Hypothyroidism is a condition in which the thyroid gland fails to secrete sufficient thyroxine (T4) and triiodothyronine (T3). The disease may reflect intrinsic thyroid dysfunction (primary hypothyroidism), or it may result from insufficient stimulation of the thyroid gland by thyroid-stimulating hormone (TSH) due to a malfunction in the pituitary (secondary hypothyroidism) or hypothalamus (tertiary hypothyroidism). The vast majority of cases of hypothyroidism represent primary thyroid disease.
Hypothyroidism affects about five percent of the US population. The most common cause worldwide is iodine deficiency. However, in iodine sufficient countries like the United States, most cases are due to autoimmune thyroiditis (Hashimoto’s disease), in which CD8+ lymphocytes and antithyroid antibodies impair the normal functioning of the thyroid gland. Other causes include pharmaceuticals (lithium, amiodarone), genetic mutations of thyroglobulin and thyroid peroxidase molecules, congenital hypothyroidism, neck surgery, and radiothyroid ablation therapy. Hypothyroidism may also rarely result from hypothalamic or pituitary disorders, such as pituitary tumors, postpartum pituitary necrosis, and head trauma, in which the production or release of TSH is impaired.
Clinical manifestations may be subtle and nonspecific, including weakness, fatigue, and weight gain. However, chronic or severe disease can manifest with goiter, dull facial expression, drooping eyelids, hoarse speech, thinning or dry, brittle hair, dry skin, myxedema (swelling of the skin and soft tissues), menstrual disorders, bradycardia, pericardial effusion, constipation, depression, paresthesias, ataxia, and anemia.
Some, but not all, patients with hypothyroidism develop a goiter (abnormal thyroid gland growth). The clinical presentation of goiter depends on its size and location, and enlargement can be symmetric or asymmetric. Most patients with a goiter have no related symptoms. However, some may experience cough, dyspnea, and wheezing due to tracheal compression; dysphagia due to esophageal compression; hoarseness resulting from laryngeal nerve compression; and Horner’s syndrome, if the cervical sympathetic chain is involved.
Myxedema coma is a rare, life-threatening complication of severe hypothyroidism manifested by mental status changes, often accompanied by hypotension, hypothermia, hypoventilation, and rarely, coma. Precipitants of myxedema coma include infection, myocardial infarction, stroke, trauma (including surgery and burns), hypoglycemia, hyponatremia, hemorrhage, noncompliance with thyroid medications, and various drugs (e.g., beta-blockers, sedatives, narcotics, and phenothiazines).
Gender. The majority of cases occur in women, particularly women who are small at birth and remain small throughout childhood.
Age. Risk of hypothyroidism and myxedema coma increases with age.
Genetics. Hypothyroidism is associated with several polymorphisms in the genes for human leukocyte antigen (HLA), T-cell antigen receptors, and other immunomodulatory molecules.
Because clinical presentation is highly variable, diagnosis relies on laboratory testing. Several factors may lead to altered thyroid test results in the absence of thyroid disease. These include malnutrition, chronic illness, severe acute illness, drugs, and pregnancy.
Initial laboratory testing includes serum TSH, plus an estimate of free T4 levels.
- Serum TSH is increased in primary hypothyroidism. This is the most sensitive test for primary hypothyroidism, but it is not useful for secondary hypothyroidism, in which TSH is usually decreased, but may also be normal or elevated.
- Serum free T4 or T4 index is decreased. A normal value, in the context of elevated TSH, represents subclinical hypothyroidism.
- Further laboratory testing may be useful in selected cases.
- Thyroid autoantibodies are present in Hashimoto’s thyroiditis.
- Radioactive iodine uptake may be low in cases of hypothyroidism. However, this study is more useful for evaluating cases of hyperthyroidism.
- Elevated cholesterol, triglycerides, and creatine phosphokinase may occur, but are nonspecific markers of hypothyroidism.
Radioimaging can evaluate the size, shape, and iodine distribution of the thyroid gland and evaluate for compression of vital structures.
In most cases, hypothyroidism requires lifelong thyroid hormone replacement with synthetic T4 (levothyroxine). The usual dose for replacement is 1.6 μ g/kg body weight per day, but the regimen typically begins at 50 μ g/day (12.5-25 μ g/day in elderly patients) and increases by 25 to 50 μ g/day every 4 to 8 weeks until a maintenance dose is reached. The dose is adjusted until a normal TSH level is attained. Levothyroxine should be taken on an empty stomach.
Treatment of subclinical hypothyroidism is not always necessary and should be considered on a case-by-case basis.
Iodine deficiency is treated with potassium iodide.
Myxedema coma is treated initially with intravenous levothyroxine, L-triiodothyronine, and corticosteroids, followed by maintenance doses of oral thyroid hormones.
Genetic factors apparently account for approximately 80% of the risk for developing autoimmune thyroid disease. Environmental factors also play a role in many cases. Individuals and populations ingesting inadequate amounts of iodine appear to be particularly at risk, as are patients with autoimmune diseases.
The use of iodized salt is a well-accepted public health strategy for decreasing the incidence of iodine deficiency disorders. Although mild iodine deficiency results in enlarged thyroid glands, evidence of clinical hypothyroidism does not necessarily follow. Conversely, even mildly to moderately excessive iodine intake ( ≥ 220 μ g/day) through foods, dietary supplements, topical medications, and/or iodinated contrast media can increase risk for hypothyroidism. Iodine excess causes a hypothyroid state partly because of a decrease in the sodium/iodide symporter that is responsible for transport of iodide into thyrocytes (Wolff-Chaikoff Effect), a fundamental step in thyroid hormone biosynthesis.
Many patients with thyroid disease also have celiac disease. , A large longitudinal study found that celiac disease was associated with a more than four-fold increased risk of hypothyroidism. Although evidence is limited, clinical trials found that most patients who strictly followed a gluten-free diet for one year experienced a normalization of subclinical hypothyroidism and a reduced need for thyroxine.
Hypothyroidism is associated with increased risk of developing diabetes. Conversely, both type 1 and type 2 diabetes increase the risk of developing hypothyroidism. Clear dietary links between hypothyroidism and diabetes have not yet been described, but it may be that chronic hyperglycemia and hyperlipidemia increase the risk of hypothyroidism, and, conversely, that hypothyroidism influences carbohydrate and lipid metabolism. In addition, while a clear dietary trigger of autoimmune diseases, including type 1 diabetes and thyroiditis, has not yet been established, some data support the role of cow’s milk in the pathogenesis of these diseases. ,
Iron deficiency may also contribute to thyroid disease risk. Although Western, meat-eating populations have greater iron stores than non-Western populations, some individuals may experience poor iron status. Plasma thyroxine and triiodothyronine concentrations were significantly lower in women with iron-deficiency anemia, compared with controls. Iron-deficiency anemia blunts the effect of iodine supplementation on thyroid function, and iron supplementation improves it. , However, iron supplements should be taken apart from levothyroxine (see below).
Selenium is a micronutrient with important roles in thyroid functioning. Selenoproteins include the iodothyronine selenodeiodinases, D1 and D2, which are responsible for the production of biologically active T 3. Low selenium blood levels are associated with lymphocyte infiltration of the thyroid, suggesting a link between this mineral and autoimmune thyroid disease. Selenium supplementation appears to be of some benefit in patients with autoimmune thyroiditis (AIT) on L-thyroxine. Controlled clinical trials, using 200 μg/day for several weeks showed 25%-55% reductions in thyroid peroxidase (an enzyme that catalyzes iodination of T4 and T3) antibody concentrations. , However, none have demonstrated a thyroid hormone-sparing effect thus far.
Organochlorine pollutants (e.g., dioxins, PCBs) are ubiquitous toxins often found in fish, meat, eggs, and dairy products. Evidence suggests that PCBs have several antithyroid effects. Thus far, most of these effects have been demonstrated only in humans exposed to these pollutants by accident or through occupational exposure. However, a weight loss study in humans found significant correlations between an increase in plasma organochlorine concentrations and decreases in triiodothyronine concentration and resting metabolic rate, even after statistical adjustment for the known effect of weight loss on T3 levels. Additional study is required to determine to what degree these pollutants might affect hypothyroidism.
When thyroid medication is used, it should be taken on an empty stomach. Meals can delay gut absorption of levothyroxine, with a particularly noticeable effect from high-fiber meals. Both calcium carbonate and iron supplements can significantly reduce absorption of levothyroxine and reduce its effectiveness., , This may have particular relevance for older women, who are more likely to need thyroid hormone replacement and to take calcium supplements.
Dietitian should instruct patient on ways to avoid diet-medication interactions that may influence TSH and T3.
What to Tell the Family
Hypothyroidism is common and treatable, in most cases with excellent outcome. Prevention of hypothyroidism requires adequate dietary intake of iodine at recommended levels. Patients who live in countries where iodine is scarce may need supplements of these minerals. In patients with established hypothyroidism, hormone replacement is needed to normalize T3 and TSH levels.
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