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EDUCATIONAL COMMENTARY – THYROID AND PARATHYROID TESTING Educational commentary is provided through our affiliation with the American Society for Clinical Pathology (ASCP). To obtain FREE CME/CMLE credits click on Continuing Education on the left side of the screen. Learning Outcomes Upon completion of this exercise, the participant will be able to: • Discuss the symptoms of Hashimoto’s thyroiditis and Graves disease. • List laboratory tests used to investigate thyroid and parathyroid dysfunction. • Interpret thyroid and parathyroid test results. An estimated 13 million Americans have thyroid-related disease, making it the second (to diabetes) most common endocrine disorder. The incidence of thyroid disease increases with age and is more prevalent in women than men. As many as 8 million cases of thyroid disease in the United States are undiagnosed. Once diagnosed, both hypo- and hyperthyroidism are easily treatable. Laboratory tests are crucial in the diagnosis and treatment monitoring of thyroid disease. Thyroid Function The thyroid gland, a large bilobed gland located in the neck anterior to the trachea, is often described as butterfly-shaped. It synthesizes and releases iodine-containing thyroid hormones, including thyroxine (tetraiodothyronine) (T4) and two forms of triiodothyronine (T3 and reverse T3). Although T4 is present in the highest concentration in plasma, T3 is the biologically most active form. Most circulating T4 and T3 is bound to the plasma proteins thyroxine-binding globulin (TBG), transthyretin (thyroxine-binding prealbumin), and albumin with only approximately 0.03 % of T4 and 0.3 % of T3 circulating as the free or unbound form. Only free hormone is available to tissues to induce the metabolic effects regulated by these hormones. Equilibrium between bound and free hormone and changes in levels of the binding proteins must be considered when interpreting hormone concentrations. Thyroid hormones are involved in the regulation of multiple metabolic processes. Large quantities of these hormones are stored in the gland and the rate of secretion to maintain normal metabolic activity is controlled by feedback mechanisms via the hypothalamic, pituitary, and thyroid axis. The hypothalamus releases thyroxine-releasing hormone (TRH) that stimulates the pituitary to produce and release thyroidstimulating hormone (TSH) that then regulates formation and release of thyroid hormones by the thyroid gland. Increased levels of T3 and T4 inhibit secretion of TRH and TSH. Thyroid Disorders The signs and symptoms of thyroid disease are nonspecific and fairly frequently encountered, and are often undiagnosed or attributed to the aging process or some other condition. These clinical features include weight loss, irritability, tachycardia, heat intolerance, and dyspnea for hyperthyroidism; and weight rd American Proficiency Institute – 2005 3 Test Event EDUCATIONAL COMMENTARY – THYROID AND PARATHYROID TESTING (cont.) gain, dry skin, cold intolerance, and bradycardia for hypothyroidism. An enlarged thyroid (goiter) may occur in both hypo- and hyperthyroidism. There is not a consensus among professional medical societies concerning general population screening for the detection of thyroid disease, but the American Thyroid Association recommends screening adults beginning at age 35 years and every 5 years thereafter. Other organizations recommend screening women over the age of 50, asymptomatic adults over the age of 60, or those at high risk, such as pregnant and postpartum women. Newborn screening programs in the US test for T4, frequently using dried blood on filter paper. Available thyroid function tests include TSH, total and free T4, and T3 as well as tests for the binding proteins and thyroid autoantibodies. Thyroid Function Testing The preferred initial test for thyroid dysfunction in an ambulatory population is TSH. Although free hormone levels mediate the metabolic processes, TSH is the preferred test because the inverse log/linear relationship between free T4 and TSH is such that a two-fold change in free T4 causes a 100-fold change in TSH levels. Current TSH immunoassays, with functional sensitivity of at least 0.02 mIU/L, are able to distinguish between hypo-, hyper-, and euthyroidism and are referred to as third-generation or ultrasensitive TSH assays. Reference ranges for TSH are being refined as more studies using the current immunoassays are published. The upper limit has declined from 10 to 4.0 or 4.5 mIU/L and there is support to lower it to 2.5 mIU/L or lower. The lower limit is typically 0.2-0.4 mIU/L, and some studies in the elderly indicate that these levels may represent thyroid hormone excess. Total T4 levels may be determined to confirm a diagnosis, but free T4 assays reflect true thyroid status. Free hormone levels can be approximated using an index method in which the fraction of free hormone is estimated using the total hormone concentration and an assessment of thyroid-binding protein concentration using either an immunoassay for TBG or more commonly a T4 or T3 “uptake” test called Thyroid Hormone Binding Ratio (THBR). In a hospitalized population, severe nonthyroidal illness (NTI) and medication can affect thyroid test results so testing should be limited to patients with symptoms or a history of thyroid dysfunction. In such cases both TSH and free T4 followed by total T4 may be necessary. If T4 and TSH results in these patients are concordant, there is probably a true thyroid dysfunction. Hypothyroidism Hypothyroidism accounts for approximately 80% of all thyroid disease and the most frequent form is the autoimmune condition known as Hashimoto’s thyroiditis. An elevated TSH is diagnostic for hypothyroidism, but additional testing may help to confirm or to refine the diagnosis. A low free T4 concentration confirms the diagnosis. The presence of autoantibodies may be determined using the thyroid peroxidase antibody (TPOAb) test. Occasionally, hypothyroidism may be caused by pituitary (secondary) or hypothalamic (tertiary) dysfunction and TSH results will be decreased. In these cases, rd American Proficiency Institute – 2005 3 Test Event EDUCATIONAL COMMENTARY – THYROID AND PARATHYROID TESTING (cont.) TRH stimulation testing in which TSH levels are measured following TRH administration helps to elucidate the cause. Hyperthyroidism Graves’ disease, the most common cause of hyperthyroidism, is caused by an autoantibody, thyroidstimulating immunoglobulin (TSI), that mimics the action of TSH and causes overproduction of the thyroid hormones. These elevated T4 and T3 levels suppress production and release of TSH resulting in the decreased TSH levels diagnostic for hyperthyroidism. The diagnosis can be confirmed by demonstration of elevated free T4 levels. One type of hyperthyroidism, known as T3 thyrotoxicosis, is characterized by decreased TSH, normal free T4, and elevated free and/or total T3. Laboratory Concerns The National Academy of Clinical Biochemistry (NACB) practice guidelines, entitled Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease (available at www.nacb.org), includes recommendations and items of particular interest to the laboratory. In addition to appropriate use of thyroid function tests, the guidelines address analytical issues. One question often asked by physicians is whether successive test values are clinically significant. Although Table 1 lists the estimated clinically significant differences when monitoring patient response to therapy, these values, which include analytical and biological variability, could be used in other situations involving successive thyroid function test values. When investigating discordant thyroid test results, laboratorians should be aware of possible interference due to heterophile antibodies or occurrence of the hook effect with the immunoassays that they use. Results of discordant results should be retested using an immunoassay from a different manufacturer in order to eliminate assay-related interferences. Table 1. Clinically significant differences in thyroid test values when monitoring a patient’s response to therapy Test Difference Total T4 2.2 µg/dL Free T4 0.5 ng/dL Total T3 35 ng/dL Free T3 0.1 ng/dL TSH 0.75 mIU/L Reproduced with permission of the National Academy of Clinical Biochemistry, Washington, DC. Laboratory Medicine Practice Guidelines: Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease, 2003. (available for download at www.nacb.org) Parathyroid Function Testing Parathyroid hormone (PTH), synthesized and secreted by the 4 parathyroid glands located beside the thyroid gland, helps to maintain blood calcium levels. PTH is released in response to low calcium levels rd American Proficiency Institute – 2005 3 Test Event EDUCATIONAL COMMENTARY – THYROID AND PARATHYROID TESTING (cont.) and helps raise the calcium by mobilizing it from bone, stimulating renal activation of vitamin D, and increasing renal retention of calcium. PTH is typically ordered to investigate hyper-or hypocalcemia, but it is also helpful when monitoring treatment for diseases affecting calcium regulation, or in chronic conditions such as renal disease. Interpretation of PTH levels is made in conjunction with calcium results. Elevated calcium and PTH levels are diagnostic for primary hyperparathyroidism. Low or normal PTH levels in the presence of low calcium levels indicates hypoparathyroidism. The short half-life of PTH (3-4 minutes) allows the use of point-of-care methods for monitoring PTH levels during parathyroid surgery for hyperparathyroidism. Samples are collected and analyzed before and at 5and 10-minute intervals after removal of abnormal parathyroid tissue. A decline of more than 50% in PTH from 0 to 5 minutes postexcision indicates successful surgery. This intraoperative PTH monitoring provides rapid feedback to the surgeon to ensure that sufficient tissue has been removed. Conclusion In summary, laboratory testing is invaluable in the diagnosis and monitoring of therapy for disorders of both thyroid and parathyroid function. Laboratorians should be aware of the characteristics of the assays that they use for this testing in order to be able to troubleshoot potential problems. © ASCP 2005 rd American Proficiency Institute – 2005 3 Test Event