Hyperthyroidism Treatment & Management

With the exception of low–¹²³ I uptake hyperthyroidism (eg, subacute thyroiditis), the treatment of hyperthyroidism includes symptom relief, as well as therapy with antithyroid medications, therapy with radioactive iodine¹³¹ I, or thyroidectomy.

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; give the patients written instructions or document verbal instructions to stop the medication and receive a blood count with differentials for a high fever (>100.5°F) or a severe sore throat.

More than 100 evidence-based guidelines have been developed by the American Thyroid Association and American Association of Clinical Endocrinologists for use in the care of patients with thyrotoxicosis.^[5]

Ophthalmopathy and dermopathy

Although 50% of patients with Graves disease have clinical evidence of thyroid eye disease, only 5% develop severe ophthalmopathy, eg, diplopia, visual-field deficits, blurred vision, tearing, and photophobia. The less serious symptoms (photophobia, irritation, 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.

Patients should be monitored by an ophthalmologist if exposure keratitis is suspected. Exposure keratitis usually occurs when eyelid closure is incomplete and the cornea is exposed at night, when the patient does not blink. Characteristically, the patient complains of irritation and tearing upon awakening. This is treated with saline gel or drops and by taping eyelids closed with paper tape prior to sleep. Some ophthalmologists are concerned about corneal abrasion from the tape and instead recommend that patients wear goggles at night to maintain a moist eye.

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 of the optical nerve may cause permanent vision loss. High-dose glucocorticoids are administered with consideration for decompressive surgery and radiation therapy. (See the image below.)

Infiltrative dermopathy, usually over the lower extremities, is characterized by an accumulation of glycosaminoglycans and inflammatory cells in the dermis. The skin changes usually 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 application of a high-potency topical steroid cream.

Many of the neurologic and cardiovascular symptoms of thyrotoxicosis are relieved by beta-blocker therapy. Prior to therapy, examine the patient for signs and symptoms of dehydration that often occur with hyperthyroidism. After oral rehydration, beta-blocker therapy can be started. Do not administer beta-blocker therapy to a patient with a significant history of asthma. Calcium channel blockers can be used for the same purposes when beta blockers are contraindicated or poorly tolerated.

Antithyroid drugs (eg, methimazole, propylthiouracil) have been used for hyperthyroidism since their introduction in the 1940s. They are employed for the long-term control of hyperthyroidism in children, adolescents, and pregnant women (propylthiouracil only for pregnancy). In women who are not pregnant, the medications are used to control hyperthyroidism prior to definitive therapy with radioactive iodine. In surveys of thyroid specialists in the United States, the preferred treatment of hyperthyroidism is radioactive iodine therapy.

Antithyroid medications inhibit the formation and coupling of iodotyrosines in thyroglobulin, which are necessary for thyroid hormone synthesis, leading to a gradual reduction in thyroid hormone levels over 2-8 weeks or longer. A second therapeutic action of propylthiouracil, but not methimazole, is the inhibition of conversion of T₄ to T₃. T₃ is a more biologically active form of thyroid hormone. A quick reduction in T₃ is associated with a clinically significant improvement in thyrotoxic symptoms.

Titrate the antithyroid drug dose 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 have a recurrence of hyperthyroidism within the following year. Nodular forms of hyperthyroidism (toxic multinodular goiter and toxic adenoma) are permanent conditions and will not go into remission.

The drug of choice for hyperthyroidism in the nonpregnant woman is methimazole. The recent US Food and Drug Administration (FDA) boxed warning for increased liver failure with propylthiouracil has limited its use to just the first trimester of pregnancy. Methimazole has rarely been associated with cloacal and scalp (cutis aplasia) abnormalities when given during early gestation. Generally, if a women desires pregnancy, the patient is switched to propylthiouracil. After the 12 weeks of gestation, the patient is switched back to methimazole. Methimazole is a more potent and longer-acting drug. Often, patient compliance is better with methimazole taken once or twice daily than with propylthiouracil given 3-4 times daily.

Propylthiouracil is still the drug of choice in uncommon situations of life-threatening severe thyrotoxicosis because of the additional benefit of inhibition of T₄ -to-T₃ conversion. Administer propylthiouracil every 6-8 hours. The reduction in T₃, which is 20-100 times more potent than T₄, theoretically helps to reduce the thyrotoxic symptoms more quickly than does methimazole. Once thyroid levels are decreasing toward normal, the patient can be switched to methimazole therapy.

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, with an equal frequency for both drugs.

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.

The FDA added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for propylthiouracil. The warning emphasizes the risk for severe liver injury and acute liver failure, some cases of which have been fatal. The boxed warning also states that propylthiouracil should be reserved for use in patients who cannot tolerate other treatments, such as methimazole, radioactive iodine, or surgery.

The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and on meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

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

Propylthiouracil 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 propylthiouracil (for more information, see the FDA Safety Alert)^[6] :

• Reserve propylthiouracil use during first trimester of pregnancy or in patients who are allergic to or intolerant of methimazole
• Closely monitor propylthiouracil therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy
• For suspected liver injury, promptly discontinue propylthiouracil therapy, evaluate the patient for evidence of liver injury, and provide supportive care
• Propylthiouracil 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

Other drugs

In severe thyrotoxicosis from Graves disease or subacute thyroiditis, iodine or iodinated contrast agents have been administered to block T₄ conversion 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. Either a saturated solution of potassium iodide (SSKI) at 10 drops twice daily or iopanoic acid/ipodate (1 g/d) can be administered, with rapid reduction in T₃ levels.

Take care to not administer these drugs 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.

Radioactive iodine therapy^[7] is the most common treatment for hyperthyroidism in adults in the United States. Although the effect is less rapid than it is in antithyroid medication or thyroidectomy, it is effective and safe and does not require hospitalization.

Concerns about radiation exposure after therapy have led to new recommendations by the American Thyroid Association. These recommendations are compliant with Nuclear Regulatory Commission regulations and are a practical guide for patient activity after radioactive iodine therapy, to provide the maximum radiation safety for the family and the public.^[8]

Radioactive iodine therapy 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, and, therefore, 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 of¹³¹ I administered is 75-200 µCi/g of estimated thyroid tissue divided by the percent of¹²³ I uptake in 24 hours. This dose is intended to render the patient hypothyroid. Lithium used in the weeks following radioactive iodine therapy may extend the retention of radioactive iodine and result in increased efficacy. However, studies looking at this are inconsistent, and the benefits of lithium used 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. No evidence of increased mortality exists for any other form of cancer, including leukemia, with radioactive iodine therapy of hyperthyroidism.

Long-term follow-up data of children and adolescents treated with radioactive iodine are lacking. Consequently, long-term antithyroid medications, rather than radioiodine therapy, usually are recommended in children.

Radioactive iodine is never administered to pregnant or lactating women; it can cross the placenta and can be excreted into milk, which can ablate the infant's thyroid and result in hypothyroidism. Checking for pregnancy prior to radioactive iodine therapy and suggesting that the patient not become pregnant for at least 3-6 months after the treatment and until thyroid functions are normal are standard practice.

Retrospective reviews have demonstrated no excess in fetal malformations or miscarriage rates 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 usually mild, but occasionally severe, worsening of thyroid eye disease occurs after radioactive iodine therapy. The risk of ophthalmopathy is worse in patients who smoke cigarettes, but it can be reduced by glucocorticoid therapy (prednisone 0.4 mg/kg for 1 mo with subsequent taper) after the 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.^{[7, 9]}

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

• Severe hyperthyroidism in children
• Pregnant women who are noncompliant or intolerant of antithyroid medication
• Patients with very large goiters or severe ophthalmopathy
• Patients who refuse radioactive iodine therapy
• 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

With current operative techniques, bilateral subtotal thyroidectomy should have a mortality rate approaching zero in patients who are properly prepared. Historically, the most common cause of thyroid storm, a physiologic decompensation in patients who are severely thyrotoxic, with a mortality rate of 50-100%, is operative stress.

Preoperative preparation

Preoperative preparation includes antithyroid medication, stable (cold) iodine treatment (to decrease gland vascularity), and beta-blocker therapy.^[9] Generally, antithyroid drug therapy should be administered until thyroid functions normalize (4-8 wk). Titrate propranolol until the resting pulse rate is less than 80 bpm. Finally, administer iodide as SSKI (1-2 drops bid for 10-14 d) before surgery.

An additional benefit from stable iodide therapy, besides the reduction in thyroid hormone excretion, is a demonstrated decrease in thyroid blood flow and possible reduction in blood loss during surgery.

Adverse surgical effects

Adverse effects of therapy include recurrent laryngeal nerve damage and hypoparathyroidism due to damage of local structures during surgery. (A Swiss study indicated that a single dose of steroid administered prior to thyroidectomy can reduce nausea, pain, and vomiting associated with the procedure, as well as improve voice function.)^[10]

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 levels are stabilized on a low dose of antithyroid medication. Perform follow-up tests of thyroid function at least every 3 months for the first year. After 12-18 months, stop antithyroid medication or decrease it in patients with Graves hyperthyroidism to determine if the patient has gone into remission.

Non-Graves hyperthyroidism rarely has remissions. Once a patient with Graves hyperthyroidism becomes euthyroid on oral antithyroid medication, consider other definitive treatment, such as radioactive iodine therapy. A significant fraction of patients with Graves disease go into remission, and most eventually, over many years, become hypothyroid from autoimmune destruction of the gland.

Care after radioactive iodine ablation

Ablation of the gland occurs over several (4-5) months after the 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, stopping antithyroid medications and considering starting a low dose of thyroid hormone replacement before the patient becomes hypothyroid is reasonable; however, some physicians prefer to document persistently elevated TSH values off antithyroid medication before starting thyroid hormone replacement.

Starting with partial or low-dose thyroid hormone replacement is recommended (25-50 mcg/d and adjusted every 6-8 wk to normalize the TSH level). Starting with full replacement doses when TSH first becomes elevated after¹³¹ I therapy leads to a higher incidence of hyperthyroidism due to overreplacement.

After¹³¹ I therapy, patients can, in rare cases, become thyrotoxic due to vigorous thyroid destruction and release of preformed hormone. Also, radioablation can cause the release of thyroid antigens and exacerbate the autoimmune thyroid disease process. When the former happens, it often is accompanied by a painful, radiation-induced thyroiditis that can be treated with nonsteroidal anti-inflammatory medication or glucocorticoids.

Care after thyroid surgery

Patients with normalization of thyroid functions after surgery require routine follow-up, because they may develop hypothyroidism (from their chronic thyroiditis), recurrent hyperthyroidism, or thyroid eye disease sometime in the future.

Most patients remain euthyroid after a lobectomy or lobectomy plus isthmusectomy. Obtain thyroid function tests 3-4 weeks postoperatively after a lobectomy to ensure normal thyroid function.

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.

After a subtotal thyroidectomy, partial replacement (T₄, 50-75 mcg/d) is recommended, to begin shortly after surgery. Monitor thyroid function tests 4-8 weeks postoperatively, and adjust the T₄ dose to maintain a normal TSH level.

Diet

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

Activity

In otherwise healthy patients with hyperthyroidism, exercise tolerance often is not significantly affected. For these people, no reduction in physical activity is necessary. For elderly patients or for persons with cardiopulmonary comorbidities, a decrease in activity is prudent until hyperthyroidism is medically controlled. With severe thyrotoxicosis, systolic and diastolic cardiac dysfunction are often manifested by dyspnea upon exertion.

In many cases, beta-blocker therapy 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 doctor (with thyroid hormone replacement therapy if necessary).

Patients with Graves thyrotoxicosis should be examined by an ophthalmologist for 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 has been detected decades later. Graves eye disease also can occur without the patient ever having developed hyperthyroidism.