THYROID FUNCTION TESTING

Transcription

1

2 THYROID FUNCTION TESTING

3 ENDOCRINE UPDATES Shlomo Melmed, M.D., Series Editor For further volumes:

4 THYROID FUNCTION TESTING Edited by Gregory A. Brent Professor of Medicine and Physiology David Geffen School of Medicine at UCLA Los Angeles, CA, USA 1 3

5 Editor Gregory A. Brent Departments of Medicine and Physiology David Geffen School of Medicine at UCLA Los Angeles, CA, USA ISSN ISBN e-isbn DOI / Springer New York Dordrecht Heidelberg London Library of Congress Control Number: Springer Science+Business Media, LLC 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (

6 Preface Thyroid function tests are utilized by essentially all medical practitioners, across every clinical setting, in patients from newborns to the elderly. They are the most frequently measured endocrine tests. The sensitive thyrotropin (TSH) assay reflects thyroid hormone feedback to the pituitary, and is diagnostic of both thyroid hormone excess as well as deficiency. The log linear relationship between serum TSH and thyroxine concentrations means that small changes in serum thyroxine are amplified by changes in serum TSH. The availability of the sensitive TSH assay in essentially all clinical laboratories has improved and simplified the assessment of thyroid function for the diagnosis of thyroid disease and to monitor treatment. Serum free thyroxine and thyrotropin concentrations, as well as other thyroid tests, can be measured utilizing an automated immunoassay platform that provides rapid and accurate results. This simplified approach to thyroid assessment, often requiring only a serum TSH measurement, and rapid availability of the thyroid function tests results, has expanded the scope of thyroid testing and clinicians ordering and interpreting thyroid tests. There remain, however, many challenges in selecting the appropriate thyroid function test to order, the correct interpretation of results, and applying these results to the diagnosis and management of thyroid diseases. It is especially important to be aware of limitations of thyroid function tests, as well as special clinical circumstances that can influence thyroid function measurements. The serum TSH concentration, for example, may not accurately reflect thyroid status in many situations including after prolonged hyperthyroidism when serum TSH remains suppressed for months, in the presence of hypothalamic or pituitary disease, or due to a number of interfering medications. The serum free thyroxine, measured by the analog method, is not accurate with high or low serum binding proteins and during pregnancy. Hospitalized patients often have thyroid function test abnormalities that are transient and return to normal after recovery from the acute illness. Iodine excess and deficiency can dramatically influence thyroid function tests. Significant insights have been gained into the regulation of thyroid hormone synthesis and especially the role of thyroid hormone metabolism in supplying tissues locally with an adequate supply of thyroid hormone. In a number of instances, these factors influence the selection and interpretation of thyroid function tests. Polymorphisms, common sequence variations, in genes of components that regulate thyroid function and thyroid hormone action may also contribute to variability in thyroid function tests in a population. v

7 vi Preface This volume draws on an outstanding international panel of experts in thyroid function tests and thyroid function assessment. They represent clinicians, clinical researchers, and basic science researchers, all with a focus on some aspect of the assessment of thyroid function. The chapters all provide a clinical perspective, but are informed by the most recent scientific advancements. The first section of the book (Chaps. 1 3) presents the most recent advances in thyroid physiology, a review of genetic influences on thyroid function tests, and a discussion on the influence of iodine on thyroid function. In Chap. 1, Drs. Huang and de Castro Neves describe thyroid hormone metabolism, emphasizing the key role of thyroid hormone activation and inactivation in thyroid hormone action. Dr. Visser is a world leader in studies of thyroid metabolism and genetic influences on thyroid function. In Chap. 2, Dr. Visser and his colleagues, Drs. van der Deure, Medici, and Peeters, provide a clear view of this important and rapidly expanding field. The population variation in the TSH set point (relationship between serum TSH and thyroxine in an individual), for example, is thought to be genetically determined, and influences the evaluation of thyroid function and thyroid function targets for treatment of thyroid disease. Dr. Zimmerman, an internationally recognized expert in iodine, and his colleague, Dr. Andersson, provide in Chap. 3 an in-depth treatment of the most significant influence on thyroid function throughout the world iodine intake. The influence of iodine deficiency and excess on individual thyroid function is discussed, as well as the population effects on thyroid diseases and especially fetal and neonatal development. The basics of thyroid function measurements, approaches, limitations, and clinical applications are described for the major categories of thyroid function tests (Chaps. 4 7). The authors of these chapters are innovators in the field, strongly identified with the origination or significant refinement of the core tests utilized in thyroid assessment. In Chap. 4, Dr. Hershman describes the measurement of TSH, the clinical application and utilization. This remains the cornerstone of thyroid testing, but must be interpreted with an understanding of the dynamics of thyroid regulation. An active controversy in thyroid measurement involves the appropriate use of serum thyroxine measurements and especially the value of the analog free thyroxine measurement, the most commonly used thyroxine assay. In Chap. 5, Dr. Stockigt provides a detailed assessment of thyroxine and triiodothyronine measurements and a clear message for their use and limitations. The most common etiology of thyroid disease is autoimmune, and the appropriate use of thyroid autoantibody measurements remains confusing to many clinicians. In Chap. 6, Dr. Weetman and his colleague, Dr. Ajjan, clearly describe the range of thyroid autoantibody tests and how they should be utilized clinically. Thyroglobulin measurement is the key tumor marker to follow thyroid cancer patients and Dr. Spencer and her colleague, Ivana Petrovic, describe the essential features of this measurement in Chap. 7. It is essential that clinicians using thyroglobulin measurements to monitor thyroid cancer are aware of the performance of the assay being used and the factors that can interfere with the measurement. Application of thyroid function testing to the key clinical settings is discussed by expert clinicians and clinical researchers in Chaps The appropriate selec-

8 Preface vii tion of thyroid function tests in the diagnosis and monitoring of thyroid disease in the ambulatory setting is discussed by Drs. Farwell and Leung in Chap. 8. This is the most common setting for thyroid function test measurement and a rational approach is described. Specific issues of thyroid function in infants and children are discussed in Chap. 9 by Drs. LaFranchi and Balogh. Screening for thyroid disease among newborns has been a highly effective approach to prevent mental retardation. The assessment of thyroid function in newborns, especially premature infants, is challenging as are the interpretation of thyroid function tests in infancy through childhood. Illness has a significant impact on thyroid function tests and assessment in this group is described by Drs. LoPresti and Patil in Chap. 10. A logical approach to these patients is provided as are ways to identify those patients with thyroid disease that need to be treated. Assessment of thyroid function in pregnancy is challenging and is being increasing recognized as a crucial time to normalize maternal thyroid status. Adverse outcome for mother and her child can result from thyroid hormone deficiency or excess. In Chap. 11, Drs. Lazarus, Soldin, and Evans carefully describe the use and limitations of thyroid tests in pregnancy and provide an approach to testing and monitoring thyroid function. The incidence of autoimmune thyroid disease increases significantly with age and in Chap. 12 Dr. Samuels provides a clear approach to the assessment of thyroid status in the elderly and interpretation of thyroid studies. The influence of drugs on thyroid function testing remains a major clinical issue with recognition of an ever increasing list of medications that influence thyroid function and thyroid testing. In Chap. 13, Drs. Pearce and Ananthakrishnan comprehensively describe these medications with a special emphasis on their mechanism of action and on iodine-containing medications. I am most grateful to my colleagues for their enthusiasm and willingness to provide such outstanding contributions to this book. The editorial team at Springer is excellent and has been highly supportive and effective. My special thanks to Editor Laura Walsh, Associate Editor Dianne Wuori, Editorial Assistant Stacy Lazar, Senior Production Editor Jenny Wolkowicki and Crest Premedia Solutions for final production. Los Angeles, CA Gregory A. Brent

9 Contents Chapter 1: Thyroid Hormone Metabolism Stephen A. Huang and Luciana A. de Castro Neves 1.1 Introduction Thyroid Hormone Synthesis and Plasma Transport Thyroid Hormone Action Thyroid Hormone Metabolism Alternative Pathways of Thyroid Hormone Metabolism Conjugation Alanine Side-Chain Modification Thyroid Hormone Deiodination The Iodothyronine Deiodinase Enzyme Family Type 1 Deiodinase (D1) Type 2 Deiodinase (D2) Type 3 Deiodinase (D3) Thyroid Hormone Metabolism and T3 Homeostasis Iodine Deficiency Hypothyroidism Hyperthyroidism Altered Thyroid Hormone Metabolism as a Cause of Abnormal Thyroid Function Testing Low-T3 Syndrome Medications that Alter Thyroid Hormone Metabolism Tumoral D3 and Consumptive Hypothyroidism Tumoral D2 in Metastatic Follicular Thyroid Carcinoma Selenium Deficiency and Inborn Errors in Selenoprotein Synthesis References ix

10 x Contents Chapter 2: Genetic Influences on Thyroid Function Tests Wendy M. van der Deure, Marco Medici, Robin P. Peeters and Theo J. Visser 2.1 The Hypothalamus-Pituitary-Thyroid Axis Influence of Genetic Variation on Thyroid Function Tests Genetic Variation in Thyroid-Regulating Genes: TRH, TRHR, TSH, TSHR Genetic Variation in Thyroid Transcription Factors: PAX8, TTF1, TTF Genetic Variation in Thyroid Hormone Synthesis Genes: NIS, Pendrin, Tg, TPO, DUOX2, DEHAL Genetic Variation in Thyroid Hormone Receptor Genes: TR, TR Genetic Variation in Serum TH Transport Proteins: TBG, TTR, and Albumin Genetic Variation in TH Transporters: MCT8, MCT10, OATPs MCT8 and MCT OATP1A2, 1B1, 1B3, and 1C Genetic Variation in Deiodinases: D1, D2, D Genome-Wide Association (GWA) Studies Concluding Remarks References Chapter 3: Influence of Iodine Deficiency and Excess on Thyroid Function Tests Maria Andersson and Michael B. Zimmermann 3.1 Introduction Iodine Metabolism and Thyroid Function Thyroid Adaptation to Iodine Deficiency Epidemiology of Thyroid Function in Areas of Low Iodine Intake Adults Pregnancy Newborns Children Introducing/Increasing Iodine Intakes and/or Iodine Excess: Effects on Thyroid Function in Populations Cross-Sectional Studies: The Epidemiology of Thyroid Function in Areas of Low and High Iodine Intakes High Iodine Intake Produces Thyroid Dysfunction in Children Longitudinal Studies: The Effects of Increasing Iodine Intakes in Populations on Thyroid Function Conclusions References

11 Contents xi Chapter 4: Regulation of Thyroid Hormone Production and Measurement of Thyrotropin Jerome M. Hershman 4.1 Introduction Production of Thyroid Hormone Sodium/Iodide Symporter Dietary Iodine Requirements Thyroid Peroxidase Hydrogen Peroxide Generation Apical Iodide Transport Thyroglobulin TSH Biochemistry and Physiology T3 Negative Regulation of TSH Thyrotropin-Releasing Hormone Diurnal Rhythmicity of TSH Other Factors that Regulate TSH Secretion Clinical Effects of TRH Measurement of TSH Normal Serum TSH Levels Factors Affecting TSH Clinically References Chapter 5: Measurements of Thyroxine and Triiodothyronine Jim R. Stockigt 5.1 Introduction The Trophic Target Gland Relationship The Basis of Total and Free Thyroid Hormone Methodology Total T4 and T3 Methods Principles of Free T4 Methods Factors that Limit the Validity of Free T4 Methods Evaluation of Serum Free T4 Methods Free T4 in Special Situations Pregnancy Thyrotoxicosis and Hypothyroidism Thyroxine Replacement Critical Illness Premature Infants Total T4 Measurement Indications for Measurement of Serum T

12 xii Contents 5.11 Approach to Anomalous Results Conclusion References Chapter 6: Thyroid Autoantibody Measurement R. A. Ajjan and A. P. Weetman 6.1 Introduction Humoral Immunity in Autoimmune Thyroid Disease Thyroid Autoantigens The Role of Thyroid Autoantibodies in Disease Pathogenesis Assays for Thyroid Antibodies Thyroid Stimulating Hormone Receptor Thyroid Peroxidase Thyroglobulin Sodium/Iodide Symporter Clinical Applications of Antibody Measurement Graves Disease Graves Ophthalmopathy Autoimmune Hypothyroidism Pregnancy and Postpartum Thyroiditis Differentiated Thyroid Cancer Recommendation for the Use of Thyroid Autoantibodies in Clinical Practice Conclusion References Chapter 7: Thyroglobulin Measurement Carole Spencer and Ivana Petrovic 7.1 Tg Biosynthesis and Metabolic Clearance Tg Assay Methodology: Technical Issues Standardization/Specificity Methodologic Sensitivity Interferences TgAb Measurements Used as a Surrogate Tumor Marker Tg mrna as a Tumor Marker The Clinical Utility of Tg Measurement when TgAb Is Present The Clinical Utility of Tg Measurement when TgAb Is Absent Factors Influencing Circulating Tg Concentrations Serum Tg Reference Range Serum Tg Measurements for Nonmalignant Thyroid Conditions Tg Measurement for Differentiated Thyroid Cancer References

13 Contents xiii Chapter 8: Thyroid Function Testing in Ambulatory Practice Angela M. Leung and Alan P. Farwell 8.1 Choice of Tests in Thyroid Function Testing Evaluation of the Symptomatic Patient Suspected Thyrotoxicosis Suspected Hypothyroidism Nodular Goiter Use of Thyroid Function Tests to Monitor Treated Thyroid Dysfunction Monitoring Hypothyroidism Monitoring Hyperthyroidism Screening of the General Population for Thyroid Dysfunction Screening of Targeted Populations Women of Childbearing Age, Pregnant Women, and Lactating Women Elderly Patients with Specific Comorbidities Conclusions References Chapter 9: Assessing Thyroid Function in Infants and Children Alicia G. Marks and Stephen H. LaFranchi 9.1 Introduction Infants Hypothyroidism Hypothyroxinemia in the Preterm Infant Hyperthyroidism Children Hypothyroidism Hyperthyroidism References Chapter 10: Assessing Thyroid Function in Hospitalized Patients Jonathan S. LoPresti and Komal S. Patil 10.1 Introduction Low T3 State Low T3/T4 State Measurement of Thyroid Hormones in Illness TSH Regulation in the Low T3 and Low T3/T4 States Interpretation of Thyroid Tests in the Hospitalized Patient Drugs that Affect Thyroid Function Tests Glucocorticoids Dopamine

14 xiv Contents Amiodarone Heparin and Low Molecular Weight Heparins Diphenylhydantoin Variants of Nonthyroidal Illness HIV and Thyroid Function Liver Disease and Thyroid Function Hyperemesis Gravidarum Psychiatric Illness and Thyroid Function Concluding Remarks References Chapter 11: Assessing Thyroid Function in Pregnancy John H. Lazarus, Offie P. Soldin and Carol Evans 11.1 Importance of Thyroid Status in Pregnancy Thyroid Physiology in Pregnancy Human Chorionic Gonadotrophin Clinical Relevance of Assessing Thyroid Function in Pregnancy Hyperthyroidism Hypothyroidism Maternal Thyroid Disease in Pregnancy: Effect on Child Development Clinical Implications of Thyroid Antibodies in Gestation Methods for Measuring Thyroid Function in Pregnancy Total and Free Thyroid Hormone Measurements in Pregnancy TSH Tests in Pregnancy Free Thyroid Hormone Testing in Pregnancy Development of Reference Intervals for Thyroid Hormones in Pregnancy Trimester-Specif ic Method-Specif ic Reference Intervals Trimester-Specific Thyroid Function Tests Screening for Thyroid Function in Pregnancy Conclusions References Chapter 12: Assessing Thyroid Function in the Elderly Mary H. Samuels 12.1 Changes in Normal Thyroid Function with Aging Hypothyroidism in the Elderly Prevalence Etiology Clinical Manifestations Diagnosis Treatment

15 Contents xv 12.3 Hyperthyroidism in the Elderly Prevalence Etiology Clinical Manifestations Diagnosis Treatment Thyroid Nodules and Cancer Challenges in Assessing Thyroid Function in the Elderly What is the Normal TSH Range in the Elderly? Altered Presentation of Thyroid Disease in the Elderly The Effects of Comorbid Conditions and Drugs on Thyroid Function in the Elderly Risks of Treatment in the Elderly References Chapter 13: Influence of Drugs on Thyroid Function Tests Sonia Ananthakrishnan and Elizabeth N. Pearce 13.1 Introduction Alterations of Thyroid Hormone Secretion Thionamides Lithium Iodides Other Medications that Decrease Thyroid Hormone Secretion Changes in T4 and T3 Serum Transport Proteins Medications that Increase TBG Medications that Decrease TBG Competition with T4 and T3 Binding Sites on Thyroid Hormone Binding Proteins Metabolism of Thyroid Hormones Hepatic Metabolism Deiodination Central TSH Suppression Medications with Multiple Effects Glucocorticoids Amiodarone Bexarotene Cytokines Other Medications with Effects on Thyroid Function Tests Levothyroxine Absorption Conclusions References Index