Thyroid Function Testing (eBook)
X, 392 Seiten
Springer US (Verlag)
978-1-4419-1485-9 (ISBN)
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 h- mone 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 requ- ing 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 interpretingth yroid 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 c- cumstances that can influence thyroid function measurements. The serum TSH concentration, for example, may not accurately reflect thyroid status in many si- ations including after prolonged hyperthyroidism when serum TSH remains s- pressed for months, in the presence of hypothalamic orpituitary 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 d- ing pregnancy. Hospitalized patients often have thyroid function test abnormalities that are transient and return to normal after recovery from the acute illness. Iodine excessand deficiency candramatically 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 t- sues 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 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 themost 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 ofthyroid 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 r- idly expanding field. The population variation in the TSH "e;set point"e; (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 int- nationally 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 t- roid diseases and especially fetal and neonatalde velopment. The basics of thyroid function measurements, approaches, limitations, and cl- ical 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 id- tified with the origination or significant refinement of the core tests utilized in t- roid 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 me- urement, the most commonly used thyroxine assay. In Chap. 5, Dr. Stockigt p- vides a detailed assessment of thyroxine andtriiodothyronine 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 measu- ments remains confusing to many clinicians. In Chap. 6, Dr. Weetman and his c- league, 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 ess- tial 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.8-13. The appropriate selec- 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 retar- tion. 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 logicalapproach 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 ch- lenging 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 ca- fully 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 p- vides a clear approach to the assessment of thyroid status in the elderly and interp- tation 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 An- thakrishnan 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 p- vide such outstanding contributions to this book. The editorial team at Springer is excellent and has been highly supportive and effective. My special thanks to E- tor Laura Walsh, Associate Editor Dianne Wuori, Editorial Assistant Stacy Lazar, Senior Production Editor Jenny Wolkowicki and Crest Premedia Solutions for final production.
Preface 6
Contents 9
Contributors 16
Thyroid Hormone Metabolism 19
1.1 Introduction 19
1.2 Thyroid Hormone Synthesis and Plasma Transport 20
1.3 Thyroid Hormone Action 23
1.4 Thyroid Hormone Metabolism 23
1.5 Alternative Pathways of Thyroid Hormone Metabolism 23
1.5.1 Conjugation 23
1.5.2 Alanine Side-Chain Modification 24
1.6 Thyroid Hormone Deiodination 25
1.7 The Iodothyronine Deiodinase Enzyme Family 26
1.7.1 Type 1 Deiodinase (D1) 27
1.7.2 Type 2 Deiodinase (D2) 27
1.7.3 Type 3 Deiodinase (D3) 28
1.8 Thyroid Hormone Metabolism and T3 Homeostasis 28
1.8.1 Iodine Deficiency 28
1.8.2 Hypothyroidism 29
1.8.3 Hyperthyroidism 30
1.9 Altered Thyroid Hormone Metabolism as a Cause of Abnormal Thyroid Function Testing 30
1.9.1 Low-T3 Syndrome 31
1.9.2 Medications that Alter Thyroid Hormone Metabolism 32
1.9.3 Tumoral D3 and Consumptive Hypothyroidism 33
1.9.4 Tumoral D2 in Metastatic Follicular Thyroid Carcinoma 33
1.9.5 Selenium Deficiency and Inborn Errors in Selenoprotein Synthesis 34
References 34
Genetic Influences on Thyroid Function Tests 39
2.1 The Hypothalamus-Pituitary-Thyroid Axis 39
2.2 Influence of Genetic Variation on Thyroid Function Tests 41
2.3 Genetic Variation in Thyroid-Regulating Genes: TRH, TRHR, TSH, TSHR 43
2.4 Genetic Variation in Thyroid Transcription Factors: PAX8, TTF1, TTF2 44
2.5 Genetic Variation in Thyroid Hormone Synthesis Genes: NIS, Pendrin, Tg, TPO, DUOX2, DEHAL 45
2.6 Genetic Variation in Thyroid Hormone Receptor Genes: TR 47
, TR 47
2.7 Genetic Variation in Serum TH Transport Proteins: TBG, TTR, and Albumin 48
2.8 Genetic Variation in TH Transporters: MCT8, MCT10, OATPs 49
2.8.1 MCT8 and MCT10 49
2.8.2 OATP1A2, 1B1, 1B3, and 1C1 50
2.9 Genetic Variation in Deiodinases: D1, D2, D3 53
2.10 Genome-Wide Association (GWA) Studies 54
2.11 Concluding Remarks 54
References 55
Influence of Iodine Deficiency and Excess on Thyroid Function Tests 62
3.1 Introduction 62
3.2 Iodine Metabolism and Thyroid Function 64
3.3 Thyroid Adaptation to Iodine Deficiency 64
3.4 Epidemiology of Thyroid Function in Areas of Low Iodine Intake 66
3.4.1 Adults 66
3.4.2 Pregnancy 67
3.4.3 Newborns 69
3.4.4 Children 71
3.5 Introducing/Increasing Iodine Intakes and/or Iodine Excess: Effects on Thyroid Function in Populations 73
3.5.1 Cross-Sectional Studies: The Epidemiology of Thyroid Function in Areas of Low and High Iodine Intakes 74
3.5.2 High Iodine Intake Produces Thyroid Dysfunction in Children 75
3.5.3 Longitudinal Studies: The Effects of Increasing Iodine Intakes in Populations on Thyroid Function 76
3.6 Conclusions 78
References 78
Regulation of Thyroid Hormone Production and Measurement of Thyrotropin 87
4.1 Introduction 87
4.2 Production of Thyroid Hormone 87
4.2.1 Sodium/Iodide Symporter 87
4.2.2 Dietary Iodine Requirements 88
4.2.3 Thyroid Peroxidase 89
4.2.4 Hydrogen Peroxide Generation 89
4.2.5 Apical Iodide Transport 89
4.2.6 Thyroglobulin 90
4.3 TSH Biochemistry and Physiology 90
4.3.1 T3 Negative Regulation of TSH 91
4.4 Thyrotropin-Releasing Hormone 91
4.5 Diurnal Rhythmicity of TSH 92
4.6 Other Factors that Regulate TSH Secretion 93
4.7 Clinical Effects of TRH 94
4.8 Measurement of TSH 95
4.9 Normal Serum TSH Levels 96
4.10 Factors Affecting TSH Clinically 97
References 98
Measurements of Thyroxine and Triiodothyronine 101
5.1 Introduction 101
5.2 The Trophic–Target Gland Relationship 101
5.3 The Basis of Total and Free Thyroid Hormone Methodology 102
5.4 Total T4 and T3 Methods 104
5.5 Principles of Free T4 Methods 104
5.6 Factors that Limit the Validity of Free T4 Methods 106
5.7 Evaluation of Serum Free T4 Methods 111
5.8 Free T4 in Special Situations 112
5.8.1 Pregnancy 112
5.8.2 Thyrotoxicosis and Hypothyroidism 113
5.8.3 Thyroxine Replacement 114
5.8.4 Critical Illness 114
5.8.5 Premature Infants 116
5.9 Total T4 Measurement 117
5.10 Indications for Measurement of Serum T3 117
5.11 Approach to Anomalous Results 118
5.12 Conclusion 119
References 120
Thyroid Autoantibody Measurement 124
6.1 Introduction 124
6.2 Humoral Immunity in Autoimmune Thyroid Disease 125
6.2.1 Thyroid Autoantigens 125
6.2.2 The Role of Thyroid Autoantibodies in Disease Pathogenesis 126
6.3 Assays for Thyroid Antibodies 128
6.3.1 Thyroid Stimulating Hormone Receptor 128
6.3.2 Thyroid Peroxidase 129
6.3.3 Thyroglobulin 129
6.3.4 Sodium/Iodide Symporter 130
6.4 Clinical Applications of Antibody Measurement 130
6.4.1 Graves’ Disease 130
6.4.2 Graves’ Ophthalmopathy 131
6.4.3 Autoimmune Hypothyroidism 131
6.4.4 Pregnancy and Postpartum Thyroiditis 132
6.4.5 Differentiated Thyroid Cancer 133
6.5 Recommendation for the Use of Thyroid Autoantibodies in Clinical Practice 133
6.6 Conclusion 134
References 135
Thyroglobulin Measurement 140
7.1 Tg Biosynthesis and Metabolic Clearance 140
7.2 Tg Assay Methodology: Technical Issues 141
7.2.1 Standardization/Specificity 142
7.2.2 Methodologic Sensitivity 144
7.2.3 Interferences 145
7.3 TgAb Measurements Used as a Surrogate Tumor Marker 147
7.4 Tg mRNA as a Tumor Marker 148
7.5 The Clinical Utility of Tg Measurement when TgAb Is Present 148
7.6 The Clinical Utility of Tg Measurement when TgAb Is Absent 150
7.6.1 Factors Influencing Circulating Tg Concentrations 150
7.6.2 Serum Tg Reference Range 151
7.6.3 Serum Tg Measurements for Nonmalignant Thyroid Conditions 152
7.6.4 Tg Measurement for Differentiated Thyroid Cancer 154
References 157
Thyroid Function Testing in Ambulatory Practice 169
8.1 Choice of Tests in Thyroid Function Testing 170
8.2 Evaluation of the Symptomatic Patient 171
8.2.1 Suspected Thyrotoxicosis 172
8.2.2 Suspected Hypothyroidism 173
8.2.3 Nodular Goiter 174
8.3 Use of Thyroid Function Tests to Monitor Treated Thyroid Dysfunction 175
8.3.1 Monitoring Hypothyroidism 175
8.3.2 Monitoring Hyperthyroidism 176
8.4 Screening of the General Population for Thyroid Dysfunction 177
8.5 Screening of Targeted Populations 178
8.5.1 Women of Childbearing Age, Pregnant Women, and Lactating Women 178
8.5.2 Elderly 179
8.5.3 Patients with Specific Comorbidities 180
8.6 Conclusions 181
References 181
Assessing Thyroid Function in Infants and Children 186
9.1 Introduction 186
9.2 Infants 187
9.2.1 Hypothyroidism 187
9.2.2 Hypothyroxinemia in the Preterm Infant 191
9.2.3 Hyperthyroidism 192
9.3 Children 193
9.3.1 Hypothyroidism 193
9.3.2 Hyperthyroidism 195
References 197
Assessing Thyroid Function in Hospitalized Patients 199
10.1 Introduction 199
10.2 Low T3 State 201
10.3 Low T3/T4 State 204
10.4 Measurement of Thyroid Hormones in Illness 205
10.5 TSH Regulation in the Low T3 and Low T3/T4 States 206
10.6 Interpretation of Thyroid Tests in the Hospitalized Patient 207
10.7 Drugs that Affect Thyroid Function Tests 210
10.7.1 Glucocorticoids 210
10.7.2 Dopamine 210
10.7.3 Amiodarone 212
10.7.4 Heparin and Low Molecular Weight Heparins 212
10.7.5 Diphenylhydantoin 213
10.8 Variants of Nonthyroidal Illness 213
10.8.1 HIV and Thyroid Function 213
10.8.2 Liver Disease and Thyroid Function 214
10.8.3 Hyperemesis Gravidarum 214
10.8.4 Psychiatric Illness and Thyroid Function 215
10.9 Concluding Remarks 215
References 216
Assessing Thyroid Function in Pregnancy 220
11.1 Importance of Thyroid Status in Pregnancy 220
11.1.1 Thyroid Physiology in Pregnancy 220
11.2 Human Chorionic Gonadotrophin 222
11.3 Clinical Relevance of Assessing Thyroid Function in Pregnancy 224
11.3.1 Hyperthyroidism 224
11.3.2 Hypothyroidism 225
11.4 Maternal Thyroid Disease in Pregnancy: Effect on Child Development 225
11.5 Clinical Implications of Thyroid Antibodies in Gestation 226
11.6 Methods for Measuring Thyroid Function in Pregnancy 226
11.6.1 Total and Free Thyroid Hormone Measurements in Pregnancy 227
11.6.2 TSH Tests in Pregnancy 228
11.6.3 Free Thyroid Hormone Testing in Pregnancy 234
11.7 Development of Reference Intervals for Thyroid Hormones in Pregnancy 234
11.7.1 Trimester-Specif ic Method-Specif ic Reference Intervals 235
11.7.2 Trimester-Specific Thyroid Function Tests 235
11.8 Screening for Thyroid Function in Pregnancy 237
11.9 Conclusions 239
References 239
Assessing Thyroid Function in the Elderly 245
12.1 Changes in Normal Thyroid Function with Aging 245
12.2 Hypothyroidism in the Elderly 246
12.2.1 Prevalence 246
12.2.2 Etiology 247
12.2.3 Clinical Manifestations 247
12.2.4 Diagnosis 249
12.2.5 Treatment 249
12.3 Hyperthyroidism in the Elderly 250
12.3.1 Prevalence 250
12.3.2 Etiology 251
12.3.3 Clinical Manifestations 251
12.3.4 Diagnosis 253
12.3.5 Treatment 253
12.4 Thyroid Nodules and Cancer 255
12.5 Challenges in Assessing Thyroid Function in the Elderly 255
12.5.1 What is the Normal TSH Range in the Elderly? 255
12.5.2 Altered Presentation of Thyroid Disease in the Elderly 257
12.5.3 The Effects of Comorbid Conditions and Drugs on Thyroid Function in the Elderly 257
12.5.4 Risks of Treatment in the Elderly 257
References 258
Influence of Drugs on Thyroid Function Tests 261
13.1 Introduction 261
13.2 Alterations of Thyroid Hormone Secretion 261
13.2.1 Thionamides 261
13.2.2 Lithium 263
13.2.3 Iodides 263
13.2.4 Other Medications that Decrease Thyroid Hormone Secretion 265
13.3 Changes in T4 and T3 Serum Transport Proteins 265
13.3.1 Medications that Increase TBG 266
13.3.2 Medications that Decrease TBG 267
13.3.3 Competition with T4 and T3 Binding Sites on Thyroid Hormone Binding Proteins 268
13.4 Metabolism of Thyroid Hormones 269
13.4.1 Hepatic Metabolism 269
13.4.2 Deiodination 270
13.5 Central TSH Suppression 271
13.6 Medications with Multiple Effects 272
13.6.1 Glucocorticoids 272
13.6.2 Amiodarone 273
13.6.3 Bexarotene 275
13.6.4 Cytokines 275
13.6.5 Other Medications with Effects on Thyroid Function Tests 276
13.7 Levothyroxine Absorption 277
13.8 Conclusions 278
References 278
Index 288
"Chapter 7 Thyroglobulin Measurement Carole Spencer and Ivana Petrovic (p. 125-126)
7.1 Tg Biosynthesis and Metabolic Clearance
The thyroglobulin (Tg) gene is encoded by human chromosome 8q24.2–8q24.3 in a 8.5 kb coding sequence covering 48 exons. As illustrated in Fig. 7. , transcription of the 330 kDa Tg monomeric protein is regulated by a number of transcription factors that include TTF- , TTF-2, and Pax-8 [ –3]. Posttranslational processing is complex and necessitates multiple molecular chaperones to control the glycosylation, appropriate folding, dimerization, and trafficking of the mature protein to the apical membrane where thyroid peroxidase catalyses the iodination of the hormonogenic sites [ , 3–6].
Comparisons between Tg derived from papillary cancers versus normal thyroid tissue show differences in carbohydrate, iodine content, sulfation, charge, and immunological properties [7– 3]. These differences likely result from defective posttranslational processing of tumor-derived Tg leading to the secretion of Tg molecules with an abnormal tertiary structure. Because Tg epitopes are conformational, any alteration in the tertiary structure of the molecule has the potential to disrupt the immunological interaction(s) with the assay reagents [7, 0, , 4– 6].
The half-life of Tg in serum approximates 3 days and is determined by the terminal sialic acid content of the molecule [ 7]. Both the sialic acid and iodine content of the Tg derived from papillary tumors tend to be lower than normal, suggesting the possibility for differences in the metabolic clearance of Tg protein secreted by different tumors [8, 7– 9].
An accelerated metabolic clearance of tumor-derived Tg could be the reason why serum Tg can be paradoxically low or even undetectable in some patients with a significant tumor burden [ , 2, 20–24]. 7.2 Tg Assay Methodology: Technical Issues Tg measurement still remains technically challenging. Most laboratories favor automated immunometric assay (IMA) methods because they are nonisotopic, require shorter incubations than radioimmunoassay (RIA; hours vs. days), and can be automated.
Manufacturers are beginning to use a two-step approach to overcome the “hook” problems that plague tumor-marker IMAs, wherein high antigen concentrations exceed the binding capacity of the capture antibody and cause inappropriately low results [25–28]. Unfortunately, Tg IMA methodology appears to have a greater propensity for interference, both from human anti-mouse antibodies (HAMA; see Sect. 7.2.3. ) and Tg autoantibodies (TgAb; see Sect. 7.2.3.2) as compared with RIA [ 6]. RIA is not influenced by HAMA; however TgAb has the potential to interfere and cause false low or high RIA values depending on the specificity of the RIA reagents employed [26, 29–33]."
| Erscheint lt. Verlag | 6.4.2010 |
|---|---|
| Reihe/Serie | Endocrine Updates | Endocrine Updates |
| Zusatzinfo | X, 392 p. 5 illus. in color. |
| Verlagsort | New York |
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Medizinische Fachgebiete ► Allgemeinmedizin |
| Medizinische Fachgebiete ► Innere Medizin ► Endokrinologie | |
| Studium ► 2. Studienabschnitt (Klinik) ► Anamnese / Körperliche Untersuchung | |
| Schlagworte | Cancer • endocrine • Function • Hormone • Thyroid • thyroid hormone |
| ISBN-10 | 1-4419-1485-4 / 1441914854 |
| ISBN-13 | 978-1-4419-1485-9 / 9781441914859 |
| Haben Sie eine Frage zum Produkt? |
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