Hypothyroidism and Myxedema Essentials of Diagnosis • Weakness, fatigue, cold intolerance, constipation, weight change, depression, menorrhagia, hoarseness. • Dry skin, bradycardia, delayed return of deep tendon reflexes. • Anemia, hyponatremia. • T4 and radioiodine uptake usually low. • TSH elevated in primary hypothyroidism. General Considerations Hypothyroidism may range in severity from mild and unrecognized hypothyroid states to striking myxedema. Hypothyroidism may be due to primary disease of the thyroid gland itself or lack of pituitary TSH. Most commonly, mild forms of hypothyroidism are not apparent clinically. Goiter is frequently noted when hypothyroidism is due to Hashimoto's thyroiditis, iodide deficiency, genetic thyroid enzyme defects, drug goitrogens (lithium, iodide, propylthiouracil or methimazole, phenylbutazone, sulfonamides, amiodarone), food goitrogens in iodide-deficient areas (eg, turnips, cassavas), or, rarely, peripheral resistance to thyroid hormone or infiltrating diseases (eg, cancer, sarcoidosis). A hypothyroid phase occurs in subacute (de Quervain's) viral thyroiditis following initial hyperthyroidism. Goiter is usually absent when hypothyroidism is due to: deficient pituitary TSH secretion, or destruction of the gland by surgery, external radiation, or 131I. Primary hypothyroidism may also be idiopathic. Amiodarone, because of its high iodine content, causes clinically significant hypothyroidism in about 8% of patients. The T4 level is normal or low, and the TSH is elevated, usually over 20 ng/dL. Another 17% of patients develop milder elevations of TSH and are asymptomatic. Low-dose amiodarone is less likely to cause hypothyroidism. Cardiac patients with amiodarone-induced symptomatic hypothyroidism are treated with just enough thyroxine to relieve symptoms. Clinical Findings These may vary from the rather rare full-blown myxedema to mild states of hypothyroidism, which are far more common. A. Symptoms and Signs: 1. Early–Frequent symptoms are fatigue, lethargy, weakness, arthralgias or myalgias, muscle cramps, cold intolerance, constipation, dry skin, headache, and menorrhagia. Physical findings may be few or absent. Features may include thin, brittle nails, thinning of hair, and pallor, with poor turgor of the mucosa. Delayed return of deep tendon reflexes is often noted. 2. Late–The principal symptoms are slow speech, absence of sweating, constipation, peripheral edema, pallor, hoarseness, decreased sense of taste and smell, muscle cramps, aches and pains, dyspnea, weight changes (usually gain, but weight loss is not rare), and diminished auditory acuity. Some women have amenorrhea; others have menorrhagia. Galactorrhea may also be present. Physical findings include puffiness of the face and eyelids, typical carotenemic skin color, thinning of the outer halves of the eyebrows, thickening of the tongue, hard pitting edema, and effusions into the pleural, peritoneal, and pericardial cavities, as well as into joints. Cardiac enlargement ("myxedema heart") is often due to pericardial effusion. The heart rate is slow; the blood pressure is more often normal than low, and reversible diastolic hypertension may be found. Hypothermia may be present. Pituitary enlargement due to hyperplasia of TSH-secreting cells, which is reversible following thyroid therapy, may be seen in long-standing hypothyroidism. Hypothyroidism rarely causes true obesity. B. Laboratory Findings: The T4 may be low or low normal. TSH is increased with primary hypothyroidism but is low or normal with pituitary insufficiency. Other laboratory abnormalities may often be seen: increased serum cholesterol, liver enzymes, and creatine kinase; increased serum prolactin; hyponatremia, hypoglycemia, and anemia (with normal or increased mean corpuscular volume). Titers of antibodies against thyroperoxidase and thyroglobulin are high in patients with Hashimoto's thyroiditis. Serum T3 is not a good test for hypothyroidism. Differential Diagnosis Hypothyroidism must be considered in states of asthenia, unexplained menstrual disorders, myalgias, constipation, weight change, hyperlipidemia, and anemia. Myxedema enters into the differential diagnosis of unexplained heart failure that does not respond to digitalis or diuretics, and unexplained ascites. The protein content of myxedematous effusions is high. The thick tongue may be confused with that seen in primary amyloidosis. Pernicious anemia may be suggested by the pallor and the macrocytic anemia sometimes seen in myxedema; the two disorders may even coexist. Some cases of depression, primary psychosis and structural diseases of the brain have been confused with myxedema. The pituitary is often quite enlarged in primary hypothyroidism due to reversible hyperplasia of TSH-secreting cells; the concomitant hyperprolactinemia seen in hypothyroidism can lead to the mistaken diagnosis of a pituitary adenoma. Complications Complications are mostly cardiac in nature, occurring as a result of advanced coronary artery disease and congestive failure, which may be precipitated by too vigorous thyroid therapy. There is an increased susceptibility to infection. Megacolon has been described in long-standing hypothyroidism. Organic psychoses with paranoid delusions may occur ("myxedema madness"). Rarely, adrenal crisis may be precipitated by thyroid therapy. Hypothyroidism is a rare cause of infertility, which may respond to thyroid medication. Pregnancy in a woman with untreated hypothyroidism often results in miscarriage. On the other hand, if the hypothyroidism is due to autoimmune disease, it may improve during pregnancy. Sellar enlargement and even well-defined TSH-secreting tumors may develop in untreated cases. These tumors decrease in size after replacement therapy is instituted. A rare complication of severe hypothyroidism is deep stupor, at times progressing to myxedema coma, with severe hypothermia, hypoventilation, hyponatremia, hypoxia, hypercapnia, and hypotension. Convulsions and abnormal central nervous system signs may occur. Myxedema coma is often induced by an underlying infection; cardiac, respiratory, or central nervous system illness; cold exposure; or drug use. It is most often seen in elderly women. The mortality rate is high. Myxedematous patients are unusually sensitive to opiates and may die from average doses. Refractory hyponatremia is often seen in severe myxedema. Inappropriate secretion of antidiuretic hormone has been observed in some patients, but a defect in distal tubular reabsorption of sodium and water has been demonstrated in many others. Treatment A. Specific Therapy: Levothyroxine is the drug of choice. Levothyroxine is readily available, inexpensive, and well standardized. It is converted in the body to T3, the most active thyroid hormone, in an enzymatically regulated manner that best meets the metabolic needs of the patient. 1. Patients who are elderly or have coronary insufficiency are treated with small doses of levothyroxine, 25–50 mg daily for 1 week, increasing the dose every 1–4 weeks by 25 mg daily up to a total of 75–150 mg daily. This dosage should be adjusted to optimally resolve symptoms while keeping TSH normal. Levothyroxine may also be administered once weekly, using a dose slightly higher than seven times the normal daily dose. 2. Patients who are younger and without coronary insufficiency may receive larger starting doses, 50–100 mg daily, increasing by 25 mg every 1–3 weeks until the TSH normalizes. 3. Maintenance–Each patient's dose must be adjusted to obtain the optimal effect. The proper dose should be decided mainly by careful clinical assessment. A serum TSH can be helpful, since persistently elevated levels usually indicate underreplacement with thyroxine, while very suppressed levels can indicate hyperthyroidism. Once a patient is feeling completely well, the dose is kept fairly constant. Frequent repeat determinations of serum thyroxine or TSH are unnecessary once the patient is feeling completely well and careful examinations show euthyroidism. In such patients, a sensitive TSH level may be obtained every 1–2 years. Serum thyroxine is usually high-normal or mildly elevated in patients receiving adequate doses of levothyroxine. Serum thyroxine levels in euthyroid patients may be quite high in patients also taking estrogen preparations. Serum TSH should be normal or slightly low. Most patients require 100–200 mg daily for maintenance. Certain substances interfere with the intestinal absorption of thyroxine, particularly sucralfate, aluminum hydroxide antacids, iron preparations, and phenytoin. Cholestyramine and other bile acid-binding resins can bind T4; absorption of T4 is reduced by 30% even when cholestyramine is given 5 hours before the thyroxine. Soybean infant formula also interferes with the absorption of thyroxine. Myxedema itself can interfere with its treatment by reducing thyroxine absorption, especially when severe. However, apparent malabsorption of thyroxine is often due to noncompliance. 4. Myxedema coma is a medical emergency with a high mortality rate. Levothyroxine sodium 400 mg is given intravenously and repeated daily in a dose of 100 mg intravenously. Hydrocortisone, 100 mg as an initial bolus, followed by 25–50 mg every 8 hours, should be given if adrenal insufficiency is suspected. The patient must not be warmed except by blanket. Infection is often present and must be aggressively treated. Assisted mechanical ventilation is almost always necessary to correct the hypercapnia. 5. There are special situations where the daily maintenance dose of thyroxine may have to be altered: Slightly higher doses may be necessary during pregnancy or in patients taking phenobarbital or bile acid-binding resins or changing their diet to one containing more fiber. Conversely, lower doses are often required in aging patients. B. Needless Use of Thyroid: Thyroid medication should not be used as nonspecific stimulating therapy. Large doses given to euthyroid individuals to induce weight loss may induce cardiac arrhythmias, osteoporosis, muscle weakness, and anxiety. The use of thyroid in cases of amenorrhea or infertility is indicated only if the patient is proved to be hypothyroid. Prognosis With early treatment, striking transformations take place both in appearance and mental function. Return to a normal state is usually the rule, but relapses will occur if treatment is interrupted. The patient may rarely die from the complications of myxedema coma. On the whole, response to thyroid treatment is most satisfactory. Chronic maintenance therapy with unduly large doses of thyroid hormone may lead to osteoporosis. References 10260:13:1 Harjai KJ, Licata AA: Effects of amiodarone on thyroid function. Ann Intern Med 1997;126:63. 10260:13:2 Grebe SKG et al: Treatment of hypothyroidism with once weekly thyroxine. J Clin Endocrinol Metab 1997;82:870. 10260:13:3 Hurley DL, Gharib H: Detection and treatment of hypothyroidism and Graves' disease. Geriatrics 1995;50:41. 10260:13:4 Klemperer JD et al: Thyroid hormone treatment after coronary-artery bypass surgery. N Engl J Med 1995;333:1522. 10260:13:5 Jordan RM: Myxedema coma. Pathophysiology, therapy and factors affecting prognosis. Med Clin North Am 1995;79:185.