Hyperthyroidism and Thyrotoxicosis Treatment & Management

Treatment of hyperthyroidism and thyrotoxicosis includes symptom relief, while hyperthyroidism also requires antithyroid pharmacotherapy, radioactive iodine-131 (¹³¹I) therapy (the preferred treatment of hyperthyroidism among US thyroid specialists), or thyroidectomy. However, antithyroid medications are not effective in thyrotoxicosis in which scintigraphy shows low uptake of iodine-123 (¹²³I), as in patients with subacute thyroiditis, because these cases result from release of preformed thyroid hormone.

If a physician treats enough patients who are hyperthyroid, eventually he or she will encounter a patient who develops agranulocytosis or hepatitis from the antithyroid medications. Discussing these adverse effects with patients before starting therapy is important; accordingly, patients should be given written or documented verbal instruction to the effect that if they develop high fever (>100.5°F) or a severe sore throat, they should stop the medication and seek medical attention.

Guidelines for the management of hyperthyroidism and other causes of thyrotoxicosis were developed by the American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists; ^[4] these were updated in 2016. ^[5]

Although 50% of patients with Graves disease have mild signs and symptoms of thyroid eye disease, only 5% develop severe ophthalmopathy (eg, diplopia, visual-field deficits, or blurred vision). ^[4] Less serious ophthalmologic symptoms (eg, photophobia, irritation, and tearing) are treated with tight-fitting sunglasses, which should be worn at all times when the patient is outside, and with saline eye drops that are taken as necessary for comfort.

If exposure keratitis is suspected, the patient should be monitored by an ophthalmologist. This condition usually occurs when eyelid closure is incomplete and the cornea is exposed at night, when the patient does not blink. Typically, patients complain of irritation and tearing on awakening. Treatment includes administering saline gel or drops and taping eyelids closed with paper tape before sleep. Some ophthalmologists are concerned about corneal abrasion from the tape and instead recommend that patients wear goggles at night to keep the eyes moist.

A medical emergency occurs when sufficient orbital edema exists to cause optic nerve compression with early loss of color vision and orbital pain. Without treatment, continued pressure on the optical nerve may cause permanent vision loss. High-dose glucocorticoids are administered, with consideration given to orbital decompression surgery, ocular radiation therapy, or a recently approved treatment from the US Food and Drug Administration (FDA), teprotumumab-trbw, a monoclonal antibody that blocks the insulin-like growth factor-1 receptor (IGF-1R) and ameliorates proptosis by reducing inflammation and preventing muscle and fat-tissue remodeling in the orbit.

Infiltrative dermopathy, usually developing over the lower extremities, is characterized by an accumulation of glycosaminoglycans and inflammatory cells in the dermis. The skin changes typically include a nonpitting erythematous edema of the anterior shins. Dermopathy can occur at other sites of repeat trauma. The dermopathy usually occurs only in the presence of significant ophthalmopathy.

No effective treatment exists. Nightly occlusive wraps of the affected site are recommended, with plastic wrap used after the application of a high-potency topical steroid cream.

Many of the neurologic and cardiovascular symptoms of thyrotoxicosis are relieved by beta-blocker therapy. Before such therapy is initiated, the patient should be examined for signs and symptoms of dehydration that often occur with hyperthyroidism. After oral rehydration, beta-blocker therapy can be started. Beta-blocker therapy should not be administered to patients with a significant history of asthma.

Calcium channel blockers (eg, verapamil and diltiazem) can be used for the same purposes when beta-blockers are contraindicated or poorly tolerated. These therapies should be tapered and stopped once thyroid functions are within the normal range.

Antithyroid drugs (eg, methimazole and propylthiouracil) have been used for hyperthyroidism since their introduction in the 1940s. These medications are employed for long-term control of hyperthyroidism in children, adolescents, and pregnant women. In adult men and nonpregnant women, they are used to control hyperthyroidism before definitive therapy with radioactive iodine.

Antithyroid medications inhibit the formation and coupling of iodotyrosines in thyroglobulin. Because these processes are necessary for thyroid hormone synthesis, this inhibition induces a gradual reduction in thyroid hormone levels over 2-8 weeks or longer. A second action of propylthiouracil (but not methimazole) is inhibition of conversion of thyroxine (T4) to triiodothyronine (T3). T3 is more biologically active than T4; thus, a quick reduction in T3 levels is associated with a clinically significant improvement in thyrotoxic symptoms.

The antithyroid drug dose should be titrated every 4 weeks until thyroid functions normalize. Some patients with Graves disease go into a remission after treatment for 12-18 months, and the drug can be discontinued. Notably, half of the patients who go into remission experience a recurrence of hyperthyroidism within the following year. Nodular forms of hyperthyroidism (ie, toxic multinodular goiter ^[28] and toxic adenoma) are permanent conditions and will not go into remission.

Methimazole is more potent than propylthiouracil and has a longer duration of action. In addition, methimazole is taken once daily, whereas propylthiouracil is taken 2-3 times daily; consequently, patient compliance is often better with methimazole than with propylthiouracil.

Methimazole is not recommended for use in the first trimester of pregnancy, because it has been associated (albeit rarely) with cloacal and scalp (cutis aplasia) abnormalities when given during early gestation. ^{[4, 29]} Generally, if a nonpregnant woman who is receiving methimazole desires pregnancy, she should be switched to propylthiouracil before conception. After 12 weeks of gestation, she can be switched back to methimazole, with frequent monitoring.

Propylthiouracil remains the drug of choice in uncommon situations of life-threatening severe thyrotoxicosis (ie, thyroid storm) because of the additional benefit of inhibition of T4-to-T3 conversion. In this setting, propylthiouracil should be administered every 6-8 hours. The reduction in T3, which is 20-100 times more potent than T4, theoretically helps reduce the thyrotoxic symptoms more quickly than methimazole would. Once thyroid levels have decreased to nearly normal values, the patient can be switched to methimazole therapy.

Except in thyroid storm, propylthiouracil is considered a second-line drug therapy. It is reserved for use in patients who are allergic to or intolerant of methimazole and in women who are in the first trimester of pregnancy or planning pregnancy.

Adverse effects of antithyroid medications

The most common adverse effects of antithyroid drugs are allergic reactions manifesting as fever, rash, urticaria, and arthralgia, which occur in 1-5% of patients, usually within the first few weeks of treatment. Serious adverse effects include agranulocytosis, aplastic anemia, hepatitis, polyarthritis, and a lupuslike vasculitis. All of these adverse effects, except agranulocytosis, occur more frequently with propylthiouracil: agranulocytosis occurs in 0.2-0.5% of patients overall and is no more common with one drug than with the other.

Patients with agranulocytosis usually present with fever and pharyngitis. After the drug is stopped, granulocyte counts usually start to rise within several days but may not normalize for 10-14 days. Granulocyte colony-stimulating factor (G-CSF) appears to accelerate recovery in patients with a bone marrow aspiration showing a granulocyte-to-erythrocyte ratio of 1:2 or greater than 0.5.

In 2010, the US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for propylthiouracil. The warning emphasized the risk for severe liver injury and acute liver failure, some cases of which have been fatal. ^[30] Severe liver injury has rarely been reported with methimazole (5 cases, 3 of which resulted in death).

The FDA recommends the following measures for patients receiving propylthiouracil (for more information, see the FDA Safety Alert) ^[30] :

• Closely monitor patients for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy

• For suspected liver injury, promptly discontinue propylthiouracil, evaluate the patient for evidence of liver injury, and provide supportive care

• Counsel patients to contact their health care provider promptly for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin

Other drugs

In severe thyrotoxicosis from Graves disease or subacute thyroiditis, iodine or iodinated contrast agents have been administered to block the conversion of T4 to T3 and the release of thyroid hormone from the gland. This therapy is reserved for severe thyrotoxicosis because its use prevents definitive therapy for Graves thyrotoxicosis with radioactive iodine for many weeks.

A saturated solution of potassium iodide (SSKI) can be administered at a dosage of 10 drops twice daily, with a consequent rapid reduction in T3 levels. Iopanoic acid/ipodate at a dosage of 1 g/day is also effective; it has not been available in the United States for several years but is available in some areas of Europe.

These drugs must not be administered to patients with toxic multinodular goiter or toxic adenomas. The autonomous nature of these conditions can lead to worsening of the thyrotoxicosis in the presence of pharmacologic levels of iodide, a substrate in thyroid hormone synthesis. This phenomenon typically presents in patients living in iodine deficient areas who relocate to an iodine sufficient geographical area or upon ingestion of iodine (Jod-Basedow syndrome).

Another drug that might be considered in management of severe thyrotoxicosis would be cholestyramine, a bile salt sequestrant. It decreases thyroid hormone levels by depleting the pool by enhancing clearance from enterohepatic circulation. Doses up to 12 grams in 3 divided daily dose have been used for 4 weeks.

Radioactive iodine therapy ^[31] is the most common treatment for Graves disease in adults in the United States. Although its effect is less rapid than that of antithyroid medication or thyroidectomy, it is effective and safe and does not require hospitalization.

A literature review by Wang and Qin of randomized, controlled trials indicated that compared with antithyroid drugs, radioiodine treatment has a higher cure rate for Graves disease and is associated with a lower recurrence rate. However, it was also found to carry a greater risk for the development or worsening of ophthalmopathy and for hypothyroidism. ^[32]

Concerns about radiation exposure after therapy have led to the issuance of new recommendations by the ATA. These recommendations are compliant with Nuclear Regulatory Commission regulations and are a practical guide for patient activity after radioactive iodine therapy, with the aim of ensuring maximum radiation safety for the family and the public. ^[33]

Radioactive iodine is administered orally as a single dose in capsule or liquid form. The iodine is quickly absorbed and taken up by the thyroid. No other tissue or organ in the body is capable of retaining the radioactive iodine; consequently, very few adverse effects are associated with this therapy. The treatment results in a thyroid-specific inflammatory response, causing fibrosis and destruction of the thyroid over weeks to many months.

Generally, the dose of ¹³¹I administered is 75-200 µCi/g of estimated thyroid tissue divided by the percent of ¹²³I uptake in 24 hours. This dose is intended to render the patient hypothyroid.

Administration of lithium in the weeks following radioactive iodine therapy may extend the retention of radioactive iodine and increase its efficacy. This may be considered in Graves disease patients with especially large Graves glands (>60 g) or in patients with extremely high thyroidal iodine uptake (>95% in 4 hours), which is associated with high iodine turnover in the gland. However, studies have yielded inconsistent results, and the benefits of using lithium with radioactive iodine must be weighed against the toxicities associated with lithium.

Hypothyroidism is considered by many experts to be the expected goal of radioactive iodine therapy. In several large epidemiologic studies of radioactive iodine therapy in patients with Graves disease, no evidence indicated that radioactive iodine therapy caused the development of thyroid carcinoma. There is also no evidence that radioactive iodine therapy for hyperthyroidism results in increased mortality for any other form of cancer, including leukemia.

Long-term follow-up data of children and adolescents treated with radioactive iodine are lacking. ATA guidelines recommend avoiding ¹³¹I therapy in children younger than 5 years of age. In children 5 to 10 years old, ¹³¹I therapy is acceptable if the calculated activity of administered ¹³¹I is less than 10 mCi. In children older than 10 years of age, radioactive iodine therapy is acceptable if the activity is greater than 150 µCi/g of thyroid tissue.

Radioactive iodine should never be administered to pregnant women, because it can cross the placenta and ablate the fetus’s thyroid, resulting in hypothyroidism. Similarly, breastfeeding is a contraindication, in that the radioisotope is secreted in breast milk. Women will continue to receive increased radiation to the breast from radioactive iodine for a few months after ceasing lactation; accordingly, initiation of this therapy should be delayed.

It is standard practice to check for pregnancy before starting radioactive iodine therapy and to recommend that the patient not become pregnant for at least 3-6 months after the treatment or until thyroid functions normalize. No excess fetal malformations or increased miscarriage rates have been found in women previously treated with radioactive iodine for hyperthyroidism.

Radioactive iodine usually is not administered to patients with severe ophthalmopathy, because clinical evidence suggests that worsening of thyroid eye disease occurs after radioactive iodine therapy. This worsening is usually mild but occasionally severe. Moreover, radioactive iodine usually is not given to patients who cannot comply with physician restrictions for avoidance of radiation exposure to others.

The risk of ophthalmopathy is greater in patients who smoke cigarettes, but it can be reduced by providing glucocorticoid therapy (prednisone 0.4 mg/kg for 1 month with subsequent taper) after radioactive iodine therapy.

Subtotal thyroidectomy is the oldest form of treatment for hyperthyroidism. Total thyroidectomy and combinations of hemithyroidectomies and contralateral subtotal thyroidectomies also have been used. ^{[31, 34]}

Because of the excellent efficacy of antithyroid medications and radioactive iodine therapy in regulating thyroid function, thyroidectomy is generally reserved for special circumstances, including the following:

• Severe hyperthyroidism in children

• Pregnant women who are noncompliant with or intolerant of antithyroid pharmacotherapy

• Patients with very large goiters or severe ophthalmopathy

• Patients who refuse radioactive iodine therapy

• Patients with refractory amiodarone-induced hyperthyroidism

• Patients who require normalization of thyroid functions quickly, such as pregnant women, women who desire pregnancy in the next 6 months, or patients with unstable cardiac conditions

Preparation for thyroidectomy includes antithyroid medication, stable (cold) iodine treatment, and beta-blocker therapy. ^[34] Generally, antithyroid drug therapy should be administered until thyroid functions normalize (4-8 weeks). Propranolol is titrated until the resting pulse rate is lower than 80 beats/min. Finally, iodide is administered as SSKI (1-2 drops twice daily for 10-14 days) before the procedure. Stable iodide therapy both reduces thyroid hormone excretion and decreases thyroid blood flow, which may help reduce intraoperative blood loss.

A Swiss study found that administration of a single dose of steroid (dexamethasone 8 mg) before thyroidectomy can reduce the nausea, pain, and vomiting associated with the procedure, as well as improve voice function. ^[35] Benefits were most pronounced in the first 16 hours after the operation. Postoperative steroid administration is not considered to be the standard of care for thyroid surgery in the United States.

With current operative techniques, bilateral subtotal thyroidectomy should have a mortality approaching zero in patients who are properly prepared. Historically, operative stress was the most common cause of thyroid storm, a physiologic decompensation in patients who are severely thyrotoxic, with a mortality of about 50%. Adverse effects of thyroidectomy include recurrent laryngeal nerve damage and hypoparathyroidism from damage to local structures during the procedure.

A literature review by Zhang et al comparing endoscopic with conventional open thyroidectomy for Graves disease reported that the endoscopic technique offers better cosmetic satisfaction and less blood loss, while open surgery is associated with reduced operation time. Complication rates for the two techniques with regard to transient recurrent laryngeal nerve palsy, recurrent hyperthyroidism, hypothyroidism, and transient hypocalcemia were equivalent. ^[36]

No special diet must be followed by patients with thyroid disease. However, some expectorants, radiographic contrast dyes, seaweed tablets, and health food supplements contain excess amounts of iodide and should be avoided because the iodide interferes with or complicates the management of antithyroid and radioactive iodine therapies.

Exercise tolerance often is not significantly affected in otherwise healthy patients with mild to moderate hyperthyroidism. For these patients, no reduction in physical activity is necessary. For patients who are elderly or have cardiopulmonary comorbidities or severe hyperthyroidism, a decrease in activity is prudent until hyperthyroidism is medically controlled.

With severe thyrotoxicosis, systolic and diastolic cardiac dysfunction often result in dyspnea on exertion. Beta-blocker therapy often greatly improves exercise tolerance until thyroid hormones levels are reduced by other therapies.

Generally, thyrotoxicosis should be evaluated and treated by an endocrinologist. Therapy, including radioactive iodine and antithyroid medication, requires careful follow-up, which is best performed by a specialist.

Generally, after definitive therapy is completed with radioactive iodine or surgical thyroidectomy, the patient can be cared for by a primary care physician. These patients may require thyroid hormone replacement therapy.

Patients with Graves thyrotoxicosis should be examined by an ophthalmologist for moderate or symptomatic thyroid eye disease, which occurs in some form in 50% of patients. Often, the eye disease is subclinical and remits with time. The eye disease usually occurs within 1 year before or after the diagnosis of hyperthyroidism, but new-onset disease has been detected decades later. Graves eye disease also can occur without the patient ever having developed hyperthyroidism.

Care after initiation of antithyroid medication

After 4-6 weeks, antithyroid medications usually must be reduced; otherwise, the patient becomes hypothyroid. Hypothyroidism causes the usual symptoms of fatigue and weight gain, and in patients with Graves disease, it has been anecdotally associated with worsening of thyroid ophthalmopathy. Initially, the patient should have thyroid function tests performed every 4-6 weeks until thyroid hormone levels are stabilized on a low dosage of antithyroid medication.

Patients with non-Graves hyperthyroidism rarely experience remissions. In patients who are placed on long-term antithyroid drug therapy with the goal of remission, follow-up tests of thyroid function should be performed at least every 3 months for the first year.

In patients with Graves disease, antithyroid medication should be stopped or decreased after 12-18 months to determine whether the patient has gone into remission. In these patients, remission is defined as a normal TSH level after cessation of antithyroid drug therapy.

Once a patient with Graves hyperthyroidism becomes euthyroid on oral antithyroid medication, other definitive treatment, such as radioactive iodine therapy or surgery, should be considered. Although a significant fraction of patients with Graves disease go into remission, as many as 20% become hypothyroid over subsequent years as a consequence of autoimmune destruction of the gland.

Care after radioactive iodine ablation

Ablation of the gland occurs over 2-5 months after radioactive iodine therapy. Most patients become hypothyroid. Checking thyroid functions every 4-6 weeks until the patient stabilizes is recommended.

Once the thyroid hormone levels start falling into the low-normal range, it is reasonable to stop antithyroid medications and to consider starting low-dose thyroid hormone replacement before the patient becomes hypothyroid; however, some physicians prefer to document persistently elevated TSH values with the patient off antithyroid medication before starting thyroid hormone replacement.

Starting with partial or low-dose thyroid hormone replacement is recommended (50-75 µg/day, adjusted every 6-8 weeks to normalize the TSH level). Several weeks after ¹³¹I therapy, patients can, in rare cases, become thyrotoxic as a result of vigorous thyroid destruction and release of preformed hormone. This process often is accompanied by a painful, radiation-induced thyroiditis that can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids.

In addition, radioablation can cause the release of thyroid antigens and exacerbate the autoimmune thyroid disease process. In such cases, Graves disease can worsen.

Care after thyroid surgery

Patients whose thyroid functions normalize after surgery require routine follow-up because hypothyroidism (from the chronic thyroiditis), recurrent hyperthyroidism, or thyroid eye disease may develop at some time in the future. Most patients remain euthyroid after a lobectomy or lobectomy plus isthmusectomy to treat a toxic adenoma or toxic multinodular goiter with a dominant nodule. To ensure normal thyroid function, thyroid function tests should be obtained 3-4 weeks after a lobectomy.

After subtotal thyroidectomy for hyperthyroidism and cessation of antithyroid therapy, most patients become hypothyroid, depending on how much functional tissue is left by the surgeon. Partial replacement (T4 50-75 µg/day) is recommended in these patients, beginning shortly after the procedure. Thyroid function tests should be monitored 4-8 weeks postoperatively, and the T4 dosage should be adjusted to maintain a normal TSH level.