Clinical Perspectives in the Diagnosis of Thyroid Disease

Transcription

1 Clinical Chemistry 45:8(B) (1999) Beckman Conference Clinical Perspectives in the Diagnosis of Thyroid Disease Michael M. Kaplan Background: The wide array of available thyroid diagnostic tests can help provide accurate diagnoses for most cases of thyroid disease but can be confusing and costly when used inappropriately. Methods: Published articles were reviewed and combined with the author s clinical experience and data collected from patients. Results: The discussions focus on confusing aspects of thyroid diagnostic tests, the use and limitations of the thyrotropin test to screen for thyroid dysfunction, biological factors that complicate the interpretation of this and other thyroid diagnostic tests, and a combined clinical and laboratory approach to (a) thyroid diseases with only one important dimension ( simplex conditions) and (b) thyroid diseases with several important dimensions ( multiplex conditions). Conclusion: The optimal use of thyroid diagnostic tests is patient-specific and depends on the patient s specific thyroid disease, the stage of disease, and coexisting medical conditions American Association for Clinical Chemistry Several tests are available to evaluate a patient whose thyroid gland is obviously abnormal or whose symptoms or physical signs raise the possibility of thyroid disease. When used and interpreted appropriately, these diagnostic tools can identify the abnormality in nearly every case, but many factors contribute to suboptimal usage of thyroid tests in clinical practice. At a trivial level, test nomenclature can be confusing (Table 1): some tests have similar names but measure different analytes, and the same test may have different names (free thyroxine index T 7 ; antithyroid microsomal antibody antithyroid peroxidase). However, most of the difficulty in thyroid diagnosis stems from more substantive causes: complexities in the biology of thyroid physiology and Associated Endocrinologists, 6900 Orchard Lake Road, Suite 203, West Bloomfield, MI 48322, and Departments of Medicine and Nuclear Medicine, William Beaumont Hospital, Royal Oak, MI Fax ; mmkallegro@aol.com. Received March 8, 1999; accepted May 4, pathophysiology; limitations in sensitivity, specificity, and diagnostic accuracy of the tests; or a misunderstanding of the meaning of results. Clinical findings can and must be integrated with thyroid diagnostic testing to yield accurate and efficient answers to questions pertinent to the diagnosis and treatment of thyroid patients. Three types of diagnostic tests will be considered in this report: blood tests performed in the clinical chemistry and immunology laboratories, imaging techniques, and fineneedle biopsies. Screening for Thyroid Disease Because most clinical manifestations of thyroid dysfunction are nonspecific (1), and some asymptomatic patients have thyroid abnormalities that can cause adverse health effects (2 7), the high-sensitivity serum thyrotropin [thyroid-stimulating hormone (TSH) 1 ] test is often performed on a screening basis when there is a low pre-test probability of disease (2 5). It is an excellent screening test because its negative predictive value is very high and the vast majority of results are negative (8). However, screening is not the same as diagnosis, and abnormal TSH values can occur in patients other than those with straightforward new cases of hyperthyroidism and hypothyroidism (Table 2) (9). In addition, because of the log-linear relationship between serum TSH and free thyroxine (T 4 ) concentrations (10), interpatient differences in the slope of the log[tsh] vs [free T 4 ] line (10) and the great variability in analytical sensitivity of currently available TSH assay methods in the range below normal, the severity of a thyroid hormone excess or deficiency cannot be determined from the TSH value alone. Therefore, when a patient with nonspecific symptoms and physical findings has an abnormal serum TSH concentration, the most appropriate response is further evaluation to verify that there is a thyroid abnormality and, if so, determination of its cause and severity. Particular caution is necessary in screening hospital- 1 Nonstandard abbreviations: TSH, thyrotropin (thyroid-stimulating hormone); T 4, thyroxine; T 3, triiodothyronine; and CT, computed tomography. 1377

2 1378 Kaplan: Diagnosis of Thyroid Disease Table 1. Confusing thyroid test nomenclature. Possible intended meanings [incorrect meanings Test name sometimes encountered] Free T 4 Free-T 4 index (or T 7 ) Free T 4 concentration T 3 Serum total T 3 concentration, serum free T 3 concentration, T 3 -uptake test to assess T 4 binding to serum proteins Thyroglobulin Serum thyroglobulin concentration, [anti-thyroglobulin antibody test], [thyroxine-binding globulin] Uptake test T 3 - (or T 4 -) uptake test to assess T 4 binding to serum proteins, radioiodine uptake by the thyroid gland, uptake scan, i.e., thyroid scintiscan combined with thyroid radioiodine uptake measurement Anti-thyroid antibody Anti-thyroglobulin antibody, anti-thyroperoxidase (or anti-microsomal) antibody, anti-tsh-receptor antibody, antibody against the thyrocyte Na/I symporter, [anti-mitochondrial antibody] ized and other severely ill patients for thyroid disease. Severe nonthyroid illness, whether physical or psychiatric, and drugs such as glucocorticoids or dopamine can change the behavior of the pituitary-thyroid axis to cause abnormally high or low serum TSH values in the absence of thyroid disease, as judged by follow-up studies after patients have recovered from their nonthyroid illnesses (11). In the absence of an abnormal thyroid gland by careful physical examination, a hospital inpatient with a mild or moderate ( 20 miu/l) increase in serum TSH and an estimated free T 4 (by either a free-t 4 test or a free-t 4 index) within the health-related reference interval can usually be followed without treatment and reevaluated later. The same holds true for a patient with a subnormal serum TSH and estimated free T 4 and serum T 3 values that are not increased. In both cases, the great majority of patients do not have clinically significant thyroid disease (11). Utility and Limitations of Thyroid Diagnostic Tests For patients with abnormal serum TSH concentrations, follow-up consists of a focused history, physical examination with special attention to the thyroid gland, a repeat TSH test for verification, determination of serum thyroid hormone concentrations, and sometimes, imaging studies. Unfortunately, it is not unheard of for patients to be told that because they have high TSH concentrations, they need to take thyroid medication lifelong and be sent a prescription for T 4 without further workup or explanation. Moreover, because goitrous changes in the thyroid gland or the development of thyroid nodules often do not alter thyroid function, a TSH concentration within the reference interval in a patient with one of these structural abnormalities provides only part of the necessary information and does not mean that the patient s thyroid condition is innocuous. Full evaluation of these cases requires some combination of antithyroid antibody tests, imaging, and fine-needle biopsy. Patients with abnormal TSH results should have serum thyroid hormone determinations. Because 99% of T 4 and triiodothyronine (T 3 ) in the blood are bound to serum proteins, but only the free thyroid hormones are biologically active, estimates of free thyroid hormone concentrations are theoretically preferable to total-t 4 and total-t 3 tests. A 1991 report from the American Thyroid Association summarized the performance of different types of free-t 4 and free-t 3 assays (12), and there have been no major changes since then. Free-T 4 index methods can be used successfully if their limitations and performance in various clinical settings are understood, but they may be more subject to false-positive results than other, more Table 2. Some causes of abnormal serum TSH concentrations. TSH below normal TSH above normal Primary hyperthyroidism Primary hypothyroidism Pituitary/hypothalamic disease with central hypothyroidism Pituitary thyrotroph adenoma Pituitary resistance to thyroid hormone (central hyperthyroidism) Generalized thyroid hormone resistance Prolonged thyrotroph cell suppression after recent hyperthyroidism in euthyroid or hypothyroid patient Thyrotoxicosis from overly rapid correction of severe hypothyroidism with parenteral T 4 Old age Old age Drugs, e.g., glucocorticoids, dopamine Drugs, e.g., amiodarone Problems with T 4 treatment Problems with T 4 treatment Overdosage in treatment for fatigue or overweight Underdosage based on misleadingly high total T 4 Altered gastrointestinal absorption because of drugs or disease Altered gastrointestinal absorption because of drugs or disease Altered T 4 clearance because of drugs Altered T 4 clearance because of drugs Patient compliance problems Patient compliance problems Prescription error Prescription error Testing too soon after T 4 dose decrease Testing too soon after T 4 dose increase Many severe systemic illnesses Recovery phase after severe systemic illness Combination of pulsatile TSH secretion and analytical precision Combination of pulsatile TSH secretion and analytical precision limits limits Antibody in patient serum against antibody in TSH assay, causing analytical artifact

3 Clinical Chemistry 45, No. 8(B), direct, free-t 4 assays (12). Free-T 3 assays are available, but are not often used. Binding protein abnormalities can increase total T 3 in the absence of hyperthyroidism, notably during estrogen treatment and pregnancy. If necessary, a T-uptake test or thyroxine-binding globulin measurement can be used to calculate a free-t 3 index, or a free-t 3 test can be obtained to clarify an ambiguous increased total-t 3 result. When hypothyroidism is suspected, a free-t 4 estimate is appropriate because total-t 3 and free-t 3 tests have inadequate sensitivity and specificity in this setting. When hyperthyroidism is suspected, the combination of a free-t 4 estimate and a total- or free-t 3 estimate provides the most complete assessment of the severity of hyperthyroidism and identifies cases of T 3 -toxicosis, i.e., a selective increase of the serum T 3 concentration. In some centers, free-t 4 and -T 3 tests are routinely used when the TSH is increased (8), but in others, serum T 3 measurements are obtained only when the TSH is low and the free T 4 is within the reference interval. I prefer to monitor both serum free T 4 and T 3 in patients with low serum TSH (other than hypothyroid patients taking T 4 ), even after the thyroid diagnosis is known, to establish patterns of increasing or decreasing values over time. In patients with subclinical hyperthyroidism or those treated with antithyroid drugs, identification of a temporal trend can be quite valuable in deciding when to initiate or modify therapy, as illustrated in the case report below. Biological factors that can cause confusing thyroid diagnostic test results are listed in Table 3. Such results frequently generate patient referrals to my associates and myself and can inappropriately raise patients hopes or fears. The first two blood test categories in Table 3 represent non-disease. Children with learning disorders have been referred to me because of serum T 3 concentrations above a laboratory s stated reference interval, with a serum TSH concentration within the reference interval. The parents have been told that either hyperthyroidism or thyroid hormone resistance (13) is the problem and that I will solve the problem by treating the thyroid. Instead, the children have serum T 3 concentrations within the ageappropriate reference intervals (14), but the laboratory reports a reference interval that actually applies only to nonpregnant adults with no other medical problems. The parents of these children are always disappointed, and sometimes are frustrated and angry. There are also ageand pregnancy-related changes in the reference intervals for serum total T 4, free T 4, TSH, and thyroxine-binding globulin (14). Imaging tests are also subject to misinterpretation (Table 3). It is common to receive a report describing a thyroid radioactive iodine uptake value in the hyperthyroid range or hypothyroid range, although thyroid secretory function cannot accurately be inferred from this test. Another problem is a thyroid ultrasound report that describes the typical features of Hashimoto thyroiditis coarse texture of the parenchyma and multiple focal 1 6 Table 3. Biological pitfalls in thyroid test interpretation. Blood tests Anomalous binding of T 4 or T 3 to serum proteins Genetic Drug induced Disease induced Pregnancy Altered reference intervals for thyroid hormones or TSH Childhood Pregnancy Old age Disrupted set point of the hypothalamic-pituitary-thyroid axis Nonthyroid illness Drugs Thyroid hormone resistance Acute psychiatric illness Imaging tests High radioiodine uptake by the thyroid gland without hyperthyroidism ( hypertrapping ) Hashimoto thyroiditis with normal or low thyroid function Congenital thyroperoxidase deficiency Antithyroid drugs Low radioiodine uptake by the thyroid gland without hypothyroidism Hyperthyroid phase of subacute and postpartum thyroiditis Exposure to high concentrations of nonradioactive iodine Altered thyroid parenchymal sonographic texture in Hashimoto thyroiditis Multiple focal changes difficult to distinguish from colloid nodules or neoplasms Very high prevalence of nonpalpable nodules 1 cm in middleaged and elderly individuals when ultrasound thyroid imaging is performed Cytology Continuum of cytologic features in benign and well-differentiated follicular neoplasms Inconclusive or suspicious thyroid fine-needle biopsy cytology mm hypoechoic areas (15) with no mention of Hashimoto disease as the most likely diagnosis, but with a summary stating only that any one of the focal changes might be a cancer. The ultrasound finding of one or two nonpalpable thyroid nodules 1 cm in diameter with regular borders and no calcifications is another nondisease, because an enormous number of people have them, and the chances of a clinically significant cancer in such lesions are so small that observation is considered appropriate management (16 18). It is a disservice to the patient and the primary physician for the ultrasound report to comment about this type of lesion only that cancer cannot be ruled out, but I encounter such reports often and only rarely see a more appropriate comment such as, this is a nonspecific finding found in more than half of all individuals over age 60 (19). In the evaluation of thyroid nodules by fine-needle biopsy, up to 20% of cases have findings of a cellular follicular lesion for which malignancy cannot be excluded (Table 3) (20). Some cytopathologists report these as

4 1380 Kaplan: Diagnosis of Thyroid Disease follicular lesions without further comment. Other experienced cytopathologists feel that they can subdivide this type of lesion into risk categories with chances of cancer ranging from 5 10% to 50% (20). Having a specific degree of cancer risk may help in the decision between surgery and observation for the patient who has an increased risk of surgical complication because of age or coexisting illness. This information can also help the surgeon decide on the extent of resection (20). Simplex Thyroid Diseases Thyroid diseases with a single important dimension can be termed simplex conditions. Examples are hypothyroidism with mild, diffuse thyroid enlargement; hyperthyroid Graves disease without ophthalmopathy; or a solitary thyroid nodule. Simplex does not, however, necessarily imply that optimal clinical management is simple. Table 4 presents the diagnoses of new patients in my practice, during a 1-year period, who had hyperthyroidism, hypothyroidism, or euthyroid goiter. When the evaluation of hyperthyroidism included antithyroid antibody tests and scintiscanning, Graves disease accounted for 86% of cases. The other 14% had diagnoses for which management differs from that of Graves disease, e.g., in the appropriate dose of radioactive iodine, the possibility of ethanol ablation for a single toxic autonomous nodule, or the advisability of observation because of the selflimited nature of the disease. Table 4. Causes of hyperthyroidism, hypothyroidism, and euthyroid goiter in consecutive patients new to the author s practice in 1 year (1991). Diagnosis n % Hyperthyroidism Graves disease Toxic multinodular goiter Single toxic adenoma Subacute or postpartum thyroiditis Pituitary resistance to thyroid hormone Hyperemesis gravidarum Hypothyroidism Hashimoto thyroiditis, new Hashimoto thyroiditis, treated Euthyroid Undertreated Overtreated Spontaneous, antibody-negative Post radioiodine, untreated Antithyroid drug overdose Iodine overload or lithium therapy Generalized thyroid hormone resistance Euthyroid goiter Diffuse, antibody-negative Diffuse, Hashimoto thyroiditis Multinodular Compensatory, post surgery Lithium therapy Approximately 90% of the cases of hypothyroidism shown in Table 4 were attributable to Hashimoto thyroiditis, but again, for the 10% with other diagnoses the optimal management may differ. A patient who has had radioiodine ablation for hyperthyroidism may require an unusually low dose of T 4 because of autonomous function in the thyroid remnant. In patients taking T 4 for hypothyroidism caused by Hashimoto thyroiditis, many factors can alter a patient s dose requirement (21, 22), and patients with problems in T 4 treatment are referred to me with some regularity (Tables 2 and 4). In patients with diffuse euthyroid goiters (Table 4), those with negative antithyroid antibody tests (almost one-half) are more likely to have autonomous function and a future risk of hyperthyroidism, whereas those with positive antibody tests ( 43%) have a greater likelihood of future hypothyroidism (23). A recent study suggested that levothyroxine treatment to shrink thyroid nodules is more likely to succeed in patients with Hashimoto thyroiditis than in patients with no evidence of autoimmunity (24). If the prognosis and appropriate management of patients with Hashimoto thyroiditis differ from those of patients with non-autoimmune conditions, we should be able to detect thyroid autoimmunity reliably. The diagnostic sensitivity of available antithyroid antibody test methods may vary. One study (25) suggested that measurement of only the anti-thyroid peroxidase (or antimicrosomal ) antibody suffices because almost no patients have increased concentrations of the antithyroglobulin antibody alone (Table 5). However, using a different method to measure the anti-thyroglobulin antibody and possibly testing a patient population selected differently, I found substantially more patients with an isolated increase of anti-thyroglobulin antibody than an isolated increase of anti-microsomal antibody (Table 5). Therefore, the conclusion that performing both antithyroid antibody tests increases the cost without an offsetting diagnostic gain (25) may be limited to specific methods and/or patient populations. It would seem premature to advise a universal abandonment of the antithyroglobulin antibody test. Another simplex condition is a solitary thyroid nodule. The diagnostic evaluation is straightforward: check the TSH and do a needle biopsy (16, 17). Management problems arise from the 5 20% of cases in which the biopsy specimens are insufficient for diagnosis and the additional 20% for which the cytology is ambiguous (20). In those cases, we must use other clinical risk factors in deciding about surgery (26 28). Even for nodules with benign cytology, controversy persists regarding the value of suppressive treatment with T 4 (29). Thus, even in simplex thyroid diseases, many patients benefit from an evaluation beyond the first-line tests. Welcome developments on the laboratory front would be better standardization of tests such as antithyroid antibodies, free T 4, and free T 3 to allow results from different

5 Clinical Chemistry 45, No. 8(B), Anti-thyroid microsomal antibody Table 5. Comparative utility of anti-thyroid antibody tests in relation to patient population and test methods. Anti-thyroglobulin antibody Agglutination method for antithyroglobulin a n %of700 positives RIA method for anti-thyroglobulin b n %of139 positives Negative Negative Positive Positive Positive Negative Negative Positive Total a Data for the agglutination anti-thyroglobulin method are those of Nordyke et al. (25) on consecutive patients referred to a clinic and hospital laboratory, most on suspicion or presence of Hashimoto s thyroiditis, a goiter, hypothyroidism, or Graves disease, using the Ames Sera-Tek kit (Ames Division, Miles Inc., Diagnostics Division). b Data for the RIA anti-thyroglobulin method are from consecutive patients, referred to my office, who had findings suggesting the same conditions or other causes of hyperthyroidism and for whom the anti-thyroglobulin antibody was measured by RIA (33), using a kit from Kronus. In both sets of data, the anti-thyroid microsomal antibody was assayed by the Ames Sera-Tek agglutination kit. laboratories to be interpreted similarly. In addition, the application of new techniques, such as PCR amplification of tumor marker genes, to fine-needle biopsy samples would help reduce the uncertainty about cellular follicular lesions and further reduce the number of patients operated on for benign thyroid nodules. Multiplex Thyroid Diseases More complicated problems, with two or more important dimensions, can be designated multiplex thyroid conditions. Examples are listed in Table 6. The general categories include coexisting diseases, single diseases that can cause several types of complications, and diseases that evolve through several phases. The identification of coexisting conditions requires a Table 6. Examples of multiplex thyroid diseases. Coexisting unrelated conditions Hashimoto thyroiditis follicular cell neoplasm Serum T 4 and T 3 protein-binding anomalies true thyroid dysfunction Coexisting related diseases Hashimoto thyroiditis Graves disease Hashimoto thyroiditis and lymphoma Diseases with several possible complications Goiter: tracheal or esophageal compression, thyroid dysfunction, unacceptable appearance Nodule: cancer risk, unacceptable appearance Graves disease: hyperthyroidism, eye abnormalities Diseases that evolve over weeks to months Subacute or postpartum thyroiditis: thyroid function, size, and discomfort all change Hemorrhage into a nodule: pain and swelling can vary Diseases that evolve over years Autonomously functioning adenoma: regression, infarction, increase in size function Simple goiter: increase in size, function, nodularity Graves disease in remission: many patients ultimately become hypothyroid Thyroid cancer: slow progression of residual disease or late recurrences high index of suspicion and sufficient experience to recognize atypical combinations of test results and clinical findings, unusual patterns of test results, per se, or unexpected responses of patients to usual treatments. It is not rare for Graves disease and Hashimoto thyroiditis to occur in the same patient, and some patients with this combination spontaneously progress from hyperthyroidism to hypothyroidism. The reverse sequence also occurs, but far less often. It is even rarer for a patient to cycle up and down more than once. Lymphoma can arise within the thyroid gland, usually against a background of Hashimoto thyroiditis (30), presumably because of malignant transformation of one or more of the inflammatory cells. Focal swelling or a generalized increase in thyroid size despite adequate levothyroxine replacement justifies cytological or surgical evaluation for lymphoma, and consultation between the clinician and the cytopathologist before a needle biopsy allows the pathologist to arrange for the specimens to be specially processed for evaluation of possible lymphoma. In the thyroid diseases with several possible complications (Table 6), the investigation of one aspect of the disease can have implications for other aspects. An example is a large multinodular goiter with autonomous function. Potential problems are tracheal narrowing, interference with swallowing, hyperthyroidism, and a disfiguring neck mass. Computed tomography (CT) is sometimes necessary to evaluate the possibility of tracheal or esophageal compression. However, if a CT contrast agent is used, the thyroid is exposed to high concentrations of stable iodine, which may cause iodine-induced thyrotoxicosis and prevent ablative treatment with radioiodine. Once again, communication between physicians is vital, in this case between the clinician and the radiologist. Although contrast-enhanced CT images are sharper, it is easy to identify the tracheal air column and obtain a satisfactory assessment of thyroid size and geometry by a non-contrast CT scan. When informed of thyroid abnormalities in patients, radiologists are happy to arrange non-contrast studies.

6 1382 Kaplan: Diagnosis of Thyroid Disease Some thyroid diseases evolve through several phases (Table 6). Medically appropriate, cost-effective use of diagnostic tests differs depending on whether the patient is at the stage of initial diagnosis, in a disease phase in which future change is expected, or under treatment requiring therapeutic monitoring. In addition, clinical and laboratory findings from each check-up must be viewed in the context of sequential test results over time. Fig. 1 shows the progressive increase in secretory activity of an autonomously functioning thyroid adenoma in a woman who was 45 years of age at the time of initial evaluation. The serum TSH initially was within the reference interval, and the contralateral lobe continued to function. After 3 years, the TSH was suppressed, as was the function of the extranodular thyroid tissue. However, the serum free T 4 was in the lower half of the reference range, the patient felt fine, and the nodule was unobtrusive. By 1997, she was menopausal and the serum free T 4 had increased, but she had no hyperthyroid symptoms and no cosmetic problems. The serum free-t 3 concentrations (not shown) paralleled the serum free-t 4 results. Radioiodine ablative treatment was administered in 1997 because the progressive increase in serum free T 4, with concentrations that predicted the development of overt hyperthyroidism within several years, and because the persistently high-normal thyroid hormone concentrations after 1994 could predispose her to postmenopausal osteoporosis (7). This treatment decision was not based on the last free-t 4 result or any other single test value. If sequential tests had been performed using a mixture of free-t 4 index and free-t 4 concentration values or in different laboratories that used different instruments or kits to measure serum free T 4, it would have been difficult, if not impossible, to discern the trend toward hyperthyroidism. The imaging studies shown in Fig. 1 established the diagnosis of an autonomous nodule rather than Graves disease, and this information was used to select a relatively high therapeutic dose of radioiodine because toxic nodular goiters are more radioresistant than Graves disease thyroid glands (31). Another test in which the pattern of sequential test results can be more important than single values is the serum thyroglobulin concentration, used as a tumor marker in the long-term follow-up of patients who have had thyroid cancer. However, currently available serum thyroglobulin assays have wide intermethod variability in results and analytical sensitivity, suboptimal interassay precision even when only one method is used, and for some methods, susceptibility to hook effects that greatly underestimate very high values (32). Conclusion The appropriate use of thyroid diagnostic tests varies according to the clinical setting: screening for thyroid dysfunction, initial evaluation of an abnormal clinical or laboratory finding, management of simplex thyroid diseases, elucidation of the components of multiplex thyroid diseases, long-term follow-up of evolving abnormalities, or monitoring of patients responses to treatment. Reduction in needless evaluation of thyroid non-disease can potentially be achieved by improvements in test nomenclature, test standardization, and the understanding of Fig. 1. Evolution of an autonomously functioning thyroid adenoma. The graph shows serum free-t 4 concentrations between 1989 and The thickened portion of the y-axis is the reference interval. The arrow denotes the time of administration of radioactive iodine ablative therapy. The upper image is a pertechnetate thyroid scintigram from 1989, showing persistent function in the left lobe; the lower image is a pertechnetate scintigram from 1992, when the serum TSH was first suppressed, showing negligible tracer uptake in the left lobe. The TSH concentration remained suppressed thereafter.

7 Clinical Chemistry 45, No. 8(B), variations of healthy thyroid function and structure. Communication among the clinician, the clinical pathologist, and the radiologist greatly increases the value of diagnostic tests. In all but the most straightforward cases of T 4 treatment of hypothyroidism, the combination of clinical findings with test results is vital in determining the best management plan for the patient. Test results alone, however sophisticated and accurate, often do not suffice. References 1. Canaris GJ, Steiner JF, Ridgway EC. Do traditional symptoms of hypothyroidism correlate with biochemical disease? J Gen Intern Med 1997;12: Singer PA, Cooper DS, Levy EG, Ladenson PW, Braverman LE, Daniels G, et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. JAMA 1995;273: Garcia M, Baskin HJ, Feld S, Cobin RH, Daniels GH, Davidson ET, et al. AACE clinical practice guidelines for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 1995;1: American College of Physicians. Screening for thyroid disease. Ann Intern Med 1998;129: Helfand M, Redfern CC. Screening for thyroid disease: an update. Ann Intern Med 1998;129: Cooper DS. Subclinical thyroid disease: a clinician s perspective [Editorial]. Ann Intern Med 1998;129: Marqusee E, Haden ST, Utiger RD. Subclinical thyrotoxicosis. Endocrinol Metab Clin N Am 1998;27: Klee GG, Hay ID. Biochemical testing of thyroid function. Endocrinol Metab Clin N Am 1997;26: Scanlon MF, Toft AD. Regulation of thyrotropin secretion. In: Braverman LE, Utiger RD, eds. Werner and Ingbar s the thyroid. A fundamental and clinical text. Philadelphia: Lippincott-Raven, 1996: Spencer CA, LoPresti JS, Patel A, Guttler RB, Eigen A, Shen D, et al. Applications of a new chemiluminometric thyrotropin assay to subnormal measurements. J Clin Endocrinol Metab 1990;70: Attia J, Margetts P, Guyatt G. Diagnosis of thyroid disease in hospitalized patients. A systematic review. Arch Intern Med 1999; 159: Hay ID, Bayer MF, Kaplan MM, Klee GG, Larsen PR, Spencer CA. American Thyroid Association assessment of current free thyroid hormone and thyrotropin measurements and guidelines for future clinical assays. Clin Chem 1991;37: Hauser P, Zametkin AJ, Martinez P, Vitiello B, Matochik JA, Mixson AJ, Weintraub BD. Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone. N Engl J Med 1993;328: Fisher DA. The Quest diagnostics manual. Endocrinology test selection and interpretation, 2nd ed. San Juan Capistrano, CA: Quest Diagnostics Nichols Institute, 1998:333pp. 15. Solbiati L, Charboneau JW, James EM, Hay ID. The thyroid gland. In: Rumack CM, Wilson SR, Charboneau JW, eds. Diagnostic ultrasound. St. Louis: Mosby, 1998: Singer PA, Cooper CS, Daniels GH, Ladenson PW, Greenspan FS, Levy EG, et al. Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. Arch Intern Med 1996;156: Feld S, Garcia M, Baskin HJ, Cobin RH, Gharib H, Hay ID, et al. AACE clinical practice guidelines for the diagnosis and management of thyroid nodules. Endocr Pract 1996;2: Tan GH, Gharib H. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med 1997;126: Mazzaferri EL. Management of a solitary thyroid nodule. N Engl J Med 1993;328: Hamburger JI, Kaplan MM. Evaluation of thyroid nodules by needle biopsy. In: Braverman LE, Utiger RD, eds. Werner and Ingbar s the thyroid. A fundamental and clinical text. Philadelphia: Lippincott- Raven, 1996: Kaplan MM. Thyroid hormone therapy. What, when and how much. Postgrad Med 1993;93: Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995;333: Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in the elderly. Microsomal antibodies as discriminant for therapy. JAMA 1987;258: Benvenga S, Alesci S, Aricò CN, Trimarchi F. The effect of thyrotropin (TSH) suppressive L-thyroxine (T 4 ) therapy in thyroid nodularity of Hashimoto s thyroiditis [Abstract]. Program of the 71st Annual Meeting of the American Thyroid Association, Portland, OR. New York. The American Thyroid Association, 1998: Nordyke RA, Gilbert FI, Miyamoto LA, Fleury KA. The superiority of antimicrosomal over antithyroglobulin antibodies for detecting Hashimoto s thyroiditis. Arch Intern Med 1993;153: Belfiore A, LaRosa GL, LaPorta GA, Giuffrida D, Milazzo G, Lupo L, et al. Cancer risk in patients with cold thyroid nodules: relevance of iodine intake, sex, age, and multinodularity. Am J Med 1992; 93: Schlinkert RT, van Heerden JA, Goellner JR, Gharib H, Smith SL, Rosales RF, Weaver AL. Factors that predict malignant lesions when fine-needle aspiration is suspicious for follicular neoplasm. Mayo Clin Proc 1997;72: Tuttle MR, Lemar H, Burch HB. Clinical features associated with an increased risk of thyroid malignancy in patients with follicular neoplasia by fine-needle aspiration. Thyroid 1998;8: Zelmanovitz F, Genro S, Gross JL. Suppressive therapy with levothyroxine for solitary thyroid nodules: a double-blind controlled clinical study and cumulative meta-analyses. J Clin Endocrinol Metab 1998;83: Hamburger JI, Miller JM, Kini SR. Lymphoma of the thyroid. Ann Intern Med 1983;99: Kaplan MM, Meier DA, Dworkin HJ. Treatment of hyperthyroidism with radioactive iodine. Endocrinol Metab Clin N Am 1998;27: Spencer CA, Takeuchi M, Kazarosyan M. Current status and performance goals for serum thyroglobulin assays. Clin Chem 1996;42: Beever K, Bradbury J, Phillips D, McLachlan SM, Pegg C, Goral A, et al. Highly sensitive assays of autoantibodies to thyroglobulin and to thyroid peroxidase. Clin Chem 1989;35: