2
Pathophysiology and Diagnosis of Thyroid Disease

The thyroid is a butterfly-shaped gland located in the front of the neck just above the trachea. It weighs approximately 15 to 20 grams in the adult human. The thyroid produces and releases into the circulation at least two potent hormones, thyroxine (T4) and triiodothyronine (T3), which influence basal metabolic processes and/or enhance oxygen consumption in nearly all body tissues. Thyroid hormones also influence linear growth, brain function including intelligence and memory, neural development, dentition, and bone development (Larsen, 2003).

The thyroid gland produces T4 and T3 utilizing iodide obtained either from dietary sources or from the metabolism of thyroid hormones and other iodinated compounds. About 100 µg of iodide is required on a daily basis to generate sufficient quantities of thyroid hormone. Dietary ingestion of iodide in the United States ranges between 200 and 500 µg/day and varies geographically; ingestion is higher in the western part of the United States than in the eastern states. The specialized thyroid epithelial cells of the thyroid gland are equipped with a Na/I symporter that helps concentrate iodide 30 to 40 times the level in plasma to ensure adequate amounts for the synthesis of thyroid hormone. The iodide trapped by the thyroid gland is subsequently oxidized to iodine by the enzyme thyroid peroxidase. The iodine then undergoes a series of organic reactions within the thyroid gland to produce tetraiodothyronine or thyroxine (T4) and triiodothyronine (T3). T3 is also produced in other tissues such as the pituitary, liver, and kidney by the removal of an iodine molecule from T4. T4 is considered to be more of a pro-hormone, while T3 is the most potent thyroid hormone produced. T4 and T3are both stored in the thyroglobulin protein of the thyroid gland and released into the circulation through the action of pituitary derived thyrotropin (thyroid stimu



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2 Pathophysiology and Diagnosis of Thyroid Disease The thyroid is a butterfly-shaped gland located in the front of the neck just above the trachea. It weighs approximately 15 to 20 grams in the adult human. The thyroid produces and releases into the circulation at least two potent hormones, thyroxine (T4) and triiodothyronine (T3), which influence basal metabolic processes and/or enhance oxygen consumption in nearly all body tissues. Thyroid hormones also influence linear growth, brain function including intelligence and memory, neural development, dentition, and bone development (Larsen, 2003). The thyroid gland produces T4 and T3 utilizing iodide obtained either from dietary sources or from the metabolism of thyroid hormones and other iodinated compounds. About 100 µg of iodide is required on a daily basis to generate sufficient quantities of thyroid hormone. Dietary ingestion of iodide in the United States ranges between 200 and 500 µg/day and varies geographically; ingestion is higher in the western part of the United States than in the eastern states. The specialized thyroid epithelial cells of the thyroid gland are equipped with a Na/I symporter that helps concentrate iodide 30 to 40 times the level in plasma to ensure adequate amounts for the synthesis of thyroid hormone. The iodide trapped by the thyroid gland is subsequently oxidized to iodine by the enzyme thyroid peroxidase. The iodine then undergoes a series of organic reactions within the thyroid gland to produce tetraiodothyronine or thyroxine (T4) and triiodothyronine (T3). T3 is also produced in other tissues such as the pituitary, liver, and kidney by the removal of an iodine molecule from T4. T4 is considered to be more of a pro-hormone, while T3 is the most potent thyroid hormone produced. T4 and T3are both stored in the thyroglobulin protein of the thyroid gland and released into the circulation through the action of pituitary derived thyrotropin (thyroid stimu

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lating hormone or TSH). A normal individual produces from the thyroid gland approximately 90 to 100 µg of T4 and 30 to 35 µg of T3 on a daily basis. An estimated 80 percent of the T3 produced daily in humans is derived from peripheral metabolism (5'-monodeiodination) of T4, with only about 20 percent secreted directly from the thyroid gland itself. On a weight basis, T3 is about 3 to 5 times more potent as a thyroid hormone than T4 and is believed to be the biologically active form of the hormone. TSH, secreted by thyrotroph cells located in the anterior pituitary gland, regulates thyroid gland function and hormone synthesis and release. The pituitary secretion of TSH in turn is influenced by the releasing factor, thyrotropin-releasing hormone (TRH) produced in the hypothalamus (see Figure 2-1). The secretion of both TSH and TRH is regulated by negative feedback from thyroid hormone, predominantly T3, from the circulation and/or T3 that is produced locally from intracellular conversion of T4 to T3. When circulating thyroid hormone levels are elevated, both the synthesis and secretion of serum TSH are blunted. In contrast, when circulating levels of T4 and T3 are low, serum TSH levels are increased in a compensatory fashion. The geometric mean level of serum TSH in normal individuals is approximately 1.5 µU/ml as recently reported in the NHANES III study (Hollowell et al., 2002). When hypothalamic pituitary function is intact, FIGURE 2-1

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serum TSH levels are markedly suppressed (to <0.05 µU/ml) in patients with hyperthyroidism and elevated circulatory levels of serum thyroxine, while a marked increase in TSH (>5 µU/ml) occurs in patients with hypothyroidism and low blood levels of serum T4. The mechanism through which TSH binds to and activates the thyroid gland is well understood. TSH binds to a specific membrane receptor located on the surface of the thyroid epithelial cell and activates the cell signaling mechanisms through the enzyme adenylate cyclase located in the plasma membrane. Activation of adenylate cyclase increases intracellular cyclic adenosine monophosphate (cAMP) levels, which in turn stimulate additional intracellular signaling events that lead to thyroid hormone formation and secretion. T4 and T3 circulate bound primarily to carrier proteins. T4 binds strongly to thyroxine binding globulin (TBG, ~ 75 percent) and weakly to thyroxine binding prealbumin (TBPA, transthyretin, ~ 20 percent) and albumin (~5 percent). T3 binds tightly to TBG and weakly to albumin, with little binding to TBPA. The geometric mean for serum T4 in normal individuals is approximately 8 µg/dl, while the mean serum T3 level is approximately 130 ng/dl. Under normal protein binding conditions, all but 0.03 percent of serum T4 and 0.3 percent of serum T3 is protein bound. Only a small amount of unbound (or free) T4 (approximately 2 ng/dl) and T3 (approximately 0.3 ng/dl) circulates in a free state, and it is this free concentration that is considered responsible for the biological effects of the thyroid hormones. There are physiologic situations associated with a change in the serum concentration of these thyroid-binding proteins—such as pregnancy, non-thyroidal illness, or ingestion of drugs—that affect the level and/or affinity of these binding proteins. Under these circumstances, the serum concentrations of total T4 and total T3 change in parallel to the changes that occur in the thyroid hormone binding proteins, but the serum concentrations of free T4 and free T3 remain normal and the individual remains euthyroid. In contrast, the serum concentration of free T4 and free T3 are raised in hyperthyroidism and decreased in hypothyroidism. THYROID FUNCTION TESTING At the present time, serum-based tests available by immunoassay for measuring the concentration of thyroid hormones in the circulation include total (TT4 and TT3) and free (FT4 and FT3) hormone. In addition, direct measurements of thyroid hormone binding plasma proteins, thyroxine binding globulin (TBG), transthyretin (TTR)/prealbumin (TBPA), and albumin are also available. However, the thyroid test measurement that has the greatest utility for evaluating patients suspected of thyroid disease is the third-generation thyroid stimulating hormone (TSH, thyrotropin) assay. Most third-generation TSH assays today that can reliably detect differences of 0.02 µU/ml or better (interassay imprecision <20 percent) can easily distinguish both hyper- and hypothyroidism from euthyroidism (normal thyroid function) and may differentiate the patient suffering

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from the “euthyroid sick syndrome” from true hyperthyroidism. Other methods in thyroid testing include the measurement of thyroid gland autoantibodies, including antithyroid peroxidase (TPOab), antithyroglobulin (Tgab), and antibodies against the TSH receptor (Trab). All of these thyroid test methods are routinely available on automated immunoassay instruments located in most hospital and reference laboratories with tight (<10 percent) method between run coefficients of variation. TESTING FOR DIAGNOSIS AND MANAGEMENT OF THYROID DYSFUNCTION The most sensitive test in an ambulatory population at risk for thyroid dysfunction is the serum TSH (Demers and Spencer, in press). Serum TSH assays today have sufficient sensitivity and specificity to identify individuals with all forms of thyroid dysfunction in the general population. However, among individuals with serious, acute illness, the serum TSH is less specific for thyroid disease because a serious illness alone can depress TSH secretion (to be discussed). TSH screening of the neonatal population to detect congenital hypothyroidism before it is clinically evident is mandated throughout the United States and in many other countries. When an abnormal serum TSH value is obtained, the usual next step is to repeat the measurement of TSH and also measure a serum free T4. The latter can be performed in several ways and among non-hospitalized individuals, most methods give results that are inversely correlated with the serum TSH result. The most common cause of discordance between the TSH and free T4 result occurs in patients with subclinical thyroid dysfunction with high or low serum TSH values and a normal serum free T4 result. Serum TSH measurements may yield misleading results for individuals with changing levels of thyroid hormones. For example, a serum TSH level may remain high for weeks in hypothyroid patients treated with T4. Similarly, serum TSH levels may remain low for weeks after the serum T4 level falls to normal in patients treated for hyperthyroidism. Reference Intervals for Thyroid Function Tests Typical reference intervals for thyroid function tests in normal adults are shown in Table 2-1. The median serum concentration in U.S. subjects 12 years and older, as reported from 1988 to 1994 in the NHANES III study, was 1.49 µU/ml, a value that is considerably below the upper limit of normal (4.5 µU/ml) reported by most laboratories (Hollowell et al., 2002). This finding has led to the suggestion that a serum TSH value above 3 µU/ml may not be normal. In the same study, median serum TSH concentrations in subjects more than 50 years old were higher than in younger individuals: 1.60 µU/ml after age 50, 1.79 µU/ml after age 60,

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TABLE 2-1 Serum TSH and Thyroid Hormone Reference Ranges in Adults Hormone Reference Range TSH 0.4 – 4.5 µU/ml Total thyroxine (total T4) 4.0 – 12.0 µg/dl Free thyroxine (free T4) 0.7 – 1.8 ng/dl Total triiodothyronine (total T3) 100 – 200 ng/dl Free triiodothyronine (free T3) 208 – 596 pg/dl 1.98 µU/ml after age 70, and 2.08 µU/ml after age 80. Serum total and free T4 levels do not change significantly with age, while serum total and free T3 do show an age-related decline in concentration. Thyroid Function Testing in the Elderly The prevalence of both low and high serum TSH levels (with normal serum free T4 results) is increased in elderly subjects compared with younger people. With respect to high serum TSH values, the increase is thought to represent an increased prevalence of autoimmune thyroiditis, especially in women, as will be discussed. The higher prevalence of low serum TSH values may be due to thyroid nodular disease or unrecognized non-thyroid illness. Diagnosis of Hypothyroidism Hypothyroidism is a hypometabolic state that results from a deficiency in T4 and T3. Its major clinical manifestations are fatigue, lethargy, cold intolerance, slowed speech and intellectual function, slowed reflexes, hair loss, dry skin, weight gain, and constipation. It is more prevalent in women than men. The most common cause of hypothyroidism is disease of the thyroid itself, primary hypothyroidism. The most common cause of primary hypothyroidism is chronic autoimmune thyroiditis (Hashimoto’s disease), in which the thyroid is destroyed by antibodies or lymphocytes that attack the gland. Other causes are radioactive iodine and surgical therapy for hyperthyroidism or thyroid cancer, thyroid inflammatory disease, iodine deficiency, and several drugs that interfere with the synthesis or availability of thyroid hormone. Hypothyroidism may also occur rarely (<1 percent of cases) as a result of deficiency of TRH or impaired TSH secretion due to hypothalamic or pituitary disease, respectively. This is known as secondary or central hypothyroidism because of the negative feedback relationship between serum T4 and T3 levels and TSH secretion. As noted earlier and shown in Figure 2-1, people with primary hypothyroidism have high serum TSH levels. If

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an individual has a high serum TSH value, serum free T4 should be measured. The concomitant finding of a high serum TSH concentration and a low free T4 level confirms the diagnosis of primary hypothyroidism. People with a high serum TSH concentration and a normal or low-normal serum free T4 level have, by definition, subclinical hypothyroidism. The diagnosis of secondary hypothyroidism is based on the findings of a low serum free T4 level and a serum TSH level that is normal or low. People with secondary hypothyroidism are unlikely to be detected by a screening program based on measurements of serum TSH, but the condition is much less common than primary hypothyroidism. Diagnosis of Hyperthyroidism Hyperthyroidism is a hypermetabolic state that results from excess production of T4 and T3. Its major clinical manifestations are nervousness, anxiety, heart palpitations, rapid pulse, fatigability, tremor, muscle weakness, weight loss with increased appetite, heat intolerance, frequent bowel movements, increased perspiration, and often thyroid gland enlargement (goiter). Most individuals with hyperthyroidism are women. The most common cause of hyperthyroidism is Graves’ disease, an autoimmune disease characterized by the production of antibodies that activate the TSH receptor, resulting in stimulation of T4 and T3 production and enlargement of the thyroid. Other caused of hyperthyroidism are a multinodular goiter, solitary thyroid adenoma, thyroiditis, iodide- or drug-induced hyperthyroidism, and, very rarely, a TSH secreting pituitary tumor. The diagnosis of hyperthyroidism is based on the findings of a high serum free T4 level and a low serum TSH concentration. Occasionally, people with hyperthyroidism have a normal serum free T4 and high serum free T3 concentrations. These patients have what is called T3-hyperthyroidism. An increase in serum thyroid hormone binding protein will raise the serum total T4 level but not free T4 concentrations. In these patients the serum TSH remains normal. Patients with a low serum TSH concentration and normal serum free T4 and free T3 levels have, by definition, subclinical hyperthyroidism. Effect of Medications on Thyroid Test Results Several medications have in vivo or in vitro effects on thyroid function tests that can create misleading results. Medications, notably estrogens, that raise serum TBG levels result in an increase in serum total T4, but no change in serum free T4 levels and no change in serum TSH concentrations. High doses of glucocorticoids (adrenal hormones) can lower the serum T3 concentration by inhibiting the peripheral conversion of T4 to T3 and lower serum T4 (and T3) by inhibiting TSH secretion. Iodide, contained in solutions used to sterilize the skin and in radiopaque contrast media used in coronary angiography and many other radiological

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procedures, can cause either hyper- or hypothyroidism, depending on whether the individual has a nodular goiter or some unsuspected thyroid injury. The iodide-containing drug amiodarone, given to patients with cardiac arrhythmias, can also cause either hypothyroidism or hyperthyroidism in appropriately susceptible individuals. Other drugs have effects that alter thyroid function test results directly. For example, the anticoagulant heparin can raise serum free T4 concentrations by stimulating release of free fatty acids from triglycerides in serum. Thyroid test methods that use fluorescence detection may be sensitive to the presence of fluorophore-containing drugs or diagnostics agents used in radiology. Thyroid Function Testing and Nonthyroidal Illness Many people who are seriously ill have abnormal thyroid test results but no other evidence of thyroid dysfunction. These abnormalities occur in people with both acute and chronic illnesses and tend to be greater in those with more serious illnesses. Thus the laboratory diagnosis of thyroid disease can be extremely difficult to make in very sick people, especially those who need to be hospitalized. The effects of illness include decreased peripheral conversion of T4 to T3, decreases in serum concentrations of thyroid hormone binding proteins, and decreases in TSH secretion. These changes are reversible and do not seem to cause clinical manifestations of thyroid deficiency. Among healthier individuals, a few may have small changes in thyroid test results as a result of unrecognized nonthyroidal illness rather than thyroid dysfunction. REFERENCES Demers LM, Spencer CA. In press. Laboratory support for the diagnosis and monitoring of thyroid disease. Laboratory Medicine Practice Guidelines. National Academy of Clinical Biochemistry. Thyroid. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE. 2002. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87(2):489–499. Larsen PR, Davies TF, Schlumberger MJ, Hay ID. 2003. Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky K, eds. Williams’ Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders Company. Pp. 389–516.