IV qd, equivalent maximal beta-blockade achieved with PO-to-IV ratio of 2.5:1

Pediatric

Not established

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels, possibly resulting in decreased pharmacologic effects; toxicity may increase with coadministration of sparfloxacin, phenothiazines, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin, verapamil, and lidocaine

Documented hypersensitivity; cardiogenic shock; myocardial infarction; heart rate <45 bpm; second- and third-degree heart block; PR interval >0.24 seconds; systolic BP <100 mm Hg; moderate-to-severe heart failure; overt cardiac failure; severe sinus bradycardia

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may reduce signs and symptoms of acute hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; monitor patient closely and withdraw drug slowly; during IV administration, carefully monitor BP, heart rate, and ECG

Iodines

Have long been used to treat thyrotoxicosis and are still important adjunctive therapy for hyperthyroidism in modern medicine. In pharmacologic concentrations (100-times normal plasma level), decrease activity of thyroid gland. Action involves decreasing thyroidal iodide uptake, decreasing iodide oxidation and organification, and blocking release of thyroid hormones (Wolff-Chaikoff effect).

Oral contrast agents ipodate or iopanoic acid also shown to be potent inhibitors of T4-to-T3 conversion, making them ideal for severe or decompensated thyrotoxicosis. Generally administered after thioamide is started. Also used as preoperative preparation for thyroid surgery for Graves disease.

In combination with thioamides and/or propranolol, iodines are used routinely before thyroidectomy. Iodines are given for 2-3 weeks before surgery and decrease vascularity of hyperthyroid gland. Making patient euthyroid before surgery prevents intraoperative and postoperative complications.


Potassium iodide; Lugol solution (SSKI, Pima)

Inhibits thyroid hormone secretion.
Contains 5% iodine and 10% potassium iodide. Contains 8 mg of iodide per drop. May be mixed with juice or water for intake.

Adult

1-2 gtt tid mixed in juice or water
Preoperative reduction of thyroid gland vascularity: 60-250 mg (approximately 1-5 gtt of solution containing 1 g/mL) PO tid for 10 d before surgery
Administration dissolved in water has been given by retention enema to patient with thyroid storm (Yeung, 1995)

Pediatric

Neonate: 1 gtt q8h
Children: 2-5 gtt q8h

Increases lithium toxicity by producing additive hypothyroid effects

Documented hypersensitivity; pulmonary edema; bronchitis; tuberculosis; hyperkalemia; severe chronic reaction (iodism)

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Use caution or avoid in acute bronchitis, hyperthyroidism, Addison disease, acute or chronic renal disease, tuberculosis, or acute dehydration; persons with goiter, autoimmune thyroid disease, or with hypocomplementemic vasculitis are at particular risk for adverse reactions; prolonged or excess use may lead to hypothyroidism, thyroid gland hyperplasia, goiter, or thyroid adenoma; use by nursing mothers may cause rash and thyroid suppression in infant; prolonged use may cause dermatitis


Diatrizoate sodium (Hypaque sodium)

Blocks release of thyroid hormones.

Adult

50-125 mL IV
Patients must be well hydrated prior to examination

Pediatric

Adjust dose proportionally to age and weight

When used with lithium, additive hypothyroid effects may be seen

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor for thromboembolic events that may cause MI and stroke


Iopanoic acid (Telepaque)

Oral contrast agent for rapid and significant inhibition of peripheral T4-to-T3 conversion. Inorganic iodide released also blocks release of thyroid hormones.

Adult

1-3 g/d PO divided bid

Pediatric

Neonates: 100-200 mg/d PO
Children: 0.6 g/m2/d PO

When used with lithium, additive hypothyroid effects may be seen

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Use caution in hypersensitivity to iodinated products; possibility of hypotension increases with increased dosage; anuria may develop if agents are administered to patients with combined hepatic and renal disease or severe renal impairment; prolonged iodine storage in tissues may lead to rebound thyrotoxicosis with potential to cause thioamide resistance

Bile acid sequestrants

Based on the observation that a small portion of L-thyroxine is usually reabsorbed in the bowel and recycled in the enterohepatic circulation, exchange resins have been used to bind thyroid hormones in the GI tract. Enterohepatic circulation of thyroxine is increased in cases of hyperthyroidism.


Cholestyramine (Questran)

Can be used to lower serum thyroid hormone levels. This cholesterol-lowering resin has been used as adjunctive therapy in management of hyperthyroid Graves disease. Proved to be effective and well-tolerated adjunctive therapy, leading to a more rapid reduction of thyroid hormone levels.

Adult

4 g PO q6h

Pediatric

Not established

Inhibits absorption of numerous drugs, including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, and penicillin G

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in constipation and phenylketonuria

Antidepressants

Act in a manner similar to iodine but is not routinely used because of transient effect and risk of potentially serious adverse effects. Now primarily used as a backup agent when other first-line agents are contraindicated because of hypersensitivity or toxicity.


Lithium (Lithotabs, Eskalith, Lithobid)

Patients intolerant to iodine can be treated with lithium, which also impairs thyroid hormone release. Can be used in patients who cannot take PTU or MMI. Use of iodine alone is debatable.

Adult

300-600 PO tid/qid in divided doses

Pediatric

<6 years: Not established
6-12 years: 15-60 mg/kg/d PO tid/qid; not to exceed usual adult dose
>12 years: Administer as in adults

Increases toxicity of thiazide diuretics, haloperidol, phenothiazines, neuromuscular blockers, carbamazepine, fluoxetine, and ACE inhibitors

Documented hypersensitivity; severe cardiovascular disease

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Toxicity is closely related to serum levels and can occur at therapeutic doses; serum determinations required to monitor therapy

Antiarrhythmics

Amiodarone, an iodinated benzofuran, is an important antiarrhythmic medication that also alters thyroid hormone metabolism. High iodine content of this molecule is responsible for hypothyroidism. On the other hand, amiodarone can lead to hyperthyroidism through 2 complex mechanisms. Type I amiodarone-induced thyrotoxicosis is due to increased thyroid hormone synthesis and release in patients with multinodular goiter or Graves disease, while type II amiodarone-induced thyrotoxicosis is a destructive thyroiditis with release of preformed thyroid hormone.


Amiodarone (Cordarone)

Case report described successful normalization of thyroid hormone level in a patient with Graves disease who had fulminant PTU-induced hepatitis. However, experience and information in treatment of Graves disease is scant.

Adult

200 mg PO qd

Pediatric

Not established

Increases effect and blood levels of theophylline, quinidine, procainamide, phenytoin, methotrexate, flecainide, digoxin, cyclosporine, beta-blockers, and anticoagulants; cardiotoxicity increased by ritonavir, sparfloxacin, and disopyramide; coadministration with calcium channel blockers may cause additive effect and further decrease myocardial contractility; cimetidine may increase levels; protease inhibitors (eg, indinavir, ritonavir, amprenavir, nelfinavir) inhibit metabolism, resulting in increased serum levels, and may prolong QT interval

Documented hypersensitivity; complete AV block; intraventricular conduction defects; coadministration with ritonavir or sparfloxacin

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in thyroid or liver disease

Glucocorticoids

Graves disease is an autoimmune disease. Although glucocorticoids have been shown to decrease T4-to-T3 conversion and decrease thyroid hormones by yet undiscovered mechanisms, the adverse effect profile of long-term glucocorticoid therapy makes it unattractive for long-term management of Graves hyperthyroidism. However, glucocorticoids may have a role in rapidly lowering thyroid hormone levels in the clinical setting of thyroid storm. With regard to Graves ophthalmopathy, current evidence indicates that glucocorticoids represent the only class of drug therapy that, either alone or combined with other therapies, has an unequivocal role in management.


Prednisone (Orasone, Deltasone, Sterapred)

Has been customarily used in management of Graves ophthalmopathy. Other oral glucocorticoids at equipotent doses may also be effective.

Adult

Prevention of exacerbation of ophthalmopathy after radioiodine treatment of Graves disease: 0.4-0.5 mg/kg body weight PO for 1 mo initially; gradually withdraw over next 3 mo
Treatment of active Graves ophthalmopathy: 60-100 mg/d PO, progressively reduced q2wk for total duration of 4-6 mo

Pediatric

Not established

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI bleeding or ulceration

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur


Methylprednisolone (Solu-Medrol)

Has been customarily used for high-dose pulse steroid therapy in management of Graves ophthalmopathy. Other glucocorticoids at equipotent doses may also be effective. Intravenous high dose glucocorticoid therapy may be more effective and better tolerated than oral steroid therapy in the management of Graves ophthalmopathy (Aktaran, 2007).

Adult

Different regimens have been used:
A) 1 g diluted in 250-500 mL of isotonic solution infused IV twice weekly for 6 wk (Macchia, 2001)
B) 15 mg/kg for 4 cycles and then 7.5 mg/kg for 4 cycles; each cycle consists of 2 infusions on alternate days at 2-wk intervals 12.5 mg/kg IV over 10 h every month for 3-6 months; 0.5 mg/kg/d prednisone given as interpulse therapy (Marcocci, 2001)

Pediatric

Not established

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics; grapefruit juice increases prednisolone concentrations; methylprednisolone and cyclosporine mutually inhibit one another, resulting in increased plasma levels of both

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications


Dexamethasone (Decadron)

In healthy persons, induces decrease in serum T3 levels without a change in serum T4 levels, suggesting an effect of dexamethasone on peripheral T3-to-T4 conversion.
In patients with Graves hyperthyroidism, induces rapid fall in serum thyroid hormone levels. Changes are too rapid to be explained by a steroid-induced fall in the level of a circulating IgG thyroid stimulator (TSI). Mechanism for this observation is unclear.

Adult

2 mg PO q6h

Pediatric

Not established

Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; decreases effect of salicylates and vaccines used for immunization

Documented hypersensitivity; active bacterial or fungal infection

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering; abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications

More on Graves Disease

Overview: Graves Disease
Differential Diagnoses & Workup: Graves Disease
Treatment & Medication: Graves Disease
Follow-up: Graves Disease
Multimedia: Graves Disease
References
Further Reading
[ CLOSE WINDOW ]

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Keywords

Graves disease, Graves’ disease, thyroid disease, hyperthyroidism, thyrotoxicosis, thyroid eye disease, Graves disease symptoms, Graves thyroid disease, Graves disease eye, Graves ophthalmopathy, Graves hyperthyroidism, autoimmune thyroid disorder, thyroglobulin, thyroperoxidase, thyroid storm, thyroid acropachy

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Contributor Information and Disclosures

Author

Sai-Ching Jim Yeung, MD, PhD, FACP, Deputy Section Chief of Emergency Care, Assistant Professor, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, University of Texas MD Anderson Cancer Center
Sai-Ching Jim Yeung, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Medical Association, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

Mouhammed Amir Habra, MD, Endocrine Fellow, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center
Mouhammed Amir Habra, MD is a member of the following medical societies: American College of Physicians, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

Alice Cua Chiu, MD, Consulting Staff, Department of Internal Medicine, Division of Endocrinology, Columbia Bayshore Medical Center
Alice Cua Chiu, MD is a member of the following medical societies: American Medical Association and Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Steven R Gambert, MD, MACP, Chairman, Department of Medicine, Physician-in-Chief, Sinai Hospital of Baltimore; Professor of Medicine, Program Director, Internal Medicine Program, Johns Hopkins University School of Medicine
Steven R Gambert, MD, MACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American Geriatrics Society, Association of Professors of Medicine, Endocrine Society, and Gerontological Society of America
Disclosure: Nothing to disclose.

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Disclosure: eMedicine Salary Employment

Managing Editor

Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Kent Wehmeier, MD is a member of the following medical societies: American Society of Hypertension, Endocrine Society, and International Society for Clinical Densitometry
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CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
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