Hypothyroidism
(Myxedema)
The clinical expression of thyroid hormone deficiency.
Epidemiology and Etiology
The prevalence of overt hypothyroidism is 2 to 5% in persons >= 65 years. Another 5 to 10% of those >= 65 have subclinical hypothyroidism (isolated elevation of TSH levels with normal T4 and T3, with or without symptoms). The prevalence rises with age, is much higher in women than in men at all ages, and is higher in elderly institutionalized patients than in elderly patients living in the community.
The causes of sustained overt and subclinical hypothyroidism in elderly persons are similar to those in younger persons. The most common causes are Hashimoto's disease, previous irradiation or surgical removal of the thyroid gland, and idiopathic hypothyroidism, which may be simply the result of nongoitrous Hashimoto's disease. Less common causes include pituitary and hypothalamic disorders causing TSH deficiency, iodine-induced hypothyroidism (from radiocontrast agents, amiodarone, or supplemental potassium iodide), and use of lithium or other antithyroid drugs. Transient hypothyroidism may occur after thyroid surgery, after treatment with radioactive sodium iodide (131I), or during episodes of subacute thyroiditis when the thyroid gland has depleted its store of hormone and the follicular cells have not yet recovered sufficiently to replace it.
Pathogenesis and Pathophysiology
Thyroid glands of older persons are more susceptible to the destructive autoimmune effects of Hashimoto's disease than are those of younger persons. The pathogenesis of Hashimoto's disease appears to change little with age. Four types of thyroid-directed antibodies may appear in the serum of patients with the disease, but the inflammatory and cytotoxic lesion is probably cell-mediated.
Hypothyroidism after 131I therapy for hyperthyroidism is common in elderly patients because the incidence of hypothyroidism continues to increase at an annual rate of 2 to 5% for 20 or 30 years after the initial treatment. Also, hypothyroidism after 131I therapy is caused by a failure of DNA repair and replication, and these processes are less efficient with age. Thyroid antibodies and Hashimoto's disease also are much more common in patients with Graves' disease; therefore, organ failure may often be due to a combination of radiation and autoimmune destruction. Thus, cases of hypothyroidism accumulate as patients with treated Graves' disease age.
Symptoms, Signs, and Complications
Hypothyroidism in older persons is a great masquerader. Elderly patients have significantly fewer symptoms of hypothyroidism than do younger adults and complaints are often subtle and vague. Chilliness, weight gain, muscle cramps, and paresthesias are significantly less common in patients >= 70 than in those <= 55. Fatigue, weakness, depression, constipation, and dry, coarse skin may also be less common. Many elderly patients with hypothyroidism present with nonspecific geriatric syndromes--confusion, anorexia, weight loss, falling, incontinence, and decreased mobility. Musculoskeletal symptoms (especially arthralgias) occur often, but arthritis is rare. Muscular aches and weakness, often mimicking polymyalgia rheumatica or polymyositis, and an elevated creatine phosphokinase level may occur.
The term subclinical hypothyroidism implies that the patient has no symptoms attributable to hypothyroidism. However, patients with isolated elevations of serum TSH levels have more symptoms consistent with hypothyroidism than do patients with normal TSH levels.
Physical findings may be difficult to interpret. Puffiness around the eyes and myxedematous facies are difficult to distinguish from normal facial changes in elderly persons. The most reliable sign--prolonged relaxation time after muscular contraction--may not be detectable in older patients because of decreased amplitude or absent reflexes. Occasionally, noninflammatory effusions may occur in the joints and in pleural, pericardial, and peritoneal cavities. Basal body temperature may decrease.
Because elderly persons have more circulating antidiuretic hormone (vasopressin), they are susceptible to excessive water retention without proportionate sodium retention. Hypothyroidism accentuates these tendencies, often leading to hyponatremia.
Complications of hypothyroidism include hypertension and hyperlipidemia. Hypothyroidism is also associated with elevation of lipoprotein(a), an independent risk factor for coronary artery disease. Myocardial infarction and heart failure are serious but uncommon complications of early disease. Untreated hypothyroidism may lead to myxedema coma, a life-threatening emergency. Mental confusion progresses to stupor and coma and is often accompanied by hyponatremia, hypoglycemia, or hypercapnia.
Diagnosis
Diagnosis is based on precise, reliable assays of serum TSH and T4 levels. The most sensitive indication of hypothyroidism due to primary thyroid gland failure is a marked elevation of serum TSH. The most specific test finding is a subnormal serum free T4 level, because it corrects for abnormalities in the T4-binding proteins. The serum T3 level has little value because it is normal in about one third of patients with hypothyroidism and because subnormal levels are often due to illness or inadequate caloric intake.
Because of its great sensitivity and adequate specificity, the serum TSH level alone should be measured in patients suspected of having hypothyroidism and in those in whom it needs to be excluded. If the serum TSH level is normal, hypothyroidism is essentially ruled out, and the serum free T4 rarely needs to be measured. A serum TSH level above normal (usually > 4.5 mU/L) suggests a possible diagnosis of hypothyroidism. Serum free T4 should be measured to differentiate overt hypothyroidism (subnormal free T4) from subclinical hypothyroidism (normal free T4).
Subclinical hypothyroidism is usually indicated by a serum TSH level between the upper limit of normal (about 5 mU/L) and 15 mU/L; occasionally the level may be higher. The serum free T4 level is, by definition, within the normal range but tends to be below the mean of the euthyroid elderly population. The serum TSH measurement may need to be repeated in patients with concurrent illnesses because it may be subnormal during the illness and elevated during the recovery phase.
Measurement of thyroid antibodies is neither sensitive nor specific; only a minority of elderly patients with elevated antibody levels have hypothyroidism, and only 40 to 70% of patients with hypothyroidism have elevated antibody levels. However, this measurement is prognostically useful in patients with subclinical hypothyroidism, in whom the rate of progression to overt hypothyroidism is much higher in those with positive antibody titers.
Although serum cholesterol and creatine kinase levels are elevated in hypothyroidism, these measurements are rarely useful diagnostically. However, obtaining serum TSH levels and thereby making a diagnosis of hypothyroidism may explain elevated cholesterol and creatine kinase levels.
Hypothyroidism must be differentiated from euthyroid sick syndrome, which is characterized by abnormal thyroid function test results in clinically euthyroid patients with severe nonthyroidal systemic illness. Findings may include low serum T3 and free T3 levels and high serum reverse T3 levels, but the difficulty arises because of low serum T4, free T4 index, and free T4 levels in the most seriously ill patients. A subnormal serum TSH level (0.02 to 0.4 mU/L) is generally but not always detectable by 3rd-generation TSH assay. Diagnosis of hypothyroidism in the critically ill patient can be made only if the serum TSH level is markedly elevated (> 15 mU/L) or if the free T4 levels are markedly subnormal (< 0.6 ng/dL [< 8 pmol/L]); hypothyroidism is more likely when both findings occur. Although pituitarigenic hypothyroidism may rarely be the cause of low serum TSH and free T4 levels, these findings are almost always explained by the euthyroid sick syndrome.
Screening, Prognosis, and Treatment
Screening every 5 years by measuring serum TSH is recommended for all men >= 65 and for all women >= 35. For those with risk factors for thyroid disease, the serum TSH level should be checked more often. Screening for hypothyroidism is as cost-effective as screening for hypertension, hypercholesterolemia, and breast cancer. This single test is highly sensitive and specific in diagnosing or excluding two prevalent and serious disorders (hypothyroidism and hyperthyroidism), both of which can be treated effectively.
Proper treatment of hypothyroidism completely corrects the metabolic condition. Long-standing, untreated hypothyroidism is a risk factor for coronary artery disease. Therefore, cardiac stress testing is indicated, and the response of blood lipid levels to treatment should be monitored.
Treatment of choice is T4 replacement with levothyroxine sodium. The average dose for patients >= 65 years is 0.075 to 0.1 mg/day po. If the patient has coronary artery disease, the initial dose of levothyroxine sodium should be only 0.0125 to 0.025 mg/day po. For patients with hypothyroidism short of myxedema coma, replacement therapy should be given cautiously, starting with a dose of 0.025 mg/day po and increasing at intervals of 2 to 4 weeks. The increases should be by 0.0125 mg/day if the interval is 2 weeks and by 0.025 mg/day if the interval is >= 4 weeks. About 1 to 2 months after reaching a dose of 0.075 mg/day po of levothyroxine sodium, the serum TSH level should be measured (always by a 2nd- or 3rd-generation TSH assay capable of detecting >= 0.01 mU/L). If the TSH level is still above normal, the dose may be increased to 0.1 mg/day. If the TSH is below normal (< 0.4 mU/L), the dose should be lowered. Serum T3 and T4 measurements usually are not needed. If the serum TSH level is still high 1 to 2 months after reaching a dose of 0.1 mg/day of levothyroxine sodium, the dose should be maintained for another 2 months. If the TSH level is still elevated, the dose should be raised to 0.112 or 0.125 mg/day.
The physician should emphasize to the newly diagnosed patient with hypothyroidism that treatment with levothyroxine sodium must be maintained for life. This counsel should be repeated at follow-up visits at least once a year.
Treatment of myxedema coma involves large IV doses of thyroid hormones (eg, 0.2 to 0.5 mg levothyroxine sodium on the first day, then 0.1 to 0.3 mg IV on day 2, and 0.05 to 0.1 mg daily thereafter [until the patient is able to take oral levothyroxine]) supplemented by IV adrenal corticosteroids (eg, hydrocortisone sodium succinate 50 to 100 mg immediately and 50 to 100 mg q 6 h thereafter) and measures to treat hyponatremia, hypoglycemia, and respiratory failure, if present.
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