Carole A. Spencer

Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease.

Guidelines Committee: The preparation of this revised monograph was achieved with the expert input of the editors, members of the guidelines committee, experts who submitted manuscripts for each section and many expert reviewers, who are listed in Appendix A. The material in this monograph represents the opinions of the editors and does not represent the official position of the National Academy of Clinical Biochemistry or any of the co-sponsoring organizations. The National Academy of Clinical Biochemistry is the official academy of the American Association of Clinical Chemistry. Single copies for personal use may be printed from authorized Internet sources such as the NACB’ s Home Page (www.nacb.org), provided it is printed in its entirety, including this notice. Printing of selected portions of the document is also permitted for personal use provided the user also prints and attaches the title page and cover pages to the selected reprint or otherwise clearly identifies the reprint as having been produced by the NACB. Otherwise, this document may not be reproduced in whole or in part, stored in a retrieval system, translated into another language, or transmitted in any form without express written permission of the National Academy of Clinical Biochemistry (NACB, 2101 L Street, N.W., Washington, DC 20037-1526). Permission will ordinarily be granted provided the logo of the NACB and the following notice appear prominently at the front of the document: Reproduced (translated) with permission of the National Academy of Clinical Biochemistry, Washington, DC Single or multiple copies may also be purchased from the NACB at the address above or by ordering through the Home Page (http://www.nacb.org/ ).

Thyroglobulin Measurement: Techniques, Clinical Benefits, and Pitfalls

The validity and reliability of serum Tg measurements is central to accurate diagnosis and cost-effective management of patients with differentiated thyroid carcinoma. Serum Tg is one of the most difficult biochemical tests for a laboratory to maintain at a high level of precision and reliability across the long clinical sampling interval typically employed when monitoring this condition. Physicians should be aware that the diagnostic value of serum Tg measurement is method-dependent, and that intermethod differences still approach 30% even after methods have been standardized on the new CBR reference preparation. This dictates that, ideally, serial serum Tg measurements in a patient should always be made in the same laboratory by the same method. Physicians need to consider a number of factors before selecting a laboratory to perform Tg measurements in patients with differentiated thyroid carcinoma. These factors include assay sensitivity, as judged by the discrimination between lower limit of the euthyroid range and the functional sensitivity limit, as well as assay specificity, especially with respect to serum TgAb interference. laboratories should use a sensitive TgAb immunoassay (not hemagglutination) to prescreen sera for TgAb and report the TgAb level if positive. Furthermore, it is the laboratorys responsibility to advise physicians fully about any change in Tg method as well as the direction of TgAb interference expected with that method. When TgAb is present, the serum Tg level should be a measure of the total (free and TgAb-bound) serum Tg level. Typically, IMA methods underestimate the serum total Tg level, especially when serum TSH is suppressed, whereas RIA methods tend to overestimate the serum total Tg level. The interpretation of a serum Tg level in a TgAb-positive patient should be made with caution and with consideration to any changes in TgAb levels. Serial TgAb monitoring of TgAb-positive patients may provide a physician with additional prognostic information on outcome. Precise, reproducible serial serum Tg measurements are critical, especially when patients are judged to have a high risk for recurrence, have tumors that are inefficient serum Tg secretors (as judged from the relationship between the preoperative serum Tg value and tumor mass or the serum Tg response to endogenous TSH stimulation), or have very high serum Tg values requiring dilution. In such patients, the banking of left-over sera (frozen) for concurrent intra-assay remeasurement with a more recent specimen significantly increases the clinical value of the test and facilitates earlier detection of recurrence or progression (see Fig. 2). Differentiated thyroid carcinoma is frequently diagnosed in young patients with decades of life expectancy. After their initial surgical treatment, these patients need life-long monitoring, because late recurrences and death from the disease can occur. The use of high-quality serum Tg measurements can significantly improve the cost-effective management of this disease by identifying low-risk patients in whom periodic radioiodine scans or therapy may be deferred in favor of serial serum Tg monitoring (on L-T4 suppression therapy). With this approach, expensive imaging procedures can be targeted to the minority of patients who are at high risk for recurrence.

Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease

Quality thyroid tests are essential for diagnosing and managing thyroid conditions. Indeed, mild (subclinical) hypoand hyperthyroidism are by definition conditions that are recognized by their biochemical profile, typified by an abnormal serum TSH concentration associated with normal range free thyroid hormone (FT4 and FT3) levels. The National Academy of Clinical Biochemistry (NACB) has recently published a consensus monograph entitled Laboratory Medicine Practice Guidelines: Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease that reviews the clinical utility and technical performance of current thyroid tests (Demers & Spencer, 2002). The current scientific literature abounds with articles relating to thyroid conditions, strategies for thyroid testing and the technical performance of different thyroid methodologies. This monograph was prompted by the need to develop a consensus concerning these issues as well as to address the unusual thyroid problems that challenge the diagnostic accuracy of the thyroid tests currently available. These atypical presentations account for a disproportionately large expenditure of laboratory resources to determine the correct diagnosis (Kricka, 2000). In ambulatory patients these unusual presentations include: binding protein abnormalities that affect the diagnostic accuracy of FT4 tests; the presence of thyroglobulin (Tg) autoantibodies that interfere with serum Tg measurements; and medications that compromise the in vivo and in vitro metabolism of thyroid hormones and influence the diagnostic accuracy of TSH measurements. In addition, severe forms of non-thyroidal illnesses (NTI) have a myriad of effects on thyroid test results. This monograph is unique because it contains consensus guidelines that were developed by a process of global review. The review process was initiated at the International Thyroid Congress in Kyoto in October 2000, after which the guidelines were displayed electronically in addition to being distributed to more than 100 thyroid specialists, representing diverse professional associations worldwide, for consensus-building. The information contained in the monograph is presented in discrete chapters. Each chapter covers the clinical utility of a specific test, and contains focused guidelines that describe the physiological strengths and limitations of the test together with its optimal technical performance parameters. Most of the guidelines appeared to have greater than 95% consensus; however, there were some geographically sensitive differences in practice patterns.

Unique Alterations of Thyroid Hormone Indices in the Acquired Immunodeficiency Syndrome (AIDS)

STUDY OBJECTIVE To determine alterations in serum thyroid hormone indices in patients with human immunodeficiency virus (HIV) infection. DESIGN Prospective, single-blind study. SETTING Large metropolitan hospital where 20% of all patients with the acquired immunodeficiency syndrome (AIDS) in Los Angeles are treated. PATIENTS Twenty-six inpatients with bronchoscopy-proven Pneumocystis carinii pneumonia and AIDS. Outpatients included 10 persons seropositive for HIV, 10 with AIDS-related complex, and 10 with AIDS. MAIN RESULTS There were 19 survivors and 7 nonsurvivors of P. carinii infection. Serum triiodothyronine (T3) values generally remained normal until hospitalization, with nonsurvivors having lower values than survivors (0.56 +/- 0.1 nmol/L compared with 1.3 +/- 0.1 nmol/L, P less than 0.002, respectively). Reverse triiodothyronine (rT3) levels were low in persons with AIDS-related complex (0.21 +/- 0.02 nmol/L, P less than 0.001) and in AIDS outpatients (0.17 +/- 0.02 nmol/L, P less than 0.001). Normalization of rT3 occurred after patients were hospitalized (0.28 +/- 0.01 nmol/L). Serum thyroxine-binding globulin values rose with progression of HIV infection (seropositive, 369.7 +/- 18.1 nmol/L, P less than 0.005; AIDS-related complex, 419.1 +/- 37.0 nmol/L, P less than 0.005; AIDS, 423.3 +/- 31.9 nmol/L, P less than 0.005; survivors, 476.3 +/- 24.6 nmol/L, P less than 0.001), whereas nonsurvivors had normal values. All values are compared with normal values (T3, 2.3 +/- 0.04 nmol/L; rT3, 0.28 +/- 0.01 nmol/L; thyroxine-binding globulin, 288.2 +/- 6.9 nmol/L). CONCLUSIONS Infection with HIV produces unique alterations in thyroid function. A progressive decline in rT3 and elevation in thyroxine-binding globulin accompany advancing HIV infection. The persistence of a normal T3 despite progression of HIV infection may contribute to weight loss. A low serum T3 on admission correlates with mortality.

C-Reactive Protein Levels and the Expansion of Screen-Detected Abdominal Aortic Aneurysms in Men

Background—C-reactive protein (CRP) levels have been shown to predict a number of cardiovascular outcomes. CRP levels have also been found to be elevated in patients with abdominal aortic aneurysms (AAAs). The aim of this study was to assess the relation between CRP levels and rates of expansion of small AAAs. Methods and Results—A cohort of men with small aneurysms was identified in a trial of screening with ultrasound scanning. After initial screening, men were rescanned at 6- to 12-month intervals. CRP levels were measured at the first follow-up visit. Rates of expansion and risk factors for expansion were assessed with the use of data from 545 men who attended for at least 1 scan after CRP levels were measured. These men were followed for a median of 48 (range, 5 to 69) months. The mean annual rate of expansion was 1.6 mm. The median CRP level was 2.6 mg/L in men with the smaller AAAs (30 to 39 mm, n=433) compared with 3.5 mg/L in men with larger AAAs (40 to 54 mm, n=112) (P=0.007). The multivariate age-adjusted logistic model confirmed initial aortic diameter to be the only factor associated with rapid expansion with an odds ratio of 7.2 (95% CI, 4.3,12.2) for an initial diameter of 40 to 54 mm relative to one of 30 to 39 mm. Conclusions—Most small aneurysms expand slowly. CRP levels are elevated in larger aneurysms but do not appear to be associated with rapid expansion. The most useful predictor of aneurysmal expansion in men is aortic diameter.

Clinical Utility of Thyroglobulin Antibody (TgAb) Measurements for Patients with Differentiated Thyroid Cancers (DTC)

CONTEXT Thyroglobulin autoantibodies (TgAb) are primarily measured in serum in conjunction with thyroglobulin (Tg)--the primary tumor marker used to monitor patients with differentiated thyroid cancers (DTC). Every specimen needs TgAb testing to authenticate that the Tg measurement is not compromised by TgAb interference. When present, TgAb concentrations per se can be monitored as a surrogate tumor marker. OBJECTIVES The aims of the study were: 1) to review published reports concerning whether there are associations between DTC, thyroid autoimmunity (Hashimotos thyroiditis), and the presence of TgAb; and 2) to evaluate the methodological factors that influence TgAb interference with serum Tg testing. DATA SOURCES PubMed was used to identify studies published over the last 55 yr that focused on DTC relationships with thyroid autoimmunity and the presence of thyroid autoantibodies. RESULTS Many studies have reported significant associations between papillary thyroid cancer and Hashimotos thyroiditis that may have a favorable prognostic significance. TgAb is detected in approximately 20% of DTC patients and may be a more specific thyroid tumor marker than thyroid peroxidase antibodies. TgAb interferes with Tg immunometric assay (IMA) measurements, causing falsely low/undetectable Tg values, especially when TgAb concentrations are high and serum Tg concentrations (measured by RIA) are low. TgAb concentrations respond to changes in Tg-secreting thyroid tissue such that the TgAb trend can be used as a more reliable surrogate DTC tumor marker than Tg IMA. Current TgAb assays may not always detect interfering TgAb because of insensitivity and specificity differences. It is critical to retain the same method for long-term TgAb monitoring. CONCLUSIONS Patients with Hashimotos thyroiditis frequently have TgAb detected and may have a higher risk for papillary thyroid cancer. Although TgAb interferes with Tg IMA measurements, TgAb trends can be used as a surrogate DTC tumor marker in preference to Tg IMA, provided that the same method is used.

Current Thyroglobulin Autoantibody (TgAb) Assays Often Fail to Detect Interfering TgAb that Can Result in the Reporting of Falsely Low/Undetectable Serum Tg IMA Values for Patients with Differentiated Thyroid Cancer

CONTEXT Specimens have thyroglobulin antibody (TgAb) measured prior to thyroglobulin (Tg) testing because the qualitative TgAb status (positive or negative) determines risk for Tg assay interference, and the quantitative TgAb concentration serves as a surrogate tumor marker for differentiated thyroid cancer. OBJECTIVE This study assessed the reliability of four TgAb methods to detect interfering TgAb [as judged from abnormally low Tg immunometric assay (IMA) to Tg RIA ratios] and determine whether between-method conversion factors might prevent a change in method from disrupting TgAb monitoring. METHODS Sera from selected and unselected TgAb-negative and TgAb-positive differentiated thyroid cancer patients had serum Tg measured by both IMA and RIA and TgAb measured by a reference method and three additional methods. RESULTS The Tg IMA and Tg RIA values were concordant when TgAb was absent. Tg IMA to Tg RIA ratios below 75% were considered to indicate TgAb interference. Manufacturer-recommended cutoffs were set in the detectable range, and when used to determine the presence of TgAb misclassified many specimens displaying Tg interference as TgAb negative. False-negative misclassifications were virtually eliminated for two of four methods by using the analytical sensitivity (AS) as the detection limit for TgAb. Relationships between values for different specimens were too variable to establish between-method conversion factors. CONCLUSIONS Many specimens with interfering TgAb were misclassified as TgAb negative using manufacturer-recommended cutoffs. It is recommended that assay AS limits be used to detect TgAb to minimize false-negative misclassifications. However, for two of four assays, AS limits failed to detect interfering TgAb in 20-30% of cases. TgAb methods were too qualitatively and quantitatively variable to establish conversion factors that would allow a change in method without disrupting serial TgAb monitoring.

Technology Insight: measuring thyroglobulin and thyroglobulin autoantibody in patients with differentiated thyroid cancer

Measurement of serum thyroglobulin is primarily used as a tumor marker in the postoperative management of patients with differentiated thyroid cancer. Unfortunately, the technical quality of current thyroglobulin assay methods varies and influences the clinical utility of this test. Two different methodologic approaches are used to measure serum thyroglobulin: the original competitive radioimmunoassay methodology and noncompetitive immunometric assay methods. Although the newer immunometric assays offer the technical benefits of eliminating the use of isotopes, using smaller specimen volumes, and having higher sensitivity potential, shorter turnaround times and the convenience of automation, immunometric assays also have a higher propensity for interference from both thyroglobulin autoantibodies and heterophilic antibodies, if present in the specimen. It is critical that physicians understand the technical limitations inherent in thyroglobulin measurement in order to effectively use this test for the postoperative management of patients with differentiated thyroid cancers.

Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man.

The present study was undertaken to define the source of endogenous triiodothyronine (T3) production responsible for maintaining serum T3 levels in euthyroid subjects with depressed serum thyroxine (T4) values. After withdrawal from 4 wk of exogenous T3 administration, a 22% decline in serum T3 values (from 129 +/- 6 to 99 +/- 4 ng/dl) was observed in six euthyroid subjects, despite a twofold reduction in serum T4 concentrations (from 7.5 +/- 0.5 to 3.2 +/- 0.5 micrograms/dl). This was accompanied by a nearly twofold increase in serum T3/T4 ratio values (17 +/- 1 to 29 +/- 6) but no significant alteration in reverse T3/T4 ratio values. This phenomenon did not appear to be thyroid stimulating hormone (TSH) dependent, since base-line serum TSH values were subnormal. Nor was it dependent on changes in thyroid gland function, since a blunted T3 response to exogenous bovine TSH occurred and pharmacologic doses of iodide did not influence the phenomenon. The finding in three athyreotic subjects that serum T3/T4 ratio values increased from 14 +/- 1 on T4 therapy (mean serum T4, 9.6 +/- 0.8 micrograms/dl and T3, 132 +/- 8 ng/dl) to 40 +/- 2 after withdrawal from 2 wk of T3 administration (serum T4 1.2 +/- 0.1 micrograms/dl and T3 46 +/- 3 ng/dl) provided direct evidence that an alteration in peripheral thyroid hormone metabolism was probably responsible for these findings previously observed in euthyroid subjects. The results of this study support the possible existence in euthyroid man of a peripheral tissue autoregulatory mechanism for maintaining serum T3 values in states of T4 deficiency. Whether this process involves an alteration in the efficiency of T4 to T3 conversion or the rate of T3 clearance is presently unknown.

Serum TSH determinations in pregnancy: how, when and why?

Improvements in the sensitivity of the serum TSH assay have revolutionized our strategies for investigating thyroid function and firmly established TSH as the first-line thyroid function test for most clinical situations, including pregnancy. As a single hormone determination, serum TSH provides the most sensitive index to reliably detect thyroid function abnormalities. Normal thyroid function is important to ensure the best possible pregnancy outcome; in addition, disorders of the thyroid gland are relatively frequent in women of childbearing age. The aim of this article is, therefore, to present relevant information on analytical, as well as clinical, aspects regarding serum TSH determination and its usefulness to detect subtle thyroid function abnormalities associated with the pregnant state, namely overt and subclinical hypothyroidism and hyperthyroidism. As these disorders are associated with poor pregnancy outcome, the authors of the present article are in favor of serum TSH measurement for all pregnant women.