Hyperthyroidism

(Thyrotoxicosis)

The clinical expression of excess thyroid hormone.

Some controversy continues over the terms hyperthyroidism and thyrotoxicosis. Some authorities refer to thyrotoxicosis as the clinical expression of excess thyroid hormone, whatever its source, and hyperthyroidism as a condition in which there is increased synthesis and secretion of thyroid hormones from the thyroid gland. In this chapter, hyperthyroidism is used synonymously with thyrotoxicosis.

Epidemiology, Etiology, and Pathophysiology

In elderly patients, the prevalence of overt hyperthyroidism is 0.2 to 2%, which is similar to that in the general population. The prevalence of subclinical hyperthyroidism (suppression of TSH levels with normal T₄ and T₃ levels and usually without symptoms) is unknown.

Hyperthyroidism in elderly patients is more often due to multinodular and uninodular toxic goiter than to Graves' disease, which is the most common cause in younger adults. Adenomas autonomously produce and secrete excessive thyroid hormone even though TSH production is fully suppressed. In Graves' disease, an autoimmune disorder, an antibody to the TSH receptor on thyroid follicular cells is produced that has TSH-like activity. In granulomatous or lymphocytic subacute thyroiditis, damaged follicles leak thyroglobulin, T₃, and T₄ into the circulation. In certain cases of Hashimoto's disease, a similar leakage may occur, usually of short duration.

A common cause of hyperthyroidism among elderly patients is iodine-induced hyperthyroidism, often from the use of amiodarone, a cardiac drug containing iodine that deposits in tissue and delivers iodine to the circulation over very long periods of time. Hyperthyroidism also may result from excessive ingestion of T₄ or T₃ (either therapeutic or patient-initiated).

Regardless of the cause of hyperthyroidism, the result is supranormal levels of thyroid hormones in T₃-responsive tissues. The various types of hyperthyroidism are characterized by overproduction of T₃ and, to a lesser extent, T₄. In T₃ hyperthyroidism, which accounts for < 5% of hyperthyroidism at all ages, the serum T₄ level is normal despite clinical evidence of hyperthyroidism.

In hyperthyroidism, extrathyroidal tissues convert the excess secreted T₄ to T₃. Thus, a supraphysiologic concentration of T₃ arrives at target tissues and is transported into the nucleus, where it binds to a receptor. The hormone-receptor complex then binds to the promoter region of T₃-responsive genes, leading to an overproduction of enzymes and other proteins that mediate the characteristic actions of T₃.

Symptoms, Signs, and Complications

Hyperthyroidism in elderly patients is even more of a masquerader than hypothyroidism. Older patients have fewer symptoms and signs and a different complex of symptoms than do younger patients. Only about 25% of hyperthyroid patients >= 65 present with typical symptoms and signs (see Table 65-1). Many of the age-related differences in symptoms are the result of the aging process and of concomitant disease that modifies the effects of excessive thyroid hormone. For example, the response to catecholamines decreases in elderly patients, possibly because of a decreased number or affinity of catecholamine receptors. Because catecholamines act synergistically with T₃ to produce the typical symptoms and signs of hyperthyroidism, reduced responsiveness to catecholamines may explain some atypical symptoms.

The classic triad in older patients is tachycardia, weight loss, and fatigue (or weakness or apathy), whereas in younger patients it is tachycardia, goiter, and exophthalmos. Ocular signs are usually absent. Decreased appetite is common; increased appetite is the exception. Because the baseline heart rate decreases with age, heart rates > 90 beats/minute (rather than the standard of 100) must be interpreted as tachycardia in elderly hyperthyroid patients. Regarding goiter, the thyroid gland is normal in size or impalpable in about 40% of cases, enlarged and nodular in 35%, and enlarged and diffuse in 25%. Diarrhea is uncommon, whereas constipation is present in > 20% of elderly patients. Sweating is also far less common in elderly hyperthyroid patients. A subjective sense of nervousness and anxiety is less commonly reported by elderly hyperthyroid patients, although observed tremor is almost as frequently seen as in younger patients. Hyperactive reflexes with quick recoil are far less common in older than in younger patients.

Symptoms of heart failure and angina may dominate the clinical picture to the exclusion of the usual features of hyperthyroidism. Because cardiac disease is common in elderly persons, the possibility of underlying hyperthyroidism may not be suspected. Gastrointestinal (GI) symptoms may be confused with GI malignancy.

The most common complication in elderly patients is atrial fibrillation, which occurs in 27% of elderly hyperthyroid patients at presentation. Prognosis for heart failure and early death is increased if atrial fibrillation does not convert to normal sinus rhythm when euthyroidism is restored. Atrial fibrillation also carries a high risk of embolic stroke. Other important complications are depression (called apathetic thyroidism), myopathy, and osteoporosis.

Thyroid storm is a rare, life-threatening episode that may occur in the course of hyperthyroidism. It usually occurs when a stressful illness or event is superimposed on hyperthyroidism or occasionally when ¹³¹I therapy leads to massive leakage of thyroid hormones into the circulation. The symptoms and signs of hyperthyroidism are present, but the following also occur: fever, extreme tachycardia, nausea, vomiting, heart failure, and changes in mental status or consciousness. Serum T₄ and T₃ levels are no higher than in patients with usual degrees of hyperthyroidism. Thus, thyroid storm is a clinical diagnosis.

Diagnosis

The best single test is the serum TSH measurement, whose sensitivity and specificity are >= 0.98. A subnormal value suggests hyperthyroidism, and an undetectable value by a 2nd- or 3rd-generation assay (< 0.01 mU/L) is almost pathognomonic.

Serum T₄, T₃, and thyroglobulin levels are on the average lower in older patients with hyperthyroidism than in younger patients.

Serum thyroid hormone levels should not be performed with the initial TSH test; they may be measured subsequently to confirm the diagnosis or to establish that the patient is not euthyroid when the serum TSH level is normal but clinical suspicion is strong. Starvation or serious disease (severe hyperthyroidism, thyroid-induced heart failure, or intercurrent disease) lowers the serum T₃ level, so a patient with hyperthyroidism may have a normal serum T₃ level. With more serious disease, the serum T₄ and free T₄ index may also decline into the normal range. If this occurs, the diagnosis is usually indicated by an elevated free T₄ level (measured by equilibrium dialysis), a supranormal radioiodine uptake test, or an undetectable serum TSH by 2nd- or 3rd-generation assay.

Hyperthyroidism must be differentiated from euthyroid hyperthyroxinemia in patients with acute systemic disease and in patients with acute psychiatric disorders. A serum TSH measurement and a repeat measurement of the serum T₄ level after 2 weeks (by which time the serum T₄ level has generally returned to normal) help establish the correct diagnosis.

Prognosis and Treatment

The prognosis for hyperthyroidism is excellent. Treatment usually leads to a euthyroid state. If hypothyroidism results, it is treated easily with levothyroxine sodium.

Treatment of choice for most elderly patients with Graves' disease or a single autonomous nodule is radioactive sodium iodide (¹³¹I). It is preferred because it is easy to administer and it avoids any age-related postoperative complications of surgery. Antithyroid drugs (eg, propylthiouracil, methimazole) are effective in the treatment of Graves' disease if the patient's adherence with the regimen is good. However, in patients with uninodular toxic goiter, antithyroid drugs are slow to work and almost never lead to permanent remission.

In multinodular toxic goiter, the response to ¹³¹I therapy is often delayed and incomplete. Because many doses of ¹³¹I may be needed, the patient remains hyperthyroid many months after the diagnosis. Thus, surgery may be preferred, at least for patients at low risk of postoperative complications. For patients at high risk, large and repeated doses of ¹³¹I should be given.

When hyperthyroidism is due to subacute thyroiditis, Hashimoto's disease, or acute radiation damage, the only effective treatment is to give -blockers and to closely observe the patient for complications. Antithyroid drugs and ¹³¹I are not helpful because they do not decrease the uncontrolled output of hormone from damaged thyroid follicles.

The usual treatment of iodine-induced hyperthyroidism is high doses of antithyroid drugs and a -blocker. Treatment may be difficult because the large store of thyroid hormone in the gland blunts the effect of antithyroid drugs, and the large pool of iodine throughout the body markedly decreases the uptake of ¹³¹I.

¹³¹I: No consensus exists on an appropriate dose of ¹³¹I for hyperthyroidism. One option is a low dose calculated on the basis of thyroid size and ¹³¹I uptake intended to produce a euthyroid state. Another option is a large, arbitrary dose (usually 10 mCi or more) intended to produce hypothyroidism (followed by levothyroxine sodium therapy when hypothyroidism occurs). Even with low-dose therapy, hypothyroidism develops in 50% of patients by 20 years, but this option cuts in half the probability that levothyroxine sodium will be needed later when patients are likely to be already taking multiple drugs. However, the large dose may be advantageous by providing the patient with more years of well-being because the relief of hyperthyroidism is faster and more reliable.

Antithyroid drugs: The indications for antithyroid drugs are similar for all ages: if ¹³¹I is refused by the patient, before or after ¹³¹I is administered to relieve hyperthyroidism faster, before surgical subtotal thyroidectomy is performed, and as primary, long-term therapy to try to keep the patient in a euthyroid state until remission of the underlying disease is achieved. The advantage of giving antithyroid drugs before ¹³¹I administration is that not only does the patient become euthyroid but also the therapy depletes the thyroid gland of its stored hormone, thus minimizing the risk of hyperthyroidism due to "dumping" into the blood after ¹³¹I therapy.

Long-term antithyroid drug treatment usually lasts 1 to 2 years. If the elderly patient follows instructions, antithyroid drug therapy is usually successful. Because mild hyperthyroidism and a small thyroid gland are characteristic in elderly patients, the chance of permanent remission is enhanced. If hyperthyroidism recurs after antithyroid drug treatment, ¹³¹I should be given.

Antithyroid drugs as primary therapy in elderly persons are administered in the same way as in younger persons. Propylthiouracil is given initially at 150 to 300 mg/day po in divided doses q 8 h. Maintenance dosing is 100 to 150 mg/day in divided doses q 8 to 12 h. The dosage is lowered sequentially based on symptoms and signs and serum hormone levels, which are monitored every 2 months. Serum TSH levels are useful. If the therapeutic response is inadequate, the dosage may be increased to 300 mg q 8 h.

Methimazole can be given as a single daily dose; the initial dose is 15 to 40 mg/day. The dose needs to be adjusted every 1 or 2 months, depending on the response. If the patient's course is erratic with methimazole or propylthiouracil (eg, the patient slips quickly into hypothyroidism after small dose increases), the simplest solution is to add a small dose of levothyroxine sodium, usually 0.05 mg/day.

A pharmacologic dose of inorganic iodide (any dose > 6 mg/day) acts by inhibiting the release of thyroid hormone. The dose is generally effective for only 10 to 14 days. Iodide may be administered as Lugol's solution (5% iodine and 10% potassium iodide), 2 to 6 drops tid (50 to 150 mg/day) or as saturated solution of potassium iodide (1 g potassium iodide/mL); the recommended dose is 5 to 10 drops tid, although this dose provides far more than is needed (750 to 1500 mg/day).

Symptomatic treatment: Propranolol and other -blockers can help manage symptoms of hyperthyroidism. Ipodate sodium and iopanoic acid (cholecystographic contrast materials) are extremely effective in lowering the serum T₃ level to the normal range within 48 to 72 hours (although they are not approved in the USA for treating hyperthyroidism). In patients with atrial fibrillation and high thyroid hormone levels, cardioversion should not be attempted until a euthyroid state is achieved. Once it is, the atrial rhythm spontaneously reverts to normal in about two thirds of patients. Psychiatric symptoms usually resolve when the patient becomes euthyroid but should be treated if necessary. Standard measures to prevent osteoporosis are indicated, particularly in elderly women.

Thyroid storm: Thyroid storm is treated as an emergency. Treatment includes large doses of propylthiouracil (150 to 300 mg q 6 h) by nasogastric tube, if necessary; propranolol (1 mg by slow IV push q 5 min to decrease heart rate to between 90 and 110 beats/minute), and a glucocorticoid IV (eg, hydrocortisone sodium succinate 100 mg immediately and 50 mg q 6 h thereafter). Oral or IV sodium iodide (500 mg/day) can also be given, but ipodate sodium (3 mg in a single dose po or by nasogastric tube) is much more effective because it lowers the serum T₃ level to normal within 24 hours.