THYROID DISORDERS

Thyroid disorders fall into two general categories:(1) dysfunction of thyroid hormone production; and (2) development of thyroid enlargements, called goiters, which include generalized enlargement of the gland and benign and malignant nodules. Thyroid dysfunction results either from increased or decreased secretion of thyroid hormones, called hyperthyroidism or hypothyroidism, respectively.

NORMAL THYROID FUNCTION

The principal role of the thyroid gland is to manufacture, store, and secrete the thyroid hormones, l-thyroxine and l-triiodothyronine. A critical and unique component of these hormones is their iodine content: 4 atoms of iodine per molecule for l-thyroxine (T4) and 3 atoms per molecule for l-triiodothyronine (T3). Iodine is a trace element in the crust of the earth, and the thyroid has evolved mechanisms to concentrate iodine from the blood plasma and retain it for the manufacture of the thyroid hormones. Once made, the hormones are stored within a protein molecule, called thyroglobulin, within tiny follicles that are lined with thyroid cells. In a controlled manner, thyroglobulin is taken back into the thyroid cells, degraded by enzymes and the thyroid hormone that is released is secreted into the circulating blood.

Function of the thyroid gland uniquely and absolutely requires thyroid-stimulating hormone (TSH; also known as thyrotroptin), which is secreted by specific cells in the anterior pituitary gland. Secretion of TSH is also negatively controlled by the blood concentrations of thyroid hormones. In this classic negative feedback system, excessive serum concentrations of thyroid hormones decrease secretion of TSH, and decreased serum thyroid hormones increase serum TSH. In the normal individual, the serum concentrations both of TSH and thyroid hormones are within the normal range.

THYROID DYSFUNCTION

Thyroid hormones regulate the rate of metabolism, heat production, and oxygen consumption of the entire organism, as well as the concentration of specific proteins in different organs and tissues. In general, symptoms of thyroid dysfunction are related to changes in the rate of metabolism and heat production, though changes in specific proteins may also have a profound impact in the body. For example, since thyroid hormones regulate the production of growth hormone, growth-hormone concentration decreases in the setting of hypothyroidism, resulting in cessation of growth in hypothyroid children.

Hyperthyroidism. In hyperthyroidism, also called thyrotoxicosis, excessive concentrations of thyroid hormones circulate through the body, affecting most tissues and organs, and producing a hypermetabolic state. In this setting, patients complain of fatigue and the feeling that their body temperature is too warm; they have increased sensitivity to external heat and a rapid heartbeat (called palpitations); and they have increased and inappropriate perspiration, nervousness, excess energy, tremors, and an increased frequency of bowel movements. On examination, patients have warm, moist skin, tremor, heat radiating from their skin; rapid heartbeat, and an abnormal thyroid examination. These symptoms reflect an increase in heat production and metabolic rate. Such patients are at increased risk for dangerous, abnormal rhythms of the heart (atrial fibrillation), muscle weakness, and loss of calcium from the bones.

In the United States, the incidence of hyperthyroidism is about 0.5 to 1.0 percent in adult populations, and in patients older than 70 years it approaches 1 to 2 percent. The most common cause of hyperthyroidism is Graves' disease, an autoimmune disorder that may occur in multiple generations, particularly in women. The inheritance appears to be a susceptibility to develop the autoimmune disorder, and its expression is likely influenced by environmental factors. In this disorder, antibodies that appear in the circulation bind to the protein receptor of TSH on the surface of thyroid cells. Once bound, the antibody, called thyroid-stimulating immunoglobulin, simulates the stimulatory action of TSH. Unlike TSH, however, the antibody is not negatively regulated by thyroid hormones, and it provides continuous stimulation of the thyroid leading to overproduction and secretion of excessive amounts of thyroid hormones.

Another cause of hyperthyroidism, particularly in middle-aged or older individuals, is benign thyroid tumors that produce thyroid hormones—even in the absence of TSH—called Plummer's disease or toxic thyroid adenoma. The TSH-independence of the thyroid tissue in these tumors, which may be single or multiple, is likely due to mutations in the TSH receptor protein or other proteins involved in transmission of the TSH signal into the cell.

A third common cause of hyperthyroidism is thyroiditis, caused either by an aberration of the immune system in patients with chronic autoimmune thyroiditis, or by a viral infection. In these disorders, the thyroid is not hyperfunctioning; rather, the structure of the thyroid is disturbed by inflammation and the hormones essentially leak out of the gland and enter the circulation in an unregulated manner. The latter conditions are self-limited and the hyperthyroidism persists only as long as previously manufactured and stored thyroid hormone remains in the thyroid. Other relatively rare causes of hyperthyroidism are pituitary tumors that secrete TSH in an unregulated manner and very high concentrations of the normal placental hormone, chorionic gonadotropin, that may occur in a small minority of pregnancies or in tumors called choriocarcinoma.

The treatments employed for hyperthyroidism are dependent on their cause. For example, the hyperthyroidism that occurs during pregnancy due to excessive chorionic gonadotropin resolves after pregnancy is over. Hyperthyroidism due to TSH-secreting tumors of the pituitary are treated by removal of those tumors, and the hyperthyroidism associated with thyroiditis is self-limited and persists only as long as previously manufactured thyroid hormones persist in the thyroid gland.

For the common causes—Graves' disease and functioning thyroid tumors—available treatments include use of antithyroid drugs (methimizole and propylthiouracil), radioactive iodine (I-131), and surgery. The antithyroid drugs decrease production of thyroid hormone and restore patients to a normal metabolic state. The natural history of Graves' disease includes remission in 25 percent of patients in North America (35–50 percent in Europe; 50–60 percent in Japan), so that control of the disease with antithyroid drugs looking forward to a possible remission is a reasonable approach for many patients. For those who do not enter remission, destructive treatment is usually recommended and accomplished by surgery (subtotal thyroidectomy), or by administration of radioactive iodine. The latter has been in use since the 1940s and is safe and effective. It has none of the immediate side effects or long-term risks that are usually attributed to radiation. Functioning thyroid tumors that are associated with hyperthyroidism do not resolve spontaneously and are therefore usually treated by surgery or radioactive iodine administration.

Hypothyroidism. In hypothyroidism, serum concentrations of thyroid hormones are decreased, resulting in a hypometabolic state. In this setting, patients complain of fatigue and sleepiness and the feeling that their body temperature is low, and they have increased sensitivity to the cold and the feeling that mental function is slow. Appetite remains normal but body weight may increase modestly. Cramping pain in the muscles and constipation are common. On examination, skin is dry and cool and the hair may be brittle. Patients have a slow heart rate, hoarse voice, and slowed mental function. Swelling around the eyes occurs and the reflexes are abnormal. Such patients also have raised concentrations of cholesterol in the blood plasma and are at increased risk for heart disease.

The incidence of hypothyroidism in the United States is 1 to 2 percent in patients under fifty years of age and then increases with age. In women who are older than seventy years of age, moderate to severe hypothyroidism occurs in 2 to 4 percent, and a milder form of hypothyroidism, sometimes called subclinical hypothyroidism, occurs in about 10 percent. Hypothyroidism occurs in males at an incidence that is about 25 percent that of females. Congenital hypothyroidism occurs in 1 in 3,500 births and can be determined by hormone measurements in one drop of blood. If treated soon after birth, affected children appear to develop quite normally. However, in untreated infants, brain development is severely impaired, resulting in cretinism.

A common cause of hypothyroidism is Hashimoto's disease, an autoimmune disorder of the thyroid that is closely related to Graves' disease. Both disorders occur in multiple generations in the same family, particularly in women, and involve an immune response within the thyroid gland and the appearance of antibodies in the blood plasma. In Hashimoto's disease, antibodies that can be easily measured are directed against thyroglobulin and another thyroid protein, thyroid peroxidase. The immune inflammation of the thyroid is painless, and involves gradual replacement of thyroid tissue with lymphocytes and fibrous (scar) tissue.

Other causes of hypothyroidism include surgical removal of the gland in the course of treatment of thyroid nodules, goiter, and cancer; destruction of the thyroid by radioactive iodine (I-131), which occurs commonly after the use of the isotope for the treatment of Graves' disease; and hyperthyroidism due to hyperfunctioning thyroid nodules. Diseases of the hypothalamus and pituitary that result in insufficient TSH for normal thyroid function can also cause hypothyroidism. Finally, areas in the world that still suffer from iodine deficiency have a high incidence of hypothyroidism and goiter. The diagnosis of hypothyroidism can be easily confirmed by measurements of thyroid hormones and TSH.

Treatment of hypothyroidism is straightforward in comparison to treatment of hyperthyroidism. No matter what the cause, the ramifications of the disease result from deficiency of thyroid hormone. Thus, simple, once-a-day treatment with thyroid hormone restores the body's thyroid hormone to normal, relieves all symptoms and signs of disease, and prevents the long-term sequelae of hypothyroidism. Most physicians prescribe synthetic l-thyroxine to accomplish this goal.

Goiters and Nodules. Goiter is an enlargement of the thyroid gland. When all of the thyroid tissue is enlarged, called a diffuse goiter, the cause may be manifold, including Graves' or Hashimoto's disease, congenital goiter, and iodine deficiency in those areas of the world where iodine intake is particularly low. Goiter is therefore a reflection of a disease process and may occur with or without thyroid dysfunction. Once the cause of goiter is determined, specific treatment can be prescribed.

Goiter is frequently caused by lumps or nodules in the thyroid, which may be cysts, inflammation, or benign or malignant tumors. The physician can feel single or multiple nodules in 4 to 7 percent of the adult population in the United States. Nodules are found at a much higher frequency by applying ultrasound (sonography) or computerized tomography to the thyroid area. Similar to other thyroid diseases, most patients are female. Current estimates are that the annual incidence of thyroid nodules discovered by examination is about 0.1 percent of the adult population. However, the annual incidence of thyroid cancer is about 0.004 percent. Therefore, only about one in twenty newly discovered thyroid nodules are likely to be malignant.

Upon discovery of a thyroid nodules(s), the physician's main concern should be to determine whether the nodule is benign or malignant. The cornerstone for this determination is the fine-needle aspiration biopsy, a procedure in which a very fine needle is inserted directly through the skin into the nodule and, with gentle suction, cells from the nodule are aspirated, placed on glass slides, stained, and evaluated by microscopy. The biopsy, done with or without direct visualization by sonography, is a simple, safe, and relatively painless office procedure. The sensitivity for detection of thyroid cancer is about 85 percent and the specificty is about 92 percent. Cytology results in a diagnosis in 85 percent of samples, with 75 percent being benign, 5 percent being malignant and 20 percent suspicious for malignancy. The remaining samples are nondiagnostic or unsatisfactory samples. The experience of the operator and cytologist has a large influence on these results.

When the aspiration biopsy demonstrates thyroid cancer, patients are usually referred for total thyroidectomy and are also frequently treated with radioactive iodine (I-131) as well as l-thyroxine at doses that at least maintain normal thyroid function. The nature of most thyroid cancers, and the success of these treatments, usually result in a lifetime cure rate that is greater than 90 percent.

Treatments for benign thyroid nodules vary according to their cause, size, location, and rate of growth. Some nodules may require no treatment at all, whereas others may require surgical excision because they cause pressure on vital structures within the neck such as the windpipe (trachea), food tube (esophagus), or blood vessels.

Martin I. Surks

(see also: Goiter; Hyperthyroidism; Hypothyroidism; Iodine; Thyroid Function Tests )

Bibliography

Brennan, M. D. (1999). "Lymphocytic Thyroiditis: Hashimoto's Disease." In Atlas of Clinical Endocrinology, Vol. I: Thyroid Diseases, ed. M. I. Surks. Philadelphia, PA: Current Medicine.

Burman, K. D.; Becker, K. L.; Cytryn, A. S.; and Goodglick, T. A. (1999). "Graves' Disease." In Atlas of Clinical Endocrinology, Vol. I: Thyroid Diseases, ed. M. I. Surks. Philadelphia, PA: Current Medicine.

Gharib, H. (1999). "Nontoxic Diffuse and Nodular Goiter." In Atlas of Clinical Endocrinology, Vol. I: Thyroid Diseases, ed. M. I. Surks. Philadelphia, PA: Current Medicine.

Hupart, K. H. (1999). "Thyroiditis." In Atlas of Clinical Endocrinology, Vol. I: Thyroid Diseases, ed. M. I. Surks. Philadelphia, PA: Current Medicine.

Kaptein, E. M., and Nelson, J. C. (1999). "Serum Thyroid Hormones and Thyroid-Stimulating Hormone." In Atlas of Clinical Endocrinology, Vol, I: Thyroid Diseases, ed. M. I. Surks. Philadelphia, PA: Current Medicine.

Medeiros-Netos, G. (1999). "Congenital and Iodine-Deficiency Goiters." In Atlas of Clinical Endocrinology, Vol. I: Thyroid Diseases, ed. M. I. Surks. Philadelphia, PA: Current Medicine.

Morris, J. C. (1999). "Hyperthyroidism from Toxic Nodules and Other Causes." In Atlas of Clinical Endocrinology, Vol. I: Thyroid Diseases, ed. M. I. Surks. Philadelphia, PA: Current Medicine.

Shapiro, L. E. (1999). "Hypothyroidism." In Atlas of Clinical Endocrinology, Vol. I: Thyroid Diseases, ed. M. I. Surks. Philadelphia, PA: Current Medicine.

Singer, P. A. (1999). "Thyroid Dysfunction in the Elderly." In Atlas of Clinical Endocrinology, Vol. I: Thyroid Diseases, ed. M. I. Surks. Philadelphia, PA: Current Medicine.

Wartofsky, L. (1999). "Hyperthyroidism." In Atlas of Clinical Endocrinology, Vol. I: Thyroid Diseases, ed. M. I. Surks. Philadelphia, PA: Current Medicine.