Thyroid Disease in Adults

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 Foreword

This book is a compilation of updated and expanded editions of two Swedish books
previously published by Nycomed AB, Thyroxine Treatment of Adults and Thyrotoxi-
cosis in Adults.
The aim was to produce a clinical handbook for thyroid disease to be used by general
practitioners and internal medicine specialists, but also to be of value for specialists
more directly devoted to thyroid disease. To facilitate reading and use in everyday
work, we have included numerous illustrations as well as concise summary boxes.
We have invested much time in harmonizing the differences that exist in the practical
management of patients with thyroid disease between clinicians and clinics in Sweden.
We thereby hope to have reached some form of consensus, which we believe will not
only be applicable to Sweden, but also have a more general acceptance.
Bo Ch. Warin at Nycomed AB has provided tremendous support and has been
an enthusiastic, patient and faithful motivator. Media Center TVB AB in Linköping,
Sweden, has been invaluable in coordinating the work on the book and contributing to
text processing, illustrations, diagrams, photos and layout.
We have also received help from our many colleagues who have contributed towards
the illustrations and offered good advice and valuable points of view. But most of all, we
wish to thank Associate Professor Leif Tallstedt of St. Erik’s Eye Hospital, Stockholm,
Sweden and Dr. Kerstin Norrsell, Ophthalmology Clinic, Sahlgrenska University
Hospital, Mölndal, Sweden, for help with matters relating to ophthalmology, Dr. Johan
Mölne, Department of Pathology, Sahlgrenska University Hospital, for contributing
to the section on cytological diagnostics, as well as for cytology/PAD images. We
thank Dr. Anders Höög, Department of Endocrine Pathology, Karolinska University
Hospital, Solna, for cytological images.
In addition, we would like to thank Agneta Lundström, at Medical Physics and
Technology, Sahlgrenska University Hospital, for help with photos. Many thanks to
Consultant Barbara Bergman, Clinical Radiology, Sahlgrenska University Hospital,
for help with ultrasound images, and Consultant Madis Suurküla for pictures from
nuclear medical investigations on patients with thyroid cancer. We have also gratefully
received photographs from Rolf Hägglund in Mölndal.
Finally we would like to thank Associate Professor Ola Winqvist, Clinical
Allergologic Research Unit, Karolinska University Hospital, Solna, for invaluable
comments on the section relating to immunology and the thyroid, Professor Robert
Eggertsen, Mölnlycke Vårdcentral (primary care), and Regional Medical Officer
Anders Ehnberg, Strömsunds Hälsocentral, for the large amount of work they have
invested in reviewing and commenting on the book from the perspective of a primary
care provider.

Sweden, November 2010 Prof. Ernst Nyström

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Chapter 1
Historical Background

1.1 Goitre and iodine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1.2 Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.3 Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Chapter 2
Anatomy and Physiology

2.1 The Embryologic Development

and Anatomy of the Thyroid Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.2 Iodine and the Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.3 TSH and TSH Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.4 Synthesis and Secretion of Thyroid Hormones . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.5 Hypothalamus–Pituitary–Thyroid Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.6 Deiodinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.7 Mechanisms of Action of Thyroid Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.8 Biochemical Indicators of the Peripheral
Effects of Thyroid Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.9 Factors Affecting Thyroid Hormone Homeostasis . . . . . . . . . . . . . . . . . . . . . . 24
2.10 Effects of General Illness and Pharmaceuticals (NTI) . . . . . . . . . . . . . . . . . . . . . . 25

Chapter 3
Biochemical Investigations

3.1 TSH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
3.2 TRH-Stimulated TSH Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.3 Thyroid Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.4 Free Thyroid Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3.5 Analytical Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3.6 Reference Ranges (Normal Values) for
Thyroid-Associated Hormone Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.7 Antibodies Against Thyroperoxidase (TPOAb) . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.8 Antibodies Against the TSH Receptor (TRAb) . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.9 Thyroglobulin (Tg) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.10 Antibodies Against Thyroglobulin (TgAb) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

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3.11 Thyroxine-Binding Globulin (TBG)

and Transthyretin (Prealbumin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.12 Calcitonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.13 Iodine in Urine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.14 Genetic Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.15 Analytical Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Chapter 4
Other Investigations

4.1 Investigations Using Radionuclides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

4.2 Positron Emission Tomography (PET) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
4.3 X-ray, CT, and MR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
4.4 Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.5 Fine-Needle Biopsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Chapter 5
Clinical Investigation of the Thyroid

5.1 Medical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

5.2 Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Chapter 6
Iodine and the Thyroid Gland in Health and Sickness

6.1 Global Aspects of Iodine Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

6.2 Thyroid Dysfunction Caused by Excessive Iodine Intake . . . . . . . . . . . . . . . 73
6.3 Iodine in Foodstuffs and Medical Preparations . . . . . . . . . . . . . . . . . . . . . . . . . 74
6.4 Iodine Blocking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Chapter 7
Autoimmunity and the Thyroid Gland

7.1 Immunological Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

7.2 Autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
7.3 Predisposing Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
7.4 Exogenous Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
7.5 Autoimmune Polyglandular Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
7.6 Immunological Markers in Clinical Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
7.7 Treatment Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

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Chapter 8
Growth Regulation of the Thyroid Gland

8.1 TSH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
8.2 Hyperplasia and Goitre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
8.3 Neoplasms and Tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Chapter 9
Thyroiditis and Pathogenesis

9.1 Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
9.2 Autoimmune Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
9.3 Other Triggering Factors for Thyroiditis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Chapter 10
Causes of Hypothyroidism

10.1 Primary Hypothyroidism and Chronic Autoimmune Thyroiditis . . . . . . . . 107

10.2 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
10.3 Hypothyroidism After Treatment for Hyperthyroidism. . . . . . . . . . . . . . . . . . 108
10.4 Hypothyroidism After Surgery for Nontoxic Multinodular Goitre . . . . . . . 108
10.5 Hypothyroidism After Surgery for Thyroid Cancer . . . . . . . . . . . . . . . . . . . . 109
10.6 Central Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
10.7 Iodine-Induced Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
10.8 Iatrogenic (Medicine-Induced) Hypothyroidism. . . . . . . . . . . . . . . . . . . . . . . 109
10.9 Hypothyroidism After External Radiation
of the Head and Neck Regions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
10.10 Other Causes of Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

Chapter 11
Symptoms of Hypothyroidism

11.1 Autoimmune Thyroiditis – Natural Progression . . . . . . . . . . . . . . . . . . . . . . . 111

11.2 Organ-Related Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
11.3 Symptoms and Findings in Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . 114
11.4 Central Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

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Chapter 12
Treatment of Hypothyroidism

12.1 Primary Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

12.2 Laboratory Tests – Special Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
12.3 Special Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
12.4 Resorption of Thyroxine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
12.5 Pharmaceutical Interaction in Thyroxine Treatment . . . . . . . . . . . . . . . . . . . 122
12.6 Oestrogens and Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
12.7 Do All Patients Tolerate Thyroxine? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
12.8 Treatment with Triiodothyronine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
12.9 Parenteral Treatment with Thyroid Hormone . . . . . . . . . . . . . . . . . . . . . . . . . 124
12.10 Overdosing with Thyroxine and Triiodothyronine . . . . . . . . . . . . . . . . . . . . . 125
12.11 Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
12.12 Temporary Treatment with Thyroxine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
12.13 Central (Secondary) Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

Chapter 13
Subclinical Hypothyroidism

13.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

13.2 Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
13.3 Substitution Treatment with Thyroxine
in Subclinical Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

Chapter 14
Myxoedema Coma

14.1 Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

14.2 Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
14.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

Chapter 15
Causes of Thyrotoxicosis – an Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Chapter 16
Symptoms of Thyrotoxicosis

16.1 Weight Loss and Energy Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

16.2 Mental Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
16.3 Muscle Weakness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
16.4 Cardiac Arrhythmia and Cardiac Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . 140
16.5 Sympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
16.6 Dermatological Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

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16.7 Reduced Glucose Tolerance and Effects on Blood Lipids. . . . . . . . . . . . . . . 142

16.8 Fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
16.9 Bones and Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

Chapter 17
Hyperthyroidism Treatment Options – an Overview

17.1 General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

17.2 Medical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
17.3 Laboratory Checks After Treatment for Hyperthyroidism . . . . . . . . . . . . . . 154

Chapter 18
Graves’ Disease

18.1 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

18.2 Symptoms Specific to Graves’ Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
18.3 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
18.4 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
18.5 Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

Chapter 19
Thyroid-Associated Ophthalmopathy

19.1 General Eye Symptoms in Thyrotoxicosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

19.2 Eye Symptoms Specific to Graves’ Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
19.3 Risk Factors and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
19.4 Symptoms and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
19.5 Practical Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
19.6 Clinical Activity Score. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
19.7 The ATA Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
19.8 TAO in Autoimmune Chronic Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
19.9 Euthyroid TAO. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
19.10 Choice of Therapy for Hyperthyroidism in Patients
with Ophthalmopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
19.11 Treatment Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
19.12 Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

Chapter 20
Autonomous Adenoma

20.1 Definition and Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

20.2 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
20.3 Specific Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

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20.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

20.5 Treatment – General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
20.6 Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
20.7 Radioiodine Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

Chapter 21
Toxic Multinodular Goitre

21.1 Development of Toxic Nodular Goitre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

21.2 Specific Symptoms and Clinical Picture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
21.3 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
21.4 Risk Groups/Risk Situations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
21.5 Differential Diagnosis: Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
21.6 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Chapter 22
Subclinical (Mild) Thyrotoxicosis

22.1 Nodular Goitre/Autonomous Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

22.2 Graves’ Disease/Thyroiditis/hCG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
22.3 Exogenous Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
22.4 Suppressed TSH After Treatment for Thyrotoxicosis . . . . . . . . . . . . . . . . . . . 196
22.5 Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
22.6 Cardiac Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
22.7 Effects on Bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
22.8 Psychological Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
22.9 Clinical Recommendations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

Chapter 23
Thyrotoxicosis in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

Chapter 24
Thyrotoxic Crisis/ Thyroid Storm

24.1 Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

24.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
24.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

Chapter 25
Thyroiditis – Clinical Aspects

25.1 Thyroiditis with Autoimmune Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

25.2 Thyroiditis from Other Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208

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 Contents

Chapter 26
Subacute Thyroiditis (de Quervain´s Disease/Giant-Cell Thyroiditis)

26.1 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

26.2 Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
26.3 Progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
26.4 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
26.5 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

Chapter 27
Other Causes of Thyrotoxicosis

27.1 Central (Secondary) Hyperthyroidism/

TSH-Producing Pituitary Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
27.2 hCG-Dependent Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
27.3 Ectopic Production of Thyroid Hormones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
27.4 Thyrotoxicosis Factitia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
27.5 Iodine-Induced Hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Chapter 28
Nontoxic Goitre

28.1 Goitre and Its Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

28.2 Goitre Due to Iodine Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
28.3 Colloid-Rich Multinodular Goitre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
28.4 Intrathoracic Goitre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

Chapter 29
Thyroid Lumps

29.1 Incidence/Prevalence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

29.2 Classification of Palpable Thyroid Lumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
29.3 Diagnosis of Thyroid Lumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
29.4 Treatment of Palpable Thyroid Lumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
29.5 Investigation Algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234

Chapter 30
Thyroid Cancer

30.1 Classification of Thyroid Tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

30.2 Characteristics of Common Thyroid Tumours . . . . . . . . . . . . . . . . . . . . . . . . . 236
30.3 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
30.4 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

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 Contents

30.5 Diagnostic Investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

30.6 Prognostic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
30.7 Prognostic Classification System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
30.8 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
30.9 Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

Chapter 31
The Thyroid and Pregnancy

31.1 Maternal Physiology During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

31.2 TSH, T4 and T3 During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
31.3 Maternal/Placental Interaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
31.4 Thyroid Function in Mother and Foetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
31.5 The Thyroid and Fertility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
31.6 Hypothyroidism and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
31.7 Hyperthyroidism and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
31.8 Goitre and Palpable Lumps in the Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
31.9 Development of Thyroid Diseases During the Postnatal Period . . . . . . . . 263

Chapter 32
Thyroid Disease in Adolescents

32.1 Goitre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

32.2 Autoimmune Thyroiditis and Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . 268
32.3 Hyperthyroidism/Thyrotoxicosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
32.4 Palpable Thyroid Lumps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

Chapter 33
Medicines and Other Medical Preparations

33.1 General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273

33.2 Iodine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
33.3 Amiodarone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
33.4 Other Iodine-Containing Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
33.5 Antithyroid Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
33.6 Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
33.7 Oestrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
33.8 Interferon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
33.9 Carbamazepine/Fenantoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
33.10 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280

Chapter 34
Thyroid Hormone Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

XIV
Presentation of Contributors

Ernst Nyström: Professor and Senior Consultant at the Endo-

crinology Section, Sahlgrenska University Hospital in Gothen-
burg. He is attached to the Thyroid Unit, and his main interests
lie within the changes in body composition, metabolism, and
mental state, during and after hyper- and hypothyroidism. He is
particularly interested in communication of medical informa-
tion to colleagues and the general public.

Gertrud Berg: Associate Professor, Senior Consultant and

Vice Chancellor in Oncology at Sahlgrenska University Hospi-
tal in Gothenburg, where she works in the Thyroid Unit. Her
main interests are iodination mechanisms in the thyroid, and
therapeutic application of radionuclides in thyroid diseases
and cancer.

Svante Jansson: Associate Professor and Senior Consultant

in Surgery at Sahlgrenska University Hospital in Gothen-
burg. Fields of special interest in clinical and research areas
are cancer of the thyroid, hyperthyroidism, parathyroid
diseases and adrenal tumours.

Ove Tørring: Associate Professor and assistant head of the Insti-

tution for clinical research and education at the Karolinska Insti-
tute, Södersjukhuset, and Senior Consultant in the Endocrinol-
ogy Section, Department of Internal Medicine, at Södersjukhuset,
Stockholm. His main interests are diseases of the thyroid gland,
osteoporosis, and calcium metabolic bone diseases. Further inter-
ests are thyrotoxicosis, ophthalmopathy and the effects of thyroid
and calciotropic hormone on bones and at cellular level.

Stig Valdemarsson: Associate Professor and until recently Senior

Consultant at the Department for Endocrinology and Diabetes,
Lund University Hospital. He has recently moved to the Depart-
ment for Oncology at Lund University Hospital, with focus on
diagnosis and treatment of thyroid diseases. He is primarily
interested in classic endocrinology, and has a particular interest
in diseases of the thyroid, pituitary and parathyroid, but also in
neuroendocrine tumours, osteoporosis and adrenal diseases.
XV
 List of Abbreviations
and Definitions

General
Adenoma
Benign tumour of glandular tissue.

Autoimmune polyglandular syndrome (APS)

Concomitant occurrence of multiple autoimmune diseases.

Basedow’s disease
See Graves’ disease.

Binding proteins
The proteins to which thyroxine (T4) and triiodothyronine (T3) are extensively bound
when the hormones are transported in the blood.

Colloid
The content of the lumen of the follicle, where thyroglobulin, iodine and thyroid hor-
mones are stored.

Deiodinases
Enzymes that catalyse deiodination of the T4/T3/rT3 molecules.
 Type I (D1) primarily converts T4 to T3 and rT3 to T2, but can also
convert T4 to rT3 and T3 to T2
 Type II (D2) converts T4 to T3 and rT3 to T2
 Type III (D3) converts T4 to rT3 and T3 to T2

Endocrine ophthalmopathy/thyroid-associated ophthalmopathy

Effects on orbital tissues can be seen in autoimmune thyroid disease, most frequently
hyperthyroidism due to autoimmune Graves’ disease. The term endocrine ophthal-
mopathy is synonymous with thyroid-associated ophthalmopathy (TAO). The latter
term is now more commonly used and is therefore generally used in this book.

Follicle
The functional unit of the thyroid built up of a single layer of epithelial cells around a
lumen in which the colloid is stored.

Graves´ disease/Basedow’s disease

These names are used synonymously and describe autoimmune diffuse toxic goitre (hy-
perthyroidism caused by TSH receptor-stimulating antibodies). The immunological
disturbances of this disease can also affect organs other than the thyroid, usually the
structures of the orbit (thyroid-associated ophthalmopathy), but also the dermis and
periosteum.

XVII
 List of Abbreviations and Definitions

Human antimouse antibodies (HAMA) can cause analytical interference.

Hyperthyroidism
Overactivity of the thyroid with increased release of thyroid hormones.

Hypothyroidism
Underactivity of the thyroid gland. Most often a result of disease in the thyroid, pri-
mary hypothyroidism. Inadequate TSH secretion can also lead to central (or second-
ary) hypothyroidism.

Sodium iodide symporter (NIS)

NIS is the common name of the iodide pump and is a membrane protein that is re-
sponsible for active transport of the iodine into the follicle cell.

Nodule
Common designation of a palpable lump in the thyroid.

Nonthyroidal illness (NTI)

NTI is also known as euthyroid sickness and is a condition in which organs other than
the thyroid affect the release and metabolism of thyroid hormones and TSH. In NTI,
thyroid function is often considered to be normal and the patient clinically euthyroid.

Pendred’s syndrome
Name of an inherited metabolic condition that leads to hypothyroidism and impaired
hearing.

Goitre
Enlarged thyroid gland without reference to function or cause.

Thyroid-associated ophthalmopathy (TAO)

Synonymous with endocrine ophthalmopathy.

Tg
Thyroglobulin. A thyroid-specific protein that is produced in the follicle cell and stored
in the follicle lumen. The iodinated thyroglobulin molecule comprises the source for
hormone synthesis and is an important depot of thyroid hormone and iodine.

Thyrotoxicosis
Symptoms that occur at excessively high concentrations of thyroid hormones in body
tissues, regardless of whether this is due to hyperthyroidism or other causes.

Thyroperoxidase (TPO)
A membrane-bound enzyme present in the thyroid gland. The enzyme is found in the
part of the follicle cell that interfaces with the follicle lumen and is important in several
stages of thyroid hormone synthesis.

XVIII
 List of Abbreviations and Definitions

Hormones
Calcitonin
A peptide that is released from the thyroid C cells. Calcitonin is not thought to play
any major physiological role in humans. Calcitonin is commonly used as a biochemi-
cal marker for medullary thyroid cancer.

Thyroid stimulating hormone (TSH)

Thyroid stimulating hormone, or thyrotropin, is released from the pituitary gland.

TSH receptors
Follicle cell receptors for TSH. When TSH is bound to its receptor, the synthesis and
release of thyroid hormone increases.

Thyroid hormone analyses

In current clinical routine, analyses of the free fraction of thyroid hormones (free T4
and free T3) are increasingly used rather than analysis of the total amount of thyroid
hormones (T4 and T3).
In sections that discuss biochemical diagnostics we have therefore chosen to
mention only the analytical methods for free hormones, well aware of the limitations
of these methods and that some clinics prefer analysis of total hormones as the first-
line analysis.

T4
Thyroxine (3, 5, 3’, 5’-tetraiodothyronine). The numbers denote the position of iodine
atoms the thyronin molecule. T4 is the thyroid hormone secreted in largest quanti-
ties from the thyroid. T4 exhibits low metabolic activity and is a prohormone, which
is deiodinated peripherally to the active hormone T3. T4 is present in the blood, to a
large extent bound to transport proteins.

T3
Triiodothyronine (3, 5, 3’-triiodothyronine) is, similarly to T4, present in the blood and
for the most part bound to transport proteins. It is the thyroid hormone which, in its
free form, is the most biologically active. Released in smaller quantities directly from
the thyroid. The largest quantities of circulating T3 comes from the peripheral deio-
dination of T4.

rT3
Reverse triiodothyronine (3, 3’, 5’-triiodothyronine). A metabolite of T4 which is bio-
logically inactive.

Free T4
The fraction of thyroxine not protein-bound.

Free T3
The fraction of triiodothyronine not protein-bound.

XIX
 List of Abbreviations and Definitions

Antibodies (Ab)
The abbreviation Ab is used in the text for antibodies.

TPOAb
Antibodies against thyroperoxidase. This is a sensitive marker for autoimmune thy-
roiditis.

TRAb
Antibodies against the TSH receptor. Stimulate or, in rare cases, block the TSH recep-
tor.

TgAb
Antibodies against thyroglobulin.

Isotopes
The word isotope (from the Greek isos meaning the same and topos meaning place)
is used to denote different forms of basic elements with the same atomic number, i.e.
with the same position in the periodic table. Depending on the composition of the
atomic nucleus (number of neutrons in relation to protons), a basic element can exist
in different forms, or isotopes. Isotopes can be stable or unstable. Unstable isotopes
decay spontaneously and emit radiation (radioactive radiation). Unstable isotopes are
also called radionuclides (see definition below).
Common for the isotopes of a basic element is that they have the same number of
protons and electrons, but different numbers of neutrons, which means that they have
the same properties in chemical reactions.

Radionuclides
Radioactive unstable isotopes used for investigation and treatment.

Iodine (I)
The most common isotope of the basic element iodine is the stable isotope I-127. Ra-
dioactive isotopes include I-131, with a half-life of 8 days, and I-123 with a half-life of
13 h. The negatively charged ion, iodide (I-), regardless of isotope number, is taken up
by the thyroid from the blood through active transport via NIS, oxidized and bound to
thyroglobulin in the follicle lumen.
By using radioactive iodine isotopes, it is possible to study both uptake of iodide by
the gland and its hormone turnover. I-131 is most frequently used for diagnosis and
treatment. The isotope I-123 is preferably used for diagnostic purposes in children
and for diagnostic scans in thyroid cancer patients in order to avoid a stunning effect
on subsequent 1-131 therapy. I-123 has a shorter half-life and in principle emits pure
γ-radiation, which results in a lower impact to the thyroid gland. It is however, more
expensive and more difficult to handle due to the shorter half-life.

Technetium (Tc)
Tc-99m is a by-product of uranium fission and decays with emission of γ-radiation.
It has a half-life of 6 h. Technetium has no stable isotopes. The pertechnetate ion, Tc-
99mO4-, is taken up by NIS in the thyroid in the same way as the iodide ion. In contrast

XX