Epidemiology of Thyroid Disorders [1 ed.] 0128185007, 9780128185001

Table of contents :
Cover
Epidemiology of Thyroid Disorders
Copyright
Dedication
Contents
About the authors
Preface
Acknowledgment
Part I: Principles and concepts
1 Global epidemiology of thyroid disorders
World population
Aging of the population
Life expectancy
Distribution of thyroid disorders by gender and age
Population-based models of thyroid disorders
Global prevalence of thyroid disorders
Global epidemiology of thyroid disorders
Global prevention of thyroid disorders
Global death rates from thyroid disorders
Disability-adjusted life years for thyroid disorders
Burden of thyroid disorders
Further reading
2 Structures and functions of the thyroid gland
Embryology
Structure of the thyroid gland
Histology
Vascular supply
Lymphatic drainage
Innervation
Imaging of the thyroid gland
Thyroid-stimulating hormone
Thyroid hormone synthesis and release
Triiodothyronine
Thyroxine
Calcitonin
Functions of the thyroid gland
Parathyroid glands
Further reading
3 Iodine and thyroid hormones
Iodine
Functions of iodine
Iodine absorption and metabolism
Iodide oxidation
Iodothyronine formation
Thyroid hormone storage and release
Dietary iodine
The effect of thyrotropin
Thyroid hormones and blood circulation
Thyroxine-binding globulin
Transthyretin
Free thyroid hormones
Transmembrane thyroid hormone
Deiodination of iodothyronine
Thyroid hormone action
The hypothalamic–pituitary–thyroid axis
Iodine deficiency
Iodine toxicity
Further reading
Part II: Thyroid dysfunction and clinical application
4 Iodine deficiency and goiter
Iodine deficiency: a global health problem
Epidemiology
Risk factors
Management
Complications
Goiter
Diffuse nontoxic goiter
Endemic goiter
Sporadic goiter
Nontoxic multinodular goiter
Toxic multinodular goiter
Amyloid goiter
Epidemiology
Pathogenesis and etiology
Clinical presentation
Diagnosis
Treatment
Clinical cases
Case 1
Case 2
Case 3
Further reading
5 Hypothyroidism
Types and etiology of hypothyroidism
Congenital hypothyroidism
Autoimmune hypothyroidism
Iatrogenic hypothyroidism
Cretinism
Myxedema
Drug-induced
Central hypothyroidism
Epidemiology of hypothyroidism
Pathogenesis of hypothyroidism
Risk factors
Clinical presentation
Central and peripheral nervous system
Cardiovascular system
Integumentary system
Gastrointestinal system
Respiratory system
Muscular system
Skeletal system
Hematopoietic system
Pituitary and adrenocortical function
Catecholamines
Reproductive function
Nutrient metabolism
Electrolyte metabolism
Diagnosis of hypothyroidism
Differential diagnoses
Treatment of hypothyroidism
Complications
Subclinical hypothyroidism
Metabolic insufficiency
Clinical cases
Clinical case 1
Clinical case 2
Clinical case 3
Clinical case 4
Clinical case 5
Further reading
6 Hyperthyroidism
Etiology of hyperthyroidism
Epidemiology of hyperthyroidism
Pathophysiology of hyperthyroidism
Clinical presentation
Nervous system
Cardiovascular system
Integumentary system
Gastrointestinal system
Respiratory system
Muscular system
Skeletal system
Hematopoietic system
Electrolyte metabolism
Reproductive system
Thyroid storm
Diagnosis of hyperthyroidism
Treatment of hyperthyroidism
Propylthiouracil and methimazole
Beta-blockers
Radioiodine
Surgery
Subclinical hyperthyroidism
Clinical cases
Clinical case 1
Clinical case 2
Clinical case 3
Clinical case 4
Further reading
7 Thyroiditis and Graves’ disease
Hashimoto’s thyroiditis
Epidemiology
Pathogenesis
Risk factors
Clinical presentation
Diagnosis
Treatment
Subacute thyroiditis
Epidemiology
Pathogenesis
Risk factors
Clinical presentation
Diagnosis
Treatment
Infectious thyroiditis
Epidemiology
Pathogenesis
Risk factors
Clinical presentation
Diagnosis
Treatment
Riedel’s thyroiditis
Epidemiology
Pathogenesis
Risk factors
Clinical presentation
Diagnosis
Treatment
Graves’ disease
Epidemiology
Pathogenesis
Risk factors
Clinical presentation
Diagnosis
Treatment
Clinical cases
Case 1
Case 2
Case 3
Case 4
Further reading
8 Thyroid dysfunction and the cardiovascular system
Hypothyroidism and cardiovascular problems
Hypotension
Heart failure
Thyroiditis and cardiovascular complications
Heart failure
Anemia
Hypercholesterolemia
Hyperthyroidism and cardiovascular problems
Arrhythmia
Syncope
Heart failure
Cardiovascular problems with thyroid storm
Shock
Coma
Graves’ disease with cardiovascular complications
Arrhythmia
Stroke
Heart failure
Clinical cases
Case 1
Case 2
Case 3
Case 4
Case 5
Further reading
9 Thyroid dysfunction and mental disorders
The link between thyroid dysfunction and mental disorders
Cretinism
Myxedema
Graves’ disease and stress
Hyperthyroidism
The burden of mental disorders
Clinical cases
Case 1
Case 2
Case 3
Case 4
Case 5
Further reading
10 Global epidemiology of thyroid neoplasms
Benign adenomas
Epidemiology
Pathogenesis
Risk factors
Clinical presentation
Diagnosis
Treatment
Malignant tumors
Etiology
Classifications
Papillary carcinoma
Follicular carcinoma
Medullary carcinoma
Anaplastic carcinoma
Epidemiology
Pathogenesis
Risk factors
Exposure to radiation
Dietary factors
Nonmalignant thyroid disorder relationships
Clinical presentation
Diagnosis of thyroid neoplasms
Initial evaluation
Initial laboratory studies
Imaging studies
Fine-needle aspiration
Staging
Treatment of thyroid neoplasms
Surgery
Radiation therapy
Chemotherapy
Targeted therapy
Global burden of thyroid cancers
Clinical cases
Case 1
Case 2
Case 3
Case 4
Further reading
11 Global impact of thyroid disorders
Global effects of iodine deficiency
The burden of hypothyroidism
The burden of hyperthyroidism
The burden of Graves’ disease
The burden of thyroid cancer
Global costs and consequences of thyroid disorders
Further reading
Part III: Special populations
12 Thyroid dysfunction in pregnancy
Thyroid function in pregnancy
Transient gestational thyrotoxicosis
Graves’ disease during and after pregnancy
Pregnancy and subclinical hypothyroidism
Pregnancy and Hashimoto’s thyroiditis
Silent lymphocytic thyroiditis
Thyroid cancer during pregnancy
Clinical cases
Case 1
Case 2
Case 3
Case 4
Case 5
Further reading
13 Thyroid dysfunction in fetuses and newborns
Fetal thyroid function
Maternal–fetal interactions
Thyroid function in the newborn
Iodine deficiency during fetal life
Congenital goiter
Endemic cretinism
Thyroid agenesis or dysplasia
Hypothyroidism in infants and children
Transient hypothyroidism
Consumptive hypothyroidism
Clinical cases
Case 1
Case 2
Case 3
Case 4
Case 5
Further reading
Glossary
Index
Back Cover

Citation preview

Epidemiology of Thyroid Disorders

Epidemiology of Thyroid Disorders

JAHANGIR MOINI, MD, MPH Professor of Science and Health (Retired), Eastern Florida State College, Palm Bay, FL, United States

KATHERINE PEREIRA, DNP, FNP-BC, FAANP, FAAN Professor of Nursing, Duke University School of Nursing, NC, United States

MOHTASHEM SAMSAM, MD, PHD Professor of Medicine, Burnett School of Biomedical Sciences and College of Medicine, University of Central Florida, FL, United States

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2020 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-818500-1 For Information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisition Editor: Tari Broderick Editorial Project Manager: Timothy Bennett Production Project Manager: Kiruthika Govindaraju Cover Designer: Mark Rogers Typeset by MPS Limited, Chennai, India

Dedication

Dr. Moini: This book is dedicated to my wonderful wife Hengameh, two gorgeous daughters Mahkameh and Morvarid, and two beautiful granddaughters, Laila Jade and Anabelle Jasmine Mabry. Dr. Samsam: I dedicate this book to my family.

Contents

About the authors Preface Acknowledgment

xi xiii xv

Part I Principles and concepts

1

1.

3

2.

3.

Global epidemiology of thyroid disorders World population Aging of the population Life expectancy Distribution of thyroid disorders by gender and age Population-based models of thyroid disorders Global prevalence of thyroid disorders Global epidemiology of thyroid disorders Global prevention of thyroid disorders Global death rates from thyroid disorders Disability-adjusted life years for thyroid disorders Burden of thyroid disorders Further reading

3 4 6 8 10 11 12 12 15 17 18 18

Structures and functions of the thyroid gland

21

Embryology Structure of the thyroid gland Thyroid-stimulating hormone Thyroid hormone synthesis and release Functions of the thyroid gland Parathyroid glands Further reading

21 22 29 32 36 38 42

Iodine and thyroid hormones

45

Iodine Functions of iodine Dietary iodine The effect of thyrotropin Thyroid hormones and blood circulation The hypothalamic pituitary thyroid axis Iodine deficiency

45 46 51 52 54 59 60

vii

viii

Contents

Iodine toxicity Further reading

Part II Thyroid dysfunction and clinical application 4.

5.

60 61

63

Iodine deficiency and goiter

65

Iodine deficiency: a global health problem Goiter Epidemiology Pathogenesis and etiology Clinical presentation Diagnosis Treatment Clinical cases Further reading

66 73 80 81 82 83 84 84 86

Hypothyroidism

89

Katherine Pereira Types and etiology of hypothyroidism Epidemiology of hypothyroidism Pathogenesis of hypothyroidism Risk factors Clinical presentation Diagnosis of hypothyroidism Differential diagnoses Treatment of hypothyroidism Complications Subclinical hypothyroidism Metabolic insufficiency Clinical cases Further reading

6.

Hyperthyroidism

90 99 100 100 101 111 112 113 114 115 116 116 120

121

Mohtashem Samsam Etiology of hyperthyroidism Epidemiology of hyperthyroidism Pathophysiology of hyperthyroidism Clinical presentation Diagnosis of hyperthyroidism

122 124 126 126 134

Contents

Treatment of hyperthyroidism Subclinical hyperthyroidism Clinical cases Further reading

7.

Thyroiditis and Graves’ disease Hashimoto’s thyroiditis Subacute thyroiditis Infectious thyroiditis Riedel’s thyroiditis Graves’ disease Clinical cases Further reading

8.

9.

Thyroid dysfunction and the cardiovascular system

136 140 141 144

147 148 152 155 157 159 166 169

171

Hypothyroidism and cardiovascular problems Thyroiditis and cardiovascular complications Hyperthyroidism and cardiovascular problems Graves’ disease with cardiovascular complications Clinical cases Further reading

172 174 178 183 186 190

Thyroid dysfunction and mental disorders

191

The link between thyroid dysfunction and mental disorders Cretinism Myxedema Graves’ disease and stress Hyperthyroidism The burden of mental disorders Clinical cases Further reading

10. Global epidemiology of thyroid neoplasms Benign adenomas Malignant tumors Risk factors Clinical presentation Diagnosis of thyroid neoplasms Treatment of thyroid neoplasms Global burden of thyroid cancers Clinical cases Further reading

192 193 194 196 197 198 200 205

207 208 211 223 226 227 235 238 239 242

ix

x

Contents

11. Global impact of thyroid disorders Global effects of iodine deficiency The burden of hypothyroidism The burden of hyperthyroidism The burden of Graves’ disease The burden of thyroid cancer Global costs and consequences of thyroid disorders Further reading

Part III Special populations 12. Thyroid dysfunction in pregnancy Thyroid function in pregnancy Transient gestational thyrotoxicosis Graves’ disease during and after pregnancy Pregnancy and subclinical hypothyroidism Pregnancy and Hashimoto’s thyroiditis Silent lymphocytic thyroiditis Thyroid cancer during pregnancy Clinical cases Further reading

13. Thyroid dysfunction in fetuses and newborns Fetal thyroid function Maternal fetal interactions Thyroid function in the newborn Iodine deficiency during fetal life Congenital goiter Endemic cretinism Thyroid agenesis or dysplasia Hypothyroidism in infants and children Clinical cases Further reading Glossary Index

243 243 245 246 252 252 253 254

257 259 260 261 263 265 265 267 268 271 275

277 277 278 279 280 281 282 283 284 287 292 295 307

About the authors

Dr. Jahangir Moini was an assistant professor at Tehran University, Medical School, Department of Epidemiology and Preventive Medicine, for 9 years. For 18 years, he was the Director of Epidemiology for the Brevard County Health Department. For 15 years, he was the Director of Science and Health for Everest University in Melbourne, FL. He was also a Professor of Science and Health at Everest University for a total of 24 years. For 6 years, he was a Professor of Science and Health at Eastern Florida State College but is now retired. He has been actively teaching for 39 years and, for 20 years, has been an international author of 38 books. Dr. Katherine Pereira is a professor at the Duke University School of Nursing in Durham, North Carolina. She is a family nurse practitioner with over 16 years of clinical experience working with patients with complex endocrine disorders. She received her BSN from the University of Virginia and her MSN and Doctor of Nursing Practice Degrees from Duke University. In recognition of her contributions to nursing and outstanding patient care, she has been named as a Fellow of the American Academy of Nursing and the American Association for Nurse Practitioners. Dr. Mohtashem Samsam is a Professor of Medicine and a faculty at the Burnett School of Biomedical Sciences and College of Medicine at the University of Central Florida. He studied medicine in the English language program of Albert Szent-Gyorgyi Medical University, in Szeged, Hungary (1991 96) and received his PhD from Department of Cell Biology and Pathology, Faculty of Medicine, University of Salamanca, Spain, in 2002. He completed his postdoc studies in Wuerzburg University, Germany (1999 2002).

xi

Preface

Today, thyroid disorders are common throughout the world. Since the thyroid gland influences nearly all of the body’s metabolic processes, thyroid diseases can have serious and complicated effects. Thyroid disorders range from small, harmless goiters to potentially life-threatening cancers. The most common thyroid problems concern abnormal production of thyroid hormones. Iodine is essential for the manufacture of thyroid hormones. Globally, about one-third of the population lives in areas of iodine deficiency, resulting in goiter and hypothyroidism. In areas of iodine sufficiency, most thyroid disorders are linked to autoimmune diseases, which range from primary atrophic hypothyroidism, Hashimoto’s thyroiditis, to thyrotoxicosis caused by Graves’ disease. Hyperthyroidism may be the result of Graves’ disease that is autoimmune in nature and is the most common cause of hyperthyroidism in the United States. The authors have focused on detailing the epidemiology of various thyroid disorders, structure and functions of the thyroid gland, and the effects of thyroid dysfunction on various systems in the body. These systems include the cardiovascular system and nervous system. There is also focus on various types of thyroid neoplasms. Thyroid dysfunction in pregnancy, fetuses, and in newborns is discussed. The global impact of thyroid disorders, including costs and consequences, is featured. The incidence and prevalence of thyroid disorders are discussed throughout the book.

xiii

Acknowledgment

The authors appreciate the contributions of everyone who assisted in the creation of this book, including Stacy Masucci, Tari K. Broderick, Timothy Bennett, Christian J. Bilbow, and Greg Vadimsky.

xv

CHAPTER 1

Global epidemiology of thyroid disorders Contents World population Aging of the population Life expectancy Distribution of thyroid disorders by gender and age Population-based models of thyroid disorders Global prevalence of thyroid disorders Global epidemiology of thyroid disorders Global prevention of thyroid disorders Global death rates from thyroid disorders Disability-adjusted life years for thyroid disorders Burden of thyroid disorders Further reading

3 4 6 8 10 11 12 12 15 17 18 18

Thyroid disorders are very common throughout the world and cause problems because of overfunctioning or underfunctioning of the thyroid gland. These disorders may lead to enlargement of the thyroid gland, causing direct symptoms such as difficulty in swallowing and neck discomfort. With today’s increased elderly population and better diagnostic methods, thyroid disorders are documented more often. The most significant problem related to thyroid is global iodine deficiency, which results in goiter and hypothyroidism. Thyroid disorders affect people of all ages and are more common in females than males. The highest incidence of overt hyperthyroidism is in people more than the age of 65. Hashimoto’s thyroiditis is the most common type of thyroiditis. Graves’ disease is an autoimmune disorder, which is eight times more prevalent in females and twice as common in African Americans as in other groups. More than 75% of thyroid cancers occur in females between ages 20 and 55. In this chapter the focuses are on the incidence and prevalence of thyroid disorders throughout the global population.

World population Currently, the world population is growing at a rate of approximately 1.07% per year. The current average population increase is estimated to be 82 million people annually. The peak annual growth rate was during the late 1960s, when it was about 2% per Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00001-3

r 2020 Elsevier Inc. All rights reserved.

3

4

Epidemiology of Thyroid Disorders

year. It is estimated to continue decreasing annually, reaching only 1% growth by the year 2023. World population doubled between the years 1959 and 1999. Even with the reduction in annual increases, the United Nations projects that the world population will reach 10 billion by the year 2056. This data comes from many sources, including the United Nations Population Division, the World Population Prospect, and the International Programs Center at the United States Census Bureau. As of May 2019, census bureaus throughout various countries have estimated that the world population presently exceeds 7.7 billion people. The top 10 most populated countries are as follows: • China (1.4 billion) • India (1.3 billion) • United States (328 million) • Indonesia (269 million) • Brazil (212 million) • Pakistan (203 million) • Nigeria (200 million) • Bangladesh (167 million) • Russia (143 million) • Mexico (132 million)

Aging of the population The world population is also increasing in age. There are two primary reasons for this. The first is that we are simply living longer due to healthier lifestyles and better medical treatments. The second is that the fertility rate is decreasing, resulting in fewer women becoming pregnant. The average life expectancy in the United States is higher today than during any other time in history. The United Nations issued a report showing that people ages 65 years and older increased from 8% of the total population in 1950 to 12% of the total population in 2000. This figure is expected to increase to 20% by the year 2050 and will probably rise steadily after that. This is primarily due to large improvements in health care, investment in medical research, and better health insurance availability. Fewer Americans are dying from diseases, such as breast cancer, colon cancer, prostate cancer, heart disease, and HIV. According to the World Health Organization, the global population is similarly increasing in age. There will soon be higher numbers of elderly people than children, and more people at extreme old age than ever in history (see Fig. 1.1). To understand this phenomenon, we must realize that in 1900, the major health threats were infectious and parasitic diseases. These often caused the deaths of infants and children. Today, noncommunicable diseases that mostly affect adults and the elderly have the greatest impact on global health. The health and economic burdens of age-related disability can be

Global epidemiology of thyroid disorders

Figure 1.1 Changes in age of the global population since 1950. https://www.nia.nih.gov/sites/ default/files/2017-06/global_health_aging.pdf.

affected by environmental factors that determine if people can remain independent, even though they may be physically limited. The longer people remain mobile and take care of themselves, the lower the costs will be for required long-term care. The facts about decreasing fertility, on a global basis, are also very important to understand. In more developed countries, fertility fell below the “replacement” rate of two live births per woman in the 1970s, while women in the 1950s averaged three live births. In less developed countries, fertility rates fell even faster. In 1950 women in these countries averaged six live births, but by 2006, the rate was at or below two live births. While Niger, an African country, has the highest fertility rate, of 7.1 children per woman, many countries with large populations are now toward the lower end of the scale. For example, the United States now ranks 135th on the list with 1.8 children per woman. The lowest fertility rate is in Taiwan with 1.2 children per woman, followed by Moldova, Portugal, Singapore, Poland, Greece, South Korea, Hong Kong, Cyprus, and Macau. Countries that are rapidly “shrinking” in population include Ukraine, which will decrease 22% by 2050. Poland, the Russian Federation, Italy, and Spain are also shrinking. The population of the European Union is expected to peak by 2050 and then gradually decline. Germany has experienced demographic decline for more than a generation and is estimated to drop 7.7% in population by 2050, not taking into account the recent immigration into the country. Bulgaria is expected to shrink 27% by 2050, and Romania will shrink by 22%. Japan will have a decrease in population

5

6

Epidemiology of Thyroid Disorders

by 15% and by 2030 will actually have more people more than 80 years than below 15 years. China’s extremely low fertility rate means that the country will have 28 million less people by 2050. Focus on aging and thyroid disorders It is well documented that the prevalence of thyroid disorders increases with age. However, since symptoms of thyroid disease are more subtle in older people, they are often attributed to normal aging. Therefore they require special attention. One of every five women more than 65 years of age has a higher-than-normal thyroid-stimulating hormone (TSH) level, indicating hypothyroidism. About 25% of the elderly population has some form of mental illness, and a large number of these cases may be caused by thyroid disease.

Life expectancy Life expectancy is also known as longevity. It is calculated by creating a life table that records the numbers of deaths and survivors within a specific year, for successive lifespan intervals. Deaths, survivors, and age-specific death rates are calculated for various age-groups, such as 0 1 year, 1 5 years, and then for successive 5-year age-groups after that. This data is used to create a second life table that represents the total mortality rates from birth to death, for 100,000 hypothetical live births. This is subject to age-specific death rates in the population being studied for a particular year. This data is used to calculate life expectancy as the average life years for all members since birth. Life expectancy equals total years of life for all members of the live table, divided by the total number of persons at birth. Therefore longevity at birth is the mean years of life, based totally on age-specific death rates for the population and the year of interest. Most people born in the year 1900 did not live past the age of 50. According to the Centers for Disease Control and Prevention, life expectancy at birth for people born in 2012 in the United States was 78.8 years. Today, nearly 1 in 10 girls will live past the age of 100 years, and nearly 1 in 20 boys will live past 100. Life expectancy for females is 81.2 years and for males is 76.4 years. The difference between them is 4.8 years, which has remained the same since 2011. As of now, a woman turning 65 in 2019 can expect to live, on average, until the age of 86.6. A man reaching 65 can expect to live, on average, until the age of 84.3. In the year 2015 the average American woman reaching age 65 had more than a one-in-three chance of reaching the age of 90. This is more than the one-in-four chance that existed 50 years ago. The countries with the oldest populations include Monaco, Japan, Germany, Italy, Greece, Sweden, Spain, Austria, Bulgaria, and Estonia. In Monaco, for example, 22.8% of the population is of 65 years or older. In 2019 13.1% of the US population is of 65 years or older (see Fig. 1.2).

Global epidemiology of thyroid disorders

Figure 1.2 Healthy life expectancy (HALE) at birth, both sexes, 2016. gamapserver.who.int/maplibrary/files/maps/global_HALE_2016.png.

People providing health care to the elderly, as well as disabled patients, increased in the United States from more than 621,000 workers in 2007 to more than 911,000 workers in 2012. As a result, revenues from this health care increased from $25.3 billion in 2007 to $34.4 billion in 2012. Every country must find a way to handle the impending crisis of caring for aging populations. Governments must plan decades ahead, with new methods to better manage the situation. Some cities are already building age-friendly housing and other infrastructure. For example, Sweden has implemented very low-cost approaches to caring for elderly citizens, which are offering extremely high quality of care. In the same country, most elderly health care is funded by municipal taxes and government grants. In 2014 while total costs for care were equivalent to $12.7 billion, only 4% of the cost was financed by patient charges. Privatization of elderly care is increasing, allowing private care companies to control operations, which now provide more than 24% of all elderly in-home care. All recipients of care can choose if they want their care to be provided by public or private operators. The “oldest old” (people aged 85 or older) make up 8% of the world’s elderly population, with the term elderly meaning age 65 or older. This is 12% in more developed countries and 6% in less developed countries. In many countries the 85-andolder group is the fastest growing part of the population. Globally, this group is projected to increase 351% between 2010 and 2050. This is compared to a 188%

7

8

Epidemiology of Thyroid Disorders

Figure 1.3 Percentage change in world population by age. WHO’s Global Health Aging PDF.

increase in the 65-and-older group, and 22% increase in the population under age 65. People reaching 100 years of age are projected to increase by 10 times as many between 2010 and 2050. It has been estimated that over the course of human history, odds of living up to age 100 have risen from 1 of every 20 million people to one in every 50 people—this figure is for females in low-mortality countries such as Japan and Sweden. Of the percentage change in world population by age shown in Fig. 1.3, the most astounding is the 100-and-older age-group, with a 1004% increase. Focus on life expectancy Globally, people are living longer and more productive lives than any time previously in history. The oldest average life expectancy is 83.7 years in Japan. This takes into account males and females to achieve the “average” figure. Using similar methods, Switzerland and Singapore rank second and third. The United Kingdom is ranked 20th, and the United States is ranked 31st (at 79.3 years). The three worst average life expectancies are Sierra Leone (50.1 years), Angola (52.4 years), and the Central African Republic (52.5 years).

Distribution of thyroid disorders by gender and age The distribution of thyroid disorders by gender and age varies with each type of disorder. For example, women, overall, have more thyroid disorders, but often, the effects of these disorders widely differ. Women are more likely than men to have iodine deficiency (see Chapter 3: Iodine and thyroid hormones). While women develop goiters more often, the effects of them differ in that the menstrual cycle is affected, while male

Global epidemiology of thyroid disorders

sperm production is not. Distribution of goiter is based on levels of iodine deficiency (see Chapter 4: Iodine deficiency and goiter). In severely iodine-deficient areas, prevalence may be as high as 80%, with four times as higher distribution in women than in men. Overall incidence declines with age. Sporadic goiter is seven to nine times more common in females, with highest incidence at puberty or in young adulthood. Nontoxic multinodular goiter and endemic goiter, however, have the same distribution between females and males. However, they affect older people, mostly along with thyroid nodules and hypothyroidism (see Chapter 5: Hypothyroidism). Actually, hypothyroidism is 10 times more common in females, usually after age 40. About 10% of older females are affected. Hypothyroidism also affects one out of every 3500 4000 births. Hyperthyroidism occurs in people more than the age of 60 years in up to 15% of cases and affects 1 in 500 pregnancies (see Chapter 6: Hyperthyroidism). Again, females are affected more often, most commonly when they are in their third and fourth decades. Globally, hyperthyroidism is 0.5% 2% more prevalent in women. It is also 0.4% 2% prevalent in elderly people. Overt hyperthyroidism affects 0.4 of every 1000 women and 0.1 of every 1000 men, with a large variance between ages regarding susceptibility. The prevalence of overt hyperthyroidism in people aged 65 years or older has been documented as being 0.33% of the population. Incidence of overt hyperthyroidism during pregnancy has been estimated between 0.1% and 0.4% of the population. Prevalence of previously unsuspected hyperthyroidism was 0.5% in women, and undetectable in men. In the United States alone, the highest incidence of overt hyperthyroidism, by age, is 1.01 of every 1000 people aged 65 and older. The 56 64 age-group, with 0.78 per 1000 affected, follows this. Hyperthyroidism is lowest in children between 12 and 17 years of age, at 0.26 per 1000 affected. Incidence of Hashimoto’s thyroiditis increases with aging (see Chapter 7: Thyroiditis and Graves’ disease). It affects about 5% of the global population, usually between ages 30 and 60, and is 8 15 times more common in females. When men are affected, they are usually also in middle age. Subacute thyroiditis is uncommon, affecting both sexes of all ages. However, it affects women three to five times more often than men. It is most common in middle age, followed by young adulthood, decreasing in frequency with increased age. Infectious thyroiditis is very rare, most commonly seen in children and young adults, between ages 20 and 40. Children are affected 92% of the time and the other 8% are young adults. Males and females are affected at the same rates. Another rare form, Riedel’s thyroiditis, affects females five times more often than males, usually between 30 and 60 years of age, with peak incidence in the fifth decade of life. Graves’ disease is eight times more common in females, usually beginning between ages 20 and 40, with a second common onset between 40 and 60 (see Chapter 7: Thyroiditis and Graves’ disease). However, it can develop any time during life. An interesting fact is that Graves’ disease affects African-American males about 2.5 times more often than other males and affects females about twice as often as other females.

9

10

Epidemiology of Thyroid Disorders

Asian or Pacific Islander women have a 78% increased risk compared to Caucasian women, whereas men have a three times higher risk than Caucasian men. Age-specific rates reveal that women have the highest incidence between 30 and 34 years of age, followed by 35 39, then 25 29. The lowest incidence in females is between ages 15 and 19. In males, Graves’ disease is most prevalent between ages 25 and 49, and least prevalent between ages 70 and 75. In middle-aged and elderly people, thyroid nodules may progress to adenomas in about 5% of cases (see Chapter 10: Global epidemiology of thyroid neoplasms). However, studies have revealed that nodules are present in about 50% of older adults. More than 75% of thyroid cancer cases occur in females, mostly between ages 20 and 55. However, a majority of new cases occur after age 45. Actually, the higher percentages are in the 45 54 age-group. The lowest percentages are for people younger than 20 or older than 84. Focus on gender, age, and thyroid disorders In general, women are much more likely to develop disorders of thyroid than men. For example, women are three times more likely to get thyroid cancer. Thyroid diseases are very common in middle-aged and older adults.

Population-based models of thyroid disorders In various populations, multinodular goiter or nodular thyroid enlargement affects as many as 12% of adults. According to the American Thyroid Association, in 2019, more than 12% of the US population will develop a thyroid condition. A goiter prevalence of 5% or higher in school-age children indicates iodine deficiency. In Germany, thyroid nodules larger than 1 cm were found in 12% of the population. When there was only one palpable nodule, 20% 48% had additional nodules detected by ultrasound. Between 1% and 10% of adults in the United States have solitary thyroid nodules, but in endemic goitrous regions, rates are much higher. Thyroid nodules arising from thyroid follicles are relatively common, and 90% 95% are benign. However, there is a higher rate of thyroid nodules in areas with significant radiation exposure. About 33% of the global population lives in areas of iodine deficiency, which increases chances for the development of hypothyroidism. In the United States, about 4.6% of the population aged 12 years and older has hypothyroidism, but usually, these cases are mild. The six populations at highest risk for hypothyroidism include older patients, those with ischemic heart disease, pregnant women, patients with persistent symptoms even with proper doses of levothyroxine, those with subclinical hypothyroidism, and those suspected of having myxedema coma. Celiac disease patients may

Global epidemiology of thyroid disorders

have a 4.4 times increased risk for hypothyroidism than the general population. Hyperthyroidism is also varied in populations, based on iodine sufficiency. Primary hyperthyroidism is increasing in various areas of the world, such as Scotland and Denmark. In the United States, about 1.2% of the population has hyperthyroidism, which is slightly more than 1 of every 100 people. Caucasians develop Hashimoto’s thyroiditis more than any other ethnic group, by 67% 78%. The other forms of thyroiditis are not significantly higher in any specific population. However, Graves’ disease retains a much higher significance in African Americans, Asians, and Pacific Islanders than in Caucasians or other populations. Thyroid cancer affects males who are Caucasian or non-Hispanic at the highest rates (7.8 out of every 100,000), and at the lowest rates in African Americans (3.8 out of every 100,000). For women, thyroid cancer affects 22.8 of every 100,000 Caucasians, just slightly more than 22.1 of every 100,000 non-Hispanics, and only affects 13.4 of every 100,000 African Americans.

Global prevalence of thyroid disorders Globally, approximately 200 million people have thyroid disorders of various types, with more than 50% remaining undiagnosed. Many cases are undiagnosed because symptoms may be easily mistaken for depression, menopause, or because of obesity. This means that thyroid disease is a current, silent epidemic. It is estimated, for example, that goiters affect up to 200 million of the 800 million people who have iodine deficiency. Thyroid nodules are extremely common, with up to 50% of all individuals having at least one nodule by the age of 60 years. About 5% of the global population has hypothyroidism, and about 2% has hyperthyroidism. Thyroiditis has been seen in as many as 12.5% of populations in various countries. Graves’ disease affects 2% 5% of females and 0.2% 0.7% of males globally. There are more than 560,000 new cases of thyroid cancer reported every year around the world. In Europe the mean prevalence of undiagnosed thyroid dysfunction was 6.71% of the population. Prevalence of undiagnosed hypothyroidism was 4.94% and of undiagnosed hyperthyroidism was 1.72%. The mean prevalence of total thyroid dysfunction in Europe was 3.82%. The prevalence of previously known and undiagnosed hypothyroidism was 3.05% and hyperthyroidism was 0.75%. In the Wickham study from the United Kingdom, 16% of the population had goiter. In the United States the prevalence of thyroid disorders is in more than 25 million people. This is about 1 of every 13 people, or 7.35%. There are more than 13 million estimated undiagnosed thyroid disorders in this country, which is about one of every 25, or 4.78% of the population. One in eight women has a risk for thyroid disorders during life.

11

12

Epidemiology of Thyroid Disorders

Focus on congenital hypothyroidism In 2010 a study reported the incidence of congenital hypothyroidism at 100% higher in Hispanic newborns than in Caucasian newborns, and 44% higher in newborns of Asian or Native Hawaiian/Pacific Islander backgrounds. The incidence was also 30% lower in AfricanAmerican newborns than in Caucasians.

Global epidemiology of thyroid disorders The incidence of total thyroid dysfunction in Europe is 259 per 100,000 annually, with a clear female preponderance of 420 per 100,000 to only 85 per 100,000 men. More than 90% of cases of goiter are linked to iodine deficiency, with many more women affected than men. Thyroid nodules detectable by palpation affect 2% 6% of the population. However, ultrasound detects thyroid nodules in 19% 35%, and autopsies reveal up to 65% of patients having them. Incidence rate of hypothyroidism was 226 per 100,000 annually overall. Of this number, 370 per 100,000 women and 72 per 100,000 men were affected. The overall incidence rate of hyperthyroidism was 51 per 100,000 annually. Of this number, 82 per 100,000 women and 16 per 100,000 men were affected. Thyroiditis is three to five times more common in women, globally. It is most common in certain regions where the summer and fall weather is more severe. Graves’ disease incidence is about 0.5% of people, being 7.5 times more common in women than in men. Thyroid cancer incidence is 3.2 million people around the world—mostly women. Rates of thyroid cancer, in a 30-year study (between 1972 and 2002), have revealed that the disease is increasing in most countries, except for Sweden, in which it is actually decreasing. Over the study period the average increase was about 67% in females and 48% in males. In Sweden, there was an approximate 18% decrease, between both genders. Generally, thyroid cancer affects three times more women than men. Figs. 1.4 and 1.5 show incidence rates of thyroid cancer for females and males, respectively, in various countries between 1998 and 2002.

Global prevention of thyroid disorders Global prevention of thyroid disorders is a mostly attainable goal but involves governmental efforts to reduce risk factors. Correcting iodine deficiency is of the utmost importance in preventing thyroid disorders. This offers improved quality of life and survival rates, elimination of cretinism (see Chapter 5: Hypothyroidism), and lesser degrees of neuromotor or cognitive dysfunction. Iodine is sparsely distributed on the Earth’s surface. Therefore iodine deficiency disorders have been extremely common in many populations. They became much less prevalent in the United States, for

Global epidemiology of thyroid disorders

Figure 1.4 Incidence rates of thyroid cancer for females (per 100,000 person-years), age standardized, between 1998 and 2002. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788231/.

example, iodine was introduced into dietary salt. The efforts of previous decades have made extensive advances in eliminating iodine deficiency through universal salt iodization. The key to prevention is monitoring of the iodine supply in each area, and the impact of the prevention program upon the target population. This includes monitoring of factories, importers, retailers, and even consumers regarding appropriate levels of dietary iodine. Another dietary prevention method is eating less soy-based foods. Though soy is good for overall health, in extremely large amounts, it may be detrimental to thyroid function. If someone is taking levothyroxine, it is important to wait for 4 hours before consuming any soy-based foods, since soy, along with calcium, fiber, and iron, interferes with the absorption of levothyroxine. Abstaining from smoking is a definite prevention method. Cigarette smoke contains toxins such as thiocyanate, which disrupts iodine uptake and blocks production of thyroid hormones. Generally, smoking causes elevated thyroxine levels and a slight decrease in TSH levels. Cigarette smokers are more likely to develop Graves’ disease and its complications.

13

14

Epidemiology of Thyroid Disorders

Figure 1.5 Incidence rates of thyroid cancer for males (per 100,000 person-years), age standardized, between 1998 and 2002. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788231/.

Selenium supplements are suggested as preventive measures. Selenium is predominantly concentrated in the body inside the thyroid. Selenium supplements also help boost the immune system and lower thyroperoxidase antibodies in people with Hashimoto’s disease as well as in pregnant women. This decreases symptoms of hypothyroidism. In pregnant women, selenium supplementation also decreases chances of developing permanent postpartum thyroiditis. Since the body absorbs the organic form of selenium, known as selenomethionine, better than the inorganic form (sodium selenite), it is better to use selenomethionine as a supplement. When receiving X-rays, patients should request a thyroid-protecting collar. This is especially true for X-rays of the mouth, head, neck, spine, or chest. The thyroid collar is heavy and lined with lead. Periodically, the neck should be self-checked for lumps, bumps, or swelling of the thyroid. Additional methods of preventing thyroid disorders include avoiding drinking well water, which may contain perchlorates. These are odorless and colorless salts dissolved in well water. Commercially, they are used to manufacture fireworks, explosives, and rocket motors. Anyone developing celiac disease, which is an autoimmune

Global epidemiology of thyroid disorders

condition, is three times more likely to develop Hashimoto’s thyroiditis or Graves’ disease. Celiac disease causes poor absorption of iodine and selenium, triggering thyroid dysfunction. Overall, regular checkups by a physician are important to monitor thyroid and overall health, in order to prevent serious diseases from developing. Prevention also involves the extremely young. A neonatal TSH screening program, universally applied, would go a long way as a preventive measure for thyroid disorders. Newborn screening, for example, for congenital hypothyroidism, is a major achievement that has resolved this condition in many developed countries. However, it is still a problem in many developing countries. This must be reversed, because hypothyroidism in the newborn period is nearly always overlooked, delaying diagnosis, and leading to mental retardation. The first screening program was performed in Canada in 1972, which detected seven hypothyroid infants out of 47,000 screened newborns over a 3-year period. The focus of newborn screening programs must be to detect all cases with thyroid disease as early as possible. Other conditions that may be screened for include hypothyroxinemia (low T4 and normal TSH), isolated hyperthyrotropinemia (normal T4 and elevated TSH), and low T4 with elevated TSH. The iodization of bread and even water has been used in countries, such as The Netherlands, Russia, Tasmania, Thailand, Indonesia, Italy, and China. It is time for governments to improve their policies, programs, technologies, and financial support concerning iodine deficiency. There are five guiding principles regarding efforts toward universal salt iodization, which include a secure political commitment, formation of partnerships and coalitions, availability of adequately iodized salt, better monitoring systems, and maintenance of education and communication. The World Bank estimates that every dollar dedicated to prevention of iodine deficiency disorders yields a gain of $28 in productivity. This shows that the elimination of iodine deficiency is also one of the world’s most cost-effective program interventions. Focus on increasing cases of thyroid cancer Thyroid cancer is one of the few types of cancer that has increased in incidence rates over the past three decades. It occurs in all age-groups from children through the elderly. Nearly all of this increase involves papillary thyroid carcinoma. The reason for this is not clear, but environmental factors are probably highly significant, including releases of radiation due to nuclear reactor accidents.

Global death rates from thyroid disorders A large amount of studies concerning global death rates from thyroid disorders have given different results. Overt and subclinical hyperthyroidism, for example, is associated with an increased risk of all-cause mortality, or death from major adverse cardiovascular events, and heart failure. Isolated heart attack and stroke risks were not increased

15

16

Epidemiology of Thyroid Disorders

in comparison to patients with normal thyroid function. Significant changes of thyroid plasma hormones are known to be life-threatening, but they are usually identifiable in patients who have documented thyroid disorders. The three primary thyroid pathologies associated with sudden, unexpected death include the following: • hyperthyroidism—usually related to Graves’ disease or toxic multinodular goiter; • hypothyroidism—usually related to Hashimoto’s thyroiditis; and • lymphocytic thyroiditis—usually related to lymphocytic inflammation of the pituitary gland. Most thyroid conditions are not fatal, while goiters may be uncomfortable and are rarely dangerous on their own. However, up to 20% of patients with multinodular goiters will later develop thyroid cancer. Very large multinodular goiters can also cause compression symptoms, including difficulty breathing or swallowing. Thyroid nodules, in and of themselves, are not fatal unless malignant. Hypothyroidism is generally managed well with medication, but if not treated, its complications include cardiovascular problems, nerve injury, infertility, and, possibly, death. Since hypothyroidism can decrease the volume of blood pumped out in every heartbeat by 30% 50%, heart failure can result from it. Most cardiac complications of hypothyroidism can be treated (see Chapter 8: Thyroid dysfunction and the heart). Serious hypothyroidism also affects kidney function, resulting in very low levels of blood sodium. Hypothyroidism can also cause breathing difficulties and trouble walking, both of which could lead to death in different ways. Hyperthyroidism is able to lead to death because it may cause atrial fibrillation, syncope, which can lead to severe injury, and heart failure (see Chapter 8: Thyroid dysfunction and the heart). Also, the acute form of hyperthyroidism known as thyroid storm can lead to cardiovascular collapse, shock, and coma. Therefore it is considered to be a life-threatening emergency that requires prompt treatment. Thyroiditis has the potential to cause heart problems, heart failure, anemia, high cholesterol, and depression, all of which may have potential fatal outcomes. Untreated Hashimoto’s thyroiditis can lead to total thyroid destruction and the development of myxedema coma. If this occurs, the prognosis is poor, with a high mortality rate that is approximately 50% of patients. Also, patients with chronic Hashimoto’s thyroiditis are 60 times more likely to develop thyroid lymphoma than other patients. Hashimoto’s thyroiditis patients nearly always have high cholesterol, which complicates the disease by increasing the likelihood of death from coronary artery disease. Graves’ disease can result in serious complications, including death, since it is often accompanied by tachycardia, atrial fibrillation, and stroke (see Chapter 8: Thyroid dysfunction and the heart). This disease can also cause miscarriage, maternal heart failure, changes in heart muscle structure and function, congestive heart failure, thyroid storm, seizures, severe hypotension, and coma.

Global epidemiology of thyroid disorders

Thyroid cancer, of most forms, is usually not extremely malignant, and seldom fatal. For papillary thyroid carcinoma, tumors are more aggressive in elderly patients (see Chapter 10: Global epidemiology of thyroid neoplasms). They can spread via the lymphatics to the regional lymph nodes, in 33% of patients, and may metastasize to the lungs. Patients under age 55, with smaller tumors confined to the thyroid, have an excellent prognosis. Follicular thyroid carcinoma is more malignant, spreading hematogenously with distant metastases. Medullary thyroid carcinoma may spread via the lymphatic system to the cervical and mediastinal nodes and, occasionally, to the liver, lungs, and bones. The most aggressive thyroid cancer is anaplastic thyroid carcinoma, which is characterized by rapid, painful enlargement. Rapid thyroid enlargement may also suggest thyroid lymphoma, especially if Hashimoto’s thyroiditis is present. Anaplastic thyroid carcinoma is usually fatal, with about 80% of patients dying within 1 year of diagnosis. According to the Columbia University report, the 5-year survival rate is less than 5% of patients. With all forms of thyroid cancer, it is important to receive follow-up assessments throughout life, with close monitoring of any thyroidreplacement hormones being taken. Overall, the death rate from thyroid cancer has increased slightly in the past decade, but still very low compared to most other cancers. For example, as of 2019, the average amount of new cases of thyroid cancer, only in the United States, is slightly more than 52,000, and about 2100 cases are fatal.

Disability-adjusted life years for thyroid disorders Disability-adjusted life years (DALYs) are important measurements that link the burden of disease in populations with the degree of illness, disability, and long-term survival. They were first developed to quantify the global burden of disease, and to provide a way for measuring health benefits and cost-effectiveness. One “DALY” can be thought of as one lost year of “healthy” life. DALYs for a disease or health condition are calculated as the sum of the years of life lost (YLL) due to premature death in the population, and the years lost due to disability (YLD) for people living with a disease or its consequences. Therefore the formula used to calculate DALYs is as follows: DALY 5 YLL 1 YLD Basically, the YLL correspond to the number of deaths, multiplied by the standard life expectancy at the age at which death occurs. The basic formula for YLL is YLL 5 N 3 L where the N stands for number of deaths. It is multiplied by L, which stands for standard life expectancy at age of death, in years.

17

18

Epidemiology of Thyroid Disorders

The basic formula for YLD is YLD 5 P 3 DW where the P stands for number of prevalent cases. It is multiplied by the “DW,” which stands for disability weight. Iodine deficiency disorders were estimated by the World Health Organization in 1990 to account for 0.1% of total DALYs. At that time, iodine deficiency disorders ranked as the 77th leading cause of global disease.

Burden of thyroid disorders The global burden of thyroid disorders is significant. Iodine deficiency disorders make up a wide range of clinical and subclinical manifestations, ranging from goiter to cretinism. The best documentation of thyroid disorder burden concerns thyroid cancer. The average costs of thyroid cancer treatments in the United States are more than $60,000 during the first year and more than $35,000 during the second year. These figures are from the year 2005. Costs related to thyroid cancer are expected to increase. However, better diagnostic procedures that can detect this cancer earlier may result in lower costs for patients in the future. This subject is heavily debated by experts. Chapter 11, Global impact of thyroid disorders, further discusses the global impact and cost burdens of thyroid disorders.

Key terms adenomas age-specific death rates celiac disease endemic goiter goiter Graves’ disease Hashimoto’s thyroiditis hyperthyroidism hyperthyrotropinemia

hypothyroidism hypothyroxinemia iodization life expectancy selenium thyroid cancer thyroid nodules thyroid storm thyroperoxidase

Further reading 1. Amdur, R.J., and Mazzaferri, E.L. Essentials of Thyroid Cancer Management (Cancer Treatment Research). (2005) Springer. 2. Anderson, B.A. World Population Dynamics: An Introduction to Demography. (2014) Pearson. 3. Bao, S.S., and Winter, B. Thyroid Nodules: Questions From Real Patients. (2018) ACE Health Publisher. 4. Celentano, D.D., and Szklo, M. Gordis Epidemiology, 6th Edition. (2018) Elsevier.

Global epidemiology of thyroid disorders

5. Centers for Disease Control and Prevention, Rasmussen, S.A., and Goodman, R.A. The CDC Field Epidemiology Manual. (2018) Oxford University Press. 6. Diamanti-Kandarakis, E., and Gore, A.C. Endocrine Disruptors and Puberty (Contemporary Endocrinology Series). (2011) Humana Press. 7. Egger, G., Sagner, M., Binns, A., and Rossner, S. Lifestyle Medicine: Lifestyle, the Environment and Preventive Medicine in Health and Disease, 3rd Edition. (2017) Academic Press. 8. Farrow, L., and Brownstein, D. The Iodine Crisis: What You Don’t Know About Iodine Can Wreck Your Life. (2013) Devon Press. 9. Gharib, H. Thyroid Nodules: Diagnosis and Management (Contemporary Endocrinology). (2018) Humana Press. 10. Harris, R.E. Epidemiology of Chronic Disease: Global Perspectives, 2nd Edition. (2019) Jones & Bartlett Learning. 11. Hoy, J. Changing Faces: The Consequences of Exposure to Gene and Thyroid Disrupting Toxins. (2017) CreateSpace Independent Publishing Platform. 12. Johnson, J., and Finn, K. Designing User Interfaces for an Aging Population: Towards Universal Design. (2017) Morgan Kaufmann. 13. Kenly, W. After the Diagnosis, Medullary Thyroid Cancer Memoirs. (2015) Outskirts Press. 14. Kuh, D., and Shlomo, Y.B. A Life Course Approach to Chronic Disease Epidemiology (Life Course Approach to Adult Health), 2nd Edition. (2004) Oxford University Press. 15. Ley, B.M. Iodine (A Health Learning Handbook). (2017) BL Publications. 16. Livi Bacci, M. A Concise History of World Population, 6th Edition. (2017) Wiley-Blackwell. 17. Macera, C.A., Shaffer, R., and Shaffer, P.M. Introduction to Epidemiology: Distribution and Determinants (Public Health Basics). (2012) Cengage Learning. 18. Macha, K., and McDonough, J.P. Epidemiology for Advanced Nursing Practice. (2011) Jones & Bartlett Learning. 19. Mancino, A.T., and Kim, L.T. Management of Differentiated Thyroid Cancer. (2017) Springer. 20. Myers, A. The Autoimmune Solution: Prevent and Reverse the Full Spectrum of Inflammatory Symptoms and Diseases. (2015) HarperOne. 21. National Comprehensive Cancer Network. NCCN Guidelines for Patients: Thyroid Cancer. (2017) National Comprehensive Cancer Network. 22. Nikiforov, Y.E., Biddinger, P.W., and Thompson, L.D.R. Diagnostic Pathology and Molecular Genetics of the Thyroid: A Comprehensive Guide for Practicing Thyroid Pathology, 3rd Edition. (2019) LWW. 23. Pearce, E.N. Iodine Deficiency Disorders and Their Elimination. (2017) Springer. 24. Remington, P.L., Brownson, R.C., and Wegner, M.V. Chronic Disease Epidemiology, Prevention, and Control, 4th Edition. (2016) American Public Health Association. 25. Roman, S.A., Sosa, J.A., and Solorzano, C.C. Management of Thyroid Nodules and Differentiated Thyroid Cancer A Practical Guide. (2017) Springer. 26. Shakespeare, T. Disability: The Basics. (2017) Routledge. 27. Sodana, W.L., Sodano, C.P., and Birdwell, J.M. Integrative Medicine Approach to Thyroid Disorders: Clinician’s Desk Reference. (2019) Sodano. 28. Stanbury, J.B. The Iodine Trail: Exploring Iodine Deficiency and Its Prevention Around the World. (2008) Farber Public Relations. 29. Van Nostrand, D. Thyroid Cancer: A Guide for Patients, 2nd Edition. (2010) Keystone Press, Inc. 30. Wartofsky, L., and Van Nostrand, D. Thyroid Cancer: A Comprehensive Guide to Clinical Management, 3rd Edition. (2016) Springer. 31. Wentz, I., and Nowosadzka, M. Hashimoto’s Thyroiditis: Lifestyle Interventions for Finding and Treating the Root Cause. (2013) Wentz LLC. 32. WHO Regional Office for the Eastern Mediterranean. Elimination of Iodine Deficiency Disorders: A Manual for Health Workers (Public Health). (2008) World Health Organization. 33. Wild, C., Vineis, P., and Garte, S. Molecular Epidemiology of Chronic Diseases. (2008) Wiley. 34. Zaidi, S. Graves’ Disease and Hyperthyroidism: What You Must Know Before They Zap Your Thyroid With Radioactive Iodine. (2013) CreateSpace Independent Publishing Platform. 35. Zaidi, S. Hypothyroidism and Hashimoto’s Thyroiditis: A Groundbreaking, Scientific and Practical Treatment Approach. (2013) iComet Press.

19

CHAPTER 2

Structures and functions of the thyroid gland Contents Embryology Structure of the thyroid gland Histology Vascular supply Lymphatic drainage Innervation Thyroid-stimulating hormone Thyroid hormone synthesis and release Triiodothyronine Thyroxine Calcitonin Functions of the thyroid gland Parathyroid glands Further reading

21 23 24 27 27 29 29 32 35 35 36 36 38 42

The thyroid gland is the largest purely endocrine gland in the body. It is located in the anterior neck and has a butterfly-like shape. It curves across the anterior surface of the trachea and is slightly inferior to the larynx. This gland regulates basal body metabolism via the various hormones that it releases. The thyroid is also involved in gluconeogenesis, protein synthesis, glycogenolysis, lipogenesis, and thermogenesis. The parathyroid glands are embedded in the posterior surface of the lateral lobes of the thyroid gland and aid in calcium homeostasis.

Embryology The thyroid gland buds from the gastrointestinal (GI) tube, starting with thickening of the endodermal epithelium in the foregut. This thickening is called the thyroid anlage and is first recognizable at day 16 or 17 of embryo development. The thickening deepens to form a small pit and then becomes an endoderm outpouching, near developing myocardial cells. Over time, the median diverticulum is caudally displaced after the descent of myocardial cells. A primitive stalk that connects the primordium with the pharyngeal floor lengthens into the thyroglossal duct. The primordium becomes Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00002-5

r 2020 Elsevier Inc. All rights reserved.

21

22

Epidemiology of Thyroid Disorders Right thymus Right parathyroid III

(A)

Pedicle of left third pharyngeal pouch Left thymus Left parathyroid III

(B) Endoderm Buccal cavity

First pharyngeal pouch Median thyroid diverticulum

Second pharyngeal pouch Third pharyngeal pouch Fourth pharyngeal pouch and caudal pharyngeal complex

Tracheoesophageal tube

(C)

Oesophagus Trachea Right lateral lobe of thyroid

Left lateral lobe of thyroid Thyroid isthmus Left fourth pharyngeal pouch

(D)

Left parathyroid III Right parathyroid III

Left fourth pharyngeal pouch (ventral portion)

Right thymus gland

Left parathyroid IV

Left parathyroid III Left parathyroid IV

Thyroid gland

Right parathyroid III

Left thymus gland Right lobe of thyroid gland

Trachea

Right thymus Left thymus

Trachea Oesophagus

Figure 2.1 Development of the thyroid gland and nearby structures. (A) The ventral aspect of the endoderm of the pharynx, showing the pharyngeal pouches. The areas of contact of the pharyngeal endoderm with the surface ectoderm are shown as flattened surfaces. Note that the colors of the pharyngeal pouches and the median thyroid diverticulum are retained in the next developments. (B) Ventral and dorsal diverticuli of the third and fourth pharyngeal pouches and midline thyroid gland at 6 weeks. (C) The thymus, thyroid and parathyroid glands at 7 weeks. (D) The thymus, thyroid and parathyroid glands at weeks. (Redrawn with permission from Hamilton WJ, Boyd JD, Mossman HW 1962 Human Embryology: Prenatal Development of Form and Function. Cambridge: W Heffer & Sons.)

bilobate in shape, contacting and fusing with the ventral part of the fourth pharyngeal pouch as it reaches its final position, approximately on day 50. Fig. 2.1 shows the development of the thyroid gland and nearby structures. In normal situations, the thyroglossal duct dissolves and fragments by about month 2 of development. It leaves behind a small depression where the middle and posterior thirds of the tongue join at the foramen cecum. Cells of the lower duct area differentiate into thyroid tissue and form the gland’s pyramidal lobe. Then, the lobes contact the ultimobranchial glands, followed by C cells being incorporated into the thyroid. At the same time, the gland’s histology is being altered. Complicated, interconnected, corded cell arrangements are mixed with vascular connective tissue. These replace the solid epithelial mass, becoming tubule-like structures in about month 3. Soon, follicular arrangements appear, without colloid, but by weeks 13 or 14, they start to fill with colloid.

Structures and functions of the thyroid gland

Figure 2.2 Thyroid gland. (A) In this drawing, the relationship of the thyroid to the larynx (voice box) and to the trachea is easily seen. (B) In this photo of a dissected cadaver, the location of the thyroid relative to the carotid arteries and jugular veins is shown.

Structure of the thyroid gland The thyroid gland is a ductless alveolar gland that is brownish-red in color, secreting hormones that regulate development, growth, and metabolism. The thyroid is extremely vascular. It is situated level with the fifth cervical vertebrae up to the first thoracic vertebrae. The pretracheal layer of the deep cervical fascia surrounds the gland. It is superior to the anterior trachea and inferior to the thyroid cartilage, which is the cartilage making up most of the anterior larynx surface (Fig. 2.2). Specifically, the thyroid is just below the Adam’s apple (laryngeal prominence). The gland has right and left lobes, and a thin isthmus connects their lower portions. The isthmus is absent in some people. It is normally about 1.25 cm vertically and transversely and usually located anterior to the second and third tracheal cartilages. However, it can be higher or lower since its location and size are quite varied. The lobes are basically coneshaped and about 5 cm in length. Their largest transverse measurement is 3 cm, and their largest anteroposterior measurement is 2 cm. They have ascending apices that are laterally diverged, to the level of the oblique lines on the thyroid cartilage laminae. The base of each lobe is level with either the fourth or fifth tracheal cartilages. The posteromedial areas of the lobes are attached to the edge of the cricoid cartilage by the lateral ligament known as Berry’s ligament. Often, there is a thin, conical pyramidal lobe, a thyroid tissue with a worm-like appearance, extending up from the isthmus. It ascends toward the hyoid bone, and sometimes originates not from the isthmus, but from the adjacent part of the left lobe, and less commonly, the right lobe. The pyramidal lobe may be detached in two or more areas. Rarely, ectopic tissue is found around the thyroglossal duct or laterally in the neck. It may also exist in the tongue (lingual thyroid), mediastinum, and subdiaphragmatic

23

24

Epidemiology of Thyroid Disorders

organs. Ectopic thyroid tissue is mostly located at the base of the tongue, usually near the foramen cecum and is often the only thyroid tissue located there. Above the thyroid lobes or isthmus, small and detached masses of thyroid tissue may develop as accessory thyroid glands. Remnants of the thyroglossal duct may remain between the isthmus and foramen cecum. These may be accessory nodules or cysts made of thyroid tissue, located near the midline or even within the tongue. In this case, they are called thyroglossal duct cysts. The superficial thyroid surface, or convex lateral surface, is covered by the sternothyroid. The attachment of the sternothyroid to the thyroid’s oblique line keeps the upper thyroid pole from extending to the thyrohyoid. The sternohyoid and superior “belly” of the omohyoid lie more anteriorly. They are inferiorly overlapped by the sternocleidomastoid’s anterior border. The medial thyroid surface is adapted to the trachea and larynx. The superior pole meets the inferior pharyngeal constrictor along with the posterior cricothyroid. These structures separate the superior pole from the posterior thyroid lamina and edge of the cricoid cartilage. Medial to this area, as it supplies the cricothyroid, is the external branch of the superior laryngeal nerve. Also medial, the trachea is inferior while the recurrent laryngeal nerve and esophagus are more posterior. The esophagus is closer on the left side. The posterolateral surface of the thyroid is near the carotid sheath, overlapping the common carotid artery. The thyroid’s anterior border is thin. Close to the anterior branch of the superior thyroid artery, it is medially slanted downward. The posterior border has a rounded shape. It is inferiorly related to the inferior thyroid artery as well as its anastomosis with the superior thyroid artery’s posterior branch. To the left, the lower part of the posterior border is located close to the thoracic duct. The sternothyroid covers the isthmus, but the pretracheal fascia separates these structures. The isthmus is more superficially covered by the anterior jugular veins, sternohyoid, fascia, and skin. Along the upper isthmus border, the superior thyroid arteries anastomose. The inferior thyroid veins leave the thyroid at its lower border. The fingers may feel the thyroid, primarily, when it is enlarged. Its size is different based on genetic, nutritional, and environmental factors. The average weight of the thyroid gland is about 25 g. It is slightly heavier in women, enlarging in menstruation and pregnancy. Abnormalities usually cause it to enlarge, becoming visible because of distortion of the neck. The size of the thyroid gland is important when various disorders are being evaluated and treated. Diagnostic ultrasound is used to noninvasively assess its size. The size of the thyroid increases with age. There is no significant difference in the volume of the gland between males and females aged 8 months to 15 years.

Histology There is a thin capsule of connective tissue in the thyroid gland. It extends into the parenchyma, dividing each lobe into irregular lobules, both in size and shape. There

Structures and functions of the thyroid gland

Figure 2.3 Thyroid gland tissue. In the drawing (A) and the photomicrograph (B), note that each of the thyroid follicles is filled with colloid. In the micrograph ( 3 140), the thyroid colloid has separated from the follicular cells during preparation of the specimen.

are large amounts of thyroid follicles in the thyroid gland. These follicles are hollow, round structures resembling cysts, which are lined by a simple cuboidal epithelium that rests on a basal lamina (Fig. 2.3). This epithelium may also be simple columnar or even squamous in structure. The follicles are only about 0.02 0.9 mm in size. They contain dense plexuses consisting of fenestrated capillaries, along with complex lymphatic networks. Sympathetic nerve fibers supply the capillaries and arterioles. Some nerve fibers terminate very near to the follicular epithelial cells.

25

26

Epidemiology of Thyroid Disorders

The follicular cells are varied because of their amounts of activity. This is mostly controlled by circulated hypophyseal thyroid-stimulating hormone (TSH). The resting follicles are large, with linings of squamous or low cuboidal epithelium and large amounts of luminal colloid. In these follicles, apical microvilli are short in length but, with TSH stimulation, can elongate and often ranch. There may be a coexistence of follicles having different activity levels. The active follicular cells are functionally highly polarized. TSH secretion results in endocytosis of droplets of colloid at the luminal epithelium. This hormone causes the cells to extend their cytoplasmic processes into the colloid, trapping droplets. The iodinated thyroglobulin in these droplets is degraded by lysosomes from the follicular cells. This liberates the hormones triiodothyronine (T3) and thyroxine (T4), which move to the base of the cell and are released. They move out from the thyroid mostly through the capillaries and the lymphatics. When circulating TSH is prolonged and at high levels, hypertrophy of the follicular cells occurs. There is also continued resorption of colloid, increased vascularity of the stroma, and, often, enlargement of the thyroid. The cells of the follicles surround a follicle cavity. This holds the viscous colloid that is a fluid with many dissolved proteins. Primarily, however, the colloid is made up of an iodinated glycoprotein called iodothyroglobulin. This is the inactive and stored form of the active thyroid hormones (THs) T3 and T4. The follicular epithelial cells produce the colloid. There is enough iodothyroglobulin stored extracellularly in the follicles to regulate body activities for as long as 3 months. A capillary network of delicate connective tissue surrounds each follicle. It delivers regulatory hormones and nutrients to the gland’s cells and removes metabolic wastes and secretory products. Fluctuations in the metabolic rate result in secretion or inhibition of TH. The metabolic rate is monitored by the brain, which stimulates TH secretion via the actions of thyrotropin-releasing hormone (TRH) and TSH. The main effect of TH is to increase the metabolic rate. This results in increased oxygen consumption, with calorigenic effects— an increase in heat production. In order to supply enough blood and oxygen to meet the increased metabolic demand, TH also raises the heart rate, strength of the heartbeat, and respiratory rate. The appetite is stimulated, and there is acceleration in the breakdown of proteins, fats, and carbohydrates for fuel. TH additionally causes faster reflexes and alertness, secretion of growth hormone, and growth of skin, bones, teeth, nails, and hair. It is also crucial for the development of the fetal nervous system. The thyroid also contains other endocrine cells known as C cells, clear cells, or parafollicular cells. They are located between the cuboidal follicle cells and their basement membrane. The C cells are larger than the follicular epithelium cells and cannot be stained as clearly for microscopic examination. The C cells are part of the amine precursor uptake and decarboxylation system of the dispersed neuroendocrine cells. They produce calcitonin in the form of thyrocalcitonin, the peptide hormone that lowers blood calcium via inhibition of bone resorption and calcium recovery from the ultrafiltrate

Structures and functions of the thyroid gland

of the renal tubules. The C cells fill the middle-third portion of each lateral thyroid lobe. They are usually scattered in the thyroid follicles, inside the basal lamina, but not in the follicle lumen. Sometimes, they cluster in the interfollicular stroma. This is why they are also called parafollicular cells.

Vascular supply The thyroid gland is supplied by the superior and inferior thyroid arteries (Fig. 2.4). The arteries are large in size. Their branches often anastomose on the gland and inside it, ipsilaterally and contralaterally. The superior thyroid artery is closely related to the superior laryngeal nerve’s external branch. It continues through the thyroid fascia. After this point, it divides into the anterior and posterior branches. The anterior branch supplies the anterior surface of the thyroid. The posterior branch supplies the gland’s lateral and medial surfaces. Near the base of the gland, the inferior thyroid artery divides into superior (ascending) and inferior branches, supplying the gland’s inferior and posterior surfaces. The superior branch also supplies the parathyroid glands. There is much variation between how the recurrent laryngeal nerve and inferior thyroid artery are interrelated. This is very important clinically. When there is iatrogenic injury to the nerves supplying the larynx after thyroid surgery, it is a significant complication. In most people, the recurrent laryngeal nerve is related to the inferior thyroid artery’s posterior branch, but a vascular network can replace this. The superior, middle, and inferior thyroid veins drain the thyroid. The superior vein emerges from the upper thyroid gland. It continues with the superior thyroid artery to the carotid sheath and drains into the internal jugular vein. Blood is collected from the lower thyroid by the middle thyroid vein. It emerges from the gland’s lateral surface, draining into the internal jugular vein. The inferior thyroid veins form a glandular venous plexus that connects the middle and superior thyroid veins. These veins form a pretracheal plexus. Then, the left inferior vein descends, joining the left brachiocephalic vein. The right inferior vein obliquely descends across the brachiocephalic artery and joins the right brachiocephalic vein at the point where it joins the superior vena cava. Often, the inferior thyroid veins open as part of a common trunk into the left brachiocephalic vein or superior vena cava. These inferior veins drain the esophageal, tracheal, and inferior laryngeal veins with valves located at their terminations.

Lymphatic drainage The thyroid gland has rich lymphatic components. The thyroid lymph nodes are actually deep, anterior, cervical lymph nodes located very close to the gland itself. These lymph nodes are found near the middle cricothyroid ligament and the trachea. Lymphatic vessels

27

28

Epidemiology of Thyroid Disorders

External carotid artery

Hyoid bone

Internal carotid artery

Superior laryngeal nerve Internal branch External branch

Infrahyoid artery Superior thyroid artery and vein

Thyroid cartilage (lamina)

Superior laryngeal artery

Median cricothyroid ligament

Thyrohyoid membrane Superior root Ansa cervicalis Inferior root Common carotid artery

Cricothyroid muscles Cricoid cartilage

Cricothyroid artery

Pyramidal lobe (often absent or small) Right lobe Left lobe Isthmus

Internal jugular vein Phrenic nerve Middle thyroid vein Inferior thyroid veins Ascending cervical artery

Thyroid gland

Pretracheal lymph nodes

Inferior thyroid artery Phrenic nerve Superficial branch Anterior scalene muscle Suprascapular artery Vagus nerve (CN X) Thyrocervical trunk

External jugular vein

Subclavian artery and vein

Anterior jugular vein First rib (cut)

Vagus nerve (CN X)

Left recurrent laryngeal nerve

Right recurrent laryngeal nerve Brachiocephalic trunk Brachiocephalic veins Superior vena cava Aortic arch

Thyroid cartilage Median cricothyroid ligament Common carotid artery

Cricothyroid muscle Cricoid cartilage Thyroid gland Cervical pleura Trachea

Figure 2.4 Blood circulation of the thyroid gland.

of the thyroid communicate with the tracheal plexus. They pass to the prelaryngeal nodes, slightly above the isthmus, onto the pretracheal and paratracheal nodes. Some vessels may drain into the brachiocephalic nodes that are related to the thymus in the superior mediastinum. Vessels along the superior thyroid veins, to the deep cervical

Structures and functions of the thyroid gland

nodes, laterally drain the thyroid gland. The thyroid lymphatics may directly drain, without any nodes, to the thoracic duct.

Innervation The superior, middle, and inferior cervical sympathetic ganglia innervate the thyroid gland. A plexus is formed on the inferior thyroid artery by the postganglionic fibers from the inferior cervical ganglion. This follows the artery to the thyroid gland. It communicates with the recurring external and laryngeal branch of the superior laryngeal nerves. It also communicates with the superior cardiac nerve and the plexus on the common carotid artery. Focus on thyroidectomy Except for thyroid enlargement that occurs in menstruation and pregnancy, any swelling of the thyroid is called a goiter. This swelling usually presses upon nearby structures with symptoms often due to pressure on the trachea or recurrent laryngeal nerves. Sometimes, the veins become engorged. Thyroidectomy is sometimes performed to treat hyperthyroidism or for thyroid enlargement, while the gland is still functionally normal. During this procedure the surgeon must be extremely careful when tearing off the superior and inferior thyroid arteries, so that the adjacent nerves are not damaged. The external laryngeal nerve is very close to the superior thyroid artery. Similarly, the recurrent laryngeal nerve is very close to the inferior thyroid artery. In thyroidectomy the parathyroid glands and recurrent laryngeal nerves are left intact.

Imaging of the thyroid gland Current imaging techniques cannot resolve the follicular structure of the thyroid gland. Therefore cross-sectional images from computed tomography, ultrasound, and magnetic resonance imaging (MRI) reveal a homogeneous texture. Ultrasonography is ideal for examining the thyroid due to the gland’s superficial location (Fig. 2.5). Because of the extreme vascularity of the gland, intense contrast enhancement and increased signal on T2-weighted MRI are seen (Fig. 2.6). Radionuclide imaging can be done using technetium ( 99mTc) pertechnetate. This commonly available radionuclide is trapped within the thyroid, similar to how iodine is trapped, but is different because it is not organified. The radionuclide reveals morphological information as well as the presence of ectopic thyroid tissue. Using 123- or 131-iodine, both of which are trapped and organified, one can assess thyroid function.

Thyroid-stimulating hormone TSH is released from the anterior pituitary gland. This hormone regulates the synthesis and release of hormones from the thyroid via a closed-loop feedback process. In order to

29

Figure 2.5 A thyroid sonogram.

Figure 2.6 A T2-weighted magnetic resonance image at the level of the thyroid isthmus. Vessels show flow void; compare with Fig. 29.21.

Structures and functions of the thyroid gland

be synthesized, iodine is required, which is obtained from the diet. The synthesis and release of the THs are essential functions of TSH, which stimulates active transport of iodide into the follicle cells. As iodide movement increases its speed in the cytoplasm of these cells, there is an acceleration of thyroglobulin, thyroperoxidase, and TH formation. This means that TSH is acting as a first messenger. It binds to the plasma membrane receptors. By stimulating the second messenger called adenylate cyclase, key enzymes involved in the production of THs are activated. When TSH is absent, the thyroid follicles are inactive, with no synthesis or secretion occurring. The primary factor that controls TH release is TSH concentration in the blood circulation. There are four steps involved, which are as follows: • Removal of thyroglobulin—Via endocytosis, the follicle cells remove thyroglobulin from the follicles; thyroglobulin undergoes proteolysis in lysosomes to cleave iodinated tyrosine residues from the larger protein; free THs are released, and the thyroglobulin “scaffold” is recycled. • Thyroglobulin breakdown—Lysosomal enzymes break down thyroglobulin. The amino acids and THs enter the cytoplasm. Then, the amino acids are recycled to be used in the synthesis of thyroglobulin. • TH release—The released T3 and T4 enter the bloodstream after diffusing across the basement membrane; nearly 90% of all thyroid secretions consist of T4, with T3 only being secreted in small amounts. • Hormone binding to transport proteins—While the THs enter the bloodstream, about 70% of T3 and 75% of T4 are attached to transport proteins known as thyroidbinding globulins; the majority of the remainder of the THs in circulation is attached to transthyretin or to the plasma protein called albumin. Small quantities of THs remain unbound, just 0.3% of circulating T3 and 0.03% of circulating T4, and these are free to diffuse into the peripheral tissues. There is equilibrium between the levels of bound and unbound THs. At any time, free THs are binding to transport proteins at the exact rate at which bound hormones are released. Equilibrium is disturbed when unbound THs diffuse from the bloodstream into other tissues. When this occurs, the transport proteins release more THs until equilibrium is restored. There is a large reserve of bound THs. The human bloodstream usually has more than 1 week’s supply of T3 and T4. Every day, the follicle cells of the thyroid gland are able to absorb 120 150 µg of iodine ions. This is the minimum amount from the diet required to maintain normal function of the thyroid. Therefore inside the thyroid follicle cells, the iodine ion concentration is about 30 times higher than the blood concentration. When blood iodine ion levels rise, the same thing happens inside the follicle cells. Most of the body’s reserves of iodide are contained in the thyroid follicles. In the United States the usual diet provides about 500 µg of iodide every day. This is about three times more than the minimum daily requirement. This excessive

31

32

Epidemiology of Thyroid Disorders

amount is largely due to the iodine ions added to table salt (iodized salt), which is present in large amounts in processed foods. Therefore the rate of TH production is rarely linked to iodide deficiency. However, in other countries, this is not always true. Excessive blood iodine ions are removed by the kidneys and eliminated via the urine. Every day, the liver excretes only about 20 µg of iodine ions into the bile, which is an exocrine product stored within the gallbladder. Then, the iodine ions, excreted via the bile, are eliminated in the feces. Since losses in the bile continue— even when there is lower-than-minimum iodide in the diet—it means that gradual depletion of the thyroid’s iodide reserve can occur. At this point, TH production declines, no matter what the circulating TSH levels may be.

Thyroid hormone synthesis and release There are two types of THs: triiodothyronine (T3) and thyroxine (T4). The follicle cells of the thyroid synthesize thyroglobulin, which is a globular protein. The cells secrete thyroglobulin into the colloid of the thyroid follicles. Thyroglobulin contains the amino acid tyrosine, which is the precursor of THs. THs are released as part of a hypothalamic pituitary thyroid axis. The hypothalamus, via negative feedback, detects low plasma concentrations of TH and releases TRH into the hypophyseal portal system. The TRH binds to receptors on thyrotropic cells of the anterior pituitary gland and causes them to release TSH into the systemic circulation (Fig. 2.7). There are three basic steps in the formation of THs, which are as follows: • Dietary iodide ion (I2) absorption—The digestive tract absorbs iodide ions from the diet and, via the bloodstream, delivers them to the thyroid gland. Then, the iodide is actively transported into the cytoplasm by TSH-sensitive carrier proteins in the basement membrane of the follicle cells. • Iodide ion diffusion—The ions diffuse to each follicle cell’s apical surface. Here, they lose one electron and are converted into an atom of iodine (I0) via the enzyme thyroperoxidase. This reaction sequence at the apical membrane surface then attaches one or two atoms of iodine to the tyrosine parts of a thyroglobulin molecule in the follicle cavity. • Tyrosine linkage—The thyroxine molecules with attached iodine atoms are linked via covalent bonds to form molecules of THs. These stay incorporated into the thyroglobulin. This pairing process is probably due to thyroperoxidase. Eventually, every molecule of thyroglobulin will contain four to eight molecules of triiodothyronine, thyroxine, or both. Both T3 and T4 enter target cells via an energy-dependent transport system. Inside these cells, the hormones bind to receptors in the three areas: the cytoplasm, the mitochondrial surfaces, and in the nucleus.

Structures and functions of the thyroid gland

Figure 2.7 Negative feedback control by the hypothalamus. In this example, the secretion of thyroid hormone (T3 and T4) is regulated by a number of negative feedback loops. A long negative feedback loop (long red arrow) allows the central nervous system (CNS) to influence hypothalamic secretion of thyrotropin-releasing hormone (TRH) by nervous feedback from the targets of T3 and T4 (and from other nerve inputs). The secretion of TRH by the hypothalamus and thyroid-stimulating hormone (TSH) by the adenohypophysis is also influenced by shorter feedback loops (shorter red arrows), allowing great precision in the control of this system.

THs bound to cytoplasmic receptors are basically stored. However, when their intracellular levels decline, bound THs will be released into the cytoplasm (Fig. 2.8). The THs that bind to mitochondria increase mitochondrial adenosine triphosphate (ATP) production rates. In the cell nucleus the binding to receptors activates the genes controlling enzyme synthesis, which is involved in transformation and use of energy. A specific effect is the speeded-up production of sodium potassium ATPase. This

33

Figure 2.8 Synthesis, storage, and release of thyroid hormone (T3 and T4).

Structures and functions of the thyroid gland

membrane protein ejects intracellular sodium ions while recovering extracellular potassium ions. It uses large amounts of ATP. Abnormalities of the THs are involved in Graves’ disease, cretinism, myxedema, and the characteristic swelling of the thyroid gland known as simple goiter.

Triiodothyronine The TH called triiodothyronine contains three iodine atoms and hence is abbreviated as T3. The THs affect nearly every body cell, producing strong, quick, yet short-lived increases in cellular metabolism rates. Although triiodothyronine is produced in lower amounts than thyroxine, it is mostly responsible for the observed effects of the THs and is approximately four times more potent than thyroxine. The thyroid gland continually releases T3; yet it makes up only 10% 15% of the T3 in the peripheral tissues. Enzymes in the liver, kidneys, and other tissues convert T4 to T3. About 85% 90% of the T3 reaching target cells is due to the conversion of T4 in the peripheral tissues. The half-life of T3 is about 2.5 days. Thyroxine is deiodinated by three deiodinase enzymes to produce triiodothyronine. There are three types of triiodothyronine, which are as follows: • Type I—present in the liver, kidneys, thyroid, and in small amounts, the pituitary gland; it makes up 80% of the deiodination of thyroxine • Type II—present in the central nervous system (CNS), brown adipose tissue, and heart vessels, mostly intracellular. In the pituitary, it mediates negative feedback upon TSH • Type III—present in the placenta, CNS, and hemangiomas. This deiodinase converts thyroxine into reverse T3, which is an inactive form.

Thyroxine The TH called thyroxine contains four iodine atoms and hence is abbreviated as T4. Thyroxine is also known as tetraiodothyronine. It is produced in large amounts by the thyroid gland—about 20 times more than T3. The fact that the thyroid gland first stores considerable amounts of both T3 and T4 is unusual. No other endocrine gland stores hormones in a different form to be released at a later time. Thyroxine binds much more strongly to plasma globulins than T3 and is not removed from the blood by target cells as quickly. The small amounts of T4 that enter the target tissues are usually converted to T3. The half-life of T4 is about 6.5 days. There are seven steps involved in the synthesis of thyroxine in the thyroid gland’s follicular cells, which are as follows: • The sodium iodide symporter transports two sodium ions across the basement membrane of the follicular cells along with one iodine ion. This is a secondary

35

36

Epidemiology of Thyroid Disorders

• • • • • •

active transporter using the concentration gradient of sodium ions to move iodine ions against its concentration gradient. Iodine ions are moved across the apical membrane into the colloid of the follicle. Thyroperoxidase causes the oxidation of two iodine ions to form iodide, which is nonreactive. Only the more reactive iodine is needed for the next step. The thyroperoxidase iodinates the tyrosyl residues of thyroglobulin in the colloid. The thyroglobulin was synthesized in the endoplasmic reticulum of the follicular cell and secreted into the colloid. TSH from the anterior pituitary gland binds the TSH receptor on the basolateral membrane of the cell, stimulating endocytosis of the colloid. The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave the thyroxine from the iodinated thyroglobulin. These vesicles are then exocytosed, and THs are released.

Calcitonin The C cells of the thyroid gland produce the hormone called calcitonin, which helps regulate the concentration of unbound calcium ions (Ca21) in body fluids. It also stimulates calcium ion excretion by the kidneys and prevents calcium ion absorption by the digestive tract. Calcitonin’s effects may be most significant during childhood, as it is then that it simulates skeletal mineral deposition and bone growth. Calcitonin is also important in reducing loss of bone mass during prolonged starvation and during the final stages of pregnancy. A woman’s skeleton competes with the developing fetus for unbound calcium ions from the diet late in pregnancy. However, calcitonin’s role regarding the bones of a healthy nonpregnant woman is unclear. Calcium ions are very important for controlling neuron and muscle cell activities. Their concentrations affect the sodium ion permeability of excitable membranes. With high calcium ion concentrations, there is decreased sodium ion permeability. Cell membranes become less responsive. These problems are very rare, however. When the unbound calcium ion concentrations become lower than normal, a dangerous situation develops. With reduced concentrations, sodium ion permeabilities are increased. The cells then become highly excitable. If the calcium ion levels become severely low, the individual may experience muscular spasms or convulsions. Adequate blood calcium levels are largely maintained by parathyroid hormone (PTH) from the parathyroid glands. The regulation of blood calcium levels is summarized in Fig. 2.9.

Functions of the thyroid gland The hormones of the thyroid gland activate genes that code for enzymes involved in ATP production and glycolysis. Along with the direct effect of these hormones upon

Structures and functions of the thyroid gland

Figure 2.9 Regulation of blood calcium levels. Calcitonin and parathyroid hormones have antagonistic (opposite) effects on calcium concentration in the blood. (Also see Fig. 25.11 on p. 565.)

the mitochondria, this effect increases cell metabolism. This is the calorigenic effect of THs, since cells consume more energy and generate more heat. In young children the production of TSH increases in cold weather. The calorigenic effect may actually help individual children in adapting to colder climates. However, this response is not seen in adults. As children grow, their THs are essential for normal development of the nervous, muscular, and skeletal systems. Almost every body cell is affected by THs. Similar to steroids, they enter target cells, bind to intracellular receptors in the cell nuclei, and begin transcription of mRNA for protein synthesis. Effects of THs include the following: • increased basal metabolic rate and production of body heat—due to starting transcription of genes related to glucose oxidation (calorigenic effect); • regulation of tissue growth and development—essential for normal development of the skeletal and nervous systems, along with maturation, and the ability to reproduce; and

37

38

Epidemiology of Thyroid Disorders

•

maintenance of blood pressure—by increasing numbers of adrenergic receptors in the blood vessels. The effects of THs upon major body organs and systems are summarized in Table 2.1. The metabolic processes that are increased by the hormones of the thyroid gland include the basal metabolic rate, gluconeogenesis, protein synthesis, glycogenolysis, lipogenesis, and thermogenesis. These increases are linked to effects upon the mitochondria, sodium potassium pumps, and beta-adrenergic receptors. The basal metabolic rate is the amount of energy needed to survive in the absence of any physical activity. Gluconeogenesis is the synthesis of glucose from noncarbohydrate sources, including amino acids and glycerol. Protein synthesis is the process in which biological cells generate new proteins, which is balanced by the loss of cellular proteins via degradation or export. Glycogenolysis is the removal of a glucose molecule from glycogen via the action of the enzyme glycogen phosphorylase, which is present in the liver, kidneys, muscles, and brain. Lipogenesis is the process of fatty-acid and triglyceride synthesis from glucose and other substrates. Thermogenesis is the metabolic process by which heat is generated via the burning of calories.

Parathyroid glands There are usually four to five parathyroid glands embedded within the posterior surface of the lateral lobes of the thyroid gland (Fig. 2.10). They are small, rounded, or lens-shaped bodies in the thyroid tissue and are made up of compacted, irregular rows of cells. These glands are of a yellow-brown color and most often located between the posterior thyroid lobe borders and the thyroid capsule. They are normally 6 mm in length, 3 4 mm wide, and 1 2 mm from front to back. The weight of each parathyroid gland is about 50 mg. In most individuals, there are two parathyroid glands on each side, superior and inferior. However, there can also be only three, or they can be formed as tiny islands of parathyroid tissue throughout the connective tissue. Rarely, an occult gland may follow a blood vessel into a thyroid surface groove. The inferior parathyroids usually move to the inferior thyroid poles. However, they sometimes descend, along with the thymus, into the thorax, or may be located above their usual level near the bifurcation of the carotid artery. The anastomoses between the superior and inferior thyroid arteries are a helpful aid in identifying the parathyroid glands. This occurs along the thyroid gland’s posterior border, usually very near to the parathyroids. The superior parathyroid glands are usually found in the same places in most patients, but the inferior glands are more likely to be found in the middle of the posterior thyroid borders and can be even higher. Because of embryological development, the inferior pair can also be in the fascial thyroid sheath, under the inferior thyroid

Table 2.1 Effects of thyroid hormones upon various body systems. System or process

Normal effects

Hypersecretion effects

Hyposecretion effects

BMR and temperature regulation

Calorigenesis, enhanced sympathetic nervous system effects, promotion of normal BMR, and oxygen use Promotion of glucose catabolism; fat mobilization; requirement for protein synthesis; enhances synthesis of cholesterol in the liver Promotion of normal heart function

BMR higher than normal, increases in body temperature and appetite; heat intolerance, weight loss Increased catabolism of glucose, proteins, and fats; loss of muscle mass; weight loss

BMR lower than normal, decreases in body temperature and appetite; cold intolerance; reduced sensitivity to catecholamines; weight gain Decreased glucose metabolism and protein synthesis; elevated cholesterol and triglyceride levels in the blood; edema

Increased sensitivity to catecholamines, resulting in palpitations, rapid heart rate, hypertension, and eventually, heart failure Irritability, insomnia, personality changes, restlessness; in Graves’ disease, it causes exophthalmos

Decreased heart-pumping efficiency; lowered heart rate and blood pressure

Metabolism of carbohydrates, lipids, and proteins Cardiovascular system

Nervous system

Skeletal system

Muscular system Reproductive system Integumentary system Gastrointestinal system

Promotion of normal nervous system development in the fetus and infant; promotion of normal adult nervous system function Promotion of normal skeletal growth and maturation

Promotion of normal muscular development and function Promotion of normal female reproduction and lactation Promotion of normal skin hydration and secretory activities Promotion of normal tone and motility; increased secretion of digestive juices

BMR, Basal metabolic rate.

In children, excessive initial skeletal growth, then early epiphyseal closure and short stature; in adults, skeleton demineralization Muscle weakness and atrophy In females, depressed function of ovaries; in males, impotence The skin becomes flushed, thin, and moist; the hair is soft and fine; the nails are thin and soft Excessive motility; diarrhea

In infants, deficient or slowed brain development and intellectual disability; in adults, depression, mental dulling, memory impairment, paresthesias, and hypoactive reflexes In children, growth retardation, skeletal stunting, retention of childhood body proportions; in adults, joint pain

Slowed muscle action; muscle cramps; myalgia Depressed ovarian function and lactation; sterility The skin is pale, dry, and thick; the hair is thick and coarse; there is facial edema Depressed tone, motility, and secretory activity; constipation

40

Epidemiology of Thyroid Disorders

Hyoid bone

Epiglottis

Larynx (thyroid cartilage)

Superior parathyroid glands

Inferior parathyroid glands Thyroid gland

S

Trachea

L

R I

Figure 2.10 Parathyroid gland. In this drawing from a posterior view, note the relationship of the parathyroid glands to each other, to the thyroid gland, to the larynx (voice box), and to the trachea.

arteries, close to the inferior lobar poles. They may also be outside the sheath, just above one of the inferior thyroid arteries, or inside the thyroid close to its inferior pole—all of these variations are surgically significant. A tumor of the inferior parathyroid can develop inside the fascial thyroid sheath and descend down the inferior thyroid veins, which are anterior to the trachea, into the superior mediastinum. If a tumor is outside the sheath, it can extend behind the esophagus, posteroinferiorly, into the posterior mediastinum. To the recurrent laryngeal nerves, the superior parathyroids are normally dorsal, while the inferior parathyroids are normally ventral. In cross-sectional imaging the parathyroid glands are extremely flattened and not usually visible by most methods—even scintigraphy—until they are enlarged. The parathyroid glands secrete PTH, which is also called parathormone. This is the primary hormone involved in maintaining calcium homeostasis. The actual area of PTH synthesis is the rough endoplasmic reticulum, which produces prepro-PTH. This is cleaved in the lumen of the endoplasmic reticulum to produce pro-PTH. Additional cleaving within the Golgi apparatus results in mature PTH, which is stored in the secretory granules until release. Like most endocrine organs, the parathyroid glands are controlled by a negative feedback loop.

Structures and functions of the thyroid gland

There are three primary actions of PTH, which increase calcium levels in the body. These are as follows: • PTH acts directly upon the bones, increasing bone resorption. It stimulates cytokine secretion from the osteoblasts, which act upon osteoclast cells, increasing their activity. The osteoclasts cause the breakdown of bone. Therefore when their activity increases, it results in increased bone breakdown and more calcium in the extracellular fluid. • PTH also increases the amount of calcium absorbed from the loop of Henle and distal kidney tubules. This is not fully understood. There is also increased phosphate excretion, which very effectively prevents formation of calcium phosphate kidney stones. • While PTH does not actively increase calcium absorption from the GI, it does stimulate vitamin D formation. This results in increased absorption from the GI tract. Focus on parathyroid hormone Hypoparathyroidism is a deficiency of PTH, which usually follows trauma to the parathyroid gland or removal of the gland during thyroid surgery. Hypocalcemia then develops, causing neurons to become more excitable. This causes tingling, tetany, and convulsions. Without treatment, these symptoms progress to respiratory paralysis and death. Hyperparathyroidism is rare and is usually caused by a tumor in the parathyroid gland. Calcium leaves the bones, making them softened, deformed, and replaced with fibrous connective tissue. Osteitis fibrosa cystica is the severe form of this disorder with spontaneous fractures occurring. Hypercalcemia develops, which depresses the nervous system and causes abnormal reflexes plus weak skeletal muscles. Excess calcium salts collect in the kidney tubules, forming kidney stones. Calcium may also collect in the body’s soft tissues, greatly impairing the vital organs.

Key terms Adam’s apple alveolar gland amine precursor uptake decarboxylation Berry’s ligament bilobate C cells calcitonin calorigenic effects cervical sympathetic ganglia

closed-loop feedback process colloid cricoid cartilage cricothyroid ectopic fascial fenestrated capillaries follicle cavity foramen cecum foregut

41

42

Epidemiology of Thyroid Disorders

goiter hyoid bone iodine iodothyroglobulin isthmus lingual thyroid lymph nodes middle cricothyroid ligament omohyoid osteoblasts osteoclast parafollicular cells parathyroid glands parathyroid hormone scintigraphy sternothyroid stroma tetraiodothyronine thyrocalcitonin

thyroglobulin thyroglossal duct thyroid anlage thyroid arteries thyroid cartilage thyroid follicles thyroid gland thyroid hormones thyroid veins thyroid-binding globulins thyroidectomy thyroid-stimulating hormone thyroperoxidase thyrotropin-releasing hormone thyroxine transthyretin triiodothyronine tyrosyl ultimobranchial glands

Further reading 1. Ali, S.Z., and Cibas, E.S. The Bethesda System for Reporting Thyroid Cytopathology Definitions, Criteria, and Explanatory Notes, 2nd Edition. (2018) Springer. 2. Al-Mudhaffar, S.A., and Hassan, S.H. The Molecular Characterization of Thyroid-Stimulating Hormone (TSH) in Thyroid Gland Tumors by Radiobinding Assay Techniques. (2015) CreateSpace Independent Publishing Platform. 3. Blokdijk, G.J. Parathyroid Hormone, 2nd Edition. (2018) CreateSpace Independent Publishing Platform. 4. Brent, G.A. Thyroid Function Testing (Endocrine Updates). (2010) Springer. 5. Brownstein, D. Iodine: Why You Need It, Why You Can’t Live Without It, 4th Edition. (2009) Medical Alternatives Press. 6. Bruneton, J.N., Reed-Rameau, N., Weill, F., Baert, L., Rafelli, C., and Dassonville, O. Applications of Sonography in Head and Neck Pathology (Medical Radiology Diagnostic Imaging). (2012) Springer. 7. Cau, P., Michel-Bechet, M., and Fayet, G. Morphogenesis of Thyroid Follicles in Vitro (Advances in Anatomy Embryology and Cell Biology). (2012) Springer. 8. Chopra, I.J., and Cody, V. Triiodothyronines in Health and Disease (Monographs on Endocrinology). (2011) Springer. 9. Dhillon, R.S., and East, C.A. Ear, Nose and Throat and Head and Neck Surgery: An Illustrated Colour Text, 4th Edition. (2012) Churchill Livingstone. 10. Garber, J.R. Thyroid Disease: Understanding Hypothyroidism and Hyperthyroidism, 4th Edition. (2015) Harvard Health Publications. 11. Icon Group International. Calcitonin: Webster’s Timeline History, 1915 2007. (2009) Icon Group International, Inc. 12. Icon Group International. Triiodothyronine: Webster’s Timeline History, 1953-2007. (2010) Icon Group International, Inc.

Structures and functions of the thyroid gland

13. Kalinin, A.P., and Pavlov, A.V. The Parathyroid Glands: Imaging and Surgery. (2013) Springer. 14. Licata, A.A., and Lerma, E.V. Diseases of the Parathyroid Glands. (2012) Springer. 15. Lokanadham, S., and SubhadraDevi, V. Thyroid Gland Morphology & Histogenesis: Fetal Thyroid Gland, Anatomy, Embryology, Histology, Morphology, Morphometry, Histogenesis & Anomalies. (2013) Lap Lambert. 16. Medeiros, L.J., and Miranda, R.N. Diagnostic Pathology: Lymph Nodes and Extranodal Lymphomas, 2nd Edition. (2017) Elsevier. 17. Nillni, E.A. Textbook of Energy Balance, Neuropeptide Hormones, and Neuroendocrine Function. (2018) Springer. 18. PM Medical Health News. 21st Century Complete Medical Guide to Thyroid Diseases, Hyperthyroidism, Goiter, Hypothyroidism, and Graves’ Disease Authoritative Government Documents, Clinical References, and Practical Information for Patients and Physicians. (2004) Progressive Management. 19. Potts, J.T., Jameson, J.L., and De Groot, L. Endocrinology Adult and Pediatric: The Parathyroid Gland and Bone Metabolism, 6th Edition. (2013) Saunders. 20. Rajendran, J., and Manchanda, V. Nuclear Medicine Cases (McGraw-Hill Radiology Series). (2010) McGraw-Hill Education. 21. Randolph, G.W. Surgery of the Thyroid and Parathyroid Glands: Expert Consult, 2nd Edition. (2012) Saunders. 22. Reese, A.M. Structure and Development of the Thyroid Gland in Petromyzon. (2012) Ulan Press. 23. Robinson, P. Recovering with T3: My Journey From Hypothyroidism to Good Health Using the T3 Thyroid Hormone, 2nd Edition. (2018) Elephant in the Room Books. 24. Rodolfo, K. Thyroidectomy: Surgical Procedures, Potential Complications and Postoperative Outcomes (Surgery-Procedures, Complications, and Results). (2014) Nova Science Publications Inc. 25. Sofferman, R.A., and Ahuja, A.T. Ultrasound of the Thyroid and Parathyroid Glands. (2012) Springer. 26. Som, P.M., and Curtin, H.D. Head and Neck Imaging (Expert Consult), 5th Edition. (2011) Mosby. 27. Sugiyama, S. The Embryology of the Human Thyroid Gland Including Ultimobranchial Body and Others Related (Advances in Anatomy and Cell Biology). (2012) Springer. 28. Wondisford, F.E., and Radovick, S. Clinical Management of Thyroid Disease. (2009) Saunders.

43

CHAPTER 3

Iodine and thyroid hormones Contents Iodine Functions of iodine Iodine absorption and metabolism Iodide oxidation Iodothyronine formation Thyroid hormone storage and release Dietary iodine The effect of thyrotropin Thyroid hormones and blood circulation Thyroxine-binding globulin Transthyretin Free thyroid hormones Transmembrane thyroid hormone Deiodination of iodothyronine Thyroid hormone action The hypothalamic
pituitary
thyroid axis Iodine deficiency Iodine toxicity Further reading

45 46 46 49 49 50 51 52 54 55 55 56 57 57 58 59 60 60 61

Iodine is a trace element that is naturally present in certain foods. It is added to other food sources and also available as a dietary supplement. It is an important component of the thyroid hormones. The secretion of thyroid-stimulating hormone (TSH) increases the thyroid’s uptake of iodine and stimulates synthesis and release of the thyroid hormones. When iodine is insufficient, TSH levels remain elevated, leading to enlargement of the thyroid gland (goiter). In food and iodized salt, iodine is present as sodium and potassium salts, inorganic iodine, iodate, and iodide, which are the reduced forms of iodine.

Iodine Iodine-deficiency diseases have been prevalent for centuries. The Chinese people ancient times described both cretinism and goiter. People of the Middle Ages, Europe, showed “cretins” as dwarfs, angels, and demons. Goiter was still common the early 1900s in the upper Midwest and other areas of the United States. The use Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00003-7

of in in of

r 2020 Elsevier Inc. All rights reserved.

45

46

Epidemiology of Thyroid Disorders

iodized salt was first demonstrated to greatly reduce goiter cases in 1922, when approximately 50,000 school children received it in their diets. As a result, table salt began to be fortified with iodine (I). However, even today in some areas of the world, iodine deficiency is still prevalent, and the WHO promotes universal salt iodization so that it can be eradicated. The best natural food source of iodine is seafood. Common sources of dietary iodine include cheese, cow milk, eggs, frozen yogurt, ice cream, iodine-containing multivitamins, iodized table salt, saltwater fish, seaweed, shellfish, soy milk, soy sauce, and yogurt. Focus on table salt versus sea salt and other forms Recent health trends have involved sea salt and Himalayan salt being substituted for traditional table salt. Making this change, however, is linked to iodine deficiency in the United States. A 2015 study by the American Association of Clinical Endocrinologists discusses a 50% decrease in iodine in the average American diet. Most of the manufacturers of sea salt and other types of salt do not voluntarily iodize their products. Since many Americans have reduced use of table salt, a large proportion of their dietary salt comes from its presence in commercially processed foods—which almost always contain noniodized salt.

Functions of iodine Iodine is a vital component of the thyroid hormones such as triiodothyronine (T3) and thyroxine (T4). These hormones control many different functions, including the regulation of basal metabolic rate, body temperature, growth, and reproduction. Triiodothyronine is approximately four times more portent than thyroxine. However, the thyroid releases about 93% thyroxine and only 7% triiodothyronine. After just a few days the body is able to convert most of the thyroxine into triiodothyronine, which is more active.

Iodine absorption and metabolism In foods a large amount of iodine is present in its reduced form, which is known as iodide, as well as iodate. An iodate is defined as a conjugate base of iodic acid, with examples, including sodium iodate, silver iodate, and calcium iodate. Nearly all iodine (95%
100%), regardless of form, is absorbed by the intestine. The human body contains between 15 and 20 mg of iodine, of which, 80% is found in the thyroid gland. Every day, this gland collects 60
120 µg of iodide, which will be incorporated into the thyroid hormones in the future. Iodide is oxidized by enzymes and then bounded to thyroglobulin—this is the storage form of the thyroid hormones. TSH causes the thyroid gland to cleave T3 and T4 from the thyroglobulin. Then, these hormones are released into the blood circulation. There are three different enzymes that convert the majority of the T4 to T3 throughout the body organs.

Iodine and thyroid hormones

These three enzymes depend upon adequate levels of selenium. This means that a selenium deficiency can cause inefficient use of iodine in the thyroid hormones. Most of the excess iodine is secreted by the kidneys via the urine. However, some iodine is lost in the sweat—primarily in climates that are hot and humid. The plasma only requires iodide in extremely low concentrations. Therefore cells of the thyroid gland must concentrate the needed amounts of iodide. This iodide trapping utilizes the sodium-iodide symporter (NIS) membrane protein, which is encoded by the sodium-iodide cotransporter (SLC5A) gene. In humans, NIS is a 643-amino acid glycoprotein that has 13 membrane-spanning domains. Iodide transport occurs as an active process based on the presence of sodium gradient across the basal membrane of each thyroid cell. The downward transport of two sodium ions causes the entry of one iodide atom against an electrochemical gradient (see Fig. 3.1). The sodium-iodide transporter is expressed in the basolateral membranes of thyroid cells and is also present in other cells that concentrate iodide. These include cells of the choroid plexus, salivary glands, lactating mammary glands, gastric mucosa, and in the

Hydrolysis

T4 T3

? 2 K+

MIT DIT

K+ Na/K-ATPase

3 Na+

Na+

1 I− 2 Na+

I−

DEHAL1

I− NIS

Tg Iodinated

I−

PDS

I−

NADP+

Na+

NADPH

DUOX2

Ca2+ H2O2

+

DUOX2A

cAMP TSH

I−

IP3

TSHR PLC D1

Capillary

Tg

AC DAG

D2

H +

TPO

O2 2 Tg Iodinated

Colloid

Figure 3.1 Schematic illustration of a follicular cell showing the key aspects of thyroid iodine transport and thyroid hormone synthesis.

47

48

Epidemiology of Thyroid Disorders

cytotrophoblast and syncytiotrophoblast. The ovary and testis also express NIS, as well as ovarian cancers, and most seminomas and embryonic testicular carcinomas. This protein is important in the concentration of iodide in breast milk, which supplies newborn babies with iodide so that their bodies can synthesize thyroid hormones. The iodide transport system creates an iodide gradient of 20
40 over the entire cell membrane. The NIS protein also transports pertechnetate, perchlorate, and thiocyanate. This explains how radioactive pertechnetate can be used in thyroid scans, as well as the ability of potassium perchlorate to block the uptake of iodide. The affinity of NIS for iodide is extremely high in comparison to other inorganic anions, including bromide and chloride. This identifies how selective the thyroid transport mechanism actually is. TSH increases transcription of the NIS gene and also lengthens the NIS protein half-life while targeting the protein to the cell membrane. The fact that the iodideconcentration mechanism is essential for normal thyroid function has been understood for many years. When absent, this is associated with congenital hypothyroidism and goiter—unless large amounts of inorganic iodide are administered. Many families have identified NIS gene mutations related to congenital hypothyroidism and defects in iodide transport. Decreases in NIS expression in thyroid adenomas and carcinomas have been well-documented. These contribute to loss of iodine uptake in neoplastic thyroid cells. These cells present as cold nodules during radioisotopic imaging studies. Changes in subcellular locations of NIS may also cause this to occur. Pendrin is an extremely hydrophobic membrane glycoprotein found at the apical membranes of thyrocytes. It may act as an apical iodide transport in cells of the thyroid. This substance is also expressed in the inner ear and kidneys. In the inner ear, it is required to generate the endocochlear potential. In the kidneys, it is important for acid
base metabolism, acting as an exchanger of chloride and bicarbonate. Pendrin is a part of the SLC26A family, encoded by the SLC26A4 gene. When this gene is mutated, it leads to Pendred syndrome. This autosomal recessive disorder is signified by goiter, sensorineural deafness, and defective iodide organification. The major phenotypic manifestation of Pendred syndrome is hearing impairment or deafness, while goiter is usually seen in childhood. Much variation exists between families and geographic areas. The chloride channel 5 (ClCn5) protein is believed to be involved in regulating apical iodide efflux or exchange of iodide and chloride. Intracellular iodide is also generated by actions of the DEHAL1 or iodotyrosine deiodinase (IYD) enzymes. Iodide is recycled via the actions of Dhal1 transcription and cyclic adenosine monophosphate (cAMP). Then, iodide is quickly reconjugated to newly synthesized thyroglobulin, after leaving the apical membrane of cells. The process is interrupted by the thioureas, a type of antithyroid drugs that inhibit thyroperoxidase, which include carbimazole, methimazole, and propylthiouracil. This interruption causes intrathyroidal iodine deficiency. Patients with elevated diiodotyrosine (DIT), goiter, and

Iodine and thyroid hormones

hypothyroidism may have mutations in homozygosity in the IYD gene. Mutations can stop IYD from being able to deiodinate monoiodotyrosine (MIT) and DIT.

Iodide oxidation Iodide inside the thyroid aids in reactions leading to synthesis of active thyroid hormones. The first reaction is when iodide is oxidated and incorporated into MIT and DIT, which are hormonally inactive iodotyrosines. This process is called organification. Iodide is usually oxidized quickly and appears immediately in organic combination with thyroglobulin. Iodination, which leads to the formation of iodotyrosines, takes place in thyroglobulin but not in free amino acids. The heme-containing protein thyroid peroxidase (TPO) mediates oxidation of thyroidal iodide. This requires hydrogen peroxide (H2O2) that is generated by the dual oxidase (DUOX1 and DUOX2) enzymes that require calcium. The TPO protein has a membrane-spanning region close to the carboxy-terminus. It is positioned in the apical membranes of thyroid cells with residues 1
844 within the follicular lumen where iodination takes place (see Fig. 3.1). The major thyroid microsomal antigen is TPO. Recombinant human TPO is used to detect antithyroid microsomal antibodies often present in the serum of Hashimoto thyroiditis patients. Thyroid hormone synthesis requires the actions of hydrogen peroxide. The speed of organic iodination depends on the amount of thyroid stimulation by TSH. When there are congenital defects of the organic-binding mechanism, goitrous congenital hypothyroidism may be caused, or in less severe cases, goiter without hypothyroidism. Thyroidal TPO may be absent in some families. Focus on iodine and iodide

The word iodine comes from the Greek word iodedes, which means “violet colored.” Iodide (I2) is the colorless negative ion of iodine. In the body, iodine either circulates bound to protein or as free iodide ions. Sodium and potassium iodide are iodide salts, commonly used in medicines.

Iodothyronine formation The active thyroid hormones have MIT and DIT as their precursors. The synthesis of thyroxine from DIT requires a fusion of two DIT molecules, catalyzed by TPO. This creates a structure having two deiodinated rings that are linked by an ether bridge, known as the coupling reaction. At the same time a residual dehydroalanine forms at the site of the DIT residue and contributes to the phenolic hydroxyl group. In the thyroid, correct synthesis of the thyroid hormones requires thyroglobulin. Its messenger RNA (mRNA) encodes a subunit that is just 10% carbohydrate by weight. There are three or four thyroxine molecules in every molecule of human thyroglobulin, when iodination is normal. However, there is only one in five molecules of human

49

50

Epidemiology of Thyroid Disorders

thyroglobulin containing a triiodothyronine residue. In untreated Graves’ disease the thyroglobulin has a content of thyroxine residues that are about the same. However, the amount of triiodothyronine residues are doubled, to about 0.4 per molecule. This is based on the iodination amounts of the thyroglobulin and occurs from thyroidal stimulation. Since the coupling reaction is catalyzed by TPO, nearly all organicbinding inhibitors, such as the thiourea drugs, also inhibit coupling.

Thyroid hormone storage and release Compared to other endocrine glands, the thyroid contains very large amount of thyroid hormones but only “turns over” the hormones at about 1% per day. This aids in homeostasis, since the reservoir gives prolonged protection, whereas depletion of circulating hormones should synthesize a stop. For normal patients, administration of antithyroid agents for up to 2 weeks will have only a slight effect upon serum thyroxine concentrations. In the normal human thyroid, there are about 250 µg of thyroxine per gram of net weight, which is equivalent to 5000 µg of thyroxine in a thyroid weighing 20 g. This is enough to maintain euthryoidism for at least 50 days. During subacute or painless thyroiditis, when released quickly and uncontrolled, this amount of thyroxine will cause extensive and transient thyrotoxicosis. Thyroglobulin is present in normal plasma, in concentration as much as 80 ng/mL. It likely leaves the thyroid via the lymphatics. Peripheral hydrolysis of thyroglobulin does not greatly contribute to the circulating thyroid hormones—even in thyroiditis, when large amounts are present. For thyroid hormone release the initial step is endocytosis of colloid from the follicular lumen. This requires two processes, which are as follows: • Macropinocytosis—by pseudopods formed at the apical membrane • Micropinocytosis—by small and coated vesicles formed at the apical surface (see Fig. 3.1) TSH stimulates both processes. In humans the micropinocytosis process dominates. After endocytosis the vesicles fuse with lysosomes. Proteolysis is catalyzed by cathepsin D and D-like thiol proteases. These are all active at the acidic pH of the lysosome. Iodotyrosines released from thyroglobulin are quickly deiodinated by nicotinamide adenosine dinucleotide phosphate
dependent IYD. The released iodine is then recycled. Thyroid hormones are released from thyroglobulin in the lysosome. It is not completely understood how the transfer of hormones occurs into the cytosol and then into the plasma. Monocarboxylate transporter 8 (MCT8) may be involved at the exit of thyroid hormones from the thyroid cell or the phagolysosome. Studies have shown that thyroxine can be released from thyroglobulin in the thyroid cells without greatly disrupting its molecular weight. This may be due to selective proteolysis that occurs because major hormonogenic peptides of thyroglobulin are found at the aminoterminus and at the carboxy-terminus of the thyroglobulin monomer.

Iodine and thyroid hormones

Deiodinases in thyroid-derived cells can regulate systemic conversion of thyroxine to triiodothyronine in patients with metastatic thyroid carcinoma. Thyroxine released from thyroid cells is inhibited by iodide and several other agents. Inhibition causes rapid improvement effected by iodide in hyperthyroid patients. Though not fully understood, iodide inhibits stimulation of thyroid adenylate cyclase by TSH and by stimulatory immunoglobulin seen in Graves’ disease. Increased iodination of thyroglobulin increases its resistance to hydrolysis by the acid proteases in lysosomes. Lithium inhibits the release of thyroid hormones but possibly in a different way than that of iodide.

Dietary iodine For normal amounts of thyroid hormone to be formed, there must be enough exogenous iodine available to allow the thyroid to uptake about 60
75 µg every day. This considers that there are fecal losses of 10
20 µg of iodine of iodothyronines, as glucuronides, and 100
150 µg as urinary iodine in people who are iodine sufficient. In biologic solutions, plasma iodide (I2) is the form of the element. It is totally filtered with 60%
70% of the filtered load passively reabsorbed. To eliminate all signs of iodine deficiency, 100 µg or more of iodine are required per day. Table 3.1 shows recommended and common values for dietary iodine intake. For healthy adults, iodide absorption is more than 90%. The North American daily intake of 75
300 µg is mostly due to iodination of salt. This contrasts with Japan, where the diet includes many foods rich in iodine, resulting in intake as high as several milligrams per day. Due to a reduction in salt consumption in the United States, iodine intake is decreasing. There is a median urinary iodine of 160 µg/L, but a low urinary iodine of less than 5 µg/dL in 11% of the population. Throughout the world, daily iodine intake is varied because of its presence in soil and water, as well as in the diet. Iodine can also be consumed in diagnostic agents, medications, dietary supplements, and food additives. Iodine deficiency is most common in mountainous and previously glacial regions. It is estimated that 1 billion people live in iodine-deficient areas. They often develop endemic goiter that is Table 3.1 Recommended and common values for dietary iodine intake. Recommended daily intake

Common iodine daily intake

Adults—150 µg In pregnancy—200 µg Children—90
120 µg

North America—75
300 µg Belgium—50
60 µg Chile—less than 50
150 µg Germany—20
70 µg Switzerland—130
160 µg

51

52

Epidemiology of Thyroid Disorders

TSH-induced compensatory enlargement of the thyroid. Severe iodine deficiency during pregnancy causes reduced fetal thyroid hormone production and extensive damage to the developing central nervous system (CNS). Various degrees of mental retardation occur, which are described as endemic cretinism. Therefore iodine-deficiency disorders are the most common thyroid-related illnesses in humans and the most common endocrine condition worldwide. Plasma iodide can be partially replenished by the amounts lost from the thyroid into the blood and by iodide freed through peripheral tissue deiodination of iodothyronines. The diet is the most important source, however, as iodine is consumed in inorganic and organically bound forms. Iodide is quickly and well absorbed within 30 minutes from the gastrointestinal (GI) tract, and only slightly lost in feces. It is also present in red blood cells and concentrated in the GI tract’s intraluminal fluids such as the saliva and gastric juice—from which it is reabsorbed to reenter the extracellular fluid. It is also concentrated in breast milk. Until it is oxidized and bound to the tyrosyl residues in thyroglobulin, iodide that enters the thyroid via active transport is in rapid equilibrium with primary iodide pools. Concentrations in the extracellular fluid are usually 10
15 µg/L. Contents in the peripheral pools are about 250 µg. The largest amount of iodine is in the thyroid—usually about 8000 µg, which is mostly in the form of DIT and MIT. Selected food sources of iodine are summarized in Table 3.2. Focus on iodination of salt Fortification of salt with iodine has been one of the most successful nutrition interventions to date. It has led to an increase in I.Q. points and significant decline in the prevalence of iodine deficiency disorders such as goiter.

The effect of thyrotropin The TSH secreted by the thyrotrophs of the pituitary gland stimulates every step in the formation and release of thyroid hormones. The thyroid cells express the TSH receptor (TSHR) that is a part of the glycoprotein G protein
coupled receptor family. The protein has a large extracellular amino-terminal domain as well as seven membrane-spanning domains. It also has an intracellular domain transducing signals by promoting exchanges of guanosine diphosphate with guanosine triphosphate on the alpha-subunit of G proteins. Induction of signaling via phospholipase C and intracellular calcium ion pathways regulates hydrogen peroxide production, iodide efflux, and thyroglobulin iodination. The signal via protein kinase A pathways, regulated by cAMP, results iodine uptake and transcription of thyroglobulin, TPO, and the NIS mRNAs, resulting in thyroid hormone production. The thyroid cell functions promoted by thyrotropin are listed in Table 3.3.

Table 3.2 Selected food sources of iodine. Food source

Approximate micrograms per serving

Percent of daily value (%)

Seaweed, sheet or whole, 1 g Cod, baked, 3 oz Yogurt, plain, low-fat, one cup Iodized salt, 1.5 g (about one-fourth teaspoon) Milk, reduced fat, one cup Fish sticks, 3 oz Bread, white, enriched, two slices Fruit cocktail, in heavy syrup, canned, half cup Shrimp, 3 oz Ice cream, chocolate, half cup Macaroni, enriched, boiled, one cup Egg, one large Tuna, canned, in oil, drained, 3 oz Corn, cream style, canned, half cup Prunes, dried, five prunes Cheese, cheddar, 1 oz Raisin bran cereal, one cup Lima beans, mature, boiled, half cup Apple juice, one cup Green peas, frozen, boiled, half cup Banana, one (medium)

16
2984 99 75 71

11
1989 66 50 47

56 54 45 42

37 36 30 28

35 30 27 24 17 14 13 12 11 8 7 3 3

23 20 18 16 11 9 9 8 7 5 5 2 2

Table 3.3 Thyrotropin-stimulated thyroid cell functions. Function

Mechanism

Iodide metabolism

Increased I2 in follicular lumen Delayed increase in NIS expression Increased thyroid blood flow Increased I2 efflux from thyroid cell

PLC cAMP Increased nitric oxide synthesis and decreased cellular iodide Not understood

Thyroid hormone synthesis

Hydrogen peroxide Thyroglobulin and TPO synthesis NADPH via pentose-phosphate pathway

PLC cAMP Not understood

Thyroid hormone secretion

Pinocytosis of thyroglobulin Thyroglobulin release into plasma via basolateral membrane Mitogenesis

cAMP cAMP (not fully understood) cAMP, PLC, and IGF— I2 and FGF-mediated kinase activation

cAMP, Cyclic adenosine monophosphate; FGF, follicular growth factor; IGF, insulin-like growth factor; NADPH, nicotinamide adenosine dinucleotide phosphate; NIS, sodium-iodide symporter; PLC, phospholipase C; TPO, thyroid peroxidase.

Epidemiology of Thyroid Disorders

Precise mechanisms of receptor activation and early events of TSHR signal transduction are not completely understood. Interactions between the ectodomain and extracellular loops of transmembrane domains in the TSHR may be required for maintaining an inactive state without constitutive activity. When these are removed, there is an open conformation. It is believed that TSHR exists in a closed or inactive and an open or active format. Therefore the open receptor format would be able to bind ligand and be activated. Truncation of the TSHR ectodomain and its constitutive activation suggests that its presence reduces constitutively active alpha-subunits.

Thyroid hormones and blood circulation In the peripheral tissues, metabolic transformation of thyroid hormones determines how biologically potent they will be and how their biologic effects will appear (Fig. 3.2). Many iodothyronines and their metabolic derivatives are present in the plasma. Thyroxine is the one that is in highest concentrations. It is the only one due 80 Serum T3 ng/100 mL

60

LID + KI LID

40 20

0 Serum T4 µg/100 mL

LID + KI 4

2

LID

0 Serum TSH ng/mL

54

2000

LID

1000 LID + KI 0 0

10

20

30

Days on LID

Figure 3.2 Effects of acute depletion of dietary iodine on serum T3, T4, and thyroid-stimulating hormone (TSH).

Iodine and thyroid hormones

to direct thyroid gland secretion. Normally, triiodothyronine is also released by the thyroid, but about 80% is from the peripheral tissues, via enzymatic removal of one 50 iodine atom from thyroxine.

Thyroxine-binding globulin Thyroxine-binding globulin (TBG) is a glycoprotein that has a molecular mass of approximately 54 kDa of which about 20% is carbohydrate. It is encoded by a 3.8-kb transcript on the X chromosome. The TBG protein sequence is similar to that of the serpin family of serine antiproteases. Since there is one iodothyronine binding site on every TBG molecule, the thyroid hormone
binding capacity of TBG in normal serum is equivalent to its concentration. This is about 270 nmol/L or 1.5 µg/dL. There is a half-life of the protein in plasma of about 5 days. Often TBG is congenitally deficient, which occurs in 1 of every 5000 newborns. This is related to a complete absence of the protein in meals. The synthesis of TBG is blocked by L-asparaginase, accounting for low thyroxine concentrations in patients receiving this substance. Glycosylation of TBG affects its clearance from the plasma, and how it acts during isoelectric focusing. In patients receiving estrogen, there is increased prevalence of the more acidic TBG bands. Highly sialylated TBG is cleared slower from the plasma than positively charged TBG. This is because sialylation inhibits the liver’s uptake of glycoproteins. In pregnant patients, women taking oral contraceptive, and patients with acute hepatitis, the serum has increased fractions of acidic TBG. In inherited TBG excess, there are normal amounts of highly sialylated TBG. This is also true in men and nonpregnant women. Since TBG is the main thyroid hormone
binding protein, changes to TBG or its binding are reflected by similar changes in total plasma thyroid hormone levels, even when their production is not significantly altered. The TBG also affects after translation following cardiopulmonary bypass surgery or in septic patients. It is subjected to cleavage by a serine protease from the polymorphonuclear leukocytes. A similar reaction occurs for cortisol-binding globulin, releasing cortisol at the site of inflammation. Released thyroxine may be critical for the response to injury, possibly by supplying iodine for antibacterial needs.

Transthyretin Transthyretin (TTR) is part of a complex with vitamin A
binding protein, which is also called retinol-binding protein. It has four identical polypeptide chains and a total molecular mass of about 55 kDa. TTR is not glycosylated. It is present in the plasma at concentrations of about 4 mmol/mL or 250 µg/mL. Every mole of TTR binds 1 mol of thyroxine with high affinity. A second thyroxine molecule is bound, with lower affinity, at high concentrations of thyroxine. Its plasma half-life is usually about 2 days, though this decreases during illnesses. TTR is expressed in the choroid plexus.

55

56

Epidemiology of Thyroid Disorders

It is the primary thyroid hormone
binding protein in the cerebrospinal fluid (CSF). High levels exist in fetal serum, which is probably produced directly by the placental cells. There is no impaired uptake of thyroxine into the brain. The role of TTR in the CSF is not completely understood regarding thyroid physiology. Familial amyloidotic polyneuropathy is related to variant forms of TTR. In some families the TTR monomer may have one of several point mutations. The TTR accumulates within amyloid tissue deposits. There have been no reports of thyroid dysfunction or altered metabolism of vitamin A. However, there is altered affinity of some mutant proteins for thyroxine. Families having high-affinity TTR have been reported, as have fewer families having increased TTR levels.

Free thyroid hormones Most circulating thyroid hormones are bound to thyroid-binding globulin, so its amount of saturation and its concentration mostly determine the free amounts of thyroxine. The metabolism of plasma proteins is altered by the binding of the thyroid hormones. The slight urinary excretion of these hormones is related to minimal filtering of hormone-binding protein complexes in the glomerulus. Interaction between thyroid hormones and binding proteins, in vitro, follows a reversible binding balance. Normal serum has thyroxine that is about 0.02% of the total. This is approximately 20 pmol/L or 1.5 ng/dL. There is a nearly 20 times lower affinity of TBG for triiodothyronine, resulting in a larger proportion of unbound T3, or about 0.30%. The free hormone available to body tissues for intracellular transport and feedback regulation is what causes its metabolic effects. It also goes through deiodination or degradation. Bound hormone acts as a reservoir. The concentration of free hormone determines the metabolic state and is defended by homeostatic activities. When a change in TBG occurs, free thyroid hormone concentrations can be regulated to remain at normal levels only if bound hormone changes the same way. An example is when TBG is increased by administering estrogen. The free thyroxine reduction reduces its clearance and allows and increases the total thyroxine concentration in the plasma. This eventually normalizes free thyroxine at a new equilibrium. There is no change in its secretion rate. Transiently decreasing free thyroid hormones slightly reduces negative feedback on the hypothalamic
pituitary
thyroid axis. This causes increased thyroid hormone production as an additional compensation and is called the free thyroid hormone hypothesis. Protein binding allows distribution of the hydrophobic thyroid hormones everywhere in the vascular system. Influx and efflux of thyroid hormone from the tissues are fast. Intracellular free thyroid hormones are in equilibrium with the plasma’s free hormone pool. This is true despite transporter activity and metabolism influencing the ratio’s magnitude. Therefore the rate of thyroid hormone metabolism is rate-limiting in the exit of the hormones from the plasma and not the dissociation rate from plasma proteins.

Iodine and thyroid hormones

OATP1C1 MCT8

T2 Astrocyte

T4

T4

D2

T3

D3

T3

T3

?

+TR T3 responsive gene

Neuron Blood-brain barrier

Figure 3.3 Potential pathways for entry of T3 into the central nervous system. Thyroid hormones are transported through the blood–brain barrier or the blood–cerebrospinal fluid (CSF) barrier.

Transmembrane thyroid hormone Cellular uptake and efflux of thyroid hormones are regulated by transporter proteins. The potential pathways for entry of T3 into the CNS are shown in Fig. 3.3. Today there is increasing evidence that tissue-specific and generalized iodothyronine transporters exist, which belong to many transporter protein families. They each have many forms with small structural variations that alter uniqueness of target substances. In most of the body cells, about 90% of intracellular T3 is found in the cytosol. This is not true in the pituitary gland, where about 50% of intracellular T3 is found in the nucleus. There may be an active transport of thyroid hormones in and out of the nucleus and also between other intracellular compartments. Mucrystallin, an intracellular T3-binding protein, is expressed at high levels in the brain and heart, yet is widely distributed. It may, along with similar proteins, actively help in subcellular localization of active hormone.

Deiodination of iodothyronine The primary pathway for thyroxine metabolism is its outer ring (50 ) monodeiodination to active T3. The reaction is catalyzed by the D1 and D2 deiodinases and supplies

57

58

Epidemiology of Thyroid Disorders

En

do

pla

D2

sm

ic

ret

icu

lum

Nucleus

GRX

GSH TRX D3 GSH

Catalytic center D1

Figure 3.4 Predicted geometric changes of the three iodothyronine deiodinases, which are integral membrane proteins that require a thiol cofactor for catalytic activity.

more than 80% of circulating T3. An inactivating step called inner ring deiodination is primarily catalyzed by D3. This inactivates T3 and prevents activation of thyroxine by converting it to reverse triiodothyronine (rT3). The three human deiodinases are similar in structure. They are homodimers and integral membrane proteins, requiring a thiol cofactor for successful catalysis (see Fig. 3.4). In their active catalytic centers, they contain the rare amino acid selenocysteine. This substance has nucleophilic properties, making it perfect for catalysis of oxidoreductive reactions. These reactions include iodothyronine deiodination and reduction of hydro peroxide by the glutathione peroxidases, which are another family of the selenoenzymes. Selenium is believed to be the iodine acceptor in deiodination reactions. The mutagenesis of selenocysteine in D1 to cystine involves replacing selenium with sulfur. This reduces enzyme velocity by about 200 times. The presence of selenocysteine means more than just catalytic activity. The cellular processes that synthesize selenoproteins are inefficient and very complicated. They occur by combining a structural selenocysteine insertion sequence (SECIS) into the 30 -untranslated region of the mRNAs that encode these proteins. There is also a specific group of selenocysteine incorporating gene products. Together, these elements are needed for complex cellular functions, in which the normal STOP codon UGA is the specific codon for inserting selenocysteine residue as protein translation is occurring.

Thyroid hormone action The mechanism of thyroid hormone action is by binding to a specific nuclear transport receptor. This then binds to DNA, usually as a heterodimer, with retinoid X receptor (RXR) at certain sequences. These sequences are thyroid hormone response elements

Iodine and thyroid hormones

rT3

D3

D3

T4

T4

D2

T3

Local T3 Plasma T3

T3

T3

Nucleus D3 D3

T2

Capillary Target tissue

Figure 3.5 Schematic diagram of thyroid hormone activation and inactivation in a cell expressing the iodothyronine deiodinases D2 and D3.

(TREs) that are controlled by the DNA binding-site preferences of the RXR
TR (or TR
TR) (thyroid receptor) complex. This is illustrated in Fig. 3.5. Note that T3 has a 15 times higher binding affinity for TRs than T4. This explains its function as the active thyroid hormone. There are two human TR genes: TR-alpha is found on chromosome 17, while TR-beta is found on chromosome 3. Alternatively spliced gene products from each gene form active as well as inactive gene products. The active proteins are TR-alpha1 and TRs beta1, beta2, and beta3. There are three major functional domains in the TR protein structure. One binds DNA, one binds ligand, and there is also a primary transcriptional activation domain in the carboxy-terminus. Tissue-specific preferences exist in expression of the TRs. This may mean that they have different functions in varying tissues. TR-alpha1 mRNA is expressed in the brain, brown adipose tissue, GI tract, skeletal muscles, heart, and lungs.

The hypothalamic
pituitary
thyroid axis There is a classical feedback control loop in which the thyroid works with the hypothalamus and pituitary gland (see Fig. 3.6). There is also an inverse relationship

59

60

Epidemiology of Thyroid Disorders

T4 + T3(−)

(D2) T4 T3

Hypothalamus TRH (+) SRIH (−)

T4 T4 + T3 T, L, K (D1) T T, SM, CM (D2) 4

(D2) T3(−) T3(−)

T3

Pituitary

TSH (+)

T4 (T3) D1 + D2

Thyroid

Figure 3.6 Roles of T4 and T3 in the feedback regulation of secretion of thyroid-regulating hormone (TRH) and thyroid-stimulating hormone (TSH).

between thyroid iodine levels and the fractional rate of hormone formation. These autoregulatory mechanisms stabilize hormone synthesis rates, regardless of changes in available iodine. Stabile hormone production is partly achieved due to the large stores of intraglandular hormone. These buffers affect the acutely increasing or decreasing hormone synthesis. Then, autoregulatory mechanisms in the thyroid gland usually maintain a constant pool of hormones. The hypothalamic
pituitary feedback mechanism then senses changes in availability of free thyroid hormones and attempts to correct them. The hypothalamus, anterior pituitary, thyroid, and higher brain centers closely interact. The entire complex’s functions are modified via negative feedback by thyroid hormones that are available. Other hormones and neuropeptides also affect this axis.

Iodine deficiency Iodine deficiency has been linked to the development of goiters since 1830. Since iodine deficiency inhibits thyroid hormone synthesis, when the body responds to a low amount of thyroid hormones, TSH is produced in greater levels. This causes the thyroid gland to enlarge, eventually becoming a goiter. Iodine deficiency is discussed in greater detail in Chapter 4, Iodine deficiency and goiter.

Iodine toxicity Since large amounts of iodine inhibit the synthesis of thyroid hormones, while stimulating thyroid gland growth, iodine toxicity can also cause goiter. The most common cause of iodine toxicity is overuse of supplements. It is very important to balance

Iodine and thyroid hormones

iodine supplements against risks for iodine-induced hyperthyroidism—especially where severe iodine deficiency is prevalent. The tolerable upper intake level (UL) of iodine is 1100 µg every day.

Key terms coupling reaction cytotrophoblast ectodomain endemic goiter goitrogens homodimers iodide iodide transport system kilobase kilodaltons mucrystallin organification

pendrin picomoles selenium serpin sialylated syncytiotrophoblast thioureas thyroglobulin thyroid-stimulating hormone (TSH) thyroxine (T4) transthyretin triiodothyronine (T3)

Further reading 1. Al-Mudhaffar, S.A. The Mechanism of Biochemical Action of Thyroid Hormones: Thyroid Hormones in Action. (2016) CreateSpace Independent Publishing Platform. 2. Bao, S., and Winter, B. Thyroid Nodules: Questions From Real Patients. (2018) ACE Health Publisher. 3. Beck-Peccoz, P. Syndromes of Hormone Resistance on the Hypothalamic-Pituitary-Thyroid Axis (Endocrine Updates Book 22). (2004) Springer. 4. Blokdijk, G.J. Thyrotropin Alfa; Complete Self-Assessment Guide. (2018) CreateSpace Independent Publishing Platform. 5. Brownstein, D. Iodine: Why You Need It, Why You Can’t Live Without It, 5th Edition. (2014) Medical Alternatives Press. 6. Carmen, A. Thyroid Support Supplement Guide. (2018) CreateSpace Independent Publishing Platform. 7. Conn, P.M. Cellular Regulation of Secretion and Release (Cell Biology). (2013) Academic Press. 8. El-Fattah, H.S.A. Thyroid Patients’ Problems & Needs With Radioactive Iodine Therapy. (2014) Lap Lambert Academic Publishing. 9. Farrow, L., and Brownstein, D. The Iodine Crisis: What You Don’t Know About Iodine Can Wreck Your Life. (2013) Devon Press. 10. Greep, R.O. Recent Progress in Hormone Research, Volume 32. (2013) Academic Press. 11. Icon Group International. Iodothyronine: Webster’s Timeline History, 1954-2007. (2010) Icon Group International, Inc. 12. Icon Group International. Transthyretin: Webster’s Timeline History, 1983-2007. (2010) Icon Group International, Inc. 13. Imam, S.K., and Ahmad, S. Thyroid Disorders: Basic Science and Clinical Practice. (2016) Springer. 14. Insel, P., Ross, D., McMahon, K., and Bernstein, M. Nutrition, 5th Edition. (2013) Jones & Bartlett Learning.

61

62

Epidemiology of Thyroid Disorders

15. Institute of Medicine, et al. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. (2002) National Academies Press. 16. Kurdybacha, P. Iodine, Nutrition, and Thyroid Dysfunction With a Descriptive Epidemiology of Benign Thyroid Disease Outpatients Treated With Radioiodine 131 From 2000-2010. (2017) White Falcon Publishing. 17. Lougheed, B.S. Tired Thyroid: From Hyper to Hypo to Healing
Breaking the TSH Rule. (2014) CreateSpace Independent Publishing Platform. 18. Neilson, A.H. Organic Bromine and Iodine Compounds (The Handbook of Environmental Chemistry), Volume 3. (2003) Springer. 19. Pearce, E.N. Iodine Deficiency Disorders and Their Elimination. (2017) Springer. 20. Richardson, S.J., and Cody, V. Recent Advances in Transthyretin Evolution, Structure and Biological Functions. (2009) Springer. 21. Robinson, P. Recovering With T3: My Journey From Hypothyroidism to Good Health Using the T3 Thyroid Hormone, 2nd Edition. (2018) Elephant in the Room Books. 22. Salter, W.T. The Endocrine Function of Iodine (Harvard University Monographs in Medicine and Public Health). (2014) Harvard University Press. 23. Stanbury, J.B. The Iodine Trail: Exploring Iodine Deficiency and Its Prevention Around the World. (2008) Farber Public Relations. 24. Van Dyke, H.B. A Study of the Distribution of Iodine Between Cells and Colloid in the Thyroid Gland. (2012) Ulan Press. 25. Wirth, T., Kita, Y., Koser, G.F., Ochiai, M., Tohma, H., Varvoglis, A., et al. Hypervalent Iodine Chemistry
Modern Developments in Organic Synthesis (Topics in Current Chemistry). (2003) Springer.

CHAPTER 4

Iodine deficiency and goiter Contents Iodine deficiency: a global health problem Epidemiology Risk factors Management Complications Goiter Diffuse nontoxic goiter Nontoxic multinodular goiter Toxic multinodular goiter Amyloid goiter Epidemiology Pathogenesis and etiology Clinical presentation Diagnosis Treatment Clinical cases Case 1 Case 2 Case 3 Further reading

66 68 70 71 72 73 74 77 79 79 80 81 82 83 84 84 84 85 85 86

Throughout the world, iodine deficiency is a major public health issue—especially for pregnant women and young children. The most serious outcomes are higher perinatal mortality rates and mental retardation. Iodine deficiency is the most significant cause of brain damage in children, which is preventable. The most visible manifestation of iodine deficiency is goiter, prevalence of which is found to be high. A goiter is a swelling in the neck resulting from an enlarged thyroid gland. It can be associated with a thyroid that is not functioning properly. The degree of thyroid enlargement is proportional to the level and duration of thyroid hormone (TH) deficiency. Goiters are broadly divided into two types: diffuse nontoxic and multinodular. Worldwide, over 90% of goiter cases are caused by iodine deficiency.

Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00004-9

r 2020 Elsevier Inc. All rights reserved.

65

66

Epidemiology of Thyroid Disorders

Iodine deficiency: a global health problem The primary factor that causes iodine deficiency is a low dietary supply of iodine. This is most common in areas where the soil has a low content of iodine, caused by significant temperature changes and effects of heavy rainfall and snowfall. When populations in these areas grow crops, the soil cannot provide enough iodine for them. Iodine in the human body is primarily present in the thyroid gland, but even in this location, the amounts of iodine are very small. The thyroid gland primarily serves to synthesize THs. Iodine deficiency causes impaired TH synthesis, and the common symptoms of hypothyroidism. These include cold intolerance, sluggishness, decreased body temperature, and weight gain. The body’s reactions to iodine deficiency also occur at the hypothalamic, pituitary, and peripheral tissue levels. A group of functional abnormalities known as iodine deficiency disorders (IDD) may develop (see Table 4.1). When iodine is insufficient in the diet, there is a quick decrease in serum thyroxine concentrations, with a simultaneous increase in serum thyroid-stimulating hormone (TSH) (Fig. 4.1). However, there is no identifiable decrease in triiodothyronine. This may indicate that the signal that increases TSH is derived from a decrease in triiodothyronine generated intracellularly from thyroxine in the pituitary, hypothalamus, or Table 4.1 Iodine deficiency disorders. Age-group

Disorders

Fetuses

Abortion Congenital anomalies Deaf mutism Endemic cretinism Increased perinatal mortality Stillbirth Endemic mental retardation Increased susceptibility of thyroid to nuclear radiation Neonatal goiter Neonatal hypothyroidism Goiter Impaired mental function Increased susceptibility of thyroid to nuclear radiation Retarded physical development Subclinical hyperthyroidism or hypothyroidism Goiter, with complications Hypothyroidism Impaired mental function Increased susceptibility of thyroid to nuclear radiation Iodine-induced hyperthyroidism Spontaneous hyperthyroidism in the elderly

Neonates

Children and adolescents

Adults

Iodine deficiency and goiter

HO

I O

MIT 3-Monoiodotyrosine HO

DIT 3,5-Diiodotyrosine

HO

OH

H

Glucuronidation (T4G)

O

I

OH Sulfation (T4S)

NH2 3,5,3′,5′-Tetraiodo-L-thyronine (Thyroxine, T4)

O OH

Inactivation via D1

NH2

Precursors

I H

I H

O I

NH2

I

Biliary excretion

I

D2

D1

D3

I

I O

HO

HO

I

O

O

I H

I O

I OH

NH2 3,5,3′-Triiodo-L-thyronine (T3)

D3

H

OH

NH2 3,3′,5′-Triiodo-L-thyronine (reverse T3) D2

D1

I HO

O

I O H

OH

NH2 3,3′-Diiodo-L-thyronine (T3)

Figure 4.1 Major pathways of thyroid hormone metabolism.

both. During pregnancy, a severe iodine deficiency increases the risks of prenatal death. It may also result in birth defects, cretinism, and death of the infant. In cretinism, most-affected children have poor development and growth and are unable to hear or speak. Mental retardation is common. Goitrogens are compounds that block the body’s ability to absorb and use iodine. They are contained in large amounts in cassava, cabbage, rutabagas, and turnips. When these foods are consumed uncooked, the goitrogens are absorbed. However, cooking inactivates the goitrogens. Therefore conditions linked to iodine deficiency are common in developing countries that have low consumption of iodine and where these vegetables make up a large part of the diet. Other food sources of goitrogens include lima beans, linseed, sorghum, sweet potato, kale, cauliflower, broccoli, soy, and millet. Additional sources of goitrogens include sulfurated organics, flavonoids, phenol derivatives, pyridines, phthalate esters and metabolites, biphenyls, various insecticides, polycyclic aromatic hydrocarbons, excessive inorganic iodine, and lithium.

67

68

Epidemiology of Thyroid Disorders

Focus on iodine and fetal development Iodine is one of the most important minerals required by a fetus for brain and cognitive development. However, the content of iodine in most of the foods and beverages is low. About 18 million babies are born mentally impaired, due to maternal iodine deficiency, with 38 million born at risk of iodine deficiency.

Epidemiology Worldwide, iodine deficiency is very common, primarily in undeveloped countries (Fig. 4.2). However, it has reemerged in many developed countries, with increases in low maternal iodine status in areas believed to be iodine-sufficient. More than 70 countries, including the United States, have salt-iodization programs. Approximately 90% of households in this country use iodized salt. However, worldwide, this figure is only 70%. In Europe and the Eastern Mediterranean regions, it is as low as 50% of households. Over the past 45 years, iodine deficiency in developed countries has increased by more than four times. Nearly 74% of normal and healthy adults may no longer consume enough iodine. Iodine is extremely critical in the early developmental stages, with the fetal brain depending upon sufficient iodine. In 2017 about 38 million babies were born globally with iodine deficiency. In severely iodine-deficient areas of the world, there has been a recorded loss of an average of 13.5 intelligence quotient points. As of 2010, World Health Organization (WHO) estimated that iodine deficiency resulting in goiter occurred in 187 million people worldwide. Iodine deficiency is most common in Africa, Southeast Asia, and the Western Pacific countries. In severely endemic locations, cretinism may affect up to 5% 15% of the population. Some affected nations, such as China and Kazakhstan, have begun taking action to combat the condition.

Figure 4.2 Worldwide prevalence of iodine deficiency (darker colors indicate more deficiency).

Iodine deficiency and goiter

Others, such as Russia, have not done so. The cost of adding iodine to dietary salt is very inexpensive. They believed that the reason for the increase in iodine deficiency in developed countries involves reductions in salt consumption and changes in dairy processing practices, which eliminate the use of iodine-based disinfectants. Australia and New Zealand have also seen increased prevalence of this condition. In one study of the United Kingdom in 2011, nearly 70% of test subjects were iodine deficient. Recent studies have shown links between iodine deficiency and obesity, psychiatric disorders, fibromyalgia, and even cancer. According to the Iodine Global Network (IGN), because of sustainable universal salt-iodization programs, iodine deficiency is on the verge of being eliminated. At the end of 2017, there were only 19 countries classified as having insufficient iodine intake. This is down from 54 countries in 2003 and 113 countries in 1993. The IGN is working to reach countries that are still vulnerable to iodine deficiency. They are extending their efforts worldwide to support the most vulnerable populations—especially pregnant women. Nineteen countries still vulnerable to iodine deficiency are Angola, Burkina Faso, Burundi, Finland, Haiti, Israel, Italy, Korea, Democratic People’s Republic of Lebanon, Mali, Madagascar, Mozambique, Russia, Samoa, South Sudan, Sudan, Ukraine, Vanuatu, and Vietnam. However, in Norway, a country no longer termed “vulnerable,” a 2018 study of about 1000 pregnant women showed iodine deficiency to be significantly high. This data was collected multiple times during their pregnancies, with follow-up until their infants reached 18 months of age, and the deficiency was still present. Over the past 25 years, more than 750 million new cases of goiter have been prevented. In North America, iodine intake is classified as optimal at the population level. The median concentrations of urinary iodine in the populations of the United States, between 1971 and 2002, are summarized in Fig. 4.3. This data is from the National Health and Nutrition Examination Survey.

Urinary iodine (ng/mL)

500 400 300 200 100 0 Total population

Children 6–11 years

1971–1974

Women 20–39 years 1988–1994

Persons 60 years and older 2001–2002

Figure 4.3 Median concentrations of urinary iodine in the United States, 1971 2002.

69

70

Epidemiology of Thyroid Disorders

Primary sources of dietary iodine in the United States and Canada have been milk and other dairy products for many years. Sales of iodized salt are low in the United States. There has been a rise in the popularity of dairy alternatives such as soymilk, which can affect iodine nutrition. In 2017 the IGN worked to increase awareness of iodine nutrition among medical providers and the general public. They also advocated for the inclusion of iodine nutrition in medical guidelines and recommended that iodine to be included in all prenatal vitamins. Recent data shows that pregnant women in the United States may be slightly iodine deficient. Nearly all countries in Central America and the Caribbean have established and sustained salt-iodization programs. In South America in 2016, iodine deficiency was virtually eliminated. In Western and Central Europe, optimal iodine nutrition has not been achieved in a number of countries, especially in pregnant women. Iodine deficiency transcends economic development. It is as much of a problem in industrialized countries as in other regions of the world. In Eastern Europe and Central Asia, most countries have successfully established iodization programs, while others still have not taken steps to do so. In the Middle East and North Africa, IGN has had to fight food insecurity and political instability in order to promote iodination programs. In West and Central Africa, there has been a constant program of education about iodized food sources. In Eastern and Southern Africa, great progress has been made in the past decade, with education and iodination programs increasing widely. As of 2017, all countries in South Asia are currently classified as “optimal” in their dietary iodine consumption. In China, new regulations have replaced the country’s long-term salt monopoly, resulting in an open and free market for the salt industry. While many countries in the Southeast Asia and Pacific region have had successful iodination programs that appears to be slowing and even reversing in some areas. Focus on iodine in seaweed The main place on earth where iodine is plentiful is within our oceans. Iodine is most highly concentrated in seaweed. Kelp and other forms of seaweed can concentrate and store iodine at extremely high levels. It is believed that seaweed uses iodine to protect itself from oxidative stress in the ocean. Iodine in seaweed is in its most biologically available form, making it ideal for a dietary source.

Risk factors There are a variety of risk factors that may lead to iodine deficiency: low dietary iodine, selenium deficiency, pregnancy, radiation exposure, increased intake and plasma levels of calcium and other goitrogens, and the female gender. Additional risk factors include smoking tobacco products, alcohol use, oral contraceptive use, perchlorates (which are used in food packaging), thiocyanates (which are competitive inhibitors of the thyroid sodium-iodide symporter), and aging.

Iodine deficiency and goiter

Management Though IDD affect entire populations, a school-based sampling method is recommended for urinary iodine and total goiter prevalence as the best way to monitor deficiencies. This is because school-age children (basically 6 12 years of age) are an easily accessible group that can be used as a model for the general population. Four primary strategies are needed to correct iodine deficiencies. These include the following: • Correcting iodine deficiency • Surveillance (monitoring and evaluation) • Intersectorial collaboration • Advocacy and communication to coordinate public health authorities and to educate the public The oral form of iodized oil is preferred over the intramuscular form. It does not require specialized storage, or training of individuals to administer doses, and can be given once per year. However, it is more expensive than iodized salt and may be harder to implement since it requires direct provider-to-patient contact. Since iodized salt has been introduced in many areas, iodized oil is now only indicated for populations in severely endemic areas that lack access to iodized salt. It is recommended to add 20 40 ppm of iodine to salt, assuming an average salt intake of 10 g per capita per day. Potassium iodate and potassium iodide are the two forms used in this case. Potassium iodate is more stable in extreme climatic conditions. Therefore it is the preferred form, especially in hot and humid climates. Adequate control of amounts of these substances must occur in order to prevent iodine toxicity in people who have previously been chronically deficient. Iodine-induced hyperthyroidism is the most common complication of iodine prophylaxis, usually affecting the elderly with chronic thyroid nodules. The most effective ways to prevent this hyperthyroidism and its consequences are to monitor salt quality and iodine status, and to properly train healthcare staff members. Governments usually determine the adequate level of iodine being added to salt, but monitoring controls the activities of the salt industry in providing safe levels. Iodine levels are monitored in factories, households, and sometimes in retail settings. When imported into a country, iodized salt is monitored at ports of entry. Field test kits that utilize titration are used to monitor iodine content. They indicate if iodine is present or not but do not provide accurate quantities. They are used for training and education of the providers. Monitoring the iodine status of each population helps ensure that changing dietary habits is not altering the amounts needed versus amounts consumed. The WHO has provided guidance and support in worldwide iodization efforts. Effective processes require collaboration between various sectors, regulated by the Global Network for Sustained Elimination of Iodine Deficiency. This body works with many Ministries of Health to design and supervise iodine deficiency control

71

72

Epidemiology of Thyroid Disorders

Table 4.2 The World Health Organization criteria for iodine deficiency disorders (IDD) elimination. Indicators

Goals

Salt-iodization coverage

Proportion of households consuming adequately iodized salt (at least 15 ppm at household level)

More than 90%

Urinary iodine

Proportion of population with urinary iodine levels below 100 µg/L Proportion of population with urinary iodine levels below 50 µg/L

Less than 50% Less than 20%

Programmatic indicators

• National body responsible to government for IDD elimination; should be multidisciplinary, with relevant fields of nutrition, medicine, education, salt industry, media, and consumers; with a chairman appointed by Minister of Health • Evidence of political commitment to universal salt iodization (USI) and elimination of IDD • Appointing a responsible executive officer for IDD elimination program • Legislation or regulation of USI • Commitment to regular IDD elimination efforts; with access to laboratories that can provide accurate data on salt and urinary iodine • A program of public education and social mobilization on importance of IDD and consumption of iodized salt • Regular data on iodized salt at the factor, retail, and household levels • Regular laboratory data on urinary iodine in school-age children with appropriate sampling for higher risk areas • Cooperation from salt industry in maintaining quality control • A database for recording results or regular monitoring procedures, especially for salt iodine, urinary iodine, and when available, neonatal thyroid-stimulating hormone, with mandatory public reporting

At least 8 of these 10

plans. The International Resource Laboratories Network to provide technical support to national laboratories requiring assistance through regional or subregional resource laboratories that monitor the programs. There is at least one resource laboratory in every WHO region. The WHO has established criteria for monitoring progress toward sustainable IDD elimination (Table 4.2).

Complications The complications of iodine deficiency are varied and differ between age-groups of affected individuals. In the fetus, complications include miscarriage, stillbirth, congenital anomalies, increased perinatal morbidity and mortality, and endemic cretinism. In the neonate, complications include goiter, hypothyroidism, endemic neurocognitive impairment, and increased susceptibility of the thyroid gland to nuclear radiation.

Iodine deficiency and goiter

In children and adolescents, complications include goiter, subclinical hypothyroidism, impaired mental function, retarded physical development, and increased susceptibility of the thyroid gland to nuclear radiation. In adults, complications include goiter and related complications, hypothyroidism, impaired mental function, spontaneous hyperthyroidism (in the elderly), iodine-induced hyperthyroidism, and increased susceptibility of the thyroid gland to nuclear radiation.

Goiter Goiter is caused by impaired TH synthesis, usually because of dietary iodine deficiency. There are two primary types of goiter: diffuse nontoxic goiter (simple goiter) and multinodular goiter (nontoxic or toxic, which is associated with overproduction of TH). Thyroid enlargement can be caused by proliferation of thyrocytes, stimulated by circulating factors, which include TSH and thyroid-stimulating autoantibodies. It can also be caused by infiltration with inflammatory or malignant cells, or from benign or malignant neoplastic changes in the thyroid gland. When a patient presents with a goiter, the three primary considerations are enlargement, which can cause localized compression or cosmetic problems, hyperfunction or hypofunction of the gland, and the possibility of malignancy. The most common cause of goiter, worldwide, is dietary iodine deficiency. In the United States, this deficiency is only among immigrants who come from iodinedeficient areas of the world. In younger patients, diffuse or simple goiters may be present, which shrink when adequate iodine supplementation is given. In older people, iodine-deficient goiters become multinodular. They do not decrease in size with iodine repletion. In these patients, excessive iodine exposure can cause thyrotoxicosis. A benign adenoma or multinodular goiter can originate from genetic defects leading to dyshormonogenesis. These include mutations of genes related to thyroglobulin, pendrin, thyroid peroxidase, and dual oxidase. Goiter is also caused by exposure to goitrogenic substances in foods, waters, or lithium carbonate. These substances inhibit normal steps in the synthesis of THs. Usually, the underlying cause of goiter is not known. In diffuse goiter the entire thyroid gland swells and is smooth to the touch. In nodular goiter, solid or fluid-filled lumps (thyroid nodules) develop. A thyroid nodule is a discrete lesion caused by an abnormal and focal growth of thyroid cells. The nodules may be inactive or toxic. A goiter may be associated with hyperthyroidism, hypothyroidism (see Chapter 5: Hypothyroidism and Chapter 6: Hyperthyroidism), or normal levels of thyroid function. It may be cystic or fibrous, containing nodules or an increased number of follicles. Goiter is caused by impaired TH synthesis, usually because of dietary iodine deficiency. Impaired synthesis of THs causes a rise in serum levels of TSH. As the thyroid gland’s functional mass increases, it overcomes the hormone deficiency, establishing a euthyroid rate of metabolism in most patients. When an

73

74

Epidemiology of Thyroid Disorders

underlying condition is relatively severe, such as an endemic iodine deficiency or a congenital biosynthetic defect, responses may be insufficient and result in goitrous hypothyroidism. The amount of thyroid enlargement is related to the levels and duration of deficient THs. Hashimoto’s thyroiditis and Graves’ disease are also related to goiter.

Diffuse nontoxic goiter Diffuse nontoxic goiter, a form of simple goiter, is the enlargement of the entire thyroid gland (see Fig. 4.4). This produces nodules and is not associated with hyperthyroidism. Since the enlarged follicles are full of colloid, this condition is also sometimes called colloid goiter. There may be either endemic or sporadic types of distribution. Diffuse nontoxic goiter evolves in two phases: the hyperplastic and the colloid involution phases. The thyroid gland is enlarged, diffusely and symmetrically, in the hyperplastic phase. The increase is usually slight, with the gland not commonly exceeding 100 150 g. Crowded columnar cells line the follicles. These may pile on one another, forming projections that appear similar to those of Graves’ disease (see Chapter 7: Thyroiditis

Figure 4.4 Diffuse nontoxic goiter.

Iodine deficiency and goiter

and Graves’ disease). This accumulation is not even throughout the thyroid gland. Some follicles are extremely distended while others remain small in size. If there is an increase in iodine, or if demand for TH decreases, the stimulated follicular epithelium undergoes involution. The surface of the thyroid is usually translucent, slightly glassy in appearance, and brown in color. Via histology, the follicular epithelium is flat and cuboidal. The colloid is abundant when involution is occurring. Most of the patients with simple goiters are clinically euthyroid. Therefore clinical manifestations are mostly related to mass effects of the enlarged gland. While serum T3 and T4 levels remain normal, serum TSH is usually elevated, or near the upper range of normal. This is expected to exist in patients who are marginally euthyroid. Dyshormonogenetic goiter, due to a congenital biosynthetic defect, may induce cretinism in children. Simple goiter in teenagers is sometimes referred to as juvenile goiter. The known causes of simple nontoxic goiter, which includes the diffuse and nodular forms, involve either intrinsic TH production defects, ingestion of foods that have substances inhibiting TH synthesis, or drugs that decrease TH synthesis. Amiodarone and lithium are examples of drugs that can decrease TH synthesis. Nontoxic nodular goiters may result from recurring cycles of stimulation and involution. Overall, true causes of most nontoxic goiters in iodine-sufficient areas are unknown. Patients may have a history of low iodine intake or overingestion of goitrogens from food sources. These conditions are rare in North America. The goiter, early in its development, is usually soft, symmetrical, and smooth. Over the time, multiple nodules and cysts may develop. Diagnosis involves thyroidal radioactive iodine uptake, thyroid scan, ultrasonography, and measuring of TH and TSH levels. Treatment is based on the cause. When medications are indicated, moderate doses of levothyroxine are useful for younger patients, reducing serum TSH to the low-normal range. Levothyroxine is contraindicated in older patients with nontoxic nodular goiter. It is because these goiters rarely shrink and may have autonomic areas, meaning that levothyroxine may cause hyperthyroidism. When large, these goiters may require surgery or 131I to shrink the thyroid enough to prevent problems with breathing, swallowing, or cosmetic appearance. Endemic goiter Endemic goiter is prevalent in areas of the world in which low levels of iodine are contained in the food, water, and soil. When goiters are present in over 10% of a region’s population, the term endemic is used. Endemic goiter is most common in mountainous areas, including the Himalayas and Andes, where there is significant iodine deficiency. It is also common in large parts of Africa, areas of Central Europe, and in Papua New Guinea. Some highly developed countries such as the United Kingdom and Australia sill have mild-to-moderate levels of iodine deficiency. Daily requirements of optimal iodine for various age-groups and conditions are listed in Table 4.3.

75

76

Epidemiology of Thyroid Disorders

Table 4.3 Optimal iodine daily requirements. Age or condition

Recommended dietary allowance for iodine (µg)

Birth to 6 months 7 12 months 1 8 years 9 13 years 14 years and older Pregnant women Breastfeeding women

110 130 90 120 150 220 290

In endemic areas, daily intake and urinary excretion of iodine are below 50 µg/ day. In areas in which iodine is extremely low, excretion is below 20 µg per day. In these areas, 90% of people have goiters, and 5% 15% of infants are delivered with myxedematous or neurologic alterations of cretinism. Lack of iodine causes decreased synthesis of TH as well as an increase in TSH. This causes hypertrophy and hyperplasia of the follicular cells and enlargement of the thyroid gland. As dietary iodine supplements have increased, endemic goiter cases have decreased in frequency and severity throughout the world. However, up to 200 million people, globally, are at risk for severe iodine deficiency. Other causative influences exist, which are shown by variations in occurrence of endemic goiter in areas that have similar amounts of iodine deficiency. These influences include dietary goitrogens. Consuming substances that interfere with TH synthesis has been proven to be goitrogenic. Dietary substances such as vegetables of the Brassicaceae or Cruciferae family may act as goitrogens. These include cauliflower, cabbage, Brussels sprouts, cassava, and turnips. The highest risk comes from cassava root that is a large part of the diet of various native populations. Cassava contains a thiocyanate, which slows iodide transport in the thyroid, exacerbating any concurrent deficiency of iodine. Cassava, or Manihot esculenta, is a woody shrub originally native to South America. It is extensively cultivated as an annual crop for its edible starchy tuberous root, a primary source of carbohydrates. Cassava, when dried to a powdery or pearly extract, is called tapioca, as used in pudding. Its fried, granular form is called garri. Cassava is also called yuca, but this term is not related to the term yucca, which is a different type of shrub with other uses. It is the third-largest source of food carbohydrates in tropical regions, after rice and corn. It is a major staple food in the developing world, providing a basic part of the diet of more than half a billion people. Nigeria is the world’s largest producer of cassava, and Thailand is the largest exporter of dried cassava. It is either classified as sweet or bitter. The bitter type has larger amounts of antinutritional substances as well as toxins. The preparation of cassava must be done correctly, or

Iodine deficiency and goiter

there will be enough residual cyanide to cause acute cyanide intoxication, goiters, ataxia, partial paralysis, and even death. Sporadic goiter Sporadic goiter is less common than endemic goiter. It is much more common in females, with highest incidence at puberty or in young adulthood. Several conditions cause sporadic goiter. These include ingesting substances that interfere with TH synthesis, and hereditary enzymatic defects interfering with TH synthesis. These defects are transmitted as autosomal-recessive conditions, such as in dyshormonogenetic goiter. However, the primary cause of sporadic goiter is not understood. Some clinicians theorize that sporadic goiter may arise from relative iodine deficiency resulting from disturbance of iodine ingestion, or from liver dysfunction. Sporadic goiter, like endemic goiter, requires a differential diagnosis with chronic autoimmune thyroiditis, Riedel’s thyroiditis, neck cysts, lipomas, other neck or mediastinal tumors, malignant neoplasms of the thyroid, and metastases of tumors in the cervical lymph nodes.

Nontoxic multinodular goiter Multinodular goiter occurs over the time, as recurrent hyperplasia and involution episodes combine, producing a more irregular thyroid enlargement. Nearly all cases of simple goiter that have been present for a long time will convert into multinodular goiters. They cause extreme enlargements of the thyroid. Nontoxic goiters are often mistaken with neoplasms. Since they evolve from simple goiter, they also occur in endemic and sporadic forms. They also have the same distribution between females and males, and possibly the same origins. However, they affect older people since they are late complications. In various populations, multinodular goiter or nodular thyroid enlargement affect up to 12% of adults. Multinodular goiter is believed to occur due to variations in follicular cells, as to their response to trophic hormones and other stimuli. Some cells in a follicle may have a growth advantage. This could be because of intrinsic genetic abnormalities that are similar to those ones that cause adenomas. Therefore these cells can develop clones of proliferating cells. This may be due to formation of a nodule with continued autonomous growth, but without an external stimulus. Primary factors that cause nontoxic multinodular goiter include functional heterogeneity of the normal follicular cells. This is probably due to genetics and the acquiring of new inheritable factors from replicating epithelial cells. An important factor is the female gender. There may also be further functional and structural abnormalities as the goiter increases in size. Secondary causative factors include elevated TSH, endogenous (gender) factors, certain drugs, smoking, stress, and the effects of IGF-1 and other thyroid stimulators.

77

78

Epidemiology of Thyroid Disorders

Polyclonal and monoclonal nodules exist at the same time within a multinodular goiter. The monoclonal nodules may have developed because of acquiring a genetic abnormality that favors their growth. Activating mutations that affect proteins in the TSH-signaling pathway have been revealed as a subgroup of autonomous thyroid nodules. Uneven follicular hyperplasia, new follicle generation, and colloid accumulation cause physical stress, which may result in rupture of follicles and vessels, and larger, hemorrhage, scarring, and occasionally, calcifications. Scarring causes nodularity to appear, which can be made more prominent by the gland’s preexisting stromal framework. Multinodular goiters can weigh more than 2000 g. They are multilobulated and asymmetrically enlarged, in extremely varying patterns. One lobe may be involved extensively, while the other is not. This produces lateral pressure on the esophagus, trachea, and other midline structures. Sometimes, the goiter enlarges behind the clavicles and sternum, producing an intrathoracic or plunging goiter. Less commonly, the majority of the goiter is hidden behind the esophagus and trachea. Sometimes just a single nodule is greatly enlarged, making it appear as if only one nodule is present. When the thyroid is sectioned, there are irregular nodules filled with varying amounts of colloid that is brown and gelatinous (Fig. 4.5). Chronic lesions show areas of calcification, cystic changes, fibrosis, and hemorrhage. Microscopically, there are follicles rich in colloid that is lined by flat, inactive epithelium and locations of follicular hyperplasia. There are often degenerative changes due to physical stress. The difference between multinodular goiters and follicular neoplasms is that the multinodular goiters do not have a prominent capsule between the hyperplastic nodules and residual, compressed parenchyma. The primary clinical features are caused by mass effects, including airway obstruction, compression of large neck and upper thorax vessels, and dysphagia. When these vessels are affected, it is called superior vena cava syndrome. The majorities of patients are euthyroid or have subclinical hyperthyroidism, which is revealed only by reduced

Figure 4.5 (A) Cross-section of goiter and (B) Histology of goiter.

Iodine deficiency and goiter

TSH levels. However, a large minority of patients with an autonomous nodule will develop a long-standing goiter and hyperthyroidism. This is known as toxic multinodular goiter.

Toxic multinodular goiter Toxic multinodular goiter is also known as Plummer syndrome. It is characterized by a hyperfunctioning nodule or adenoma and thyrotoxicosis. Toxic multinodular goiter does not involve infiltrative ophthalmopathy and dermopathy, as seen in Graves’ disease. It is believed that clinically obvious autonomous nodules develop in about 10% of multinodular goiters, in 10-year follow-ups. There is a low incidence of malignancy in long-term multinodular goiters. This is less than 5%, but goiters that suddenly change in size or symptoms, such as hoarseness, have a higher risk for malignancy. Dominant nodules may present as a solitary thyroid nodule that mimics a thyroid neoplasm. Radioiodine scans show uneven iodine uptake, with occasional “hot” nodules, which are related to diffuse parenchymal involvement. Radioiodine scans also reveal admixtures of hyperplastic and involuting nodules. Fine-needle aspiration biopsy is productive and sometimes allows the distinction of follicular hyperplasia from thyroid neoplasms. Genetic abnormalities that confer functional autonomy are not usually present in the autonomous areas of toxic multinodular goiter. These include activating TSH receptor (TSHR) or GS-alpha mutations. The patient with toxic multinodular goiter is usually an elderly adult and may have mild thyrotoxicosis or subclinical hyperthyroidism. Signs and symptoms include heat intolerance, hyperactivity, muscle weakness and wasting, fatigue, irritability, osteoporosis, increased appetite, and tracheal compression. There are sometimes atrial fibrillation or palpitations, nervousness, tachycardia, tremor, or weight loss. Recent iodine exposures may precipitate or worsen thyrotoxicosis. The TSH levels are low, and uncombined T4 levels are normal or slightly increased. The T3 levels are often higher. Thyroid scan reveals heterogeneous uptake, with many regions of increased and decreased uptake. The 24-hour uptake of radioiodine may not be higher but is most often in the upper-normal range. Ultrasound should be done to assess any discrete nodules related to areas of decreased uptake— known as “cold” nodules. If these are present, fine-needle aspiration may be indicated. Treatment is based on these considerations. Medications include propylthiouracil or methimazole and radioactive iodine. Another option is injection of ethanol into the nodules. If there are undefined or suspicious cytology results, surgery may be required.

Amyloid goiter Amyloid goiter is a symptomatic mass, or clinically detected thyroid enlargement, due to deposition of amyloid, which is an aggregate of various proteins. Amyloids become folded into a shape that allows a large amount of protein copies to stick together and

79

80

Epidemiology of Thyroid Disorders

form fibrils. The presence of amyloid, related to thyroid enlargement, is seen in 50% 80% of medullary carcinoma of the thyroid cases (see Chapter 10: Global epidemiology of thyroid neoplasms). Amyloid goiter occurs with primary and secondary systemic amyloidosis but is more common in the secondary form. Though rare, it should be suspected in patients with a diffuse, enlarging thyroid gland, and in people with appropriate clinical history. The neck mass usually causes pressure symptoms of hoarseness, and the patient is usually euthyroid. If there is a thyroid swelling of soft consistency, with vascularization, biopsy should be made and frozen sections should be sent in for examination. Amyloid goiter in secondary amyloidosis is characterized by amyloid deposits that are associated with atrophic follicles. More rarely, amyloid goiter can present as a first manifestation of systemic amyloidosis. There is no effective treatment for amyloidosis. Overall prognosis is better for patients with secondary amyloidosis. Colchicine treatments may prevent amyloid deposits.

Epidemiology According to the American thyroid association in 2019, more than 12% of the population of the United States will develop a thyroid condition at some point in life. A goiter prevalence of 5% or more in school-age children indicates iodine deficiency in a specific population. Therefore the goiter rate in school-age children is used to determine severity of a population’s iodine deficiency since they are easily susceptible to this deficiency. In areas where daily iodine intake is less than 50 µg, goiter is usually endemic. When daily intake falls below 25 µg, congenital hypothyroidism is seen. Prevalence of goiter in areas of severe iodine deficiency can be as high as 80%. The most common thyroid disease is simple (diffuse) goiter. Nodular thyroid disease is common, affecting 3% 7% of adults, from physical examination alone. The use of ultrasound, however, reveals nodules present in as much as 50% of adults. Most of these nodules are less than 1 cm in diameter. Thyroid nodules can be multiple or single, and functional or nonfunctional. In pregnant women, enlargement of the goiter is physiologic. It usually subsides after delivery. The prevalence of goiter among females is basically four times as often as males, and this primarily involves premenopausal women. According to the Framingham, England survey, for patients aged 60 years or older, clinically apparent thyroid nodules were present in 6.4% of females and 1.5% of males. The prevalence of single thyroid nodule was 3% and multinodular was 1%. Autopsy surveys have revealed that up to 50% of patients had thyroid nodules. Ultrasound of females revealed that 20% 76% had at least one thyroid nodule. In Germany, thyroid nodules or goiter were found via ultrasound in 33% of working adults between ages 18 and 65. Thyroid nodules larger than 1 cm were found in 12% of this population, increasing with age. In those with only one palpable nodule, 20% 48% had additional

Iodine deficiency and goiter

nodules detected by ultrasound. Variables related to the epidemiology of goiter include regional iodine intake levels, smoking, age, gender, and even the methods used to assess thyroid size.

Pathogenesis and etiology The pathogenesis and etiology of goiter can be complex to understand. Not every inhabitant of an iodine-deficient area will develop goiter. Low dietary intake of iodine contributes greatly to development of goiter. Therefore increasing dietary intake of iodine by consuming iodized salt is the key to eradicate goiters caused by iodine deficiency. Also, endemic goiter has occurred in areas with no iodine deficiency, and even in some areas with excessive iodine. Also, it has not occurred in certain regions that have severe iodine deficiency. This is probably related to genetic or other factors. Genetic factors are emphasized by the clustering of goiters in certain families, a higher concordance rate in monozygotic than in dizygotic twins, different female-to-male ratios, and the amount of goiters in areas where large iodine prophylaxis programs have been correctly introduced. An important consideration is that in endemic goiter, the female-to-male ratio is 1:1 while 7:1 9:1 for sporadic goiters. Environmental factors are also involved. Endocrine disrupting agents include drugs, tobacco products, insulin resistance, selenium deficiency, oral contraceptives, alcohol use, and parity. Increased serum TSH concentrations usually cause thyroid enlargement in the rare case of functional TSH-secreting pituitary adenomas. Also, goiter is typical in Graves’ disease, where stimulation of thyroid tissue growth is due to thyroid-stimulating antibody via TSHR activation. Thyroid enlargement can appear in Graves’ disease when increased levels of TSH occur from overadministration of antithyroid drugs. Autoimmune thyroiditis often produces a moderate goiter because of glandular infiltration with lymphocytes, fibrosis, and inflammatory alterations of thyrocytes. Toxic thyroid hyperplasia is often seen in nonautoimmune autosomal dominant hyperthyroidism. This disorder is related to germ-line activating TSHR gene mutations. This highlights the role of TSH TSHR system activation in thyroid hyperplasia. In most patients with nontoxic goiter, serum TSH concentration is normal. It has been shown in studies that iodine depletion promotes thyroid growth by normal TSH levels. Therefore anything that impairs intrathyroidal iodine levels can cause gradual goiter development, responding to normal TSH levels. Iodine supplies and TSH levels are also interrelated. Slight differences in iodine intake are linked to significant TSH changes. This has been shown in 11-year followup studies. TSH-dependent and TSH-independent pathways are complex. They control thyroid follicular cell growth and function, while also acting in the goitrogenic process. A group of growth factors from the bloodstream or either autocrine or paracrine secretion may help regulate thyroid cell proliferation and differentiation. Early

81

82

Epidemiology of Thyroid Disorders

goiter formation involves areas of microheterogeneity in structure and function. These are intermingled with areas of functional autonomy and others of focal hemorrhage. Hyperplastic nodules may indicate that thyroid nodules are either monoclonal or polyclonal. Monoclonal adenomas in hyperplastic thyroid glands may show one progressive stage of the hyperplasia neoplasia spectrum. Multiple accumulating somatic mutations may provide a selective growth advantage to this single-cell clone. Histological examination shows nodules with irregularly enlarged and involuted follicles. These are distended with colloid or clustered, smaller follicles lined by higher epithelium, with small colloid droplets. Usually, these nodules are totally encapsulated. They are poorly demarcated from internodular tissue and also merged with it, additionally with alterations of structure. Nodules in certain glands are localized, accompanying areas of normal structural appearance. It may be hard in this case to distinguish them from follicular adenomas. Therefore the lesions are often called colloid or adenomatous.

Clinical presentation Patients often discover swelling of the thyroid upon self-examination, which lead them seeking medical advice. Usually, appropriate examination by a medical professional results in the diagnosis of a goiter or nodule being benign. With multinodular goiter, autonomous nodules or functional areas may cause increased TH secretion, followed by subclinical or clinical thyrotoxicosis. Goiter is rare in the United States since it is primarily related to iodine deficiency. Generally, thyroid nodules are not related to abnormal secretion of TH. The affected patient does not show clinical signs of thyroid dysfunction and, often, is asymptomatic. Nontoxic goiter may simply cause thyroid enlargement and no other features. With cross-sectional imaging, many clinically relevant thyroid nodules are detected during routine carotid ultrasonography or via CT or MRI of the head, neck, and chest. However, even if discovered accidentally, the same risk of malignancy exists as with nodules identified during clinical examination. The majority of thyroid nodules are asymptomatic. When they become large, they can displace or compress the esophagus, trachea, and blood vessels of the neck. Rarely, there may be signs and symptoms of dysphagia, neck tightness, and a sensation of choking. Such obstructive symptoms may be accentuated by the Pemberton maneuver, which involves the patient keeping the arms elevated against the sides of the head. If a substernal goiter is present, there will be venous congestion, which causes congestion and cyanosis of the face, with distress. Rarely, thyroid nodules cause compression or invasion of the recurrent laryngeal nerve, which may cause hoarseness, suggesting advanced thyroid carcinoma. More often, acute hemorrhaging into a cystic nodule can cause acute and painful neck enlargement and is able to worsen or cause obstructive symptoms. Most thyroid nodules are benign hyperplastic or colloid nodules or benign follicular adenomas. Many studies show that 5% 15% of clinically relevant nodules are malignant. Thyroid cancer has been steadily increasing in most countries. This is

Iodine deficiency and goiter

related to better detection and reporting of small malignancies. Also, more advanced thyroid cancers have been discovered with regularity, but fortunately, mortality rates from these are extremely low.

Diagnosis Clinical evaluation of a suspected goiter must exclude any extra skin or subcutaneous fat in the lower anterior neck. Palpating the thyroid beneath the soft tissue, and observing that the fullness will not rise or fall when swallowing is usually sufficient, confirmed by ultrasound. Patient history helps evaluate any previous iodine deficiency. Symptoms of hypothyroidism can suggest autoimmune thyroiditis. Evidence of thyrotoxicosis can suggest toxic multinodular goiter or Graves’ disease. Also, diagnostic is any pain, in subacute thyroiditis, or postpartum status, in lymphocytic thyroiditis. Any symptom suggesting invasion of nearby structures increases concerns of malignancies or Riedel’s thyroiditis. Diffuse enlargement suggests a type of thyroiditis, Graves’ disease, or a diffuse, infiltrative malignancy. Enlargement of thyroid nodules more often reflects a benign multinodular goiter or a malignant neoplasm. There must be accurate documentation of the size of the thyroid gland. Any cervical lymphadenopathy, dysphonia, tracheal deviation, or venous engorgement in the neck must be recorded. If the patient is asked to touch the hands together above the head, known as Pemberton’s maneuver, a subtotal obstruction of the thoracic outlet may be revealed, as the examiner checks for signs of facial plethora and cervical venous distention. The TSH level determines if there is primary hypothyroidism or thyrotoxicosis. Suspected autoimmune thyroiditis may be confirmed by elevating antithyroid peroxidase antibody titers. If there is a modest diffuse goiter, and the patient is asymptomatic, no additional evaluation may be needed. If clinical clues suggest a specific diagnosis, other blood tests that may be useful include erythrocyte sedimentation rate for subacute thyroiditis, or calcitonin for medullary thyroid cancer. To define the size and shape of a goiter that is limited only to the neck, cervical ultrasonography is preferred, which helps in assessing if the goiter is diffuse or nodular. It also shows if the thyroid gland is impinging upon other cervical structures and lymphadenopathy is present. Ultrasonography is a vital component of guidance of fine-needle aspiration for differential cytologic diagnosis. If a goiter is extended posteriorly or beneath the sternal notch into the thorax, a CT scan or MRI may be needed. Radiocontrast dye containing iodine is usually avoided when evaluating goiters since the stable load of iodide may interfere with later radioiodine studies or therapies. The functional abilities of the gland can be determined by using thyroid radionuclide uptake studies that feature 123I or 99mTc pertechnetate. The etiology of the goiter, and if any superior mediastinal mass is thyroid tissue, can be determined with radionuclide scanning. Symptoms directly related to esophageal compression can be determined by using barium swallow radiographs with

83

84

Epidemiology of Thyroid Disorders

controlled-diameter markers. Symptoms directly related to tracheal compression can be determined by using pulmonary function testing with flow-volume loops. In a patient with possible recurrent laryngeal nerve involvement, laryngoscopy is useful for evaluating the function of the vocal cords.

Treatment It is important to understand that in endemic areas, the total goiter prevalence may not return to normal for months or years after iodine deficiency is corrected. For simple nontoxic goiter, in iodine-deficient areas, treatments include iodine supplementation of salt, oral administration of iodized oil, intramuscular administration of iodized oil once per year, and iodination of water, crops, or animal foods. Any goitrogens being ingested must be stopped. In some cases, suppression of the hypothalamic pituitary axis with TH blocks TSH production. Moderate doses of levothyroxine, 100 150 µg per day orally based on serum TSH, are useful in younger patients, reducing serum TSH to the low-normal range. Levothyroxine is contraindicated in older patients with nontoxic nodular goiter since these goiters rarely shrink and may contain areas of autonomy. Levothyroxine therapy would therefore result in hyperthyroidism. Large goiters sometimes require surgery or 131I to shrink the gland enough to prevent interferences with respiration or swallowing, or to correct cosmetic appearance. For congenital goiter, surgery is performed to correct thyroid enlargement that is compromising breathing or swallowing. Hypothyroidism is treated with TH. For multinodular goiter, treatments include observation of the patient, radioactive iodine, medications to decrease TH levels, and if breathing or swallowing is compromised, surgical removal of part or all of the thyroid. Surgery is generally preferred when the patient has significant thyroid enlargement, with compressive complications, primarily when there is substernal goiter extension, or acute obstruction. When surgery cannot be performed due to health status, radioactive iodine therapy can reduce goiter size by an average of 50%, over a course of 1 2 years. Ultrasonography is a great technique for monitoring the size of an enlarged thyroid. Thyroxine therapy that suppresses TSH levels only shrinks goiters in a small number of patients. Chronic TH treatment brings with it risks for symptomatic thyrotoxicosis, atrial fibrillation, and loss of bone minerals.

Clinical cases Case 1 1. Where do the highest levels of iodine occur on earth? 2. Why may iodine deficiency result in a goiter? 3. How should this patient be treated?

Iodine deficiency and goiter

A 25-year-old Brazilian woman was examined because of a goiter. She was allergic to shellfish and did not use iodized salt by choice. Previously, her aunt had been diagnosed with hyperthyroidism. The thyroid gland was palpable, and she had a normal thyroid function test but was negative for thyroid peroxidase antibody. Thyroid sonogram revealed a diffuse goiter. All these facts are combined to raise the suspicion of iodine deficiency. Answers: 1. The highest levels of iodine on earth are found in the seaweed that grows in the oceans. 2. Iodine deficiency may result in a goiter because thyroid hormone requires iodine in order for it to be manufactured. When there is insufficient thyroid hormone, release of TSH from the pituitary gland increases, which stimulates the thyroid to work harder and release more hormone, causing it to enlarge. 3. Treatments include use of iodized salt and a multivitamin that contains iodine.

Case 2 1. Based on your study, which continents have the highest incidence of goiter? 2. If the multiple nodules are benign, what would be the treatment? 3. How can multinodular goiters be differentiated from simple goiters? A 57-year-old Asian woman is examined, having had a long history of multinodular goiter. Sonography confirms multiple solid and cystic nodules. The largest of the nodules is in the isthmus, measuring 1.5 cm. The patient is referred for fine-needle aspiration of the dominant nodule. Answers: 1. The continents with the highest incidence of goiter include Asia and South America. This is especially true in extremely mountainous regions, such as the Himalayas and Andes. 2. Treatments include observation, radioactive iodine, medications to decrease thyroid hormone levels, and surgery. 3. In simple (diffuse) goiters, the entire thyroid is enlarged but smooth. In multinodular goiter, there are solid or fluid-filled lumps.

Case 3 1. Based on the symptoms, and appearance of this patient’s thyroid tissues, what was the likely diagnosis?

85

86

Epidemiology of Thyroid Disorders

2. If this patient had recurrent episodes of painful inflammation of the abdomen, chest, or joints, plus a fever and rash, what would this point toward in relation to her diagnosis? 3. Is this condition visibly different that other forms of goiter? A 44-year-old woman presented with a large, growing goiter that she said had been present for years. She had no history of pain but experienced regular hoarseness of her voice. She was euthyroid, with normal blood and biochemistry results. Fineneedle aspiration cytology revealed a nodular goiter. A bilateral subtotal thyroidectomy was performed, preserving the parathyroid glands and laryngeal nerves. Examination of the tissue revealed that the thyroid lobes and isthmus were enlarged, soft, and extremely vascular. There were obvious amyloid and fatty deposits throughout. Answers: 1. The likely diagnosis is amyloid goiter. 2. These symptoms indicate the presence of amyloidosis and would be understood to be related to an amyloid goiter. 3. Amyloid deposits and fatty deposits would be visible throughout the thyroid tissue, which is different than the appearance of nodular or smooth goiters.

Key terms amyloidosis colloid goiter colloid involution cretinism endemic goiter euthyroid goitrogens hyperplastic

involution juvenile goiter multinodular goiter Riedel’s thyroiditis sporadic goiter superior vena cava syndrome thyroid nodules toxic multinodular goiter

Further reading 1. Ameen, M. Thyroid Dysfunctions and Emergency of Goiter. (2017) Lap Lambert. 2. Aronson, J.K. Meyler’s Side Effects of Endocrine and Metabolic Drugs (Meyler’s Side Effects of Drugs). (2009) Elsevier Science. 3. Bao, S.S., and Winter, B. Thyroid Nodules: Questions From Real Patients. (2018) ACE Health Publisher. 4. Bram, I. Exophthalmic Goiter and Its Nonsurgical Treatment. (2015) Andesite Press. 5. Brownstein, D. Iodine: Why You Need It, Why You Can’t Live Without It. (2014) Medical Alternative Press. 6. Cooper, D.S., and Sipos, J. Medical Management of Thyroid Disease, 3rd Edition. (2018) CRC Press. 7. Dennison, J., Oxnard, C., and Obendorf, P. Endemic Cretinism. (2011) Springer.

Iodine deficiency and goiter

8. Farrow, L., and Brownstein, D. The Iodine Crisis: What You Don’t Know About Iodine Can Wreck Your Life. (2013) Devon Press. 9. Gharib, H. Thyroid Nodules: Diagnosis and Management (Contemporary Endocrinology). (2018) Humana Press. 10. Gnepp, D.R. Diagnostic Surgical Pathology of the Head and Neck, 2nd Edition. (2009) Saunders. 11. Halenka, M., and Frysak, Z. Atlas of Thyroid Ultrasonography. (2017) Springer. 12. Honda, M., and Sellman, S. Reverse Thyroid Disease Naturally: Alternative Treatments for Hyperthyroidism, Hypothyroidism, Hashimoto’s Disease, Graves’ Disease, Thyroid Cancer, . . . and More. (2018) Hatherleigh Press. 13. Icon Group International. The World Market for Fluorine, Bromine, and Iodine: A 2018 Global Trade Perspective. (2018) Icon Group International, Inc. 14. Kocjan, G., Gray, W., Levine, T., Kardum-Skelin, I., and Vieth, P. Diagnostic Cytopathology Essentials: Expert Consult. (2013) Churchill Livingstone. 15. Lathrop Steman, T. Twentieth Century Practice: Diseases of the Vascular System and Thyroid Gland. (2015) Sagwan Press. 16. Lawrence, M. Food Fortification: The Evidence, Ethics, and Politics of Adding Nutrients to Food. (2013) Oxford University Press. 17. Miller, J.L., and Pribitkin, E.D.A. Thyroid Nodules and Cancer: A Simplified Case Oriented Approach Endocrinology Research and Clinical Developments. (2017) Nova Science Publishers Inc. 18. Monaco, F. Thyroid Diseases. (2012) CRC Press. 19. Orell, S.R., and Sterrett, G.F. Orell and Sterrett’s Fine Needle Aspiration Cytology, 5th Edition. (2011) Churchill Livingstone. 20. Pearce, E.N. Iodine Deficiency Disorders and Their Elimination. (2017) Springer. 21. Randolph, G.W. Surgery of the Thyroid and Parathyroid Glands, 2nd Edition. (2012) Elsevier. 22. Roman, S.A., Sosa, J.A., and Solorzano, C.C. Management of Thyroid Nodules and Differentiated Thyroid Cancer. (2017) Springer. 23. Vitti, P., and Hegedus, L. Thyroid Diseases: Pathogenesis, Diagnosis, and Treatment (Endocrinology). (2018) Springer. 24. William, A. Medical Medium Thyroid Healing: The Truth Behind Hashimoto’s, Graves’, Insomnia, Hypothyroidism, Thyroid Nodules & Epstein-Barr. (2017) Hay House Inc. 25. Ziessman, H.A., O’Malley, J.P., and Thrall, J.H. Nuclear Medicine: The Requisites (Requisites in Radiology), 4th Edition. (2013) Saunders.

87

CHAPTER 5

Hypothyroidism Contents Types and etiology of hypothyroidism Congenital hypothyroidism Autoimmune hypothyroidism Iatrogenic hypothyroidism Cretinism Myxedema Drug-induced Central hypothyroidism Epidemiology of hypothyroidism Pathogenesis of hypothyroidism Risk factors Clinical presentation Central and peripheral nervous system Cardiovascular system Integumentary system Gastrointestinal system Respiratory system Muscular system Skeletal system Hematopoietic system Pituitary and adrenocortical function Catecholamines Reproductive function Nutrient metabolism Electrolyte metabolism Diagnosis of hypothyroidism Differential diagnoses Treatment of hypothyroidism Complications Subclinical hypothyroidism Metabolic insufficiency Clinical cases Clinical case 1 Clinical case 2 Clinical case 3 Clinical case 4 Clinical case 5 Further reading Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00005-0

90 91 92 94 94 95 97 98 99 100 100 101 101 104 104 105 106 106 107 107 108 108 108 109 110 111 112 113 114 115 116 116 116 117 117 118 118 120 r 2020 Elsevier Inc. All rights reserved.

89

90

Epidemiology of Thyroid Disorders

Hypothyroidism is a clinical state that is mostly identified by reduced production of thyroid hormone (TH) and decreased circulating levels of free TH. Resistance to hormone action may also cause it. There can be permanent loss or destruction of the thyroid gland. Hypothyroidism is a common disorder. It occurs at all ages but is most common in the elderly and more common in women. Although usually easy to diagnose in younger adults, hypothyroidism can be subtle, manifesting atypically in the elderly.

Types and etiology of hypothyroidism Iodine deficiency is still a common cause of hypothyroidism across the globe. Where iodine sources are adequate, the most common causes of hypothyroidism include autoimmune disease, such as Hashimoto’s thyroiditis, and iatrogenic causes such as treatments for hyperthyroidism. Hypothyroidism may be caused by a defect of the hypothalamic
pituitary
thyroid axis. The etiology of the various types of hypothyroidism is diverse. Basically, the etiologies are classified under two different titles: primary and secondary (Fig. 5.1). Primary hypothyroidism is due to the impaired function of the thyroid gland,

Figure 5.1 Adult Cretin. Note characteristic facial features, dwarfism (44 inches), absent axillary and scant pubic hair, poorly developed breasts, potbelly, and small umbilical hernia.

Hypothyroidism

Table 5.1 Etiology of various types of hypothyroidism. Primary

Secondary

Congenital: absent or ectopic thyroid gland, dyshormonogenesis, TSH-receptor mutation

Hypopituitarism: genetic forms of combined pituitary-hormone deficiencies, infiltrative disorders, pituitary surgery or irradiation, Sheehan’s syndrome, trauma, tumors, pituitary infarct Isolated thyroid-stimulating hormone inactivity or deficiency

Iatrogenic: external irradiation of the neck for cancer or lymphoma, Iodine 131 (131I) treatment, subtotal or total thyroidectomy Autoimmune: atrophic thyroiditis, Hashimoto’s thyroiditis Medications: aminoglutethimide, antithyroid drugs, interferon alpha and other cytokines, iodine excess including iodine-containing contrast media and amiodarone, lithium, p-aminosalicylic acid, tyrosine kinase inhibitors such as sunitinib Iodine deficiency Infiltrative disorders: amyloidosis, cystinosis, hemochromatosis, Riedel’s thyroiditis, sarcoidosis, scleroderma Overexpression of type 3 deiodinase in infantile hemangioma and other tumors

Bexarotene treatment for lymphoma Hypothalamic disease: idiopathic, infiltrative disorders, trauma, tumors

resulting in increased thyroid-stimulating hormone (TSH). The second most common cause is posttherapeutic hypothyroidism—especially following radioactive iodine therapy or surgical treatment of hyperthyroidism or goiter. Primary hypothyroidism causes about 99% of cases with less than 1% being due to any other causes. Reduced action of TH at the tissue level, regardless of whether there is normal or increased TH production from the thyroid gland, is also related to clinical hypothyroidism. Table 5.1 explains the etiology of the various types of hypothyroidism. Primary hypothyroidism accounts for the majority of cases and may be accompanied by goiter.

Congenital hypothyroidism Congenital hypothyroidism is a severe condition that is present at birth. Rare forms of congenital hypothyroidism include inborn errors of thyroid metabolism, also called dyshormonogenetic goiter. Any one of the various steps that result in TH synthesis may be defective. These include the following: • Transport of iodide into the thyrocytes • Organification of iodine in which iodine binds to tyrosine residues of the storage protein (thyroglobulin)

91

92

Epidemiology of Thyroid Disorders

• •

Iodotyrosine coupling, which forms hormonally-active T3 and T4 Thyroxine-binding globulin deficiency If the thyroid gland is congenitally absent, it results in the infant being of usually normal appearance and growth due to maternal hormones transmitted through the placenta before birth. There may be a complete lack of the thyroid parenchyma, known as thyroid agenesis. The gland may sometimes be extremely small, called thyroid hypoplasia, because of germline mutations of genes responsible for development of the thyroid gland. The first sign of congenital hypothyroidism may be prolonged physiologic jaundice due to delayed maturing of the hepatic system responsible for conjugating bilirubin. Respiratory difficulties and a hoarse sound to the infant’s crying may occur, partially because of the tongue being enlarged. Feeding difficulties can include sluggish movements, disinterest, somnolence, and even choking during nursing. The abdomen is often enlarged and an umbilical hernia is present. Regardless of the cause, closely monitored levothyroxine supplementation to maintain normal TH levels usually results in normal intelligence. Newborns receive mandatory screening for hypothyroidism in most developed countries. A drop of blood is taken from the infant’s heel and analyzed for T4 or TSH. Screening is performed 24
48 hours after birth, usually in the nursery of the hospital. TH replacement is used to treat congenital hypothyroidism. It is important to normalize T4 levels quickly, because delays result in worsened psychomotor and mental development. As a child grows, the dosage of hormone requires adjustment. Transient congenital hypothyroidism has been identified more often as a result of neonatal screening. High TSH levels, with low or normal TH levels, characterize it. Transient hypothyroidism may be due to maternal or infant exposure to povidoneiodine or other substances, any of which are used as disinfectants. Fetal and infant thyroid glands are sensitive to excessive iodine exposure, which crosses the placenta and mammary glands, and iodine is easily absorbed through the skin of an infant. Also, antithyroid drugs taken by the mother can cross the placenta. These include methimazole and propylthiouracil. In large doses, these medications impair fetal thyroid function. Affected infants usually have replacement therapy stopped at 6
12 months of age. With early screening and treatments performed adequately, risks for mental retardation from congenital hypothyroidism are basically nonexistent.

Autoimmune hypothyroidism Chronic autoimmune hypothyroidism is also commonly referred to as Hashimoto’s thyroiditis and can occur with or without a goiter. In addition, another form of autoimmune thyroiditis is painless thyroiditis. Both usually result in the development of hypothyroidism. Autoimmune destruction of the thyroid gland results in progressive

Hypothyroidism

loss of thyroid function, causing a compensation phase when normal levels of TH are maintained by a rise in TSH. While some patients have minor symptoms, this state is described as subclinical hypothyroidism. Further in the disease course, free T4 levels decrease and TSH levels increase further. The symptoms then become more obvious, usually with the TSH over 10 mU/L. This is called clinical or overt hypothyroidism. The course of changes in thyroid function, over time, is shown in Fig. 5.2. Autoimmune hypothyroidism affects approximately four of every 1000 females and one of every 1000 males. It is most common in Japan, most likely because of genetics and chronic, high-iodine diets. Individuals with type 1 diabetes, another autoimmune disorder, also have a 25% risk of developing autoimmune hypothyroidism in their lifetime and thus are screened for hypothyroidism on an annual basis. The prevalence of overt hypothyroidism increases with age, with the mean age at diagnosis being 60 years. In Hashimoto’s thyroiditis, there is a significant lymphocytic infiltration of the thyroid with germinal center formation. This means an extremely specific immune reaction that is usually only seen in lymphoid tissues. Lymphocytes have become organized into a reactive-attack pattern, promoting production of antibodies. Circulating autoantibodies include antithyroid peroxidase (anti-TPO), antimicrosomal, and antithyroglobulin antibodies. There is atrophy of the thyroid follicles, oxyphil metaplasia, lack of colloid, and fibrosis, which can be mild to moderate. Atrophic thyroiditis involves much more extensive fibrosis with less lymphocyte infiltration. The thyroid follicles are almost totally absent. This form probably represents the final stage of Hashimoto’s thyroiditis instead of a separate disorder. Autoimmune thyroid disorders are discussed in detail in Chapter 11, Global impact of thyroid disorders.

T4 and T3 Normal range

TSH Hyperthyroid phase 1–6 months

Hyperthyroid phase 2–8 months

Recovery

Figure 5.2 Time course of changes in thyroid-function tests in patients with thyroiditis. T3, Triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone. Reprinted with permission from Ross D. Medical Diseases in Women. In: Carlson KJ, Eisenstat SA, eds. Primary Care of Women, 2nd Edition. (2002) St. Louis: Mosby, p. 92.

93

94

Epidemiology of Thyroid Disorders

Iatrogenic hypothyroidism Iatrogenic hypothyroidism typically occurs after treatment for hyperthyroidism within 2
4 months after screening prior to symptom development, which can often identify receiving radioactive iodine, and is a common cause of hypothyroidism. Within 3
4 months after treatment for hyperthyroidism with radioiodine, reversible radiation damage may cause transient hypothyroidism, requiring TH replacement with thyroxine. If recovery occurs, low-dose thyroxine treatment can be withdrawn. Since TSH levels are decreased by hyperthyroidism, it is more accurate to measure free levels of T4 to measure thyroid function, rather than measuring TSH over the months that follow radioiodine treatment. If a subtotal thyroidectomy was performed, mild hypothyroidism may resolve within several months, because increased TSH levels stimulate the remaining parts of the gland. Iodine deficiency is the most common cause of hypothyroidism globally and is more common in countries where there is low iodine in the diet including areas of Africa and Asia. Other dietary contributors to hypothyroidism may include selenium deficiency or the consumption of thiocyanates found in cassava-derived foods such as tapioca. Thiocyanates decrease the amount of thyroxine produced by the thyroid. When iodine becomes deficient, it is best to simply increase iodine intake rather than treat the patient with thyroxine. Iodized salt or bread, or a single bolus of oral or intramuscular iodized oil has been quite successful. Iodine deficiency was discussed in greater detail in Chapter 3, Iodine and thyroid hormones. Contradicting this is the fact that chronic iodine excess can also cause hypothyroidism and goiter. Though not fully understood, patients with autoimmune thyroiditis are highly susceptible to these occurrences. Excessive iodine causes hypothyroidism in up to 13% of patients treated with amiodarone. Lithium and other drugs may also cause hypothyroidism.

Cretinism Cretinism occurs when congenital hypothyroidism is untreated for long periods and is a form of severe hypothyroidism. Cretinism occurs in areas of the world where there is a severe deficiency of iodine. Often, these children are born to mothers who are also iodine-deficient. Maternal TH deficiency is believed to make the condition more severe. If there is an accompanying deficiency of selenium, this may also worsen the neurologic manifestations of cretinism. The prevalence of cretinism has been greatly reduced by the mandated screening for hypothyroidism at birth in developed countries and by supplementing the diet with foods high in iodine including bread and salt. However, iodine deficiency is still the most common cause of preventable mental deficiency worldwide. This is often true because of various societies that resist food additives or because of the cost of iodine or TH supplementation. Iodine and THs are discussed in greater detail in Chapter 3, Iodine and thyroid hormones.

Hypothyroidism

Myxedema The term myxedema describes the “full-blown” expression of acquired hypothyroidism. Adult myxedema resembles the effects of cretinism in children, but develops in later childhood or in adulthood. In 1873 English physician Sir William Gull first linked myxedema with thyroid dysfunction. He described this as the development of the cretinoid state in adults. Clinical manifestations are different based on the patients’ age of onset. In older children the signs and symptoms resemble those of cretinism as well as adult hypothyroidism. In adults the condition is of insidious onset and may require years before becoming clinically recognized. Myxedema affects women much more often than men, and most affected patients are in their middle age. In all patients with myxedema, there are destructive changes to the thyroid gland. Usually, delicate fibrous tissue replaces the normal thyroid gland structures. This fibrous development also often occurs in the skin and less often in the visceral organs, suggesting an irritative or inflammatory process. There is slowed mental and physical activity and the patient becomes apathetic. Mental sluggishness may resemble depression. Speech and intellectual functions are slower and affect is flat. Other signs and symptoms include hair and tooth loss; alterations in speech, movement, sensation, consciousness, and intellect; plus large collections of mucin on the skin, fibrous tissues, blood, and salivary glands. There is shortness of breath and lowered exercise tolerance. Cardiac output is decreased because of the lowered expression of several sarcolemmal genes including the calcium ATPases and the beta-adrenergic receptor. There are increases in total cholesterol and low-density lipoprotein (LDL) levels, contributing factors of this disease’s higher mortality rates. In adults the common features of hypothyroidism, once it surpasses the mild stage, include easy fatigue, sensitivity to cold, weight gain of usually 10
20 lb, constipation, menorrhagia and other menstrual abnormalities, and muscle cramps. The skin may become cool, rough, and dry as glycosaminoglycans and hyaluronic acid accumulate. A yellowish skin color is common because of reduced conversion of carotene to vitamin A, causing increased blood levels of carotene. The face and hands become puffy in appearance due to nonpitting edema (Fig. 5.3). The facial features broaden and the tongue enlarges. The voice becomes hoarse and husky, and the reflexes are slowed. Some or all of these signs and symptoms are reduced or absent when the patient has a milder degree of thyroid failure. Diagnosis of hypothyroidism and myxedema is most commonly done when a patient complains of fatigue, weight gain, or depressed mood. The most sensitive screening test is the measurement of serum TSH. TSH is increased in primary hypothyroidism due to poor production of TH by the thyroid. In hypothalamic or pituitary disease (central hypothyroidism) the TSH can be low. All forms of hypothyroidism result in lower T4 levels.

95

96

Epidemiology of Thyroid Disorders

Figure 5.3 Myxedema.

Myxedema coma is an extremely rare condition that is actually the final stage of untreated hypothyroidism. Progressive weakness, hypothermia, hypoventilation, hypoglycemia, hyponatremia, and stupor develop, which can lead to shock and death. It is most common in winter in older females with pulmonary and vascular disease. The mortality rate may be more than 50% of patients. It may follow previous thyroid disease, radiation or radioiodine therapy to the neck area, or thyroidectomy. Medical history will show gradual onset of lethargy that progressively worsens. Bradycardia and significant hypothermia are seen. The body temperature may be as low as 75 F. The tongue is enlarged, the patient has all the previously described myxedema symptoms, and there is ileus present. Additional illnesses may accompany the condition, including myocardial infarction, pneumonia, cerebral thrombosis, or gastrointestinal bleeding. Also, there may be other bleeding episodes, hypercalcemia, hypocalcemia, and seizures. Diagnoses of myxedema coma are based on high serum carotene, lactescent serum, elevated blood urea nitrogen (BUN) and creatinine, hyponatremia, elevated serum cholesterol, and increased cerebrospinal fluid (CSF) proteins. There may be high protein content in the pericardial, abdominal, or pleural effusions. The serum will have very low FT4 and markedly elevated TSH. Thyroid autoantibodies are often highly positive, which indicates underlying Hashimoto’s thyroiditis. On an electrocardiogram, there will be low voltage and sinus bradycardia. Diagnosis must be made clinically if laboratory studies are not immediately available.

Hypothyroidism

Myxedema coma has three major pathophysiologic features: • Retention of carbon dioxide and hypoxia—likely because of marked depression in ventilatory responses to hypoxia and hypercapnia; contributing factors include heart failure, obesity, immobilization, ileus, pleural or peritoneal effusions, pneumonia, central nervous system (CNS) depression, and weakened chest muscles; ventilatory drive impairment may be severe; assisted respiration is usually required; TH therapy corrects hypothermia and improves ventilatory response to hypoxia. • Fluid and electrolyte imbalance—mostly, this involves water intoxication because of reduced renal perfusion and impaired free water clearance; this causes hyponatremia and is best controlled by free water restriction. • Hypothermia—this may not be recognized due to limitations of common clinical thermometers; therefore thermometers with larger scales must be used to obtain an accurate temperature reading; active rewarming must not be performed because it can cause vasodilation and vascular collapse; increased body temperature is a useful indicator of successful T4 therapy. Myxedema coma can be precipitated by heart failure, pneumonia, and administration of sedatives or narcotics when the patient has severe hypothyroidism. Sometimes, adrenal insufficiency occurs due to either functional pituitary impairment or concurrent autoimmune adrenal insufficiency, which is known as Schmidt syndrome. There should be glucocorticoid therapy, which is administered until normal adrenal function is documented, and treatment with intravenous T4 is given. Myxedema coma must be differentiated from primary thyroid gland failure related to pituitary failure, or central hypothyroidism. In this situation, glucocorticoid replacement is essential. Focus on life expectancy and mortality Hypothyroidism has been linked to many conditions that limit life expectancy. These include atherosclerosis, cardiac dysfunction, coagulopathy, and hypertension. A review of available studies on hypothyroidism-related morbidity revealed varied, inconsistent data that supported the increased mortality related to subclinical or overt hypothyroidism. Oppositely, data from NHANES III indicated that hypothyroidism is associated with greater mortality than euthyroidism in blacks, than in nonblacks.

Drug-induced Many drugs have been associated with thyroid inflammation or the activation of autoimmune thyroid destruction. Lithium is commonly associated with hypothyroidism as it blocks the release of TH from the gland. The incidence of lithium-associated hypothyroidism varies widely, from 6% to 52% in those taking lithium. The antiarrhythmic amiodarone is associated with both hypo- and hyperthyroid disorders and therefore thyroid function is monitored regularly with individuals taking this drug. A high

97

98

Epidemiology of Thyroid Disorders

incidence, due to thyroid destruction, is with the tyrosine kinase inhibitors (TKIs) such as sunitinib. This drug is used for renal cell carcinoma and gastrointestinal stromal tumors. It inhibits many cellular pathways, including the stem-cell factor receptor called KIT, plasma-derived growth factor, vascular endothelial growth factor, and pathways that are rearranged during transfection. Abnormal TSH levels were found in 62% of patients receiving sunitinib, followed over 37 weeks. Via ultrasound, the patients demonstrated no thyroid tissue. Although 40% of hypothyroid patients first had suppressed TSH levels, which suggested thyroiditis, over a longer time, they were most consistent with sunitinib-induced follicular cell apoptosis. Therefore these patients need repeated thyroid-function tests. The TKIs have been shown to slow disease progression in advanced thyroid cancer, which is unresponsive to radioiodine. However, they may increase TH requirements because of increased D3 expression.

Central hypothyroidism Central hypothyroidism is caused by TSH deficiency from acquired or congenital hypothalamic or pituitary gland disorders. Causes of TSH deficiency may be classified as pituitary origin (secondary hypothyroidism) or hypothalamic origin (tertiary hypothyroidism). However, this distinction is not required in the initial separation between primary and central hypothyroidism. Often, TSH hyposecretion occurs along with decreased secretion of other hormones from the pituitary. This shows that gonadotroph, somatotroph, and corticotroph failure is concurrent. Hyposecretion of TSH as a monotropic deficiency is not as common, but does sometimes occur, in both acquired and congenital forms. Hypothyroidism from pituitary insufficiency has varied severity. It can be mild and not as severe as gonadal and adrenocortical failure symptoms or it may be the predominant manifestation. Since a small but significant portion (about 10%
15%) of thyroid gland function is independent of TSH, hypothyroidism from central causes is not as severe as primary hypothyroidism. Central hypothyroidism is either acquired or congenital. As well as hypothalamic disorders, pituitary tumors, and related conditions, an uncommon cause of secondary hypothyroidism occurs in patients who are given bexarotene. This drug is a retinoid X receptor agonist used to treat T-cell lymphoma. It suppresses activity of the human TSH beta-subunit promoter in vitro. There is an approximate 50% reduction in serum T4 concentrations. The patients experience clinical benefits from TH replacement. Dobutamine, dopamine, high doses of glucocorticoids, and severe illnesses may suppress the transient release of TSH. This can result in a pattern of TH abnormalities that suggest central hypothyroidism. This severe hypothalamic
pituitary
thyroid suppression reveals stage 3 illness. Although these agents are thought to have similar effects over the long term, they do not. Somatostatin, also, does not have a similar

Hypothyroidism

effect when given for acromegaly, even though it blocks the response of TSH to thyroid-regulating hormone (TRH). This drug has been given to patients with thyrotropin-secreting pituitary adenomas. Rare causes of congenital hypothyroidism include congenital defects of TSH stimulation, synthesis, or structure. These include the results of effects in several homeobox genes. Various examples of these genes encode factors required for the development of the pituitary, hypothalamus, and olfactory brain areas. Certain defects cause hereditary hypothyroidism, usually with deficient growth hormone and prolactin. Structural TSH defects also occur.

Epidemiology of hypothyroidism Hypothyroidism is among the most prevalent medical conditions. Approximately onethird of the world’s population lives in areas of iodine deficiency. Its prevalence is in 0.3% of the population, while subclinical hypothyroidism is in more than 4%. Prevalence of hypothyroidism increases with age. It is 10 times more common in women than in men, predominantly after the age of 40 years. Risk factors include increased age, family history of autoimmune diseases, such as type 1 diabetes mellitus, history of Graves’ disease, and previous head or neck irradiation. According to the National Health and Nutrition Examination Survey in 2012, about one of every 300 people in the United States has hypothyroidism. According to the National Institute of Health, approximately 4.6% of the United States population aged 12 years and older has hypothyroidism, but most of these cases are mild. In the United States and other areas of adequate iodine intake, autoimmune thyroid disease (Hashimoto’s disease) is the most common form of hypothyroidism. Worldwide, iodine deficiency remains the primary cause. Six populations must receive special consideration. These include • older patients, • those with known or suspected ischemic heart disease, • pregnant women—congenital hypothyroidism affects one out of every 3500
4000 births, • patients with persistent hypothyroidism symptoms, despite taking proper doses of levothyroxine, • patients with subclinical hypothyroidism, and • patients suspected of having myxedema coma. According to the Honor Society of Nursing, hypothyroidism is one of the most common chronic disorders in the United States. It is most common in older women with about 10% of this group being affected.

99

100

Epidemiology of Thyroid Disorders

In areas of the world with severe iodine deficiency, prevalence of goiter can be as high as 80%. Most people in these areas have autoimmune disease that ranges from primary atrophic hypothyroidism, Hashimoto’s thyroiditis, to thyrotoxicosis caused by Graves’ disease. Cross-sectional studies in the United States, Japan, and Europe have determined the prevalence of hypothyroidism as well as hyperthyroidism and the frequency and distribution of thyroid autoantibodies. There are differences in the frequency of thyroid dysfunction and serum thyroid antibody concentrations between different ethnic groups. For congenital hypothyroidism, in iodine-deficient areas, 85% of cases are due to sporadic developmental defects of the thyroid gland or a complete absence of the thyroid. The remaining 15% have thyroid dyshormonogenesis defects transmitted by an autosomal-recessive mode of inheritance. Chronic autoimmune thyroiditis, via postmortem studies, has been proven to be present in 27% of adult women, which has risen in frequency over the past five decades. With iodine deficiency the prevalence of spontaneous hypothyroidism is only between 1% and 2%. Focus on prevalence and incidence In reference to hypothyroidism the term prevalence usually refers to the estimated population of people who are managing the condition at any given time. The term incidence refers to the annual diagnosis rate or the number of new cases diagnosed each year. Therefore these two types of statistics can be different. A short-lived disease, such as the flu, can have a high annual incidence but low prevalence. Oppositely, a lifelong disease, such as diabetes, has a low annual incidence but high prevalence.

Pathogenesis of hypothyroidism Deficiency of TH affects almost all body tissues, causing multiple symptoms. The most pathologically characteristic finding is the accumulation of glycosaminoglycans and primarily hyaluronic acid in the interstitial tissues. These accumulations, plus increased capillary permeability to albumin, explain the interstitial nonpitting edema seen in the skin, heart muscle, and striated muscle. The accumulation is caused by decreased metabolism of glycosaminoglycans and not excessive synthesis of them.

Risk factors The risk factors for hypothyroidism include increasing age and personal or family history of autoimmune disorders, including type 1 diabetes. Previous postpartum thyroiditis, previous head or neck irradiation, and history of Graves’ disease are additional risk factors, as are treatments with lithium or iodine-containing antiarrhythmics.

Hypothyroidism

Clinical presentation For individuals with longer term unrecognized and untreated hypothyroidism, signs and symptoms are more pervasive and involve multiple body symptoms. Most symptoms resolve with sufficient TH replacement. In many cases, however, signs and symptoms of primary hypothyroidism are often insidious and subtle. They may include cold intolerance, constipation, forgetfulness, and depressed mood. Modest weight gain is usually the result of decreased metabolism and fluid retention. Paresthesias of the hands and feet are common, often because of carpal
tarsal tunnel syndrome, which is caused by deposition of proteinaceous ground substance in the ligaments surrounding the wrists and ankles. Females with hypothyroidism may develop menorrhagia or secondary amenorrhea. The patient’s facial expression will be dull, with the voice sounding hoarse, and the speech becoming slowed. Facial puffiness and periorbital swelling occurs because of infiltration with mucopolysaccharides known as hyaluronic acid and chondroitin sulfate. The eyelids droop due to decreased adrenergic drive. The hair is coarse, dry, and sparse. The skin is also coarse, dry, scaly, and thickened. The relaxation phase of the deep tendon reflexes becomes slowed, and hypothermia is common. Dementia or frank psychosis (myxedema madness) may develop. Hypothyroidism affects various organ systems in the body, including the central and peripheral nervous systems, and the cardiovascular, integumentary, gastrointestinal, respiratory, muscular, and hematopoietic systems. Hypothyroidism also affects electrolyte metabolism. Its manifestations are mostly independent of the underlying condition but are functionally related to the amount of hormone deficiency. This section discusses mild-to-severe TH deficiency and related effects. Myxedema formerly described the condition of hypothyroidism, but today, this term refers to the appearance of the skin and subcutaneous tissues when severe hypothyroidism is present (see Fig. 5.4). This type of severe hypothyroidism is rare today. Therefore the term “myxedema” is only used to describe the physical signs that manifest. Focus on older adults Characteristic signs and symptoms of hypothyroidism in the elderly can be difficult to recognize and changes in mental status are sometimes attributed to dementia or just advancing age. The American Thyroid Association estimates that one in four nursing-home patients have undiagnosed hypothyroidism. Diagnosis is based on laboratory criteria.

Central and peripheral nervous system Development of the CNS requires TH. When it is deficient in fetal life or at birth, there will be impaired neurologic development. This includes hypoplasia of the cortical neurons, poorly developed cellular processes, slowed myelination, and decreased

101

102

Epidemiology of Thyroid Disorders

Figure 5.4 (A) Typical appearance with moderately severe primary hypothyroidism or myxedema. Note dry skin and sallow complexion; the absence of scleral pigmentation differentiates the carotenemia from jaundice. Both individuals demonstrate periorbital myxedema. (B) This patient illustrates the loss of the lateral aspect of the eyebrow, sometimes termed Queen Anne’s sign. That finding is not unusual in the age group that is commonly affected by severe hypothyroidism and should not be considered to be a specific sign of the condition.

vascularity. When not corrected early in postnatal life, the damage will be irreversible. When TH deficiency begins in an adult, manifestations are less severe, and symptoms usually respond easily to hormone therapy. There is decreased cerebral blood flow. However, cerebral oxygen consumption is usually normal. Therefore oxygen consumption of isolated brain tissue in vitro, unlike most other tissues, is not stimulated by the administration of THs. For severe cases, cerebral hypoxia can be caused by reduced cerebral blood flow. Deficiency of TH slows all intellectual functions including speech. There may be loss of initiative to perform tasks, and memory defects are very common. There is prominent lethargy and somnolence. Symptoms of dementia in the elderly may be mistaken for those of senile dementia. For a hypothyroid patient, positron emission tomography brain scans, before and following T4 therapy, will show reversible reduced glucose uptake in certain brain areas, including the limbic system, which is also related to behavioral and psychiatric symptoms. Hypothyroidism commonly causes psychiatric disorders, usually of the paranoid or depressive type, and may cause agitation, known as myxedema madness. Headaches are usually experienced. Circulatory

Hypothyroidism

alterations, resulting in cerebral hypoxia, may cause confusional attacks and syncope, which can be prolonged, leading to stupor or coma. Other factors leading to coma in hypothyroidism patients include infection, severe cold temperatures, hypoventilation with carbon dioxide retention, trauma, and depressant drugs. There may be epileptic seizures usually occurring in myxedema coma. Night blindness is caused by the reduced synthesis of the pigment needed for dark adaption. Perceptive hearing loss is common because of myxedema of the eighth cranial nerve and serous otitis media. This type of deafness may also occur along with a defect in organic binding of thyroidal iodide, known as Pendred syndrome. However, when this occurs, it is not only related to hypothyroidism. Myxedematous infiltration of the tongue causes thick, slurred speech. When this infiltration affects the larynx, it causes hoarseness. The body movements become slowed and clumsier with cerebellar ataxia sometimes occurring. There is frequent numbness and tingling of the extremities. When occurring in the fingers, this may be due to compression by glycosaminoglycan deposits within and around the median nerve in the carpal tunnel, known as carpal tunnel syndrome. The tendon reflexes become slower, especially in the relaxation phase, causing hung-up reflexes due to decreased rates of muscle contraction and relaxation and not delays in nerve conduction. If extensor plantar responses or diminished vibration sensing are present, there may be coexisting pernicious anemia with multiple system disease. Electroencephalographic alterations include general loss of amplitude and slowed alpha-wave activity. Protein concentration within the CSF is often raised, although CSF pressure is normal. Histopathologic brain examination, with untreated hypothyroidism, reveals an edematous state of the nervous system with mucinous deposits in and around the nerve fibers. With cerebellar ataxia the cerebellum may contain neural myxedematous infiltrates of glycogen and mucinous material. There may be areas of degeneration and increases in glial tissue. The cerebral vessels exhibit atherosclerosis, which is much more common along with coexistent hypertension. Hypothyroidism is related to certain neurologic conditions, but no significant etiologic link is established. A proven link is the amyloid deposition in Down syndrome, related to the higher incidence of Hashimoto’s disease. TH regulates amyloid gene processing in many studies. However, subclinical hyperthyroidism is also related to Alzheimer’s disease. In Alzheimer patients, there are increased CSF reverse liothyronine levels, with normal circulating TH levels. This suggests that altered TH metabolism is occurring in the brain. We do not fully understand the impact of normalizing T3 levels in the brain. Encephalopathy that responds to corticosteroids is related to chronic Hashimoto’s thyroiditis but may be linked to autoimmunity instead of any process specifically mediated by thyroid autoantibodies or low TH levels. Thyroid dysfunction and mental disorders are discussed in greater detail in Chapter 13, Thyroid dysfunction in fetuses and newborns.

103

104

Epidemiology of Thyroid Disorders

Cardiovascular system In hypothyroidism the resting cardiac output is reduced due to decreased stroke volume and heart rate. This shows that there is a loss of both inotropic and chronotropic effects of THs. Resting peripheral vascular resistance is increased, while blood volume is decreased. Such hemodynamic alterations cause pulse pressure to be narrowed, circulation time to be prolonged, and a reduction in blood flow to body tissues. Decreased cutaneous circulation causes coolness and pallor of the skin as well as cold sensitivity. Most tissues experience decreased blood flow proportional to reduced oxygen consumption. Therefore arteriovenous oxygen differences remain normal. Changes in hemodynamics while at rest are similar to those with congestive heart failure. The difference is that hypothyroidism causes increased cardiac output and decreased peripheral vascular resistance in response to exercise—unless the hypothyroidism is severe and chronic. Thyroid dysfunction related to the heart is discussed in detail in Chapter 12, Thyroid dysfunction in pregnancy.

Integumentary system The composition of the ground substance of the dermis and other tissues is altered by the accumulation of hyaluronic acid, which occurs because of hypothyroidism. This material easily takes up and retains moisture. It produces mucinous edema, which causes thickening of the features and a puffy appearance—the actual description of myxedema—due to full-blow hypothyroidism. The myxedematous tissue is spongy, nonpitting, and occurs around the eyes, on the dorsal parts of the hands and feet, and in the supraclavicular fossae. The tongue enlarges, and the pharyngeal and laryngeal mucous membranes become thicker. In patients with Graves’ disease a clinically similar edematous condition may occur, but usually over the pretibial area, known as infiltrative dermopathy or pretibial myxedema. The two forms can be differentiated by histologic studies. The skin is puffy but also pale and cool due to cutaneous vasoconstriction. There may be anemia that adds to the pallor. If hypercarotenemia is present, the skin has a yellow tint, but there is no scleral icterus. Secretions of the sebaceous glands and sweat glands are decreased. This leads to the skin becoming dry and coarse. In extreme situations the skin can resemble the skin of patients with ichthyosis. Skin wounds usually heal slowly, and easy bruising occurs because of increased fragility of the capillaries. The hair of the head and body becomes dry and brittle, loses its lustrous appearance, and often falls out. Hair may be lost from the temporal aspects of the eyebrows, but this may not only be due to hypothyroidism. Because of slowed hair growth, the patient may not need to shave as often or have haircuts. The nails become brittle and slow growing. Topical T3 may be used to accelerate wound healing and stimulated hair growth.

Hypothyroidism

When the skin is examined histopathologically, there is hyperkeratosis along with plugged hair follicles and sweat glands. The dermis is edematous. Connective tissue fibers are divided by increased amounts of mucinous material described as metachromatically staining, periodic acid-Schiff positive. It contains protein complexed with the mucopolysaccharides called hyaluronic acid and chondroitin sulfate B. Hydroscopic glycosaminoglycans are mobilized when TH is used in early treatment. This leads to increased urinary excretion of tissue water, nitrogen, and hexosamine. Hypothyroidism caused by Hashimoto’s thyroiditis may also show skin lesions with loss of pigmentation, a characteristic of vitiligo, an autoimmune skin condition. This feature is not because of reduced TH. Instead, it reveals the common relationship between autoimmune endocrine disease and vitiligo, recognized as a common part of autoimmune polyendocrine syndromes. Autoimmune thyroid disorders are discussed in detail in Chapter 11, Global impact of thyroid disorders.

Gastrointestinal system In hypothyroidism, most patients have a reduced appetite, yet have a modest weight gain. This is partly due to fluid retention by the hydrophilic glycoprotein tissue deposits and usually does not exceed 10% of body weight. There is reduced peristalsis. Along with decreased food intake, this participates in frequent constipation. There may eventually be fecal impaction (myxedema megacolon). Symptoms that mimic mechanical ileus may occur, including gaseous abdominal distention (myxedema ileus), colicky pain, and vomiting. An obstruction is often erroneously suspected because of elevated serum carcinoembryonic antigen, which can develop simply to the hypothyroidism on its own. Ascites, without another cause, is unusual in hypothyroid patients. However, it can develop, usually related to pleural and pericardial effusions. Along with these effusions, the ascitic fluid will be rich in proteins and glycosaminoglycans. In primary hypothyroidism, achlorhydria, following maximal histamine stimulation, may be present. In about 33% of primary hypothyroidism patients, circulating antibodies against gastric parietal cells have been found. These may be secondary to gastric mucosa atrophy. Hypothyroid patients with positive parietal-cell antibodies require more T4 replacement in comparison with those who are antibody-negative. In a study of Swedish celiac-disease patients, they had a 4.4-times increased risk for hypothyroidism than the general population. About 12% of primary hypothyroidism patients report overt pernicious anemia. When this anemia or other autoimmune diseases coexist with primary hypothyroidism, it shows that autoimmunity is a central part of these diseases’ pathogenesis. Hypothyroidism affects intestinal absorption in a variety of ways. It may decrease absorption of many substances, while the total amount absorbed may be normal or increased since decreased bowel motility allows more time for absorption.

105

106

Epidemiology of Thyroid Disorders

Malabsorption is sometimes excessive. Liver function tests are usually normal, although impaired clearance may cause elevated levels of aminotransaminases. There is sluggish contraction of the gallbladder and, sometimes, distention. One study of patients without diagnosed thyroid disease revealed that men, but not women, who had elevated TSH levels, had a 3.8-times higher risk of cholelithiasis. Hypothyroidism is believed to be a predisposing factor for nonalcoholic fatty liver disease. Histologic examination may reveal atrophy of the gastric and intestinal mucosa, with myxedematous infiltration of the bowel wall. There may be extensive distention of the colon. There is usually an increase in volume of fluid in the peritoneal cavity. The liver and pancreas are normal.

Respiratory system Hypothyroidism affects the respiratory system and breathing. This is due to the actions upon the central regulation of respiration, and innervation and function of respiratory muscles, the upper airways, and the tongue. Radiologic examination may reveal pleural effusions, which can rarely cause dyspnea. Generally, lung volumes are normal, but there are reductions of maximal breathing capacity and diffusing capacity. Severe hypothyroidism involves myxedematous changes in respiratory muscles, with depression of the hypoxic and hypercapnic ventilatory drives. This may result in alveolar hypoventilation and carbon dioxide retention. These can contribute to the development of a myxedema coma. Hypothyroid patients have an increased likelihood for obstructive sleep apnea, which is usually resolved by restoration to the euthyroid state.

Muscular system Hypothyroidism is also related to muscle aching and stiffness, which is worsened by cold temperatures. There is delayed muscle contraction and relaxation. This causes slowness of movement and delayed tendon jerks. Muscle mass may be enlarged or decreased because of interstitial myxedema. There may be slightly increased muscle mass, with the muscles usually being firm. In rare cases the main manifestation is a large increase in muscle mass with slowness of muscular activity—this is known as Kocher
Debré
Sémélaigne syndrome or Hoffmann syndrome. Myoclonus may be evident. An electromyogram may show normal conditions, or there may be disordered discharges, polyphasic action potentials, and hyperirritability. The muscles usually appear pale and swollen upon histopathologic examination. Muscle fibers may be swollen with loss of normal striations and separation via mucinous deposits. The type I muscle fibers usually predominate other types of fibers.

Hypothyroidism

Skeletal system TH is required for normal skeletal growth and maturation. Growth failure occurs from impaired general protein synthesis and reductions in growth hormone, but even more so, reductions of insulin-like growth factor 1. The TH receptor isoforms alpha and beta play specific roles in bone maturation. Prior to puberty, TH is essential in bone maturation. Deficiency of TH, early in life, causes delayed development and epiphyseal dysgenesis, which is signified by a stippling appearance of the epiphyseal centers of ossification. Impaired linear growth results in dwarfism. The limbs are shorter than normal in relation to the trunk, yet cartilage growth is normal. With prolonged hypothyroidism, even with proper treatment, a child will not reach predicted height based on midparental calculations. There is decreased urinary excretion of calcium and reduced glomerular filtration rate. Fecal excretion of calcium and urinary as well as fecal excretion of phosphorus are varied. Calcium balance is also varied with only slight changes. Exchangeable calcium and its turnover rate are reduced. This reflects decreased bone formation and resorption. Slightly increased levels of parathyroid hormone result in some resistance to its actions. Levels of dihydroxyvitamin D are also increased. Serum calcium and phosphorus are usually normal, or the calcium is slightly elevated. In infantile and juvenile hypothyroidism the alkaline phosphatase level is usually below normal. There may be increased bone density.

Hematopoietic system Hypothyroidism causes less oxygen requirements, decreased erythropoietin production, and, as a result, smaller red blood cell mass. This is shown by the mild normocytic and normochromic anemia that is often present. Less often, macrocytic anemia occurs, sometimes due to vitamin B12 deficiency. Remember that there is a high incidence of pernicious anemia and also of achlorhydria with vitamin B12 deficiency without over anemia, along with primary hypothyroidism. Oppositely, overt hypothyroidism is present in 12% of patients with pernicious anemia, and subclinical hypothyroidism is present in 15% of these patients. Macrocytic anemia may be caused by folate deficiency due to malabsorption or dietary inadequacy of folate. Menorrhagia and defective iron absorption caused by achlorhydria may add to a microcytic, hypochromic anemia. There are usually normal total and differential white blood cell counts, and platelets are sufficient. However, platelet adhesiveness may be reduced. Pernicious anemia or significant folate deficiency will cause characteristic alterations of the peripheral blood and bone marrow. Due to decreased plasma concentrations of factors VIII and IX, the intrinsic clotting mechanism may be defective. Along with increased capillary fragility and decreased platelet adhesiveness, this may result in a tendency for bleeding.

107

108

Epidemiology of Thyroid Disorders

Pituitary and adrenocortical function Primary hypothyroidism of long-term presence results in hyperplasia of the thyrotropes and pituitary gland enlargement. This can be seen in radioimaging as increased volume of the pituitary fossa. In rare cases, pituitary enlargement compromises functions of other pituitary cells. It causes pituitary insufficiency or visual field defects. Severe hypothyroidism may cause increased serum prolactin, stimulated by elevated TRH, and proportional to serum TSH elevation. Galactorrhea may develop. Treatment with TH balances serum prolactin and TSH and eradicates galactorrhea. TH does not directly regulate growth hormone, but thyroid status affects the growth hormone axis. In children, hypothyroidism causes delayed growth. The response of growth hormone to certain stimuli may be subnormal. Decrease turnover rate of cortisol, due to decreased liver 11beta-hydroxysteroid dehydrogenase type 1 causes 24-hour urinary excretion of cortisol and 17hydroxycorticosteroids to be decreased, yet the plasma cortisol is usually normal. Responses of urinary 17-hydroxycorticosteroid to exogenous adrenocorticotropic hormone are mostly normal or slightly decreased. Plasma cortisol response to insulininduced hypoglycemia can be impaired. Severe, long-term primary hypothyroidism may cause secondary decreases of pituitary and adrenal function. Adrenal insufficiency may be precipitated by stress or by rapid TH replacement therapy. The turnover of aldosterone is decreased, yet plasma levels are normal. Plasma renin activity is reduced. Sensitivity to angiotensin II is increased. This may be linked to hypertension that occurs along with hypothyroidism.

Catecholamines In hypothyroidism the plasma cyclic adenosine monophosphate (cAMP) response to epinephrine is decreased. This may reveal decreased adrenergic responsiveness. Since responses of plasma cAMP to glucagon and parathyroid hormone are also decreased, this may suggest that THs have a general modulating influence upon cAMP generation. The reduced adrenergic responsiveness of hypothyroidism is related to every step of catecholamine signaling. This includes receptor and postreceptor actions resulting in impaired cAMP responses. In the abdominal fat of hypothyroid patients, there are reduced levels of norepinephrine and reduced production of glycerol as a response to adrenergic agonist stimulation. Catecholamine responsiveness may also be reduced by augmentation of alpha2-receptor signaling.

Reproductive function Thyroid hormone affects male and female sexual development and reproductive function. Untreated infantile hypothyroidism leads to sexual immaturity. Juvenile hypothyroidism results in delayed onset of puberty and then, anovulatory cycles. Primary

Hypothyroidism

hypothyroidism may rarely cause precocious sexual development and galactorrhea. This could be due to elevated TSH that stimulates the luteinizing hormone (LH) receptor, and elevated TRH that causes excessive release of prolactin. In adult females, severe hypothyroidism may be linked to reduced libido and failure of ovulation. There is insufficient secretion of progesterone, and as a result, endometrial proliferation continues and results in excessive, irregular breakthrough menstrual bleeding. The changes may be from deficient LH secretion as well as pulse frequency and amplitude. In primary hypothyroidism, rarely, secondary depression of pituitary function may result in ovarian atrophy and amenorrhea. There is reduced fertility and increase in spontaneous abortion and preterm delivery. However, pregnancies are often successful. Pregnancy complications are related to overt and subclinical hypothyroidism. In some studies, levothyroxine treatment for pregnant women, who are thyroid peroxidase (TPO) antibody positive, but have normal TSH ranges, has shown that treatment can reverse incidence of preterm deliveries and spontaneous abortions. Spontaneous ovarian insufficiency (formerly called primary ovarian failure) can occur in females with Hashimoto’s thyroiditis, as a factor in an autoimmune polyendocrine syndrome. In men, hypothyroidism can cause reduced libido, erectile dysfunction, and oligospermia. Some men with hypothyroidism as well as hyperthyroidism have moderate-to-severe erectile dysfunction. This improves with thyroid disease treatment, however. Plasma gonadotropins are usually normal with primary hypothyroidism. In postmenopausal women, levels are slightly lower than in euthyroid women of the same age, yet still in the menopausal range. This provides a good way to differentiate between primary and secondary hypothyroidism. Metabolism of androgens and estrogens is altered by hypothyroidism. Androgen secretion is decreased. Testosterone metabolism is more toward etiocholanolone instead of androsterone. Hypothyroidism also favors metabolism of estradiol and estrone via 16-alpha-hydroxylation instead of 2-oxygenation. This results in increased formation of estriol, but decreased formation of 2hydroxyesterone and its derivative, called 2-methoxyestrone. There is decreased plasma sex hormone
binding globulin. Plasma concentrations of testosterone and estradiol are decreased, while unbound fractions are increased. Restoration of euthyroidism will correct alterations in steroid metabolism.

Nutrient metabolism Decreases in energy metabolism and heat production are shown by a low basalmetabolic rate, reduced appetite, cold intolerance, and slightly lower-than-normal basal body temperature. Synthesis and degradation of proteins are decreased—with degradation being more significant. Nitrogen balance, then, is usually slightly positive. Decreased protein synthesis is signified by the retardation of skeletal and soft-tissue growth. Capillary permeability to proteins is increased, shown by high protein levels

109

110

Epidemiology of Thyroid Disorders

in effusions and CSF. The albumin pool is increased as well, from greater decrease in albumin degradation compared to its synthesis. A higher than normal amount of exchangeable albumin is in the extravascular space. Total serum protein concentration may be increased. Hypothyroidism is linked to reduced glucose disposal to adipose tissue and skeletal muscle. TH can stimulate expression of the insulin-sensitive glucose transporter (GLUT4). Hypothyroidism reduces levels of this transporter. There is also reduced gluconeogenesis. There is usually only a slight effect upon serum glucose levels. TH lessens expression of prohormone-processing enzymes. These, therefore, have more activity in hypothyroidism. There is slowed degradation of insulin and, sometimes, increased sensitivity to exogenous insulin. A patient with diabetes mellitus, who then develops hypothyroidism, may have reduced insulin requirements. At the tissue level, another influence upon glucose uptake may develop. Impaired glucose disposal is linked to polymorphisms in the 50 -deiodinase type 2 (D2) gene, which may affect local T3 production. Synthesis and degradation of lipids are depressed, with degradation being more significant. The effect is accumulation of LDL and triglycerides. Decreased lipid degradation may reveal a decrease in postheparin lipolytic activity and reduced LDL receptors. There are decreased plasma levels of free fatty acids. There is impaired mobilization of free fatty acids, responding to catecholamines, fasting, and growth hormone. Impaired free fatty acid mobilization is reflected by impaired lipolysis of white fat in hypothyroid patients, at baseline, as well as responses to catecholamines. Treatment can relieve all of these abnormalities. Elevated serum LDL cholesterol is usually associated with over as well as subclinical hypothyroidism. Serum high-density lipoprotein and triglyceride levels are not usually influenced, however, reduced LDL with T4 therapy is mostly related to the original amount of LDL and TSH elevation. If initial levels are higher, the reduction in LDL is also greater. A typical LDL reduction is 5%
10% of the original level. Adipocytokines, such as adiponectin, leptin, and resistin, play important roles in metabolic regulation and may interact with TH. Leptin regulates central adaptation between the starved and fed states. Falling leptin levels, related to starvation, cause suppression of the thyroid axis. Leptin infusion into cerebral ventricles reverses some metabolic changes, including reduced skeletal muscle fat and improved glucose disposal. There are inconsistent changes in adipocytokines in hypothyroidism.

Electrolyte metabolism Hypothyroidism causes reversible reductions in glomerular filtration rate, renal blood flow, and maximum tubular reabsorption and secretion. While uric acid levels may be increased, serum creatinine and BUN levels are normal. There is decreased urine flow.

Hypothyroidism

Delayed excretion of water may cause reversal of normal urine excretion diurnal patterns. Water excretion delay may be due to decreased volume delivery to the nephrons’ distal diluting segments, caused by diminished renal perfusion. Inappropriate vasopressin secretion, a syndrome of inappropriate antidiuretic hormone (ADH) secretion, is not fully understood. Hypothyroidism is extremely prevalent along with chronic kidney disease. Improved renal function has been shown after treatment with T4. Impaired excretion of water by the kidneys and retention of water by hydrophilictissue deposits cause increased total body water, while plasma volume is reduced. The increase explains hyponatremia that sometimes occurs, since the level of sodium that can be exchanged is increased. Exchangeable potassium levels are usually normal compared to the amount of lean body mass. There may be increased serum magnesium, but exchangeable levels of magnesium and urinary magnesium excretion are reduced.

Diagnosis of hypothyroidism In all types of hypothyroidism, decreased TH secretion is common—except for rare disorders of TH action or metabolism. These disorders include consumptive hypothyroidism and resistance to TH. In primary thyroid disease, more than 99% of patients have hypothyroidism. There is a large increase in basal serum TSH, and TSH is the preferred initial diagnostic test for hypothyroidism. If suspicion is strong, a goiter is present, or central hypothyroidism is part of the differential diagnosis, a free levels of thyroxine (free T4 or fT4) assay should be performed. When TSH is elevated, an fT4 assay can be added. With disease progression, serum TSH rises as serum fT4 falls. At the severest stage, serum T3 may be subnormal. Persistence of normal serum T3 is partially due to preferential synthesis and secretion of T3 by remaining functioning thyroid tissue, controlled by increased plasma TSH. Also, there is decreased efficiency of the conversion of T4 to T3 by D2 as the serum T4 levels are falling. Therefore serum T3 may remain in the normal range. The main differential diagnosis is between primary and central hypothyroidism. Serum TSH is the most important laboratory determination. It generally allows the cause to be identified when serum fT4 is reduced. This does not occur if the patient has a recent history of thyrotoxicosis with suppressed TSH. In this case the low fT4 level may be related to reduced TSH for several months after treatment for thyrotoxicosis. In primary hypothyroidism, absence of TPO antibodies increases possible diagnosis of transient hypothyroidism after an undiagnosed painful subacute thyroiditis. This is also called postviral, de Quervain’s, granulomatous, or pseudotuberculous thyroiditis. The most critical decision is to differentiate the condition as being caused by intrinsic thyroid failure or by diminished TSH secretion due to hypothalamic or pituitary disease. Low TH, with normal or low TSH, should result in evaluation for other endocrine-system failures requiring trophic pituitary hormones for normal functioning.

111

112

Epidemiology of Thyroid Disorders

For some people with central hypothyroidism, basal serum TSH and response to thyrotropin-releasing hormone may be slightly elevated. However, TSH, while being immunologically reactive, has reduced biologic potency. With elevated TSH but reduced fT4, presence or absence of TPO antibodies must be assessed. If present, they generally suggest autoimmune thyroid (Hashimoto’s) disease. If absent, there must be an evaluation of less-common causes, including transient hypothyroidism, infiltrative disorders, and external irradiation. However, in rare cases, Hashimoto’s disease patients will not have detectable TPO antibodies or thyroglobulin. For evaluation, measurement of radioactive iodine uptake (RAIU) is not usually needed. Based on the underlying disorder, tests using radioiodine to assess thyroid function show varying patterns. Diagnostically, low RAIU is of limited value because of the higher dietary iodine intake in North America. This reduces uptake of the tracer dose. Also, each person has varying iodine intake over daily meal plans. Currently, iodine intake in North America is at a stabilized rate. If hypothyroidism is caused mostly from a biochemical defect in TH synthesis instead of thyroid-cell destruction the results in compensatory enlargement, the RAIU may be normal or even higher. Regardless, RAIU measurement is almost never needed for diagnostic evaluation of hypothyroidism. Anemia is often present, usually normocytic
normochromic, and of unknown etiology. However, it may be hypochronic, because of menorrhagia, and sometimes macrocytic because of associated pernicious anemia or decreased folate absorption. Serum cholesterol is usually high in primary hypothyroidism but not as high in central hypothyroidism.

Differential diagnoses Abnormalities of developed hypothyroidism can be overlooked if the diagnosis is not considered adequately. Severe primary hypothyroidism is often not recognized. For milder hypothyroidism, there may be significant clinical overlaps. These disorders often happen in older patients, contributing to diagnostic confusion. Sometimes, slowed mental and physical activity, dry skin, and hair loss can mimic similar hypothyroidic findings. Older individuals often become hypothermic from cold exposure. When there is chronic renal insufficiency, hypothyroidism may be suggested by anorexia, periorbital puffiness, torpor, anemia, and a sallow complexion. Specific testing is required. It may be more difficult to distinguish hypothyroidism from nephrotic states by clinical examination on its own. Edema, waxy pallor, hypometabolism, and hypercholesterolemia may suggest hypothyroidism. Also, total serum thyroxine concentrations may be decreased when large amounts of thyroid-binding globulin in lost via the urine, yet the fT4 and TSH would be normal.

Hypothyroidism

Other signs and symptoms, which can mimic hypothyroidism, include pernicious anemia, pallor, psychiatric abnormalities, and extremity numbness and tingling. There is a large amount of overlap between pernicious anemia and primary hypothyroidism. In severely ill patients, especially those who are elderly, hypothyroidism is often suspected. Total thyroxine concentrations may be greatly decreased, yet the fT4 is usually normal unless there is a severe illness. When these occur together, and there is a lack of elevated serum TSH, a euthyroid patient with another illness can be differentiated from primary hypothyroidism. Serum TSH may be transiently increased up to 20 mU/L during recovery from a severe illness, and this is termed euthyroid sick syndrome. Hypothyroidism can develop from an extrinsic factor, acquired condition, or due to a congenital defect that impairs TH biosynthesis. When there is not enough TH synthesis, it leads to the hypersecretion of TSH, producing a goiter and stimulating the steps of hormone biosynthesis, which can cause a response. Sometimes, compensatory TSH response overcomes the abnormalities in hormone biosynthesis. Then, the patient will be euthyroid, yet still have a goiter. Less often, hypothyroidism is related to an atrophic gland or a gland that never developed normally. About 20% of patients having a surgical lobectomy develop hypothyroidism. There is an increased risk in locations of iodine insufficiency or in patients who have anti-TPO antibodies.

Treatment of hypothyroidism Primary hypothyroidism and central hypothyroidism usually respond extremely well to TH. Levothyroxine is nearly always used. A main advantage of this therapy is that peripheral deiodination can continue to produce enough T3 for body tissues under normal physiologic controls. Therefore the use of levothyroxine as a prohormone allows it to be activated in the peripheral tissues by regulated mechanisms. Levels of levothyroxine are adjusted until TSH levels are in the mid-normal range. There are also synthetic preparations of levothyroxine, liothyronine, combinations of both of these hormones, and desiccated animal thyroid extract. Levothyroxine is usually given once per day orally, based on age, body mass index, and absorption. It starts with low doses and is adjusted every 6 weeks until maintenance dose is achieved. The suggested initial starting dose for older adults is 25 µg daily. Pregnant women should increase their daily dose of levothyroxine by 30% once pregnancy is diagnosed and have thyroid function checked every trimester as pregnancy results in increased binding globulins, resulting in less free T4. Patients are counseled to take the medication on an empty stomach, since bioavailability is best in this state. Absorption is also markedly decreased when consumed with iron, calcium, and dietary fiber. The dose may also need to be increased if the patient is taking medications that decrease levothyroxine absorption or increase its biliary excretion.

113

114

Epidemiology of Thyroid Disorders

The individual patient dose should be the lowest one that restores serum TSH levels to normal. In those with secondary hypothyroidism, free T4 should be measured with the goal of normal free T4 levels, as TSH is not an accurate measure of efficacious TH dose. Levothyroxine is contraindicated in patients with thyrotoxic heart disease and uncorrected adrenocorticoid insufficiency. Liothyronine is not used alone for long-term replacement because it is inexpensive, has a short half-life, and causes large peaks in serum T3 levels. Administration usually results in quickly increased serum T3 due to nearly complete absorption. However, these levels normalize within 24 hours. Also, patients taking liothyronine are chemically hyperthyroid for at least a few hours every day, which may increase cardiac risks. Similar patterns of serum T3 occur when combined T3 and T4 are taken orally. However, peak T3 is lower since less T3 is given. When synthetic T4 is used, there is a different pattern in serum T3 response. The available desiccated animal thyroid preparations have varying amounts of either hormone and are not prescribed unless the patient is already taking the preparation and has normal serum TSH. In secondary hypothyroidism, levothyroxine is not given until there is proof of adequate secretion of cortisol, or cortisol therapy is provided. This is because levothyroxine could precipitate an adrenal crisis. For myxedema coma, treatment involves intravenous T4, corticosteroids, supportive care, and conversion to oral T4 once the patient is stable. A large initial dose of either hormone is given first and then maintenance doses of T4 are given intravenously. Corticosteroids are given due to the possibility of central hypothyroidism. The patient should not be rewarmed quickly since this can result in hypotension or arrhythmias. Since hypoxemia is common, the partial pressure of oxygen must be monitored. Immediate mechanical ventilatory assistance is required if ventilation is compromised. Precipitating factors must be quickly, correctly treated. Fluid replacement is given carefully since the hypothyroid patient does not excrete water normally. All medications are administered with caution since they are metabolized more slowly in hypothyroid patients.

Complications Hypothyroidism patients on therapeutic doses of levothyroxine replacement and mildto-moderate hypothyroidism patients can tolerate surgery with complications and have a mortality similar to those who are euthyroid. For elective surgery the patient should be brought to the euthyroid state before the procedure. If the surgery is urgent, it should occur along with individualized replacement therapy, both preoperatively and postoperatively. Complications of hypothyroidism can include treatment-induced congestive heart failure when there is coronary artery disease. There may be a lifethreatening myxedema coma. The patient usually has increased susceptibility to

Hypothyroidism

infections and hypersensitivity to opiates. Other complications may include megacolon, organic psychosis with paranoia, and infertility. With vigorous treatments, an adrenal crisis can occur, especially if the patient has an undiagnosed polyendocrine syndrome. Overtreatment for long time periods can result in bone demineralization. For subclinical hypothyroidism, there is an association with increased ischemic heart disease and increased mortality from all causes—in men, but not in women.

Subclinical hypothyroidism The state of having elevated TSH levels while are normal is referred to as subclinical hypothyroidism. In previous times, this term described low-normal fT4 levels with slightly elevated serum TSH levels. Subclinical hypothyroidism is also known as early thyroid failure, mild hypothyroidism, decreased thyroid reserve, and preclinical hypothyroidism. It is caused by the same thyroid disorders that cause over hypothyroidism. In affected patients, there is a slight elevation of TSH. Values are usually between 5 and 15 mU/L. However, those with levels above 10 mU/L usually have a reduced fT4, sometimes with true symptoms of hypothyroidism. Primarily, the reference ranges for normal TSH concentrations define this syndrome. It is most common in patients who have early Hashimoto’s disease. It is quite common, affecting 7%
10% of older females, increasing with age. Many studies of subclinical hypothyroidism have had varying results from the use of physiologic “end points.” These include measurements of serum enzymes, serum lipids, psychometric tests, and systolic time intervals. Most careful studies have shown a return in one or several parameters to normal, in 25%
50% of test subjects. Generally, TSH and fT4 levels return to normal, while free T3, which is usually normal at the beginning of testing, does not change. Most studies have revealed slight improvements in lipid profiles and cardiac results. Middle-aged patients have had proven benefits related to cardiovascular risks. Some studies have shown a link between mild hypothyroidism and increased risks for atherosclerotic heart disease. Subclinical hypothyroidism is associated with depression, which is refractory to antidepressant drugs and TH. Other features of this condition include hysteria, memory impairment, anxiety, depressive features without actual depression, and somatic complaints. The likelihood of developing significant hypothyroidism is an important factor recommended levothyroxine therapy. Risks of subclinical hypothyroidism progressing to overt disease are directly related to the extent of serum TSH elevations and whether anti-TPO antibodies are present. In females with subclinical hypothyroidism, studies have shown progression rates from about 3% to 8% per year. Higher rates were seen in those with initial TSH concentrations greater than 10, and in those having positive anti-TPO antibodies. Most patients slowly progress to overt hypothyroidism. However, rapid progression, only over weeks to months, has been seen. The factors

115

116

Epidemiology of Thyroid Disorders

predisposing a patient for this rapid progression include high levels of TPO antibodies, increased age, concurrent systemic infection or inflammation, iodine contrast agents, and medications including lithium and amiodarone. When deciding to use levothyroxine for treatment, the cost and inconvenience of such a daily medication must be considered. Iatrogenic hyperthyroidism can occur as a result of overvigorous TH replacement. Also, there is the possibility that accidental overdosage may worsen osteoporosis or cause cardiac arrhythmia. Therefore the ultimate decision to use this medication is based on individualized consideration of the patient and the patient’s own preference. If a trial of therapy is undertaken, TSH concentrations should be measured after 8 weeks of treatment, along with patient response to treatment. Once on a stable dose of TH, TSH can be monitored annually. Dose requirements usually do not change once a patient is on a stable dose of TH unless there is significant weight loss or gain, or during the life events of pregnancy or menopause, where changes in binding globulins affect free T4 levels.

Metabolic insufficiency True hypothyroidism causes nonspecific symptoms that include fatigue, slight lassitude, mild anemia, apathy, constipation, cold intolerance, loss of hair, menstrual irregularities, and weight gain. Therefore some patients with these manifestations, who still have normal thyroid function or slightly at the edge of normal lab values, sometimes think that a trial of levothyroxine may improve symptoms. At the outset, response to TH therapy is sometimes good; this is likely a placebo effect. However, symptomatic improvement usually stops after a certain period of time. This approach can be associated with iatrogenic hyperthyroidism and serious adverse events. Therefore without biochemical documentation of impaired thyroid function, TH therapy should not be used. Also, even for subclinical hypothyroidism patients, symptoms may be nonproportional to fT4 abnormalities. The patient should know that correcting mild biochemical imbalances would not relieve the symptoms.

Clinical cases Clinical case 1 1. How is congenital hypothyroidism usually diagnosed? 2. What medications will be required to manage this condition? 3. Can congenital hypothyroidism affect a patient’s offspring? A baby boy was diagnosed with congenital hypothyroidism early in childhood. He was relatively inactive and growing slower than the normal rate for his age. When participating in outdoor activities with other children, he always required more clothing than the others due to his inability to keep warm. However, with daily medication, the boy was able to live a nearly normal life.

Hypothyroidism

Answers: 1. Congenital hypothyroidism is usually diagnosed after a standard heelprick blood sample obtained at 1
2 days of age, which measures levels of T4 and TSH. If the first result is positive, another sample is taken, but from a vein instead of the heel, for confirmation. An ultrasound exam or thyroid scan may be recommended to determine the specific cause of the condition. 2. Usually, levothyroxine—a synthetic but identical form of thyroxine—will be used on a daily basis. Often, this medication will be needed throughout the patient’s life. 3. Congenital hypothyroidism has been linked to miscarriage, preeclampsia, anemia, stillbirth, and the offspring of patients with the condition developing it themselves. It may also cause infertility.

Clinical case 2 1. What is the likely diagnosis for this patient? 2. What TSH level should be maintained for this patient? 3. Is this condition related to other autoimmune conditions? A 38-year-old woman had been previously diagnosed with an underactive thyroid gland. She visits her physician complaining of increasing fatigue, fluid retention, weight gain, and constipation. Tests reveal that her antithyroglobulin antibodies and anti-TPO antibodies were extremely high, as was her TSH level. Answers: 1. The diagnosis is probably the autoimmune condition known as Hashimoto’s thyroiditis. 2. For this condition, it is usually recommended that the TSH level be kept under 3.0 mIU/L. 3. Yes, Hashimoto’s thyroiditis is related to lupus erythematosus, type 1 diabetes, rheumatoid arthritis, and other autoimmune conditions.

Clinical case 3 1. What is the likely diagnosis for this infant? 2. What is the chance of this infant being mentally impaired? 3. Are there any preventative measures for this infant’s condition? A 6-month-old male infant was brought to a pediatrician with severe constipation. His mother explains that the symptoms began recently and they also included jaundice, thickening of the nose and lips, umbilical hernia, and a protruding tongue.

117

118

Epidemiology of Thyroid Disorders

Answers: 1. This infant has signs and symptoms of cretinism. 2. When treatment for cretinism is not started in the first few weeks of life, there may be irreversible mental impairment. 3. A simple preventative measure for cretinism is the addition of iodine into the diet when a woman is pregnant. In addition, studies have shown that adequate iodine before conception increases the chances of giving birth to a completely normal child.

Clinical case 4 1. What condition does this patient probably have? 2. Based on the signs and symptoms, was this patient possibly close to developing a coma? 3. What are the other common signs and symptoms of this condition? A 55-year-old woman was hospitalized with signs of hypothermia, hypoglycemia, hypotension, and respiratory depression. She had swelling around her eyes and in her hands and feet. Her speech was hard to understand because of slurring and the hoarseness of her voice. She was very slow to respond to questions and her skin appeared very dry and flaky. Answers: 1. This patient probably has myxedema. 2. Yes, this patient’s swelling, respiratory depression, lack of responsiveness, and hypothermia all signal that a myxedema coma was developing. 3. Myxedema is also signified by brittle hair or fingernails, constipation, decreased sweating, depression, pale skin, fatigue, malaise, musculoskeletal pain, thickening of the skin, weakness, and weight gain.

Clinical case 5 1. What is the likely diagnosis for this patient? 2. What other tests help to confirm this diagnosis? 3. What are the treatment options for this patient? A 50-year-old woman visits her physician complaining of a weight gain of 20 lb in the last year, fatigue, memory loss, dizziness when she stands up from sitting, changes in her voice, constipation, intolerance to cold, and constipation. She is slightly obese and her face appears puffy, with her skin being pale, dry, and cool. Her thyroid gland is not palpable, and she has a deep tendon reflex time that is delayed. Answers: 1. This patient probably has secondary hypothyroidism, although tertiary hypothyroidism is possible but less likely. The features that are most suggestive for hypothyroidism include her voice changes, delayed deep tendon reflex, and bradycardia.

Hypothyroidism

2. Additional confirmative tests include MRI with gadolinium enhancement to document any masses that are present, baseline and dynamic anterior pituitary hormone tests, and tests for other tumor markers. 3. Treatment options include evaluation and treatment of secondary hypoadrenalism, followed by treating the secondary hypothyroidism; this is followed by evaluating if hypogonadism and/or growth hormone deficiency is present, and treating them.

Key terms achlorhydria adipocytokines amenorrhea aminotransaminases ascitic atrophic thyroiditis autoimmune hypothyroidism carcinoembryonic antigen celiac disease central hypothyroidism cerebellar ataxia chondroitin chronotropic congenital hypothyroidism cretinism cyclic adenosine monophosphate (cAMP) deiodination dyshormonogenetic goiter epiphyseal dysgenesis galactorrhea goiter Hashimoto’s thyroiditis Hoffmann syndrome homeobox hung-up reflexes hyaluronic acid hypercarotenemia hypothyroidism ichthyosis

inotropic interstitial myxedema isoenzymes iatrogenic hypothyroidism lactate hydrogenase lactescent levothyroxine liothyronine megacolon menorrhagia metachromatically staining monotropic deficiency myxedema myxedema coma myxedema madness myxedema megacolon myxedematous organic psychosis oxyphil metaplasia Pendred syndrome periodic acid-Schiff (PAS) positive pernicious anemia polyendocrine syndromes polyphasic pretibial myxedema Schmidt syndrome secondary hypothyroidism tapioca thyrocytes

119

120

Epidemiology of Thyroid Disorders

thyroid agenesis thyroid hypoplasia thyroiditis

thyroxine (T4) type I muscle fibers tyrosine kinase inhibitors

Further reading 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

Adult Hypothyroidism and Myxedema. ,https://www.ncbi.nlm.nih.gov/books/NBK285561/.. Batabyal, B. An Overview of Congenital Hypothyroidism. (2017) Lap Lambert Academic Publishing. Casaneuva, F.F., and Ghigo, E. Hypothalamic-Pituitary Diseases (Endocrinology). (2018) Springer. Chaker, L., Bianco, A.C., Jonklaas, J., and Peeters, R.P. Hypothyroidism, Lancet 2017; 390: 1550
62. DeLange, F., Fisher, D.A., and Glinoer, D. Research in Congenital Hypothyroidism (Natao Science Series). (2012) Springer. Dennison, J., Oxnard, C., and Obendorf, P. Endemic Cretinism. (2011) Springer. Epidemiology of Thyroid Disease and Swelling. ,https://oxfordmedicine.com/view/10.1093/med/ 9780199235292.001.1/med-9780199235292-chapter-317.. Gardner, D.G., and Shoback, D.M. Greenspan’s Basic and Clinical Endocrinology, 10th Edition. (2017) McGraw-Hill Education/Medical. Icon Group International. Myxedema: Webster’s Timeline History, 1885-2007. (2010) Icon Group International, Inc. Jameson, J.L. Harrison’s Endocrinology, 4th Edition. (2016) McGraw-Hill Education/Medical. Koibuchi, N., and Yen, P.M. Thyroid Hormone Disruption and Neurodevelopment (Contemporary Clinical Neuroscience). (2017) Springer. Loriaux, L. Endocrine Emergencies: Recognition and Treatment (Contemporary Endocrinology). (2014) Humana Press. Lougheed, B.S. Tired Thyroid: From Hyper to Hypo to Healing
Breaking the TSH Rule. (2014) Grain of Salt Publications LLC. Melmed, S., Polonsky, K.S., Larsen, P.R., and Kronenberg, H.M. Williams Textbook of Endocrinology, 13th Edition. (2015) Elsevier. Myers, A. The Thyroid Connection: Why You Feel Tired, Brain-Fogged, and Overweight
and How to Get Your Life Back. (2016) Little, Brown and Company. Myxedema. ,https://www.ncbi.nlm.nih.gov/books/nbk285561/.. Pearce, E.N. Iodine Deficiency Disorders and Their Elimination. (2017) Springer. Porter, R.S. The Merck Manual, 19th Edition. (2011) Merck. Porth, C. Essentials of Pathophysiology: Concepts of Altered States, 4th Edition. (2014) LWW. Radovick, S., and Misra, M. Pediatric Endocrinology: A Practical Clinical Guide, 3rd Edition. (2018) Springer. Vitti, P., and Hegedus, L. Thyroid Diseases: Pathogenesis, Diagnosis, and Treatment (Endocrinology). (2018) Springer. Weiss, R.E., and Refetoff, S. Genetic Diagnosis of Endocrine Disorders, 2nd Edition. (2015) Academic Press. Wentz, I., and Nowosadzka, M. Hashimoto’s Thyroiditis: Lifestyle Interventions for Finding and Treating the Root Cause. (2013) Wentz LLC. Zayed, R. Epidemiology of Congenital Hypothyroidism in the UAE: A Population Based Study. (2009) VDM Verlag.

CHAPTER 6

Hyperthyroidism Mohtashem Samsam Contents Etiology of hyperthyroidism Epidemiology of hyperthyroidism Pathophysiology of hyperthyroidism Clinical presentation Nervous system Cardiovascular system Integumentary system Gastrointestinal system Respiratory system Muscular system Skeletal system Hematopoietic system Electrolyte metabolism Reproductive system Diagnosis of hyperthyroidism Treatment of hyperthyroidism Propylthiouracil and methimazole Beta-blockers Radioiodine Surgery Subclinical hyperthyroidism Clinical cases Clinical case 1 Clinical case 2 Clinical case 3 Clinical case 4 Further reading

122 124 126 126 129 129 130 131 131 131 132 132 133 133 134 136 137 138 139 139 140 141 141 142 143 143 144

The various manifestations of excessive amounts of thyroid hormones (THs) are described today as either hyperthyroidism or thyrotoxicosis. However, these two terms are not synonymous. The difference is that thyrotoxicosis is a state of excessive TH, while hyperthyroidism is the result of excessive thyroid function. Hyperthyroidism, however, is just one cause of thyrotoxicosis. Primary hyperthyroidism may arise from an intrinsic thyroid abnormality. Secondary hyperthyroidism may arise from processes outside of the thyroid, such as a thyroid-stimulating hormone (TSH)-secreting pituitary tumor. Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00006-2

r 2020 Elsevier Inc. All rights reserved.

121

122

Epidemiology of Thyroid Disorders

The terms thyrotoxicosis and hyperthyroidism will therefore be used interchangeably in this chapter. The thyroid gland is usually enlarged, secreting greater than normal amounts of THs. The metabolic processes of the body become accelerated.

Etiology of hyperthyroidism Hyperthyroidism may occur from increased TH synthesis and secretion, due to thyroid stimulators in the blood, or from autonomous thyroid hyperfunction. It can also develop from excessive release of TH from the thyroid, without increased synthesis. This release is usually due to destructive changes from various forms of thyroiditis. Various clinical syndromes also cause hyperthyroidism. The following three common causes of thyrotoxicosis are related to hyperfunction of the thyroid gland: • Diffuse hyperplasia of the thyroid—associated with Graves’ disease (approximately 85% of cases) • Hyperfunctional multinodular goiter • Hyperfunctional thyroid adenoma The etiology of hyperthyroidism is due to overproduction of T4, T3, or both. Diagnosis of overactive thyroid and treatment of underlying causes can relieve symptoms and prevent complications. Causes of hyperthyroidism include the autoimmune disorder known as Graves’ disease; as well as excess iodine, thyroiditis, toxic adenomas, and other tumors, toxic multinodular goiter, and large amounts of tetraiodothyronine received through dietary supplements of medications (Fig. 6.1). Overstimulation of the thyroid gland by the TSH receptor and mutations of this receptor are common causes of hyperthyroidism. Other causes include damage to thyroid follicles that cause them to passively release thyroid hormones. Additional causes of hyperthyroidism include as follows: • Thyroiditis (inflammatory thyroid disease)—includes Hashimoto’s thyroiditis, subacute granulomatous thyroiditis, and silent lymphocytic thyroiditis; there are destructive thyroid gland changes and release of stored hormone not because of increased synthesis; hypothyroidism may then follow. • Excessive iodine ingestion—there is a low thyroid radioactive iodine uptake (RAIU); this usually occurs with a nontoxic nodular goiter of patients (mostly in elderly) who are given iodine-containing drugs or who have radiologic studies that use iodine-rich contrast agents; the excess iodine may provide substrate for non-TSH regulated, autonomous areas of the thyroid to produce hormone; hyperthyroidism usually lasts as long as the excess iodine is in the circulation. • Thyrotoxicosis factitia—due to conscious or accidental overingestion of TH. • High human chorionic gonadotropin (hCG) levels—due to molar pregnancy, choriocarcinoma, or hyperemesis gravidarum; levels of hCG are highest in the first trimester of pregnancy, causing decreased serum TSH and slightly increased

Hyperthyroidism

Graves disease (TSH receptor antibodies) TSH receptor TSH IgG

4

Low TSH

1

Nodular goiter

Thyroid pill

2 3

T3, T4

Adenoma

Figure 6.1 Various causes of hyperthyroidism.

serum fT4; increased thyroid stimulation may be due to higher levels of partially desialated hCG, which seems to be stronger in its thyroid stimulation than more sialated hCG; overall, this cause is transient; normal function resumes once the condition resolves or is treated. • Plummer’s disease—also called toxic solitary or multinodular goiter; may be due to TSH receptor gene mutations that produce continuous thyroid stimulation; toxic nodular goiter results in no autoimmune manifestations or circulating antibodies seen in patients with Graves’ disease; toxic solitary and multinodular goiters usually do not remit. • Drug-induced hyperthyroidism—can be from amiodarone and interferon alfa; these can cause thyroiditis with hyperthyroidism and other disorders; lithium, in rare cases, can cause hyperthyroidism but is more commonly a cause of hypothyroidism; patients receiving these drugs require close monitoring.

123

124

Epidemiology of Thyroid Disorders

•

Struma ovarii—occurs when ovarian teratomas have enough thyroid tissue to cause true hyperthyroidism; in the pelvis, RAIU occurs; uptake by the thyroid is usually suppressed. • Nonautoimmune autosomal dominant hyperthyroidism—in infancy, this results from TSH receptor gene mutations, producing continuous thyroid stimulation. • Metastatic thyroid cancer—rarely, overproduction of thyroid hormone occurs from functioning metastatic follicular carcinoma—especially in pulmonary metastases. • Inappropriate TSH secretion—rare; in hyperthyroidism, TSH is basically undetectable, except when there is a TSH-secreting anterior pituitary adenoma or pituitary resistance to TH; the TSH levels are high; the TSH produced by both disorders is biologically of higher activity than normal TSH; increased alpha-subunits of TSH in the blood occur when there is a TSH-secreting pituitary adenoma. Graves’ disease will be discussed in detail in Chapter 7, Thyroiditis and Graves’ disease. Various causes of hyperthyroidism are illustrated in Fig. 6.1.

Epidemiology of hyperthyroidism Hyperthyroidism occurs in people over the age of 60 years in as many as 15% of cases. However, hyperthyroidism affects 1 in 500 pregnancies. In the United States, about 1.2% of the population has hyperthyroidism, which is slightly more than 1 of every 100 people. This is equivalent to approximately 3,290,000 individuals. Hyperthyroidism is also varied in populations based on iodine sufficiency. According to the National Health and Nutrition Examination Survey (NHANES III), along with United Kingdom surveys, females are also more affected than males, and there is a lower prevalence of hyperthyroidism in comparison to hypothyroidism. The predominant ages for the condition are in the third and fourth decades. It is important to note that the various studies have only been of small amounts of volunteers. The global prevalence of hyperthyroidism in women is between 0.5% and 2%. It is 10 times more common in women than in men. The prevalence in elderly people ranges between 0.4% and 2%. A higher prevalence is seen in iodine-deficient areas. Overt hyperthyroidism affects 0.4 of every 1000 women and 0.1 of every 1000 men, but there is a large variance between ages regarding susceptibility. The risk factors for hyperthyroidism include positive family history, female gender, other autoimmune disorders, and iodide repletion after iodide deprivation—especially in multinodular goiter. However, various studies have shown different results concerning hyperthyroidism. In 1992 the Cardiovascular Health Study that revealed the prevalence of overt hyperthyroidism in people aged 65 years or older was 0.33%. An article that examined various studies between 1990 and 2013 showed that the relative incidence of overt hyperthyroidism during pregnancy was estimated as ranging between 0.1% and 0.4%. In the United Kingdom the 20-year follow-up of the Whickham Study revealed annual

Hyperthyroidism

incidence of hyperthyroidism to be 0.008% in females but undetectable in males. Prevalence of previously unsuspected hyperthyroidism was 0.5% in women and, again, undetectable in men. In Scotland an increase in primary hyperthyroidism, between 1994 and 2001, was shown in a population-based study. The overall prevalence increased in females from 0.86% to 1.26% and in males from 0.17% to 0.24%. Standardized incidence increased from 0.68 to 0.87 per 1000 women annually. This represented a 6.3% annual increase. More recently, a study in Denmark showed mild-to-moderate iodine deficiency in two major cities. Overall standardized incidence rate per 100,000 person-years was 81.6. The ratio between mild- versus moderate iodine-deficiency areas was 1.6. There is limited incidence data for hyperthyroidism in the United States. This is based on the number of new prescriptions of thionamide antithyroid drugs. The incidence per 1000 subjects, by age group, in 2010 is shown in Table 6.1. Referring back to the NHANES III study, prevalence of hyperthyroidism only differs slightly by ethnicity. Table 6.2 summarizes the prevalence of hyperthyroidism for patients aged 12 years and older, by race or ethnicity in the United States. In reference to hyperthyroidism and mortality a study of British patients who presented with their first episode of hyperthyroidism between 1989 and 2003 included a follow-up until 2012. This study found that 32% of the initial cohort of patients, aged 40 years and older, had died. This was 15% higher for all-cause mortality than expected deaths for this population. Comorbidities were also high in the population. Those with atrial fibrillation had a 59% higher risk of death. Cardiovascular and Table 6.1 Incidence per 1000 subjects of overt hyperthyroidism, by age. Age (years)

Incidence per 1000 subjects

4 11 12 17 18 44 56 64 65 and older

0.44 0.26 0.59 0.78 1.01

Table 6.2 Prevalence of overt and subclinical hyperthyroidism in the United States. Race or ethnicity

Overt (%)

Subclinical (%)

Overall (%)

All Black, non-Hispanic Mexican American White, non-Hispanic Other races or ethnicities

0.5 0.5 0.2 0.6 0.4

0.7 0.6 0.5 0.8 0.3

1.3 1.1 0.7 1.4 0.7

125

126

Epidemiology of Thyroid Disorders

cerebrovascular causes were 20% higher than anticipated. Excessive mortality was not seen in the subgroup of patients who had no preceding comorbidities. In those with Graves’ disease, all-cause mortality was increased by 16%. A 2013 study focused on long-term adverse effects due to subclinical hyperthyroidism. This included an increased 24-hour heart rate and increased frequency of atrial and ventricular ectopic beats. Large studies of older adults revealed a 13% increase in the frequency of atrial fibrillation. The highest risk of coronary heart disease mortality and atrial fibrillation was found in patients with serum TSH under 0.10 mU/L. Focus on prevalence of hyperthyroidism Hyperthyroidism is about five times more common in women than in men. Overall prevalence is about 1.3%, but this increases in older women from 4% to 5%. The condition is also more common in smokers.

Pathophysiology of hyperthyroidism With hyperthyroidism, serum T3 usually increases more than thyroxine. This is probably due to increased T3 secretion, along with conversion of thyroxine to T3 in the peripheral tissues. Sometimes, just the T3 is elevated—known as T3 toxicosis. This may occur in any disorders commonly causing hyperthyroidism, including Graves’ disease, multinodular goiter, and autonomously functioning solitary thyroid nodule. When T3 toxicosis is not treated, the patient usually develops abnormalities such as elevated thyroxine and 123I uptake. Various types of thyroiditis usually have a hyperthyroid phase, followed by a hypothyroid phase.

Clinical presentation The clinical manifestations of hyperthyroidism are common to all causes of thyrotoxicosis and also Graves’ disease. The condition may be dramatic or subtle, with or without a goiter or nodule. Common signs and symptoms resemble those of adrenergic excess, including nervousness, hyperactivity, palpitations, heat hypersensitivity, increased sweating, fatigue, increased appetite, insomnia, weight loss, frequent bowel movements that may involve diarrhea, and weakness (Fig. 6.2). Hypomenorrhea can be present. Signs include tremor, warm and moist skin, tachycardia, atrial fibrillation, widened pulse pressure, and palpitations. Elderly patients, especially with toxic nodular goiter, may have atypical presentations. This apathetic (masked) hyperthyroidism may resemble depression or dementia, usually without exophthalmos or tremor. More likely symptoms include atrial fibrillation, altered sensorium, syncope, heart failure, and weakness. Signs and symptoms may only affect one organ system.

Hyperthyroidism

Hypofunction Loss of hair coarse, brittle hair Periorbital edema Puffy face Normal, enlarged, or small thyroid Heart failure (bradycardia)

Hyperfunction Thin hair Exophthalmos Normal or enlarged thyroid: • Diffuse (warm on palpation) • Nodular • Solitary "toxic" nodule Heart failure (tachycardia)

Weight loss Constipation

Diarrhea

Cold intolerance Warm skin, sweaty palms

Muscle weakness Hyperreflexia Decreased bone mineral density (osteoporosis) Edema of the extremities

Pretibial myxedema

Figure 6.2 Symptoms of Graves’ disease.

Excessive adrenergic stimulation may cause staring, eyelid lag or retraction, and mild conjunctival injection. With adequate treatment, these usually remit. Infiltrative ophthalmopathy is more serious and specific to Graves’ disease. It involves lacrimation, orbital pain, irritation, increased retro-orbital tissue, photophobia, exophthalmos, and lymphocytic infiltration of the extraocular muscles. This results in ocular muscle weakness, and often, double vision. Infiltrative dermopathy is confusedly also called pretibial myxedema (Fig. 6.3) and is signified by nonpitting infiltration by proteinaceous ground substances that is usually

127

128

Epidemiology of Thyroid Disorders

Mechanisms of hypothyroidism Secondary causes Primary thyroid malfunction

Pituitary malfunction

Hypothalamic malfunction

Lack of TH negative feedback on pituitary TSH secretion and hypothalamic TRH secretion

Lack of negative feedback to hypothalamic release of TRH by TSH and thyroid TH

Decreased TRH

Low levels of TH and high levels of TSH and TRH

Low levels of TSH and TH and high levels of TRH

Low levels of TRH, TSH, and TH

Figure 6.3 Mechanisms of hypothyrodism. Table 6.3 Thyrotoxicosis signs and symptoms, from most common to least. Signs

Symptoms

1. 2. 3. 4. 5. 6. 7. 8.

1. 2. 3. 4. 5. 6. 7. 8.

Tachycardia; atrial fibrillation in elderly patients Tremor Goiter Skin that is warm and moist Muscle weakness; proximal myopathy Eyelid retraction or lag Gynecomastia Oligomenorrhea

Hyperactivity, dysphoria, irritability Heat intolerance, sweating Palpitations Fatigue and weakness Weight loss with increased appetite Diarrhea Polyuria Loss of libido

Note: The “signs” listed in this table do not include ophthalmopathy and dermopathy, which are specific for Graves’ disease (see Chapter 7: Thyroiditis and Graves’ disease).

in the pretibial area. It rarely occurs without Graves’ ophthalmopathy. Lesions are usually erythematous and pruritus in early stages, then becoming brawny. This condition can appear years before or after hyperthyroidism. The most common signs and symptoms of thyrotoxicosis, from those of highest frequency to least, are listed in Table 6.3. Clinical presentation is based on severity of the thyrotoxicosis, disease duration, the patient’s susceptibility to excessive thyroid hormone, and age. In elderly patients, signs and symptoms may be subtle or hidden. The patient may primarily present with fatigue and weight loss. This is known as apathetic thyrotoxicosis. With thyrotoxicosis, there may be unexplained weight loss even with an increased appetite. This is because of the increased metabolic rate. About 5% of patients

Hyperthyroidism

experience weight gain, however, due to increase food intake. Other primary features include hyperactivity, irritability, and nervousness that lead to easy fatigue in some patients. Commonly, impaired concentration and insomnia are seen. For elderly patients, apathetic thyrotoxicosis is sometimes mistaken for depression. Fine tremor is common, usually induced by having the patient stretch out the fingers while feeling the fingertips with the palm of the hand. Hyperthyroidism affects various body systems that are explained further.

Nervous system As the nervous system functions are altered, the patient experiences nervousness, hyperkinesia, and emotional lability. Fatigue may occur from insomnia and muscle weakness. Emotional lability is common. Rarely, mental disturbances are severe, including manic depressive, paranoid, and schizoid reactions. Hyperkinesia is characteristic of the thyrotoxic patient. The patient, when interviewed, changes position often. Movements are fast, exaggerated, jerky, and often without any purpose. In children, these movements are usually more severe. There may be an inability to focus, resulting in poor school performance, and suggesting attention deficit hyperactivity disorder. Fine tremors may affect the eyelids when they are lightly close, the hands, or the tongue. An electroencephalogram will reveal increased fast wave activity. If the patient has convulsions, there is increased frequency of seizures. Sympathetic nervous system activation and thyrotoxicosis manifestations are often similar. However, in patients with thyrotoxicosis, plasma epinephrine and norepinephrine, along with urinary excretion of these substances and their metabolites, are not increased. Thyroid hormones have separate effects to those of the catecholamines, but are similar to them, and also additive to them. Improved cardiac function in hyperthyroidism by beta-adrenergic blockade has resulted in the idea that there is increased sympathetic tone or cardiac sensitivity to the sympathetic nervous system. Animal studies have shown that overexpression of heart type 2 deiodinase increases myocardial T3 and cyclic adenosine monophosphate (cAMP) responses to norepinephrine in cardiac myocytes because of altered G proteins. Also, adipocytes in thyrotoxic patients have 3 times higher levels of norepinephrine-induced lipolysis, 15 times higher levels of responses to beta2-adrenergic receptor agonists, and 3 times higher increases in response to cAMP or forskolin. Therefore thyroid hormones increase sensitivity to catecholamines in adipocytes and cardiomyocytes in many ways.

Cardiovascular system In hyperthyroidism, altered cardiovascular function is partly due to increased circulatory demands caused by hypermetabolism and a need to dissipate excess heat. During resting, there is decreased peripheral vascular resistance. Cardiac output increases as a

129

130

Epidemiology of Thyroid Disorders

result of increased heart rate and then, with more severe disease, stroke volume. Excess thyroid hormones have a direct inotropic effect upon heart contraction, regulated by an increased ratio of alpha- to beta-myosin heavy chain expression. Tachycardia is nearly always present. It is caused by increased sympathetic and decreased vagal tone. Widened pulse pressure is caused by increased systolic and decreased diastolic pressure, due to reduced resistance. The decreased resistance is caused by increased production of nitric oxide via the PI3K/protein kinase B (AKT) signaling pathway. The patient often feels increased systolic force, experienced as a palpitation. This is evident on inspection or palpation of the precordium. The heart can be enlarged due to the diffuse, forceful nature of the apex beat. Echocardiography reveals an increased size of the ventricles. Also, the preejection period is shortened. There is a decrease in the ratio of the preejection period to left ventricular ejection time. Heart sounds are enhanced—especially S1. There is a scratch-like systolic sound along the left sternal border. This is similar to a pleuropericardial friction rub called the Means Lerman scratch. Once a normal metabolic state is restored, these occurrences disappear. If the patient has never been in heart failure, the increased cardiovascular demands of standard workloads or metabolic challenges are met. Cardiac competence is maintained in most patients with no underlying heart disease. Without heart failure, mild peripheral edema may still occur. Heart failure usually occurs in patients with preexisting heart disease. It is more common in elderly, but sometimes it may not be determined to exist until thyrotoxicosis is relieved. Atrial fibrillation decreases efficient cardiac response to increased circulatory demands. It may be causative for cardiac failure. While thyrotoxicosis is present, there should be no attempts to convert atrial fibrillation to sinus rhythm. Approximately 60% of patients revert spontaneously to sinus rhythm following treatment, usually within 4 months. Because of this, and the fact that thromboembolism is rare in patients under age of 50 years with hyperthyroidism, routine anticoagulation is not suggested for younger patients who have no history of underlying heart disease or a thrombotic disorder. For thyrotoxicosis-induced atrial fibrillation, medical or electrical cardioversion is usually successful even after 1 year has passed.

Integumentary system The most significant change due to long-standing hyperthyroidism is that the skin feels warm and moist. This occurs due to cutaneous vasodilation and excessive sweating. There may be a smoothness and pink color of the elbows. The patient has a rosy complexion and blushes easily. Palma erythema may resemble the palms of a liver patient, and telangiectasia may develop. The hair becomes fine and brittle, with hair loss sometimes increasing. The nails also become soft and brittle. Uncommonly, there are Plummer nails or onycholysis that usually affects the fourth and fifth fingers.

Hyperthyroidism

Another autoimmune disease, vitiligo is more common if the patient has autoimmune thyroid disease. Thyroid dermopathy is a condition that usually does not require treatment. It may cause cosmetic problems or interfere with how the patient’s shoes fit. Surgical removal is not helpful. If required, treatments involve topical, high-strength glucocorticoid ointments under occlusive dressings. Octreotide may be beneficial for some patients.

Gastrointestinal system The appetite often increases but not when the disease is only mild. With more severe disease, increased food intake is insufficient to meet increased caloric needs. Weight is lost at various rates. Usually, the patient reports good success with weight loss that previously did not occur. There are more bowel movements. Diarrhea is rare but can become problematic. With thyrotoxicosis, increased gastric emptying and intestinal motility may cause slight fat malabsorption. These functions normalize once a normal metabolic state has been restored. Celiac and Graves’ diseases are coexisting more often than previously believed. There is an increased prevalence of pernicious anemia. When thyrotoxicosis is severe, hepatic dysfunction occurs more commonly. There may be hypoproteinemia, increased serum alanine aminotransferase, and elevated bone or liver alkaline phosphatase.

Respiratory system In severe hyperthyroidism, dyspnea is common. There may be several contributing factors. There is usually a reduction of vital capacity, mostly from weakness of the respiratory muscles. With exercise, ventilation is increased, but this is not proportional to the increase in oxygen uptake. The diffusing capacity of the lungs remains normal. Due to the general oxygen consumption increase related to thyrotoxicosis, the patient with a chronic lung disease may have a severe worsening of the condition when he or she becomes thyrotoxic.

Muscular system Muscle disease along with hyperthyroidism is not usually suggested by weakness or fatigue. There is usually generalized wasting related to weight loss. Weakness is most common in the proximal limb muscles. The patient has difficulty climbing stairs or becomes fatigued just from lifting relatively lightweight objects. Proximal muscle wasting may be out of proportion for overall weight loss. This is often called thyrotoxic myopathy. In very severe forms, myopathy may affect more distal muscles of the extremities, and the trunk or facial muscles. Myopathy of the ocular muscles is unusual but, if present, may mimic myasthenia gravis or ophthalmic myasthenia. Muscle

131

132

Epidemiology of Thyroid Disorders

strength improves once a normal metabolic state is restored, but muscle mass takes a longer time to recover.

Skeletal system Hyperthyroidism is usually related to increased excretion of calcium and phosphorus in the urine and stool. There is an increase in bone turnover, with a net demineralization of bone—shown by routine bone densitometry. Sometimes, especially in elderly women, there are pathologic fractures. In these, pathologic changes are varied. They may include osteitis fibrosa, osteomalacia, or osteoporosis, usually with varied vitamin D levels. Urinary excretion of telopeptides, which are collagen breakdown products, is increased. Kinetic studies show increased exchangeable calcium and acceleration of bone resorption and accretion—especially resorption. The T3 hormone accelerates osteoclast activity, and TSH may have localized actions, which can balance TH action upon osteoclasts and enhance osteoblast activity. This TSH action would be absent in hyperthyroidism and allows accentuated TH effects. These changes lead to decreased bone density in many individuals. With treatment, bone density of younger patients can normalize. In postmenopausal females, there may be accelerated bone density reduction, requiring treatment. Induction of decreased bone density via TSHsuppression therapy, with thyroid cancer, is controversial. Postmenopausal women given a TSH-suppressive dosage of TH are at risk of osteopenia. They require prophylaxis with calcium and vitamin D, or more aggressive treatments. Relaxation of TSH suppression in low-risk patients may be based on bone status. Hypercalcemia may develop along with severe hyperthyroidism for the same reasons. Total serum calcium is increased in up to 27% of patients. Ionized serum calcium is elevated in 47% of them. There are common elevations of heat labile serum alkaline phosphatase and osteocalcin. This resembles primary hyperparathyroidism, but concentrations of parathyroid hormone in the serum are usually low normal. Try primary hyperparathyroidism and hyperthyroidism sometimes exist at the same time. Plasma 25-hydroxycholecalciferol levels are decreased in thyrotoxic individuals. This change could add to the decreased intestinal absorption of calcium and osteomalacia that sometimes develops.

Hematopoietic system Thyrotoxicosis increases red blood cell (RBC) mass, but the RBCs are otherwise normal. The increased erythropoiesis is related to direct effects of thyroid hormone upon the erythroid marrow and to increased erythropoietin production. There is a parallel increase in plasma volume. Therefore the hematocrit remains normal. There are normal platelet levels, and the intrinsic clotting mechanism is also normal. Concentration of factor VIII is commonly increased. It normalizes once

Hyperthyroidism

thyrotoxicosis is treated. There is enhanced sensitivity to warfarin due to accelerated clearance of vitamin K dependent clotting factors. Therefore warfarin dosage must be reduced. This is important to remember when beginning anticoagulant treatment for atrial fibrillation in older patients. Coincidental autoimmune thrombocytopenia may occur.

Electrolyte metabolism The only symptoms related to the urinary tract produced by hyperthyroidism are mild polyuria and, possibly, nocturia. Renal blood flow, glomerular filtration, and tubular resorptive and secretory functions are increased. There is a decrease in total exchangeable potassium. This may be linked to decreased lean body mass. Electrolytes are normal, except when there is hypokalemic periodic paralysis.

Reproductive system In early life, there may be delayed sexual maturation. However, physical development will be normal, and there may be accelerated skeletal growth. After puberty, hyperthyroidism affects reproductive function—especially in females. There may be prolongation of the intermenstrual interval—or it may be shortened. Menstrual flow is at first diminished and eventually stops. There may be reduced fertility. If conception occurs, there is a higher risk of miscarriage and various complications. Sometimes, menstrual cycles are mostly anovulatory with oligomenorrhea. Mostly, ovulation occurs, indicated by a secretory endometrium. In anovulatory patients a subnormal mid-cycle increase of luteinizing hormone (LH) may be causative. In the premenopausal female with thyrotoxicosis, there are usually normal basal plasma concentrations of LH and folliclestimulating hormone (FSH). However, these may have enhanced responsiveness to gonadotropin-releasing hormone (GnRH). Whether the condition is spontaneous or caused by exogenous hormone, it is accompanied with an increase in concentration of sex hormone binding globulin in the plasma. Therefore plasma concentrations of total testosterone, estradiol, and dihydrotestosterone are increased. However, their unbound fractions are normal or slightly decreased. Increased binding in the plasma may cause decreased metabolic clearance rates of testosterone and dihydrotestosterone. The metabolic clearance rate of estradiol will be normal, which suggests increased tissue metabolism of this hormone. There is increased conversion of androstenedione to testosterone, estrone, and estradiol, along with testosterone to dihydrotestosterone. The increased conversion of androgens to estrogenic byproducts may cause gynecomastia and erectile dysfunction in about 10% of thyrotoxic men. It could be once cause of menstrual irregularities in females. Another possible cause of menstrual changes is disruption in amplitude and frequency of LH FSH pulses, caused by thyroid hormone influences upon GnRH signaling.

133

134

Epidemiology of Thyroid Disorders

Thyroid storm Thyroid storm is also called thyrotoxic crisis. It is a severe and acute form of hyperthyroidism that results from lack of treatment or inadequate treatment. Thyroid storm is a rare but life-threatening condition, occurring in patients with Graves’ disease or toxic multinodular goiter. Its incidence is estimated at only 0.20 cases per 100,000 populations. Delirium, fever, seizures, vomiting, diarrhea, jaundice, and coma accompany thyroid storm. Mortality rates are due to cardiac failure, arrhythmia, or hyperthermia. They are as high as 30% even when treatment is given. Thyroid storm is usually precipitated by an acute illness or surgery. Acute illnesses that may cause thyroid storm include infections, stroke, diabetic ketoacidosis, and trauma. Intensive monitoring and supportive care are required. Thyroid storm can also be caused by overreplacement of thyroid hormones or when medications used to treat hyperthyroidism are discontinued abruptly. The precipitating cause must always be identified and treated. Steps are taken to reduce synthesis of thyroid hormone. Treatments include propylthiouracil, iodine, Lugol’s solution, sodium iodide, propranolol, esmolol, intravenous dextrose, cooling blankets, calcium channel blockers, adenosine, beta-blockers, and corticosteroids. Focus on geriatrics The characteristic signs and symptoms may be absent, known as apathetic hyperthyroidism. They can mimic depression or malignancy. Atrial fibrillation is common in patients over age of 60 years when TSH is less than 0.1 mU/L.

Diagnosis of hyperthyroidism Diagnosis of hyperthyroidism is based on history, physical examination, and thyroid function tests. The best test is serum TSH measurement, since TSH is suppressed, except rarely, when the etiology is a TSH-secreting pituitary adenoma or pituitary resistance to TH. Screening certain populations for TSH levels is suggested. In hyperthyroidism, there will be increased fT4. However, thyroxine may be false-normal when the patient has a severe systemic illness and in T3 toxicosis. If the fT4 is normal and the TSH is low, with subtle signs and symptoms of hyperthyroidism, the serum T3 must be measured to detect T3 toxicosis. An elevated level is confirmative. Fig. 6.4 shows the relationship between TSH, fT4, and clinical conditions. Exposure to a drug or Graves’ disease manifestations can often be clinically diagnosed. If not, the use of 123I may help obtain thyroid RAIU. When the cause is hormone overproduction, thyroid RAIU is usually elevated. TSH receptor antibodies may be measured to detect Graves’ disease. However, this is rarely needed, except in the third trimester of pregnancy, to assess risks of neonatal Graves’ disease. TSH receptor antibodies easily cross the placenta and stimulate the fetal thyroid. Most of the

Hyperthyroidism

TSH Deficient T3/T4 receptor or autonomous TSH secretion

Primary failure of thyroid gland

Euthyroid reference values

Failure of pituitary gland

Autonomous function of thyroid gland

Free T4 concentration

Figure 6.4 The relationship between TSH, fT4, and clinical conditions. World Health Organization.

Graves’ patients have circulating antithyroid peroxidase (TPO) antibodies. Less of them have antithyroglobulin antibodies. Inappropriate TSH secretion is rare. Diagnosis is confirmed if hyperthyroidism occurs with elevated circulating free-TH concentrations and normal or elevated serum TSH. Serum thyroglobulin can be measured if thyrotoxicosis factitia is suspected. The thyroglobulin is usually low or low-normal—different from all other causes of hyperthyroidism. If excess iodine ingestion is the cause, low RAIU is common, since uptake is inversely proportional to iodine intake. There are various types of diagnostic methods used to determine the presence and cause of hyperthyroidism. For secondary hyperthyroidism caused by a TSH-secreting pituitary tumor, there will also be a diffuse goiter. This diagnosis can be suggested by the presence of a nonsuppressed TSH level, with pituitary tumor (found on computed tomography scan or magnetic resonance imaging). The clinical features of thyrotoxicosis can be mimic mania, panic attacks, pheochromocytoma, and weight loss that is related to malignancies, diabetes mellitus, and menopause. Diagnosis of thyrotoxicosis is easily excluded when TSH and unbound T4 and T3 levels are normal. A normal TSH level also excludes Graves’ disease as a cause of a diffuse goiter. Usually, increases in thyroid iodide uptake and clearance rate are reflected in the RAIU test, over 24 hours. This can be inappropriately normal in patients with milder disease related to the suppressed serum TSH level. It can also be relatively low compared with 24-hour uptake in patients with very fast iodine turnover in a hyperactive thyroid gland. Free T4 concentration levels are suggested to be measure for diagnosis. Determining the RAIU is not helpful when the clinical presentation is compatible

135

136

Epidemiology of Thyroid Disorders

Hyperthyroidism Elevated TH and suppressed TSH

Radioactive iodine uptake and scan

Low uptake

Thyroiditis -Postpartum -Painless -de Quervain (viral) Exogenous thyroid hormone

Normal or elevated uptake*

Graves disease Toxic multinodular goiter Toxic adenoma

*Isotope scan aids in differentiation of causes

Figure 6.5 Evaluation of hyperthyrodism.

with clear Graves’ disease symptoms, or in a thyrotropin receptor antibodies (TRAb)positive thyrotoxic patient. However, it may be useful to exclude thyrotoxicosis not caused by Graves’ disease. Very low RAIU values or absent thyroid uptake on a thyroid scan related to thyrotoxicosis signal the presence of either: thyroiditis, factitious thyrotoxicosis, ectopic thyroid tissue, or iodine contamination by recent administration of an iodinated contrast agent. Fig. 6.5 displays how hyperthyroidism is evaluated. Focus on differential diagnosis Hyperthyroidism must be distinguished from anxiety, diabetes mellitus, malignancy, pregnancy, menopause, and pheochromocytoma.

Treatment of hyperthyroidism Treatment of hyperthyroidism is based on the cause. Pharmacologic doses of iodine inhibit release of TH within hours, as well as the organification of iodine. This transitory effect lasts from a few days to a week, with inhibition usually stopping. Iodine helps in the emergency management of thyroid storm, for hyperthyroid individuals having emergency nonthyroid surgery, and since it decreases thyroid vascularity, for preoperative preparation before subtotal thyroidectomy. Iodine is not usually used for routine hyperthyroidism treatment. Complications include salivary gland inflammation, conjunctivitis, and rash. For infiltrative dermopathy and ophthalmopathy, treatments include corticosteroids, orbital radiation, and surgery.

Hyperthyroidism

Propylthiouracil and methimazole The primary antithyroid drugs are called thionamides. These include propylthiouracil and methimazole. They function by inhibiting TPO to reduce oxidation and organification of iodide. They also reduce thyroid antibody levels by unclear mechanisms, appearing to enhance remission rates. Propylthiouracil inhibits the deiodination of T4 to T3. This minor effect, except for the most severe cases of thyrotoxicosis, is offset by the extremely short half-life of the drug—only 90 minutes—compared to the 6-hour half-life of methimazole. Propylthiouracil has significant hepatotoxicity. Therefore the FDA has limited its use to the first trimester of pregnancy, for treating thyroid storm and in patients with slight adverse reactions to methimazole. When propylthiouracil is used, there must be monitoring of liver function. There are many variations of antithyroid drug treatments. Initially, methimazole may be given twice or three times per day, though once per day is usually enough after euthyroidism has been restored. Propylthiouracil is given three-to-four times per day, often with divided doses. In areas of low iodine intake, lower doses of either drug may be sufficient. Starting doses can be slowly reduced as the condition resolves. Also, high doses may be given in combination with supplements of levothyroxine to avoid drug-induced hypothyroidism. This is called a block replace regimen. Titration helps minimize doses and provides an index of response to treatment. After treatment begins, thyroid function tests and clinical manifestations are reviewed every 4 6 weeks. Doses are titrated based on unbound T4 levels. Euthyroidism is not usually achieved until 6 8 weeks of treatment have occurred. Since TSH levels are often suppressed for several months, they do not give a sensitive index of response. For block replace regimens, initial doses are kept constant while doses of levothyroxine are adjusted to maintain normal unbound T4 levels. Once TSH suppression stops, TSH levels can be used to monitor therapy. The block replace regimen achieves maximum remission rates of up to 30% 60% in some populations within 6 months, and the titration regimen achieves similar rates within 12 18 months. Remission rates seem to differ between geographic areas. Those most likely to relapse once treatment stops are males, younger patients, smokers, and those with severe hyperthyroidism and large goiters. All patients must be followed closely for relapse during the first year following treatments and at least once per year after that. Between 1% and 5% of patients experience minor side effects of arthralgia, fever, urticaria, and rash. These can resolve on their own or after a different antithyroid drug is substituted. Propylthiouracil is not used in children and can rarely cause hepatitis in adults. Rare but major side effects with methimazole include cholestasis, a systemic lupus erythematosus like syndrome, and, most significantly, agranulocytosis. Antithyroid drugs must be stopped and not restarted if major side effects develop. Written instructions must be given to the patient regarding symptoms of

137

138

Epidemiology of Thyroid Disorders

agranulocytosis, which include fever, mouth ulcers, and sore throat. The patient must be educated about stopping treatment until an immediate complete blood count is performed to confirm that agranulocytosis is not present. Since agranulocytosis occurs idiosyncratically and abruptly, monitoring blood counts prospectively is not helpful. Large doses of propylthiouracil are given orally, via nasogastric tube, or via the rectum. It is the antithyroid drug of choice because of its inhibitory action on T4 to T3 conversion. If it is not available, methimazole may be used in controlled doses. Stable iodide is given 1 hour of the initial dose of propylthiouracil to block thyroid hormone synthesis via the Wolff Chaikoff effect. In this effect the delay allows the antithyroid drug to prevent excessive iodine from being incorporated into new thyroid hormone. A saturated solution or potassium iodide, ipodate, or iopanoic acid can be given orally. Sodium iodide is also an option but is usually not available. Propranolol may help reduce tachycardia and other adrenergic effects, and doses can be easily adjusted. However, other beta-adrenergic blockers can be used. It is important to avoid acute negative inotropic effects. Controlling heart rate is important since some patients develop a type of high-output heart failure. Short-acting intravenous esmolol helps decrease heart rate as signs of heart failure are monitored. Other therapies include glucocorticoids such as hydrocortisone, antibiotics for infections, cooling, oxygen, and IV fluids. Thyroid cells are progressively destroyed by radioiodine. It can be used initially, or for relapses after a trial regimen of antithyroid drugs. There is a slight chance of thyrotoxic crisis following radioiodine. This can be minimized with antithyroid drug pretreatment for at least 1 month prior to treatment. Additional antithyroid drug treatments must be considered for elderly patients, or if there are cardiac problems, to use up thyroid hormone stores prior to administration of radioiodine. Methimazole must be stopped 3 5 days before radioiodine is administered in order to achieve the highest iodine uptake. Propylthiouracil is believed to have a lengthened radioprotective effect. It should be stopped for a longer time period prior to administration of radioiodine. If not, a larger dose of radioiodine will be needed. Beta-blockers To control adrenergic symptoms, mostly in early stages before antithyroid drugs can take effect, propranolol or a longer acting selective beta1 receptor blocker such as atenolol may be effective. For those with thyrotoxic periodic paralysis, beta-blockers are also effective, as long as thyrotoxicosis is corrected. For those with cardiovascular conditions, anticoagulation with warfarin must be considered if the patient has atrial fibrillation. These patients often spontaneously revert to sinus rhythm when hyperthyroidism is controlled. If the patient is thyrotoxic, decreased doses of warfarin are required. If digoxin is being used, increased doses are often required.

Hyperthyroidism

Radioiodine After a few days of radioiodine, there are radiation safety precautions required. Generally, the patient should not have any close, prolonged contact with children or pregnant women for 5 7 days, so that the residual isotope and radiation emanating from the thyroid gland cannot be transmitted. After treatment, there are rare reports of mild pain due to radiation thyroiditis within 1 2 weeks. Hyperthyroidism can continue for 2 3 months prior to radioiodine taking its full effect. Therefore beta-adrenergic blockers or antithyroid drugs may help control symptoms in this period. A second dose of radioiodine, usually 6 months after the fist, can be effective for persistent hyperthyroidism. Risks of hypothyroidism following radioiodine are based on dosage. They are at least 10% 20% in the first year, and 5% each year after that. The patient must be informed of these facts before treatment. Close follow-up is required during the first year, and then annual thyroid function tests should occur. Radioiodine cannot be used during pregnancy or breast-feeding, though patients can conceive safely 6 months following treatment. If severe ophthalmopathy is present, caution must be taken. Some physicians suggest using prednisone during radioiodine treatment that is tapered over 6 12 weeks to prevent worsening of ophthalmopathy. Overall cancer risk after radioiodine treatment in adults is not increased. Many physicians avoid radioiodine in children and adolescents due to possible malignancy. However, new evidence suggests that it can be safely used in older children. There is no optimal dose of radioiodine to achieve euthyroidism without significant relapses or progression to hypothyroidism. Some patients relapse after just one dose, since radiation has varied biologic effects between patients. Hypothyroidism cannot be avoided on a regular basis even with accurate doses. Therefore a fixed dose is suggested, based on clinical features such as thyrotoxicosis severity, goiter size (which increases needed doses), and radioiodine uptake level which decreases needed doses. Most physicians focus on thyroid ablation instead of euthyroidism, if levothyroxine replacement is straightforward. Most patients become hypothryoidic over 5 10 years, often with a delay in its diagnosis. Surgery For patients who relapse after antithyroid drugs or prefer this treatment over radioiodine, subtotal or near-total thyroidectomy is an option. In younger patients, especially when the goiter is very large, surgery is often recommended. Before surgery, to avoid thyroid storm and reduce vascularity of the gland, careful control of hyperthyroidism is required. This utilizes antithyroid drugs followed by potassium iodide. Primary complications of surgery include bleeding, hypoparathyroidism, laryngeal edema, and damage to recurrent laryngeal nerves. However, these are rare when

139

140

Epidemiology of Thyroid Disorders

experienced surgeons perform the surgery. Recurrence rates are at best less than 2%. However, hypothyroidism rates are only slightly less than those after radioiodine treatment. Focus on alternative therapies Traditional Chinese herbal medications are not currently recommended due to the quality of available trials, which suggest that they may have a therapeutic potential for people with hyperthyroidism.

Focus on pediatrics Neonates and children are treated with antithyroid medications for 12 24 months. Less than 50% of them will obtain permanent remission from this method. Up to 25% of children experience significant adverse effects of antithyroid drugs. Radioactive iodine is controversial in patients under the age of 15 18 years. An alternate treatment plan should be developed for any child who does not obtain remission with antithyroid drugs.

Subclinical hyperthyroidism Subclinical hyperthyroidism was identified as a result of sensitive assays for TSH. Serum TSH is subnormal while free thyroid hormone concentrations in the serum are normal. The preferred clinical term for subclinical hyperthyroidism is mild thyroid dysfunction. The hypothalamic pituitary axis is sensitive to free thyroid hormones in the serum, while the heart and other peripheral tissues mostly sense only free T3. Therefore individuals with a low-normal free thyroxine set point for TSH secretion likely have reduced TSH, if that concentration was increased by 50% yet could still remain in the normal range. The reported overall prevalence of subclinical hyperthyroidism is about 3% of the global population. Prevalence is highest in people aged 20 39 years and also in those more than age 79. The prevalence of subnormal serum TSH levels is higher in iodine-deficient populations, by 6% 10%, because of functional autonomy from nodular goiters. Patients with primary hypothyroidism but normal TSH levels, if given small amounts of levothyroxine, will have decreased TSH below normal, with no supranormal free thyroxine. Older studies showed cumulative incidence of atrial fibrillation, over 10 years, at 28% in patients with serum TSH of 0.1 mU/L or lower. This was only 11% in patients with serum TSH between 0.1 and 0.4 mU/L, only slightly more than that of the normal population. Regardless, heart failure is the primary cause of cardiovascular mortality rates, for over as well as mild hyperthyroidism. Also, thyroid hormone causes a net resorption of cortical bone. This may be added to by a lack of TSH. Lower bone density has been shown in some studies of patients

Hyperthyroidism

with mild thyrotoxicosis. This is much more common than overt thyrotoxicosis (0.7% of the population). It is a significant factor concerning diagnosis, treatment, and follow-ups. Basically, normalized thyroid function in postmenopausal women who have subclinical hyperthyroidism appears to improve bone density and some amount of cardiac function. Although this information may support treatment for older adults, no large random studies have been conducted to assist risks versus benefits. Diagnosis of subclinical hyperthyroidism uses tests that reveal several subnormal TSH concentration results. These are done months apart, along with normal free T3 and T4 concentrations. Suppressed TSH may normalize on its own over several years, especially when the patient does not have a nodular goiter. Similarly to over thyrotoxicosis, the two sources of excessive thyroid hormones are endogenous and exogenous. Approximately 58% of patients with a TSH lower than 0.3 mU/L received thyroid hormone therapy. If this is not being administered to treat a persistent thyroid carcinoma, it is easily treated by careful use of levothyroxine and measuring serum TSH. Endogenous subclinical thyrotoxicosis is caused by the same factors as overt thyrotoxicosis. In adults over the age of 60 years, multinodular goiter is more causative of hyperthyroidism than in younger people. Not enough is known regarding whether hyperthyroidic people with serum TSH over 0.1 mU/L will actually be benefitted from treatment. When the patient has consistently subnormal TSH, less than 0.1 mU/L, with normal free thyroid hormones, he or she should be evaluated for conditions benefitting from treatment, as well as finding the cause. In older adults, primary indications for treatment include some cardiac diseases and postmenopausal osteoporosis. In young females, menstrual disorders or infertility are important to consider. Identifying the cause correctly will determine treatment. The patient with subclinical hyperthyroidism from toxic nodular goiter or a single hyperfunctioning adenoma may often be treated with just one dose of radioactive iodine. This carries a relatively low risk of resultant hypothyroidism. Therefore threshold for treatment of these patients is lower. All rationales for treatment must be fully discussed with the patient.

Clinical cases Clinical case 1 1. To assess this patient further, what tests will be performed? 2. If, over time, this patient’s thyroid nodule enlarged, or multiple nodules formed, what laboratory and imaging studies should be performed? 3. What is the significance of a thyroid nodule? A 65-year-old woman presents with a palpable mass in her right anterior neck. She has no neck pain, dysphagia, hoarseness, or symptoms of any compression. She has no symptoms of thyroid dysfunction and is not taking any medications. Physical

141

142

Epidemiology of Thyroid Disorders

examination reveals an enlarged thyroid with a 2-cm thyroid nodule that moves when the patient swallows. There is no palpable cervical lymphadenopathy. Family history is negative for thyroid cancer, but several of her family members have had a goiter. The patient has no history of irradiation to the head or neck. Answers: 1. A TSH level and a thyroid ultrasound will be performed. The normal reference range for TSH will be between 0.29 and 5.1 mIU/L. 2. With these developments, there should be tests of TSH, free thyroid hormone, radionuclide thyroid testing, ultrasound, fine-needle aspiration, and sometimes if needed, serum calcitonin tests. 3. The prevalence of palpable thyroid nodules is 4% 7% of patients. Increased prevalence is associated with older age, iodine deficiency, female gender, and exposure to ionizing radiation. Colloid nodules, cysts, and thyroiditis occur in 80% of cases. Benign follicular neoplasms occur in 10% 15% of cases, and thyroid carcinoma occurs in only 5% of cases.

Clinical case 2 1. Are this patient’s symptoms consistent with hyperthyroidism as well as hypothyroidism? 2. To distinguish between the two conditions, what tests are needed? 3. If this patient has thyroid nodules, are these likely to occur with hyperthyroidism or hypothyroidism? A 49-year-old woman presents to her physician with significant weight gain over the previous months. She tells the physician that she sleeps for as many as 15 hours every day, and her movements are obviously slowed. She has a slight enlargement of her neck area, with coarse-textured hair and dry skin. A blood test reveals thyroxine levels lower than the normal range and high levels of TSH. Answers: 1. Somewhat, yes. Her weight gain could be linked to hyperthyroidism, hypothyroidism, or Cushing syndrome. The slowed movements could be due to hypothyroidism or Addison’s disease. The dry skin could be related to hypothyroidism. The swelling in her neck could be linked to hyperthyroidism or a thyroid tumor. Therefore her signs and symptoms could be described as consistent with hyperthyroidism as well as hypothyroidism. 2. A T4 (thyroxine) and a TSH test are required. The TSH test is usually chosen for evaluation of thyroid function and for the patient’s symptoms; it is often performed with or following the T4 test. 3. Thyroid nodules are common in both hyperthyroidism and hypothyroidism and are usually benign. In hyperthyroidism, they can lead to increased size of the thyroid or the production of too much T4.

Hyperthyroidism

Clinical case 3 1. What is the most likely cause of this patient’s illness? 2. What tests are needed to confirm the cause? 3. What are the treatment options? A 35-year-old woman complained of nervousness, weakness, and palpitations with exertion. These symptoms have existed for about 6 months. She recently noticed excessive sweating. Her weight is the same as it was over the past year, yet she is able to eat much more food than previously. Her menstrual periods were regular but have involved less bleeding than before. Examination revealed warm and moist skin, a fine tremor, bounding cardiac apical impulses, and three thyroid nodules. Answers: 1. The likely cause is a toxic multinodular goiter, resulting in symptoms of hyperthyroidism. 2. A thyroid scan is needed to verify the autonomy of the thyroid nodules. 3. Treatment options include radioactive iodine or surgery with antithyroid drug and iodine pretreatment.

Clinical case 4 1. What is the likely diagnosis? 2. In type 1 diabetes mellitus patients with hyperthyroidism, what considerations must be made? 3. What is the standard thyroid hormone replacement therapy? A 32-year-old man who has had type 1 diabetes mellitus for 8 years visited his doctor because of an unintentional 22-lb weight loss. Laboratory studies showed a suppressed TSH concentration and an elevated thyroxine level. This antithyroid peroxidase antibodies were positive. His thyroid-stimulating immunoglobulin test was negative. Uptake of radioactive iodine by scanning was 0.5% at 24 hours. Answers: 1. The likely diagnosis is hyperthyroidism caused by autoimmune thyroiditis. 2. In patients with type 1 diabetes mellitus who present with hyperthyroidism, Graves’ disease and other types of hyperthyroidism must be excluded, since autoimmune thyroiditis can quickly progress to hypothyroidism, requiring thyroid hormone replacement therapy. 3. Synthetic thyroxine (T4) is the standard form of replacement therapy. The reason for this is that most of the T3 in the body came from T4. The benefit of taking just T4 therapy is that the body is allowed to perform normal actions, including the changing of T4 into T3. Also, the half-life of T4 is longer, so it remains for a longer time in the body after administration.

143

144

Epidemiology of Thyroid Disorders

Key terms Addison disease anovulatory apathetic thyrotoxicosis catecholamines celiac disease chemosis cholestasis diabetic ketoacidosis epigenetic influences erythropoietin forskolin Graves’ disease Graves’ orbitopathy Hashimoto’s thyroiditis immunomodulating intermenstrual interval Means Lerman scratch multinodular nitric oxide

organification paranoid pheochromocytoma pleuropericardial Plummer nails schizoid scintigraphy stochastic telangiectasia thionamides thyroiditis thyroid storm thyrotoxic myopathy thyrotoxicosis transantral V genes vitiligo Wolff Chaikoff effect

Further reading 1. Baker, M., Barliya, T., et al. Perspectives on Nitric Oxide in Disease Mechanisms (Targeted Therapy Opportunities). (2013) Leaders in Pharmaceutical Business Intelligence. 2. Blum, S. The Immune System Recovery Plan: A Doctor’s 4-Step Program to Treat Autoimmune Disease. (2013) Scribner. 3. Brownstein, D. Overcoming Thyroid Disorders. (2002) Medical Alternatives Press, Inc. 4. Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey (NHANES): Balance Procedures Manual. (2014) CreateSpace Independent Publishing Platform. 5. Eaton, J.L. Thyroid Disease and Reproduction: A Clinical Guide to Diagnosis and Management. (2018) Springer. 6. Garber, J.R. Thyroid Disease: Understanding Hypothyroidism and Hyperthyroidism, 4th Edition. (2015) Harvard Health Publications. 7. Halenka, M., and Frysak, Z. Atlas of Thyroid Ultrasonography. (2017) Springer. 8. Icon Group International. Telangiectasia: Webster’s Timeline History, 1925 2007. (2010) Icon Group International, Inc. 9. Johnson, G. Atlas of Gallium-67 Scintigraphy: A New Method of Radionuclide Medical Diagnosis. (2011) Springer. 10. Loriaux, L. Endocrine Emergencies: Recognition and Treatment (Contemporary Endocrinology). (2014) Humana Press. 11. Mertens, L., and Bogaert, J. Handbook of Hyperthyroidism Etiology, Diagnosis and Treatment. (2010) Nova Science Publishers. 12. Nystrom, E., and Berg, G.E.B. Thyroid Disease in Adults. (2011) Springer.

Hyperthyroidism

13. Oertli, D., and Udelsman, R. Surgery of the Thyroid and Parathyroid Glands, 2nd Edition. (2012) Springer. 14. Osansky, E.M. Natural Treatment Solutions for Hyperthyroidism and Graves’ Disease, 2nd Edition. (2013) Natural Endocrine Solutions. 15. Osman, F. The Cardiovascular Consequences of Hyperthyroidism. (2010) LAP Lambert Academic Publishing. 16. Ozulker, T., Adas, M., and Gunay, S. Thyroid and Parathyroid Diseases: A Case-Based Guide. (2018) Springer. 17. Randolph, G.W. Surgery of the Thyroid and Parathyroid Glands: Expert Consult, 2nd Edition. (2012) Saunders. 18. Simpson, K., and Hertoghe, T. The Women’s Guide to Thyroid Health: Comprehensive Solutions for All Your Thyroid Symptoms. (2009) New Harbinger Publications. 19. Skugor, M., and Wilder, J.B. The Cleveland Clinic Guide to Thyroid Disorders. (2009) Kaplan Publishing. 20. Smith, P.W. What You Must Know About Thyroid Disorders & What to Do About Them. (2016) Square One. 21. Taaru, H. The Battle I Fought Against Heart Failure, Hypertension and Thyrotoxicosis: A Living Nightmare. (2010) Xlibris U.K. 22. United States Department of Health and Human Services, Agency for Healthcare Research and Quality. Screening and Treatment of Subclinical Hypothyroidism or Hyperthyroidism: Comparative Effectiveness Review, Number 24. (2013) CreateSpace Independent Publishing Platform. 23. Vitti, P., and Hegedus, L. Thyroid Diseases: Pathogenesis, Diagnosis, and Treatment (Endocrinology). (2018) Springer. 24. Walker, M.H. Forskolin: Sources, Mechanisms of Action and Health Effects. (2015) Nova Science Publishers Inc. 25. Wondisford, F.E., and Radovick, S. Clinical Management of Thyroid Disease. (2009) Saunders.

145

CHAPTER 7

Thyroiditis and Graves’ disease Contents Hashimoto’s thyroiditis Epidemiology Pathogenesis Risk factors Clinical presentation Diagnosis Treatment Subacute thyroiditis Epidemiology Pathogenesis Risk factors Clinical presentation Diagnosis Treatment Infectious thyroiditis Epidemiology Pathogenesis Risk factors Clinical presentation Diagnosis Treatment Riedel’s thyroiditis Epidemiology Pathogenesis Risk factors Clinical presentation Diagnosis Treatment Graves’ disease Epidemiology Pathogenesis Risk factors Clinical presentation Diagnosis Treatment

Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00007-4

148 148 149 150 151 151 152 152 152 152 153 153 154 155 155 155 155 156 156 156 157 157 157 157 158 158 158 158 159 159 160 160 162 163 164

r 2020 Elsevier Inc. All rights reserved.

147

148

Epidemiology of Thyroid Disorders

Clinical cases Case 1 Case 2 Case 3 Case 4 Further reading

166 166 167 168 168 169

There are many different types of thyroid disorders that are very common globally, including thyroiditis and Graves’ disease. Thyroiditis is inflammation of the thyroid gland. It includes a group of four disorders that are characterized by various types of thyroid inflammation. These types include autoimmune (Hashimoto’s) thyroiditis, subacute thyroiditis, infectious thyroiditis, and Riedel’s thyroiditis. However, thyroiditis can also cause rapid thyroid cell damage and destruction, with leaking of thyroid hormone into the blood, and symptoms of thyrotoxicosis. Graves’ disease is another type of autoimmune disorder, which is the most common autoimmune cause of hyperthyroidism. It is also known as toxic diffuse goiter and was discussed in Chapter 4, Iodine deficiency and goiter.

Hashimoto’s thyroiditis Hashimoto’s thyroiditis, also called chronic lymphocytic thyroiditis, is the most common thyroid disorder occurring in the United States. Hashimoto’s thyroiditis is chronic autoimmune inflammation of the thyroid, with lymphocytic infiltration. Hashimoto’s thyroiditis is believed to be the most common cause of primary hypothyroidism in North America and is much more prevalent in females.

Epidemiology Incidence of Hashimoto’s thyroiditis increases with aging, and in patients with chromosomal disorders that include Down syndrome, Klinefelter syndrome, and Turner syndrome. Hashimoto’s thyroiditis affects about 5% of the global population, usually beginning between the ages of 30 and 60, and is 8 15 times more common in females. Approximately 1 1.5 of every 1000 people have this form of thyroiditis. When men are affected, they usually in middle age. Rates of the disease appear to be increasing. It also occurs in children and is more common in areas of high iodine dietary intake, as well as among genetically susceptible people. Primary thyroid B-cell lymphoma affects less than 1 of every 1000 people and is more common in those with long-term autoimmune thyroiditis. Caucasians develop Hashimoto’s thyroiditis more than any other ethnic group by 67% 78%.

Thyroiditis and Graves’ disease

149

Pathogenesis In Hashimoto’s thyroiditis the development of thyroid tumors may be increased, and in rare cases, there may be the development of thyroid lymphoma. Pathologic findings show extensive infiltration of lymphocytes, with lymphoid follicles and scarring. Various autoantibodies may be present against thyroid peroxidase, thyroglobulin, and thyroid-stimulating hormone (TSH) receptors. A small number of patients do not have any of these antibodies present; however, some patients have the antibodies without ever developing Hashimoto’s thyroiditis. Antibody-dependent cell-mediated cytotoxicity is a significant factor, regardless. Activation of cytotoxic T lymphocytes, or CD8 1 T cells, in response to cell-mediated immune response that is affected by helper T lymphocytes (CD4 1 T cells) is the reason for the destruction of thyrocytes (see Fig. 7.1). Similar to type IV hypersensitivities, macrophage recruitment occurs because of T-lymphocyte activation. Helper T lymphocytes are subdivided into Th1 and Th2 lymphocytes and they produce their own forms of cytokines. The Th1 lymphocytes produce inflammatory cytokines in thyroid tissue, further activating macrophages and encouraging their migration into the thyroid gland, causing a direct effect. Large-scale morphological changes occur, with much more localized nodules and irregularities developing. The capsule remains intact, and the thyroid is still distinct from any surrounding tissues, but microscopic examination reveals the extent of Thyroid epithelium Breakdown in self-tolerance and induction of thyroid autoimmunity Plasma cell CD8+ cytotoxic T-cell FasL Fas

CD4+ TH1 cell

Antithyroid antibodies

γ-IFN Activated macrophages

T-cell-mediated cytotoxicity

Fc receptor NK cell

Thyrocyte injury

Figure 7.1 Pathogenesis of Hashimoto’s thyroiditis.

Antibody-dependent cell-mediated cytotoxicity

150

Epidemiology of Thyroid Disorders

Figure 7.2 Hashimoto thyroiditis. The thyroid parenchyma contains a dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles lined by deeply eosinophilic Hürthle cells are also seen.

damage. The hypersensitivity appears as diffuse parenchymal infiltration by mostly plasma B cells as well as other lymphocytes (Fig. 7.2). Often, these appear as secondary lymphoid follicles that are germinal centers. They are different from the colloid-filled follicles that make up the thyroid gland. Colloid body atrophy is lined with Hürthle cells that have an extremely eosinophilic and granular cytoplasm. This is a metaplasia from normal cuboidal cells lining the thyroid follicles. Severe atrophy of the thyroid often occurs with more dense, fibrotic bands of collagen remaining in the thyroid capsule.

Risk factors Patients often have a family history of thyroid disorders, with the HLA-DR5 gene usually linked to a three times higher risk for Hashimoto’s thyroiditis. This disorder is sometimes related to other autoimmune disorders, which include Addison’s disease, hypoparathyroidism, type 1 diabetes mellitus, premature hair graying, vitiligo, pernicious anemia, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, celiac disease, and type 2 polyglandular deficiency syndrome (Schmidt syndrome). This is a combination of Addison’s disease with hypothyroidism that is secondary to Hashimoto’s thyroiditis, type 1 diabetes, or both. Monozygotic twins have an extremely high concordance, up to 80%, of circulating thyroid antibodies that are not related to clinical presentation. These twins also have a genetic component concordance of 38% 55%. Hashimoto’s thyroiditis is linked to cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene polymorphisms. This antigen transmits inhibitory signals to T cells. Therefore reduced function is associated with higher T-lymphocyte activity.

Thyroiditis and Graves’ disease

In genetically predisposed individuals, the development of Hashimoto’s thyroiditis is related to preventable environmental factors including high iodine intake, deficiency of selenium, infectious diseases, and certain drugs. As the cytotoxic immune response causes higher levels of primary hypothyroidism, there are low thyroid hormone levels with compensatory increases of TSH.

Clinical presentation In Hashimoto’s thyroiditis the thyroid becomes painlessly enlarged, and symptoms of hypothyroidism appear. The patient complains of fullness in the throat or painless enlargement of the thyroid. Examination will reveal a nontender goiter that is smooth or nodular, firm and feels more “rubbery” than normal thyroid tissue. Symptoms of hypothyroidism are present in many patients, though some actually present with hyperthyroidism caused by thyroiditis. The most common symptoms include fatigue, weight gain, facial paleness or puffiness, joint and muscle pain, feeling cold, constipation, dry and thinning hair, depression, heavy menstrual flow or irregular periods, bradycardia, panic disorder, and difficulties becoming pregnant or maintaining pregnancy. Hashimoto’s thyroiditis may also present as mania and is then called Prasad’s syndrome. Rare cases of fibrous autoimmune thyroiditis cause severe dyspnea and dysphagia, which resembles the effects of aggressive thyroid cancers. These symptoms, however, improve with corticosteroid therapy or surgery.

Diagnosis Diagnostic testing for Hashimoto’s thyroiditis consists of measuring thyroxine, TSH, and thyroid autoantibodies. Early in the disease course, thyroxine and TSH levels will be normal. There will be high levels of thyroid peroxidase antibodies, and less often, antithyroglobulin antibodies. Early assessment may show elevated levels of thyroglobulin, due to transient thyrotoxicosis, as inflammation in the thyroid damages the integrity of thyroglobulin storage in the thyroid follicles. Usually, thyroxine is the preferred hormone tested. If there are palpable nodules, thyroid ultrasonography should be performed. This often reveals a heterogeneous, hypoechoic echotexture of thyroid tissue, with septations forming hypoechoic micronodules. Testing for various other autoimmune disorders is warranted only if there are clinical manifestations. Hashimoto’s thyroiditis is often misdiagnosed as cyclothymia, depression, premenstrual syndrome, chronic fatigue syndrome, fibromyalgia, and, less commonly, an anxiety disorder or erectile dysfunction. Periorbital myxedema may be present, based on the amount of disease progression. If a germinal center is found within the thyroid, it is histologically significant.

151

152

Epidemiology of Thyroid Disorders

Treatment Sometimes the condition is transient, but the majority of patients require lifelong thyroid hormone replacement. This usually involves the intake of levothyroxine daily, or other agents such as triiodothyronine or desiccated thyroid extract. For Hashimoto’s thyroiditis and resultant hypothyroidism, TSH levels may be recommended to be kept below 3.0 mU/L. About 5% of the patients with subclinical hypothyroidism and chronic autoimmune thyroiditis progress to thyroid failure annually.

Subacute thyroiditis Subacute thyroiditis is also known as de Quervain, giant cell, or granulomatous thyroiditis. It is an acute inflammatory disorder of the thyroid gland. Subacute thyroiditis is self-limited and usually subsides within a few months. Therefore it is described as a form of resolving thyroiditis. Sometimes, it recurs and may cause permanent hypothyroidism, if the follicular destruction is widespread. Subacute thyroiditis should not be confused with De Quervain syndrome, which is a condition of tendon inflammation not related to the thyroid gland. There are subforms of subacute thyroiditis known as subacute lymphocytic thyroiditis, postpartum thyroiditis, and autoimmune thyroiditis. All of these are usually painless, or described as “silent.”

Epidemiology Subacute thyroiditis is uncommon and affects both sexes, of all ages. Some cases of this disease develop postpartum. The condition affects women three to five times more often than men. The overall incidence is reported at 12 people out of every 100,000. It is most common in middle age, followed by young adulthood, and decreases in frequency with increasing age. There is a seasonal incidence, with most cases occurring in the summer.

Pathogenesis A viral infection usually triggers the condition, with most patients having had a recent upper respiratory infection. Clusters of cases have been associated with coxsackievirus, the mumps virus, the measles virus, adenovirus, and other viral infections. The pathogenesis of subacute thyroiditis is unclear but appears to involve less lymphocytic infiltration of the thyroid than in Hashimoto’s thyroiditis or silent lymphocytic thyroiditis. However, there is giant cell infiltration, polymorphonuclear lymphocytes, and follicular disruption (see Fig. 7.3). Serial studies of various viral antibody titers have not been definitive, and viral inclusion bodies are not seen in the thyroid tissue. Different from autoimmune thyroid disease, the immune response is started by a virus and is not selfperpetuating, meaning that its progression is limited.

Thyroiditis and Graves’ disease

Figure 7.3 Granulomatous or subacute thyroiditis.

Risk factors Subacute thyroiditis is an acute inflammatory disease of the thyroid that is believed to be caused by a virus. Pathologic examination reveals moderate thyroid enlargement and a mild inflammatory reaction involving the capsule. Commonly, a preceding viral upper respiratory infection occurs. Possible viral causes include the coxsackievirus, mumps virus, and adenoviruses. There may be a seasonal component to this disorder, but this is uncertain.

Clinical presentation Subacute thyroiditis is characterized by painful enlargement of the thyroid and fever. The neck pain usually moves from side to side and may settle into one area, often radiating to the jaw and ears. It may be confused with dental pain, otitis, or pharyngitis. Swallowing or turning the head aggravates the pain. Symptoms of hyperthyroidism usually occur early in the disease course, due to the release of hormone from disrupted follicles. The patient feels hot, experiences tremors, is anxious, loses weight, has tachycardia, sweats profusely, and the hair appears greasy. The hyperthyroidism eventually subsides, as the damaged cells can no longer take up iodine to manufacture thyroid hormone, and the patient returns to a hypothyroid state. The symptoms include feeling cold, depressed, and tired, with weight gain and dryness of skin and hair. There are low levels of free thyroid hormones, and eventually, increased TSH. Compared to other thyroid disorders, there is more fatigue and prostration. Physical examination reveals asymmetric thyroid enlargement, firmness, and tenderness.

153

154

Epidemiology of Thyroid Disorders

Focus on postpartum thyroiditis Postpartum thyroiditis usually occurs in 6 12 months after delivery in as many as 5.4% of women. It is a similar course to that of painless thyroiditis but is pathologically related to Hashimoto’s thyroiditis. In most cases, it resolves on its own, but persistent hypothyroidism has occurred.

Diagnosis Diagnosis is based on the thyroid symptoms and appropriate clinical history. Thyroid testing with TSH and at least a measurement of free thyroxine are usually done (see Fig. 7.4). Confirmation can be received via radioactive iodine uptake (RAIU) or technetium testing. Early in the disease course, there is an increase in free thyroxine and also triiodothyronine, along with a significant decrease in TSH and thyroid RAIU, plus a high erythrocyte sedimentation rate of more than 100 mm/h using the Westergren scale. Thyroid autoantibodies are usually not able to be detected in the serum. Within a few weeks, the thyroid becomes depleted of thyroid hormones. Transient hypothyroidism develops, with a decrease in free thyroid hormones, an increase in TSH, and recovery of thyroid RAIU. There may be weakly positive thyroid antibodies. The disease stages are identified by measuring free thyroid hormones and TSH every 2 4 weeks. Fine-needle aspiration biopsy is usually diagnostic. Histologic features include the destruction of thyroid parenchyma, and the presence of 24-hour 131 | uptake %

T4 μg/dL 20

40

T4

15

30

10

20

5

10

0 Phase: Weeks:

131 | Hyper 7

0 Eu 4

Hypo 11

Eu –

Figure 7.4 Changes in serum thyroxine and radioactive iodine uptake in patients with subacute thyroiditis.

Thyroiditis and Graves’ disease

many large phagocytic cells (giant cells). Thyroid ultrasonography with color Doppler will show many irregular sonolucent areas, and reduced blood flow, which contrasts with the increased blood flow of Graves’ disease. Over time, as the gland recovers, the RAIU rises. Differential diagnosis involves differentiation of subacute thyroiditis from other viral illnesses because of the thyroid gland involvement. It is differentiated from Graves’ disease due to pain in the thyroid, low RAIU because of elevated serum T3 and free thyroxine, suppressed serum TSH, and lack of thyroid antibodies.

Treatment For patient discomfort, high doses of aspirin or NSAIDs are given. In severe cases, or when the patient does not respond to nonsteroidal drugs, a glucocorticoid such as prednisone 20 mg, three times daily for 7 10 days, may be required to reduce inflammation. When there are significant hyperthyroid symptoms, a short course of a betablocker maybe given. If hypothyroidism is significant or persisting, thyroid hormone replacement therapy may be required, but this is rarely permanent. Between 90% and 95% of the affected patients experience full resolution of subacute thyroiditis.

Infectious thyroiditis Infectious thyroiditis is also called suppurative thyroiditis, microbial inflammatory thyroiditis, pyrogenic thyroiditis, and bacterial thyroiditis. It is a rare condition. Normally, the thyroid is extremely resistant to infection. The large amount of iodine in the tissue, along with high vascularity and lymphatic drainage, makes it difficult for pathogens to infect thyroid tissues.

Epidemiology Though the incidence of infectious thyroiditis is very low, cases have been rising in recent years, due to more patients who are immunocompromised. Infectious thyroiditis only makes up 0.1% 0.7% of all types of thyroiditis. It is most common in children and young adults, between the ages of 20 and 40. Children are affected 92% of the time, and the other 8% are young adults. Males and females develop the disease at the same rates. Subacute thyroiditis is more common in the summer months.

Pathogenesis The pathogenesis of infectious thyroiditis begins if a persistent fistula from the piriform sinus causes the left lobe of the thyroid to become susceptible to infection and the formation of abscesses.

155

156

Epidemiology of Thyroid Disorders

Risk factors Infectious thyroiditis is usually caused by a bacterial infection, as the result of direct spread of Gram-positive or Gram-negative pathogens through fistulas that communicate with the piriform sinus or the skin. Hematogenous spread of bacterial, mycobacterial, fungal, or parasitic organisms, primarily Pneumocystis carinii, can occur when the patient is immunocompromised. Implicated bacteria include Staphylococcus aureus, Streptococcus pyogenes, Staphylococcus epidermidis, and Streptococcus pneumoniae. Less common causative organisms include Klebsiella species, Haemophilus influenza, Streptococcus viridans, Eikenella corrodens, Enterobacteriaceae, and Salmonella species. Usually, infectious thyroiditis develops after previous thyroid conditions, such as Hashimoto’s thyroiditis or thyroid cancer. In children the most common cause is a congenital abnormality, such as piriform sinus fistula, usually originating in the piriform sinus, then spreading to the thyroid through the fistula. An upper respiratory tract infection precedes infectious thyroiditis in about 66% of the cases. Additional causes include repeated fineneedle aspirates, perforation of the esophagus, and regional infections.

Clinical presentation Upon examination, affected patients are usually febrile, with asymmetrical swelling of the thyroid, and warmness, firmness, reddening, or tenderness in the anterior area of the neck. These symptoms may occur together or only a few of them may develop. The patient will present with a sudden fever, malaise, dysphagia, and dysphonia. Symptoms may last from 1 day to 6 months, but most symptoms last for an average of 18 days. The pain, fever, and swelling are usually much more severe than in other thyroid conditions and continue to worsen.

Diagnosis It is important to correctly differentiate infectious thyroiditis from the other more common forms of thyroiditis, as well as different thyroid disorders. When infectious thyroiditis is suspected, the patient often undergoes testing for elevated white blood cell counts and ultrasound to reveal unilobular swelling or an abscess. Based on patient age and immune status, more invasive procedures may be required. These include fine-needle aspiration of the neck mass. If the infection is believed to be linked to a sinus fistula, this often needs to be confirmed via laryngoscopic examination or surgery. Newer methods involve computed tomography (CT) to visualize and detect a sinus fistula. Diagnostic tests include blood tests of thyroid function, including TSH and thyroid hormones, which are usually normal. Ultrasonography often reveals an abscess or thyroid inflammation. A gallium scan will be positive. Barium swallow will reveal a fistula connected to the piriform sinus and left lobe. There will be an elevated white blood cell count and erythrocyte sedimentation rate.

Thyroiditis and Graves’ disease

Treatment Treatment of infectious thyroiditis requires appropriate antibiotics, based on the identified causative organism. Systemic antibiotics are required for severe infection. Medications include penicillinase-resistant penicillins, or a combination of a penicillin and a beta-lactamase inhibitor. If the patient is allergic to penicillin, clindamycin, or a macrolide may be used. Most anaerobic organisms are susceptible to penicillin. However, some Gram-negative bacilli are showing increased resistance to penicillin because of the production of beta-lactamase. Therefore clindamycin or a combination of metronidazole with a macrolide or a penicillin with a beta-lactamase inhibitor may be recommended. Fungal thyroiditis can be treated with fluconazole and amphotericin B. Early treatment prevents additional complications of this disease. If the infection is not managed by antibiotics, surgical drainage is indicated by continued fever, high white blood cell count, and localized inflammation. Draining is based on clinical examination or ultrasound/CT scan if these procedures showed an abscess or gas formation. There can also be surgical removal of the fistula, which is often recommended for pediatric patients. When there is an antibiotic-resistant infection or necrotic tissue, a lobectomy is recommended. If diagnosis or treatment are delayed, this disease can be fatal, with a 12% mortality rate.

Riedel’s thyroiditis Riedel’s thyroiditis or struma is a chronic form of thyroiditis. It is believed to be one manifestation of a systemic disease that may affect multiple organ systems, known as immunoglobulin G4 (IgG4)-related disease. The pancreas, liver, kidneys, salivary tissues, orbital tissues, and retroperitoneum are most often affected by fibrosis and infiltration with IgG4-secreting plasma cells.

Epidemiology Riedel’s thyroiditis is rare. The disease affects females five times more often than males. Most patients are between 30 and 60 years of age, with peak incidence during the fifth decade of life. Incidence has dramatically decreased over recent decades, for unknown reasons. This disease occurs in less than 0.3% of the cases.

Pathogenesis Riedel’s thyroiditis develops from replacement of the normal thyroid parenchyma with dense fibrosis, invading nearby neck structures, and extending beyond the thyroid capsule. The thyroid gland becomes extremely hard, asymmetrical and fixed to nearby structures. Inflammation infiltrates muscles, causing tracheal compression. Rarely will only one lobe of the thyroid be affected, and the color of the gland is pale tan to

157

158

Epidemiology of Thyroid Disorders

white. The disease may be associated with more generalized fibrosis, known as idiopathic multifocal fibrosclerosis.

Risk factors There is a significant link between Riedel’s thyroiditis and smoking. Rarer associations include celiac disease, hypereosinophilic syndrome, Peyronie’s disease, systemic lupus erythematosus, lupus anticoagulant, Budd Chiari syndrome, autoimmune hemolytic anemia with hyperthyroidism, Graves’ disease, ulcerative skin or soft palate lesions, erythrocyte hyperaggregation, idiopathic thrombocytopenic purpura, pure red cell aplasia, and extrahepatic sarcoidosis.

Clinical presentation The signs and symptoms of Riedel’s thyroiditis are related to localized compression upon the esophagus and trachea. Usually, symptoms are more significant than the actual goiter size and include stridor, dyspnea, fever, neck pain, and dysphagia. The swelling of the thyroid may be described as feeling like wood or a rock. The majority of patients are euthyroid, but about 30% become hypothyroid over a period of years. A very small number of patients become hyperthyroid. There may be eventual damage to the laryngeal nerve, causing vocal cord paralysis and hoarseness, or to the sympathetic trunk, causing Horner syndrome. Advanced fibrosis may produce vascular compromise, such as superior vena cava syndrome, or hypoparathyroidism that is secondary to parathyroid gland destruction.

Diagnosis Diagnosis of Riedel’s thyroiditis is by open biopsy. Surgical margins of the specimen are usually ragged, from extension of the fibrosing process into perithyroidal soft tissue. Remnants of strap muscle may be adhered to the surface of the thyroid. Laboratory tests include thyroid function tests. Antithyroid peroxidase antibodies are present in more than 60% of the patients. Serum calcium is tested, with hypocalcemia occurring if fibrosis affects the nearby parathyroid glands. Imaging includes radioiodine uptake and scan. There will be low uptake, in contrast to what occurs in Graves’ disease. CT scans show low attenuation of the thyroid with poor enhancement. A magnetic resonance imaging reveals homogeneous hypointensity on both T1- and T2-weighted images, which is distinct from all other forms of thyroiditis as well as thyroid neoplasia.

Treatment Prednisolone is usually used to treat Riedel’s thyroiditis. Other agents include different corticosteroids, mycophenolate, and methotrexate. Tamoxifen may also be used to

Thyroiditis and Graves’ disease

suppress proliferation of fibroblasts. Surgical excision is difficult or impossible. However, a surgical treatment called isthmectomy may be needed to relieve tracheal or esophageal obstruction. Outcome is worsened if there is fibrosis of other organs. Focus on other forms of thyroiditis Some drugs cause inflammation of the thyroid gland, such as amiodarone, which can produce a painless thyroiditis associated with thyrotoxicosis. Another example is that interferon-alpha may induce a painless thyroiditis related to transient thyrotoxicosis. This must be distinguished from interferon-alpha-provoked Graves’ disease.

Graves’ disease Graves’ disease is also called toxic diffuse goiter and is an autoimmune disease of the thyroid. It is the most common cause of hyperthyroidism (50% 80% of cases), as well as thyrotoxicosis. The thyroid usually enlarges, and there is an increase in synthesis and release of thyroid hormones. Thyroid-stimulating immunoglobulins or TSH-receptor antibodies bind to the TSH receptors in thyroid cell membranes. This stimulates the gland and leads to hyperfunction.

Epidemiology Graves’ disease is much more common in females, by eight times, than in males. Onset usually starts between the ages of 20 and 40, with a second common onset between the ages of 40 and 60. However, it can develop at any time during life. There is an increased incidence of Graves’ disease in countries that fortify salt products with potassium iodide, and the increase in Graves’ disease lasts for about 4 years after such programs are implemented. It develops in about 3% of females and 0.5% of males and is about 7.5 times more prevalent in women. Graves’ disease affects African-American males about 2.5 times more often than other males and affects African-American females about twice as often as other females. Asian or Pacific Islander women had a 78% increased risk of Graves’ disease compared to Caucasian women, and Asian or Pacific Islander men had a three times higher risk than Caucasian men. Age-specific rates in various studies reveal that women have highest incidence of Graves’ disease between 30 and 34 years of age, followed by 35 39, and then 25 29. Lowest incidence in women is between 15 and 19 years of age. Men have an almost equal incidence of this disease between the ages of 25 and 49 years. Lowest incidence in men is between the ages of 70 and 75.

159

160

Epidemiology of Thyroid Disorders

Focus on smoking and thyroid diseases Smoking is associated with a higher risk for Graves’ disease, yet a lower risk for Hashimoto’s thyroiditis. Quitting smoking temporarily increases risks for Hashimoto’s, but this resolves after about 2 years. After quitting, there is an abrupt reduction in thiocyanate compounds in the blood, meaning that iodine uptake will suddenly increase, leading to secondary hypothyroidism.

Pathogenesis The pathogenesis of Graves’ disease is of autoimmune nature, as the body produces antibodies to the receptor for TSH. In hyperthyroidism, serum T3 usually increases more than T4. This is probably because of increased T3 secretion, as well as conversion of T4 to T3 in the peripheral tissues. In some patients, only the T3 is elevated, which is known as T3 toxicosis. This occurs as a component of Graves’ disease as well as multinodular goiter, and autonomously functioning solitary thyroid nodules. If untreated, the patient usually develops elevated T4 and 123I uptake. The thyroid becomes diffusely and symmetrically enlarged, with a deep red-colored parenchyma, and the follicles are lined by tall, columnar epithelium, projecting into the lumens of the follicles to resorb colloid. The pathogenesis of infiltrative ophthalmopathy is not fully understood. It may result from immunoglobulins direct to TSH receptors in the orbital fibroblasts and fat. This results in release of proinflammatory cytokines, inflammation, and accumulation of glycosaminoglycans. The ophthalmopathy may occur prior to the onset of hyperthyroidism or up to 20 years afterward. It often worsens or abates independently of the course of hyperthyroidism. Typical ophthalmopathy when there is normal thyroid function is called euthyroid Graves’ disease. The histopathologic features of the thyroid gland in Graves’ disease are shown in Fig. 7.5.

Risk factors Many patients with Graves’ disease have a family history of this condition, or Hashimoto’s thyroiditis. Heredity increases risks for Graves’ disease, though the involved genes are unknown. The human leukocyte antigen DR (especially DR3) is believed to play a role. Also, genes that may be involved include those for thyroglobulin, thyrotropin receptor, protein tyrosine phosphatase nonreceptor type 22, and cytotoxic T-lymphocyte-associated antigen 4. If one twin is affected, there is a 30% chance that the other twin will also have the disease. Onset maybe triggered by stress, infection, giving birth, and other autoimmune diseases. Smoking increases risks and may worsen eye problems. Triggers may include viral or bacterial infections that influence antibodies to cross-react with the human TSH receptor. This is known as

Thyroiditis and Graves’ disease

Figure 7.5 Histopathologic features of the thyroid gland in Graves disease. (A) Normal. (B) and (C) Graves’ disease. (Courtesy of Dr. Pamela Unger, Mount Sinai School of Medicine, New York, NY.)

161

162

Epidemiology of Thyroid Disorders

antigenic mimicry. For example, the bacterium Yersinia enterocolitica has a structural similarity with the human thyrotropin receptor and may influence thyroid autoimmunity in genetically susceptible people. The Epstein Barr virus may be another possible trigger. Dietary iodine supplementation may trigger the onset of Graves’ disease. Patients being treated with potassium iodide or iodine-containing drugs such as amiodarone have an increased risk of developing Graves’ disease. Chemotherapy that uses immune checkpoint inhibitors may also cause Graves’ disease. These inhibitors include atezolizumab, ipilimumab, pembrolizumab, and tremelimumab. It is important to distinguish the cause as being from hyperthyroidism or from autoimmune thyroiditis, which can be caused by these inhibitors. Patients with Graves’ disease have a higher risk of other systemic autoimmune disorders, including celiac disease, Sjögren syndrome, Addison’s disease, pernicious anemia, alopecia areata, type 1 diabetes mellitus, vitiligo, hypoparathyroidism, cardiomyopathy, and myasthenia gravis.

Clinical presentation Graves’ disease is often accompanied by infiltrative ophthalmopathy, known as Graves’ exophthalmos. Less often, there is infiltrative dermopathy, or pretibial myxedema. A symmetric, nontender goiter is present in 70% of the patients, and there is an audible bruit when it is examined. These signs and symptoms are caused by the disease’s autoimmune processes. Infiltrative dermopathy is thickening of the skin on the shins. The “orange-peel” appearance may be due to infiltration of antibodies under the skin, causing an inflammatory reaction and fibrous plaques. Serum antinuclear antibody levels are usually elevated. Between 25% and 80% of people with Graves’ disease develop various eye problems. Common symptoms of related hyperthyroidism include tachycardia (in 80% of the patients), fatigue (70%), weight loss (60%), muscle weakness (55%), heat hypersensitivity (55%), palpitations (50%), and hand tremor (40%). Other manifestations include irritability, nervousness, hyperactivity, profuse sweating, increased appetite, hair loss, itching, insomnia, frequent bowel movement and occasional diarrhea, and hypermenorrhea. Signs include warm and moist skin, widened pulse pressure, hypertension, premature ventricular contractions, and atrial fibrillation. Elderly patients, especially with toxic nodular goiter, may have atypical symptoms resembling depression or dementia. They may have atrial fibrillation, altered sensorium, heart failure, syncope, and weakness. A single organ system is sometimes involved. Predominantly in Asian patients, there may be periodic partial muscle weakness or paralysis, along with skin warmth and moistness. Eye signs include eyelid lag or retraction, staring, and slightly conjunctival injection. These usually remit with treatment. Infiltrative ophthalmopathy is the most serious development, characterized by orbital pain, lacrimation, irritation, photophobia,

Thyroiditis and Graves’ disease

Figure 7.6 Characteristic signs of Graves orbitopathy (A) subseuently corrected by orbital decompression surgery (B). Note the thyroid star, the asymmetry, the proptosis, and the periorbital edema prior to correction. (Courtesy of Dr. Jack Rootman, University of British Columbia, Vancouver, BC, Canada.)

increased retro-orbital tissue, exophthalmos, and lymphocytic infiltration of extraocular muscles (see Fig. 7.6). This can result in ocular muscle weakness, leading to double vision. Infiltrative dermopathy involves nonpitting infiltration by a protein-rich ground substance, usually in the pretibial area. This rarely occurs if Graves’ ophthalmopathy is absent. Lesions are often itchy and reddened in early stages, becoming larger over time. Infiltrative dermopathy may appear years before or after hyperthyroidism. A rare development of Graves’ disease is thyroid storm, which causes abrupt symptoms of fever, significant weakness and muscle wasting, confusion, extreme restlessness with wide emotional alterations, psychosis, nausea, vomiting, diarrhea, hepatomegaly, mild jaundice, cardiovascular collapse, shock, and coma. Thyroid storm is a life-threatening emergency that requires prompt treatment.

Diagnosis Diagnosis of Graves’ disease involves measuring the TSH-receptor antibodies. Measurement is undertaken in pregnant women with the history of Graves’ disease during the third trimester. This assesses risks of neonatal Graves’ disease. The TSH-receptor

163

164

Epidemiology of Thyroid Disorders

antibodies easily cross the placenta, stimulating the fetal thyroid. Most patients with Graves’ disease have circulating antithyroid peroxidase antibodies. Less of them have antithyroglobulin antibodies. However, inappropriate secretion of TSH is uncommon. Diagnosis is confirmed if hyperthyroidism occurs with elevated circulating free thyroid hormone concentrations, and normal or elevated serum TSH. Evaluation of the severity of eye disease uses the “NO SPECS” system. There are seven classes of eye disease seriousness. These include Classes 0 6, as follows: • Class 0—no signs or symptoms • Class 1—only signs, which are limited to upper eyelid retraction and stare, with or without eyelid lag • Class 2—soft tissue involvement, with edema of the conjunctivae and eyelids, or conjunctival injection • Class 3—proptosis • Class 4—extraocular muscle involvement, usually with diplopia • Class 5—corneal involvement, mostly due to lagophthalmos • Class 6—sight loss, due to optic nerve involvement Usually, the natural history of thyroid-associated ophthalmopathy follows Rundle’s curve. This describes a quickly worsening course during the initial phase, up to a peak of maximum severity. There is then an improvement to a stable plateau, though the condition does not resolve back to normal.

Treatment The treatment of Graves’ disease includes antithyroid drugs, radioactive iodine I131, and thyroidectomy. Antithyroid drugs reduce the production of thyroid hormones. Since operating on a significantly hyperthyroid patient is dangerous, preoperative treatment with antithyroid drugs is given so that the patient becomes euthyroid; then the surgical procedure can occur. There is no one treatment approach that is best for all patients. Antithyroid medications are given for between 6 months and 2 years. Sometimes, when the medications are stopped, hyperthyroidism recurs. Risk of recurrence is about 40% 50%. Lifelong treatment with antithyroid drugs has adverse effects such as agranulocytosis and liver disease, along with a possibly fatal reduction in white blood cell counts. The most common treatment for Graves’ disease in the United States is radioiodine therapy. The rest of the world primarily uses antithyroid medications, thyroidectomy, or both. Beta-blockers such as propranolol may be used to inhibit the sympathetic nervous system symptoms of tachycardia and nausea until antithyroid medications can take effect. Pure beta-blockers do not inhibit eyelid retraction, which is mediated by alpha adrenergic receptors. The primary antithyroid drugs include methimazole, propylthiouracil, and carbimazole, which block binding of iodine and coupling of iodotyrosines.

Thyroiditis and Graves’ disease

Agranulocytosis must be monitored for, primarily with propylthiouracil. Other dangerous adverse effects include dose-dependent granulocytopenia, and aplastic anemia. If the patient develops a sore throat or fever, he or she must see a physician. The overall most common adverse effects are rash and peripheral neuritis. These medications cross the placenta and are secreted in breast milk. Lugol’s iodine is often used to block hormone synthesis before surgery. Radioiodine is indicated when medications or surgery are not successful or contraindicated. Hypothyroidism may be a complication of radioiodine therapy but can be treated with thyroid hormones. Radioactive iodine accumulates in the thyroid and irradiates the gland with its beta and gamma radiations. About 90% of the total radiation is emitted by the beta (or electron) particles. Usually, radioiodine is administered in a specific amount, in microcuries per gram of thyroid tissue, based on palpation or imaging over 24 hours. Patients must be monitored regularly with blood tests to ensure treatment with thyroid hormone before becoming symptomatically hypothyroid. Contraindications to radioiodine therapy include pregnancy, ophthalmopathy, or solitary nodules. Up to 80% of the patients will develop hypothyroidism and need thyroid hormone supplementation on a daily basis. Radioiodine acts slowly, over years to months, to destroy the thyroid gland. Graves’ disease-related hyperthyroidism is not cured in all patients. It has a relapse rate based on the dose of radioiodine administered. Pregnancy must be delayed for 6 months after radioactive iodine treatment. Thyroidectomy is most effective for young and pregnant patients. Indications may be absolute or relative. Absolute indications include a large goiter, especially when the trachea is compressed, suspicious nodules or suspected cancer, ophthalmopathy, and if the patient prefers this treatment or does not want radioiodine treatment. Surgical methods include bilateral subtotal thyroidectomy and the Hartley Dunhill procedure, which is hemithyroidectomy on one side with partial lobectomy on the other side. The advantages are an immediate cure and possible removal of any present carcinoma. Risks include injury of the recurrent laryngeal nerve, hypoparathyroidism from removal of the parathyroid glands, hematoma that may be life-threatening if it compresses the trachea, relapse, infections, and scarring. Increased risk for nerve injury can be due to the increased vascularity of the thyroid parenchyma, and links that develop between the thyroid capsule and surrounding tissues. After complete thyroidectomy, there is a 1% chance of permanent recurrent laryngeal nerve paralysis. If the gland is removed, a complete biopsy can be performed to find evidence of cancer in any part of the thyroid. Needle biopsies are not as accurate at predicting a benign thyroid. No further treatment of the thyroid would be needed unless cancer was found. After surgery a radioiodine uptake study may be done to ensure all thyroid cells are destroyed and cancer-free. The only other treatment would be levothyroxine or thyroid replacements taken throughout life. As of 2013, total thyroidectomy is now the preferred surgical option for Graves’ disease.

165

166

Epidemiology of Thyroid Disorders

The eye problems of Graves’ disease are treated, when mild, lubricating eye drops or NSAID drops. If the problems are severe, treatments include steroids or orbital decompression. Cessation of smoking is essential. Double vision can be corrected with prism glasses, and if the process has been stable for a time, surgery. Difficulty closing the eyes can be treated with a nighttime lubricant gel, or with a special tape on the eyes, to allow for full, deep sleep. Orbital decompression helps in allowing the eyes to withdraw back into the skull. Bone is removed from behind the eyes, making space for the muscles and fatty tissues. Eyelid surgery can reverse the effects of Graves’ disease upon the eyelids. The eyelid muscles may have become tight, making it impossible to fully close the eyes. An incision is made along the natural eyelid crease, and some of the muscle that holds the eyelid open is scraped away. This weakens the muscle, allowing the eyelid to better extend over the eyeball. This also helps reduce or eliminate dry eye symptoms. For orbitopathy with a clinical activity score of more than 2, intravenous glucocorticoids are the treatment of choice. Usually, methylprednisolone is administered via a pulse intravenous technique. This is preferred over oral glucocorticoids, with better effectiveness and decreased adverse effects. Without treatment, serious complications of Graves’ disease include birth defects in pregnancy, increased risk of miscarriage, loss of bone minerals, and even death. Graves’ disease usually involves increased heart rate, which can cause additional complications such as atrial fibrillation, leading to stroke. When the eyes are bulging (proptotic) and the lids do not totally close at night, dryness occurs, risking a corneal infection that may lead to blindness. Pressure upon the optic nerve, behind the eye globe, can cause visual field defects and loss of vision. Prolonged, untreated hyperthyroidism may lead to bone loss, but this resolves with treatment. Today, agents that act as antagonists on TSH receptors are being investigated as a possible Graves’ disease treatment.

Clinical cases Case 1 1. If an antithyroid antibody test was positive, what might this indicate? 2. If her neck mass was a goiter that was affecting range of motion, what might be done regarding her medications? 3. What would differentiate Hashimoto’s thyroiditis from subacute thyroiditis, via cytologic studies? A 46-year-old woman reports fatigue that has lasted for several months. She has muscle aches and stiffness, especially in her neck, which are not relieved by analgesics or heat. The patient has a tender, palpable mass on the anterior aspect of her neck, and both personal and family history of hypothyroidism. The range of motion of cervical and thoracic is limited in several directions. She also has hypertension and

Thyroiditis and Graves’ disease

type 2 diabetes mellitus and is taking the antihypertensive medication lisinopril, multivitamins, and Synthroid. Answers: 1. Based on the information in this case, a positive antithyroid antibody test would indicate Hashimoto’s thyroiditis. 2. Likely, her Synthroid dose would be changed to better manage her thyroiditis. 3. In Hashimoto’s thyroiditis, reactive lymphoid cell infiltrations with Hürthle cell changes and multinucleate histiocytes would be seen. In subacute thyroiditis, numerous multinucleate histiocytes are usually seen, but Hürthle cell changes are not.

Case 2 1. What are the most likely causes of this patient’s condition? 2. How can this disease be differentiated from other types of thyroiditis? 3. What are the treatment options? A 51-year-old postmenopausal woman complained of pain in the anterior neck, restlessness, insomnia, and heat intolerance. She had a history of subacute thyroiditis for the last 10 years, and was treated with prednisolone for 3 months, but relapsed 2 months after stopping treatment. She was then prescribed prednisolone again for 2 months. The patient admitted to recently having recovered from the flu. Physical examination revealed enlargement and severe tenderness of the thyroid that was worse on the left side. Imaging studies revealed normal anatomic location of the thyroid and no areas of abnormality. The impression was of a diffuse goiter, and she was prescribed naproxen for symptomatic pain relief. After 2 weeks, there was no relief of symptoms. Upon reexamination, she revealed that her two sisters were both taking thyroxine. After further testing, subacute thyroiditis was revealed. Answers: 1. The most likely causes of subacute thyroiditis include viral infections such as the flu or mumps, which can cause the thyroid to swell and also disrupt hormone production, resulting in inflammation and many symptoms. 2. Subacute thyroiditis can be differentiated from other forms of thyroiditis in that the thyroid is usually very tender and may be painful. The other forms usually do not cause this manifestation. 3. Treatment options include OTC painkillers such as NSAIDs, aspirin, and ibuprofen. Corticosteroids are used when OTC medications are not sufficient to reduce swelling. Prednisone is a commonly used corticosteroid. If there are early signs of hyperthyroidism as a result of this

167

168

Epidemiology of Thyroid Disorders

condition, beta-blockers may be prescribed. Treatment is important early in the disease course. Once the later stages develop, and hypothyroidism is present, levothyroxine or other hormones will probably be needed.

Case 3 1. What are the risk factors for Riedel’s thyroiditis? 2. What is the treatment for this condition following surgery? 3. Why is cytological evaluation only of limited use for this condition? A 48-year-old woman with Riedel’s thyroiditis presented nonspecific cervical discomfort that lacked pain or compression symptoms. The thyroid was enlarged, painless, and very firm. TSH and free thyroid hormones were in normal ranges. Based on benign cytology of the nodules and lack of compression symptoms, a subtotal thyroidectomy was performed, revealing a hard, white thyroid appearance. Answers: 1. The primary risk factor for Riedel’s thyroiditis is smoking. Rarer associations include celiac disease, hypereosinophilic syndrome, Peyronie disease, systemic lupus erythematosus, lupus anticoagulant, Budd Chiari syndrome, autoimmune hemolytic anemia with hyperthyroidism, Graves’ disease, ulcerative skin or soft palate lesions, erythrocyte hyperaggregation, idiopathic thrombocytopenic purpura, pure red cell aplasia, and extrahepatic sarcoidosis. 2. The treatment for Riedel’s thyroiditis is daily levothyroxine, usually at approximately 100 µg/day. 3. Cytological studies are of limited use with Riedel’s thyroiditis because of firm thyroid tissue consistency, and a small amount of cellular material. Therefore most thyroid specimens are nondiagnostic. Also, Riedel’s thyroiditis often resembles aggressive thyroid cancers such as undifferentiated thyroid carcinoma.

Case 4 1. What tests can be performed for diagnosis? 2. If the diagnosis was Graves’ disease, what are the causes and pathogenesis? 3. What are the other likely symptoms? A 32-year-old woman presents with anxiety, excessive sweating, tachycardia, diarrhea, and puffy eyes. Upon examination, her blood pressure is elevated and her thyroid is enlarged.

Thyroiditis and Graves’ disease

Answers: 1. Diagnostic testing includes blood tests for TSH and thyroid hormone levels, measurement of the rate of radioactive iodine uptake, and ultrasonography. 2. Graves’ disease in women under 40 is usually genetic but can be caused by smoking. It develops from thyroid autoantibodies that result in the stimulation of follicular cell growth, causing thyroid enlargement, and increased production of thyroid hormones. 3. Other symptoms include headache, weight loss, nervousness, emotional instability, tremor, goiter, arrhythmias, nausea, oligomenorrhea, and muscle weakness.

Key terms alopecia areata cyclothymia echotexture germinal centers giant cell infiltration Hashimoto’s thyroiditis Hürthle cells isthmectomy lagophthalmos laryngoscopic microcuries perithyroidal

piriform sinus pretibial myxedema proptotic prostration septations sonolucent struma subacute thyroiditis technetium thyroiditis thyrotoxicosis

Further reading 1. Alt, F.W. Advances in Immunology, Volume 126. (2015) Academic Press. 2. Bankova, S. Thyroid Eye Disease and Its Healing (Graves’ Disease and Hyperthyroidism). (2010) Amazon Digital Services LLC. 3. Brownstein, D. Overcoming Thyroid Disorders, 3rd Edition. (2008) Medical Alternatives Press. 4. Callen, J.P., Jorizzo, J.L., Zone, J.J., Piette, W., Rosenbach, M.A., and Vleugels, R.A. Dermatological Signs of Systemic Disease, 5th Edition. (2016) Elsevier. 5. Eaton, J.L. Thyroid Disease and Reproduction: A Clinical Guide to Diagnosis and Management. (2018) Springer. 6. Heyman, A., Yang, J., and Bowthorpe, J.A. Stop the Thyroid Madness II: How Thyroid Experts Are Challenging Ineffective Treatments and Improving the Lives of Patients. (2014) Laughing Grape Publishing. 7. Icon Group International. Myxedema: Webster’s Timeline History, 1885-2007. (2010) Icon Group International, Inc. 8. Jameson, J.L., and De Groot, L.J. Endocrinology: Adult and Pediatric, 7th Edition. (2015) Saunders.

169

170

Epidemiology of Thyroid Disorders

9. Kelly, T. The Art and Science of Thyroid Supplementation for the Treatment of Bipolar Depression. (2018) CreateSpace Independent Publishing Platform. 10. Lavin, N. Manual of Endocrinology and Metabolism (Lippincott Manual), 5th Edition. (2018) LWW. 11. Llahana, S., Follin, C., Yedinak, C., and Grossman, A. Advanced Practice in Endocrinology Nursing. (2019) Springer. 12. Loriaux, L. Endocrine Emergencies: Recognition and Treatment (Contemporary Endocrinology). (2014) Humana Press. 13. McGill, J. Washington Manual Endocrinology Subspecialty Consult, 4th Edition. (2019) LWW. 14. Melmed, S., Polonsky, K.S., Larsen, P.R., and Kronenberg, H.M. Williams Textbook of Endocrinology, 13th Edition. (2015) Elsevier. 15. Moore, E.A., and Moore, L.M. Advances in Graves’ Disease and Other Hyperthyroid Disorders (McFarland Health Topics). (2013) McFarland & Company. 16. Moore, E.A., and Moore, L. Graves’ Disease: A Practical Guide (McFarland Health Topics). (2001) McFarland & Company. 17. Moore, E. The Thyroid Eye Disease Book: Understanding Graves’ Ophthalmopathy. (2013) Your Health Press. 18. Myers, A. The Thyroid Connection: Why You Feel Tired, Brain-Fogged, and Overweight and How to Get Your Life Back. (2016) Little, Brown and Company. 19. Osansky, E.M. Hashimoto’s Triggers: Eliminate Your Thyroid Symptoms by Finding and Removing Your Specific Autoimmune Triggers. (2018) National Endocrine Solutions. 20. Price, P. The Cyclothymia Workbook: Learn How to Manage Your Mood Swings and Lead a Balanced Life (A New Harbinger Self-Help Workbook). (2005) New Harbinger Publications. 21. Sataloff, R.T., Hawkshaw, M., Sataloff, J.B., DeFatta, R., and Eller, R. Atlas of Laryngoscopy, 3rd Edition. (2012) Plural Publishing, Inc. 22. Shoenfeld, Y., Meroni, P.L., and Gershwin, M.E. Autoantibodies, 3rd Edition. (2014) Elsevier. 23. Taaru, H. The Battle I Fought Against Heart Failure, Hypertension and Thyrotoxicosis. (2010) Xlibris. 24. Vitti, P., and Hegedus, L. Thyroid Diseases: Pathogenesis, Diagnosis, and Treatment (Endocrinology). (2018) Springer. 25. Wartian Smith, P. What You Must Know About Thyroid Disorders & What to Do About Them: Your Guide to Treating Autoimmune Dysfunction, Hypo- and Hyperthyroidism, Mood Swings, Cancer, Memory Loss, Weight Issues, Heart Problems & More. (2016) Square One. 26. Wentz, I., and Nowosadzka, M. Hashimoto’s Thyroiditis: Lifestyle Interventions for Finding and Treating the Root Cause. (2013) Wentz LLC. 27. Wentz, I. Hashimoto’s Protocol: A 90-Day Plan for Reversing Thyroid Symptoms and Getting Your Life Back. (2017) Wentz LLC. 28. Wiersinga, W.M., and Kahaly, G.J. Graves’ Orbitopathy: A Multidisciplinary Approach Questions and Answers, 3rd Edition. (2017) S. Karger. 29. William, A. Medical Medium Thyroid Healing: The Truth Behind Hashimoto’s, Graves’, Insomnia, Hypothyroidism, Thyroid Nodules & Epstein-Barr. (2017) Hay House, Inc. 30. Zaidi, S. Graves’ Disease and Hyperthyroidism: What You Must Know Before They Zap Your Thyroid With Radioactive Iodine. (2013) CreateSpace Independent Publishing Platform. 31. Zolle, I. Technetium-99m Pharmaceuticals: Preparation and Quality Control in Nuclear Medicine. (2007) Springer.

CHAPTER 8

Thyroid dysfunction and the cardiovascular system Contents Hypothyroidism and cardiovascular problems Hypotension Heart failure Thyroiditis and cardiovascular complications Heart failure Anemia Hypercholesterolemia Hyperthyroidism and cardiovascular problems Arrhythmia Syncope Heart failure Cardiovascular problems with thyroid storm Graves’ disease with cardiovascular complications Arrhythmia Stroke Heart failure Clinical cases Case 1 Case 2 Case 3 Case 4 Case 5 Further reading

172 173 174 174 174 175 176 178 178 180 180 181 183 183 184 184 186 186 186 187 188 189 190

The thyroid gland and its hormones modulate all components of the cardiovascular system. When cardiovascular disease is present, thyroid function tests are often needed to determine if overt thyroid disorder or even subclinical dysfunction may be present. Since hypothyroidism, hypertension, and cardiovascular disease all increase with advancing age, it is important to monitor thyroid-stimulating hormone (TSH), since it is the most sensitive test for hypothyroidism. More thorough understanding of the impact of thyroid status upon cardiovascular physiology allows health-care providers to make better decisions about evaluation and treatment of hypertension and cardiovascular disease. Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00008-6

r 2020 Elsevier Inc. All rights reserved.

171

172

Epidemiology of Thyroid Disorders

Hypothyroidism and cardiovascular problems Hypothyroidism has proven effects upon cardiovascular function. This form of thyroid disease is much more common than hyperthyroidism. However, both forms are dangerous when the cardiovascular system is affected. Hypothyroidism slows down the heart rate because of lower levels of thyroxine in the bloodstream. Hypertension develops since the blood vessels become less elastic and the heart must pump more blood in order to maintain the blood circulation. The heart also cannot fully relax after each heartbeat, producing diastolic dysfunction. When hypothyroidism is not treated, or undiagnosed, heart failure can eventually be expected. Hypothyroidism is a dangerous cardiovascular issue that must be diagnosed and treated early. If not, the patient’s life is in danger. Cardiac symptoms can occur in any individual with hypothyroidism, but they are more likely in those who already have underlying heart disease. Common cardiac problems associated with hypothyroidism include the following: • Bradycardia—The heart rate is modulated by thyroid hormone (TH). With hypothyroidism, the rate is usually 10–20 beats per minute slower than normal. Hypothyroidism may worsen the risk for premature beats, such as premature ventricular complexes, and may cause atrial fibrillation. • Coronary artery disease (CAD)—Worsening of this condition may be accelerated by hypothyroidism. However, reduction in THs can actually make angina less frequent, when already present; but increased low-density lipoprotein (LDL) (bad) cholesterol and C-reactive protein, due to hypothyroidism, worsens CAD. • Diastolic hypertension—It increases because the arteries become stiffer, causing the diastolic blood pressure to rise. • Dyspnea—Shortness of breath and poor exercise tolerance in hypothyroidism is usually because of skeletal muscle weakness. In patients who also have heart disease, this may be caused by progressive heart failure. • Edema—It is the swelling that occurs due to worsening heart failure. Hypothyroidism itself may also produce myxedema, which is caused by accumulation of abnormal proteins and other molecules in the interstitial fluid, which is outside the body’s cells. • Heart failure—It either worsens if already present, or new onset of heart failure is caused. Hypothyroidism is often very subtle, with a gradual onset. In older patients, hypothyroidism usually occurs without any of the commonly expected symptoms. It is treated with TH therapy. However, treatment of hypothyroidism is often not easy, and there is much controversy about the best method to use. Hypothyroidism is discussed in detail in Chapter 5, Hypothyroidism.

Thyroid dysfunction and the cardiovascular system

Hypotension Initially, it is common to have hypotension along with hypothyroidism or when being treated with thyroxine. Hypotension is caused by the reduced force of blood flow due to the lowered metabolism of hypothyroidism. When this happens, the systolic blood pressure is lower than normal. If there is adrenal insufficiency, which is common in the hypothyroid state, it can create a low circulating blood volume because insufficiency of aldosterone means that sodium cannot be reabsorbed from the kidneys. Over time, however, hypertension replaces hypotension. The kidneys become unable to sufficiently filter waste products when the blood pressure (BP) is low. Angiotensin causes vasoconstriction and increases BP. It also stimulates the release of aldosterone from the adrenal cortex, which promotes sodium retention by the kidneys. An increase in cortisol from the adrenal glands, to try and maintain homeostasis, causes an increase in hypertension. Blood is shunted from the extremities into the core of the body, which usually raises BP by forcing an identical volume of blood into a smaller vessel network. The shunting is caused by constriction of the peripheral vessels. Hypothyroid patients produce excessive noradrenalin (norepinephrine) from the adrenal medulla. This constricts blood vessels throughout the body in another attempt to combat hypotension and is partly related to an attempt to increase blood sugar levels. The production of norepinephrine may be as much as 30 times higher than normal. Hypotension is most common in patients who are females, 60 years of age or more, and take levothyroxine. Medications for hypotension can be compromised by coronary bypass and other surgeries. The body may also spontaneously require higher doses over time. These factors can cause symptoms of hypotension that previously did not exist such as orthostatic hypotension. This occurs when there is a sudden, extreme drop in BP when the individual changes positions such as standing up after lying down or being seated, and then immediately walking. BP changes are regulated by the autonomic nervous system. Therefore when sudden position changes occur, the BP is adjusted as needed. However, this does not work properly when orthostatic hypotension is present. The individual may feel as if they are about to pass out, may feel dizzy or faint, or feel light-headed. Sometimes, syncope actually occurs, creating a hazard due to falling. A major cause of orthostatic hypotension is poor adrenal-gland function, referred to as adrenal fatigue. Hypothyroidism alters adrenal-gland functions. However, adrenal deficiency can be diagnosed via blood testing. For orthostatic hypotension, it is important to confirm the condition—as well as having the TH levels tested—even if medications are being taken for hypothyroidism, and past blood-testing revealed normal TSH levels. Treatments for orthostatic hypotension include increasing salt and fluid intake, and use of adrenal-support hormones such as cortisol, dehydroepiandrosterone, fludrocortisone, and pregnenolone.

173

174

Epidemiology of Thyroid Disorders

Heart failure According to the Journal of Clinical Endocrinology and Metabolism, a large study has shown that patients who had congestive heart failure as well as hypothyroidism (even if mild) have a much higher risk of death compared to people with normal thyroid function. Heart failure can also be caused by hypothyroidism, since it interferes with myocardial function and aerobic capacity. Hypothyroidism challenges the entire body but is often not closely monitored when a patient is being treated for a cardiovascular condition, such as heart failure, until the heart disease becomes more serious. When a patient has high TSH levels and valid symptoms of hypothyroidism, along with elevated lipids, treatment is usually indicated. Prospective randomized studies are still being performed to determine the benefits of various treatments. Hypothyroidism is known to cause systolic dysfunction as well as lower ventricular dilatation, but it is not clear whether it can lead to heart failure on its own. It leads to cardiac unloading, which is not identical to heart failure. Various studies have indicated that chronic hypothyroidism leads to excessive myocyte lengthening from addition of sarcomeres, which is definitely related to heart failure. Focus on hypothyroidism Hypothyroidism has proven effects upon multiple cardiovascular pathways. These include adverse effects on systolic and diastolic function, endothelial function, and lipid levels. If a patient has an underlying cardiovascular risk factor, he or she may be more vulnerable to the effects of hypothyroidism. In heart-failure patients, overt hypothyroidism, as well as subclinical hypothyroidism, increase the risks of death.

Thyroiditis and cardiovascular complications Thyroiditis has definite links to cardiovascular complications. For example, Hashimoto’s thyroiditis can lead to high cholesterol, an enlarged heart, heart failure, reduced heart rate and BP, fluid around the heart, as well as a variety of autoimmune disorders, including Addison’s disease and Graves’ disease. Thyroiditis can slow the heart rate, decrease BP, and cause fluid to accumulate around the heart. Prior to treating patients with high doses of statins to lower cholesterol, it is very important to first control any underlying thyroid problem. Thyroiditis causes the heart to become unable to pump enough blood to meet the body’s needs (heart failure) and can also cause anemia. Thyroiditis is discussed in detail in Chapter 7, Thyroiditis and Graves’ disease.

Heart failure Thyroiditis, or inflammation of the thyroid gland, causes the heart muscle to be unable to completely relax after each heartbeat. This can produce diastolic dysfunction, a

Thyroid dysfunction and the cardiovascular system

condition that can lead to heart failure. Also, the blood vessels become stiffer, which can produce hypertension. Thyroiditis actually includes a group of individual disorders that cause the thyroid to become inflamed but may present in several different ways. Hashimoto’s thyroiditis is the most common cause of hypothyroidism in the United States. Subacute thyroiditis is the major cause of pain in the thyroid. Thyroiditis is generally caused by an autoimmune attack by the immune system upon the thyroid. This causes inflammation and damage to thyroid cells. It is associated with immunoglobulin G–related systemic disease, which may also cause pancreatitis, retroperitoneal fibrosis, and noninfectious inflammation of the aorta of the heart. Typical symptoms include fatigue, constipation, weight gain, depression, dry skin, and poor exercise tolerance. As thyroiditis progresses, symptoms can include puffiness around the eyes, slowed heart rate, reduced body temperature, and, finally, symptoms of impending heart failure. The changes that occur to heart contraction and rhythm are the primary factors that lead to heart failure. If thyrotoxicosis is present, betablockers are used to decrease tachycardia and tremors. As symptoms improve, these drugs are tapered off since the thyrotoxic phase is only temporary. If Hashimoto’s thyroiditis is present, treatment begins with TH replacement for hypothyroidism.

Anemia Thyroiditis, as well as hypothyroidism, is also connected to anemia, including macrocytic, normocytic, and microcytic anemia. Macrocytic anemia is defined as the insufficient concentration of hemoglobin in which the red blood cells (RBCs) (erythrocytes) are larger than their normal volume. Normal erythrocyte volume is between 80 and 100 μm³. The condition of having erythrocytes that are too large is called microcytosis. The larger RBCs are always related to insufficient numbers of cells as well as, usually, insufficient hemoglobin content per cell. These factors finally result in a total blood hemoglobin concentration that is lower than normal, which is clinically described as anemia. In normocytic anemia the RBCs are of normal size, and in microcytic anemia, they are smaller than normal. Normocytic anemia is a common condition in men and women over 85 years of age. Its prevalence increases with age, reaching 44% of men older than the age of 85 years. In this condition, there is a mean corpuscular volume of 80– 100, but hematocrit and hemoglobin are both decreased. In microcytic anemia the RBCs are usually not only smaller, but hypochromic as well, meaning that they are paler in color. This is because of a lower-than-normal mean corpuscular hemoglobin concentration. With hypothyroidism, 20%–60% of patients have one of these forms of anemia. The low plasma volume can lead to a false increase in hemoglobin levels. Therefore radioisotopic analysis is performed to estimate the true hemoglobin value.

175

176

Epidemiology of Thyroid Disorders

When anemia of an unknown cause is present, hypothyroidism should be suspected, since overt hypothyroidism does not show any evident signs in many cases. Similar to symptomatic hypothyroidism, incidence of anemia is twice as high as that of the normal population. In overt hypothyroidism, prevalence of anemia is about 43%. In subclinical hypothyroidism, nearly 39% have anemia. All patients tested have similar levels of iron, folic acid, and vitamin B12. Hypothyroidism leads to impaired RBC production in the bone marrow. The anemic condition is related to various chronic inflammatory conditions such as autoimmune disease. Hypothyroidism is also related to pernicious anemia, which occurs in about 10% of patients with Hashimoto’s thyroiditis. Pernicious anemia is caused by impaired absorption of vitamin B12 from food due to lack of intrinsic factor in the stomach. This causes reduced RBC production and anemia. Absorption problems in the intestine can also cause vitamin B12 deficiency and anemia. This is related to reduced gastrointestinal (GI) motility, a component of hypothyroidism. Intestinal problems can also cause folic acid deficiency–related anemia or iron-deficiency anemia. Iron deficiency can affect TH function. It is very important for the production of TH. In the case of severe iron deficiency that leads to anemia, thyroid function can be affected, resulting in hypothyroidism. When hypothyroidism causes anemia, it is important to treat the hypothyroidism in order to correct the anemia. By treating only the anemia, it is not possible to bring RBCs to normal levels, since the underlying thyroid disease is still present. A combination of THs, such as levothyroxine, followed by supplemental iron is used. In some cases, when the anemia is severe, blood transfusions may be indicated.

Hypercholesterolemia Hypercholesterolemia is the presence of high cholesterol in the blood. It is a form of hyperlipidemia, high blood lipids, and hyperlipoproteinemia, which means that there are elevated levels of lipoproteins in the blood. Elevated levels of LDL cholesterol may be due to hypothyroidism as well as factors such as diet, obesity, inherited diseases, or type 2 diabetes mellitus. It is estimated by many specialists that over 60% of people with hypercholesterolemia and untreated hypothyroidism would have normal cholesterol levels once their hypothyroidism was treated. High-density lipoprotein cholesterol is good for the heart, helping in removing bad cholesterol from the body, which protects against heart disease. Men with 40 mg/dL or less and women with 50 mg/dL or less are at increased risk of heart disease. Reaching above 60 mg/dL is recognized as an improving factor for heart function and reduced risks for cardiovascular disease. LDL cholesterol is bad for the heart and when levels are too high, the arteries become clogged, which contributes to heart disease, heart attack, and stroke. The LDL levels should be below 100 mg/dL for optimal

Thyroid dysfunction and the cardiovascular system

health. Numbers above 130 mg/dL increase risks for cardiovascular disease. Hypothyroidism results in the breakdown and removal of LDL cholesterol to become less efficient and it then builds up in the blood. Thyroid hormone levels do not even have to be extremely low for this to occur. Even in subclinical hypothyroidism, LDL can be higher than normal. High TSH levels alone can directly increase cholesterol levels even when TH levels are not low. Hyperthyroidism has the opposite effect, causing cholesterol levels to become abnormally low. Thyroid hormones help regulate cholesterol synthesis in the liver. For example, TSH increases expression and activity of the HMG-CoA reductase enzyme, which controls rates of cholesterol synthesis. Therefore hypothyroidism increases the amount of cholesterol that is produced in the liver. The cholesterol is combined with triglycerides into very-LDL (VLDL) particles and sent to the bloodstream. They reach the small blood vessels, encountering the enzyme called lipoprotein lipase (LPL). This enzyme breaks down the triglycerides within the VLDL particles into fatty acids. The heart, adipose, and muscle cells take these up. Triiodothyronine stimulates LPL to increase the breakdown of the triglyceride-rich VLDL. Over time, the cholesterol content of the lipoprotein becomes higher than the triglyceride content. This means that the particles then form LDL. The LDL particles circulate in the bloodstream, binding to LDL receptors, which triggers capture of LDL particles in cells. Inside cells, the particles are degraded with their contents being used for membrane structure or converted to various steroid hormones. Triiodothyronine increases expression of LDL receptors, reducing the time of LDL particles continuing circulation in the bloodstream, as well as the total number of LDL particles in the blood. Excess LDL particles cause other particles to contact blood vessel walls and be taken into the inner lining. Once they are there, the LDL particles may become oxidized, triggering inflammation. This is believed to be the primary event that begins the formation of arterial plaque. Triiodothyronine functions to protect cells from damage and may protect LDL from oxidation. However, high levels of free thyroxine also enhance LDL oxidation. Therefore hypothyroidism (as well as hyperthyroidism) is able to result in LDL oxidation. Lipid metabolism abnormalities are associated with development of atherosclerotic CAD. Decreased thyroid function increases the number of LDL particles as well as promoting their oxidability. Thyroid failure is strongly associated with diastolic arterial hypertension to a large degree and systolic arterial hypertension to a lesser degree. Overt hypothyroidism also causes impaired endothelial function, higher uric acid and phosphate levels, and therefore increased risks for cardiovascular disease. It is important to receive adequate thyroid and cholesterol testing. Biochemical screening for thyroid dysfunction is of extreme importance in all dyslipidemic patients as well as for patients with unexpected changes in their lipid profiles. Receiving levothyroxine for hypothyroidism will help lower cholesterol levels. When TH levels

177

178

Epidemiology of Thyroid Disorders

are only marginally low, TH-replacement therapy may not be needed. In these cases, use of cholesterol-lowering drugs may be sufficient. However, use of statins is dangerous with hypothyroidism because of how these drugs affect creatine kinase levels. Both statins and hypothyroidism cause the release of the creatine kinase enzyme into the blood with a cumulative effect of severe elevation of this enzyme. This can intensify the adverse effects of statins, including damage and inflammation of skeletal muscle, increasing risks for myopathy and rhabdomyolysis. It is very important to exclude hypothyroidism and other diseases that cause high cholesterol before any statins are administered. Hypothyroidism also impacts BP, C-reactive protein (a marker of inflammation), lipoprotein levels, the proinflammatory enzyme phospholipase A2, plasma homocysteine, insulin resistance, and body mass index. Focus on thyroiditis Inflammation of the thyroid, regardless of whether it is Hashimoto’s thyroiditis or another form, first affects the heart because of low blood pressure and a slower heartbeat. Eventually, it results in high levels of cholesterol, which can block off blood vessels or break off to become lodged in the heart or lungs. Once the patient goes into a hyperthyroid state, there will be an increased heart rate, palpitations, and arrhythmias, which can lead to atrial fibrillation and death.

Hyperthyroidism and cardiovascular problems Hyperthyroidism occurs when the thyroid gland makes too much TH or a patient is taking thyroid supplementation in excessive high doses. When hyperthyroidism is untreated, the heart must beat faster and work much harder. This leads to a variety of heart problems, which include arrhythmia, hypertension, angina, syncope, and heart failure. If thyroid storm develops, common outcomes will be shock and coma. Hyperthyroidism is discussed in detail in Chapter 6, Hyperthyroidism.

Arrhythmia Hyperthyroidism causes several different arrhythmias, which are heart rhythm disturbances. Most commonly, atrial fibrillation or sinus tachycardia occurs. Atrial fibrillation is a disorganized rhythm in the atria, which are the heart’s upper chambers (see Fig. 8.1). Hyperthyroidism also may cause a complete atrioventricular heart block and accelerated junctional rhythm. Atrioventricular block is the partial or complete interruption of impulse transmission from the atria to the ventricles. More than 2.7 million Americans have atrial fibrillation, according to the American Heart Association. It is the most common and most serious arrhythmia, and its diagnoses and treatment are important since the condition can cause blood to pool in the heart and form a dangerous clot. This increases risks for stroke by five times, according to the National Stroke Association.

Thyroid dysfunction and the cardiovascular system

Figure 8.1 Normal electrocardiogram (ECG) tracing with atrial fibrillation tracing below. ,https:// commons.wikimedia.org/wiki/Category:Atrial_fibrillation#/media/File:Atrial_Fibrillation.jpg..

Symptoms include fatigue, a rapid or irregular heartbeat, dizziness, faintness, or confusion. Atrial fibrillation can be difficult to diagnose, because its symptoms may resemble many other conditions. It is also possible to have no symptoms at all, yet still have atrial fibrillation. If caused by hyperthyroidism, treatment of this underlying condition greatly aids in the management of atrial fibrillation. Excessive TH interferes with the heart’s normal electrical impulses, which can cause it to be out of rhythm. Since atrial fibrillation may cause stroke, anticoagulants are often prescribed as physicians are attempting to get the heart back to its normal rhythm. Drugs may also be prescribed to slow the heart rate and manage arrhythmia symptoms. These drugs include beta-blockers and calcium channel blockers. Based on the severity and persistence of the patient’s hyperthyroidism, treatments include antithyroid medications and radioactive iodine. Amiodarone is a drug used for atrial fibrillation, since it sets the heart back to its normal rhythm. However, use of this drug can negatively impact the thyroid because of its high iodine content. Sinus tachycardia is an abnormally fast heart rate of more than 100 beats per minute. It is an example of a supraventricular rhythm, in which the sinoatrial node fires 100–180 beats per minute, which is faster than normal. The condition usually has a gradual start and ending. The most common electrocardiographic abnormality is sinus tachycardia with a shortened PR interval. Often, intraatrial conduction is prolonged, observed as an increase in the duration of the P wave. Approximately, 6% of thyrotoxic patients develop heart failure, and less than 1% develop dilated cardiomyopathy involving impaired left ventricular systolic dysfunction. This is due to a tachycardia-related mechanism, which causes a higher level of cytosolic calcium during diastole. There is a reduced contractility of the ventricle and diastolic dysfunction, often with tricuspid

179

180

Epidemiology of Thyroid Disorders

valve regurgitation. Hyperthyroidism may worsen any preexisting cardiac disease because of increased myocardial oxygen demand, increased contractility, and faster heart rate. It may cause silent CAD, angina, compensated heart failure, and endothelial dysfunction. Treatment of heart failure with tachycardia should include a beta-blocker after consideration of individual patient contraindications. Sinus tachycardia presents in over 33% of patients with acute myocardial infarction. When the condition is sustained for a longer period of time, infarcts are usually larger, with prominent left ventricular dysfunction and higher rates of mortality and morbidity. Tachycardia along with acute myocardial infarction can reduce coronary blood flow, increase myocardial oxygen demand, and worsen the situation severely. Beta-blockers can be used to slow the rate, and radiofrequency catheter ablation may be indicated.

Syncope Hyperthyroidism causes a large variety of signs and symptoms, which may be varied based on the age of the patient. In elderly patients, for example, there may be atypical symptoms, referred to as apathetic hyperthyroidism. Symptoms may resemble those of depression or dementia, usually without exophthalmos or tremor. Syncope is a prime example of a sign of hyperthyroidism along with altered sensory awareness and weakness. Signs and symptoms often involve only a single organ system. Hyperthyroidism can cause high BP and pulse rate, potentially causing lightheadedness. A combination of palpitations, vision changes, and dizziness may signify an abnormal heart rhythm affecting BP. It is important to understand that hyperthyroidism results in high levels of circulating THs in the blood, speeding up metabolism. This can increase heart rate, alter heart rhythm, and cause increased activity levels even while the patient feels tired and weak. The elderly often have more subtle symptoms, which include light-headedness, dizziness, and syncope. Syncope can be linked to hyperthyroidism as well as hypothyroidism. Once the thyroid is being attacked by an autoimmune condition, its attempt to compensate often results in tachycardia and lowered BP, resulting in fainting. Thyrotoxicosis is also an unusual cause of syncope. Even patients with new-onset hyperthyroidism have experienced episodes of fainting.

Heart failure Hyperthyroidism causes the heart to work faster and harder, which can overcome the heart’s ability to function, and result in its failure. When heart failure occurs, the heart cannot pump enough blood to meet the body’s needs. In the elderly, heart failure is another outcome of hyperthyroidism, but this is not an extremely common outcome. However, when preexisting heart disease is present, worsening of heart failure with hyperthyroidism is more common and extremely difficult to treat. Overt heart failure

Thyroid dysfunction and the cardiovascular system

in hyperthyroidism occurs in 6%–19% of patients, with incidence increasing with age. However, various cardiac symptoms may exist in 33% of patients treated for hyperthyroidism, with more than half of these having preexisting ischemic, hypertensive, or valvular heart disease. Cardiac failure in hyperthyroidism is not associated with any changes in histopathology. Atrial premature depolarizations, paroxysmal atrial tachycardia, atrial flutter, and atrial fibrillation all occur in hyperthyroidism. Difficulties in managing heart failure with hyperthyroidism involve the average older ages of patients, who often have underlying cardiovascular disease and, sometimes, related tachyarrhythmias. Correction of underlying hyperthyroidism is the main consideration, but this can take days, and rapid control of symptoms is crucial. Initial management of congestive heart failure is with loop diuretics. Hyperthyroidism is associated with decreased systemic vascular resistance and with vasodilation. If this is apparent, vasodilators, such as nitrates, must be avoided. It is important to understand that invasive monitoring of hyperthyroid patients with heart failure has shown depressed myocardial function in response to betaadrenoceptor blockade. This is proven by decreased stroke volume and increased pulmonary artery diastolic pressure. The ultrashort-acting beta-adrenoceptor blocker called esmolol has been used successfully to treat hyperthyroid-related heart failure.

Cardiovascular problems with thyroid storm Thyroid storm is an acute form of hyperthyroidism. It is caused by untreated or inadequately treated severe hyperthyroidism. Though rare, it occurs in patients with Graves’ disease or toxic multinodular goiter and can be precipitated by infection, surgery, trauma, diabetic ketoacidosis, embolism, and preeclampsia. Thyroid storm causes abrupt, intense symptoms of hyperthyroidism, including fever, extreme restlessness, wide emotional swings, significant weakness and muscle wasting, confusion, psychosis, nausea, vomiting, diarrhea, hepatomegaly, mild jaundice, cardiovascular collapse, shock, and coma. It is a life-threatening emergency that requires prompt treatment. Thyroid storm causes dangerously high levels of heart rate, BP, and body temperature. It is also known as thyroid crisis. Thyroid storm–related shock and coma are discussed below. Shock After the initial signs and symptoms of thyroid storm, there is usually a wide pulse pressure, followed in the later stages by hypotension that accompanies shock. Heart failure or heart attack may then occur and death is possible, even with treatment. The diagnostic criteria for thyroid storm include the following: • Presence of thyrotoxicosis with elevated levels of free triiodothyronine or thyroxine • Central nervous system (CNS) manifestations—restlessness, delirium, mental aberration or psychosis, somnolence or lethargy, coma • Fever of more than 100.4°F

181

182

Epidemiology of Thyroid Disorders

• Tachycardia of 130 beats per minute or higher, or heart rate of 130 or higher in atrial fibrillation • Congestive heart failure signified by pulmonary edema, moist rales over more than half of the lung field, cardiogenic shock • GI or hepatic manifestations—nausea, vomiting, diarrhea, or a total bilirubin level of more than 3 mg/dL There are five areas important in the treatment of thyroid storm, which are as follows: • Thyrotoxicosis—reduction of TH secretion and production • Systemic symptoms and signs—high fever, dehydration, shock, and disseminated intravascular coagulation • Organ-specific manifestations—cardiovascular, neurological, and hepato-GI • Triggers—usually, Graves’ disease, but also destructive thyroiditis, toxic multinodular goiter, TSH-secreting pituitary adenoma, human chorionic gonadotropin–secreting hydatidiform mole, or metastatic thyroid cancer • Definitive therapy—directly based on the identified causes Direct causes of death in patients with thyroid storm include sepsis, septic shock, disseminated intravascular coagulation, and pneumonia. Patients with potentially fatal conditions such as shock, disseminated intravascular coagulation, and multiple organ failure must be immediately admitted to an intensive care unit (ICU), because these conditions can also progress to brain damage. Coma The four primary findings of thyroid storm are significant fever, sinus tachycardia or supraventricular arrhythmia, GI symptoms, and CNS symptoms (which include coma). If urgent treatment of thyroid storm is not given, to lower the TH levels circulating throughout the body, seizures and coma often develop. According to the Burch– Wartofsky Point Scale for thyroid storm, a body temperature of 102°F–102.9°F, with a heart rate of 130–139, plus pulmonary edema, will usually be present when seizures and then coma develop. This point scale is summarized in Table 8.1. Based on the factors listed in Table 8.1, a score is derived to calculate the severity of a patient’s thyroid storm, with treatment based on that score. The incidence of thyroid storm is between 0.57 and 0.76 of every 100,000 persons, annually. However, it occurs in 4.8–5.6 of every 100,000 hospitalized patients annually. Focus on hyperthyroidism Even with mild hyperthyroidism, patients may be at an increased risk of death from cardiovascular disease. If a person has a family history of any type of thyroid problem, or any signs of thyroid abnormalities, he or she should schedule a thyroid and cardiovascular evaluation. Any sign of thyroid abnormality is able to affect cardiovascular health, and practitioners must be aware of this so that they can offer the highest quality of health care.

Thyroid dysfunction and the cardiovascular system

Table 8.1 The Burch–Wartofsky Point Scale for thyroid storm. Temperature (°F)

Heart rate

Symptoms of heart failure

Presence of atrial fibrillation

Symptoms of CNS dysfunction

GI or liver dysfunction

99–99.9 100–100.9

90–109 110–119

None Mild (pedal edema)

Absent Present

None Mild (signs of agitation)

101–101.9

120–129

Moderate (bibasilar rales)

Present

102–102.9

130–139

Present

103–103.9

140 or more 140 or more

Severe (pulmonary edema) Severe

Present

Moderate (delirium, psychosis, lethargy) Severe (seizures or coma) Severe

None Moderate (diarrhea, nausea, vomiting, abdominal pain) Severe (unexplained jaundice)

Severe

Present

Severe

104 or more

Severe

Severe Severe

CNS, Central nervous system; GI, gastrointestinal.

Graves’ disease with cardiovascular complications Graves’ disease causes many different types of complications. However, its cardiovascular complications include arrhythmia, stroke, heart failure, angina, and a resultant form of severe hypotension. The cardiovascular complications are most common in elderly patients and in those who have preexisting cardiovascular abnormalities. It also causes pregnancy issues, thyroid storm, and brittle bones. Graves’ disease is discussed in detail in Chapter 7, Thyroiditis and Graves’ disease.

Arrhythmia Graves’ disease may be complicated by severe cardiovascular manifestations, including tachyarrhythmias and, most often, atrial fibrillation. Significant sinus tachycardia is often seen. Sometimes, when physicians attempt to correct arrhythmias, they are usually unsuccessful because of persistent atrial fibrillation. Once euthyroidism is restored, atrial fibrillation can spontaneously resolve or may be treated with medications or electroconversion. Approximately, 66% of patients have spontaneous reversion to sinus rhythm after therapy for thyrotoxicosis, usually within 4 months. Spontaneous conversion is less likely after this time frame. It is important to evaluate thyroid function in

183

184

Epidemiology of Thyroid Disorders

patients who are clinically euthyroid but have atrial arrhythmias, with or without heart disease. This is because for about 20% of patients, the TSH and/or free thyroxine tests reveal an overactive thyroid. In 50% of these patients, normal sinus rhythm resumes, following treatment with antithyroid drugs. Subclinical hyperthyroidism is related, in patients of age 60 years or higher, with a three to five times higher risk for atrial fibrillation.

Stroke Graves’ disease, in people younger than age 45 years, is linked to a 44% higher risk for early stroke. Overall, stroke is uncommon but increasing in adults in their 20s, 30s, and 40s. Stroke rates in older adults in the United States actually appear to be declining, though hyperthyroidism is a causative factor. Hyperthyroidism is a risk factor for atrial fibrillation in older adults, which is in itself a risk factor for stroke. Other known risk factors include hypertension, diabetes mellitus, and history of atrial fibrillation. Hyperthyroidism and Graves’ disease are risk factors for cerebral venous thrombosis (CVT), which is associated with stroke. A CVT is a blood clot in one of the brain’s cerebral veins. These veins are responsible for draining blood out of the brain. When blood collects in them, they can leak into brain tissues, causing a hemorrhage or severe swelling. When CVT is severe, stroke-like symptoms can appear, including speech impairment, one-sided body numbness, weakness, and decreased alertness. These symptoms require immediate action by calling 911 and being transported for emergency treatment. Additional symptoms may include fainting, limited mobility of certain body parts, and seizures. The symptoms can progress to coma and death. The two best diagnostic methods are a magnetic resonance imaging venogram of the vessels in the head and neck and a computed tomography venogram to show arterial vessels and bones. Treatments involve anticoagulants, such as heparin, followed by oral anticoagulants such as warfarin. Antiseizure medications may be needed, and often, the patient must be admitted into a stroke unit or an ICU. Brain activity must be monitored. Followup venograms and imaging tests are used to assess thrombosis and any additional clots. It is also important to assess any other clotting disorders, tumors, or complications. Surgery may be needed to remove blood clots and repair vessels, which is known as thrombectomy. Stents may need to be inserted to prevent closure of vessels. A CVT is life-threatening if untreated. When caught early, CVT can be treated simply with medications.

Heart failure Hyperthyroidism causes overactivity of the heart, which can result in heart failure. This is because hyperthyroidism leads to cardiac hypertrophy from an increased

Thyroid dysfunction and the cardiovascular system

workload. Excessive TH affects duration of action potentials and repolarization currents. Thyroid hormone regulates sinoatrial node–related genes. Hyperthyroidism may predispose atrial fibrillation by combining genomic and nongenomic actions upon atrial ion channels, along with enlargement of the atrium due to expanded blood volume. The pulse pressure becomes widened and arterial stiffness is increased. Usually, the systolic BP rises. This increase can be dramatic in older patients who have impaired arterial compliance because of atherosclerosis. Hyperthyroidism may actually present as right-sided heart failure, with tricuspid valve regurgitation. Primary pulmonary hypertension is a progressive disease. It leads to right-sided heart failure and premature death and is often of idiopathic origin. This is most common in young women, defined by a pulmonary artery pressure of more than 25 mmHg at rest and more than 30 mmHg during exercise. Cardiac output can be increased by 50%–300% over normal ranges. Also, exaggerated sinus tachycardia or atrial fibrillation may produce rate-related left ventricular dysfunction and heart failure. Many patients with hyperthyroidism, low cardiac output, and impaired left ventricular function may be in atrial fibrillation when they are diagnosed. The hyperthyroid patient may be predisposed for heart failure by preexisting ischemic or hypertensive heart disease. Mitral valve prolapse is also seen more often in hyperthyroid patients. The signs of right-sided heart failure include ankle swelling, fatigue, fullness in the neck or abdomen, right upper quadrant abdominal discomfort, intestinal congestion, coolness of the extremities, postural lightheadedness, nocturia, decreased daytime urination, and skeletal muscle wasting. Signs such as neck vein distension or peripheral edema may be due to right-sided heart strain. A considerable amount of exercise intolerance and exertional dyspnea may be due to decreased pulmonary compliance, or decreased respiratory and skeletal muscle function. Treatment of thyrotoxic cardiac patients with beta-adrenergic blockage is indicated. For overt heart failure with pulmonary congestion, digitalis and diuretics are appropriate. The definitive treatment of choice for the hyperthyroidism is radioiodine131. Once hyperthyroidism is treated, there is often a reversion of the atrial fibrillation to sinus rhythm and resolution of symptoms of heart failure. Focus on Graves’ disease Untreated Graves’ disease leads to a 1.3 times higher increase in death from cardiovascular disease. Even with treatment, patients suffer greater rates of related mortality. Part of the prognosis of Graves’ disease concerns the fact that when untreated, it can cause thyrotoxicosis that greatly influences heart problems. Fortunately, Graves’ disease is treatable with antithyroid medications, radioactive iodine, TH replacement therapy, and surgery.

185

186

Epidemiology of Thyroid Disorders

Clinical cases Case 1 1. In which individuals is hypotension most common? 2. In the elderly, what is the main test for detecting hypothyroidism? 3. What is the treatment regimen for elderly patients with overt hypothyroidism? A 76-year-old man was admitted to the hospital for a total hip replacement. Following the surgery, he had significant hypotension of 45/29 mmHg. This was managed well by dopamine administration, and tests were run to determine the cause of the hypotension. He did not show any clinical evidence of hypothyroidism initially, but 24 hours later, further testing revealed that he was indeed hypothyroid. Oral levothyroxine was administered, and his BP was then well-controlled. Dopamine was tapered off, and the patient’s TH levels were soon back in the normal range. Answers: 1. Hypotension is most common in people with hypothyroidism, especially for females, people 60 years or older, and those who take TH replacement therapy. 2. Thyrotropin measurement is considered to be the main test for detecting hypothyroidism. Combined elevations of TSH and free thyroxine can detect overt hypothyroidism as well as subclinical hypothyroidism. 3. Overt hypothyroidism is treated with levothyroxine and elderly patients require a low initial dose that is increased every 4–6 weeks until TSH levels are normalized. After stabilization, TSH levels are monitored annually.

Case 2 1. What are the most serious potential cardiovascular complications of Hashimoto’s thyroiditis? 2. Can Hashimoto’s thyroiditis also affect the brain? 3. What are the risks of thyroid cancer in relation to Hashimoto’s thyroiditis? A 46-year-old woman was treated for high cholesterol and her physician found her heart to be enlarged. She was diagnosed with Hashimoto’s thyroiditis previously and also had a goiter, reduced cognitive function, and depression. The patient was also slightly anemic and had white patches of her skin in various areas. Testing revealed that she was negative for any thyroid nodules. In addition, she complained of newonset carpal tunnel syndrome, which she experienced at work when she did a lot of computer data entry.

Thyroid dysfunction and the cardiovascular system

Answers: 1. The most serious potential complications include reduced heart rate and BP, fluid around the heart, high levels of LDL cholesterol, breathing problems, and heart failure. 2. Yes, Hashimoto’s encephalopathy is a rare complication in which brain swelling causes profound, debilitating neurological symptoms. Though rare, it can cause tremors, sleepiness, confusion, hallucinations, dementia, seizures, sudden stroke-like attacks, and rarely, coma. 3. Hashimoto’s thyroiditis increases risks for thyroid cancer and also colorectal cancer. Cancer tends to develop in patients with this type of thyroiditis between ages of 35 and 55 years. As soon as Hashimoto’s thyroiditis is diagnosed, cancer-prevention efforts must begin, including dietary changes and removal of the thyroid gland, if risks are significantly high. Routine colorectal screening should also be performed.

Case 3 1. Are supraventricular cardiac arrhythmias more common in hyperthyroid patients than in euthyroid patients? 2. What factors are more likely to predict a successful return to normal sinus rhythm with proper treatment? 3. Does subclinical hyperthyroidism also have significant impact upon cardiovascularrelated morbidity and mortality? A 50-year-old woman with overt hyperthyroidism presented with a supraventricular cardiac arrhythmia. She described her condition as feeling like her heart wanted to “leap out of her chest” but did not have any angina. Her BP, however, was only slightly increased, at 126/84. Answers: 1. Yes, there is a higher prevalence of supraventricular cardiac arrhythmias in hyperthyroid patients than in euthyroid patients. Other types of arrhythmias are also more common in hyperthyroid patients. 2. Predictors for successful return to normal sinus rhythm for arrhythmias in hyperthyroid patients include an initial lower BP measurement and the development of a hypothyroid state following antithyroid therapy. 3. Yes, subclinical hyperthyroidism is increasingly recognized as causing significant cardiovascular-related morbidity and mortality. For example, subclinical hyperthyroidism is a known risk factor for subsequent development of atrial fibrillation.

187

188

Epidemiology of Thyroid Disorders

Case 4 1. How common is atrial fibrillation in patients with hyperthyroidism compared to the general population? 2. What medications are indicated to alleviate symptoms of thyrotoxicosis? 3. Can amiodarone be used as a first-line agent for thyrotoxicosis? An 80-year-old female was admitted to the hospital with a high respiratory rate, sweating, paleness, and a pulse rate of 155 beats per minute. There was a history of increasing shortness of breath and orthopnea in the preceding days but none of chest pain. She was taking nifedipine for hypertension. Her bowel habit was normal, and her weight was said to be stable. An electrocardiogram revealed sinus tachycardia and a chest radiograph demonstrated pulmonary edema. Over time, atrial fibrillation, with a ventricular rate of 170 beats per minute, developed. Digoxin was administered and intravenous heparin was commenced. The heart rate remained uncontrolled and the patient was unwell. Chemical cardioversion was attempted with amiodarone. By the following morning, the rhythm had reverted to sinus and the symptoms of cardiac failure had resolved. However, by the third hospital day, fast atrial fibrillation had returned with recurrence of pulmonary edema. At this time, thyroid function tests from the time of admission became available and revealed thyrotoxicosis. A cardiac enzyme series was normal over 3 days. In light of the recurrent atrial dysrhythmia in the context of proven thyrotoxicosis, propranolol was commenced. The rate and rhythm were controlled and heart failure did not recur. The echocardiogram in sinus rhythm showed good left ventricular function. Carbimazole was added and the patient was anticoagulated with warfarin. She was discharged, well, on the seventh day. Follow-up at 2 weeks showed that there had been no recurrence of heart failure. Answers: 1. Atrial fibrillation incidence ranges from 10% to 21% of patients with hyperthyroidism. This is compared to only 0.4% of the overall population. 2. Beta-adrenoceptor antagonists are used to alleviate thyrotoxic symptoms. They are also used for thyroid storm. These antagonists, along with propranolol, are effective for both hyperthyroidism and in controlling heart rate. 3. Amiodarone is indicated for atrial fibrillation and may be combined with propylthiouracil to accelerate reduction of serum triiodothyronine and thyroxine. However, because of its potential for unwanted effects in thyroid disease, it should not be used as a first-line agent.

Thyroid dysfunction and the cardiovascular system

Case 5 1. Why is it important to identify underlying thyroid dysfunction in a patient who has atrioventricular block? 2. What are the complications of hyperthyroidism-related arrhythmias? 3. Is there any difference between Graves’ disease and hyperthyroidism? A 41-year-old man with no significant past medical history was taken to the emergency department after he fainted. He described feeling no chest pain, dyspnea, or palpitations before he passed out. However, he had a fever and nonproductive cough for several days prior. He had no history of arthralgia, rashes, or insect bites. Upon examination, he was hypertensive, and an electrocardiogram revealed sinus tachycardia with a complete atrioventricular heart block and accelerated junctional rhythm. His TSH level was severely depressed, and free thyroxine was significantly elevated. Tests showed that his heart was functionally normal with a left ventricular ejection fraction of 59%. During his hospitalization, he had recurrent fainting spells along with 10- to 13-second periods of complete heart block. Further tests revealed a positive thyroid receptor antibody of a high level, suggesting Graves’ disease. He was treated with methimazole. Ultimately, a pacemaker was implanted. After 5 months of follow-up, his TH levels were normal and he had no recurrent fainting spells. Holter monitoring showed normal sinus rhythm with atrial pacing. Answers: 1. Identifying underlying thyroid dysfunction in a patient with atrioventricular block is critical, since treating the underlying thyroid dysfunction can help remove the stimulus that is triggering the arrhythmias. Also, medications used to treat hyperthyroidism include beta-blockers, which can be harmful for patients with atrioventricular block. 2. Hyperthyroidism-related arrhythmias increase the risk of blood clot formation inside the heart. These clots may cause an embolism, stroke, or other conditions. 3. Yes, the key difference between Graves’ disease and hyperthyroidism is that Graves’ disease is a pathological condition. Hyperthyroidism is a functional abnormality, which results from an ongoing pathological process. Graves’ disease is one such pathological condition that causes hyperthyroidism.

Key terms adrenal fatigue adrenal insufficiency

aerobic capacity angiotensin apathetic

189

190

Epidemiology of Thyroid Disorders

arrhythmia atrial fibrillation atrial flutter autonomic nervous system cardiomyopathy creatine kinase electroconversion exophthalmos heart failure HMG-CoA reductase homocysteine hyperlipoproteinemia moist rales

norepinephrine orthostatic hypotension oxidability paroxysmal atrial tachycardia phospholipase A2 premature beats pulmonary edema pulmonary hypertension retroperitoneal fibrosis radiofrequency catheter ablation rhabdomyolysis sinus tachycardia thyroid crisis

Further reading 1. Ali, S.Z., and Cibas, E.S. The Bethesda System for Reporting Thyroid Cytopathology: Definitions, Criteria, and Explanatory Notes, 2nd Edition. (2018) Springer. 2. Derwahl, C.M., Duntas, L.H., and Butz, S. The Thyroid and Cardiovascular Risk: Merck European Thyroid Symposium, Berlin. (2004) Thieme. 3. Felker, G.M., and Mann, D.L. Heart Failure: A Companion to Braunwald’s Heart Disease, 4th Edition. (2019) Elsevier. 4. Grubb, B.P., and Olshansky, B. Syncope: Mechanisms and Management, 2nd Edition. (2005) WileyBlackwell. 5. Hochman, J.S., and Ohman, E.M. Cardiogenic Shock. (2009) Wiley-Blackwell. 6. Iervasi, G., Pingitore, A., Ladenson, P.W., and Maseri, A. Thyroid and Heart Failure: From Pathophysiology to Clinics. (2009) Springer. 7. Kaur, R., Krishan, P., and Debnath, B. Cardiovascular Risks in Patients With Subclinical Hypothyroidism. (2016) Lap Lambert Academic Publishing. 8. Kruger, W. Acute Heart Failure: Putting the Puzzle of Pathophysiology and Evidence Together in Daily Practice, 2nd Edition. (2017) Springer. 9. Lilly, L.S. Pathophysiology of Heart Disease: A Collaborative Project of Medical Students and Faculty, 6th Edition. (2015) LWW. 10. Loriaux, L. Endocrine Emergencies: Recognition and Treatment (Contemporary Endocrinology). (2014) Humana Press. 11. Lowrance, J.M. Cardiac Effects of Hypothyroidism and Hyperthyroidism: Heart Problems Caused by Thyroid Disease. (2012) CreateSpace Independent Publishing Platform. 12. Osman, F. The Cardiovascular Consequences of Hyperthyroidism: Cardiac Manifestations Before, During and After Effective Antithyroid Therapy – Amiodarone-induced Hyperthyroidism. (2010) Lap Lambert Academic Publishing. 13. Rapoport, B., and McLachlan, S.M. Graves’ Disease (Endocrine Updates). (2012) Springer. 14. Scherbaum, W.A., Bogner, U., Weinheimer, B., and Bottazzo, G.F. Autoimmune Thyroiditis: Approaches Towards Its Etiological Differentiation. (1991) Springer. 15. Schummer, G. Endocrine Emergencies: A Pocket Guide to Endocrine Emergencies. (2009) GLS Education LLC. 16. Suh, G.J. Essentials of Shock Management: A Scenario-Based Approach. (2018) Springer. 17. Da, Tang Yi Thyroid and Cardiovascular Disease. (2000) Central South University Press. 18. Wondisford, F.E., and Radovick, S. Clinical Management of Thyroid Disease. (2009) Saunders.

CHAPTER 9

Thyroid dysfunction and mental disorders Contents The link between thyroid dysfunction and mental disorders Cretinism Myxedema Graves’ disease and stress Hyperthyroidism The burden of mental disorders Clinical cases Case 1 Case 2 Case 3 Case 4 Case 5 Further reading

192 193 194 196 197 198 200 200 201 202 203 204 205

About 18% of adults in the United States have anxiety disorders, which include posttraumatic stress disorder, obsessive-compulsive disorder, and various phobias. About 7% of adults had at least one major depressive episode in the past year. Bipolar disorder affects about 2.5% of adults, and just over 1% of adults have schizophrenia. Serious mental-illness costs Americans more than $193 million in lost earnings annually. Thyroid dysfunction may be related to a variety of mental disorders. Depression is an example of a mental disorder that actually may be one of the first symptoms of thyroid dysfunction. Patients may be mislabeled as having a major mental disorder even though hypothyroidism or hyperthyroidism is causing their symptoms. When thyroid function is not normal, a variety of mental symptoms and conditions may develop. These include anxiety, bipolar disorder, depression, irritability, aggression, obsessivecompulsive disorder, panic attacks, phobia, and even schizophrenia. As many as 15% of patients treated for depression have elements of mild or overt hypothyroidism. Conditions commonly linked to mental disorders include cretinism, myxedema, and Graves’ disease with stress.

Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00009-8

r 2020 Elsevier Inc. All rights reserved.

191

192

Epidemiology of Thyroid Disorders

The link between thyroid dysfunction and mental disorders Thyroid dysfunction has a proven link with various mental disorders. For example, undiagnosed Hashimoto’s thyroiditis is often preceded by mental abnormalities, depression, confusion, and irritability. Sometimes, symptoms of thyroid dysfunction are even mistaken for mental illnesses. In the case of Hashimoto’s thyroiditis, patients have been misdiagnosed with paranoid schizophrenia, psychotic depression, and mania. A 1987 study revealed that 15% of patients admitted to psychiatric facilities for depression had mild or overt hypothyroidism. Even today, thyroid testing is not standard for patients being evaluated for mental illnesses. Other studies have shown that thyroid hormone (TH) replacement therapy has been as effective as the drug lithium in treating resistant depression. The two drugs have been used together for an even greater effect. THs that are not correctly balanced have been linked to anxiety, bipolar disorder, depression, aggression, irritability, obsessive-compulsive disorder, panic attacks, schizophrenia, and a variety of phobias. Because of undiagnosed thyroid dysfunction, many people may be suffering from mental issues and yet not be aware of their true cause. When Hashimoto’s thyroiditis initially causes temporary spikes in TH, the individual may experience anxiety, hyperactivity, insomnia, and uncontrolled, sudden mood swings. As the disease causes decreased thyroid function, fatigue and depression develop. The generic symptoms of Hashimoto’s thyroiditis include many types of mental abnormalities and also confusion. In the postpartum period, immune function is altered, which often causes a hyperthyroid state for many months after childbirth. Then, there is a reduction in thyroid activity, and hypothyroidism begins. A new mother may experience anxiety, irritability, insomnia, and other examples of mental dysfunction. The symptoms are often misdiagnosed as mental disorders caused by chemical imbalances (neurotransmitters) in the brain. It is also common for patients suffering from depression to have decreased levels of TH in the bloodstream. Factors that cause this include poor thyroxine (T4) to triiodothyronine (T3) conversion, poor TH transport across the blood brain barrier, and inhibited TH uptake. Unfortunately, standard thyroid tests do not reveal these areas of dysfunction, and many patients are therefore not properly diagnosed. Many physicians dismiss the thyroid gland as a contributing factor to mental dysfunction. They often are quick to prescribe psychotropic medications, which often have severe adverse effects. Another point to consider is that many of these medications also alter thyroid function, which can actually increase the severity of the symptoms. A large percentage of patients could benefit much more from thyroid testing and adequate treatment instead of psychotropic medications. Though thyroxine is often used for many thyroid patients, triiodothyronine is the active form of TH. Therefore if a patient’s body is not effectively converting T4 into T3, using T4 as treatment is not going to resolve symptoms. Therefore research has proven that T3 is the

Thyroid dysfunction and mental disorders

preferred form to use for thyroid-related mental symptoms. In one study, bipolar disorder patients who did not respond well to various psychotropic medications experienced improvement of their conditions when treated with T3. Out of the test group, 84% improved and an astounding 33% had full remission of their bipolar disorder. As early as 1969, depression was recognized as one of the first symptoms of thyroid dysfunction. Even with this knowledge, thyroid testing is still not standard for patients being evaluated for various forms of mental disorders. Numerous studies have shown that many patients with thyroid dysfunction respond favorably to TH replacement therapy. Triiodothyronine has been shown to be equally as effective as lithium in the treatment of resistant depression. The largest study of the efficacy of antidepressants was the Star D report, which combined over 120 journal articles assessing the use of these medications globally. It screened patients with major depression who had other comorbid conditions. This study found that 66% of patients experienced significant adverse effects or did not respond positively to antidepressants. Also, more than 50%, who improved with their use, relapsed within 1 year. However, the study proved that T3 was 50% more effective and caused fewer adverse effects. Therefore optimizing thyroid function may be a highly effective method for treating mental disorders, specifically depression and bipolar disorder. Less aggressive dysfunction, such as confusion, irritability, and malaise, may also be resolved through proper thyroid treatment. Patients should seek out a comprehensive test of their thyroid-stimulating hormone (TSH), free T4, free T3, reverse T3, and thyroid antibodies.

Cretinism Cretinism is hypothyroidism that develops during infancy or in early childhood. In earlier times, cretinism was relatively common in areas of the world with dietary iodine deficiency, such as parts of China, Africa, and in the Himalayas and other mountainous areas. Because of widespread iodine supplementation, cretinism is much less common. One of the primary components of cretinism is severe mental retardation. The severity of mental abnormalities appears to be influenced by the time that thyroid deficiency occurs during gestation. When the mother has thyroid deficiency before the thyroid gland of the fetus develops, the mental retardation will be severe. Oppositely, when TH deficiency occurs later, after the fetal thyroid gland is functioning, the brain develops normally. Today, cretinism is clinically referred to as congenital iodine deficiency syndrome. By racial group, there is a higher prevalence of this condition for Hispanic females, with 1 in 1886 diagnosed. Overall, taking into account all groups, the condition affects one of every 4000 newborns. It affects females twice as often as males and occurs about 12 times more often in twin births. Diagnosed individuals are monitored for mental development in four areas. These areas, which are described later, include

193

194

Epidemiology of Thyroid Disorders

communication/personality behavior, motor ability, adaptive behavior, and language ability. There are six standardized, global tests of behavioral development, used for individuals of all mental capacities, which are as follows: • Bayley Scales of Infant Development—for infants 1 42 months old; it assesses cognitive, language, and motor development with social/emotional and adaptive behavior subtests. • Brunet Lézine Scale—for infants 2 30 months old; it assesses posture, coordination, language, and social development. • Battelle Developmental Inventory—for infants and children up to 7 years of age; it assesses adaptive, personal/social, communication, motor, and cognitive development. • Denver Developmental Screening Test—for infants and children between 2 weeks and 6 years of age; it assesses fine motor/adaptive, gross motor, personal/social, and language development. • Sequenced Inventory of Communication Development—for infants 4 48 months old; it assesses receptive communication age and expressive communication age. • MacArthur Bates Communicative Development Inventories—for infants 8 18 months of age and for toddlers 16 30 months of age; it assesses vocabulary, word use, grammar, irregular words, overregularized words, word combination, sentence length, and sentence complexity Congenital iodine deficiency syndrome can lead to mental-health issues, such as depression and cognitive impairment. Children and teenagers often show poor mental development, and mental disabilities are often seen in early childhood. Focus on the Bayley Scales of Infant Development These scales are a standard series of measurements used mostly to assess the development of infants and toddlers between 1 and 42 months of age. They consist of a series of developmental play tasks that take between 45 and 60 min to administer. They derive a developmental quotient instead of an intelligence quotient. The scores are used to determine a child’s performance compared with normal values from typically developing children of the same age.

Myxedema The term myxedema refers to the nonpitting edema that is common to hypothyroidism, but this is by far not its most significant sign or symptom. In previous times a term known as myxedema madness or myxedematous psychosis referred to the relationship between hypothyroidism and psychosis. Studies have shown that between 5% and 15% of patients with myxedema have some forms of psychosis. An interesting delusion was reported in one patient who stated that an identical-looking person

Thyroid dysfunction and mental disorders

had replaced his partner. This particular delusion is described as Capgras syndrome. Myxedema has been linked to other delusions, visual and auditory hallucinations, repeating the same words or movements without recurrent stimuli (perseveration), loose associations of thoughts and ideas, and paranoia. These symptoms can occur without the impaired level of consciousness that is seen in delirium or dementia. Some individuals have even committed suicide after suffering from myxedema-related depression. Psychosis usually emerges after physical symptoms, often over months or years. Thought disorders can occur in patients with clinical or subclinical hypothyroidism. This suggests that psychosis may not be related to the degree of TH deficit. Overall, myxedema madness is relatively uncommon, such as in Hashimoto’s thyroiditis or in patients after thyroid removal surgery, who are not taking thyroxine. When the thyroid is chronically underactive, this can slowly lead to progressive dementia, delirium, and in extreme cases (usually in the elderly), to hallucinations, psychosis, and coma. Standard treatment for myxedema is oral thyroxine, but in severely acute cases, liothyronine is used. These treatments usually reverse the psychosis but may not affect cognitive deficits caused by changes in metabolic activity within the central nervous system. The delusions and hallucinations that often characterize myxedema madness usually get resolved in about 1 week after starting appropriate TH replacement therapy. However, when this therapy is started at an excessively high dose, or is titrated too quickly, an acute confusional state or exacerbation of the psychosis may occur. Adding antipsychotic medications may result in earlier remission of psychotic symptoms than thyroid replacement alone. Atypical antipsychotics started in low doses are usually well tolerated. Discontinuation of thyroid supplementation may lead to the return of symptoms. Rarely, there has been a type of myxedema madness without significant presence of myxedema. Patients with long-term psychiatric histories have been cured of psychotic depression with thyroid replacement therapy. Recent studies have identified a connection between depression and disturbances in the hypothalamic pituitary thyroid axis. Selective pituitary insufficiency and a defect in TSH release upon thyrotropin releasing factor (TRF) loading may be implicated. Focus on myxedema madness This consequence of hypothyroidism, such as from Hashimoto’s thyroiditis or in patients who have had their thyroid gland surgically removed and are not taking thyroxine, has many serious effects. A chronically underactive thyroid can lead to slowly progressive dementia and delirium. In extreme cases, it leads to hallucinations, psychosis, and coma— especially in the elderly.

195

196

Epidemiology of Thyroid Disorders

Graves’ disease and stress The hyperthyroidism of Graves’ disease can also be accompanied by prominent mental disorders. Many patients complain of frequent mood changes, emotional lability, and hysterical outburst. Periods of depression may alternate with mania. Some patients experience symptoms resembling panic attacks. Due to disturbed sleep and recurring palpitations, Graves’ disease patients may have even more emotional disturbances. This disease is also linked to increased anxiety, tension, inpatients, irritability, and abnormalities of appetite. All disorders related to or as a result of hyperthyroidism or Graves’ disease are classified as “mental disorders due to a general medical condition.” According to the American Psychiatric Association classification book, this type of condition is characterized by the presence of mental symptoms considered to be the direct psychological consequence of a general medical condition. Disorders often associated with Graves’ disease include mood disorders such as bipolar disorder. This consists of two primary episodes. The depressed episode involves a depressed mood for most of each day, nearly every day, along with feelings of sadness and emptiness, irritable mood, greatly reduced interest or pleasure in most activities, significant weight loss when not dieting or weight gain when not overeating, and chronic insomnia. The manic episode is a distinct period of abnormality and chronically elevated, expansive, or irritable mood that lasts for at least 1 week. During the period of mood disturbance, three or more of these symptoms persist: inflated selfesteem or grandiosity, decreased need to sleep, and being more talkative than usual or feeling pressure to continue talking. Anxiety disorders are also related to Graves’ disease. Panic attacks are often mistaken with palpitations, accelerated heart rate, and shortness of breath. A panic attack only actually exists when there is intense fear or discomfort. Graves’ disease is also related to histrionic personality disorder, described as a pattern of excessive emotionality and attention seeking. The individual being uncomfortable when he or she is not the center of attention, inappropriate sexual statements or behaviors, quickly shifting expression of emotions, or use of physical appearance to draw attention from others indicates this. Often, mental symptoms precede Graves’ disease itself. More serious mental disturbances used to accompany thyroid crisis in previous years because of lack of awareness and availability of treatments. These disturbances included acute psychosis, delirium, and fever. Stress that is experienced chronically also affects mental health. The stress response of the body does not respond well when it is continuously engaged. Stressors are everywhere, including work, money, family, health, relationships, and even the overwhelming types of media around us. Chronic stress increases risks for a variety of physical as well as mental-health problems. Therefore along with a thyroid disorder, a person with chronic stress is even more likely to experience mental disorders. Physical

Thyroid dysfunction and mental disorders

or mental stress affects thyroid problems and can lead to thyroid storm since it causes high levels of dopamine, epinephrine, and norepinephrine to be released into the bloodstream. When these hormones are combined with high levels of TH, nearly every body system experiences overactivity. Managing emotional stressors can decrease levels of some hormones. People with Graves’ disease should learn how to manage stress. There are a variety of suggestions that help patients learn to do this, which include the following: • Talking to others or writing in a journal about what is bothering you • Not taking on more than you can handle • Learning time-management skills • Keeping as positive an attitude as possible • Understanding and accepting that there are some things you cannot control • Exercising regularly • Watching your diet—keeping it low in sugar, caffeine, and alcohol • Getting plenty of sleep • Allowing time to relax every day—a bath or shower, a cup of your favorite beverage, reading, or listening to music It is also very important to be aware of the symptoms of thyroid storm, since it can be fatal without prompt and aggressive treatment. In fact, the mortality rate for untreated thyroid storm patients is estimated to be 75%. The heart rate, blood pressure (BP), and body temperature can become dangerously high. The condition may follow severe emotional distress, trauma, surgery, stroke, diabetic ketoacidosis, congestive heart failure, or pulmonary embolism. Symptoms of thyroid storm include tachycardia (over 140 beats per minute), atrial fibrillation, high fever, persistent sweating, shaking, agitation, restlessness, confusion, diarrhea, and finally, unconsciousness. Treatment requires antithyroid medications such as propylthiouracil or methimazole. It is important to avoid taking iodine since it can worsen the condition.

Hyperthyroidism Hyperthyroidism is strongly linked to symptoms of psychosis. Patients with hyperthyroidism are much more likely than others to report feeling isolated, having impaired social functioning, anxiety, and mood disturbances. They are also much more likely to be hospitalized for some type of affective disorder, which is characterized by dramatic changes or extremes of mood. People with subclinical or over biochemical hyperthyroidism report above-average mood and lower-than-average anxiety. Hyperthyroidism affects approximately 2.5% of population of the United States. Nearly 50% of these people are unaware of their condition. Women are more than five times as likely to have hyperthyroidism compared to men. Psychiatric symptoms of hyperthyroidism

197

198

Epidemiology of Thyroid Disorders

also include apathy (more common in elderly patients), cognitive impairment, delirium, depression, emotional lability, fatigue, hypomania or mania, impaired concentration, insomnia, irritability, and psychomotor agitation. With thyrotoxicosis, patients have reported anxiety, thoughts of violence, strange sexual thoughts, and paranoia. Pseudo-psychiatric symptoms are reported as the initial sign of hyperthyroidism in 2% 12% of patients. The American Association of Clinical Endocrinologists states that patients often show signs of anxiety with no underlying psychiatric condition. Occasionally, depression is the first manifestation. Research also shows that symptoms associated with a generalized anxiety disorder and subclinical hyperthyroidism are very slight. It is important to visit an experienced endocrinologist in order to correctly diagnose which condition is present. With appropriate treatments for the causative hyperthyroidism, most patients begin to feel normal again very quickly.

The burden of mental disorders According to the World Health Organization (WHO), mental disorders are common in most countries. Combined statistics on anxiety, mood, externalizing, and substance use disorders is between 18% and 36% of the global population. An “externalizing disorder” is a mental disorder characterized by maladaptive behaviors directed toward an individual’s environment, which cause impairment or interference in normal life functions. Externalizing disorders are often referred to as disruptive behavior disorders. They include attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder. These disorders affect children as well as adults. Many mental disorders begin in childhood or adolescence, with significant adverse effects upon later life. Adult mental disorders are associated with such extensive impairment of normal functioning that today’s clinical interventions offer very positive cost-effectiveness of treatment. Expansion of treatment could be, therefore, beneficial to employers as well as the overall society. The WHO World Mental Health Survey Initiative was designed to help countries carry out and analyze epidemiological surveys of the prevalence and other statistics of mental disorders. It provides centralized instrument development, training, and data analysis. There are four areas utilized in the survey, in which patients are asked to determine which particular disorder interfered with normal activities of living. These four areas are as follows: • Home management—cleaning, shopping, taking care of home • Ability to work • Social life • Ability to form and maintain close relationships with others In each area the level of interference by a mental disorder is scored as none (0), mild (1 3), moderate (4 6), severe (7 9), and very severe (10). Patients were also asked to

Thyroid dysfunction and mental disorders

respond to the question, “How many days out of 365 days in the past year were you totally unable to work, or to carry out your normal activities because of the mental illness?” Serious disorders are defined as the following: • Nonaffective psychosis—the type that is not related to emotions or moods • Bipolar I disorder—also known as manic-depressive disorder, or formerly, manic depression • Substance dependence with a physiological dependence syndrome—the substance abuser is physically dependent upon the substance due to chronic use of a tolerance-forming substance; abrupt or gradual drug withdrawal causes unpleasant physical symptoms • Attempted suicide in conjunction with any other disorder—the most common disorders in relation to suicide attempts include posttraumatic stress disorder, panic disorder, and social phobia; much less commonly related disorders include generalized anxiety disorder, specific phobias, separation anxiety disorder, and agoraphobia (an anxiety disorder involving situations where the environment is perceived to be unsafe) • Severe role impairment due to a mental disorder in at least two areas of functioning Nonserious disorders are defined as the following: • Substance dependence without a physiological dependence syndrome—the substance abuser is not physically dependent upon the substance, and withdrawal causes no, or only slight physical symptoms • Moderate role impairment due to a mental disorder in at least two areas of functioning All other disorders were classified as “mild.” According to the United States Healthy People 2020 program, the burden of mental illness in this country is among the highest of all diseases. Mental disorders are among the most common causes of disability. Approximately one in four adults has some form of mental disorder—usually anxiety or depression. In 2010 one in five children had a mental disorder—most commonly, attention-deficit hyperactivity disorder. It is not uncommon for adults and children to have more than one mental disorder at a time. People with untreated mental-health disorders are at high risk for unhealthy and unsafe behaviors. These include alcohol or drug abuse, violent or self-destructive behavior, and suicide, which is the 11th leading cause of death for all age-groups, and the second leading cause of death in people of ages 25 34. Mental-health disorders have serious impacts upon physical health. They are linked to the prevalence, progression, and outcome of many chronic diseases, including diabetes, heart disease, and cancer. Mental-health problems can have harmful, longlasting effects that include extreme psychosocial and economic costs. This is not only

199

200

Epidemiology of Thyroid Disorders

for patients but also for their families, work environments, school environments, and communities. Prevention of mental-health disorders is an expanding area of research and practice, and many disorders can be effectively treated. However, early diagnosis and treatment are essential in reducing the burden of mental-health disorders, and their associated chronic diseases. Also, it is important to understand that chronic diseases can intensify symptoms of mental-health disorders, creating a “cycle” of continued poor health. This cycle actually decreases the ability of patients to participate in treatments and recovery. Therefore improving mental health is critical to improving overall health. While there are no precise figures for the number of first episodes of psychosis every year in the United States, incidence data from other countries suggests that about 100,000 people every year are affected. The World Economic Forum estimates mental disorders to be the largest area of cost for health care, at over $2.5 trillion globally. They predict this figure to increase to more than $6 trillion by the year 2030. The costs for mental disorders are greater than the costs of diabetes, respiratory disorders, and cancer combined. The Substance Abuse and Mental Health Administration has estimated that the United States’ national expenditure for mental health care is over $200 billion annually. If this figure is combined with projections of lost earnings and public disability insurance payments related to mental illness, the estimated financial cost of mental disorders will be over $500 billion annually. The Social Security Administration reported in 2012 that more than 5.3 million people under age 65 with mental-illness disabilities received social security payments. Different from many other brain disorders, treatments are effective for most mental disorders, even highly severe disorders. For example, about 85% of severely depressed patients respond well to electroconvulsive therapy (ECT). Bipolar disorder and many other mental disorders are also extremely treatable.

Clinical cases Case 1 1. How common is hypothyroidism in elderly women? 2. What is the primary difference between a patient with hypothyroidism and hallucinations compared to one with hypothyroidism and delirium or dementia? 3. Which tests are usually first performed for suspected hypothyroidism? A 73-year-old woman visited her local hospital complaining of auditory and visual hallucinations over the past 2 weeks. She also has had progressively decreasing vision in both eyes. She described her auditory hallucinations as sounding like radio or television announcers inside her head. Her visual hallucinations started after the audio hallucinations. Physical examination revealed her body temperature to be 97 F, a BP of 175/89, and both dry skin and brittle hair. The patient was fully conscious and alert with no

Thyroid dysfunction and mental disorders

cognitive deficits. Her thyroid gland was of normal size. She had a significant delay in the relaxation phase of her deep tendon reflexes. She reported auditory hallucinations occurring during the examination. The patient was admitted to the hospital. Further testing revealed extremely high TSH levels, and extremely low levels of T4 and T3. A computed tomography scan of her head revealed only mild small-vessel ischemic changes, and a follow-up magnetic resonance imaging revealed nonspecific periventricular white-matter changes. Low-dose thyroid replacement therapy was started, along with risperidone for the hallucinations. Within 2 3 weeks, all psychiatric symptoms were gone. Answers: 1. Hypothyroidism is more common in older women than in younger women, and 10 times more common in women than in men. In general, hypothyroidism affects 4% 10% of women, increasing with age. About 10% of women over age 55 have subclinical hypothyroidism. 2. With hypothyroidism, manifestations of hallucinations occur without the impaired level of consciousness seen in delirium or the cognitive deficits of dementia. 3. Initial evaluation of the patient with suspected hypothyroidism usually starts with the measurement of TSH levels, since these are the most sensitive for detecting primary hypothyroidism. The free thyroxine level is also important in distinguishing primary and secondary hypothyroidism. Primary hypothyroidism is usually diagnosed when the TSH levels are high and the thyroxine levels are low.

Case 2 1. How could Hashimoto’s thyroiditis be mistaken for bipolar disorder? 2. What other conditions may be related to Hashimoto’s thyroiditis? 3. Is it possible to be hypothyroid even though a blood test does not confirm this? A female college student began suffering from severe depression. She lacked energy, lost interest in life, and even her hair was affected, becoming dry and brittle. She gained weight and developed syncope, arrhythmia, and bradycardia, followed by psychotic symptoms. These worsened to the point that she was institutionalized for a short time because of her seemingly bipolar behavior. After years of suffering from these symptoms, she was prescribed T3, which successfully returned her to normal. This followed previous treatments with antipsychotic medications and even ECT, which had done nothing to improve the symptoms. Further study revealed that the patient actually had Hashimoto’s thyroiditis and no psychiatric disorder at all. Answers: 1. When autoimmune Hashimoto’s thyroiditis flares up, the immune system attacks and destroys the thyroid gland. Excess TH enters the bloodstream,

201

202

Epidemiology of Thyroid Disorders

causing symptoms that can easily be confused with the manic episode of bipolar disorder. These include hyperactivity, irritability, and an inability to sleep. When the immune attack resolves, more thyroid tissue is lost, and the hypothyroid state that develops often includes depression and fatigue, mimicking the depressive state of bipolar disorder. 2. There is also a significant correlation between Hashimoto’s thyroiditis and mood and anxiety disorders, including depression. There is a higher frequency of lifetime depressive episode, generalized anxiety disorders, and social phobias. Another complicating factor is the fact that lithium, the drug used to treat bipolar disorder, also suppresses thyroid function. 3. Yes, studies have shown that many people have subclinical or “low” levels of TH but do not meet the official diagnosis of being hypothyroid, with a TSH of more than five. However, their TSH is still at the low end of the scale. Many people with bipolar symptoms, especially depressive symptoms, have such subclinical low TH levels. Thyroid malfunction is a very important complication in bipolar disorder, which is commonly overlooked.

Case 3 1. What are the psychiatric symptoms of hypothyroidism? 2. There is also a link between hypothyroidism during pregnancy and the risk of schizophrenia in offspring; according to internet sources, what is the incidence of this occurrence? 3. Can hyperthyroidism also be linked to schizophrenia-like symptoms? A 16-year-old girl was admitted to a hospital for the treatment of schizophrenia that had been present for almost 2 years. She had not responded to prolonged medications at all, no matter what was tried. Her symptoms included hatred toward her parents, whom she believed wanted to kill her; a feeling that the end of the world was coming soon; hallucinations; disorganized speech; uncontrolled body movements; and insufficient hygiene. Family history revealed that her mother had been hypothyroid during pregnancy. An experienced specialist, well acquainted with thyroid disorders, visited her and asked if her thyroid function had been assessed, which had not. Tests reviewed her to be hypothyroid. She was started on TH replacement therapy, with doses increased as needed until her condition began to improve. The psychotic symptoms steadily lessened. The therapy was continued after her eventual release, and her condition remained normal. Answers: 1. The psychiatric symptoms of hypothyroidism include psychosis, depression, mood instability, mania, anxiety, hypersomnia, apathy, lack of energy, impaired memory, slowed psychomotor skills, and problems with

Thyroid dysfunction and mental disorders

attention. The psychotic symptoms are able to resemble severe psychological conditions such as schizophrenia. 2. Testing of more than 1000 mothers of children with schizophrenia revealed that, from samples collected between the first and second trimesters of pregnancy, 11.8% of these children had a mother with hypothyroxinemia, compared to 8.6% of children without schizophrenia. 3. Yes, hyperthyroidism can mimic the symptoms of schizophrenia. The psychiatric symptoms can include psychosis, paranoia, anxiety, social withdrawal, intrusive thoughts of violence or bizarre sexual ideation, cognitive impairment, apathy, depression, mania, irritability, and emotional. Patients can also have subclinical hyperthyroidism that coexists with the psychiatric conditions, or vice versa.

Case 4 1. Is thyrotoxicosis linked to some or all of the symptoms described in this case study? 2. Can Graves’ disease also affect any preexisting psychiatric disorders? 3. What are the effects of Graves’ disease with mental disorders upon a person’s ability to work? A 31-year-old woman presented with weight loss, heat intolerance, cognitive problems, and eye abnormalities. She had a family history of thyroid disease. Complete thyroid-function tests were ordered. Results showed high levels of free thyroxine and triiodothyronine, low TSH, and high antithyroglobulin antibodies. Graves’ disease was diagnosed. The patient was highly agitated, restless, and showing signs of psychosis that included visual hallucinations. Medications were not successful, so the patient was scheduled for radioiodine ablation of the thyroid, for which she underwent thyroid imaging with uptake, revealing gland enlargement, with homogeneous increased uptake. The radioiodine ablation took place, and she was stable, taking atenolol twice a day. Her condition resolved, and all psychotic symptoms disappeared. Answers: 1. Thyrotoxicosis and its physical manifestations can be associated with several psychiatric symptoms. These include confusion, anxiety, and agitated depression. In severe cases, there may be memory impairment, difficulties with orientation, poor judgment, manic excitement, delusions, and hallucinations. 2. Yes, in patients with preexisting psychiatric disorders, symptoms usually worsen with Graves’ disease. Lack of diagnosis of Graves’ disease compromises efficacy of treatment of psychiatric disorders. 3. Often, patients with Graves’ disease related mental disorders are unable to keep their jobs. Persistent mental problems may result in as many as

203

204

Epidemiology of Thyroid Disorders

33% of Graves’ disease patients becoming unable to resume their normal work. Some patients have even been granted disability pensions based on related mental function.

Case 5 1. How can hyperthyroidism trigger mania-like symptoms? 2. How can an affective disorder be mistaken for hyperthyroidism? 3. For a man of the age listed in this case study, what is a major concern of treatment? A 65-year-old man with no personal or family history of mental illness began experiencing symptoms of mania, irritability, hyperactivity, and insomnia. These were replaced after 1 month by depressive episodes, anxiety, and guilt. The insomnia continued. Originally diagnosed with late-onset bipolar disorder, he was treated with mood-stabilizing drugs. However, further study revealed that he had hyperthyroidism. Treatment resulted in TH levels normalizing, and his mental state improved. Answers: 1. An overactive thyroid gland can trigger restlessness, hyperactivity, insomnia, and irritability. These symptoms can easily be mistaken for mania. 2. There are some similarities between the symptoms of affective disorder and hyperthyroidism. Affective disorder is subdivided into depressive symptoms, bipolar symptoms, and anxiety symptoms. The most similar symptoms between the two conditions include tachycardia, tremor, sweating, irritability, anxiety, increased appetite, and difficulty sleeping. 3. For hyperthyroidism, drugs include carbimazole, methylthiouracil, and potassium perchlorate. They are usually prescribed in combination with a beta-blocker such as propranolol. However, beta-blockers are contraindicated in patients with cardiac failure, asthma, and diabetes. This is a primary concern when treating hyperthyroidism in the elderly, since cardiac conditions and diabetes are much more common in senior citizens.

Key terms affective disorder bipolar disorder Capgras syndrome delirium delusions dementia diabetic ketoacidosis

hallucinations mania myxedema madness neurotransmitters obsessive-compulsive disorder psychotropic thyroid storm

Thyroid dysfunction and mental disorders

Further reading 1. Ali, S.Z., and Cibas, E.S. The Bethesda System for Reporting Thyroid Cytopathology Definitions, Criteria, and Explanatory Notes, 2nd Edition. (2018) Springer. 2. Alonso, J., Chatterji, S., and He, Y. The Burdens of Mental Disorders: Global Perspectives from the World Health Organization World Mental Health Surveys. (2013) Cambridge University Press. 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5), 5th Edition. (2013) American Psychiatric Publishing. 4. Anisman, H., Hayley, S., and Kusnecov, A. The Immune System and Mental Health. (2018) Academic Press. 5. Bahn, R.S. Graves’ Disease: A Comprehensive Guide for Clinicians. (2015) Springer. 6. Ballou, M., and Brown, L.S. Rethinking Mental Health & Disorder: Feminist Perspectives. (2002) The Guilford Press. 7. Bankova, S. Mental, Emotional, and Psychological Aspects of Thyroid Disorders: Your Mind Can Heal Your Thyroid!. (2014) CreateSpace Independent Publishing Platform. 8. Brambilla, P., Mauri, M.C., and Altamura, A.C. Hallucinations in Psychoses and Affective Disorders: A Clinical and Biological Approach. (2018) Springer. 9. Dennison, J., Oxnard, C., and Obendorf, P. Endemic Cretinism. (2011) Springer. 10. Dobbins, C. What a Life Can Be: One Therapist’s Take on Schizoaffective Disorder. (2011) Bridgeross Communications. 11. Friedman, T.C., and Yu, W. The Everything Health Guide to Thyroid Disease: Professional Advice on Getting the Right Diagnosis, Managing Your Symptoms, and Feeling Great. (2006) Everything. 12. Heyman, A., Yang, J., and Bowthorpe, J.A. Stop the Thyroid Madness II: How Thyroid Experts are Challenging Ineffective Treatments and Improving the Lives of Patients. (2014) Laughing Grape Publishing. 13. Icon Group International. Myxedema: Webster’s Timeline History, 1885-2007. (2010) Icon Group International, Inc. 14. Imam, S.K., and Ahmad, S. Thyroid Disorders: Basic Science and Clinical Practice. (2016) Springer. 15. Kelly, T. The Art and Science of Thyroid Supplementation for the Treatment of Bipolar Depression. (2018) CreateSpace Independent Publishing Platform. 16. Kharrazian, D. Why Do I Still Have Thyroid Symptoms? (When My Lab Tests Are Normal). A Revolutionary Breakthrough in Understanding Hashimoto’s Disease and Hypothyroidism. (2010) Elephant Press. 17. Loriaux, L. Endocrine Emergencies: Recognition and Endocrinology (Contemporary Endocrinology). (2014) Humana Press. 18. Lowrance, J.M. The Depression of Hypothyroidism: Mood Problems from Untreated or Undertreated Thyroid. (2012) CreateSpace Independent Publishing Platform. 19. Meikle, A.W. Endocrine Replacement Therapy in Clinical Practice (Contemporary Endocrinology). (2003) Humana Press. 20. Miklowitz, D.J., and Gitlin, M.J. Clinician’s Guide to Bipolar Disorder Integrating Pharmacology and Psychotherapy. (2015) The Guilford Press. 21. Moore, E.A., and Moore, L.M. Advances in Graves’ Disease and Other Hyperthyroid Disorders (McFarland Health Topics). (2013) McFarland. 22. Moore, E.A., and Moore, L. Graves’ Disease: A Practical Guide (McFarland Health Topics). (2001) McFarland & Company. 23. Rio, L.M., et al. The Hormone Factor in Mental Health: Bridging the Mind-Body Gap. (2013) Jessica Kingsley Publishers. 24. Romm, A. The Adrenal Thyroid Revolution: A Proven 4-Week Program to Rescue Your Metabolism, Hormones, Mind & Mood. (2017) HarperOne. 25. Schildkrout, B. Masquerading Symptoms: Uncovering Physical Illnesses That Present as Psychological Problems. (2014) Wiley. 26. Shames, R., Shames, K., Shames, G.G., and Von Reiche, S. Thyroid Mind Power: The Proven Cure for Hormone-Related Depression, Anxiety, and Memory Loss. (2011) Rodale Books. 27. Simpson, K., and Hertoghe, T. The Women’s Guide to Thyroid Health: Comprehensive Solutions for All Your Thyroid Symptoms. (2009) New Harbinger Publications.

205

206

Epidemiology of Thyroid Disorders

28. Skaer, D.H. Depression & Other Mental Illnesses Caused by Medical Diseases: It’s Not All in Your Head. (2018) CreateSpace Independent Publishing Platform. 29. Thacker, M. Seven Steps to Heal Your Thyroid: A Proven Plan to Increase Energy, Elevate Mood, and Optimize Weight. (2018) Dr. Meghna Thacker. 30. Wartian Smith, P. What You Must Know About Thyroid Disorders & What to Do About Them: Your Guide to Treating Autoimmune Dysfunction, Hypo- and Hyperthyroidism, Mood Swings, Cancer, Memory Loss, Weight Issues, Heart Problems & More. (2016) Square One. 31. Wilson, D. Evidence-Based Approach to Restoring Thyroid Health. (2014) Muskeegee Medical Publishing Company. 32. Zaidi, S. Graves’ Disease and Hyperthyroidism: What You Must Know Before They Zap Your Thyroid with Radioactive Iodine. (2013) CreateSpace Independent Publishing Platform. 33. Zoska, S. The Thyroid Fix: Reduce Fatigue, Lose Weight, and Get Your Life Back. (2018) Evergreen Integrative Medicine, LLC.

CHAPTER 10

Global epidemiology of thyroid neoplasms Contents Benign adenomas Epidemiology Pathogenesis Risk factors Clinical presentation Diagnosis Treatment Malignant tumors Etiology Classifications Epidemiology Pathogenesis Risk factors Clinical presentation Diagnosis of thyroid neoplasms Treatment of thyroid neoplasms Global burden of thyroid cancers Clinical cases Case 1 Case 2 Case 3 Case 4 Further reading

208 208 208 209 209 210 210 211 211 212 219 221 223 226 227 235 238 239 239 239 240 241 242

A solitary thyroid nodule is a palpable swelling of the thyroid gland, which otherwise appears normal. Between 1% and 10% of adults in the United States experience solitary nodules of the thyroid. However, in endemic goitrous regions, rates are much higher. Solitary nodules are about four times more common in females, and incidence of these nodules increases throughout a person’s lifetime. The primary concern is that a swollen nodule will develop into a malignant neoplasm. Most nodules are localized and nonneoplastic, or benign neoplasms that include follicular adenoma. Benign neoplasms occur 10 times more often than thyroid carcinomas. Overall, there are about

Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00010-4

r 2020 Elsevier Inc. All rights reserved.

207

208

Epidemiology of Thyroid Disorders

15,000 new cases of thyroid carcinomas in the United States annually. More than 90% of patients have survived them for 20 years after diagnosis. Solitary nodules are usually more likely to be neoplastic than multiple nodules. Nodules in younger aged patients are more likely to be neoplastic than those in older patients. Nodules in males are also more likely to be neoplastic than in females. An increased incidence of thyroid malignancy is linked to a history of radiation treatment to the head and neck. “Hot nodules” are those that take up radioactive iodine (RAI) in imaging studies. They are much more likely to be benign than malignant.

Benign adenomas Thyroid nodules that arise from the thyroid follicles are relatively common in occurrence. They are found about three times as often in women compared to men. About 90% 95% of solitary thyroid nodules are benign. Adenomatous hyperplasia of the thyroid sometimes occurs in patients with multiple endocrine neoplasia type 1, which is a hereditary syndrome. Adenomas of the thyroid are derived from the follicular epithelium and are therefore known as follicular adenomas. A large majority of them are nonfunctional, but a small amount produce thyroid hormones, causing clinically apparent thyrotoxicosis. The hormone production of functional adenomas, which are described as toxic, is not dependent on thyroid-stimulating hormone (TSH) stimulation.

Epidemiology In middle-aged and elderly people, palpation reveals nodules that may progress to adenomas in about 5%. Also, ultrasonography studies and autopsies have suggested that nodules are present in about 50% of older adults. Adenomas may result from nodules and be related to hyperplastic colloid goiter, cysts, and thyroiditis. These adenomas, along with goiter, are significant risk factors for thyroid cancer.

Pathogenesis Benign adenomas of the thyroid are encapsulated, surrounded by fibrous capsules (see Fig. 10.1). They are difficult to diagnose cytopathologically since invasion through the capsule cannot be excluded without examining the entire capsule. A subset of thyroid adenomas has atypical morphology and may be an intermediate step in the progression of an adenoma to an invasive carcinoma. Somatic TSH receptor (TSHR) signaling pathway mutations are present in toxic adenomas and in toxic multinodular goiter. Mutations that usually occur in the gene that encodes the TSHR causes the follicular cells to secrete thyroid hormone. This secretion is not dependent on TSH stimulation and is known as thyroid autonomy. It causes symptoms of hyperthyroidism

Global epidemiology of thyroid neoplasms

Figure 10.1 Follicular adenoma of the thyroid. (A) A solitary, well-circumscribed nodule is seen. (B) The photomicrograph shows well-differentiated follicles resembling normal thyroid parenchyma.

and also produces a functional hot nodule in imaging studies. Mutations of the TSHR-signaling pathway are found in just more than 50% of toxic thyroid nodules. However, the TSHR and guanine nucleotide alpha stimulating (GNAS) mutations are not common in follicular carcinomas. Therefore toxic adenomas and toxic multinodular goiter are not preemptive factors for malignancy.

Risk factors The major risk factors for thyroid adenoma include exposure to radiation, iodine deficiency or excess, and history (personal or family) of thyroid conditions. Many different doses of ionizing radiation can increase the risk for benign thyroid adenomas and nodules. Elevations in risk continue for decades after exposure. In studies of infants exposed to X-ray treatment for thymus enlargement, followed for as long as 50 years, there were linear increases in thyroid adenoma based on the level of radiation exposure. Risk increases continued throughout the entire period of follow-up.

Clinical presentation Pain may suggest thyroiditis or hemorrhage into a thyroid cyst. Asymptomatic nodules can be malignant but are usually benign. Symptoms of hyperthyroidism suggest hyperfunction of an adenoma or thyroiditis. There may be lymphadenopathy and hoarseness. The common thyroid adenoma is solitary, round, and encapsulated. It is demarcated from the surrounding parenchyma by a well-defined capsule. This is important in distinguishing the adenoma from a multinodular goiter. Follicular adenomas are usually about 3 cm in diameter but can be larger than 10 cm. Many follicular adenomas are unilateral and painless, often found in a routine examination. When larger, there may be difficulty swallowing. Nonfunctioning adenomas take up

209

210

Epidemiology of Thyroid Disorders

less RAI than normal thyroid parenchyma. Therefore nonfunctioning adenomas appear as cold nodules in comparison to nearby thyroid tissue. Up to 10% of cold nodules are malignant. Ultrasound and fine-needle aspiration (FNA) biopsy aid in diagnosis.

Diagnosis Diagnosis of benign adenomas involves physical examination and testing of thyroid hormones, especially TSH and antithyroid peroxidase (TPO) antibodies. When TSH is suppressed, radioiodine scanning is performed. FNA biopsy helps distinguish benign from malignant tumors. When resected, the adenoma bulges from the cut surface, compressing the thyroid. Color ranges from grayish-white to reddish-brown, based on the cellularity and amount of colloid. Especially in larger adenomas, areas of hemorrhage, calcification, fibrosis, and cystic changes are common. These may resemble those of multinodular goiters. Histologically, there are often uniform follicles containing colloid. The follicular growth pattern is usually quite different from the nearby nonneoplastic thyroid. Neoplastic cells show only slight variation in sizes, shapes, or nuclear morphology. Mitotic components are rare. Sometimes, neoplastic cells have bright eosinophilic granular cytoplasm, known as the oxyphil or Hürthle cell change. The most significant feature of follicular adenomas is an intact, well-formed capsule that surrounds the tumor. Ultrasonography helps determine the size of the adenoma. It is important to carefully evaluate integrity of the capsule around the tumor, to distinguish a follicular adenoma from a follicular carcinoma, which will instead have capsular or vascular invasion, or both. Close inspection should evaluate extensive mitotic activity, necrosis, and high cellularity.

Treatment Simple excision is curative, but there must be a careful histological examination of the tissue to exclude any malignant changes. Treatment of any underlying disorders linked to the benign tumor should be undertaken. It is important to understand the suspected adenomas of the thyroid are removed surgically to exclude malignancy. They do not recur or metastasize and have an excellent prognosis. Focus on benign adenomas There are four major types of follicular adenomas: trabecular/solid, with few or no follicles; microfollicular, with follicles smaller than those of the normal parts of the thyroid; normo-follicular/simple, with follicle sizes close to those of the normal thyroid; and macrofollicular, with follicles larger than normal, sometimes resembling those of hyperplastic nodules.

Global epidemiology of thyroid neoplasms

Malignant tumors Malignant thyroid tumors are rare, but all thyroid nodules must be carefully examined using a microscope. Most (90% 95%) thyroid malignancies are carcinomas arising from the cuboidal epithelium lining the thyroid follicles. These cells, in normal function, synthesize the thyroid hormones (T3 and T4) as well as thyroglobulin (Chapter 3: Iodine and thyroid hormones). The subtypes of thyroid malignancies include papillary carcinoma, follicular carcinoma, medullary carcinoma, anaplastic carcinoma, and miscellaneous malignancies. Overall, thyroid carcinomas only make up about 1.5% of all cancers in the United States, with a female predominance when they develop in early and middle adulthood. Cases that present in childhood or later adult life are nearly equal between males and females. The majority of thyroid carcinomas are well-differentiated lesions.

Etiology The only understood environmental case of thyroid carcinoma—primarily papillary— is ionizing radiation. This is prevalent in children since their thyroid glands have some of the highest risks for cancer of all organs. Iodine-131 (131I) and other radioiodines with short lives are potent thyroid carcinogens for pediatric patients. In earlier years, radiographic treatments often used for a variety of conditions were implicated in childhood thyroid cancer. Today, when radiography is used for children, a lead-lined protective apron, with a special neck collar, protects the thyroid from excess radiation. The overall risks for radiation-induced thyroid cancer are higher in females, people of certain Jewish backgrounds, and in those with a family history of the disease. We understand more than ever before about the genetic mutations that are involved. Oncogenes affect the ability of DNA to maintain and repair cells. Tumor suppressor genes cause a slowing of cell division or cause apoptosis. The primary gene alterations in thyroid cancer include the K-Ras mutations, p53 mutations, and rearranged during transfection (RET) mutations. The most common genetic alteration of thyroid cancer is the rearrangement of the RET gene, also called the RET/PTC rearrangement. This is prevalent in 10% 30% of papillary cancers and usually acquired with aging instead of being inherited. Every individual has two RET genes, meaning that the chance of passing a mutation to offspring is 50%. A mutation of the B-type Raf kinase (BRAF) gene exists in 28% 83% of pupillary thyroid cancers. This is less common in children, and uncommon in individuals whose cancers are caused by radiation. The BRAF and RET/PTC mutations are believed to be oncogenes and not tumor suppressor genes. Both mutations are seldom present at the same time. The BRAF mutation usually causes more aggressive tumor growth that has a higher occurrence of metastasis.

211

212

Epidemiology of Thyroid Disorders

In follicular thyroid cancer (FTC), various activating Ras mutations predominate. In follicular anaplastic thyroid cancer, p53 gene mutations are also seen. Those with medullary thyroid cancer (MTC) also have an RET gene mutation, but this occurs on a different point of the gene than those of PTC. Almost all cases of inherited MTC and 40% 50% of those with sporadic MTC have an RET gene mutation. In people with sporadic MTC the mutation is within the cancer cells. However, in those with inherited MTC, the mutation occurs in all types of cells.

Classifications Thyroid neoplasms may develop in the gland’s follicular cells, lymphocytes, C cells (that produce calcitonin), stroma, vascular components, and also as metastases from other areas of the body. Aside from the AJCC’s staging system, there are other methods used to classify thyroid neoplasms. Some focus on histology, others on patient age, and others on gender. Table 10.1 summarizes benign and malignant thyroid neoplasms with their approximate prevalence. Papillary carcinoma Papillary carcinoma is the most common subtype of thyroid malignancy. It may be solitary or multifocal. It accounts for about 80% 90% of all thyroid cancers. It is commonly diagnosed between the ages of 30 and 60 years but can occur at any age. Females are affected three times as often as males. A papillary thyroid carcinoma is an encapsulated tumor that is well differentiated and has a papillary growth pattern when viewed under a microscope. This means that its projections appear like “fingers.” Papillary carcinoma may resemble normal thyroid tissue. The tumor may have areas of fibrosis and calcification and, often, are cystic. This form is often more aggressive in elderly patients. It may spread but usually not beyond the neck. Tumor development is often related to radiation treatments for acne or adenoid problems during childhood. The majority of papillary carcinomas have gain-of-function gene mutations related to the RET. In most cases, papillary carcinoma presents as an asymptomatic nodule, but sometimes as a cervical lymph node mass. Presence of isolated cervical nodal metises does not greatly influence prognosis, which is usually good. Most are single nodules moving freely in the thyroid gland when the patient swallows. They cannot be distinguished from benign nodules during examination. Advanced disease is suggested by dysphagia, hoarseness, cough, or dyspnea. In a small amount of patients, hematogenous metastases are present at diagnosis, usually in the lungs. Many diagnostic tests are used to determine benign from malignant disease. These include radionuclide scanning and FNA. Using a scintiscan, papillary carcinomas appear as cold masses. Today, FNA is highly reliable diagnostically. Nuclear features are usually clearly seen when aspirated specimens are viewed.

Global epidemiology of thyroid neoplasms

Table 10.1 Thyroid neoplasm classifications. Malignant

Prevalence

Follicular epithelial cells

Well-differentiated carcinomas Papillary carcinomas Pure papillary Follicular variant Diffuse sclerosing variant Tall cell, columnar cell variants Follicular carcinomas Minimally invasive Widely invasive Hürthle cell carcinoma (oncocytic) Insular carcinoma Undifferentiated (anaplastic) carcinomas

80% 90%

5% 10%

C cell (calcitonin-producing)

Medullary thyroid cancer Sporadic Familial MEN 2

Less than 10%

Other malignancies

Lymphomas Sarcomas Metastases Others

1% 2%

MEN, Multiple endocrine neoplasia.

Papillary carcinoma is being diagnosed more often today because of the recognition of follicular variants that were previously misclassified. After biopsy and cutting the cut surface may reveal papillary foci. Microscopically, there are diagnostic differences (see Fig. 10.2). There may be branching papillae and a fibrovascular stalk that is covered by one or more layers of cuboidal epithelial cells. Usually, the covering epithelium has well-differentiated, uniform, and orderly cuboidal cells. However, some have anaplastic epithelium with varied morphologies. If present, the papillae are different from other areas of hyperplasia, and more complex, with dense fibrovascular cores. The nuclei of the cells have dispersed chromatin, making them appear clear or empty, termed ground glass or Orphan Annie eye nuclei. Cytoplasmic invaginations may have intranuclear grooves or inclusions. Diagnosis may be based on these features even if papillae are absent. Calcified psammoma bodies may be present in the papillae cores. These are hardly ever found in follicular or medullary carcinomas and strongly indicate papillary carcinomas. Foci of lymphatic tumor invasion may be present. Blood vessels

213

214

Epidemiology of Thyroid Disorders

Figure 10.2 Papillary carcinoma of the thyroid. (A) The macroscopic appearance of a papillary carcinoma with grossly discernible papillary structures. (B) This particular example contains wellformed papillae. (C) High power shows cells with characteristic empty-appearing nuclei, sometimes called “Orphan Annie eye” nuclei. (D) Cells obtained by fine-needle aspiration of a papillary carcinoma. Characteristic intranuclear inclusions are visible in some of the aspirated cells.

are usually not involved, especially in smaller lesions. In up to 50% of cases, metastasis to nearby cervical lymph nodes occurs. More than 12 different variants of papillary carcinoma exist, with the most common variant being follicular. It has papillary features and a nearly complete follicular structure. It can be encapsulated or poorly circumscribed and infiltrative. The encapsulate type has a better prognosis. A tall-cell variant is more common in older patients, with more common cervical and distant metastases. An unusual diffuse sclerosing variant occurs in children and younger patients. Lymph node metastasis is usually present. The papillary microcarcinoma is less than 1 cm in size and are usually found during surgeries. They may be precursors of typical papillary carcinomas. Papillary thyroid cancers have an excellent prognosis, with a 10-year survival rate over 95%. Between 5% and 20% of cases have local or regional recurrence, and 10% 15% show distant metastases. Prognosis is based on the patient’s age, with less favorability in those over 40 years of age, extrathyroidal extension, and stage of metastases.

Global epidemiology of thyroid neoplasms

Focus on papillary carcinoma There is a higher chance of developing papillary carcinoma of the thyroid because of familial adenomatous polyposis, Gardner syndrome, Cowden disease, family history, radiation therapy, and the female gender. Also, disease recurrence is relatively common, occurring in about 33% of patients.

Follicular carcinoma Follicular carcinoma makes up about 10% of thyroid cancers and is more common in areas of dietary iodine deficiency. In these areas, it makes up 25% 40% of thyroid cancers. This form is more common in adults between the ages of 40 and 60 years, with females affected three times more than men. Follicular carcinoma also has welldifferentiated cells but does not have any papillary formations. It also may resemble normal thyroid tissue. Larger lesions may penetrate the capsule, infiltrating beyond the capsules into the nearby neck areas. They appear gray, tan, or pink and may be slightly translucent because of large follicles filled with colloid (see Fig. 10.3). Degenerative changes, including fibrosis and calcification, may be present. Most of these carcinomas have uniform cells with small follicles containing colloid, highly resembling normal thyroid cells. Sometimes, there are cellular sheets that lack colloid. There may be granular and eosinophilic cytoplasm, known as Hürthle cell carcinoma. There are no present psammoma bodies, and the nuclear features help to distinguish this form from papillary carcinoma. However, there is no reliable cytologic difference between minimally invasive follicular carcinomas and follicular adenomas. Extensive histologic samples are required to make this distinction (see Fig. 10.4). However, lymphatic spread is not common in follicular carcinoma.

Figure 10.3 Follicular carcinoma. (A) Cut surface of a follicular carcinoma with substantial replacement of the lobe of the thyroid. The tumor has a light-tan appearance and contains small foci of hemorrhage. (B) A few of the glandular lumens contain recognizable colloid.

215

216

Epidemiology of Thyroid Disorders

Figure 10.4 Capsular integrity in follicular neoplasms. In adenomas (A), a fibrous capsule, surrounds the neoplastic follicles and no capsular invasion is seen (arrows). In contrast, follicular carcinomas demonstrate capsular invasion (B, arrows) that may be minimal, as in this case, or widespread. The presence of vascular invasion is another feature of follicular carcinomas.

Follicular carcinomas present as slowly enlarging nodules, without pain. They are usually cold nodules on scintigrams. However, lesions with more differentiation may be hyperfunctional, taking up RAI, and therefore appearing warm. Vascular (hematogenous) dissemination is common. The cancer cells may invade blood vessels and metastasize to other areas, such as the bones, lungs, or liver. It may be more aggressive in older patients. Overall, this type is more malignant than papillary carcinoma. It spreads hematogenously, with distant metastases. Treatment requires near-total or total thyroidectomy, with postoperative radioiodine ablation of remaining thyroid tissue. Metastases are highly responsive to radioiodine therapy. After treatment, TSH-suppressive doses of levothyroxine are administered. To detect any recurrent or persistent disease, serum thyroglobulin and neck ultrasonography must be monitored. Prognosis is based on extent of invasion and staging. If wildly invasive, there are often systemic metastasis presentations, and up to 50% of patients will die within 10 years. The minimally invasive follicular carcinomas, however, have a 10-year survival rate of more than 90%. Focus on follicular carcinoma Distant and nonresectable metastases that respond to iodine occur more often in patients with invasive follicular thyroid carcinoma. They can be treated with repeated doses of 131I. Symptomatic hilar node and bone metastases may be treated with external beam radiation therapy (EBRT), and surgery can be used for isolated metastases.

Medullary carcinoma Medullary carcinoma is a smaller subset of neuroendocrine malignancies and is the only type arising from the parafollicular C cells. These cells secrete calcitonin, which is a

Global epidemiology of thyroid neoplasms

polypeptide hormone aiding in regulation of calcium and phosphorus for bone remodeling. Medullary carcinomas make up 3% 5% of thyroid cancers. This form may be sporadic in 70% of cases, usually unilateral, but is often familial from a mutation of the RET proto-oncogene. Sporadic and familial medullary carcinomas mostly affect people in their 40s or 50s. The familial type may occur in isolation or as part of multiple endocrine neoplasia MEN syndrome type 2A and MEN 2B. Serum calcium is normal since the high level of calcitonin eventually downregulates its receptors. There are characteristic amyloid deposits that stain red (see Fig. 10.5). Metastases occur via the lymphatic system, to the cervical and mediastinal nodes, and sometimes, to the liver, lungs, and bones. The sporadic form is usually solitary while the familial form is usually bilateral and multicentric. Larger lesion often has necrosis and hemorrhage and may extend through the thyroid capsule. The tissue is firm, infiltrative, and pale gray to tan. The cells are polygonal or spindle shaped and can form follicles, trabeculae, or nests. Some tumors have smaller and more anaplastic cells. Amyloid deposits, from calcitonin polypeptides, may be present in the stroma. There are varying numbers of membrane-bound electron-dense granules in the cytoplasm (see Fig. 10.6). Multicentric C-cell hyperplasia exists in the familial medullary form. The patient usually presents with an asymptomatic thyroid nodule. However, many cases are diagnosed during routine screening before a palpable tumor has developed. The patient usually has a mass in the neck, sometimes with dysphagia or hoarseness. Initial signs may indicate a paraneoplastic syndrome, due to peptide hormone secretion, such as diarrhea or Cushing syndrome. Hypocalcemia is not a significant feature even though calcitonin levels are raised. Secretin of carcinoembryonic antigen is a useful biomarker, especially to assess tumor load and in calcitonin-negative tumors. Familiar syndromes may show symptoms localized to the thyroid or from endocrine neoplasms of the adrenal or parathyroid glands.

Figure 10.5 Medullary carcinoma of thyroid. (A) These tumors typically show a solid pattern of growth and do not have connective tissue capsules. (B) Histology demonstrates abundant deposition of amyloid, visible here as homogeneous extracellular material, derived from calcitonin molecules secreted by the neoplastic cells.

217

218

Epidemiology of Thyroid Disorders

Figure 10.6 Electron micrograph of medullary thyroid carcinoma. These cells contain membranebound secretory granules that are the sites of storage of calcitonin and other peptides.

There may be a significant biochemical presentation if there is ectopic production of ACTH, vasoactive intestinal polypeptide, kallikreins, prostaglandins, or serotonin. Measurement of serum calcitonin, which will be greatly elevated, is the best diagnostic test. A challenge test using calcium will provoke excessive calcitonin secretion. On X-ray, there may be a dense, homogenous, conglomerate calcification. Genetic testing is required since relative of patients with mutations are at risk and should also receive measurement of basal and stimulated calcitonin levels. Total thyroidectomy is indicated as early as possible, even if there is no obvious bilateral involvement. The lymph nodes are also dissected. If hyperparathyroidism is present, hyperplastic or adenomatous parathyroid glands are removed. If pheochromocytoma is present, it is usually bilateral and should be removed before thyroidectomy since there is a danger of provoking hypertensive crisis. Long-term survival is common with medullary carcinoma and MEN 2A with more than 66% of patients surviving 10 years or more. However, medullary carcinoma that is sporadic, and in MEN 2B, had a worsened prognosis. This more commonly affects younger patients. Any relatives with elevated calcitonin and no palpable thyroid abnormalities should have a thyroidectomy since there is a greater chance of cure at this stage. Some relatives with normal basal and stimulated serum calcitonin levels, who have the RET proto-oncogene mutation, should also have this surgery. Anaplastic carcinoma Anaplastic carcinoma of the thyroid makes up less than 5% of thyroid cancers. It is undifferentiated, within the follicular epithelium, and occurs mostly in elderly patients (with a peak incidence at 65 years), with a slight predominance in females. The tumor has a rapid and painful enlargement. However, rapid thyroid enlargement may also

Global epidemiology of thyroid neoplasms

suggest thyroid lymphoma, especially if accompanying Hashimoto’s thyroiditis. About 25% of patients with these carcinomas have previous history of a well-differentiated thyroid carcinoma. Another 25% shows a concurrent and well-differentiated tumor in resected specimens. These neoplasms are made up of extremely anaplastic cells with variable morphology. The three forms include large pleomorphic giant cells, spindle cells, or mixed spindle and giant cells. The giant cells may have occasional osteoclast-like multinucleate giant cells. The spindle cells have a sarcomatous appearance. There may be papillary or follicular foci, which suggested an origin from a more differentiated type of carcinoma. Epithelial markers such as cytokeratin are expressed but usually negative for thyroglobulin or other markers of thyroid differentiation. There is usually a quickly enlarging, bulky neck mass. Usually, the disease has spread beyond the thyroid capsule, into adjacent neck structures, or to the lungs by the time it is discovered. Common symptoms are related to compression and invasion. These include dysphagia, dyspnea, cough, and hoarseness. There is no effective therapy for anaplastic thyroid carcinoma. The disease is usually fatal, with about 80% of patients dying within 1 year of diagnosis, due to growth and compromise of vital neck structures. The overall mortality rate of this aggressive carcinoma is close to 100%. In some patients, when the tumors are smaller, thyroidectomy followed by EBRT has been curative. Chemotherapy is primarily experimental at this time. Focus on anaplastic carcinoma Anaplastic thyroid carcinoma is the most advanced and aggressive form of thyroid cancer. It is very rare and usually occurs in older patients. It is also known as undifferentiated thyroid cancer since the cells do not appear or function like normal thyroid cells.

Epidemiology Thyroid cancer is the most common type of endocrine cancer. Incidence of the majority of head and neck cancers is decreasing in the United States. However, incidence of thyroid cancers has increased from 4.9 to 14.3 cases per every 100,000 people. There has been a 5.5% increase in new cases, every year, from 2002 to 2015 (see Fig. 10.7). This trend may be related to overdiagnosis, which occurs when cancer is identified, even without symptoms or causing early death. Over 75% of thyroid cancers occur in females. It is found more often in people between ages of 20 and 55 years, but majority of new cases occur after the age of 45 years. The percent of new cases by age-group for thyroid cancer is shown in Fig. 10.8. Notice that the highest percent is in the 45 54 years age-group, with the lowest percentages in people under 20 or over 84 years of age.

219

220

Epidemiology of Thyroid Disorders

Figure 10.7 Number of new cases per 100,000 persons by race/ethnicity and sex: thyroid cancer. Data from , seer.cancer.gov..

Figure 10.8 Percent of new cases by age group: thyroid cancer. Data from , seer.cancer.gov..

Global epidemiology of thyroid neoplasms

Fortunately, thyroid cancer is highly curable. For all types of thyroid cancer, the 5-year survival rate is 97%, and the 10-year survival rate is 85% 93%. However, age reflects greatly in determining the prognosis. Patients under the age of 45 years have a much better prognosis than older patients. Thyroid cancer is the only form of cancer that features age as a component of its staging system, according to the American Joint Committee on Cancer. The presence of nodal metastasis, also, has no effect on prognosis. About 35% of cases have recurrence within 40 years, and about 66% of these recurrent cases occur in the first 10 years after initial treatment. About 68% of recurrence is local disease. The remaining 32% involves distant metastasis, usually to the lungs. All types of recurrence occur more often in patients under the age of 20 years and in those over the age of 60 years. Thyroid cancer is of highest incidence in women, especially in the Southeast Asian and Pacific Island populations living in Hawaii and California. Rates are highest in Filipino women (14.6 per 100,000), Vietnamese women (10.5 per 100,000), and Hawaiian women (9.1 per 100,000), with the lowest incidence in African American women (3.3 per 100,000). In men the highest rates occur in the Filipino population (4.1 per 100,000) and lowest in the Japanese (1.6 per 100,000) and African American (1.4 per 100,000) populations. Mortality rates are lower than incidence rates by 8 20 in women and 5 10 in men. Since the gender difference for mortality is less, this shows that women have better survival rates than men. Most deaths from thyroid cancer occur in older patients, often more than 10 years following diagnosis. The number of deaths per 100,000 persons by race/ethnicity and sex for thyroid cancer is shown in Fig. 10.9. Thyroid cancers are at highest incidence in young adults, remaining fairly consistent throughout life. However, in Hispanic men, incidents rates rise from 2.3 of every 100,000, in the 30- to 54-year-old group, to 4.5 of 100,000, in the 55- to 69-yearold group, to a high of 9.2 of 100,000 in those who are 70 and older. Also, medullary carcinomas of the thyroid, making up about 3% of thyroid cancer cases, are often part of the inherited disease complex called multiple endocrine neoplasia syndrome. Fig. 10.10 shows a graph of new cases of thyroid cancer, along with deaths in the United States, from 1992 to 2015.

Pathogenesis For all types of thyroid carcinomas except for medullary carcinomas, genetic alterations are in growth factor receptor signaling pathways (see Fig. 10.11). In normal cells the pathways are activated by a binding of soluble growth factor ligands to the extracellular domain of receptor tyrosine kinases. There is autophosphorylation of the cytoplasmic domain of each receptor. Then, RAS is activated and two signaling arms involve MAP kinase and PI-3 kinase. Like many cancers, thyroid carcinomas utilize gain-of-function

221

Epidemiology of Thyroid Disorders

Figure 10.9 Number of deaths per 100,000 persons by race/ethnicity and sex: thyroid cancer. Data from , seer.cancer.gov..

18 Number per 100,000 persons

222

16 14 12 10 8 6 4 2 0 1975

1980

1985

1990

1995

2000

2005

2010

2016

Year New cases - SEER 9

Deaths - US

New cases come from SEER 9 Incidence. Deaths come from US mortality. 1975–2016, all races, both sexes. Rates are age-adjusted. Modeled trend lines were calculated from the underlying rates using the Jointpoint Trend Analysis Software.

Figure 10.10 New cases of thyroid cancer, with deaths, in the United States, from 1992 to 2015. Data from , seer.cancer.gov..

Global epidemiology of thyroid neoplasms

Figure 10.11 Genetic alterations in follicular cell-derived malignancies of the thyroid gland.

mutations in various pathway components. This leads to their activation, encouraging excessive cellular proliferation and increased survival of the cells.

Risk factors All thyroid disorders, including cancer, are more common in females. Iodine deficiency, Graves’ disease, and Hashimoto’s thyroiditis, for example, are two to three times more common in women than in men. Part of this may involve the fact that women are more likely to have regular screening and procedures that can detect thyroid disorders. Women may be biologically predisposed to thyroid disorders of all types. Serum levels of TSH are elevated by menarche, pregnancy, oophorectomy, oral contraceptive use, and estrogen replacement therapy. It is known that TSH promotes thyroid hyperplasia. It is believed that since the paternal or maternal X chromosome is inactivated in cell lineages in early embryogenesis, a female’s genotype is a mixture of active and inactivated paternal and maternal X chromosomes. Inactivated X chromosomes are known as Barr bodies. Incompatibility of paternal and maternal

223

224

Epidemiology of Thyroid Disorders

X chromosomes may result in immunoreactivity—especially if the thyroid tissues have the active X chromosome from one parent while the immune cells have the active X chromosome from the other parent. There may be other mechanisms increasing female predisposition to autoimmune thyroiditis along with other types of autoimmunity. In pregnancy, fetal cells are able to cross the placenta, entering the maternal circulation. These cells can survive in the thyroid gland and other maternal tissues. This condition is called microchimerism and is more common in patients with autoimmune thyroiditis than in individuals without the condition. Focus on thyroid cancer risk factors The risk factors for thyroid cancer include the female gender, age (40s or 50s peak incidence for women; 60s or 70s peak incidence for men), hereditary conditions, familial adenomatous polyposis, Cowden disease, Carney complex type 1, family history of thyroid cancer, low dietary iodine, and radiation exposure.

Exposure to radiation Exposure to medical radiation sources or to environmental radiation, such as radioactive fallout, has a proven link to thyroid cancer. More recent studies have revealed that there is a synergistic connection between radiation exposure and iodine deficiency in increasing risks for developing thyroid cancer. Environmental contamination, especially with RAI isotopes such as 131I and Cs-137, has been implicated. Overall risks for thyroid cancer increased with increasing doses of radioactivity. Diets deficient in iodine potentiate risks of radiation-induced thyroid cancer. This suggests that iodine supplements have a protective effect against carcinogenesis. Radioactive isotopes released by nuclear power plant accidents, such as the Chernobyl accident of 1986 and the Fukushima Daiichi accident of 2011. The Chernobyl incident occurred in a late-night safety test that was simulating a nuclear station blackout power-failure. Safety systems were intentionally turned off, resulting in uncontrolled explosions and fires from the nuclear reactor. Radioactive materials were propelled into parts of western Russia and other European countries. Hundreds of people died as a result of exposure to lethal doses of nuclear radiation. In the Fukushima Daiichi nuclear disaster, a tsunami following a large earthquake in Japan caused a nuclear reactor to shut down. Unable to cool down properly, three nuclear meltdowns occurred, along with hydrogen air explosions, and release of radioactive materials for about 3 days. An estimated 1600 deaths occurred as a result of radiation poisoning. It was predicted that as a result of such events, populations in the most contaminated areas had a 70% higher relative risk of developing thyroid cancer for females

Global epidemiology of thyroid neoplasms

exposed as infants, a 7% higher relative risk of leukemia in males exposed as infants, and a 6% higher relative risk of breast cancer in females exposed as infants. About 33% of involved emergency workers had increased cancer risks. By 2013 more than 40% of children screened near the Fukushima site were diagnosed with thyroid nodules or cysts. Fukushima Medical University reported 33 children diagnosed with thyroid cancer. In 2015 there were 166 children from the region diagnosed with thyroid cancer or showing signs of developing the disease. Dietary factors Hawaii has one of the highest incidence rates of thyroid cancer in the world in both women and men. In that state, obese men have a five times greater risk and obese women have a two times greater risk than nonobese individuals. There are also risk increases in heavier women using fertility drugs or who had miscarriages or stillbirths of their first pregnancies. There is a dose response relationship between body weight and thyroid carcinogenesis. Increased thyroid cancer risk is associated with fertility drugs, including the most common drug, clomiphene. There is a need for further studies with larger sample sizes to confirm the association between fertility drugs and the risk of developing thyroid cancer. Also, certain inflammatory adipokines secreted from adipocytes have been linked to carcinogenesis. The increased storage of fat, then, may cause adipocytes to secrete inflammatory adipokines that target the thyroid gland. Women with high iodine intake, who took fertility drugs or had a miscarriage or stillbirth at first pregnancy, are more at high risk for thyroid cancer. There is a 4.8 higher risk factor for women with high iodine intake and a first-pregnancy miscarriage. There is a 7.3 risk factor for women with high iodine intake who used fertility drugs. These results oppose findings that showed protective effects of potassium iodine supplementation. Further study is needed to evaluate all of the possible risk factors for thyroid cancer. Nonmalignant thyroid disorder relationships Thyroid cancer is also linked to some nonmalignant thyroid disorders. Highest risks involve autoimmune conditions, and the autoantibodies against thyroglobulin and other thyroid-specific factors. Thyroiditis leads to Graves’ disease and Hashimoto’s thyroiditis, both of which are linked to thyroid adenomas and thyroid cancer. Graves’ disease usually causes hyperthyroidism. Hypothyroidism is often caused by Hashimoto’s thyroiditis (see Chapter 7: Thyroiditis and Graves’ disease). The human leukocyte antigen (HLA) locus on chromosome 6 encodes many molecules related to autoimmune conditions. Both Graves’ disease and Hashimoto’s thyroiditis are known to have an autoimmune basis that is related to certain genes of the HLA locus. Genetic variants at the HLA locus increase susceptibility to Graves’ disease and Hashimoto’s thyroiditis.

225

226

Epidemiology of Thyroid Disorders

The HLA-DR3 protein may increase susceptibility, via special affinity for thyroid antigens, creating an autoimmune response against the thyroid gland. The cytotoxic T lymphocyte associated antigen-4 is also implicated along with various susceptibility genes. Genetic polymorphisms of vitamin D binding protein confer susceptibility to Graves’ disease. Genetic regulation of vitamin D activity affects thyroid autoimmunity and development of Graves’ disease. The link between such conditions and thyroid cancer has been understood for nearly 75 years. Graves’ disease may increase risks for benign thyroid adenomas and thyroid carcinoma by 1.7% 15%. Up to 2.5% of Graves’ patients with nodules develop cancer, while only 0.25% of nodules from other patients become cancerous. This means a seven- to onefold risk increase of thyroid cancer among patients with Graves’ disease. Specific antithyroid antibodies are linked to thyroid cancer. Elevated antibodies against thyroglobulin have an overall risk of 1.57, and those with antithyroid antibodies had an overall risk of 2.2. In one study a larger amount of malignant nodules tested positive for autoantibodies (31%) than benign nodules (21%). Autoantibodies against the TSHR are a diagnostic component of Graves’ disease. These antibodies are linked to development and progression of thyroid cancer. In patients with localized or metastatic thyroid cancer, 93% were positive for TSHR antibodies. There are also links between Hashimoto’s thyroiditis and thyroid cancer. When thyroid cancers are surgically removed, the cellular changes of Hashimoto’s thyroiditis are commonly seen surrounding the tumors. It is unclear if the thyroid inflammation of Hashimoto’s thyroiditis causes the cancer, or vice versa. It is also uncertain if the cancers surrounded by the inflammation have better or worse outcomes than those without the surrounding thyroiditis. Hashimoto’s thyroiditis is more likely to be detected around papillary thyroid cancer (40%) than around benign thyroid nodules (21%). It is also more common in female patients (23%) than in males (11%), and is present with papillary thyroid cancer only in 17% of cases. Hashimoto’s thyroiditis is only present in 8% of other thyroid cancers. Patients with papillary cancer that also had Hashimoto’s thyroiditis were less likely to have cancer recurrence upon follow-up when compared to patients with papillary cancer but no Hashimoto’s thyroiditis.

Clinical presentation When malignant, thyroid neoplasms are usually asymptomatic for a long amount of time. They usually present as solitary thyroid nodules. Benign and malignant nodules are usually asymptomatic, with no clinical clues to diagnosis. About half of all malignant nodules are found in a routine physical examination, in imaging studies, or during surgery for benign lesions. The remaining half are usually discovered by patients themselves as asymptomatic nodules. Common symptoms that patients experience as nodules grow include a frontal neck lump, voice changes or hoarseness, swollen neck

Global epidemiology of thyroid neoplasms

lymph nodes, difficulty breathing or swallowing, and throat or neck pain that does not subside. Usually, these symptoms are not caused by cancer, but by a benign thyroid nodule, or another condition. It is difficult to evaluate all types of nodules for malignancy since benign nodules are highly prevalent, and thyroid cancer is relatively uncommon.

Diagnosis of thyroid neoplasms To diagnose thyroid neoplasms, there is physical examination, personal and family history assessment, laboratory testing, and imaging. This is followed by biopsy to confirm the diagnosis. Since half of all thyroid malignancies are found in routine physical examination, this is an important part of diagnosis. The thyroid and neck structures are palpated, and the patient must be assessed for any symptoms of possible malignancy. According to the American Association of Clinical Endocrinologists, assessment for these malignancies must include family history of any thyroid disease; neck mass growth; previous neck diseases or treatments; dysphonia; hoarseness; dyspnea; dysphagia; nodule location, mass, and size; neck pain or tenderness; cervical adenopathy; use of iodine-containing drugs; and symptoms of hyperthyroidism or hypothyroidism. There is a higher risk of malignancy in males with fixed nodules, cervical adenopathy, age under 20 or over 70 years, persistent hoarseness, dysphonia, dysphagia, dyspnea, nodule growth, firmness or harness of nodules, history of head and neck radiation treatments, and family history of MTC or multiple endocrine neoplasia 2 (MEN2). Measurement of serum TSH concentration is a good way to evaluate thyroid nodules. This is because there is a high sensitivity of the TSH assay in detecting any level of thyroid dysfunction. Low levels of TSH are related to a lessened risk of malignancy. When TSH is low, a radionuclide thyroid scan is performed to determine the functionality of the thyroid gland. In those with a history of familial MTC or MEN2, calcitonin testing is required. This is controversial, however, due to cost. There is also a risk of false-positive results because high levels of serum calcitonin may be present in other conditions, including C-cell hyperplasia, kidney failure, pulmonary or pancreatic tumors, systemic inflammatory response syndrome, and sepsis. Routine use of serum calcitonin levels is therefore not recommended. Useful imaging studies include ultrasound and nuclear medicine scans. These include radioiodine scans and positron emission tomography (PET). The most sensitive test to detect thyroid lesions is high-resolution ultrasound. This allows measurement of dimensions with accuracy, structural identification, and evaluations of diffuse glandular changes. Ultrasound aids in determining nodules that are solid or fluid-filled, along with the number and size of nodules. This type of imaging must be performed in all patients with history of thyroid cancer in the family, history of MEN2, and

227

228

Epidemiology of Thyroid Disorders

when there has been childhood cervical irradiation, even when palpation shows only normal findings. The most common scan used to diagnose thyroid malignancies is the radioiodine thyroid scintigraphy scan. This is more often described as a “thyroid scan.” It is the only method that allows assessment of regional thyroid function and detection of tissue that is functional. Based on how much radioisotope is taken up by the tissue, it is classified as “hot” (hyperfunctional) or “cold” (hypofunctional). Cold nodules have a documented risk of malignancy, while hot nodules are usually not clinically significant malignant lesions. Radioiodine scans perform the best for patients with a high level of TSH. Since iodine in the body may interfere with test results, patients are usually told not to eat foods or take medicines that increase iodine for 1 day before the examination. The only definitive diagnostic method for thyroid cancer is biopsy. FNA is reliable and safe, as well also cost effective. Results are classified as follows: • Benign—60% 80% of specimens • Suspicious for malignancy—50% 75% of specimens • These have a 20% 30% risk for malignancy • Follicular lesion of undetermined significance with a 5% 10% risk for malignancy—20% 30% of specimens • Nondiagnostic or unsatisfactory—10% 15% of specimens • Malignant—3.5% 10% of specimens • Indeterminate—2.5% 10% of specimens • These have a 5% 10% risk for malignancy Results are important for determining if the patient should be treated medically or surgically. When diagnosis cannot be made with FNA, the entire nodule is surgically removed. Also, if FTC is suspected, complete surgical excision may be required for diagnosis. Focus on diagnosis of thyroid neoplasms Thyroid cancer may be diagnosed after assessing signs and symptoms that include a lump or swelling in the neck, pain in the front of the neck that may move upwards to the ears, hoarseness or voice changes that do not dissipate, difficulty swallowing or breathing, and a constant cough that is not related to a cold.

Initial evaluation Thorough patient history and physical examination are performed to evaluate the patient, followed as needed by laboratory testing, imaging, and, for some cases, FNA. These steps allow for better and more accurate treatment. Malignancy is more prevalent in patients under 20 30 years, who are male, with a history of external neck

Global epidemiology of thyroid neoplasms

radiation in childhood or adolescence, and rapid growth of nodules or continuing changes in breathing, speaking, or swallowing. In rare cases, a family history of multiple endocrine neoplasia type 2 is detected, which requires evaluation. For clinical evaluation, a thorough patient history and detailed physical examination is required, along with laboratory testing, imaging studies including neck ultrasonography, and the most important of all, and evaluation of whether FNA is needed. This procedure allows for assessment of any malignancies and related morbidity and mortality risks. It allows for determination of the best treatments for the individual patient. Historically, malignancy has been suggested by the following factors: male gender, age between 20 and 30 years, history of external neck radiation in childhood or adolescence, fast nodule growth, or persistent changes in speaking, breathing, or swallowing. In rare cases, family history of multiple endocrine neoplasia type 2 is detected, prompting evaluation. Initial laboratory studies For suspected or known thyroid nodules, serum TSH should be measured. A low or undetectable level, even with normal free thyroid hormone levels, suggests toxic nodules with autonomous function and indicates thyroid scintigraphy. Higher TSH in the serum, even in normal reference ranges, may increase risks that a nodule is cancerous. Serum anti-TPO antibody measurements may help with diagnosis of chronic lymphocytic thyroiditis (Hashimoto’s) if TSH serum levels are elevated. This form causes a heterogeneous parenchymal appearance during sonography, which may mimic a pseudonodule. If an elevated TPO antibody and heterogeneous sonographic pattern are found, the nodule must be sonographically discrete, in three different dimensions, to indicate evaluation. Hashimoto’s disease may also be related to bilateral, enlarged, but benign-looking lymphadenopathy. This is because of the immune nature of the disease. Follicular cell thyroid carcinomas (FCTCs) can release larger amounts of thyroid globulin (Tg) into the bloodstream. There is an overlap between serum Tg levels in FCTCs and, unfortunately, most benign conditions. Because of this, measurement of serum Tg is not useful in initial diagnosis of nodular thyroid disease. Some practitioners routinely measure serum calcitonin levels in cases of nodular thyroid disease to screen for MTC. Due to the rarity of unsuspected malignant thyroid cancer, large amounts of falsepositive results often require additional diagnostic measures or thyroidectomy. There is also the consideration of unknown relevance of medullary microcarcinomas, which are less than 1 cm in size. It is not cost effective or necessary to measure serum calcitonin levels in initial evaluation of nodular thyroid disease. When more suspicious situations exist, such as the presence of microcalcifications in the nodule, measurement of serum calcitonin may be helpful. If unstimulated serum calcitonin is more than 100 pg/mL, MTC is probably present.

229

230

Epidemiology of Thyroid Disorders

Imaging studies The best way to evaluate the thyroid’s structure is through ultrasonography. It allows for assessment of size, morphology, and cancer risks. Ultrasonography can detect even tiny thyroid nodules. Up to 65% of normal test subjects had nodularity detected by high-resolution sonography. Many studies have shown that ultrasound can effectively assess thyroid nodule malignancies. This aids in diagnosis and evaluation for patients. FNA of higher risk nodules is usually recommended when they are 1 cm or larger in size. Very low risk nodules may not require aspiration until they grow beyond 2 cm. The features most specific for thyroid cancer include microcalcifications, hypoechoic parenchyma, and margins that are infiltrative or irregular. These features are more predictive when several of them are present. Abnormal adenopathy, especially when unilateral in the lower neck, increases cancer risk when a thyroid nodule is found. Macrocalcifications do not predict malignancy unless they are present with microcalcifications. Some studies revealed that taller rather than wider shapes, with the anteroposterior dimension being larger than the transverse dimension on a transverse image, have a higher malignancy risk. However, there is no agreement on why this growth pattern would have more malignancies. Purely cystic nodules, a spongiform parenchyma, and homogeneously hyperechoic lesions carry the lowest risk of malignancy. Extensive research that confirms sonographic risk assessments, plus great improvements in ultrasound, has results in commonly recommended sonographic risk classifications for all thyroid nodules. These are now classified into high-, intermediate, low-, and very low suspicion groups. This supports future interventions or follow-ups. High-risk nodules are hypoechoic and solid, with microcalcifications or irregular borders. Risk for cancer is 70% 90% in these lesions. The most commonly seen nodules are of intermediate-risk and low-risk. Intermediate-risk nodules are hypoechoic and solid but lack the other worrying features of high-risk nodules. Low-risk nodules are isoechoic or hyperechoic and solid, and sometimes, partially cystic. They also do not have the microcalcifications, irregular margins, or abnormal adenopathy of high-risk nodules. Cancer risks for intermediate-risk nodules are 20% and for low-risk nodules, 5% 15%. Nodules at indeterminate or high risk are usually recommended for FNA when the diameter is more than 1 cm. Low-risk nodules are not recommended for FNA until growth exceeds 1.5 cm. Very low risk nodules are primarily cystic or spongiform. Risks for malignancy are extremely low. Because of this, FNA is not performed in these nodules until maximal nodule diameter exceeds 2 cm. Purely cystic nodules are hardly ever malignant, and FNA is not indicated diagnostically. These guidelines can provide a guide for consideration, though they must be individually assessed. Some factors result in biopsy of low-risk nodules even when smaller than 1 cm or, oppositely, choosing to observe a high-risk nodules even without using FNA. Overall risk for thyroid cancer is considered along with comorbidities, patient desires, and risks of various procedures.

Global epidemiology of thyroid neoplasms

Ultrasound elastography (USE) involves pressure with ultrasound to measure tissue stiffness. Usually, the stiffer a nodule is, the higher the risk for cancer. This procedure was first reported as extremely predictive of benign or malignant nodules. However, today USE has been shown to be less accurate compared to ultrasound assessments. Computed tomography (CT) and magnetic resonance imaging of the neck are also used. These procedures are good for assessing nearby neck structures before surgery, but they are still not as accurate as ultrasound. Cancer risks are not as easily defined as with ultrasound. Before ultrasound-guided FNA, thyroid scintigraphy was used for imaging, using 131 123 I, I, or 99mTc. The majority of thyroid carcinomas do not trap or organify iodine to a great extent. They appear as areas of reduced isotope uptake and are called cold nodules. This reflects an early decrease of sodium/iodide symporter (NIS) expression in tumorigenesis. It is unfortunate that most benign nodules also lack iodine concentration. Not all nodules having normal or slightly increased 99mTc uptake are benign. Some appear cold in thyroid scans with RAI. This is confirmative of the limited use of thyroid scintigraphy. Iodine scans can only exclude malignancies with some certainty when there is a toxic (hot) adenoma. These nodules have focal 123I uptake via greatly suppressed or absent uptake in the other parts of the gland. The lesions are usually related two suppressed serum TSH levels. They make up less than 5% 10% of thyroid nodules and are usually benign. Thyroid scintigraphy is used much less often than in previous years. It can still be valuable, however, in assessing patients with multiple thyroid nodules or borderline-low serum TSH. In these cases, scintigraphy allows for initially aspirate nonfunctional nodules. Also, fluorodeoxyglucose (FDG)-PET is performed more often when evaluating patients with various diseases. It is not recommended for routine evaluation of thyroid nodules. Incidental PET-positive nodules have cancer risks of 30% 40%. FNA is indicated. Diffuse FDG-PET uptake is usually found with Hashimoto’s disease and should not be considered as pathologic or malignant, when ultrasound confirms that there are no nodules. Fine-needle aspiration FNA of thyroid nodules is the method of choice for diagnosing thyroid cancer, with rates of sensitivity and specificity more than 90% in iodine-sufficient areas. This simple technique is very safe and causes only slight discomfort but must be done correctly to collect enough cells for examination. FNA requires about 20 minutes to perform and may or may not be guided by ultrasound. The use of guidance ultrasound is usually when the nodule cannot be felt without difficulty or if the nodule has areas inside it that should be specifically biopsied. Sometimes, the patient is asked not to take any blood-thinning medications before or on the day of the biopsy. An examination is made to pinpoint the nodule. The patient lies down and the neck is exposed, and

231

232

Epidemiology of Thyroid Disorders

sometimes must change into a gown. The area around the neck is draped and the neck is cleaned, usually with iodine. A local anesthetic may or may not be injected. The needle used for the aspiration biopsy is so thin that anesthesia is often not used. Another option is applying a topical anesthetic 10 20 minutes before beginning the procedure. The small, fine-gauge needle is inserted into the nodule. This needle is usually a smaller than needles used to draw blood. The patient holds his or her breath, to minimize movement of neck structures, while the needle is rocked back and forth gently to obtain as much tissue as possible. The needle is then withdrawn. Pressure is applied over the thyroid area to minimize bleeding. The procedure is usually repeated four to six times to ensure that enough tissue has been collected. After the procedure, pressure is applied for 5 10 minutes to assure that bleeding has stopped. The pressure also helps reduce any swelling that may occur. There may be slight discomfort for a few hours after biopsy, relieved by acetaminophen or other pain relievers, and an ice pack may be helpful. Complications are exceedingly rare and include bleeding, infection, and the formation of cysts. Patients should contact their physician if there is an excessive bruising, swelling, persistent pain, or a fever. The tissue samples are examined under a microscope and reported as benign, malignant, suspicious, or indeterminate. The chance of a false-positive result is less than 5% and is usually caused by the presence of degenerating or atypical cells. Results are usually reported back to the physician’s office within 1 week. Staging The two most important factors for staging and prognosis of thyroid malignancies are histological diagnosis and patient age. There are several staging and clinical prognostic scoring methods that utilize a patient age older than 45 years as a primary feature in identifying cancer mortality from these malignancies. However, the American Joint Committee on Cancer’s “TNM” staging system is preferred over the other systems. The abbreviations used in the staging system are as follows: • Tumor—T • Node N • Metastasis—M Table 10.2 summarizes the “TNM” staging system for thyroid cancer. The stage of thyroid cancer upon diagnosis refers to the amount of cancer in the body and aids in determining treatment options. It also greatly influences the length of the patient’s survival. Generally, cancer that is localized, sometimes called Stage 1, has a much better survival rate than stages described as regional or distant. About 67% of thyroid cancers are diagnosed while they are localized. The 5-year survival rate for localized thyroid cancers is 99.9%. Fig. 10.12 shows percent of thyroid cancer cases by stage and 5-year relative survival rates.

Global epidemiology of thyroid neoplasms

Table 10.2 The TNM staging system for thyroid cancer. Tumor stage

Comments

TX T0 (T plus zero) T1 T1a T1b T2

T4b

Primary tumor cannot be evaluated No evidence of a tumor Tumor is 2 cm or smaller, and limited to the thyroid Tumor is 1 cm or smaller Tumor is larger than 1 cm but smaller than 2 cm Tumor is larger than 2 cm but smaller than 4 cm and limited to the thyroid Tumor is larger than 4 cm but does not extend beyond the thyroid Tumor is any size and has extended beyond the thyroid Tumor has spread beyond thyroid to nearby soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve Tumor has spread beyond regions in T4a

(Lymph) Node stage

Comments

NX N0 (N plus zero) N1 N1a

Regional lymph nodes cannot be evaluated No evidence of cancer in regional lymph nodes Cancer has spread to lymph nodes Cancer has spread to lymph nodes around the thyroid, known as the central compartment, including the pretracheal, paratracheal, and prelaryngeal lymph nodes

Metastasis stage

Comments

MX M0 (M plus zero) M1

Distant metastasis cannot be evaluated Cancer has not spread to other parts of the body Cancer has spread to other parts of the body

Papillary or follicular cancer (age under 55 years)

Comments

Stage I

Any tumor, with or without spread to any lymph nodes, and no distant metastasis Any tumor, with any metastasis, regardless of whether it has spread to any lymph nodes

T3 T4 T4a

Stage II Papillary or follicular cancer (age 55 years or older)

Comments

Stage I

Any small tumor with no spread to lymph nodes and no metastasis A larger, noninvasive tumor with no spread to lymph nodes and no metastasis

Stage II

(Continued)

233

234

Epidemiology of Thyroid Disorders

Table 10.2 (Continued) Papillary or follicular cancer (age 55 years or older)

Comments

Stage III

Stage IVC

A tumor larger than 4 cm, still contained in the thyroid, with no spread to lymph nodes and no metastasis; or any localized tumor with spread to the central compartment of lymph nodes, but no distant spread A tumor has spread to nearby structures, regardless of whether it has spread to the lymph nodes but has not spread to distant places; or a localized tumor with lymph node spread beyond the central compartment, but no distant spread A tumor has spread beyond nearby structures, regardless of spread to lymph nodes, but no distant spread All tumors when there is evidence of metastasis

Medullary thyroid cancer

Comments

Stage I

A small tumor, with no spread to lymph nodes, and no distance metastasis A larger localized tumor, with no spread to lymph nodes, and no metastasis Any localized tumor that has spread to the central compartment of lymph nodes, but has not metastasized A tumor that has spread to nearby structures, regardless of whether it has spread to lymph nodes but has not spread to distant places; or a localized tumor with lymph node spread beyond the central compartment, but no distant spread A tumor that has spread beyond nearby structures, regardless of spread to lymph nodes, but no distant spread There is evidence of metastasis

Stage IVA

Stage IVB

Stage II Stage III Stage IVA

Stage IVB Stage IVC Anaplastic thyroid cancer

Comments (Note: all anaplastic thyroid tumors are classified as Stage IV, regardless of size, location, or metastasis, with these subclassifications)

Stage IVA

A tumor has spread to nearby structures, regardless of whether it has spread to lymph nodes, but has not spread to distant places A tumor has spread beyond nearby structures, regardless of spread to lymph nodes, but no distant spread There is evidence of metastasis Cancer has returned after treatment

Stage IVB Stage IVC Recurrent

Global epidemiology of thyroid neoplasms

120

Percent surviving

100 80 60 40 20 0 1975

1980

1985

1990

1995 Year

2000

2005

2010

2016

5-Year survival

SEER 9 5-Year relative survival percent from 1975 to 2011, All races, both sexes. Modeled trend lines were calculated from the underlying rates using the Jointpoint Survival Model Software.

Figure 10.12 Percent of cases and 5-year relative survival by stage at diagnosis: thyroid cancer. Data from , seer.cancer.gov..

Treatment of thyroid neoplasms The primary treatment for thyroid cancer is surgery, to remove the tumor and all or part of the remaining thyroid gland, in most cases. Other treatments include radiation therapy, chemotherapy, and targeted therapy. Surgery Thyroidectomy is used for all types of thyroid cancer. A near-total or total thyroidectomy with central neck dissection is recommended for any of the following conditions: • Primary thyroid carcinoma—larger than 1 cm • Contralateral thyroid nodules • Regional or distant metastases • Patient has personal history of radiation therapy to head and neck • Patient has a first-degree family history of differentiated thyroid cancer Age more than 45 years may also be evaluated for near-total or total thyroidectomy, due to higher recurrence rates. The same recommendations apply to children and younger adults, since 60% 80% have regional lymph node involvement, and 10% 20% have distant metastases. When all thyroid tissue cannot be removed, whatever is remaining will be destroyed with RAI at a later time. With follicular or papillary thyroid cancer, a lobectomy may be performed instead, in which one lobe and the isthmus are removed. Sometimes, a second surgery is required to remove the remaining lobe, but usually, RAI or radiation is used to destroy remaining thyroid tissue. Since the removed tissue contains the cells that

235

236

Epidemiology of Thyroid Disorders

produce thyroid hormone, there will be a need for daily thyroid hormone replacement therapy following a thyroidectomy. Postoperative complications include temporary or permanent hoarseness or loss of voice, parathyroid gland damage, excessive bleeding or hematoma, recurring laryngeal nerve paralysis, vocal cord paralysis, wound infection, and thyroid storm. Parathyroid gland damage may cause hypoparathyroidism. This can result in low serum calcium levels, followed by muscle spasms and peripheral neuropathies. A thyroid storm (thyrotoxic crisis) is acute thyroid overactivity, with high fever, delirium, tachycardia, dehydration, and extreme excitability. After surgery, there must be close assessment for manifestations of bleeding, infection, hypocalcemia, tetany, vocal cord paralysis, and thyrotoxic crisis. Respiratory status must be assessed closely immediately after surgery. This must include vital signs every 4 hours, inability to speak, crowing respirations, dyspnea, retraction of neck muscles, cyanosis, hematoma, hoarseness, and vocal cord paralysis. The head of the patient’s bed should be kept elevated to more than 45 degrees at all times. Neck support is maintained by placing the hands behind the neck, with the elbows raised, when moving or sitting. The patient must turn, cough, and deep breathe every 2 hours. Daily calcium level monitoring is needed, since 0.4% 53% will experience hypoparathyroidism after thyroidectomy. This is usually temporary, but permanent hypoparathyroidism occurs in 0.4% 13.8% of patients after the surgery. Hypoparathyroidism causes hypocalcemia, followed by numbness, cramps, or tingling in the extremities, numbness and tingling around the mouth, stiffness, positive Chvostek sign, twitching or spasms in the extremities, and a positive Trousseau sign. A positive Chvostek sign involves an abnormal reaction to facial nerve stimulation. If the facial nerve is tapped at the jaw angle, the muscles on the same side will contract momentarily. For the Trousseau sign a blood pressure cuff is inflated to beyond the systolic blood pressure for 3 minutes. Carpopedal spasms will occur, including wrist flexion, metacarpophalangeal joint flexion, interphalangeal joint extension, and thumb as well as finger adduction. The patient may need calcium gluconate in order to prevent hypocalcemia. The patient should be instructed about avoiding foods that suppress calcium absorption. These include spinach, beets, Swiss cheese, bran, and whole-grain cereals. Radiation therapy RAI therapy with 131I improves patient survival rates with metastatic FTC or PTC and is now standard practice for these cases. However, benefits of RAI therapy are not as clear for nonmetastatic thyroid cancers of small size. About 4 6 weeks following surgery, RAI is given to destroy remaining functional thyroid tissue and any residual local, metastatic tumors. The patient must consume a low-iodine diet for 1 2 weeks before RAI treatment. He or she will then stop taking thyroid replacement medications or

Global epidemiology of thyroid neoplasms

thyrogen injections, so that TSH levels can increase. The RAI therapy is not used for anaplastic or medullary thyroid carcinomas, since these forms do not take up iodine. Short-term adverse effects of RAI include nausea, neck tenderness, dry mouth, salivary gland swelling and tenderness, fatigue, bone-marrow suppression, headache, and other pain. Males receiving large doses of RAI may have lowered sperm counts or become infertile. RAI may affect the ovarian function of females, and some may experience irregular period for up to 1 year. Some physicians recommend women avoiding pregnancy for 6 months to 1 year after treatment. Both sexes, after RAI, may have slightly higher risk for developing future leukemia. Most studies have found this to be very rare or not of significant risk increase. The patient should receive review of the purpose and administration of RAI. The patient may be hospitalized or discharged after treatment. The RAI can be administered as an oral liquid or in a single-dose pill form. The patient must avoid contact with the pill prior to swallowing it. Hospitalized patients must not bring any articles from home that can become contaminated with radiation, and radiation-safety procedures must be followed. Visitors can only stay for 30 minutes at a time, and no pregnant women can visit. If RAI is given on an outpatient basis, the patient must remain at least 6 ft. away from other people. Education should be given about nausea, vomiting, headache, tiredness, mucositis, and neutropenia. Discharge instructions must include information about the patient remaining radioactive for a few days. He or she must sleep alone, avoid sexual activity and kissing, and not holding children or pets close for at least 3 days. Precautions include sitting on the toilet when urinating to avoid splattering from stand-up urination and to flush the toilet three times after voiding. The patient must drink at least two quarts of fluid for several days to help the body remove all traces of RAI. EBRT may be used for anaplastic tumors that do not take up RAI, for recurring tumors, or to treat bone pain caused by metastasis. The goal of EBRT is to achieve localized control but may be extremely toxic. The 2-year survival rate with EBRT is only 9%. Fractionation regimens have developed, working along with radiationchemotherapy and surgical resection, which achieve localized control of about 60%. However, toxicity is still a major issue. Careful patient selection is required for EBRT therapies. If the patient has adequate health and no metastasis, standard fractionation up to 50 or 60 Gy, or accelerated hyperfractionated EBRT without chemotherapy, 60 Gy in 40 fractions (1.5 Gy/fraction bid) over 4 weeks. Note that a Gy is a derived unit of ionizing radiation dose in the International System of Units, defined as absorption of 1 J of radiation energy per kilogram of matter. Regardless of regimen, efficacy of EBRT must balance with toxicity, which is based on how much radiation is received, and the area of the body being treated. Neck radiation may cause mucositis and xerostomia that requires intravenous fluids or enteral tube feedings. Local skin

237

238

Epidemiology of Thyroid Disorders

irritation progresses, ranging from redness to moist desquamation. Most patients also have excessive fatigue during treatment. Chemotherapy Adjuvant chemotherapy is not useful to manage differentiated thyroid cancer. Doxorubicin may be a radiation sensitizer in some thyroid tumors and has been considered for locally advanced disease while EBRT is being administered. Since anaplastic forms are not receptive to RAI, there have been partial remissions with use of chemotherapy. Though doxorubicin is the most common chemotherapeutic for thyroid cancer, monotherapy results are poor, and only 17% of cases achieve partial remission. However, when doxorubicin is combined with cisplatin, there is higher therapeutic activity and more complete responses, with 30% of patients responding successfully. Targeted therapy Elevated levels of vascular endothelial growth factor (VEGF) are present in thyroid tumor tissue compared with normal tissue. Therefore VEGF antagonists may be helpful in treating disseminated or MTCs. Medications include motesanib, axitinib, sorafenib, sunitinib, selumetinib, and vandetanib. Additional therapies are under continued investigation.

Global burden of thyroid cancers Thyroid cancer affects women by three to four times as often as men. For 2019 the American Cancer Society estimated that there were about 52,070 new cases of thyroid cancer (37,810 females and 14,260 males). There were also about 2710 deaths from the disease (1150 females and 1020 males). Globally, there were 567,233 new cases of thyroid cancer diagnosed in 2018. A total of 436,344 females and 130,889 males were affected, but documentation of actual deaths is lacking. Over previous decades, the annual number of new cases of thyroid cancer has increased dramatically. Fortunately, however, the death rate changed only slightly. The opposing trends between incidence and mortality may reveal that increased early detection of small papillary thyroid malignancies, treated by total surgical resection, is highly successful. Incidence rates for thyroid cancer are much higher in developed countries such as the United States than in developing countries. Oppositely, thyroid cancer mortality rates are much higher in less developed regions. Incidence rates of thyroid cancer have more than doubled in the United States since the 1970, while mortality rates have remained nearly the same. In one study, from 1970 to 2005, the incidence of papillary thyroid carcinoma increases by 185%, from 2.7 people of every 100,000 to 7.7 per 100,000. However, incidence of follicular thyroid carcinoma did not change during

Global epidemiology of thyroid neoplasms

the years studied. The mortality rates of thyroid cancer actually declined, from 0.57 per 100,000 in 1973 to 0.47 per 100,000 in 2003. This may suggested that better diagnostic methods are proving effective. Ultrasound is commonly used to identify small thyroid nodules, only a few millimeters in diameter. FNA and pathologic examination of tissue from small papillary tumors is now standard practice. Therefore increased early detection of smaller papillary tumors treated by complete surgical resection explains these trends. Typical costs for thyroid cancer treatment range, for patients without health insurance, between $20,000 and $40,000 for surgery in the United States and up to $4000 for RAI treatment, which is often recommended. The total cost for metastatic thyroid cancer can reach over $60,000 in the first year, after the cancer was discovered to have spread, and about $35,000 the following year. These prices include imaging, physician visits, surgery, chemotherapy, and hospitalization.

Clinical cases Case 1 1. How common are follicular thyroid adenomas? 2. What is the “clearing” of the cells caused by? 3. How is the appearance of this type of adenoma described? A 29-year-old woman presented with a 2-cm clear-cell follicular thyroid adenoma located in her submandibular region. Diagnosis was established via light microscopic morphology, a positive thyroglobulin immunohistology, and presence of normal thyroid tissue around the mass. Preoperative computed tomography (CT) scan and postoperative ultrasound studies revealed a normal thyroid gland, and no additional tumors have since been found. Answers: 1. Follicular thyroid adenomas are the most common type of thyroid neoplasms. They are encapsulated lesions surrounded by a fibrous capsule. 2. The clearing is due to intracellular lipid and mucin. 3. The cytologic features include cellular smears with many disrupted cells and a granular background. The cytoplasm is usually abundant and filled with empty, membrane-bound vacuoles.

Case 2 1. Because of this patient’s age, what is her likely prognosis? 2. What are the common metastases of this type of thyroid cancer? 3. Is this form of thyroid cancer increasing or decreasing in incidence?

239

240

Epidemiology of Thyroid Disorders

A 35-year-old woman presented with papillary thyroid cancer. Surgery was performed, and radioactive iodine was administered. Eight years later, she developed multiple pulmonary metastases and bulky swelling in the neck. Scans were conducted every 3 months, revealing rapid tumor growth. Surgery was undertaken to reduce the disease burden in her neck. Since high-risk factors were not present, initiation of systemic therapy was delayed, and treatment with sorafenib produced a strong response. Answers: 1. The prognosis is closely related to age. People with papillary thyroid cancer who are younger than 55 years old have a much better prognosis than those over the age of 55 years. Overall, this form is rarely fatal. 2. In more than half of cases, papillary thyroid cancer moves to the lymph nodes of the neck and can rarely spread to the liver, lungs, or bones. 3. Papillary thyroid cancer is increasing in incidence globally. It is one of the few cancers becoming more common, of unknown reason.

Case 3 1. How common is follicular thyroid cancer? 2. Is this cancer more or less malignant than papillary carcinoma, and what is the prognosis for younger patients, such as the woman in this case study? 3. What type of follow-up is essential for this type of thyroid cancer? A 19-year-old African American woman with a history of several benign ovarian cystic teratomas presented to the emergency department with worsening abdominal pain. Sonogram revealed a mixed solid and cystic pelvic mass with widespread nodules, including a well-differentiated follicular thyroid carcinoma of ovarian origin. The tissue was positive for thyroglobulin and thyroid transcription factor-1 (TTF-1). Before being scheduled for surgery, this patient was clinically and biochemically euthyroid. A total thyroidectomy was performed, and no lesions were found in the tissues. Radioactive iodine ablation treatment followed the surgery. Answers: 1. Follicular thyroid cancer makes up approximately 10% of all thyroid cancers in the United States. 2. Follicular thyroid cancer is usually more malignant (aggressive) than papillary carcinoma, but it is usually most aggressive in patients older than the age of 55 years. Therefore this patient’s age results in a better prognosis. 3. The patient must receive an annual chest X-ray and a check of thyroglobulin levels. This is because a high serum thyroglobulin level that had previously been low following total thyroidectomy, especially if gradually increased with TSH stimulation, is a sign of recurrence.

Global epidemiology of thyroid neoplasms

Case 4 1. What is the significant difference between the origination of medullary thyroid carcinoma compared to other forms of thyroid cancer? 2. How likely is medullary thyroid cancer regarding occurrence in families? 3. Since inherited medullary thyroid cancer involves mutation of the RET protooncogene, why are early blood tests helpful? A 40-year-old woman presented with a single thyroid nodule that caused increasing swelling on the right side of her neck. Upon examination, she was clinically euthyroid, but had a 2-cm firm, smooth mass on the right side of the thyroid that moved when she swallowed. Thyroid function tests were normal. Fine-needle aspiration biopsy of the nodule was consistent with a diagnosis of medullary thyroid carcinoma. A total thyroidectomy was performed, with limited cervical dissection. There was no lymph node involvement. Answers: 1. Medullary thyroid carcinoma originates from the parafollicular C cells of the thyroid gland. Other types of thyroid cancer originate from thyroid follicular cells. The C cells do not make thyroid hormone but do make calcitonin. 2. The inherited forms of medullary thyroid cancer are likely to run in families, in up to 25% of diagnoses and can be associated with other endocrine tumors, in syndromes called multiple endocrine neoplasia (MEN) 2A and MEN 2B. 3. Early blood tests are important because in family members of a patient with an inherited form of MTC, a blood test for a mutation in the RET proto-oncogene can lead to an early diagnosis of medullary thyroid cancer and to curative surgery to remove it.

Key terms ACTH adipokines autophosphorylation Barr bodies Carney complex type 1 Chvostek sign Cowden disease Cushing syndrome diffuse sclerosing variant follicular carcinoma

Gardner syndrome human leukocyte antigen (HLA) Hürthle cell hypoechoic parenchyma kallikreins medullary carcinoma MEN syndrome microchimerism mucositis oophorectomy

241

242

Epidemiology of Thyroid Disorders

papillary carcinoma pheochromocytoma pleomorphic giant cells RET proto-oncogene scintiscan spindle cells

tall-cell variant thyroid autonomy trousseau sign ultrasound elastography xerostomia

Further reading 1. Ali, S.Z., and Cibas, E.S. The Bethesda System for Reporting Thyroid Cytopathology: Definitions, Criteria, and Explanatory Notes, 2nd Edition. (2018) Springer. 2. Al-Mudhaffar, S.A., Hasan, H.H., and Hanas, H.R. Biochemical Studies on Thyroid Carcinoma. (2015) CreateSpace Independent Publishing Platform. 3. Amdur, R.J., and Mazzaferri, E.L. Essentials of Thyroid Cancer Management (Cancer Treatment and Research). (2005) Springer. 4. Boerner, S.L., and Asa, S.L. Biopsy Interpretation of the Thyroid (Biopsy Interpretation Edition), 2nd Edition. (2019) Wolters Kluwer. 5. Braunstein, G.D. Thyroid Cancer (Endocrine Updates). (2012) Springer. 6. Cooper, D.S., and Durante, C. Thyroid Cancer: A Case-Based Approach. (2015) Springer. 7. DeVita, V.T., Rosenberg, S.A., and Lawrence, T.S. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology, 11th Edition. (2018) LWW. 8. Erickson, L.A. Atlas of Endocrine Pathology (Atlas of Anatomic Pathology). (2014) Springer. 9. Gharib, H. Thyroid Nodules: Diagnosis and Management (Contemporary Endocrinology). (2018) Humana Press. 10. Halenka, M., and Frysak, Z. Atlas of Thyroid Ultrasonography. (2017) Springer. 11. Haugen, B., and Draznin, B. Thyroid Neoplasms, Volume 4 (Advances in Molecular and Cellular Endocrinology. (2005) Elsevier. 12. Kakudo, K. Thyroid FNA Cytology: Differential Diagnosis and Pitfalls, 2nd Edition. (2019) Springer. 13. Kenly, W. After the Diagnosis, Medullary Thyroid Cancer Memoirs. (2015) Outskirts Press. 14. Lalwani, A. Current Diagnosis & Treatment Otolaryngology Head and Neck Surgery, 3rd Edition. (2019) McGraw-Hill/Lange. 15. McDougall, I.R. Management of Thyroid Cancer and Related Nodular Disease. (2006) Springer. 16. National Comprehensive Cancer Network. NCCN Guidelines for Patients: Thyroid Cancer. (2017) National Comprehensive Cancer Network (NCCN). 17. Nikiforov, Y.E., Biddinger, P.W., and Thompson, L.D.R. Diagnostic Pathology and Molecular Genetics of the Thyroid: A Comprehensive Guide for Practicing Thyroid Pathology. (2009) LWW. 18. Randolph, G.W. Surgery of the Thyroid and Parathyroid Glands: Expert Consult, 2nd Edition. (2012) Saunders. 19. Raue, F. Medullary Thyroid Carcinoma: Biology-Management-Treatment (Recent Results in Cancer Research). (2015) Springer. 20. Suster, S. Atlas of Mediastinal Pathology (Atlas of Anatomic Pathology). (2015) Springer. 21. Thompson, L.D.R. Head and Neck Pathology: A Volume in the Series: Foundations in Diagnostic Pathology, 2nd Edition. (2012) Saunders. 22. Van Nostrand, D.V., Wartofsky, L., Bloom, G., and Kulkarni, K. Thyroid Cancer: A Guide for Patients, 2nd Edition. (2010) Keystone Press, Inc. 23. Vitti, P., and Hegedus, L. Thyroid Diseases: Pathogenesis, Diagnosis, and Treatment (Endocrinology). (2018) Springer. 24. Wartofsky, L., and Van Nostrand, D.V. Thyroid Cancer: A Comprehensive Guide to Clinical Management, 3rd Edition. (2016) Springer. 25. Yang, G.C.H. Thyroid Fine Needle Aspiration. (2013) Cambridge University Press.

CHAPTER 11

Global impact of thyroid disorders Contents Global effects of iodine deficiency The burden of hypothyroidism The burden of hyperthyroidism The burden of Graves’ disease The burden of thyroid cancer Global costs and consequences of thyroid disorders Further reading

243 245 246 252 252 253 254

The global impact of thyroid disorders, including hypothyroidism, hyperthyroidism, Graves’ disease, and thyroid cancer, is increasing by about 3.3% each year. The key determinant of thyroid disease risks is iodine nutrition. However, other factors that influence the epidemiology of thyroid disorders include aging, smoking, genetics, ethnicities, endocrine disruptors, and the use of various treatments. Hypothyroidism and hyperthyroidism, in all their forms, affect every population throughout the world. However, the prevalence and incidence of thyroid dysfunction is always changing because of differences in diagnostic thresholds, sensitivity of various tests, the populations being selected for study, and changes in the availability of dietary iodine. The burden of thyroid disorders reaches up to billions of dollars, globally, every year.

Global effects of iodine deficiency Iodine deficiency is a significant global health issue. For example, in India, in 2000, there were an estimated 100 million iodine-deficient people, 4 million with goiter, and 500,000 suffering from cretinism. Other iodine-deficient areas included Southeast Asia, the Western Pacific, Africa, and the Russian Federation. In 2011 there was information about iodine-insufficiency prevalence in 115 countries, covering about 96% of the global population. Results showed that 1.88 billion people were estimated to have insufficient iodine intake. This was a reduction of approximately 6% from the 2003 estimate of 2 billion people being iodine deficient. In school-aged children, global prevalence fell from 285 million in 2003 to 241 million in 2011. The countries classified as iodine deficient decreased from 54 in 2003 to 32 in 2011. However, severe iodine deficiency existed in 12.5 million children. Among children with insufficient iodine intake, 76 million lived in Southeast Asia and 58 million lived in Africa. Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00011-6

r 2020 Elsevier Inc. All rights reserved.

243

244

Epidemiology of Thyroid Disorders

Though the problem was rare in Western countries, it is becoming more prevalent in North America. This may be related to a lack of minerals in the soil and to modern industrial agricultural methods. Since environmental pollutants have reduced natural mineral levels in the soil, it results in a low content of iodine in foods. In the United States, some areas have low levels of iodine today, which in previous years had much higher levels. Iodine is highly important for pregnant women and their babies as well as for young children. Deficiency of iodine can lead to severe developmental issues. For example, studies have shown a link between iodine deficiency and autism. Regarding endemic goiter on a global scale, it is important to understand that there is a close relationship between low iodine content in food and water, and the appearance of the disease. There is also a sharp reduction in incidence once iodine is added to the diet. The metabolism of iodine by patients with endemic goiter follows the expected patterns as the condition resolves. Also, in tested animals, iodine deficiency causes thyroid gland changes similar to those seen in humans. In nearly all cases, careful assessment of iodine intake, where goiter is prevalent, reveals iodine levels that are well below normal. Assessment of iodine status in various global regions is done by studying urinary iodine concentration, goiter rates, serum thyroid-stimulating hormone (TSH), and serum thyroglobulin. The urinary iodine concentration is a sensitive indicator of recent iodine intake. Insufficient iodine intake is indicated by urinary values that are lower than 100 µg/L. Severe iodine deficiency is indicated by values lower than 20 µg/L. Iodized salt is considered to be the best measure for iodine fortification in the diet. The daily requirement is 150 µg per adult. Salt iodization is the most cost-effective method of delivering iodine and for improving cognition in iodine-deficient populations. Globally, the annual costs of salt iodization are only estimated to be the equivalent of 2 5 cents for each child. Costs per child death that are avoided are about $1000. Before widespread salt iodization, annual potential losses, attributed to iodine deficiency in developing countries, were estimated at $35.7, compared with the estimated $0.5 billion annual cost for salt iodization. This is a benefit-to-cost ratio of 70:1. Until 1990, only a few countries were completely iodine-sufficient. These included Switzerland, Australia, the United States, and Canada. Since that time, globally, the number of households using iodized salt has grown from less than 20% to more than 70%, greatly reducing iodine deficiency. Today, over 75% of households, worldwide, have access to iodized salt. The International Child Development Steering Group has identified iodine deficiency as one of four key global risk factors for impaired child development, in which the need for intervention is urgent. Iodine supplementation has proven value in preventing disease. Assessing individual regional situations and communicating these results to health professionals, political authorities, and the public are reducing the burden of global iodine deficiency. Salt iodization programs must be monitored. This requires assessment of the deficiency situation, better communication, development of action plans and proper

Global impact of thyroid disorders

implementation, and evaluation of impacts of these plans upon the population. Monitoring is often insufficient due to lack of financial or technical resources supporting laboratories that can correctly monitor iodine status and the quality of available dietary salt. Focus on global iodine deficiency Iodine is an essential element that keeps our thyroid hormones in balance, helping to avoid metabolic disorders such as hypothyroidism. Much of the world, however, continues to suffer from iodine deficiency. Most foods that are rich in iodine come from the sea; hence, many global areas that face iodine deficiency are mountainous. Another concern is that pregnant women require higher amounts of iodine to meet not only their needs but also the needs of the developing fetus. Pregnant women suffering from mild iodine deficiency have been shown to develop more severe deficiencies, with potentially long-term effects.

The burden of hypothyroidism In iodine-deficient countries the burden of hypothyroidism has also been studied. Between 1995 and 2004, studies within the United Kingdom revealed an annual incidence of hypothyroidism as being 3.5 5 per 1000 in females and 0.6 0.9 per 1000 in males. In the United States the National Health and Nutrition Examination Survey (NHANES), conducted from 1988 to 1994 and from 2007 to 2012, revealed rates of subclinical and clinical hypothyroidism. For subclinical hypothyroidism, studies evaluated elevated TSH with normal thyroxine. For clinical hypothyroidism, studies evaluated normal TSH with low thyroxine. People with subclinical hypothyroidism are usually asymptomatic, only being diagnosed by laboratory testing. Clinical hypothyroidism causes the classic symptoms of the condition. In the 2007 12 NHANES study, subclinical hypothyroidism was prevalent in 3.8% of females and 3.1% of males. Between ethnic groups, Caucasians had the highest prevalence (4.4%). African Americans had the lowest prevalence (0.6%). For all groups, prevalence steadily increased, with a peak age of those 65 years and older, at 5.8%. However, in the 1988 94 study, subclinical hypothyroidism was slightly more prevalent, at 4.3% overall. In both studies, subclinical hypothyroidism was much higher in prevalence than clinical hypothyroidism. Clinical hypothyroidism prevalence was at 0.3 per 1000 in 1988 94 and at 0.2 per 1000 in 2007 12. Consequences of subclinical hypothyroidism are attributed to thyroid deficiency, biochemical or physiological abnormalities, and risks for progression to more severe thyroid dysfunction. Consequences of overt hypothyroidism are similar but more severe. The risk of progression of subclinical hypothyroidism to overt hypothyroidism ranges between 3% and 20% annually. The average rate of progression to a clinical diagnosis of hypothyroidism in females is 3% per year for those with high serum TSH and 4% per year for those

245

246

Epidemiology of Thyroid Disorders

with high serum TSH plus high serum antithyroid peroxidase antibodies. Risk of progression is higher in men, but there are simply far fewer cases of the condition overall. In England a 1991 study showed that 18% of patients over age 60 who had subclinical hypothyroidism at the time of first testing developed overt hypothyroidism within 1 year. The financial burden of hypothyroidism, in the United States, takes into account copayments for physicians and medications. Usually, health insurance programs cover treatments for hypothyroidism. When a patient is not covered by health insurance, treatments average between $180 and $1200 per year, just for the commonly prescribed synthetic TH. Many physicians and hospitals give discounts of 30% or more to patients who are uninsured or who are paying in cash. Some drug manufacturers offer free or discounted medications via patient assistance programs. Further, cost breakdowns start at an average of the following prices: • Initial thyroid consultation: $350 • Follow-up visit: $200 • Blood tests: $60 • Ultrasound: $150 • Thyroflex testing: $150 (this is a test that measures the reaction time of the brachioradialis muscle of the forearm, using a reflex hammer, with responses measured by a computer program; a low reflex score indicates low thyroid-hormone activity due to reduced metabolic activity; a higher than normal reflex score indicates overactivity of THs) However, complete thyroid blood panels can reach over $500 based on the specific testing that is needed, location of the patient, and availability of insurance coverage. Usually, the T3, T4, and TSH tests have widely differing prices. The estimates of medical services to screen, evaluate, and treat thyroid dysfunction, per one 1 people screened, for subclinical and overt hypothyroidism, are shown in Table 11.1. Table 11.2 shows the prices of services required for follow-up and treatment after abnormal results of thyroid screening for subclinical and overt hypothyroidism. Focus on hypothyroidism Hypothyroidism is the most common thyroid disorder. There is no definitive way to prevent hypothyroidism. However, synthetic thyroid supplements are widely available and are the preferred treatment for hypothyroidism. For most people, treatment for hypothyroidism must be lifelong.

The burden of hyperthyroidism The estimated prevalence of overt hyperthyroidism ranges between 0.1% and 0.5% and is higher in females than in males. According to the NHANES III study, prevalence of overt hyperthyroidism in patients of age 12 years and older is 0.5%. In a

Table 11.1 Estimated medical services for subclinical and overt hypothyroidism. Screening serum TSH value lowa (1% of all people screened) Follow-up

Base case

Office visit Repeat serum TSH test Serum free T4 test

10,000 10,000 10,000

Lowest case

Highest case

Outcome 1: Normal—repeat serum TSH value normalb 1000 (10% of people with low screening value)

Years 2 5: follow-up serum TSH

800

200

900

Outcome 2: Subclinical hyperthyroidismb—serum TSH low and free T4 normal 8500 (85% of people with low screening value)

Serum triiodothyronine test Serum antithyroid antibody test Radioiodine tests Endocrine consultation Antithyroid treatment Radioactive iodinec Antithyroid drug treatmentd

4250 2550 2550 4250 2550 1275 1275

1700 425 850 1700 850 425 425

6800 5100 5100 6800 5950 2975 2975

25 50 100 300 350 175 175

300 400 400 500 500 250 250

Outcome 3: Overt hyperthyroidismb—serum TSH low and free T4 normal 500 (5% of people with low screening value)

Serum triiodothyronine test Serum antithyroid antibody tests Radioiodine tests Endocrine consultation Antithyroid treatment Radioactive iodinec Antithyroid drug treatmentd

150 250 250 400 450 225 225

Follow-up after any treatment started (people with either subclinical or overt hyperthyroidism) Year 1, after treatment started (all treated people)

Follow-up office visits, 3 Serum free T4 tests, 3 Serum TSH tests, 3 Hypothyroidism after radioactive iodine treatment (all treated with T4)

3000 3000 3000 750

1200 1200 1200 300

6450 6450 6450 1612

300 300

1612 1612

Years 2 and beyond Follow-up of group with hypothyroidism after radioactive iodine treatment

Lifelong T4 treatment Follow-up office visits, 2/year

750 750

TSH, Thyroid-stimulating hormone. a Prevalence data for high and low serum TSH concentrations extrapolated from Hollowell et al. (2002). b Distribution of people among overt and subclinical subgroups (and normal repeat serum TSH subgroups) estimated from Canaris et al. (2000), Vanderpump et al. (1995), and Parle et al. (1991). c Some people, given an antithyroid drug, initially would probably be given radioactive iodine in year 2 or later, but it is very uncertain what that percentage would be. d About 75% of the people, who were given an antithyroid drug, may receive it in year 2 and later as well. It may be discontinued with relapse of hyperthyroidism in some people, and others would be given radioactive iodine; the percentages are very uncertain.

248

Epidemiology of Thyroid Disorders

Table 11.2 Costs of subclinical and overt hypothyroidism. CPT codea

Cost ($)b

99,213 84,443 84,439 86,376

47.18 23.47 12.60 20.33

84,443

23.47

99,241

43.83 0.315/day

99,242

81.70 0.315/day

Screening serum TSH value high Follow-up Office visitc Repeat serum TSH test Serum free T4 test Serum antithyroid antibody testd Outcome 1: Normal Repeat serum TSH value normal Years 2 5: Follow-up serum TSH tests Outcome 2: Subclinical hypothyroidism Year 1 Endocrine consultation Levothyroxine treatment, 0.1 mg/day Outcome 3: Overt hypothyroidism Year 1 Endocrine consultation Levothyroxine treatment, 0.1 mg/day

Follow-up after treatment (either subclinical or overt hypothyroidism) Year 1, after treatment started Follow-up office visits,c 2 Follow-up serum TSH tests, 2 Years 2 and beyond Lifelong levothyroxine treatment Follow-up office visits,c 2/year Follow-up serum TSH tests, 2/year

99,212 84,443

33.57 23.47 0.315/day

99,212 84,443

33.57 23.47

TSH, Thyroid-stimulating hormone. a Common Procedural Terminology codes, copyright 2003, American Medical Association. b All prices except for prescription drugs (levothyroxine, methimazole, and propylthiouracil) are from 2003 Medicare Fee Schedules. Prescription drug prices were obtained from the DestinationRx (2003) website. c Initial office visits after a screening test, found to be positive in all groups, are estimated as requiring more than minimum time. d Measurement of serum antithyroid peroxidase (microsomal) antibody.

review of studies conducted between 1990 and 2013, relative incidence of overt hyperthyroidism in pregnant women ranged between 0.1% and 0.4%. Studies in the United Kingdom revealed hyperthyroidism to range between 0.86% and 1.26% in females and 0.17% and 0.24% in males. There is an increase in cases of hyperthyroidism at about 6.3% per year. In the United States, incidence per 1000 people for overt hyperthyroidism was highest in those 65 and older, with 1.01 of every 1000 being affected. This was followed by 0.78 of every 1000 in the 56 64 years of age-group, and the lowest incidence was 0.26 in patients between ages 12 and 17 years. The NHANES III study

Global impact of thyroid disorders

reported prevalence of subclinical hyperthyroidism in patients of age 12 or older as 0.7%. In adults 65 and older, this prevalence rate was 1.2%. Overt hyperthyroidism was most common in Caucasians (0.6%) and least common in Mexican Americans (0.2%). Subclinical hyperthyroidism was most common, again, in Caucasians (0.8%) and least common in races not included in Caucasian, African American, or Mexican American groupings, at 0.3%. The combined rate of subclinical hyperthyroidism (in all ethnic groups) was 0.7% of the population, compared to 0.5% for overt hyperthyroidism. A study of British patients who presented with a first episode of hyperthyroidism between 1989 and 2003, followed until 2012, found that 32% of the initial patients of age 40 years and older had died. This was 15% higher for all-cause mortality than expected deaths for this population. Comorbidity was, however, high. Cardiovascular and cerebrovascular causes were 20% higher than expected. In those who had atrial fibrillation as well as hyperthyroidism, the risk of death was 59% higher. Costs of hyperthyroidism are based on a variety of factors. Potential costs include evaluation for treatment detected by screening and actual treatment detected by screening. Evaluation includes serum triiodothyronine tests, serum antithyroid antibody tests, radioiodine tests, and endocrine consultations. Treatments require office visits for follow-up serum free thyroxine tests, serum TSH tests, antithyroid drug or radioactive iodine treatment, blood counts, liver function tests, and TH therapy for hypothyroidism that results from radioactive iodine treatments. However, potential savings also exist, from better screening methods. There may be a reduction in consultations and tests for the unrecognized symptoms of hyperthyroidism such as anxiety, weight loss, or cardiac arrhythmia. Reductions in treatment, morbidity, or mortality are also seen. These may be related to secondary disorders or progression toward more severe hyperthyroidism such as atrial fibrillation, fractures from osteoporosis, and heart failure. Table 11.3 contains estimates of medical services to screen, evaluate, and treat thyroid dysfunction, per 1 million people, screened for subclinical and overt hyperthyroidism. Table 11.4 lists prices of services required for follow-up and treatment after abnormal results of thyroid screening for subclinical and overt hyperthyroidism. Focus on hyperthyroidism Hyperthyroidism is highly treatable and tends to run in families. Treatments include antithyroid medications, radioactive ablation, and thyroidectomy. Hyperthyroidism can lead to thyrotoxicosis, which is a toxic condition caused by excessive THs, from any cause. In its most severe form, hyperthyroidism can result in thyroid storm, which can be lifethreatening.

249

Table 11.3 Medical services for subclinical and overt hyperthyroidism. Screening serum TSH value lowa (1% of all people screened) Follow-up

Base case

Office visit Repeat serum TSH test Serum free T4 test

10,000 10,000 10,000

Lowest case

Highest case

Outcome 1: Normal—repeat serum TSH value normalb 1000 (10% of people with low screening value)

Years 2 5: follow-up serum TSH

800

200

900

Outcome 2: Subclinical hyperthyroidismb—serum TSH low and free T4 normal 8500 (85% of people with low screening value)

Serum triiodothyronine test Serum antithyroid antibody test Radioiodine tests Endocrine consultation Antithyroid treatment Radioactive iodinec Antithyroid drug treatmentd

4250 2550 2550 4250 2550 1275 1275

1700 425 850 1700 850 425 425

6800 5100 5100 6800 5950 2975 2975

25 50 100 300 350 175 175

300 400 400 500 500 250 250

Outcome 3: Overt hyperthyroidismb—serum TSH low and free T4 normal 500 (5% of people with low screening value)

Serum triiodothyronine test Serum antithyroid antibody tests Radioiodine tests Endocrine consultation Antithyroid treatment Radioactive iodinec Antithyroid drug treatmentd

150 250 250 400 450 225 225

Follow-up after any treatment started (people with either subclinical or overt hyperthyroidism) Year 1, after treatment started (all treated people)

Follow-up office visits, 3 Serum free T4 tests, 3 Serum TSH tests, 3 Hypothyroidism after radioactive iodine treatment (all treated with T4)

3000 3000 3000 750

1200 1200 1200 300

6450 6450 6450 1612

300 300

1612 1612

Years 2 and beyond Follow-up of group with hypothyroidism after radioactive iodine treatment

Lifelong T4 treatment Follow-up office visits, 2/year

750 750

TSH, Thyroid-stimulating hormone. a Prevalence data for high and low serum TSH concentrations extrapolated from Hollowell et al. (2002). b Distribution of people among overt and subclinical subgroups (and normal repeat serum TSH subgroups) estimated from Canaris et al. (2000), Vanderpump et al. (1995), and Parle et al. (1991). c Some people, given an antithyroid drug initially, would probably be given radioactive iodine in year 2 or later, but it is very uncertain what that percentage would be. d About 75% of the people, given an antithyroid drug, may receive it in year 2 and later as well. It may be discontinued with relapse of hyperthyroidism in some people, and others would be given radioactive iodine; the percentages are very uncertain.

Table 11.4 Costs of subclinical and overt hyperthyroidism. CPT codea

Cost ($)b

Screening serum TSH value low Follow-up Office visitc Repeat serum TSH test Serum free T4 test

99,213 84,443 84,439

47.18 23.47 12.60

Outcome 1: Normal (repeat serum TSH value normal) Years 2 5: Follow-up serum TSH tests

84,443

23.47

84,480 86,376 78,000 99,242

19.81 20.33 43.64 81.70

79,000

177.41 87.50

Outcomes 2 and 3: Hyperthyroidism Year 1 Serum triiodothyronine test Serum antithyroid antibody testd Radioiodine test Endocrine consultatione Antithyroid treatment Radioactive iodine Radiopharmaceutical therapyf Radioactive iodineg Antithyroid drug treatment Methimazole 10 mg/day Propylthiouracil 300 mg/day

0.685/day 1.20/day

Follow-up after any treatment started (either subclinical or overt hyperthyroidism) Year 1 Follow-up office visits,c 3 Serum free T4 tests, 3 Serum TSH tests, 3

99,212 84,439 84,443

33.57 12.60 23.47

Hypothyroidism after radioactive iodine treatment (all treated with T4) Years 2 and beyond Follow-up of group with hypothyroidism after radioactive iodine treatment in year 1 Lifelong levothyroxine treatment Follow-up office visits,c 2/year Follow-up serum TSH tests, 2/year

99,212 84,443

0.315/day 33.57 23.47

Follow-up of all other groups (euthyroid after radioactive iodine and antithyroid drug treatment) Follow-up office visits,c 3/year Follow-up serum TSH tests, 3/year Follow-up serum free T4 tests, 3/year

99,212 84,443 84,439

33.57 23.47 12.60

TSH, Thyroid-stimulating hormone. a Common Procedural Terminology codes, copyright 2003, American Medical Association. b All prices except for prescription drugs (levothyroxine, methimazole, and propylthiouracil) are from 2003 Medicare Fee Schedules (Centers for Medicare & Medicaid Services, 2003). Prescription drug prices were obtained from the DestinationRx (2003) website. c Initial office visits after a screening test is found to be positive in all groups is estimated as requiring more than minimum time, whereas later visits are minimum-time visits. d Measurement of serum antithyroid peroxidase (microsomal) antibody. e Office endocrine consultation visits are categorized as requiring 30 min for both subclinical and overt thyroid dysfunction. f Office consultation with nuclear medicine physician for radioiodine treatment. g I-131 capsules, 15 mCi dose.

252

Epidemiology of Thyroid Disorders

The burden of Graves’ disease The global burden of Graves’ disease is expensive since it is estimated to affect 2% 3% of the population and is the most common cause of hyperthyroidism. Among causes of spontaneous thyrotoxicosis, Graves’ disease is the most common. It represents 60% 90% of all causes of thyrotoxicosis in different regions of the world. In the Wickham Study conducted in the United Kingdom, the incidence was 100 200 cases per 100,000 population, annually. Hyperthyroidism due to Graves’ disease has a female-to-male ratio of between 7:1 and 8:1. This means that it affects about 2.5% of females and about 0.23% of males. In the United States, Graves’ disease causes 50% 80% of cases of hyperthyroidism. In the United States, there are about 30 new cases of Graves’ disease per 100,000 people, annually. Its prevalence is similar in Caucasians and Asians but lower in African Americans. There is a 20% concordance rate among monozygotic twins with the disease. This is lower in comparison to that of dizygotic twins. The costeffectiveness between antithyroid medications, radioactive iodine, and total thyroidectomy is considered as part of treatment of Graves’ disease. The most cost-effective therapy is total thyroidectomy, with radioactive iodine treatment being the most expensive. In the United States a cost-effectiveness study was conducted regarding optimal treatment for Graves’ disease patients who fail to achieve euthyroidism after 18 months of antithyroid medications. Findings revealed that total thyroidectomy was most cost-effective compared to radioactive iodine or lifelong antithyroid medications, until the cost of total thyroidectomy became greater than $19,300. At that point, lifelong antithyroid medications became the most cost-effective. Subtotal thyroidectomy can also be extremely cost-effective, but this is based on a 49.5% initial postoperative euthyroid rate. In the United States, prices for various forms of thyroidectomy are between $8000 and $25,000.

The burden of thyroid cancer The burden of thyroid cancer is based on it being the most common endocrine malignancy and its increase in prevalence over time. It is two to three times more common in females than in males. It also makes up 10% of malignancies in patients aged 15 29 years. The most common form is papillary thyroid cancer, making up about 80% of cases. The most aggressive form is anaplastic thyroid cancer, which only makes up about 2% of cases. Overall, however, more than 90% of patients with various forms of thyroid cancer are still alive at 10 years after diagnosis. Five-year survival is lower in patients with distant disease (56%) compared to local disease (99.7%) or regional disease (96.9%). Since recurrences of thyroid cancer have been seen even decades after initial treatment, lifelong monitoring is required.

Global impact of thyroid disorders

Costs associated with the increasing incidence of thyroid cancers are being studied. Since most are nonmetastatic but increasing in incidence, costs are expected to rise. The primary factor concerning total health-care expenditures for thyroid cancer is inpatient care, making up 43% of all costs. Radiation therapy is used in 23%, radioiodine-131 therapy in 19%, thyroid surgery in 13%, and chemotherapy in 11%. Costs totaled more than $60,000 per patient in the first year and more than $35,000 during the second year of follow-up. Newer therapies are expected to increase treatment costs further. Controlling costs while continuing to provide optimal care requires improved risk determination for low-risk patients. Current diagnostic tools must be improved in order to accurately predict which patients will do better with only minimal therapy. Future molecular genetic procedures, to detect more or less aggressive cancers, may help in the recommendation of the most appropriate therapies. Costs in the United States for thyroid cancer are estimated at being between $18 and $21 billion dollars. However, thyroid cancer research is relatively underfunded by comparison. The lifetime costs for thyroid cancer without metastasis are currently estimated at over $33,000 per patient, but with metastasis, is over $58,000. It is predicted that the sustained increase in thyroid cancer incidence will incur additional costs of $4.5 $7.5 billion over the next 10 years—this is added to the current $18 $21 billion in costs. While thyroid cancer is the seventh most common cancer in incidence in the United States, it was only the 30th most funded type of cancer research. This is because of the fact that many in the health-care profession feel that thyroid cancer is a disease with a minimal burden upon society, due to its generally high survivability. However, since recurrences are common even after many years, patients must have constant lifelong monitoring and stress from the possible return of the disease. The psychological impact of thyroid cancer has not been well-studied, but this is another considerable burden upon patients. Thyroid cancer should receive a higher priority in funding, so that there can be more research on its etiology, prevention, and improved treatment. Focus on thyroid cancer Thyroid cancer is the most common type of endocrine cancer. It is one of the few cancers, which has increased in incidence over recent years and affects people of all ages. Fortunately, for papillary and follicular thyroid carcinomas, early detection and treatment is usually highly successful. The uncommon form called anaplastic thyroid carcinoma is highly aggressive with a much poorer outcome. It is important to understand that thyroid cancers recur in up to 30% of cases.

Global costs and consequences of thyroid disorders The most common global thyroid disorders include hyperthyroidism, hypothyroidism, Hashimoto’s thyroiditis, Graves’ disease, and other forms of thyroiditis. The global thyroid disorders’ health-care market is estimated to reach $2.3 billion by 2023. Iodine

253

254

Epidemiology of Thyroid Disorders

nutrition is a key factor in determining thyroid disease risk. In developed countries, prevalence of undiagnosed thyroid disease is decreasing due to more available thyroid function testing and earlier treatments. It is important that there is continued monitoring for iodine deficiency in many developed countries, however. The prevalence of overt hyperthyroidism is between 0.2% and 1.3% in the iodine-sufficient parts of the world. The prevalence of overt hyperthyroidism is almost the same in the United States and Europe. About 1 of every 13 people in the United States has some form of diagnosed thyroid disorder. The undiagnosed prevalence rate is believed to be about 1 in 20. Globally, approximately 200 million people have thyroid disorders and more than 50% are undiagnosed. The reason for this amount of undiagnosed people may be linked to symptoms that vary and are often nonspecific, meaning that the correct diagnosis can be easily missed. Often, symptoms of hypothyroidism are mistaken for depression, menopause, or obesity. Symptoms of hyperthyroidism are often mistaken for anxiety, eating disorders, or stress. The complications of thyroid disease must also be considered. For hypothyroid conditions, complications can include birth defects, goiter, heart problems, infertility, mental health issues, and myxedema. All of these conditions have their own complications, which can potentially result in unimagined health-care costs. Complications of hyperthyroidism include arrhythmia, congestive heart failure, sudden cardiac arrest, hypertension, and osteoporosis, all of which also have their own complications and resultant costs. When thyroid disorders cause nervous system problems and nerve damage, an entire new area of complications begins. In addition, heart problems are often related to altered levels of cholesterol, which affect the process of atherosclerosis. Breathing problems, such as sleep apnea, are another area of concern since these can lead to fatalities.

Further reading 1. Agarwal, A. Atlas of Thyroid Disorders and Thyroid Surgery. (2013) Jaypee Brothers Medical Publishing. 2. Ali, S.Z., and Cibas, E.S. The Bethesda System for Reporting Thyroid Cytopathology: Definitions, Criteria, and Explanatory Notes, 2nd Edition. (2018) Springer. 3. Al-Mudhaffar, S.A., Hasan, H.H., and Hanas, H.R. Biochemical Studies on Thyroid Carcinoma. (2015) CreateSpace Independent Publishing Platform. 4. Amdur, R.J., and Mazzaferri, E.L. Essentials of Thyroid Cancer Management (Cancer Treatment and Research). (2005) Springer. 5. Bankova, S. Thyroid Eye Disease and its Healing (Graves’ Disease and Hyperthyroidism). (2010) Amazon Digital Services LLC. 6. Blanchard, K. Functional Approach to Hypothyroidism: Bridging Traditional and Alternative Treatment Approaches for Total Patient Wellness. (2012) Hatherleigh Press. 7. Boerner, S.L., and Asa, S.L. Biopsy Interpretation of the Thyroid (Biopsy Interpretation Edition), 2nd Edition. (2019) Wolters Kluwer. 8. Braunstein, G.D. Thyroid Cancer (Endocrine Updates). (2012) Springer.

Global impact of thyroid disorders

9. Brownstein, D. Iodine: Why You Need It, Why You Can’t Live Without It. (2014) Medical Alternatives Press. 10. Brownstein, D. Overcoming Thyroid Disorders, 3rd Edition. (2008) Medical Alternatives Press. 11. Cooper, D.S., and Durante, C. Thyroid Cancer: A Case-Based Approach. (2015) Springer. 12. Cox, J. Iodine: The Hidden Chemical at the Center of Your Health and Well-Being. (2016) CreateSpace Independent Publishing Platform. 13. DeVita, V.T., Rosenberg, S.A., and Lawrence, T.S. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology, 11th Edition. (2018) LWW. 14. Erickson, L.A. Atlas of Endocrine Pathology (Atlas of Anatomic Pathology). (2014) Springer. 15. Gharib, H. Thyroid Nodules: Diagnosis and Management (Contemporary Endocrinology). (2018) Humana Press. 16. Haugen, B., and Draznin, B. Thyroid Neoplasms, Volume 4 (Advances in Molecular and Cellular Endocrinology). (2005) Elsevier. 17. Heyman, A., Yang, J., and Bowthorpe, J.A. Stop the Thyroid Madness II: How Thyroid Experts are Challenging Ineffective Treatments and Improving the Lives of Patients. (2014) Laughing Grape Publishing. 18. Institute of Medicine. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Panel on Micronutrients. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. (2002) National Academies Press. 19. Kakudo, K. Thyroid FNA Cytology: Differential Diagnosis and Pitfalls, 2nd Edition. (2019) Springer. 20. Kini, S.R. Thyroid Cytopathology; An Atlas and Text, 2nd Edition. (2015) LWW. 21. McDougall, I.R. Management of Thyroid Cancer and Related Nodular Disease. (2006) Springer. 22. Miccoli, P., Terris, D.J., Minuto, M.N., and Seybt, M.W. Thyroid Surgery: Preventing and Managing Complications. (2013) Wiley-Blackwell. 23. Moore, E. The Thyroid Eye Disease Book: Understanding Graves’ Ophthalmopathy. (2013) Your Health Press. 24. Moore, E.A., and Moore, L.M. Advances in Graves’ Disease and Other Hyperthyroid Disorders (McFarland Health Topics). (2013) McFarland Publishing. 25. Lowrance, J.M. Common and Rare Thyroid Disease Complications: Secondary Problems Needing Special Attention. (2010) CreateSpace Independent Publishing Platform. 26. National Comprehensive Cancer Network. NCCN Guidelines for Patients: Thyroid Cancer. (2017) National Comprehensive Cancer Network (NCCN). 27. Nikiforov, Y.E., Biddinger, P.W., and Thompson, L.D.R. Diagnostic Pathology and Molecular Genetics of the Thyroid: A Comprehensive Guide for Practicing Thyroid Pathology. (2009) LWW. 28. Pearce, E.N. Iodine Deficiency Disorders and Their Elimination. (2017) Springer. 29. Raue, F. Medullary Thyroid Carcinoma: Biology-Management-Treatment (Recent Results in Cancer Research). (2015) Springer. 30. Smith, P.W. What You Must Know About Thyroid Disorders & What to Do About Them: Your Guide to Treating Autoimmune Dysfunction, Hypo- & Hyperthyroidism, Mood Swings, Cancer, Memory Loss, Weight Issues, Heart Problems & More. (2016) Square One. 31. Stanbury, J.B. The Iodine Trail: Exploring Iodine Deficiency and its Prevention around the World. (2008) Oxford University Press. 32. Van Nostrand, D.V., Wartofsky, L., Bloom, G., and Kulkarni, K. Thyroid Cancer: A Guide for Patients, 2nd Edition. (2010) Keystone Press, Inc. 33. Vitti, P., and Hegedus, L. Thyroid Diseases: Pathogenesis, Diagnosis, and Treatment (Endocrinology). (2018) Springer. 34. Wallace, T.C. Dietary Supplements in Health Promotion. (2015) CRC Press. 35. Wiersinga, W.M., and Kahaly, G.J. Graves’ Orbitopathy: A Multidisciplinary Approach Questions and Answers, 3rd Edition. (2017) S. Karger. 36. William, A. Medical Medium Thyroid Healing: The Truth Behind Hashimoto’s, Graves’, Insomnia, Hypothyroidism, Thyroid Nodules & Epstein-Barr. (2017) Hay House, Inc.

255

256

Epidemiology of Thyroid Disorders

37. World Health Organization Regional Office for the Eastern Mediterranean. Elimination of Iodine Deficiency Disorders: A Manual for Health Workers (Public Health). (2008) World Health Organization. 38. Yang, G.C.H. Thyroid Fine Needle Aspiration. (2013) Cambridge University Press. 39. Zaidi, S. Graves’ Disease and Hyperthyroidism: What You Must Know Before They Zap Your Thyroid with Radioactive Iodine. (2013) CreateSpace Independent Publishing Platform. 40. Zaidi, S. Hypothyroidism and Hashimoto’s Thyroiditis: A Groundbreaking, Scientific and Practical Treatment Approach, 2nd Edition. (2013) iComet Press.

CHAPTER 12

Thyroid dysfunction in pregnancy Contents Thyroid function in pregnancy Transient gestational thyrotoxicosis Graves’ disease during and after pregnancy Pregnancy and subclinical hypothyroidism Pregnancy and Hashimoto’s thyroiditis Silent lymphocytic thyroiditis Thyroid cancer during pregnancy Clinical cases Case 1 Case 2 Case 3 Case 4 Case 5 Further reading

260 261 263 265 265 267 268 271 271 271 272 273 274 275

Pregnancy affects the thyroid gland and its function in many ways because of the influences of hormones. Diagnosis and treatment of thyroid dysfunction during pregnancy, and in the postpartum period, is complicated. However, knowledge about the interaction between pregnancy and the thyroid gland has vastly improved overtime. Because of this interaction, laboratory tests of thyroid function must be interpreted very carefully. Thyroid function tests change as gestation continues, mostly from the influence of human chorionic gonadotropin (hCG) and estrogen, which is the primary female hormone. The thyroid is functioning normally if all hormones are normal throughout pregnancy. For the first part of pregnancy the fetus is totally dependent on the mother for the production of thyroid hormone. The World Health Organization recommends iodine intake of 200 µg/day while pregnant, in order to maintain adequate thyroid hormone function. The most common forms of thyroid dysfunction in pregnancy include thyrotoxicosis, Graves’ disease, subclinical hypothyroidism, Hashimoto’s thyroiditis, silent lymphocytic thyroiditis, and thyroid cancer.

Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00012-8

r 2020 Elsevier Inc. All rights reserved.

259

260

Epidemiology of Thyroid Disorders

Thyroid function in pregnancy When a woman is pregnant, there are five different influencing factors upon her thyroid gland. In the first trimester, there is a transient increase in hCG that results in stimulation of the thyrotropin receptor [thyroid-stimulating hormone (TSH) receptor (TSH-R)]. Also in the first trimester, there is an estrogen-induced increase in thyroxine-binding globulin (TBG), which continues to be at higher levels throughout pregnancy. Total serum T4 and T3 rises about 1.5 times higher in pregnant women compared to nonpregnant women (see Fig. 12.1). This is due to increased TBG concentrations in the first trimester. The pregnant woman’s immune system is altered, resulting the start, worsening, or improvement of any underlying autoimmune thyroid disease. The placenta acts to increase metabolism of thyroid hormones. The final component is increased urinary iodide excretion. This can cause impairment of thyroid hormone production in areas where there are low levels of available iodine. Any woman who consumes less than 50 µg of iodine per day is at a high risk of developing a goiter sometime during pregnancy or of giving birth to a baby who has a goiter as well as hypothyroidism. Therefore the World Health Organization recommends a daily iodine intake of 250 µg during pregnancy and prenatal vitamins that contain 150 µg of iodine per tablet. In the first trimester the increased circulating hCG levels are accompanied by a related reduction in TSH. This continues into the middle of the pregnancy and reveals that hCG binds weakly to the TSH-R. In rare cases, mothers with variant TSH-R sequences experience enhanced hCG binding and TSH-R activation. Because of hCG, changes in thyroid function can cause transient gestational hyperthyroidism. Mother TBG Total T4

hCG Free T4 Thyrotropin

0

10

20

30

40

Week of pregnancy

Figure 12.1 Changes in various critical components of the thyroid-pituitary axis during pregnancy.

Thyroid dysfunction in pregnancy

This may be related to hyperemesis gravidarum, in which there is severe nausea and vomiting, with risks of volume depletion. However, because the hyperthyroidism does not cause symptoms, antithyroid drugs are not appropriate for use, unless there is suspicion of Graves’ disease. Until the condition resolves, parenteral fluid replacement is usually adequate. In pregnancy, about 2% of women develop subclinical hypothyroidism. However, overt hypothyroidism is present in only 1 of every 500 women. Various studies have not shown any benefit for universal thyroid disease screening during pregnancy. Women who are planning to become pregnant and have a strong family history of autoimmune thyroid disease, type 1 diabetes or other autoimmune disorders, previous preterm delivery or recurrent miscarriage, or any signs or symptoms of thyroid disease should have targeted TSH testing. During pregnancy, thyroid hormone requirements are increased by as much as 50% in hypothyroid women treated with levothyroxine. Focus on thyroid dysfunction during pregnancy Gestational thyroid dysfunction is common and related to maternal and child morbidity and mortality. Profound changes in thyroid physiology occur, resulting in different TSH and free T4 reference intervals. Even very small, subclinical variations in thyroid function have to be linked to poor pregnancy outcomes, including low birth weight and loss of pregnancy. Maternal thyroid dysfunction is also associated with increased risks of hypertensive disorders, preterm delivery, and decreased intelligence quotient (IQ) of the baby.

Transient gestational thyrotoxicosis A woman who is in the later part of the first trimester often has a mild transient gestational thyrotoxicosis (GTT) or hyperthyroidism. In some women, this may be highly increased in relation to 100,000 200,000 U/L of hCG. This is often a component of twin pregnancies and often involves hyperemesis. GTT may be difficult to identify in comparison with early Graves’ disease. Therefore a TRAb test may be helpful. It measures the TSH-R antibody, also known as the thyrotropin receptor antibody, which stimulates production of T4 and T3. The receptor for this antibody is mostly found not only on the surface of thyroid epithelial cells but also on adipose tissue and fibroblasts. It is widely recommended that TRAb levels be measured at 20 24 weeks of gestation. Some patients have an inherited variant of GTT, with a mutation of the TSH-R gene that causes in a receptor protein with increased responsiveness to hCG. These patients develop hyperthyroidism with every pregnancy, due to regulation of physiologic serum hCG concentrations. The use of gonadotropins as part of in vitro fertilization, or use of a gonadotropin-releasing hormone agonist (GnRH agonist), has been linked to thyroid dysfunction. A GnRH agonist is a type of medication that affects

261

262

Epidemiology of Thyroid Disorders

gonadotropins and sex hormones. Early recognition, accurate diagnosis, and appropriate treatment of thyrotoxicosis during pregnancy are important to decrease risks of adverse maternal and fetal outcomes. Thyrotoxicosis during pregnancy is suggested by a suppressed serum TSH level. The prevalence of gestational thyrotoxicosis, in the United States, is between 0.2% and 0.7% of pregnant women. In Europe, it is more prevalent, between 2% and 3%, and in one Asian study, it reached the highest level yet, 11% of those surveyed. Differential diagnoses of GTT include subtypes of overt hyperthyroidism, including Graves’ disease, toxic multinodular goiter, and toxic adenoma, as well as thyroiditis and exogenous thyroid hormone use. A rare cause of thyrotoxicosis in pregnancy is trophoblastic disease. Signs and symptoms include anxiety, heat intolerance, tremor, palpitations, weight loss or lack of weight gain, goiter, hyperreflexia, and tachycardia. It is important to distinguish between GTT and intrinsic hyperthyroidism. Maternal complications of GTT include preterm delivery, hypertension, miscarriage, and heart failure. It also increases risks for induced labor, preeclampsia, and the need for maternal intensive care after delivery. Most of the time, this condition is self-limited. However, risks for birth defects mean that antithyroid drugs should not be used in early pregnancy. In rare cases, low doses of propylthiouracil, at 100 200 mg/day or less, may be needed for several weeks, until the hCG level reduces on its own. The patient may be able to be switched to methimazole after the first trimester, but it cannot be used in the first trimester since it is linked to rare congenital abnormalities during embryogenesis. These include aplasia cutis, omphalocele, esophageal atresia, and symptomatic omphalomesenteric duct anomaly. Other defects occur in the upper airways (choanal atresia), urinary system, eyes (dysmorphic astigmatism), and as a ventricular septal defect of the heart (see Fig. 12.2). In early pregnancy, about 1 of every 30 women exposed to carbimazole or methimazole will give birth to children who have medication-related defects. This number is in addition to the risks in the general population, which are at 5%, for having children with birth defects diagnosed before the age of 2 years. Also, propylthiouracil has teratogenic effects, which occur in about 1 of every 40 births. The abnormalities are usually less severe than with methimazole and include urinary abnormalities and preauricular sinuses and cysts. When the infant begins breastfeeding, antithyroid drugs are considered safe and can be used in moderate doses. They should be given in divided doses immediately following each feeding. The breastfeeding infant must be monitored for development of thyroid dysfunction. For pregnant women who are unable to tolerate antithyroid medications, require large doses, or are nonadherent, thyroidectomy is the definitive treatment option. It is safest during the second trimester but can still cause complications such as a higher rate of hypoparathyroidism, recurrent laryngeal nerve injury, and general surgical complications. Use of radioiodine (I-131) during pregnancy is contraindicated, but it can be used prior to conception. Appropriate treatment of maternal

Thyroid dysfunction in pregnancy

Figure 12.2 Examples of methimazole embryopathy: (A) Dysmorphic astigmatism. (B) Aplasia cutis. Source: (From Bowman P, Osborne NJ, Sturley R, et al. Carbimazole embryopathy: implications for the choice of antithyroid drugs in pregnancy. Q J Med. 2012; 105: 189 193.)

hyperthyroidism during pregnancy and close monitoring of both mother and baby are essential. Treatment is focused on achieving serum TSH concentrations that are within established ranges during pregnancy.

Graves’ disease during and after pregnancy Actual overactivity of the thyroid gland is not common in established pregnancies. It affects only about 0.2% of pregnant women but is seen more often in clinical practice. The reason for this low rate of incidence is that pregnancy usually suppresses autoimmune responses. Also, Graves’ disease is the most common cause of thyrotoxicosis in younger women. The mechanisms of immunosuppression in pregnancy that lead to immune privilege involve the mother’s peripheral immune system and the mother-tofetus relationship, via interactions between trophoblasts and immune cells. In the mother’s peripheral immune system, regulatory T cells suppress fetal-reactive immune cells. Sex steroids affect the immune system, negatively regulating B cells. Between mother and fetus, apoptosis is induced in activated T cells via Fas expression on the trophoblast cells. Proliferation of T cells is inhibited by local chemokines and cytokines. Natural killer cells are inhibited by the expression of human leukocyte antigen G. Finally, the complement system is inactivated. In addition, although thyrotoxicosis has many negative influences upon fertility, it is also related to increased losses of pregnancy and serious medical problems for the

263

264

Epidemiology of Thyroid Disorders

mother and infant if the condition continues. Most often, a women who is being treated for hyperthyroidism becomes pregnant, but no matter in what order these occur, pregnancy will complicate the diagnosis and treatment of hyperthyroidism in Graves’ disease, affecting its course and severity. The immune system is highly influenced by the changes of pregnancy and the growth of the placenta. Overall suppression of autoimmune responses is mediated by placental factors. This allows the fetus, with its 50% paternal antigens, to survive assault from immune system factors. Therefore maternal fetal tolerance is promoted. However, increased effects of regulatory T cells and their suppression of the mother’s responses to the fetus, are believed to be the primary and longest acting component. Major shifts in T-cell control reduce effects of all inflammatory T cells. Possible symptoms of Graves’ disease during pregnancy include goiter, insomnia, hand tremors, tachycardia, frequent bowel movements, fatigue, muscle weakness, weight loss, irritability, heat intolerance, and increased sweating. Graves’ ophthalmopathy develops in some women. Reddening or thickening of skin, usually on the feet and shins, may occur. Potential factors for Graves’ disease include family history, stress, and infections. The disease can cause fetal thyroid abnormalities, brain development problems, low birth weight, preterm birth, preeclampsia, placental abruption, and miscarriage. Treatment is based on symptom occurrence, which is usually in the first and third trimesters. Thyroid hormone monitoring is indicated, and medications include propylthiouracil first, followed by methimazole. Beta-blockers may be needed during the first few weeks to reduce symptoms. Regular ultrasound monitoring is very helpful. When Graves’ disease worsens during pregnancy, severe hyperthyroidism known as thyroid storm may develop. Symptoms include dehydration, diarrhea, fever, fast and irregular heartbeat, and shock. Since thyroid storm can be fatal, it is extremely important to seek emergency care immediately if any of these symptoms develop. After delivery, Graves’ disease symptoms usually worsen during the first 3 months. Both methimazole and propylthiouracil cross into the breast milk. Therefore physicians usually recommend limiting doses and monitor thyroid function of both mother and baby for several months. Mothers with remission from Graves’ disease are still at risk for symptoms returning up to 1 year following delivery. Focus on Graves’ disease in pregnancy Untreated or poorly treated Graves’ disease during pregnancy can cause preeclampsia, premature birth, placental abruption, miscarriage, and heart failure. For the fetus, it can cause tachycardia, low birth weight, birth defects, thyroid problems, and stillbirth. Pregnant woman should see an endocrinologist and cannot receive radioiodine therapy. Antithyroid medications may be indicated, and propylthiouracil is safe throughout pregnancy. Treatment often changes during pregnancy, with symptoms usually being worse in the first trimester.

Thyroid dysfunction in pregnancy

Pregnancy and subclinical hypothyroidism Subclinical hypothyroidism shows biochemical signs of thyroid hormone deficiency, while the patient has no obvious clinical signs and symptoms of hypothyroidism, or only a few signs and symptoms. Subclinical hypothyroidism has no accepted methods of management. However, levothyroxine is recommended for women who want to become pregnant or those who already are pregnant. It is also indicated when TSH levels are higher than 10 mIU/L. If TSH levels are less than 10 mIU/L, treatment is considered if the patient has symptoms suggesting hypothyroidism, positive thyroid peroxidase [TPO antibodies (TPO-Ab)], or signs of heart disease. Any TSH elevation must be confirmed as sustained more than a 3-month period before starting treatment. Slightly increased TSH is of no concern as long as excessive treatment is avoided. Treatment begins with a low dose of levothyroxine, between 25 and 50 µg/day, aimed at normalizing TSH. If the drug is not given, thyroid function must be evaluated every year. Women who have a history or a high risk of hypothyroidism must ensure that they are euthyroid before becoming pregnant, and in early pregnancy, since maternal hypothyroidism can negatively affect fetal neural development, and cause preterm delivery. In euthyroid women the presence of thyroid autoantibodies is all that is required to potentially cause miscarriage or preterm delivery. It is not fully understood if levothyroxine therapy will improve these outcomes. Once pregnancy is confirmed, thyroid function must be evaluated immediately. It must be reevaluated every 4 weeks during the first half of pregnancy. After 20 weeks of gestation, testing can be less frequent, performed every 6 8 weeks based on whether levothyroxine dose adjustment is continuing. Doses may need to be increased by as much as 50% while the pregnancy is ongoing. The goal is TSH lower than 2.5 mIU/L in the first trimester and lower than 3 mIU/L in the second and third trimesters. When the baby is delivered, thyroxine doses usually return to their prepregnancy levels. Pregnant women must be counseled about taking prenatal vitamins and iron supplements 4 hours or more apart from levothyroxine doses.

Pregnancy and Hashimoto’s thyroiditis Hashimoto’s thyroiditis is, along with Graves’ disease, one of the most common causes of maternal hypothyroidism. It is widely associated with thyroglobulin antibody (TgAb) and TPO-Ab during pregnancy. Both of these types of autoantibodies exist in nearly 100% of patients, though TPO-Ab has higher affinity. It occurs in larger concentrations. Therefore testing for TPO-Ab is more helpful. Maternal immune suppression in pregnancy often resolves Hashimoto’s thyroiditis. However, hypothyroidism or hyperthyroidism that requires treatment may develop.

265

266

Epidemiology of Thyroid Disorders

It is important that every woman receives thyroid testing before trying to conceive. They must receive a full thyroid panel that includes free T4, free T3, reverse T3, TPO-Ab, and Tg-Abs. Some women with Hashimoto’s thyroiditis test negative for thyroid antibodies. This is because their overall immune health is extremely weakened and not enough antibodies are produced. A thyroid ultrasound is indicated. Treated hypothyroid patients who are receiving thyroid hormone replacement medication, and planning to conceive, must have their dose adjusted to optimize serum TSH values (less than 2.5 mIU/mL). Lower preconception TSH levels, within the nonpregnant reference range, reduce risks of TSH elevation in the first trimester. Possible underlying causes for Hashimoto’s thyroiditis include nutritional deficiencies, low iron levels, gluten and other food intolerances or sensitivities, dysfunction of the adrenal glands, abnormal sex hormone levels, bacterial and viral infections, heavy metal toxicity, Candida infections, gastrointestinal leakage, and blood sugar imbalances. These must be tested for and treated. If conception is difficult, fertility testing is indicated. When untreated autoimmune conditions, including Hashimoto’s thyroiditis, are present, the patient is more vulnerable to other autoimmune conditions. After the body has attacked its own tissues in one location, it is likely to attack the reproductive tissues and even the embryo. The three major immunological fertility tests include antiphospholipid antibodies, natural killer cells, and antinuclear antibodies. Pregnancy should be confirmed as early as possible. The mother should not wait for a missed period to test for pregnancy or for the first prenatal visit with her physician. Most practitioners do not schedule the first prenatal visit until 8 weeks of pregnancy—this is too long to wait for thyroid testing. It must occur as soon as pregnancy is confirmed. There must also be regular monitoring of the thyroid throughout pregnancy. Trimester-specific ranges for TSH are as follows: • First trimester: 0.1 2.5 mIU/mL • Second trimester: 0.2 3 mIU/mL • Third trimester: 0.3 3 mIU/mL For pregnant patients with treated hypothyroidism, maternal serum TSH must be monitored every 4 weeks in the first half pregnancy, because further dose adjustments are often needed. Also, maternal TSH should be checked at least once between 26 and 32 weeks of gestation. Hashimoto’s thyroiditis can cause significant TSH increases and decreases. For the safety of the baby, there must be rigid monitoring of the signs of hypothyroidism and hyperthyroidism.

Thyroid dysfunction in pregnancy

Focus on Hashimoto’s thyroiditis in pregnancy Hashimoto’s thyroiditis may affect the ability to conceive, develops very slowly during pregnancy, and can cause serious complications, including heart attack, coma, and death. It is quickly diagnosed by simple blood testing. It is genetically linked, extremely treatable, of uncertain cause, and sometimes can lead to thyroid cancer. The obvious signs and symptoms include facial puffiness, paleness, thinning hair, and more weight gain than is normal during pregnancy.

Silent lymphocytic thyroiditis Silent lymphocytic thyroiditis is also called painless thyroiditis. It develops in patients with underlying autoimmune thyroid disease. Its development is similar to the way that subacute thyroiditis evolves. Silent lymphocytic thyroiditis occurs in as many as 10% of women, 2 12 months following pregnancy. At that time, it is referred to as postpartum thyroiditis. The term “silent” refers to the lack of thyroid tenderness. In most cases the patient has a brief phase of thyrotoxicosis that lasts for 2 8 weeks. Then, hypothyroidism develops, lasting for 2 12 weeks before resolving. In many cases, only one phase is clinically apparent. There are TPO-Abs present antepartum, and the condition is three times more common in women who have type 1 diabetes. Less often, antiTg-Abs may be present in pregnancy and postpartum. Also similar to subacute thyroiditis, uptake of 99mTc pertechnetate or radioactive iodine is suppressed at first. Along with a painless goiter, silent lymphocytic thyroiditis is different from subacute thyroiditis because of a normal erythrocyte sedimentation rate and the presence of TPO-Abs. Nonspecific symptoms of thyrotoxicosis include anxiety, insomnia, and weight loss. Many women are diagnosed once they become hypothyroid, which is signified by depression and fatigue. Often, the complaints of thyrotoxic and hypothyroid symptoms are overlooked or considered normal postpartum components. The thyroid gland will not be tender, and either of normal size, or slightly enlarged. Because of the presence of the TPO and/or anti-Tg-Ab, silent lymphocytic thyroiditis may be a variant of Hashimoto’s thyroiditis. It is often undiagnosed and does not cause eye abnormalities or pretibial myxedema. Diagnosis can be easily confirmed or excluded by laboratory testing. Thyroid function tests are different in the various stages of the condition. At first, serum T4 and T3 are increased while TSH is suppressed. This reverses in the hypothyroid phase. White blood cell count, such as the erythrocyte sedimentation rate, is normal. Silent lymphocytic thyroiditis must be distinguished from Graves’ disease, which can also occur in the same time period following delivery.

267

268

Epidemiology of Thyroid Disorders

Relative levels of thyroid hormone elevation can reveal which condition is present. This condition is usually characterized mostly by increased thyroxine. Needle biopsy provides diagnosis but is usually not needed. When biopsy of thyroid tissue occurs, there will be lymphocytic infiltration that is similar to what occurs in Hashimoto’s thyroiditis. However, there will not be lymphoid follicles or scarring. Glucocorticoids, antithyroid drugs, radioiodine therapy, and surgery are not indicated for silent lymphocytic thyroiditis. If there are severe thyrotoxic symptoms, treatment involves a short course of a beta-blocker such as propranolol, at 20 40 mg, three to four times per day. For the hypothyroid phase, if overt, thyroxine replacement may be required. However, this must be withdrawn after 6 9 months. After this, annual follow-up should occur since some patients develop permanent hypothyroidism. While most patients eventually return to a euthyroid state, about one in four develop persistent hypothyroidism caused by classic autoimmune thyroiditis. In subsequent pregnancies, silent lymphocytic thyroiditis can recur. Focus on silent lymphocytic thyroiditis Silent lymphocytic thyroiditis is most common in postpartum. It is a common cause of transient hyperthyroidism and is often confused with subacute thyroiditis due to many similar symptoms. Its hallmark features include lack of thyroid pain or tenderness and a greatly reduced radioactive iodine uptake. It begins with hyperthyroidism, followed by hypothyroidism. Women of all ethnic and racial groups are affected.

Thyroid cancer during pregnancy Thyroid cancer is the most common endocrine malignancy and is often seen in young, female patients. Approximately 10% of thyroid cancers that occur during a woman’s reproductive years are diagnosed during pregnancy, or in the early postpartum period. Thyroid cancer has a prevalence of 3.6 14 of every 100,000 live births in the United States. Fortunately, differentiated thyroid cancer in younger women usually has an excellent prognosis. In diagnosed women, survival rates are not very different from those of nonpregnant women with thyroid cancer who are of the same age. When thyroid cancer is detected during pregnancy, the concerns are when treatments should take place, and how to manage the health of both mother and baby. Differentiated thyroid cancer, which arises from the follicular thyroid cells, includes follicular as well as papillary cancer. These forms usually have an overall 90% 95% long-term disease-free survival rate, when tumors are early stage or low risk. Differentiated thyroid cancers, with or without lymph node invasion, for patients under the age of 45 years, are classified as Stage I tumors. Usually, pregnant patients are below this age. Gene expression in thyroid cancer is usually extremely consistent,

Thyroid dysfunction in pregnancy

but tumors may also develop via fetal cell carcinogenesis, based on which cancer cells derive from remnants of fetal thyroid cells, or from stem cells instead of differentiated follicular cells. Medullary thyroid cancer arises from the parafollicular thyroid cells. It makes up 5% 10% of thyroid cancers, but there are no accurate figures for incidence and survival. This is because it varies widely between different countries, due to its often familial pattern. Familial cases make up about 30% of medullary thyroid cancers. Diagnosed patients must be suspected of carrying the genetic form. Prior to thyroidectomy, patients must be evaluated for presence of related conditions such as pheochromocytoma. Screening of the patient’s relatives enables an earlier diagnosis. This may reduce the amount of surgery required as well as recurrences. Biochemical screening consists of serum calcitonin evaluation, and genetic screening of family members with a rearranged during transfection mutation may be performed. Medullary lesions are visible in echography as solid masses that often have calcifications. Fine-needle aspiration will reveal round, polyhedral (having multiple angled surfaces), and also spindle-shaped cells that may appear undifferentiated or resemble extracellular amyloid. Follow-up of these patients to check for recurrence utilizes the somatostatin analog called octreotide. Medullary thyroid cancers are more aggressive than other types, and total thyroidectomy is usually performed. There are three primary objectives in the clinical monitoring of pregnant thyroid cancer patients. These include the following: • Reaching a balance of maternal calcium and thyroid hormones, which is required by the fetal central nervous system for normal maturation • Maintaining optimal levels of maternal thyroxine to avoid recurrence or spread of the disease • Performing safe follow-ups to plan for further therapy when it is needed For patients receiving suppressive or substitutive thyroxine therapy, fetal thyroid growth is shown to be normal in ultrasound studies. Newborn thyroid status is also normal. Incidence of maternal morbidity is not affected by the pregnancy. It is highly important to adjust levothyroxine and calcium therapies as needed. However, the primary difference in treating thyroid cancer in pregnant women, as compared to nonpregnant women, is that radioactive iodine is contraindicated due to potential fetal harm. The best treatment for almost all identified malignant thyroid neoplasms is surgery. Adequate excision of the primary tumor and any locoregional extension is the surgical goal. Based on extent of the disease, hemithyroidectomy or radical thyroidectomy is undertaken. Lymphatic node spreads are relatively common. Therefore initial surgical exploration must include close examination of the central compartment nodes, termed the paratracheal and tracheoesophageal nodes, along with dissection of clinically suspicious nodes so that they can be frozen and sectioned for examination. If there is nodal involvement, total thyroidectomy and modified radical neck dissection are indicated. Adjuvant therapies include thyroid hormones and

269

270

Epidemiology of Thyroid Disorders

radioactive iodine. After surgery, oral doses of levothyroxine are used as needed. The goal for basal serum TSH should be 0.1 0.4 mIU/L. After radical thyroidectomy, nonpregnant patients can also receive radioactive iodine to destroy occult microscopic carcinoma in remaining thyroid tissues. Follow-ups to surgery are based on the stage of the disease and the extent of the surgery that was performed. Neck ultrasound is essential, along with serum assay for human thyroglobulin (HTG) and HTG antibodies, free thyroxine, and TSH. Nonpregnant patients also require an iodine-131 scan and serum HTG measurements. Neck ultrasound is the best follow-up method of these and should be followed by a detailed physical examination and, sometimes, ultrasound-guided fine-needle aspiration. It is used to confirm any clinical suspicion of neck recurrence. This procedure is safe even in pregnant patients. Although thyroid cancer in pregnancy can have a faster growth rate, based on hormonal factors, the overall impact of pregnancy upon the disease is minimal. No metastases of differentiated thyroid cancer to the placenta or fetus have ever been reported. During pregnancy, cellular immunity changes, with decreased T cells. Pregnant women with thyroid cancer have favorable outcomes, regardless of the timing of the diagnosis. For patients with no prior history of cancer, surgery can be safely performed during the second trimester, or delayed until after delivery, without worsening prognosis. There are no indications for termination of the pregnancy. Surgery is not done during the first trimester since general anesthetics have some teratogenic potential and can increase risks for miscarriage. In third trimester, surgery can induce premature labor. Postponing surgery to at least 6 months after differentiated thyroid cancer diagnosis does not adversely affect prognosis. Thyroxine is started immediately after surgery, since untreated hypothyroidism can expose the mother to a higher risk of recurrence and may affect the baby’s cognitive function and growth. TSH and free thyroxine levels are assessed every 6 8 weeks during pregnancy and breastfeeding. Radioiodine therapy, if needed, is postponed until after breastfeeding. Pregnant women with a history of previously treated differentiated thyroid cancer but no recurrence can be treated without any extensive problems. For pregnant women with evidence of persistent or recurrent thyroid cancer, even with therapy, surgery is scheduled based on ultrasound results. After surgery, thyroxine therapy is focused on suppressing pituitary TSH secretion, as indicated by serum TSH levels under 0.05 mIU/L. Doses of levothyroxine higher than 150 200 µg (at least 2 µg/ kg/day) are usually required. Dosage often needs to be increased as early as the fifth week of gestation. Monitoring of free thyroxine and TSH should be done every 6 weeks for adequate dosage adjustment. After delivery, thyroxine can be gradually reduced to prepregnancy levels. TSH levels must be constantly monitored. For medullary thyroid cancer, when tumors are not TSH-dependent because they are not

Thyroid dysfunction in pregnancy

derived from C cells, thyroxine replacement therapy after surgery is given. Dosages are the same as those used to treat hypothyroidism. Doses of thyroxine and ferrous sulfite must be spaced apart by at least four hours, in order to assure proper absorption.

Clinical cases Case 1 1. How is this patient’s condition differentiated from Graves’ disease? 2. Which medications are effective to control the related hypermetabolic symptoms? 3. What are the difficulties in identifying transient gestational thyrotoxicosis? A 24-year-old woman, who has been pregnant for 12 weeks, was taken to the emergency department with abdominal pain, vomiting, and vaginal bleeding. She reported having two previous spontaneous fetal losses. Examination revealed tachycardia, no goiter, and stability of other vital signs. Pelvic scan suggested a molar pregnancy with an ovarian cyst. Thyroid function tests showed free thyroxine higher than 100 pmol/L. She was treated with propranolol, neomercazole, iodine, and supportive care. Unfortunately, 9 days later, she lost the pregnancy. Answers: 1. Women with transient gestational thyrotoxicosis can be differentiated from those with Graves’ disease by the lack of goiter and negative antithyroid antibodies of which the titer decreases from midtrimester onwards. Since gestational thyrotoxicosis is mediated by hCG, no thyroid antibodies should be present. Hyperthyroidism is transient and self-limiting. 2. Beta-blockers are effective for controlling the hypermetabolic symptoms. They may be used along with thionamides until symptoms are resolved. Propylthiouracil and carbimazole are similarly effective in blocking thyroid hormone synthesis. 3. Transient gestational thyrotoxicosis may be difficult to identify because the increase in cardiac output, tachycardia, skin warmth, and heat intolerance that are common in pregnancy can mimic hyperthyroidism.

Case 2 1. What is the likelihood that Graves’ disease will cause fertility problems? 2. What are the common menstrual disturbances related to this patient’s condition? 3. During pregnancy, why is it important to achieve rapid, adequate control of Graves’ disease? A 38-year-old woman with history of Graves’ disease for 7 years visited her physician at the 21st week of her first pregnancy. She was on long-term carbimazole (10 mg/day) and was clinically euthyroid. Thyroid function tests showed subclinical hyperthyroidism,

271

272

Epidemiology of Thyroid Disorders

with free thyroxine of 19.6 pmol/L (high normal), free triiodothyronine of 5.2 pmol/L (normal), and TSH of 0.05 mIU/L (which was lower than the normal range). Her TRAbs assay was negative, and this continued throughout the pregnancy. The baby was delivered normally without complications, and the patient continued on carbimazole. In a few months, she became pregnant once again but had symptoms of thyrotoxicosis. Thyroid function tests revealed her free thyroxine levels to be five times higher, her free triiodothyronine levels to be six times higher, and her TSH levels to be extremely low. Answers: 1. Graves’ disease and its hyperthyroid state are generally associated with fertility, though there is limited and conflicting evidence of this. It is surprising in this case study that the patient never had menstrual disturbances and, while thyrotoxic, was able to become pregnant twice. 2. Menstrual disturbances with Graves’ disease include mostly amenorrhea, oligomenorrhea, and hypomenorrhea. These occur in 21% 65% of women with hyperthyroidism. According to endometrial biopsies, most hyperthyroid women, however, still remain ovulatory. 3. It is important to achieve control of Graves’ disease during pregnancy because thyrotoxicosis is associated with adverse events for the mother as well as the fetus. Sporadic cases of medication-resistant thyrotoxicosis have been reported. Outcomes of thyrotoxicosis include heart failure, tracheal compression, infections, and thrombocytopenia (abnormally low levels of platelets). Other outcomes include fetal tachycardia, goiter, ascites, craniosynostosis (premature fusion of the skull sutures), fetal growth retardation, maceration (excessive skin moisture), and hydrops (accumulation of fluid in at least two fetal compartments).

Case 3 1. What is the primary cause of hypothyroidism during pregnancy? 2. Why must maternal iodine intake be increased during pregnancy? 3. Can subclinical hypotension cause placental abruption, preterm labor, and also gestational hypertension? A 21-year-old pregnant woman was seen by her physician with symptoms of hypothyroidism. Tests revealed positive TPO antibodies. She was given thyroxine replacement as a measure to prevent early pregnancy preterm delivery. Answers: 1. The primary cause of hypothyroidism during pregnancy may be either iodine deficiency or chronic autoimmune thyroiditis. Additional causes include radioiodine ablation or surgery for hyperthyroidism, congenital hypothyroidism, thyroid tumor surgery, and, rarely, lymphocytic hypophysitis.

Thyroid dysfunction in pregnancy

2. During pregnancy, thyroid hormone synthesis increases by 20% 40%, compensating for estrogen-induced thyroid-binding globulin and for increased iodine clearance. Therefore maternal iodine intake must be increased during pregnancy. 3. Yes, subclinical hypothyroidism causes placental abruption three times more often than when the condition is not present. It causes preterm labor 1.8 times more often. Subclinical hypothyroidism also is responsible for gestational hypertension, while 36.1% of women with overt hypothyroidism will develop gestational hypertension. Mild or overt hypothyroidism causes preterm delivery in 80% of pregnancies.

Case 4 1. How often must pregnant women with Hashimoto’s thyroiditis be monitored in relation to their TSH levels? 2. Approximately how much addition thyroid hormone therapy may be required by pregnant women with Hashimoto’s thyroiditis? 3. What are the trimester-specific reference ranges for TSH in pregnant women? A 19-year-old woman with history of Hashimoto’s thyroiditis became pregnant. Thyroid function tests were ordered during her first trimester, at week 6. The patient was well educated about her condition and requested a blood thyroid panel, including TSH, free T4, and free T3. As a result of the effects of pregnancy, her TSH had increased from 1 to 9, and her T3 and T4 were lower than before. Her thyroid hormone treatments were increased by about 50% to stabilize her levels. This successfully managed her condition and her pregnancy went to full term without any problems. Answers: 1. In pregnant patients with treated Hashimoto’s thyroiditis, maternal serum TSH should be monitored approximately every 4 weeks during the first half of pregnancy. This is because further dose adjustments are often required. Later, it should be checked at least once between 26 and 32 weeks gestation. 2. The amount of increased thyroid treatment necessary to maintain a normal TSH throughout pregnancy is extremely varied between individuals. Some women require only a 10% 20% increase. Others may require up to an 80% increase. 3. In the first trimester, TSH should be between 0.1 and 2.5 mIU/mL. In the second trimester, they should be between 0.2 and 3 mIU/mL. In the third trimester, they should be between 0.3 and 3 mIU/mL.

273

274

Epidemiology of Thyroid Disorders

Case 5 1. What are the risk factors increasing a woman’s chance of developing postpartum thyroiditis? 2. What is the recurrence rate for this condition? 3. Is there a direct link between postpartum and silent thyroiditis? A 35-year-old pregnant woman had a history of hyperthyroidism. She was referred to as thyroid clinical for treatment of her condition. Her previous treatments were with propylthiouracil. Thyroid function tests were initially in the normal range. Since she was in the second trimester, her medication was switched to methimazole. She remained euthyroid in the postpartum period and had negative thyroid-stimulating immunoglobulin, which meant that the methimazole had to be stopped. Five months later, she was diagnosed with postpartum thyroiditis, manifesting with palpitations and tremors. Neck examination did not reveal tenderness or thyroid enlargement. A new thyroid panel revealed suppressed TSH and elevated free T4 and T3, plus her thyroglobulin was elevated. Symptomatic treatment was started with propranolol. This was effective for 2 months, after which she reverted back to her euthyroid state. Then, 11 months later, she developed episodes of recurrent thyroiditis. Answers: 1. Women with thyroid peroxidase antibodies in early pregnancy have a 30% to 50% chance of developing postpartum thyroiditis. The titer of thyroid peroxidase antibodies is a predictor of the severity of postpartum thyroiditis and possible disease recurrence. Women with a past history of thyroid disease have a 40% risk of developing postpartum thyroiditis, while those with type 1 diabetes or a family history of thyroid disease have only a 20% risk. 2. In women with positive thyroid peroxidase antibodies who recover from postpartum thyroiditis, for subsequent pregnancies, there is a 70% recurrence rate. Although clinical features of silent thyroiditis are similar to postpartum thyroiditis, recurrence rates are much lower (5% 10%). The largest number of recurrences ever occurring in a single patient is nine. 3. It is not clear if there is a direct link between postpartum and silent thyroiditis. It is understood however that postpartum thyroiditis may be followed by episodes of silent thyroiditis, but this is relatively uncommon.

Key terms 99m

Tc pertechnetate antinuclear antibodies aplasia cutis chemokines cytokines

echography embryogenesis euthyroid Fas expression GnRH agonist

Thyroid dysfunction in pregnancy

human chorionic gonadotropin human leukocyte antigen G (HLA-G) hyperemesis hyperemesis gravidarum hypoparathyroidism intrinsic hyperthyroidism octreotide omphalomesenteric duct anomaly pheochromocytoma placental abruption

preeclampsia pretibial myxedema RET mutation silent lymphocytic thyroiditis teratogenic thyroid peroxidase antibodies thyroxine-binding globulin TRAb test trophoblastic disease trophoblasts

Further reading 1. Adams Media. Thyroid Disease at Different Ages: The Most Important Information You Need to Improve Your Health (The Everything Healthy Living Series). (2012) Adams Media. 2. Ain, K., and Rosenthal, M.S. The Complete Thyroid Book, 2nd Edition. (2010) McGraw-Hill Education. 3. Ali, S.Z., and Cibas, E.S. The Bethesda System for Reporting Thyroid Cytopathology: Definitions, Criteria, and Explanatory Notes, 2nd Edition. (2018) Springer. 4. Bercu, B.B., and Shulman, D.I. Advances in Perinatal Thyroidology (Advances in Experimental Medicine and Biology, Volume 299). (1992) Springer. 5. Bernstein, C., and Takoudes, T.C. Medical Problems During Pregnancy: A Comprehensive Clinical Guide. (2017) Springer. 6. Brook, K. A Guide Through Your Hyperemesis Pregnancy: For Women With Uncontrolled Nausea and Vomiting During Pregnancy. (2018) Krystal Brook. 7. Chian, R.C., Nargund, G., and Huang, J.Y.J. Development of In Vitro Maturation for Human Oocytes: Natural Approaches to Clinical Infertility Treatment. (2017) Springer. 8. Cole, L.A. Human Chorionic Gonadotropin (hCG), 2nd Edition. (2014) Elsevier. 9. Dean, C., and Shortman, A. Hyperemesis Gravidarum The Definitive Guide. (2014) Spewing Mummy. 10. Eaton, J.L. Thyroid Disease and Reproduction: A Clinical Guide to Diagnosis and Management. (2019) Springer. 11. Hancock, E. Thyroid Management Journal: Track Your Symptoms, Energy Levels, Fatigue, Medications, Blood Results and More! (2019) Hancock. 12. Heyden, E.L. Preventing Birth Defects: Understanding the Iodine/Thyroid Hormone Connection. (2014) Impact Health Publishing. 13. Hiepe, F., Burmester, G.R., and Dorner, T. Antinuclear Antibodies (International Archives of Allergy and Immunology). (2000) Karger. 14. Hui, P. Gestational Trophoblastic Disease: Diagnostic and Molecular Genetic Pathology (Current Clinical Pathology). (2012) Humana Press. 15. Imam, S.K., and Ahmad, S. Thyroid Disorders: Basic Science and Clinical Practice. (2016) Springer. 16. Leveno, K.J., Corton, M.M., and Bloom, S.L. Williams Manual of Pregnancy Complications, 23rd Edition. (2012) McGraw-Hill Education/Medical. 17. Levine, M.A. Hypoparathyroidism, An Issue of Endocrinology and Metabolism (The Clinics: Internal Medicine). (2018) Elsevier. 18. Loriaux, L. Endocrine Emergencies: Recognition and Treatment (Contemporary Endocrinology). (2014) Humana Press.

275

276

Epidemiology of Thyroid Disorders

19. Lougheed, B.S. Tired Thyroid: From Hyper to Hypo to Healing Breaking the TSH Rule. (2014) CreateSpace Independent Publishing Platform. 20. Luster, M., Duntas, L.H., and Wartofsky, L. The Thyroid and Its Diseases: A Comprehensive Guide for the Clinician. (2019) Springer. 21. Matfin, G. Endocrine and Metabolic Medical Emergencies: A Clinician’s Guide. (2014) Endocrine Press. 22. Minagar, A. Neurological Disorders and Pregnancy (Elsevier Insights). (2010) Elsevier. 23. Millinga, F., Aboud, S., and Mbugi, E. Human Leukocyte HLA-B7and HLA-B27 Antigen Typing Among Healthy Adults. (2018) Lap Lambert. 24. Misra, S. Thyroid Dysfunction and Pregnancy (ECAB Clinical Update: Obstetrics and Gynecology). (2012) Elsevier. 25. Myers, A. The Thyroid Connection: Why You Feel Tired, Brain-Fogged, and Overweight and How to Get Your Life Back. (2016) Little, Brown and Company. 26. Net, C.E., and Delong, M.F. Thyroid Dysfunction. (2018) Amazon Digital Services LLC. 27. Nikiforov, Y.E., Biddinger, P.W., and Thompson, L.D.R. Diagnostic Pathology and Molecular Genetics of the Thyroid: A Comprehensive Guide for Practicing Thyroid Pathology, 3rd Edition. (2019) LWW. 28. Osansky, E.M. Hashimoto’s Triggers: Eliminate Your Thyroid Symptoms by Finding and Removing Your Specific Autoimmune Triggers. (2018) Natural Endocrine Solutions. 29. Posner, G.D., Black, A.Y., Jones, G.D., and Dy, J. Oxorn-Foote Human Labor and Birth, 6th Edition. (2013) McGraw-Hill Education/Medical. 30. Robinson, P. The Thyroid Patient’s Manual: Recovering From Hypothyroidism From Start to Finish. (2018) Elephant in the Room Books. 31. Saito, S. Preeclampsia: Basic, Genomic, and Clinical (Comparative Gynecology and Obstetrics). (2018) Springer. 32. Schreiber, R. Cytokines: From Basic Mechanisms of Cellular Control to New Therapeutics (Perspectives CSHL). (2018) Cold Spring Harbor Laboratory Press. 33. Smith, P.W. What You Must Know About Thyroid Disorders & What to Do About Them. (2016) Square One. 34. Thorpe-Beeston, J.G., and Nicolaide, K.H. Maternal and Fetal Thyroid Function in Pregnancy (Frontiers in Fetal Medicine Series). (1995) CRC Press. 35. Trentini, D., and Shomon, M. Your Healthy Pregnancy With Thyroid Disease: A Guide to Fertility, Pregnancy, and Postpartum Wellness. (2016) Da Capo Lifelong Books. 36. Tschammer, N. Chemokines and Their Receptors in Drug Discovery. (2015) Springer. 37. U.S. Department of Health and Human Services, and Agency for Healthcare Research and Quality. Screening and Treatment of Subclinical Hypothyroidism or Hyperthyroidism: Comparative Effectiveness Review Number 24. (2013) CreateSpace Independent Publishing Platform. 38. Vitti, P., and Hegedus, L. Thyroid Diseases: Pathogenesis, Diagnosis, and Treatment (Endocrinology). (2018) Springer. 39. Weaver, N. Hyperthyroidism: The Middle Aged Woman’s Disease Affecting Infants and Children. (2016) Amazon Digital Services LLC. 40. Weaver, N. Understanding Hypothyroidism: Coping With Illness in Infants and Children. (2016) Amazon Digital Services LLC.

CHAPTER 13

Thyroid dysfunction in fetuses and newborns Contents Fetal thyroid function Maternal fetal interactions Thyroid function in the newborn Iodine deficiency during fetal life Congenital goiter Endemic cretinism Thyroid agenesis or dysplasia Hypothyroidism in infants and children Transient hypothyroidism Consumptive hypothyroidism Clinical cases Case 1 Case 2 Case 3 Case 4 Case 5 Further reading

277 278 279 280 281 282 283 284 286 286 287 287 288 289 290 290 292

There is an increased demand for thyroid hormones (THs) during pregnancy. This is due to an increase in thyroxine-binding globulin (TBG), placental type 3 deiodinase, and placental transfer of maternal thyroxine to the fetus. Thyroxine is essential for fetal neurodevelopment. Therefore it is critical that maternal delivery of thyroxine to the fetus is ensured early in gestation. Cretinism occurs from severe iodine deficiency because the mother’s body is unable to manufacture thyroxine for transport to the fetus, especially in the first trimester. Persistently low levels of thyroxine at 12 weeks of gestation are associated with an 8 10-point deficit in mental and motor function scores in infants, compared to children of mothers with normal thyroid function. Other thyroid conditions in fetuses and newborns include congenital goiter, thyroid agenesis or dysplasia, transient hypothyroidism, and consumptive hypothyroidism.

Fetal thyroid function In the fetus, peripheral metabolism of T4 is extremely different from adults in quantity and quality. Generally, rates of production and degradation, compared to units per Epidemiology of Thyroid Disorders DOI: https://doi.org/10.1016/B978-0-12-818500-1.00013-X

r 2020 Elsevier Inc. All rights reserved.

277

278

Epidemiology of Thyroid Disorders

body mass, are 10 times higher than in adults. Type 1 deiodinase (D1) catalysis is reduced, while type 3 deiodinase (D3) is increased. This supports the formation of inactive reverse triiodothyronine (rT3) in exchange for T3 itself. The fetal liver, skin, tracheobronchial, gastrointestinal (GI), and urothelial epithelia highly express D3. This causes a consistently subnormal serum T3 concentration and elevated serum rT3. This situation allows highly regulated conversion of T4 to T3 via type 2 deiodinase (D2), acting as the major method of generating tissue T3. Fetal thyroid function starts near the end of the first trimester. After that, steady increases occur in fetal TBG and total T4 and T3. As gestation continues, serum thyroid-stimulating hormone (TSH) values are higher than in maternal circulation and also higher than expected in adults who are euthyroid. This means that an increasing hypothalamic pituitary resistance to T4 in fetal development is present. This may be caused by increased thyroid-regulating hormone secretion. Even with low circulating T3, fetal free T4 concentration is close to that of the maternal circulation, from the gestational age of 28 weeks forward. Cordocentesis allows the study of fetal thyroid function within the uterus. In the fetus, total and free thyroxine concentrations reach adult levels at about 36 weeks of gestation, while total triiodothyronine and free triiodothyronine levels are always below adult concentrations. It is believed that there is independent and autonomous maturation of the pituitary gland, thyroid gland, and liver. Focus on fetal thyroid function Cordocentesis permits the study of fetal thyroid function in utero. In a normal fetus, thyroidstimulating hormone (TSH), thyroxine-binding globulin (TBG), and thyroid-hormone concentrations increase progressively through gestation. Fetal TSH concentrations are always high compared to nonpregnant adult values. TBG concentrations reach adult levels at term. Total and free thyroxine levels reach adult levels at about 36 weeks of gestation, while total and free triiodothyronine levels are always below adult concentrations.

Maternal fetal interactions Basically, the pituitary thyroid axis function of the fetus is separate from that of the mother. There is only slight transplacental movement of TSH from the mother to the baby. However, this is not the case with maternal thyroxine. If the infant has congenital hypothyroidism from genetic thyroid peroxidase (TPO) deficiency or athyreosis, the serum thyroxine concentrations in umbilical cord blood will be 33% 50% of normal, in most cases. Therefore at the very least, when maternal fetal concentration gradients are high, a large transfer of maternal thyroxine to the fetal circulation is possible. This is important on the basis of fetal brain’s capacity to increase efficiency of conversion of thyroxine to triiodothyronine. Thyroxine is also found in coelomic fluid and amniotic

Thyroid dysfunction in fetuses and newborns

fluid before thyroid function begins. The primary factor that limits TH transfer from the mother to the baby is the D3 that is expressed in the uterus, placenta, and fetal epithelial tissues. Generally, pregnancy involves profound changes in thyroidal actions—hypothyroidism or hyperthyroidism. These result from complicated factors that are specific to pregnancy. They occur together, stimulating the maternal thyroid functions. Maternal TH deficiency, in the first trimester, can affect neurodevelopment of the fetus. Migrations of neurons in the cortex are affected, as is fetal brain development.

Thyroid function in the newborn Prior to birth, mean total T4 level in umbilical cord serum is 150 nmol/L, which is 12 µg/dL. There are elevated serum TBG concentrations, but these are lower than in the maternal serum. In a full-term pregnancy, free T4 concentrations are just below those of the mother. The umbilical cord serum T3 concentrations are low, at 0.8 nmol/L, which is 50 ng/dL, and the rT3 and triiodothyronine sulfate (T3SO4) are elevated. Following delivery, serum TSH levels in neonates quickly increase. They peak between 2 and 4 hours after birth but return to starting values in 48 hours. Levels higher than 60 mU/L are common. The TSH surge is believed to occur as a response to quick reductions in the environmental temperature when the baby is delivered. As a result, serum T4, T3, and Tg concentration rise quickly in the first few hours following delivery. They are in the hyperthyroid range by the time the baby is 24 hours old. The neonatal TSH surge is part of the increase in serum T3 concentration. However, another important factor is the enhancement of extrathyroidal conversion of T4 to T3 via D1 or D2. Adrenergic stimulation of the Dio2 gene and D2 reactivation by its deubiquitination (cleavage of ubiquitin from protein) in brown adipose tissue are believed to be important contributors to the increase. Ubiquitin is a small regulatory protein that is present in most body tissues. There is an immature hypothalamic pituitary thyroid axis in premature infants, with low levels of thyroxine, triiodothyronine, and TSH. Gestational age usually correlates with serum thyroxine, TBG, and free thyroxine. Preterm infants additionally have a controlled surge of TSH following delivery. If prematurity is also accompanied with complications, such as respiratory distress syndrome or nutritional abnormalities, serum thyroxine, and especially triiodothyronine, can fall to low levels. This is due to combined reductions of TBG production, thyroid gland immaturity, suppression of the hypothalamic pituitary axis because of illness, impaired thyroxine to triiodothyronine conversion, and increased De activity. All of these changes are highly similar to those taking place in adults with severe illnesses. They need to be considered when a preterm infant’s thyroid status is evaluated. This is especially true with the higher prevalence of congenital hypothyroidism in these infants.

279

280

Epidemiology of Thyroid Disorders

The rates of TH production are higher, per unit of body weight, in neonatal infants and children, than in adults. Daily levothyroxine requirements are about 10 µg/kg in newborns, which progressively decreases to about 1.6 µg/kg in adults. Focus on newborn screening of thyroid function If an infant has a positive screen for congenital hypothyroidism, additional tests are required for confirmation. Blood tests, for detecting the amount of thyroxine and thyroid-stimulating hormone, are routinely performed. Sometimes, an imaging test of the thyroid, either an ultrasound examination or a thyroid uptake and scan, will help determine the cause of the condition. This allows physicians to see if the thyroid is present, where it is located, if it is misshapen, or if it is smaller than normal.

Iodine deficiency during fetal life It is extremely important for the development of the fetus to receive adequate iodine in order to ensure normal development. Prenatal vitamins should contain sufficient iodide, and after delivery, women should continue taking them during the breastfeeding period. The fetal brain needs sufficient T3, generated from maternal free T4, for TH-dependent neurodevelopment. This begins in the second half of the first trimester. Near the start of the second trimester, the fetal thyroid begins to produce hormones, but reserves are low. Therefore maternal THs contribute to total fetal TH concentrations until birth. Iodine is an integral part of these hormones. In order for the mother to produce enough THs for herself and her baby, a 50% increase in iodine intake is indicated. If the mother becomes iodine deficient, so will the fetus. As a result, low maternal free T4, or hypothyroxinemia, damages the developing fetal brain, which is additionally aggravated by fetal hypothyroidism. The most serious consequence of iodine deficiency is cretinism, which involves profound mental retardation. Cretinism is always associated with significant impairment of mental function with or without defects in hearing, speech, gait, stance, hypothyroidism, and growth. The most common form of cretinism is neurological cretinism. This is characterized by deaf-mutism, mental retardation, spastic diplegia, squinting, and disorders of gait and stance. The less common form is called myxedematous cretinism or hypothyroid cretinism. In this form, less severe mental retardation, dwarfism, hypothyroidism, coarse and dry skin, a husky voice, and delayed sexual maturation occur. Normal intelligence quotient (IQ) in a population is 100, while the IQ of a cretin is about 30. Additional outcomes of iodine deficiency in fetal include poor psychomotor development, lower orientation abilities, abnormal visual attention and processing, and poor fine motor skills. Improved neurodevelopment occurs in the children of mothers who began taking prenatal vitamins containing iodine earlier in pregnancy. With less severe

Thyroid dysfunction in fetuses and newborns

iodine deficiency, there is much less data about the effects upon cognitive function in the fetus. Focus on dietary sources of iodine Besides prenatal vitamins that contain iodine, pregnant women can consume the following foods to ensure adequate dietary iodine. These foods include iodized salt, cod, plain low-fat yogurt, low-fat milk, fish sticks, enriched bread, shrimp, enriched macaroni, eggs, canned tuna, creamed corn, cheddar cheese, dried prunes, raisin bran cereal, boiled lima beans, apple juice, and seaweed. However, dietary nitrates must be avoided since they impact the body’s ability to absorb iodine. Foods with high levels of nitrates include hot dogs, packaged lunch meats, and sausages. Another important factor to consider is about prenatal iodine supplements, which may actually contain too much iodine—these should not be taken unless approved by a physician.

Congenital goiter Congenital goiter is an enlargement of the thyroid gland at birth. It may be caused by a deficiency of enzymes or iodine required for the production of thyroxine. Rare causes of goitrous hypothyroidism include inherited defects in hormone biosynthesis. These account for 10% 15% of causes of newborns with congenital hypothyroidism. Incidence of this condition is 1 of every 3000 newborns. Usually, the defect is transmitted as an autosomal-recessive trait. Affected babies are believed to be homozygous for the abnormal gene. Their relatives, when having slight thyroid enlargement, are believed to be heterozygous. In this group, thyroid function tests may show a slight abnormality of an identical biosynthesis activity that is defective in a homozygous baby. Opposite to nontoxic goiter, these defects only affect females slightly more often than males. Nontoxic goiter is much more common in females. Goiter usually appears several years after birth but may be present at birth. Lack of goiter in a child with functional thyroid tissue does not exclude hypothyroidism. At first, the goiter is diffusely hyperplastic. This may be extreme, suggesting papillary carcinoma. Over time, it becomes nodular. Generally, the goiter appears earlier when the biosynthetic defect is more severe. Also, these goiters will be larger, and hypothyroidism or cretinism is more likely to occur. There are five specific defects in hormone synthesis that are involved, which are as follows: • Iodide transport—a defect resulting from the sodium/iodide symporter (NIS) protein mechanism. This is rare, identified by defective iodide transport in the thyroid, gastric mucosa, and salivary glands. Some mutations cause reduced activity, while others totally inactivate NIS via prevention of the protein from transport and insertion into the membrane. In milder NIS mutations, iodide administration raises plasma and intrathyroidal iodide concentrations, allowing the synthesis of normal hormone quantities.

281

282

Epidemiology of Thyroid Disorders

•

Expression or function of TPO—a defect involving thyroid peroxidase precursor, which is a protein required for normal iodothyronine synthesis. Abnormalities may be in quantity or quality. These alterations of TOP occur in about 1 of 66,000 infants. There are 16 identified mutations. The most common mutation has been identified as a GGCC sequence insertion in exon 8, which leads to a premature stop codon (a type of point mutation in a sequence of DNA). An “exon” is a part of a gene, which encodes a portion of the final mature RNA produced after introns have been removed by RNA splicing. An “intron” is a nucleotide sequence in a gene. • Pendred syndrome—a defect in iodine organification with sensory nerve deafness. The PDS gene that encodes pendrin is affected. Pendrin is involved in apical secretion of iodide into the follicular lumen, and thyroid function is only slightly impaired. • Thyroglobulin synthesis—a rare defect of genetic causes, which may lead to premature translation termination. Other defects of this type cause deficiency in endoplasmic reticulum processing of thyroglobulin. There is a complicated regulation and large size of this gene, making screening for mutations difficult. • Iodotyrosine dehalogenase—a complex defect, with impaired intrathyroidal and peripheral deiodination of iodotyrosines. This is believed to be due to the dysfunction of the iodotyrosine dehalogenase 1B (DEHAL1B) gene. Because of intensive thyroid stimulation and poor intrathyroidal recycling of iodide from dehalogenation, iodine is quickly accumulated in the thyroid gland and then rapidly released. In the plasma, monoiodotyrosine (MIT) and diiodotyrosine (DIT) are elevated. Along with their deaminated derivatives, these are also elevated in the urine. Hypothyroidism is believed to occur from the loss of large amounts of MIT and DIT in the urine, as well as secondary iodine deficiency. Goiter and hypothyroidism are relieved by high doses of iodine. Focus on congenital goiter The most common manifestation of congenital goiter is firm, nontender enlargement of the thyroid gland. This enlargement is usually diffuse but may be nodular. It can be noticed at birth or detected later. Sometimes, the enlargement is not easily seen, but continued growth may cause deviation or compression of the trachea, which compromises swallowing and breathing. Many children with goiters are euthyroid, though some have hypothyroidism or hyperthyroidism.

Endemic cretinism A developmental disorder, endemic cretinism occurs in the areas of severe endemic goiter. The parents of an endemic cretin are usually also goitrous. Along with features of sporadic cretinism, an endemic cretin often has deaf-mutism, spasticity, motor

Thyroid dysfunction in fetuses and newborns

dysfunction, and basal ganglia abnormalities. These may be visible using magnetic resonance imaging. There are three types of cretins, which are as follows: • Hypothyroid cretins—The mental abnormalities and other manifestations are less severe. • Neurological cretins—The nervous system is affected due to a lack of THs from the mother during the third to sixth month of pregnancy. The severe lack of iodine means that the fetus cannot produce THs during this period. Neurological cretins may not be hypothyroid later in life if they receive enough iodine to cause the thyroid to produce sufficient hormones. Damage that occurs during brain development is however irreversible. Pathogenesis of this form is obscure and may be from severe TH deficiency during an important early phase of central nervous system development. • Combined-feature cretins—Manifestations are similar to both of the other forms, with variance in their severity. Some cretins are goitrous, with the thyroid also being atrophic. This may be due to exhaustion atrophy from continuous overstimulation or from the lack of iodine.

Thyroid agenesis or dysplasia Hypothyroidism in newborns is often caused by developmental thyroid defects, which may involve total lack of thyroid tissue (agenesis) or failure of the gland to properly descend in embryologic development (dysplasia). Then, thyroid tissue can be located in any location along the normal route of descent, which may be from the foramen cecum (where the anterior two-thirds and posterior one-third of the tongue join), known as the lingual thyroid, to the normal site or below it. Scintigraphy can reveal the lack of thyroid tissue or an ectopic location. Many proteins are needed for the normal development of the thyroid gland. These include thyroid-specific transcription factor PAX8 and thyroid transcription factors 1 and 2 (TTF-1 and TTF-2). Defects in one or several of these proteins may explain abnormalities of the thyroid gland development. The abnormalities have been seen in patients with PAX8 mutations. One mutation of the human TTF-2 gene was linked to thyroid agenesis, choanal atresia, and cleft palate. There have been no mutations discovered that involve the TTF-1 gene in infants who have congenital hypothyroidism. There are families who have thyroid hypoplasia, increased TSH, and low free thyroxine. These factors are all linked to loss-of-function mutations in the TSH receptor. In tested patients the thyroid gland was in the proper location but did not trap the radioactive substance known as technetium-99m pertechnetate, which is an inorganic compound that is injected intravenously to assess thyroid function. However, thyroglobulin levels were still detected. This group of patients is still being studied. Another abnormality that causes TSH unresponsiveness is a mutation of the GS protein, occurring in pseudohypoparathyroidism type 1A. Pseudohypoparathyroidism is a condition

283

284

Epidemiology of Thyroid Disorders

mostly related to resistance against the parathyroid hormone. It occurs because of dysfunctional G proteins. These patients have inactivating mutations of the alpha-subunit of the GS protein and, therefore, mild hypothyroidism. Other patients, unexplainably, have increased TSH levels and hypothyroidism. In these patients the molecular defect has not been identified. Focus on thyroid agenesis and dysplasia Congenital hypothyroidism is caused by an absent or defective thyroid gland, classified as agenesis in 22% 42% of cases. However, the condition is due to an abnormal location of the gland in 35% 42% of cases and also exists when the thyroid gland is in normal position in 24% 36% of cases.

Hypothyroidism in infants and children At birth, severe hypothyroidism is usually not apparent. This may be due to some protection that occurs via the transplacental transfer of maternal THs, explaining the need for systematic screening for congenital hypothyroidism. The condition may be caused by total thyroid agenesis, ectopic thyroid, or incomplete development of the gland. Mutations of genes needed for thyroid development have been identified. Sometimes, this explains related developmental abnormalities of the heart, since there is a spatial association while development is ongoing. Symptoms appear at different ages, based on the amount of impaired thyroid function. In infancy, severe hypothyroidism is also called cretinism. As the age of onset increases, clinical manifestations begin to resemble those of juvenile hypothyroidism. There is retardation of growth and mental development, but this only appears in later infancy. The mental retardation is usually irreversible. Therefore early identification of the condition is essential. This has occurred via universal screening of the populations in developed countries, via measurement of serum thyroxine or TSH on a routine basis. Filter paper blood spots are examined from neonates. In the first few months after birth, signs and symptoms include problems with feeding, constipation, failure to thrive, hoarseness when the baby cries, jaundice, and somnolence. In the following months, especially when the condition is severe, the abdomen protrudes, the skin becomes dry, there is poor hair and nail growth, and the deciduous teeth do not erupt until a later-than-normal time. There are delays in reaching the normal developmental milestones, including holding up the head, sitting, walking, and talking. Bone development requires significant TH. The TH receptors are expressed in the osteoblasts and osteoclasts. The primary targets of TH are within the epiphyseal plates. Dwarfism results from impaired linear growth in congenital hypothyroidism. The limbs are shorter in proportion compared to the length of the trunk. The head is large compared to the body because of delayed closure of the fontanels. The naso-orbital

Thyroid dysfunction in fetuses and newborns

configuration retains the infantile appearance. The gait is described as waddling because of the maldevelopment of femoral epiphyses. The teeth are not formed normally and are highly susceptible to cavities. Overall, the nose is flat and broad, the eyes are set widely apart, there is periorbital puffiness, the tongue is large and protruding, the hair is sparse, the skin is rough, the neck is short, and the protruding abdomen has an umbilical hernia. Mental capacity is usually severely reduced. When the skeleton is radiologically examined, the skull shows poor development of its base. There is delayed fontanel closure, widely set orbits, and shortening and flattening of the nasal bone. There may be enlargement of the pituitary fossa. There is also delayed shedding of the deciduous teeth and eruption of the permanent teeth. Epiphyseal dysgenesis is almost entirely characteristic of hypothyroidism in infancy and childhood. Any center of endochondral ossification may be involved, based on the age at onset of the hypothyroidism state. Usually, this is seen in the femoral and humeral heads, and the navicular foot bone. Centers of ossification appear later. Bone age is therefore retarded in relation to chronological age. When they do appear, instead of just one center, there are many small centers throughout the misshaped epiphysis. The small ossification centers will unite, forming one center with an irregular outline, and a dot-like appearance, known as stippled epiphysis. Epiphyseal dysgenesis is obvious only where there is normal ossification, after the start of hypothyroidism. Following a normal metabolic state being restored by treatment, centers that will ossify at a later time will develop normally. Hypothyroidism beginning in childhood is usually Hashimoto’s thyroiditis. This can be transient in this age-group. In children and adolescents, subclinical hypothyroidism is also seen. Patients may be obese, with a family history of thyroid disease. Clinical manifestations in children are intermediate. Their developmental retardation is not as severe as in cretinism. Manifestations of full-blown adult myxedema are uncommon. Mostly, growth and sexual development are affected. When kept untreated, linear growth is severely retarded. Sexual maturation and onset of puberty will be delayed. Upon radiologic examination, epiphyseal dysgenesis may be seen. Epiphyseal union is always delayed. The bone age appears younger in relation to the chronologic age. Focus on pediatric hypothyroidism Rates of pediatric hypothyroidism appear to be increasing in the United States, but from unknown reasons. Hypothyroidism is the most common thyroid disorder in children of all ages. Its symptoms may not be identified since they are not specific to thyroid disease. For most children, being overweight is not caused by hypothyroidism. Parents should be aware that if they ask their child to look up to the ceiling, and they can easily see the outline of the thyroid gland, it is enlarged. The gold standard of treatment is the administration of synthetic thyroid hormone.

285

286

Epidemiology of Thyroid Disorders

Transient hypothyroidism Transient hypothyroidism involves a period of reduced free thyroxine and suppressed, normal, or elevated TSH levels. Eventually, this is followed by a euthyroid state. This form usually occurs along with painful or painless subacute thyroiditis. The patient has mild-to-moderate symptoms of hypothyroidism lasting only for a short period of time. Serum TSH is usually slightly elevated. There is often a preceding set of symptoms that are consistent with mild or moderate thyrotoxicosis. If the symptoms cannot be derived from patient history, it may be hard to distinguish the condition from permanent hypothyroidism. Early in the disease course of postthyroiditis hypothyroidism, TSH levels may be suppressed even while the free thyroxine is low. This is due to the delayed recovery of pituitary TSH synthesis, such as in Graves’ disease or toxic nodules (who have had surgery and experienced rapid relief of hypothyroidism symptoms). In this situation, TSH response may be suppressed for many months. In postthyroiditis hypothyroidism, this is usually not longer than 3 4 weeks. About 50% of women with autoimmune thyroiditis, but with normal thyroid function, have hypothyroidism episodes in the postpartum periods. Sometimes, the previous thyrotoxicosis is mostly asymptomatic, which makes accurate diagnosis difficult. In those who had typical painful subacute thyroiditis, involving pain, tenderness, and thyrotoxicosis, diagnosis is much simpler. Diagnostic evaluation should include evaluation for TSH, free thyroxine, and TPO antibodies. A nonautoimmune cause is likely if there are negative or low antibodies. Significantly, it may be possible for the patient to be temporarily treated for hypothyroidism. A trial of low levothyroxine, after 3 6 months, may show that thyroid function has normalized. This can occur in patients with hypothyroidism following painless subacute thyroiditis, such as in the postpartum period. However, it is slightly less likely to occur since the underlying autoimmune thyroiditis is usually progressive. In patients with hypothyroidism from painful subacute thyroiditis, the gland is usually smaller and atrophic. In those with hypothyroidism following painless subacute thyroiditis, it is usually slightly enlarged and firmer. This shows the underlying scarring and infiltrate related to the condition.

Consumptive hypothyroidism Consumptive hypothyroidism is unusual. It has been identified in infants who have visceral hemangiomas or related tumors. The first reported case involved abdominal distention due to a large hepatic hemangioma with respiratory compromise. This was secondary to upward displacement of the diaphragm. The clinical signs suggested hypothyroidism, confirmed by a markedly elevated TSH level, and undetected TH levels. The infant responded to an initial intravenous (IV) infusion of liothyronine transiently. Then, parenteral TH replacement was used

Thyroid dysfunction in fetuses and newborns

to relieve the severe hypothyroidism. Accelerated degradation of TH became apparent because 96 µg of liothyronine and 50 µg of levothyroxine were needed to normalize TSH levels. The equivalent dose of levothyroxine on its own is about nine times what is usually required to treat an infant with congenital hypothyroidism. Unfortunately, in this case the infant died from heart failure due to the size of the hemangioma. Other complications include ulceration of the tumor, disruption of breathing, amblyopia (blockage of the eye), bone erosion, and cosmetic abnormalities. Postmortem tumor biopsy showed D3 activity in the tumor at levels eight times higher than those usually present in a term placenta. Serum rT3 was highly elevated, at 400 ng/dL. Serum thyroglobulin was more than 1000 ng/mL. This indicated a highly stimulated thyroid gland. Two other patients with a similar state were discovered, but the cause of their hypothyroidism was not found. In all proliferating cutaneous hemangiomas, there has been significant D3 expression. Though cutaneous hemangiomas of infancy express D3, these are not related to hypothyroidism due to their small size. Most infantile hemangiomas become involuted with the use of propranolol. The patient must also receive proper doses of TH to prevent permanent neurologic complications related to untreated hypothyroidism in this critical neurologic developmental phase. There is also a similar syndrome in adults. One patient had an epithelioid hemangioendothelioma. Another had a fibrous tumor and many GI stromal tumors. Some of the tumors expressed D3. However, D3 expression may be induced during treatment with tyrosine-kinase inhibitors. Focus on severe hypothyroidism Severe hypothyroidism can lead to the decreased metabolism and decreased use of calories. It can also cause myxedema, which is characterized by skin swelling. Myxedematous children suffer from dwarfism, late eruption of the teeth, slowed bone growth, nail brittleness, and mental disorders. Treatment requires regular administration of thyroid hormones. Infantile myxedema develops after birth and is manifested by slow development of the body, waxy puffiness of the skin, and swelling of the lips and nose. Complications include coronary heart disease, cardiovascular insufficiency, psychosis, osteoporosis, and reduced immunity.

Clinical cases Case 1 1. What is the likely initial treatment of this infant’s condition? 2. What are the suggested guidelines in monitoring infants and children regarding thyroid hormones? 3. What does the presence of a congenital goiter in a newborn suggest? A 6-day-old male newborn was born to a 21-year-old mother with no past history of thyroid disease. Normal thyroid levels were present during pregnancy. The infant

287

288

Epidemiology of Thyroid Disorders

was delivered by cesarean section because of delayed progression of labor, with a birth weight of 5.5 lb. The infant had delayed passage of meconium, decreased activity, abdominal distension, and difficulty in latching onto the mother’s breasts. Vital signs were normal, but there was a middling neck swelling, which was soft, mobile, noncystic, without inflammatory signs, and no audible bruits. The newborn was otherwise normal except for generalized hypotonia. Thyroid hormones were in the normal ranges. X-rays revealed absence of the distal femoral epiphyses, and postnatal ultrasound showed diffuse enlargement of thyroid gland. The diagnosis was neonatal goiter with hypothyroidism. Answers: 1. The likely initial treatment would be thyroxine, which should decrease the size of the goiter and improve most of the other signs within about 1 week or slightly longer. 2. The American Academy of Pediatrics recommends child monitoring for T4 and TSH values every 1 2 months for up to 6 months; every 3 4 months (between 6 and 12 months of age); and every 6 12 months (from the age of 3 years to the completion of growth). 3. The presence of a goiter in a newborn with primary hypothyroidism suggests transient hypothyroidism or an intrinsic defect in TH synthesis. In this case, since the mother was euthyroid, dyshormonogenesis was considered to be the most probable cause of the hypothyroidism.

Case 2 1. What is the primary cause of endemic cretinism? 2. How is endemic cretinism differentiated from sporadic congenital hypothyroidism? 3. Why are prompt diagnosis and treatment of congenital hypothyroidism and endemic cretinism essential for a good prognosis? A 5-month-old male child was brought to his pediatrician with severe constipation. The pregnancy had been normal and his birth weight was 6.1 lb. The signs of constipation had first appeared at 4 months of age. Physical examination revealed typical features of cretinism: thin hair, paleness, jaundice, thickening of the nose and lips, and a protruding tongue. The abdomen was protruding with an umbilical hernia, the skin was very dry, and there was muscular hypotonia. The child could not yet hold his head up. After diagnostic testing the child was started on levothyroxine. Over time, he regained a normal growth pattern and reached normal developmental milestones. Answers: 1. Endemic cretinism occurs when iodine intake is below a critical level of 25 µg/day. It may affect newborns living in conditions of severe iodine deficiency.

Thyroid dysfunction in fetuses and newborns

2. Endemic cretinism is associated with severe iodine deficiency between the mother and the fetus. Sporadic congenital hypothyroidism is caused by developmental anomalies or genetic defects. 3. Prompt diagnosis and treatment can prevent severe intellectual delays and growth failure. Ideally, the goal of newborn screening programs is to detect and start treatment within the first 1 2 weeks of life. Treatment involves levothyroxine tablets being crushed and given to infants with a small amount of water or milk. Within a few weeks, hormone levels are checked to confirm that they are being returned to normal. The dose will increase as the child grows. Congenital hypothyroidism is the most common preventable cause of intellectual disability.

Case 3 1. If a person is born without a thyroid gland, or with a nonfunctional thyroid, as in this case study, what hormones will be required for supplementation? 2. What is the likely outcome since treatment began shortly after birth? 3. How is this condition usually inherited? A baby girl was born with a normal-appearing but nonfunctional thyroid gland. The mandatory heel stick blood test, conducted at birth to measure for thyroid hormone, alerted physicians to her condition. Being congenitally hypothyroid, as a result, she was started on thyroid hormone replacement in order to prevent the resultant signs and symptoms. Answers: 1. In this case, since the baby was started on levothyroxine (supplying only thyroxine or T4), she will also need T3 supplementation since normal T4 T3 conversion is not occurring. Supplementation only with levothyroxine can cause symptoms of hypothyroidism because she will be low in active thyroid hormone. Therefore liothyronine or natural desiccated thyroid hormone will be added to the treatment. 2. Children with this condition, who receive treatment soon after birth, usually have normal growth and intelligence and live average, healthy lives. However, some will have problems with cognitive activities and may need extra help. Some will have delayed growth compared to other children of their age. 3. Most cases are inherited in an autosomal-recessive manner, affecting males and females equally. A specific pair of genes is not working correctly, and these children inherit one nonworking gene for the condition from each parent. Though the thyroid was of normal appearance, its lack of function meant that no thyroid hormones were being manufactured.

289

290

Epidemiology of Thyroid Disorders

When both parents are carriers, there is a 25% chance for the child to have this condition.

Case 4 1. What is the clinical definition of transient hypothyroidism? 2. What are the four recognized causes of transient hypothyroidism? 3. How do thyrotropin-blocking antibodies develop? A 1-day-old female infant had increased TSH and normal thyroid hormone levels, which resolved over time, indicating transient hypothyroidism. Her 28-year-old mother had hypothyroidism and was taking oral thyroxine throughout pregnancy. The mother had five failed pregnancies before the current pregnancy and had also given birth to another child prematurely, but the child had survived. Answers: 1. Transient hypothyroidism is clinically defined as low thyroxine with elevated TSH levels following birth, but then normal serum thyroxine and TSH on a follow-up serum test at 1 2 months of age. A definitive diagnosis can be achieved during this period and since by 2 months, the causes of the condition will have usually resolved. 2. The four recognized causes of transient hypothyroidism are transplacental passage of thyrotropin-blocking antibodies (TRBAbs), transplacental passage of antithyroid drugs used to treat maternal thyroid conditions, iodine deficiency, and iodine excess. Also, rarely, some forms of thyroid dyshormonogenesis, caused by gene mutations, can cause transient hypothyroidism. 3. Thyrotropin-blocking antibodies develop in the context of maternal autoimmune thyroid diseases. These include Graves’ disease, chronic lymphocytic thyroiditis, and acquired hypothyroidism. The antibodies cause hypothyroidism in the fetus and newborn via transplacental passage and blockage of the access of thyrotropin to fetal thyrotropin receptors.

Case 5 1. How is consumptive hypothyroidism diagnosed? 2. Will a child with this condition require TH supplementation for a long time? 3. When the two conditions described in the case study coexist, what may a progressive increase in TH replacement requirements indicate? In the first identified case of consumptive hypothyroidism, a 6-week-old infant with hepatic hemangiomatosis (HHE) had elevated TSH levels and low serum free thyroxine. The infant was treated with prednisolone for the hemangioma and levothyroxine replacement for the hypothyroidism. After 16 days, the TSH level was

Thyroid dysfunction in fetuses and newborns

still high. At an age of 3 months, the child had intermittent bradycardia and hypothermia. Blood tests resulted in increased hormone-replacement therapy and IV administration of liothyronine. The TSH and triiodothyronine levels became normalized, yet the thyroxine levels remained low. Following surgery for multiple hemangiomas, the child died from systemic complications. Answers: 1. Consumptive hypothyroidism is diagnosed based on the detection of D3 activity in the tumor tissue of the patient who has biochemical and clinical signs of hypothyroidism. A biopsy may be risky due to the high vascularity of the tumor. Therefore consumptive hypothyroidism should be suspected in each HHE patient when TH values quickly change, especially in the proliferative phase. 2. Yes, all cases of consumptive hypothyroidism in children with hepatic hemangiomatosis required TH supplementation for months or years, despite whether or not there was liver transplantation, spontaneous disease regression, hepatic artery ligation, or radiotherapy of the tumors. 3. A progressive increase in thyroid hormone replacement requirements, with these two conditions, may indicate continued tumor growth. It reflects the body’s overall T3 deiodinase activity. It is recommended that rapid, aggressive TH replacement be initiated.

Key terms amniotic fluid athyreosis coelomic fluid consumptive hypothyroidism cordocentesis deaf-mutism dehalogenation deubiquitination Dio2 gene endemic cretinism epiphyseal dysgenesis epithelioid filter paper blood spots GS protein hemangiomas

hemangiomatosis heterozygous homozygous lingual thyroid myxedematous cretinism neurological cretinism osteoblasts osteoclasts reverse triiodothyronine (rT3) scintigraphy stippled epiphysis thyroid-regulating hormone (TRH) type 1 deiodinase (D1) type 2 deiodinase (D2) type 3 deiodinase (D3)

291

292

Epidemiology of Thyroid Disorders

Further reading 1. Ahmed, A. Maternal-Newborn Thyroid Dysfunction: Developmental Neuroendocrinology. (2012) Lap Lambert Academic Publishing. 2. Bona, G., De Luca, F., and Monzani, A. Thyroid Diseases in Childhood: Recent Advances From Basic Science to Clinical Practice. (2015) Springer. 3. Braverman, L.W., and Cooper, D. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text, 10th Edition. (2012) LWW. 4. Courtney, J., and Worley, D. Clinical Handbook of Pediatric Endocrinology, 2nd Edition. (2013) Thieme. 5. Dattani, M., and Brook, C.G.D. Brook’s Clinical Pediatric Endocrinology, 7th Edition. (2019) WileyBlackwell. 6. Dennison, J., Oxnard, C., and Obendorf, P. Endemic Cretinism. (2011) Springer. 7. Eaton, J.L. Thyroid Disease and Reproduction: A Clinical Guide to Diagnosis and Management. (2018) Springer. 8. Garber, J.R., Watson, S., and Underwood, A. Thyroid Disease: Understanding Hypothyroidism and Hyperthyroidism. (2018) Harvard Health Publishing. 9. Haggblom, M.M., and Bossert, I.D. Dehalogenation: Microbial Processes and Environmental Applications. (2003) Springer. 10. Hammer, G.D., and McPhee, S.J. Pathophysiology of Disease: An Introduction to Clinical Medicine (Lange Medical Books), 7th Edition. (2014) McGraw-Hill Education/Medical. 11. Hochberg, Z. Practical Algorithms in Pediatric Endocrinology, 3rd Edition. (2017) S. Karger. 12. Hoffmann, G.F., Zschocke, J., and Nyhan, W.L. Inherited Metabolic Diseases: A Clinical Approach, 2nd Edition. (2017) Springer. 13. Jameson, J.L., and De Groot, L.J. Endocrinology: Adult and Pediatric, 2-Volume Set, 7th Edition. (2015) Saunders. 14. Kappy, M.S., Allen, D.B., and Geffner, M.E. Pediatric Practice: Endocrinology, 2nd Edition. (2014) McGraw-Hill Education/Medical. 15. Kharchenko, V.P., Kotlyarov, P.M., Mogutov, M.S., Alexandrov, Y.K., Sencha, A.N., Patrunov, Y.N., and Belyaev, D.V. Ultrasound Diagnostics of Thyroid Diseases. (2010) Springer. 16. Lifshitz, F. Pediatric Endocrinology, 5th Edition (Two-Volume Set). (2006) CRC Press. 17. Mattassi, R., Loose, D.A., and Vaghi, M. Hemangiomas and Vascular Malformations: An Atlas of Diagnosis and Treatment, 2nd Edition. (2015) Springer. 18. Misra, S. Thyroid Dysfunction and Pregnancy. (2012) Elsevier. 19. Nikiforov, Y.E., Biddinger, P.W., and Thompson, L.D.R. Diagnostic Pathology and Molecular Genetics of the Thyroid: A Comprehensive Guide for Practicing Thyroid Pathology, 3rd Edition. (2019) LWW. 20. Phillips, C., and Roach, D. Hypothyroidism in Childhood and Adulthood: A Personal Perspective and Scientific Standpoint. (2006) Nottingham University Press. 21. Radovick, S., and Misra, M. Pediatric Endocrinology: A Practical Clinical Guide, 3rd Edition. (2018) Springer. 22. Reissland, N., and Kisilevsky, B.S. Fetal Development: Research on Brain and Behavior, Environmental Influences, and Emerging Technologies. (2016) Springer. 23. Sarafoglou, K., Hoffmann, G.F., and Roth, K.S. Pediatric Endocrinology and Inborn Errors of Metabolism, 2nd Edition. (2017) McGraw-Hill Education/Medical. 24. Seckl, J.R., and Christen, Y. Hormones, Intrauterine Health and Programming (Research and Perspectives in Endocrine Interactions). (2014) Fondation Ipsen. 25. Sperling, M.A. Pediatric Endocrinology: Expert Consult, 4th Edition. (2014) Saunders. 26. Styne, D.M. Pediatric Endocrinology: A Clinical Handbook. (2016) Springer. 27. Thomas, P. Endocrine Gland Development and Disease, Volume 106 (Current Topics in Developmental Biology). (2013) Academic Press. 28. Thompson, L.D.R. Head and Neck Pathology: A Volume in the Series: Foundations in Diagnostic Pathology, 2nd Edition. (2012) Saunders. 29. Thorpe-Beeston, J.G., and Nicolaide, K.H. Maternal and Fetal Thyroid Function in Pregnancy (Frontiers in Fetal Medicine Series). (1995) CRC Press.

Thyroid dysfunction in fetuses and newborns

30. Ulloa-Aguirre, A., and Conn, P.M. Cellular Endocrinology in Health and Disease. (2014) Academic Press. 31. Vandana, J., Ram, K.M., Desai, M.P., and Paul, V.K. Case Based Reviews in Pediatric Endocrinology. (2015) Jaypee Brothers Medical Publishing. 32. Vitti, P., and Hegedus, L. Thyroid Diseases: Pathogenesis, Diagnosis, and Treatment (Endocrinology). (2018) Springer. 33. Weaver, N. Understanding Hypothyroidism: Coping With Illness in Infants and Children. (2016) Amazon Digital Services LLC. 34. White, B., and Porterfield, S. Endocrine and Reproductive Physiology: Mosby Physiology Monograph Series, 4th Edition. (2012) Mosby. 35. Wondisford, F.E., and Radovick, R. Clinical Management of Thyroid Disease. (2009) Saunders. 36. Zacharin, M. Practical Pediatric Endocrinology in a Limited Resource Setting. (2013) Academic Press. 37. Zaoutis, L.B., and Chiang, V.W. Comprehensive Pediatric Hospital Medicine. (2007) Mosby.

293

Glossary 99m

Tc pertechnetate One of the technetium radiopharmaceuticals used in imaging of the thyroid, colon, bladder, and stomach.

Achlorhydria Absence of hydrochloric acid from the gastric juice. ACTH Adrenocorticotropic hormone, also called corticotropin; secreted by the anterior lobe of the pituitary gland, it stimulates the adrenal cortex’s secretions.

Adam’s apple The laryngeal prominence at the front of the throat, produced by the thyroid cartilage of the larynx.

Addison disease Chronic adrenocortical insufficiency, usually caused by idiopathic atrophy or destruction of both adrenal glands.

Adenomas Benign epithelial tumors, with cells forming glandular structures, or being derived from glandular epithelium.

Adipocytokines Also called adipokines. Adipokines Cell-signaling proteins secreted by adipose tissue, such as leptin. Adrenal fatigue A condition in which the adrenal glands cannot produce enough cortisol and other adrenocortical hormones.

Adrenal insufficiency Abnormally diminished activity of the adrenal gland, also called hypoadrenalism. Aerobic capacity The maximal amount of physiological work that an individual can do, as measured by oxygen consumption.

Affective disorder A condition marked by changes in affect (moods or emotions), which is not attributable to physical disease.

Age-specific death rates Also called life tables; the probabilities that a person will die based on current age, compared to average life expectancies.

Alopecia areata Hair loss in sharply defined areas, usually the scalp or beard. Alveolar gland A gland in which the secretory units have a sac-like form and an obvious lumen, such as the active mammary glands.

Amenorrhea The absence of menstrual periods. Amine precursor uptake and decarboxylation A function of the endocrine system, referring to neuroendocrine activities; it involves the C cells of the thyroid.

Aminotransaminases Amino acid-derived enzymes; their activity is frequently measured to determine liver function.

Amniotic fluid The albuminous fluid in the amniotic sac in which the fetus floats. Amyloidosis A progressive, incurable metabolic disease characterized by abnormal deposits of protein in one or more organs or body systems.

Angiotensin A vasoconstrictive substance formed in the blood when renin is released from the juxtaglomerular apparatus in the kidney.

Anovulatory Absence of the development of a mature ovarian follicle and/or the discharge of the oocyte during a menstrual cycle.

Antinuclear antibodies Autoantibodies that attack substances found in the center, or nucleus, of all cells. Apathetic Indifferent; exhibiting apathy (lack of emotion). Apathetic thyrotoxicosis Chronic thyrotoxicosis, presenting as cardiac disease or wasting syndrome, with weakness of proximal muscles and depression but with few of the more typical clinical manifestations of thyrotoxicosis.

295

296

Glossary

Aplasia cutis Localized failure of development of skin, most commonly of the scalp; the defects are usually covered by a thin translucent membrane or scar tissue, or may be raw, ulcerated, or covered by granulation tissue; usually lethal. Arrhythmia Loss or abnormality of rhythm; denoting especially an irregularity of the heartbeat. Ascitic Related to ascites, which is an abnormal accumulation of fluid in the abdomen. Atrophic thyroiditis A type of autoimmune thyroiditis with atrophy of the follicles and without goiter. Atrial fibrillation A cardiac arrhythmia marked by rapid randomized contractions of the atrial myocardium, causing a totally irregular rapid atrial rate. Atrial flutter A cardiac arrhythmia in which the atrial contractions are rapid (230 380 per minute), but regular. Athyreosis Hypothyroidism. Autoimmune hypothyroidism Lymphocytic thyroiditis, including Hashimoto’s thyroiditis; a condition in which the thyroid is infiltrated with lymphocytes. Autonomic nervous system The branch of the nervous system that works without conscious control. Autophosphorylation A type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. Barr bodies Sex chromatins; persistent masses of material of inactivated X chromosomes in cells of normal females. Berry’s ligament The suspensory ligament of the thyroid gland that passes to the trachea. Bilobate Having two lobes. Bipolar disorder Formerly known as manic depression, a mood disorder that causes radical emotional changes and mood swings, from manic, restless highs to depressive, listless lows. C cells Calcitonin-secreting cells located in the thyroid gland. Calcitonin A polypeptide, calcium-regulating hormone produced by the ultimobranchial bodies; also known as thyrocalcitonin. Calorigenic effects Those that are capable of generating heat or energy, increasing oxygen consumption. Capgras syndrome The delusional belief that a person (or people) close to the schizophrenic patient has been substituted for by one or more impostors; may have an organic etiology. Carcinoembryonic antigen A glycoprotein antigen present in fetal tissue, found in many other cancers and some nonmalignant conditions. Its primary use is in monitoring the response of patients to cancer treatment. Cardiomyopathy A chronic disease of the heart muscle (myocardium), in which the muscle is abnormally enlarged, thickened, and/or stiffened. Carney complex type 1 An autosomal dominant condition, with tumors of the heart and skin, hyperpigmentation, and endocrine overactivity; usually caused by tumor-suppressor gene mutations. Catecholamines The group of amines, which includes adrenaline, noradrenaline, dopamine and chemically related amines. These are derived from the amino acid tyrosine, and act as neurotransmitters or hormones. Celiac disease A disease of the digestive system that damages the small intestine and interferes with the absorption of nutrients from food. Central hypothyroidism Low thyroid function caused by pituitary or hypothalamic disease in relation to tumors or vascular defects. Cerebellar ataxia Failure of muscular coordination due to disease of the cerebellum. Cervical sympathetic ganglia The superior, middle, and inferior ganglia, which are extensions of the thoracic paravertebral sympathetic trunk lying inferiorly; they function to distribute fibers to the head and neck. Chemokines Also called intercrines; several groups composed of usually 8-10 polypeptide cytokines that stimulate leukocyte movement and attraction. Chemosis Edema of the conjunctiva of the eye, forming a swelling around the cornea.

Glossary

Cholestasis A condition caused by rapidly developing or long-term interruption in the excretion of bile. Chondroitin Any of several sulfated glycosaminoglycans that are a major constituent of various connective tissues, especially blood vessels, bone, and cartilage; used as an over-the-counter dietary supplement alone or in combination with glucosamine for joint pain in arthritis. Chronotropic Affecting the rate of rhythmic movements, such as the heartbeat. Chvostek sign Unilateral spasm due to muscle tetany, which is induced by tap over the facial nerve, which occurs in severe hypocalcemia. Closed-loop feedback process Any biological system in which the components involved interact only with each other; there are no “outside” influences upon the process. Coelomic fluid The fluid inside the coelom, which is the main body cavity, which is circulated by mesothelial cilia of contraction of muscles in the body walls. Colloid A translucent, yellowish, homogeneous material of the consistency of glue, found in the cells and tissues as part of a degenerative process. Colloid goiter A goiter that is large and soft and has distended spaces filled with colloid. Colloid involution A rolling or turning inward movement of colloid. Congenital hypothyroidism Deficiency of thyroid hormone at birth, usually as a result of improper development of the thyroid gland, a genetic disorder affecting hormone production, or iodine deficiency during pregnancy. Consumptive hypothyroidism Low thyroid function caused by overexpression of deiodinase, which inactivates thyroid hormones. Cordocentesis Percutaneous umbilical fetal blood sampling, which allows for more rapid test results than amniocentesis. Coupling reaction A general term for a variety of reactions where two hydrocarbon fragments are coupled with the aid of a metal catalyst; basically, the two types of coupling reactions are heterocouplings and homocouplings. Cowden disease Excessive body hair and gingival enlargement from infancy, accompanied by fibroadenomatous breast enlargement after puberty; papules of the face are characteristic of multiple trichilemmomas (benign neoplasms of the lower outer root sheaths of the hair). Creatine kinase An enzyme catalyzing the transfer of a phosphate group from phosphocreatine to ATP. Cretinism Arrested physical and mental development with dystrophy of bones and soft tissues, due to congenital lack of thyroid gland secretion from hypofunction or absence of the gland. Cricoid cartilage A ring-like cartilage forming the lower and back part of the larynx. Cricothyroid Pertaining to the cricoid and thyroid cartilages. Cushing syndrome A disorder resulting from increased adrenocortical secretion of cortisol due to ACTHdependent adrenocortical hyperplasia or tumor, ectopic ACTH-secreting tumor, or excessive administrations of steroids. Cyclic adenosine monophosphate (cAMP) A cyclic nucleotide, involved in the action of many hormones, including catecholamines, ACTH, and vasopressin. Cyclothymia Also called cyclothymic disorder; mental disorder characterized by noticeable, clinically significant swings of mood, largely unrelated to life events, from depression to hypomania, of lesser magnitude than in bipolar disorder. Cytotrophoblast The inner cellular layer of the trophoblast of a blastocyst. Deaf mutism The condition of being unable to hear or speak. Dehalogenation The removal of halogens, such as bromine, chlorine, fluorine, or iodine from molecules. Deiodination The removal of iodine atoms from organic compounds. Delirium A temporary state of mental confusion and fluctuating consciousness resulting from high fever, intoxication, shock, or other causes.

297

298

Glossary

Delusions Unshakable beliefs in something untrue. These irrational beliefs defy normal reasoning, and remain firm even when overwhelming proof is presented to dispute them.

Dementia A loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.

Deubiquitination Removal of ubiquitin, a small regulatory protein found in most tissues; this process occurs via enzymes that cleave the amide bond between two of the proteins.

Diabetic ketoacidosis A dangerous complication of diabetes mellitus in which the chemical balance of the body becomes far too acidic.

Diffuse sclerosing variant A type of papillary thyroid carcinoma, in which the thyroid becomes diffusely firm, white, and “gritty”; it makes up only 0.8% of papillary thyroid carcinomas.

Dio2 gene The gene that encodes type II iodothyronine deiodinase, an enzyme. Dyshormonogenetic goiter A rare type of goiter in which thyroid dyshormonogenesis occurs from genetic defects in thyroid hormone synthesis.

Echography Sonography, or medical ultrasonography; an echograph is more commonly called an ultrasound display.

Echotexture The characteristic pattern or structure of tissue layers as seen during ultrasonic imaging. Ectodomain The domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction. Ectopic Referring to an abnormal location or position of an organ or a body part, occurring congenitally or as the result of injury. Electroconversion Also called electrical cardioversion, a medical procedure in which tachycardia or other cardiac arrhythmia is converted to a normal rhythm using a therapeutic dose of electric current to the heart. Embryogenesis Embryonic development. Endemic cretinism The form of cretinism that results from congenital hypothyroidism in specific populations. Endemic goiter A goiter that develops in areas of iodine deficiency. Epigenetic influences Factors produced or formed at or near the surface of the earth. Epiphyseal dysgenesis Defective or abnormal development of the ends of long bones. Epithelioid Resembling epithelial tissue. Erythropoietin A glycoprotein hormone that stimulates production of red blood cells by stem cells in the bone marrow. Euthyroid A state of normal thyroid gland function. Exophthalmos Abnormal protrusion of the eyeballs. Fas expression The expression of Fas, also known as apoptosis antigen 1; the Fas receptor is a death receptor on the surface of cells that leads to programmed cell death. Fascial Related to the fascia, the bands or sheets of connective tissue that attach, stabilize, enclose, and separate muscles and internal organs. Fenestrated capillaries The smallest blood vessels, but those that specifically have perforated openings in them. Filter paper blood spots A testing method in which blood spots on filter paper are used for DNA examination. Follicle cavity A sac-like depression containing colloid within the thyroid gland. Follicular carcinoma Cancer of the thyroid composed of well-differentiated or poorly differentiated epithelial follicles without papillary formation. Foramen cecum The remnant of median thyroid diverticulum in early embryonic development. Foregut The anterior part of the alimentary canal, from the mouth to the duodenum at the entrance of the bile duct, attached to the abdominal walls by mesentery.

Glossary

Forskolin A substance often used to raise levels of cyclic AMP (cAMP) in the study and research of cell physiology.

Galactorrhea The spontaneous flow of milk from the breast, unassociated with childbirth or nursing. Gardner syndrome An autosomal dominant form of polyposis, with multiple polyps developing in the colon and outside of the colon, which may affect the thyroid gland.

Germinal centers Areas in the center of a lymph node containing aggregations of actively proliferating lymphocytes.

Giant cell infiltration The infiltration of tissues with masses formed by the union of histiocytes or other distinct cells, which often form a granuloma.

GnRH agonist Gonadotropin-releasing hormone agonist; a type of medication that affects gonadotropins and sex hormones.

Goiter A swelling in the neck resulting from an enlarged thyroid gland. Goitrogens Substances that disrupt the production of thyroid hormones by interfering with iodine uptake in the thyroid gland.

Graves’ disease Also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Graves’ orbitopathy Also called Graves’ ophthalmopathy, it is an autoimmune inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction, lid lag, swelling, redness, conjunctivitis, and bulging eyes (exophthalmos). GS protein The G protein subunit that activates the cAMP-dependent pathway by activating adenylyl cyclase. Hallucinations Perceptions in the absence of external stimuli that have qualities of real perceptions. Hashimoto’s thyroiditis Also called chronic lymphocytic thyroiditis and Hashimoto’s disease; it is an autoimmune disease in which the thyroid gland is gradually destroyed. Heart failure Also known as chronic heart failure (CHF), in which the heart is unable to pump sufficiently to maintain blood flow to meet the body's needs. Hemangiomas Congenital vascular malformations consisting of benign tumors made up of newly formed blood vessels clustered together; they may be present at birth in various parts of the body, including the liver and bones. Hemangiomatosis The presence of multiple hemangiomas. Heterozygous Having different alleles at one or more corresponding chromosomal loci; or, related to a heterozygote. HMG CoA reductase A rate-controlling enzyme of cholesterol synthesis. Activity of the enzyme may be as much as 60 times higher than normal in patients with low-density lipoprotein receptor disorder. Hoffmann syndrome Muscular enlargement, weakness, and stiffness occurring in adult hypothyroidism. Homeobox A sequence of DNA encoding a protein structure that binds to specific parts of DNA and affects transcription of DNA into RNA. Homocysteine A naturally occurring amino acid found in blood plasma. High levels of homocysteine in the blood are believed to increase the chance of heart disease, stroke, Alzheimer's disease, and osteoporosis. Homodimers Chemical structures formed by two identical subunits. Homozygous Having identical alleles at one or more loci. Human chorionic gonadotropin A hormone that is produced by cells of the fetal placenta and maintains the function of the corpus luteum during the first few weeks of pregnancy. Human leukocyte antigen (HLA) Any one of the four significant histocompatibility antigens controlled by genes of the HLA complex. Human leukocyte antigen G (HLA-G) A protein that is encoded by the HLA-G gene; it is expressed on fetal-derived placental cells.

299

300

Glossary

Hung-up reflexes Deep tendon reflexes in which, after a stimulus is given and the reflex action takes place, the limb slowly returns to its neutral position. This prolonged relaxation phase is characteristic of reflexes in persons with hypothyroidism. Hürthle cells Large, granular eosinophilic cells derived from thyroid follicular epithelium by accumulation of mitochondria, for example, in Hashimoto’s disease. Hyaluronic acid A substance found in lubricating proteoglycans of synovial fluid, vitreous humor, cartilage, blood vessels, skin, and the umbilical cord. Hyoid bone A horseshoe-shaped bone at the base of the tongue. Hypercarotenemia An elevated level of carotene in the blood, often characterized by skin yellowing. Hyperemesis Excessive vomiting. Hyperemesis gravidarum Excessive and pernicious vomiting during pregnancy, usually in the first trimester; a more serious condition than the simple morning sickness that is common during the first trimester. Hyperlipoproteinemia Excessive lipids in the blood; also called hyperlipidemia and hyperlipemia. Hyperplastic Related to an abnormal increase in volume of a tissue or organ, due to formation and growth of new, normal cells. Hyperthyroidism The overproduction of thyroid hormones by an overactive thyroid. Hyperthyrotropinemia Excessive levels of thyrotropin in the blood. Hypoechoic parenchyma A low amount of ultrasound echoing of the essential or functional elements of a body organ. Hypoparathyroidism The result of a decrease in production of parathyroid hormones by the parathyroid glands located behind the thyroid glands in the neck. The result is a low level of calcium in the blood. Hypothyroidism Underactive thyroid, which develops when the thyroid gland fails to produce or secrete as much thyroxine (T4) as the body needs. Hypothyroxinemia A subnormal thyroxine concentration in the blood. Iatrogenic hypothyroidism Inadequate secretion of thyroid hormone by the thyroid gland due to treatments that include medications (such as amiodarone), radioactive iodine ablation of the gland, or surgical excision of the thyroid. Ichthyosis A congenital disease that is represented by thick, scaly skin. Immunomodulating Having the capacity for, and used for immunomodulation, which is adjustment of the immune response to a desired level. Intermenstrual interval The time occurring between two consecutive menstrual periods. Inotropic Affecting the force of muscular contractions. Interstitial myxedema A condition resulting from hypothyroidism, or deficiency of thyroxine, which affects the spaces within tissues or organs. Intrinsic hyperthyroidism Excessive thyroid function situated entirely within the gland itself. Isthmectomy Surgical excision of an isthmus, especially of the isthmus of the thyroid. Involution A rolling or turning inward. Iodide A binary compound of iodide, such as potassium iodide; it inhibits the release of thyroxine from the thyroid gland. Iodide transport system A method in which iodide is moved between the bloodstream and gastric juice. Iodine The chemical element that is essential in nutrition, being especially prevalent in the colloid of the thyroid gland. It is used in the treatment of hypothyroidism and as a topical antiseptic. Iodization To treat or impregnate with iodine or an iodide. Iodothyroglobulin Another term for thyroglobulin, which is produced by the follicular cells of the thyroid. Isoenzymes Also called isozymes; enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isthmus The band of tissue joining the lobes of the thyroid. Juvenile goiter Thyroid swelling occurring in childhood.

Glossary

Kallikreins Serine endopeptidases that cleave kinin precursors to form kinins. Kilobase A length of nucleic acid equal to 1000 bases or nucleotides. Kilodaltons One thousand daltons. A dalton is the weight of a hydrogen atom. The kilodalton is the standard unit used to represent the weight of large molecules such as proteins.

Lactate hydrogenase The conjugate base of lactic acid’s enzyme that catalyzes the reversible oxidation of molecular hydrogen; lactate dehydrogenase is an enzyme that catalyzes conversion of lactate to pyruvate and back. Lactescent Resembling milk. Lagophthalmos Inability to shut the eyes completely. Laryngoscopic Relating to examination of the interior of the larynx, via the use of a small, long-handled mirror. Levothyroxine The substance obtained from the thyroid gland of domesticated food animals or prepared synthetically; used as the sodium salt in the treatment of hypothyroidism and the treatment and prophylaxis of goiter and thyroid carcinoma. Life expectancy The number of years, based on statistical averages, that a person of a specific age, class, or other demographic variable may be expected to continue living. Lingual thyroid Residual thyroid tissue at the base of the tongue that failed to descend into the neck during embryologic development. Liothyronine A synthetic pharmaceutical preparation of the levorotatory isomer of triiodothyronine; used for replacement therapy in hypothyroidism, and for the prophylaxis and treatment of goiter and thyroid cancer. Lymph nodes Small oval or bean-shaped bodies, up to 2 cm in length, situated in groups along the course of the lymph drainage vessels. The nodes have fibrous capsules and are packed with lymphocytes. Mania An abnormally elated mental state, typically characterized by feelings of euphoria, lack of inhibitions, racing thoughts, diminished need for sleep, talkativeness, risk taking, and irritability. Means-Lerman scratch An uncommon type of heart murmur, in patients with hyperthyroidism. It is a mid-systolic scratching sound best heard over the upper part of the sternum or second left intercostal space at the end of expiration. Medullary carcinoma Thyroid cancer that is composed mainly of epithelial elements with little or no stroma. Megacolon Dilatation and hypertrophy of the colon. MEN syndrome A syndrome of multiple endocrine neoplasia, a group of rare hereditary disorders of autonomous hyperfunction of endocrine glands. Menorrhagia Also called hypermenorrhea; excessive menstruation. Metachromatically staining A procedure in which the same dye is used to stain cells, but which results in different colors of different elements that are present. Microchimerism A genetic hybrid caused by migration of cells from an allograft into recipient tissue. Microcuries Fragments that are one-millionth of curies, which are units of radioactivity in which the number of disintegrations per second is 3.700 x 1010. Middle cricothyroid ligament The center ligament uniting cricoid and thyroid cartilages. Moist rales Rattling and gurgling sounds, due to fluid in the tracheobronchial tree. Monotropic deficiency A lack of thyrotropin as part of secondary hypothyroidism, usually because of a pituitary adenoma. Mucositis The painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucrystallin A specific form of crystallin, a water-soluble structural protein in the lens and cornea of the eye, and in the heart as well as breast tumors; the mu-crystallin homolog is also called nicotinamide adenine dinucleotide phosphate (NADP)-regulated thyroid-hormone-binding protein. Multinodular Having multiple nodules.

301

302

Glossary

Multinodular goiter A goiter with circumscribed nodules within the gland. Myxedema A condition resulting from advanced hypothyroidism, or deficiency of thyroxine; it is the adult form of the disease whose congenital form is known as cretinism.

Myxedema coma An often-fatal complication of long-term hypothyroidism, in which the patient is comatose with hypothermia, depression of respiration, bradycardia, and hypotension.

Myxedema madness Also called myxedema psychosis; a clinical form of hypothyroidism which is more common in the elderly, characterized by dementia, delirium, impaired hearing and memory, inability to solve mathematical calculations, somnolence, mental withdrawal, and paranoia. Myxedema megacolon Pseudo-obstruction due to reduced GI motility. Myxedematous Relating to myxedema. Myxedematous cretinism A type of cretinism in an infant caused by myxedema in the mother; treatment with iodine normalizes thyroid function if it is begun early in the postnatal period. Neurological cretinism The form of congenital hypothyroidism that affects the nervous system; it is caused by lack of thyroid hormone from the mother in the third to sixth months of pregnancy. Neurotransmitters Substances (such as norepinephrine, acetylcholine, dopamine) released from the axon terminal of a presynaptic neuron on excitation, traveling across the synaptic cleft to either excite or inhibit target cells. Nitric oxide A naturally occurring gas that in the body is a short-lived dilator released from vascular epithelial cells in response to the binding of vasodilators to endothelial cell receptors; it causes inhibition of muscular contraction, and thus relaxation. Norepinephrine Also called noradrenalin, a catecholamine that is the neurotransmitter of most sympathetic postganglionic neurons and also of certain tracts in the central nervous system. Obsessive-compulsive disorder A type of anxiety disorder characterized by distressing repetitive obsessive thoughts, followed by ritualized compulsive actions that are usually bizarre and irrational. Octreotide A synthetic analogue of somatostatin, used as the acetate ester in palliative treatment of symptoms of gastrointestinal endocrine tumors and in treatment of acromegaly. Omohyoid Pertaining to the shoulder and the hyoid bone. Omphalomesenteric duct anomaly An abnormality of the umbilical and mesenteric duct, formerly called the “yolk stalk”. Oophorectomy The surgical removal of one or both ovaries. Organic psychosis A condition characterized by a loss of contact with reality caused by an alteration in brain tissue function. Organification The addition of inorganic iodine to tyrosine residues in the thyroid, by thyroid peroxidase. Orthostatic hypotension An abnormal decrease in blood pressure when a person stands up. This may lead to fainting. Osteoblasts Cells in the body that build new bone tissue. Osteoclasts Bone cells that break down and remove bone tissue. Oxidability Able to be converted into an oxide. Oxyphil metaplasia Transformation into another form of glandular cells or tissues. Papillary carcinoma The most common type of thyroid cancer; it is often well-differentiated, slowgrowing, and localized, though it can metastasize. Parafollicular cells The cells present between follicles or interspersed among follicular cells; they are rich in mitochondria and are believed to be the source of thyrocalcitonin. Paranoid Suffering from delusions, but not from psychosis. Parathyroid glands Four small endocrine bodies in the region of the thyroid gland; they contain two types of cells: chief cells and oxyphils (eosinophils). Parathyroid hormone A polypeptide hormone secreted by the parathyroid glands that influences calcium and phosphorus metabolism and bone formation.

Glossary

Paroxysmal atrial tachycardia A period of very rapid and regular heartbeats that begins and ends abruptly. The heart rate is usually between 160 and 200 beats per minute; also known as paroxysmal supraventricular tachycardia. Pendred syndrome An autosomal recessive condition associated with developmental defects of the cochlea, sensorineural hearing loss and diffuse thyroid enlargement; it is the most common syndrome-related form of deafness. Pendrin A chloride-iodide transporter protein encoded by the gene responsible for Pendred syndrome, important in function of thyroid gland, kidney, and inner ear. Periodic acid-Schiff (PAS) positive Having a suspected anomaly, as revealed by staining to detect polysaccharides, glycoproteins, glycoplipids (lipids that contain carbohydrates), and mucins; aldehydes react with the Schiff reagent to give a purple-magenta color. Perithyroidal Related to the capsule or tissues that surround the thyroid. Pernicious anemia A disease in which the red blood cells are abnormally formed, due to an inability to absorb vitamin B12. Pheochromocytoma A tumor of special cells (called chromaffin cells), most often found in the middle of the adrenal gland. Phospholipase A2 An enzyme that cleaves fatty acid in position number 2 of phospholipids; it hydrolyzes the bond between the second fatty acid tail and the glycerol molecule. Piriform sinus The pear-shaped recess on either side of the laryngeal orifice; it is involved in speech. Placental abruption The early separation of the placenta from the uterus before childbirth, most commonly occurring around 25 weeks of pregnancy, causing bleeding, abdominal pain, and dangerously low blood pressure. Pleomorphic giant cells A variable appearance or morphology of giant cells, which are of large size and often have many nuclei. Pleuropericardial Relating to the pleura and pericardium. Plummer nails Onycholysis, or separation of the nails from the nail beds, particularly affecting the ring and little fingers, in patients with thyrotoxicosis. Polyendocrine syndromes Heterogeneous rare diseases characterized by autoimmune activity against more than one endocrine organ. Polyphasic Consisting of multiple peaks or phases. Preeclampsia A condition of hypertension occurring in pregnancy, typically accompanied by edema and proteinuria. Also called toxemia of pregnancy. Premature beats Early heart contractions that result in momentary cardiac arrhythmia; also referred to as extrasystole. Pretibial myxedema An infiltrative dermopathy, resulting as a rare complication of Graves' disease, with an incidence rate of about 1-5% in patients. Proptotic Referring to proptosis, which is forward displacement or bulging of the eyes. Prostration A marked loss of strength, as in exhaustion. Psychotropic Capable of affecting the mind, emotions, and behavior; denoting drugs used in the treatment of mental illnesses. Pulmonary edema Capable of affecting the mind, emotions, and behavior; denoting drugs used in the treatment of mental illnesses. Pulmonary hypertension A rare lung disorder characterized by increased pressure in the pulmonary artery. Radiofrequency catheter ablation Destruction of an accessory conduction pathway or other troublesome area of dysrhythmia by means of high frequency alternating current delivered by a bipolar or unipolar catheter. RET mutation An alteration of the “rearranged during transfection” proto-oncogene; it is linked to medullary thyroid carcinoma.

303

304

Glossary

Ret proto-oncogene The gene that encodes a receptor tyrosine kinase for members of the glial cell linederived neurotrophic factor family of extracellular signalling molecules.

Retroperitoneal fibrosis A chronic inflammatory process in which fibrous tissue surrounds the large blood vessels in the lower lumbar area.

Reverse triiodothyronine (rT3) A conversion product of thyroxine, the level of which reflects the rate of peripheral conversion of thyroid hormone.

Rhabdomyolysis A paroxysmal, potentially fatal syndrome caused by the breakdown of skeletal muscle fibers.

Riedel’s thyroiditis A chronic type of autoimmune thyroiditis with a proliferating, fibrosing, inflammatory process involving usually one but sometimes both lobes of the gland, which becomes hard and enlarged and adherent to the trachea and other adjacent structures. Schizoid Having characteristics resembling schizophrenia; or a person with such characteristics, but not actual schizophrenia. Schmidt syndrome Paralysis on one side, affecting the vocal cord, soft palate, trapezius muscle, and sternocleidomastoid muscle; resulting from a brain lesion. Scintigraphy An imaging process that shows distribution and intensity of radioactivity in various tissues and organs following administration of a radiopharmaceutical. Scintiscan A photographic display of the distribution of a radiopharmaceutical within the body. Secondary hypothyroidism The type of hypothyroidism caused by a thyrotropin deficiency. Selenium A metalloid element of the sulfur group that occurs mainly in iron, copper, lead, and nickel ores; it is needed in the diet, in small amounts. Septations Divisions of a structure into compartments, by a septum or several septa. Serpin Any of a superfamily of inhibitors of serine proteinase, found in plasma and tissue. Sialylated Having been reacted with sialic acid or its derivatives; used especially with oligosaccharides. Silent lymphocytic thyroiditis Self-limited hyperthyroidism that resolves in two to five months; the thyroid is infiltrated with lymphocytes. Sinus tachycardia A rapid heartbeat generated by discharge of the sinus node; the rate is generally 100 to 180 beats per minute. Sonolucent In ultrasonography, permitting passage of ultrasound waves without reflecting them back to their source; containing few or no echoes. Spindle cells Various cells shaped like spindles, being more or less round in the middle with two ends that are pointed. Sporadic goiter A goiter that occurs at scattered, intermittent, and random intervals. Sternothyroid Referring to the sternum and thyroid. Stippled epiphysis A dot-like appearance of the end of a long bone. Stochastic Referring to anything produced at random without a threshold dose level; in radiation safety, the primary stochastic effects are carcinogenesis and genetic mutations. Stroma The supporting tissue or matrix of an organ, as distinguished from its parenchyma. Struma A goiter. Subacute thyroiditis Also called de Quervain thyroiditis; inflammation of thyroid after an infection such as mumps, influenza, coxsackievirus, or adenovirus. Superior vena cava syndrome A condition of edema and engorgement of the veins of the upper body caused by obstruction of the superior vena cava by thrombi or primary pulmonary tumors. Syncytiotrophoblast The outer syncytial layer of the trophoblast of an early mammalian embryo; it erodes the uterine wall during implantation, and gives rise to the villi of the placenta. Tall-cell variant A form of papillary thyroid carcinoma that is more aggressive; the cells appear twice as high as they are wide.

Glossary

Tapioca Tiny, starchy balls or flakes made from the dried paste of grated cassava root, it has goitrogenic effects.

Technetium A radioactive, metallic element; its isotopes are used in radioisotope scanning of internal organs. Telangiectasia Permanent dilation of groups of superficial capillaries and venules. Teratogenic Able to interfere with normal prenatal development, causing abnormalities. Tetraiodothyronine Another term for thyroxine. Thionamides Also called thioureylenes; a group of antithyroid agents used in the treatment of hyperthyroidism; they include methimazole, carbimazole, and propylthiouracil.

Thioureas Antithyroid compounds of the thioamide group, with the same actions and uses as thiouracil. Thyrocalcitonin Another term for calcitonin. Thyrocytes The primary epithelial cells of the thyroid gland. Thyroglobulin An iodine-containing glycoprotein in the colloid of the thyroid gland follicles; it forms the active hormones thyroxine and triiodothyronine.

Thyroglossal duct The embryonic duct connecting the thyroid gland and tongue. Thyroid agenesis Absence of the thyroid due to nonappearance of its primordium in the embryo. Thyroid anlage The first beginning formation, in the embryo, of the thyroid. Thyroid arteries The inferior or superior thyroid arteries. Thyroid autonomy The ability of the thyroid to function independently. Thyroid cancer A neoplasm of the thyroid gland, usually characterized by slow growth and a slower, more prolonged clinical course than that of other malignancies.

Thyroid cartilage The largest cartilage of the larynx, consisting of two laminae fused together at an acute angle in the midline of the anterior neck to form the Adam’s apple.

Thyroid crisis A sudden exacerbation of symptoms of thyrotoxicosis, characterized by fever, sweating, tachycardia, extreme nervous excitability, and pulmonary edema.

Thyroid follicles The small, round, vesicular components of the thyroid gland lined with epithelium and containing colloid in varying amounts; the colloid serves for storage of the thyroid hormone precursor, thyroglobulin. Thyroid gland The highly vascular organ at the front of the neck, consisting of bilateral lobes connected in the middle by a narrow isthmus; it secretes thyroxine, triiodothyronine, and calcitonin. Thyroid hormones Iodine-containing compounds secreted by the thyroid gland, including thyroxine and triiodothyronine. Thyroid hypoplasia Incomplete development or underdevelopment of the thyroid. Thyroid nodules Visible or palpable masses in the thyroid gland that are usually benign. Thyroid peroxidase antibodies The antibodies to thyroid peroxidase, which functions to catalyze incorporation of iodide to tyrosine residues, in the production of thyroxine. Thyroid storm A crisis of uncontrolled thyrotoxicosis, caused by the release into the bloodstream of increased amounts of thyroid hormone; also called thyroid crisis. Thyroid veins The inferior, middle, and superior veins of the thyroid. Thyroid-binding globulins Glycoproteins to which thyroid hormone binds in the blood, and from which they are released into tissue cells; also called thyroxine-binding globulins. Thyroid-regulating hormone (TRH) The hormone that regulates the functions of the thyroid gland. Thyroid-stimulating hormone (TSH) A substance secreted by the anterior lobe of the pituitary gland that controls the release of thyroid hormone, and is necessary for the growth and function of the thyroid gland. Thyroidectomy The surgical removal of the thyroid gland. Thyroiditis Inflammation of the thyroid gland. Thyroperoxidase A protein that participates in iodine metabolism in the thyroid follicle or in the follicular space.

305

306

Glossary

Thyrotoxic myopathy A condition in thyrotoxicosis consisting of severe weakness in the limb and trunk muscles, including those used in speech and swallowing.

Thyrotoxicosis The condition caused by excessive quantities of thyroid hormones; it may be due to overproduction by the thyroid gland, as in Graves’ disease, overproduction originating outside the thyroid, or loss of storage function and leakage from the gland. Thyrotropin-releasing hormone A substance produced in the hypothalamus that stimulates the release of thyrotropin from the anterior lobe of the pituitary gland. Thyroxine (T4) A hormone of the thyroid gland, derived from tyrosine and deiodinated in the periphery to triiodothyronine that stimulates the metabolic rate; also called tetraiodothyronine. Thyroxine-binding globulin A plasma protein that binds with and transports thyroxine in the blood. Toxic multinodular goiter An enlarged thyroid gland characterized by many discrete nodules and hypersecretion of thyroid hormones. TRAb test A blood test that aids in diagnosis of Graves’ disease, since the antibodies that it tests for are present in 90% of people with this disease. Transantral Performed across or through an antrum. Transthyretin Also called prealbumin; an alpha-globulin secreted by the liver that transports retinol-binding protein and thyroxine in the blood. Triiodothyronine (T3) A thyroid hormone that helps regulate growth and development, control metabolism and body temperature, and inhibits secretion of thyrotropin by the pituitary gland. Trophoblastic disease A condition affecting the outermost layer of tissue forming the wall of the blastocysts in the early stages of embryonic development. Trophoblasts The outermost layers of tissue that form the walls of the blastocysts in the early stages of embryonic development. Trousseau sign A test for latent tetany in which carpal spasm is induced by inflating a blood pressure cuff on the upper arm to a pressure exceeding systolic blood pressure for three minutes; the test may be positive in hypocalcemia and hypomagnesemia. Type 1 deiodinase (D1) The primary deiodinase enzyme responsible for converting thyroxine into triiodothyronine, throughout the entire body. Type I muscle fibers The type of muscle fibers that are slowly oxidative, high in myoglobin, with many mitochondria, that fatigue slowly; they have a dark red color and are narrow in diameter. Type 2 deiodinase (D2) The enzyme that plays the most crucial role in the pituitary gland, for the determination of how much thyroid activity is required. Type 3 deiodinase (D3) The enzyme that primarily opposes the effects of D1 and D2, inhibiting conversion of thyroxine into triiodothyronine. Tyrosine kinase inhibitors Substances that oppose the actions of tyrosine kinase, which is the enzyme that phosphorylates tyrosine in certain proteins, and plays an important role in cell signaling. Tyrosyl A derivative of phenethyl alcohol that is a natural antioxidant; in the diet, it primarily comes from olive oil. Ultimobranchial glands The tissues that originate from the fifth branchial (gill-like) pouch, which combines with the buccal cavity outgrowth, forming the thyroid gland. Ultrasound elastography A non-invasive technique that assesses the elasticity of soft tissue during application of mechanical compression or vibration. V genes The genes coding for the major part of the variable region of an immunoglobulin chain. Vitiligo A benign acquired skin disease of unknown cause, consisting of irregular patches of various sizes totally lacking in pigment, and often having hyperpigmented borders. Wolff-Chaikoff effect The decreased formation and release of thyroid hormone in the presence of an excess of iodine. Xerostomia Dryness of the mouth caused by cessation of normal salivary secretion.

Index Note: Page numbers followed by “f,” “t,” and “b” refer to figures, tables, and boxes, respectively.

A Achlorhydria, 105 ACTH, 218 Adam’s apple, 23 Addison’s disease, 142, 150 151 Adenomas, 10 Adenomatous, 82 Adenomatous hyperplasia, 208 Adenosine triphosphate (ATP), 33 35 Adenylate cyclase, 29 31 Adipocytokines, 110 Adipokines, 225 Adrenal fatigue, 173 Adrenal insufficiency, 173 Adrenocorticoid insufficiency, 113 114 Aerobic capacity, 174 Affective disorder, 197 198, 204 Age-specific death rates, 6 Agranulocytosis, 137 138, 164 165 Albumin, 31 Alopecia areata, 162 16-alpha-hydroxylation, 109 Alveolar gland, 23 Alzheimer’s disease, 103 Amenorrhea, 101 Amine precursor uptake, 26 27 Aminotransaminases, 105 106 Amiodarone, 75, 179, 188 Amniotic fluid, 278 279 Amphotericin B, 157 Amyloid goiter, 79 80, 86 Amyloidosis, 79 80, 86 Anaplastic carcinoma, 211 Anaplastic thyroid carcinoma, 17 Androsterone, 109 Anemia, 112, 175 176 Angiotensin, 173 Anovulatory cycle, 133 Antiarrhythmic amiodarone, 97 98 Antibody-dependent cell-mediated cytotoxicity, 149

Antigenic mimicry, 160 162 Antinuclear antibodies, 266 Antithyroid peroxidase antibodies, 134 135, 158, 210 Anxiety disorders, 196 Apathetic hyperthyroidism, 134, 180 Apathetic thyrotoxicosis, 128 Aplasia cutis, 262 Aplastic anemia, 164 165 Arrhythmias, 178 180, 183 184, 189 Ascites, 105 Aspirin, 155, 167 168 Atezolizumab, 162 Athyreosis, 278 279 Atrial fibrillation, 130, 172, 178 179, 179f, 184 185, 187 188 Atrial flutter, 180 181 Atrophic thyroiditis, 93 Attention-deficit hyperactivity disorder, 198 199 Autoimmune hypothyroidism, 92 93, 93f Autoimmune thyroiditis, 143, 152, 162, 224, 286 Autonomic nervous system, 173 Autophosphorylation, 221 223 Axitinib, 238

B Barr bodies, 223 224 Basal metabolic rate, 38 Battelle Developmental Inventory, 194 Bayley Scales of Infant Development, 194, 194b Benign adenomas, 73, 208 210 clinical presentation, 209 210 diagnosis, 210 epidemiology, 208 pathogenesis, 208 209, 209f risk factors, 209 treatment, 210 Benign follicular neoplasms, 142 Berry’s ligament, 23 Beta-adrenergic blockers, 138 Beta-adrenoceptor antagonists, 188

307

308

Index

Beta-blockers, 138, 164, 179 180, 189, 204, 264, 271 Beta-lactamase inhibitor, 157 Bexarotene, 98 99 Bilateral subtotal thyroidectomy, 165 Bile, 32 Bilobate, 21 22 Bipolar disorder, 191, 193, 196, 200 202 Bipolar I disorder, 199 Block replace regimen, 137 Bradycardia, 172 Brunet Lézine Scale, 194 B-type Raf kinase (BRAF) gene, 211 Burch Wartofsky Point Scale for thyroid storm, 182, 183t

C Calcitonin, 26 27, 36, 37f, 216 218 Calcium channel blockers, 179 Calcium iodate, 46 Calorigenic effects, 26, 36 37 Candida infections, 266 Capgras syndrome, 194 195 Carbimazole, 48 49, 164 165, 204, 271 Carcinoembryonic antigen, 105 Cardiovascular complications with Graves’ disease, 183 185, 185b arrhythmia, 183 184 heart failure, 184 185 stroke, 184 and hyperthyroidism, 178 182 arrhythmia, 178 180 heart failure, 180 181 syncope, 180 with thyroid storm, 181 182 and hypothyroidism, 172 174 bradycardia, 172 coronary artery disease (CAD), 172 diastolic hypertension, 172 dyspnea, 172 edema, 172 heart failure, 172, 174 hypotension, 173 and thyroiditis, 174 178, 178b anemia, 175 176 heart failure, 174 175 hypercholesterolemia, 176 178 with thyroid storm, 181 182

coma, 182, 183t shock, 181 182 thyroid crisis, 181 Cardiovascular Health Study, 124 125 Cardiovascular system, 104, 129 130 hyperthyroidism, 129 130 hypothyroidism, 104 Carney complex type 1, 224 Carpal tunnel syndrome, 103 Cassava, 76 77 Catecholamines, 108, 129 Cathepsin D, 50 C cells, 26 27, 36 Celiac disease, 10 11, 14 15, 105 Centers for Disease Control and Prevention, 6 Central hypothyroidism, 97 99, 111 112 corticosteroids, 114 treatment of, 113 Central nervous system, 101 103 Cerebellar ataxia, 103 Cerebral venous thrombosis (CVT), 184 Chemokines, 263 Chemotherapy, 162, 219 Cholestasis, 137 138 Chondroitin sulfate, 101, 105 Chronic autoimmune hypothyroidism. See Hashimoto’s thyroiditis Chronic autoimmune thyroiditis, 100, 152 Chronic Hashimoto’s thyroiditis, 103 Chronic lymphocytic thyroiditis. See Hashimoto’s thyroiditis Chronic stress, 196 197 Chronotropic effects of thyroid hormones, 104 Chvostek sign, 236 Clear cells, 26 27 Clindamycin, 157 Clinical hypothyroidism, 92 93, 245 Clomiphene, 225 Closed-loop feedback process, 29 31 Coelomic fluid, 278 279 Colchicine, 79 80 Cold nodules, 79, 228, 231 Colloid, 26, 82 Colloid body atrophy, 149 150 Colloid goiter, 74 75 Colloid involution phases, 74 75 Coma, 182, 183t Combined-feature cretins, 283

Index

Conduct disorder, 198 Congenital biosynthetic defect, 75 Congenital goiter, 84, 281 282, 282b Congenital hypothyroidism, 12b, 15, 48 49, 91 92, 100, 116 117, 279, 281, 284, 289 Congenital iodine deficiency syndrome. See Cretinism Conical pyramidal lobe, 23 Consumptive hypothyroidism, 111, 286 287, 291 Cordocentesis, 278 Coronary artery disease (CAD), 172 Corticosteroids, 114, 151, 158 159, 167 168 Coupling reaction, 49 50 Cowden disease, 215 Creatine kinase enzyme, 177 178 Cretinism, 33 35, 45 46, 66 67, 94, 118, 193 194, 277, 280, 284 Cricoid cartilage, 23 Cricothyroid, 24 Cushing syndrome, 142, 217 Cyclic adenosine monophosphate (cAMP), 48 49, 108, 129 Cyclothymia, 151 Cytokines, 263 Cytotrophoblast, 47 48

D Deaf-mutism, 280 Decarboxylation, 26 27 Decreased thyroid reserve, 115 Dehalogenation, 282 Deiodinases, 51 Deiodination, 113 of iodothyronine, 57 58, 58f Delirium, 194 195 Delusions, 195 Dementia, 194 195 Denver Developmental Screening Test, 194 Depression, 191, 193 De Quervain’s thyroiditis, 111 De Quervain syndrome, 152 Deubiquitination, 279 Diabetic ketoacidosis, 134, 197 Diastolic hypertension, 172 Dietary iodide ion (I) absorption, 32 Dietary iodine, 51 52, 51t, 70, 162 Diffuse hyperplasia, 122 Diffuse nontoxic goiter, 73 77, 74f

causes of, 75 colloid goiter, 74 75 colloid involution phases, 74 75 endemic goiter, 75 77 hyperplastic phase, 74 75 involution, 74 75 juvenile goiter, 75 mass effects, 75 sporadic goiter, 77 Diffuse sclerosing variant, 214 215 Digoxin, 138 Dihydroxyvitamin D, 107 Diiodotyrosine (DIT), 48 50, 282 Dilated cardiomyopathy, 179 180 Dio2 gene, 279 Disability-adjusted life years (DALYs), 17 18 Disruptive behavior disorders. See Externalizing disorder D-like thiol proteases, 50 Down syndrome, 148 Doxorubicin, 238 Drug-induced hyperthyroidism, 123 Drug-induced hypothyroidism, 97 98 Dyshormonogenesis, 73 Dyshormonogenetic goiter, 75, 77, 91 92 Dysplasia, 283 284 Dyspnea, 172

E Early thyroid failure, 115 Echography, 269 Ectodomain, 54 Ectopic thyroid tissue, 23 24, 29 Edema, 172 Electroconversion, 183 184 Electroconvulsive therapy (ECT), 200 Electrolyte metabolism, 110 111 hyperthyroidism, 133 hypothyroidism, 110 111 Embryogenesis, 262 Encephalopathy, 103 Endemic cretinism, 51 52, 282 283, 288 289 Endemic goiter, 8 9, 51 52, 81, 244 Endogenous subclinical thyrotoxicosis, 141 Epiphyseal dysgenesis, 107, 285 Epithelioid hemangioendothelioma, 287 Erythropoietin, 132 Esmolol, 181

309

310

Index

Ether bridge, 49 50 Etiocholanolone, 109 Euthyroid, 73 75, 265 Euthyroid Graves’ disease, 160 Excessive iodine ingestion, 122 Exophthalmos, 180 External beam radiation therapy (EBRT), 216, 219, 237 238 Externalizing disorder, 198 Eye disease, 164

F Familial amyloidotic polyneuropathy, 56 Fascial thyroid sheath, 38 40 Fas expression, 263 Fenestrated capillaries, 24 25 Ferrous sulfite, 270 271 Fetal thyroid function, 277 278, 278b Filter paper blood spots, 284 Fine-needle aspiration (FNA) biopsy, 79, 209 210, 228, 230 Fluconazole, 157 Follicle cavity, 26 Follicular adenomas, 208 209 clinical presentation, 209 210 diagnosis, 210 types of, 210 Follicular carcinoma, 211 Follicular cell thyroid carcinomas (FCTCs), 229 Follicular hyperplasia, 78 79 Follicular thyroid adenomas, 239 240 Follicular thyroid cancer (FTC), 17, 212 Food sources of iodine, 53t Foramen cecum, 22 Foregut, 21 22 Forskolin, 129 Free thyroid hormone, 56 Free thyroxine, 154 155, 201 Fungal thyroiditis, 157

G Galactorrhea, 108 109 Gardner syndrome, 215 Garri, 76 77 Gastrointestinal system, 105 106 hyperthyroidism, 131 hypothyroidism, 105 106 Germinal centers, 93, 149 150

GGCC sequence insertion in exon 8, 282 Giant cells, 152, 219 infiltration, 152 Global epidemiology of thyroid disorders aging of population, 4 6, 5f, 6b burden of thyroid disorders, 18 disability-adjusted life years, 17 18 distribution by gender and age, 8 10 global death rates, 15 17 global prevalence, 11 15 population-based models, 10 11 world population, 3 4 Global impact of thyroid disorders, 243 global costs and consequences, 253 254 Graves’ disease, burden of, 252 hyperthyroidism, burden of, 246 251, 250t, 251t hypothyroidism, burden of, 245 246, 247t, 248t global effects of iodine deficiency, 243 245, 245b global effects of thyroid cancer, 252 253, 253b Glucocorticoids, 138, 155, 166, 268 Gluconeogenesis, 38 Glycogenolysis, 38 Glycogen phosphorylase, 38 Goiters, 8 12, 29, 45 46, 48 49, 85, 166, 260, 288 amyloid, 79 80, 86 cause of, 73 clinical presentation, 82 83 definition of, 65 diagnosis, 83 84 diffuse nontoxic goiter, 74 77, 74f dyshormonogenesis, 73 epidemiology, 80 81 etiology of, 81 82 nontoxic multinodular goiter, 77 79, 78f pathogenesis, 81 82 thyroid nodule, 73 74 toxic multinodular goiter, 79 treatment, 84 types of, 73 Goitrogens, 67 68, 75 76, 84 Goitrous hypothyroidism, 73 74 Gonadotropin-releasing hormone agonist (GnRH agonist), 261 262 Granulomatous thyroiditis, 111, 152, 153f

Index

Graves’ disease, 3, 9 11, 13 16, 33 35, 49 51, 73 75, 79, 83, 100, 104, 122 124, 126, 134 135, 148, 155, 158 166, 169, 189, 203 204 bipolar disorder, 196 with cardiovascular complications, 183 185, 185b arrhythmia, 183 184 heart failure, 184 185 stroke, 184 clinical presentation, 162 163 complications, 16 diagnosis, 163 164 epidemiology, 159 160 histrionic personality disorder, 196 incidence of, 12 infiltrative ophthalmopathy, 127 mental disorders, 196 197 pathogenesis, 160, 161f and pregnancy, 263 264, 264b, 272 risk factors, 160 162 smoking and thyroid diseases, 160b thyroid cancers, 225 226 treatment, 164 166 Graves’ exophthalmos, 162 Graves’ ophthalmopathy, 162 163 GS protein, 283 284 Guman chorionic gonadotropin (hCG), 260

H Hallucinations, 195, 201 Hartley Dunhill procedure, 165 Hashimoto’s encephalopathy, 187 Hashimoto’s thyroiditis, 3, 11, 14 17, 49, 73 74, 90 93, 96, 99, 103, 105, 108 109, 117, 122, 148 152, 160 162, 167, 174 175, 187, 192, 201 202, 285 286 clinical presentation, 151 diagnosis, 151 epidemiology, 148 incidence of, 9 pathogenesis, 149 150, 149f, 150f and pregnancy, 265 267, 267b, 273 risk factors, 150 151 treatment, 152 Heart failure, 172, 174 175, 180 181, 184 185 Hemangiomas, 286 Hematopoietic system, 107

hyperthyroidism, 132 133 hypothyroidism, 107 Heparin, 184 Hepatic hemangiomatosis, 291 Heterozygous, 281 High-density lipoprotein cholesterol, 176 177 High human chorionic gonadotropin (hCG) levels, 122 123 Histrionic personality disorder, 196 HMG-CoA reductase enzyme, 177 Hoffmann syndrome, 106 Homeobox genes, 99 Homocysteine, 177 178 Homodimers, 57 58 Homozygous, 281 Honor Society of Nursing, 99 Horner syndrome, 158 Human leukocyte antigen G, 263 Human thyroglobulin (HTG), 270 Hung-up reflexes, 103 Hürthle cells, 149 150, 167 Hyaluronic acid, 101, 104 105 17-hydroxycorticosteroid, 108 2-hydroxyesterone, 109 Hyoid bone, 23 Hypercalcemia, 132 Hypercarotenemia, 104 Hypercholesterolemia, 176 178 Hyperemesis gravidarum, 260 261 Hyperfunctional multinodular goiter, 122 Hyperfunctional thyroid adenoma, 122 Hyperkinesia, 129 Hyperlipoproteinemia, 176 Hyperparathyroidism, 41 Hyperplastic phases, 74 75 Hypertension, 172 Hyperthyroidism, 3, 9, 11 12, 16, 85, 121 122, 153 154, 160, 167 168, 176 177, 182b, 184 185, 189, 197 198, 201, 204 burden of, 246 251, 250t, 251t and cardiovascular problems, 178 182 arrhythmia, 178 180 heart failure, 180 181 syncope, 180 with thyroid storm, 181 182 clinical presentation, 126 134, 127f cardiovascular system, 129 130 electrolyte metabolism, 133

311

312

Index

Hyperthyroidism (Continued) gastrointestinal system, 131 hematopoietic system, 132 133 integumentary system, 130 131 muscular system, 131 132 nervous system, 129 pretibial myxedema, 127 128 reproductive system, 133 134 respiratory system, 131 signs and symptoms, 126 skeletal system, 132 thyrotoxicosis signs and symptoms, 128t complications, 16 diagnosis of, 134 136, 135f, 136f differential diagnosis, 136b epidemiology of, 124 126 etiology of, 122 124, 123f incidence rate of, 12 pathophysiology of, 126 prevalence of, 126b schizophrenia, 203 subclinical hyperthyroidism, 140 141 treatment of, 136 140 beta-blockers, 138 iodine, 136 methimazole, 137 138 propylthiouracil, 137 138 radioiodine, 139 surgery, 139 140 Hyperthyrotropinemia, 15 Hypocalcemia, 158 Hypochronic anemia, 112 Hypoechoic echotexture of thyroid tissue, 151 Hypoechoic parenchyma, 230 Hypoparathyroidism, 41, 150 151, 236, 262 263 Hypotension, 173, 186 Hypothalamic pituitary thyroid axis, 59 60, 60f, 140, 195, 279 Hypothermia, 97 Hypothyroid cretinism, 280, 283 Hypothyroidism, 3, 6, 8 12, 16, 66, 84, 155, 167 168, 243, 282 anemia, 175 176 burden of, 245 246, 247t, 248t and cardiovascular problems, 172 174 bradycardia, 172 coronary artery disease, 172 diastolic hypertension, 172

dyspnea, 172 edema, 172 heart failure, 172, 174 hypotension, 173 clinical presentation, 101 111, 102f cardiovascular system, 104 catecholamines, 108 central and peripheral nervous system, 101 103 chondroitin sulfate, 101 electrolyte metabolism, 110 111 gastrointestinal system, 105 106 hematopoietic system, 107 hyaluronic acid, 101 integumentary system, 104 105 muscular system, 106 myxedema, 101 nutrient metabolism, 109 110 pituitary and adrenocortical function, 108 reproductive function, 108 109 respiratory system, 106 skeletal system, 107 complications, 16, 114 115 definition of, 90 diagnosis of, 111 112 differential diagnoses, 112 113 epidemiology of, 99 100 incidence rate of, 12 in infants and children, 284 287, 285b consumptive hypothyroidism, 286 287, 291 cretinism, 284 epiphyseal dysgenesis, 285 filter paper blood spots, 284 transient hypothyroidism, 286 life expectancy and mortality, 97b mechanisms of, 128f metabolic insufficiency, 116 on older adults, 101b pathogenesis of, 100 prevalence and incidence, 100b psychiatric symptoms of, 202 203 risk factors for, 100 subclinical, 115 116 treatment of, 113 114 types and etiology of, 90 99, 90f, 91t autoimmune, 92 93, 93f central, 98 99 congenital, 91 92

Index

cretinism, 94 drug-induced, 97 98 iatrogenic, 94 myxedema, 95 97, 96f primary, 90 91 Hypothyroxinemia, 15, 280

I Iatrogenic hyperthyroidism, 116 Iatrogenic hypothyroidism, 94 Ibuprofen, 167 168 Ichthyosis, 104 Idiopathic multifocal fibrosclerosis, 157 158 Immunoglobulin G4 (IgG4)-related disease, 157 159 Inappropriate thyroid-stimulating hormone secretion, 124 Inborn errors of thyroid metabolism, 91 92 Infantile hemangiomas, 287 Infectious thyroiditis, 9, 155 157 clinical presentation, 156 diagnosis, 156 epidemiology, 155 pathogenesis, 155 risk factors, 156 treatment, 157 Inferior cervical sympathetic ganglia, 29 Infiltrative dermopathy, 104, 127 128, 162 163 Infiltrative ophthalmopathy, 127, 160, 162 163 Inflammatory thyroid disease, 122 Inotropic effects of thyroid hormones, 104 Insulin-like growth factor 1, 107 Integumentary system, 104 105 hyperthyroidism, 130 131 hypothyroidism, 104 105 Interferon-alpha-provoked Graves’ disease, 159 Intermenstrual interval, 133 International Child Development Steering Group, 244 Interstitial myxedema, 106 Intrathoracic goiter, 78 Intrinsic hyperthyroidism, 262 Introns, 282 In vitro fertilization, 261 262 Iodate, 46 Iodide, 46, 49b ion diffusion, 32 oxidation, 49

transport, 47 48, 281 trapping, 46 47 Iodine (I), 29 31, 45 46, 54f, 231 deficiency, 60 dietary, 51 52, 51t, 281b and fetal development, 68b functions of, 46 51 absorption and metabolism, 46 49, 47f iodide oxidation, 49 iodothyronine formation, 49 50 thyroid hormone storage and release, 50 51 hyperthyroidism, 136 hypothalamic pituitary thyroid axis, 59 60, 60f optimal iodine daily requirements, 76t pregnancy, thyroid dysfunction in, 260 in seaweed, 70b sources of dietary iodine, 45 46 table salt vs. sea salt, 46b thyroid hormones and blood circulation, 54 59, 54f deiodination of iodothyronine, 57 58, 58f free thyroid hormones, 56 thyroid hormone action, 58 59, 59f thyroxine-binding globulin, 55 transmembrane thyroid hormone, 57, 57f transthyretin (TTR), 55 56 thyrotropin, effect of, 52 54, 53t toxicity, 60 61 Iodine deficiency, 8 13, 15, 45 46, 51 52, 60, 65, 67f, 85, 99 100, 243 245, 245b, 289 causes, 66 complications of, 72 73 cretinism, 66 67 DALYs, 18 epidemiology, 68 70, 68f, 69f during fetal life, 280 281 global effects of, 243 245, 245b goitrogens, 67 68 hypothyroidism, 90 91, 94 iodine deficiency disorders (IDD), 66, 66t management, 71 72 risk factors, 70 Iodine deficiency disorders (IDD), 66, 66t, 71 World Health Organization criteria for, 72t Iodine Global Network (IGN), 69 Iodine-induced hyperthyroidism, 71 Iodization, 12 13, 15

313

314

Index

Iodothyroglobulin, 26 Iodothyronine formation, 49 50 Iodotyrosine dehalogenase, 282 Iodotyrosine deiodinase (IYD) enzymes, 48 49 Ipilimumab, 162 Isthmectomy, 158 159 Isthmus, 24

J Juvenile goiter, 75 Juvenile hypothyroidism, 108 109, 284

K Kallikreins, 218 Klinefelter syndrome, 148 Kocher Debré Sémélaigne syndrome, 106

L Lactescent serum, 96 Lagophthalmos, 164 Large pleomorphic giant cells, 219 Laryngeal prominence, 23 Laryngoscopic examination, 156 Leptin, 110 Levothyroxine, 13, 75, 84, 92, 108 109, 113 114, 116 117, 139, 141, 152, 165, 167 168, 176, 186, 216, 265, 269 271, 280, 286 287, 289 Life expectancy, 6 8, 7f, 8b, 8f Life table, 6 Lingual thyroid, 23 24, 283 Liothyronine, 114, 195, 286 287, 289 Lipogenesis, 38 Lipoprotein lipase (LPL), 177 Lithium, 75, 94, 97 98, 100, 192 Longevity. See Life expectancy Low-density lipoprotein (LDL), 110, 172, 176 177 Lugol’s iodine, 164 165 Lymphatic drainage, 27 29 Lymph nodes, 27 29 Lymphocytic thyroiditis, 16, 83

M MacArthur Bates Communicative Development Inventories, 194 Macrocalcifications, 230

Macrocytic anemia, 107, 112, 175 Macropinocytosis, 50 Magnetic resonance imaging (MRI), 29 Malignant thyroid tumors anaplastic carcinoma, 218 219, 219b follicular carcinoma, 215 216, 215f, 216f medullary carcinoma, 216 218, 217f, 218f papillary carcinoma, 212 215, 214f Mania, 192 Manic-depressive disorder, 199 Maternal fetal interactions, 278 279 Maternal TH deficiency, 94 Means Lerman scratch, 129 130 Medullary thyroid cancer (MTC), 17, 211 212, 241, 269 Megacolon, 114 115 Menorrhagia, 101, 107 Mental disorders, 192 193 bipolar I disorder, 199 burden of, 198 200 cretinism, 193 194 externalizing disorders, 198 Graves’ disease, 196 197 hyperthyroidism, 197 198, 201 myxedema, 194 195 nonaffective psychosis, 199 stress, 196 197 Metabolic insufficiency, 116 Metachromatically staining, 105 Metastatic thyroid cancer, 124 Methimazole, 48 49, 79, 92, 137 138, 164 165, 197, 262 Methimazole embryopathy, 263f Methotrexate, 158 159 2-methoxyestrone, 109 Methylprednisolone, 166 Methylthiouracil, 204 Metronidazole, 157 Microcalcifications, 230 Microcarcinomas, 229 Microchimerism, 224 Microcuries, 165 Micropinocytosis, 50 Middle cricothyroid ligament, 27 29 Mild hypothyroidism, 115 Mild thyroid dysfunction, 140 Miscellaneous malignancies, 211 Moist rales, 182

Index

Monocarboxylate transporter 8 (MCT8), 50 Monoclonal adenomas, 82 Monoclonal nodules, 78 Monoiodotyrosine (MIT), 282 Monotropic deficiency, 98 Motesanib, 238 Mucositis, 237 238 Mucrystallin, 57 Multinodular goiter, 73, 77 78, 82, 85, 123, 141 Multiple endocrine neoplasia (MEN) syndrome, 221 MEN 2A, 217, 241 type 1, 208 type 2, 227, 229 Muscular system, 106 hyperthyroidism, 131 132 hypothyroidism, 106 Mycophenolate, 158 159 Myxedema, 33 35, 95 97, 96f, 101, 102f, 118, 172, 194 195, 287 cretinoid state in adults, 95 definition of, 194 195 diagnosis of, 95 myxedema coma, 96 97 signs and symptoms, 95 Myxedema coma, 96 97, 106 diagnoses of, 96 pathophysiologic features, 97 Schmidt syndrome, 97 symptoms, 96 treatment, 114 Myxedema ileus, 105 Myxedema madness, 101 103, 194 195, 195b Myxedema megacolon, 105 Myxedematous cretinism, 280 Myxedematous psychosis, 194 195 Myxedematous tissue, 104

N National Health and Nutrition Examination Survey (NHANES III), 99, 124 125 Near-total thyroidectomy, 139 140 Neonatal thyroid-stimulating hormone screening program, 15 Nervous system, 129 Neurological cretinism, 280, 283 Neurotransmitters, 192 Nitric oxide, 129 130

Nonaffective psychosis, 199 Nonautoimmune autosomal dominant hyperthyroidism, 124 Non-communicable diseases, 4 5 Noniodized salt, 46 Nontoxic multinodular goiter, 8 9, 77 79, 78f Nontoxic nodular goiters, 75 Norepinephrine, 173 Normochromic anemia, 112 Normocytic anemia, 112, 175 NSAID, 155, 166 168 Nutrient metabolism, 109 110

O Obsessive-compulsive disorder, 192 Octreotide, 131, 269 Omohyoid, 24 Omphalocele, 262 Omphalomesenteric duct anomaly, 262 Onycholysis, 130 131 Oophorectomy, 223 224 Oppositional defiant disorder, 198 Organic psychosis, 114 115 Organification, 49, 137 Orphan Annie eye nuclei, 213 214 Orthostatic hypotension, 173 Osteitis fibrosa cystica, 41 Osteoblasts, 41, 284 285 Osteoclasts, 41, 284 285 Overt hyperthyroidism, 15 16, 124, 249, 254 costs of, 251t incidence, 125t, 248 249 medical services for, 250t prevalence of, 9, 125t Overt hypothyroidism, 92 93, 107, 177, 245 246 costs of, 248t estimated medical services for, 247t levothyroxine, 186 Oxidability, 177 2-oxygenation, 109 Oxyphil metaplasia, 93

P Painless thyroiditis. See Silent lymphocytic thyroiditis Palma erythema, 130 131 Palpable thyroid nodules, 142

315

316

Index

Panic attacks, 196 Papillary carcinoma, 211 Papillary microcarcinoma, 214 215 Papillary thyroid cancer, 15, 17, 240 Parafollicular cells, 26 27 Paranoid reactions, 129 Parathormone, 40 Parathyroid glands, 21, 36 Parathyroid hormone (PTH), 36, 41b Paratracheal nodes, 269 270 Paroxysmal atrial tachycardia, 180 181 Pemberton maneuver, 82 83 Pembrolizumab, 162 Pendred syndrome, 48, 102 103, 282 Pendrin, 48 Penicillin, 157 Penicillinase-resistant penicillins, 157 Periodic acid-Schiff positive, 105 Periorbital myxedema, 151 Peripheral nervous system, 101 103 Perithyroidal soft tissue, 158 Pernicious anemia, 107, 113, 150 151, 176 Pheochromocytoma, 135, 218, 269 Phospholipase A2, 177 178 Piriform sinus, 156 Pituitary and adrenocortical function, 108 Placental abruption, 264 Plasma gonadotropins, 109 Pleuropericardial friction rub, 129 130 Plummer nails, 130 131 Plummer syndrome. See Toxic multinodular goiter Plunging goiter, 78 Pneumocystis carinii,, 156 Polyclonal nodules, 78 Polyendocrine syndrome, 105, 114 115 Polyphasic action, 106 Postpartum thyroiditis, 152, 154b, 267, 274 Postthyroiditis hypothyroidism, 286 Postviral thyroiditis, 111 Potassium iodate, 71 Potassium iodide, 71 Potassium perchlorate, 204 Prasad’s syndrome, 151 Preclinical hypothyroidism, 115 Prednisolone, 158 159, 167 Prednisone, 167 168 Preeclampsia, 262 Pregnancy, 259

Graves’ disease, 263 264, 264b, 272 Hashimoto’s thyroiditis, 265 267, 267b, 273 hypothyroidism, 272 silent lymphocytic thyroiditis, 267 268, 268b and subclinical hypothyroidism, 265, 273 thyroid cancer, 268 271 thyroid function in, 260 261, 260f, 261b transient gestational thyrotoxicosis, 261 263, 263f, 271 Premature beats, 172 Pretibial myxedema, 104, 127 128, 128f, 162, 267 268 Primary hyperthyroidism, 10 11, 125 Primary hypothyroidism, 90 91, 91t, 101, 102f, 105, 108 109, 111, 113, 140, 150 151, 201, 288 achlorhydria, 105 signs and symptoms of, 101 treatment of, 113 Primary thyroid B-cell lymphoma, 148 Propranolol, 138, 188, 204, 287 Proptotic eyes, 166 Propylthiouracil, 48 49, 79, 92, 137 138, 164 165, 197, 262, 271 Prostration, 150 151 Proteinaceous ground substance, 101 Protein synthesis, 38 Proteolysis, 50 Psammoma bodies, 213 214 Pseudohypoparathyroidism type 1A, 283 284 Pseudotuberculous thyroiditis, 111 Psychotropic medications, 192 193 Pulmonary edema, 182 Pulmonary hypertension, 185 Pyramidal lobe, 23

R Radioactive iodine, 79, 85, 140, 143, 154f, 208, 236 238, 253, 267 Radioactive iodine uptake (RAIU), 112, 122, 134 136, 154 155 Radiofrequency catheter ablation, 180 Radioiodine therapy, 138 139, 164 165, 228, 270 Rearranged during transfection (RET) mutations, 211, 269 Rearranged during transfection (RET) protooncogene, 217

Index

Reproductive system, 108 109 hyperthyroidism, 133 134 hypothyroidism, 108 109 Resolving thyroiditis, 152 Respiratory system, 106 hyperthyroidism, 131 hypothyroidism, 106 Retinoid X receptor (RXR), 58 59, 98 99 Retinol-binding protein, 55 56 Retroperitoneal fibrosis, 174 175 Reverse triiodothyronine (rT3), 57 58, 277 278 Rhabdomyolysis, 177 178 Rheumatoid arthritis, 150 151 Riedel’s thyroiditis, 9, 83, 157 159, 168 clinical presentation, 158 diagnosis, 158 epidemiology, 157 levothyroxine, 168 pathogenesis, 157 158 risk factors, 158 treatment, 158 159 Rundle’s curve, 164

S Salt iodization, 12 13, 52b, 71, 85, 244 Schizoid reactions, 129 Schizophrenia, 203 Schmidt syndrome, 97, 150 151 Scintigraphy, 38 40, 283 Scintiscan, 212 Secondary hyperthyroidism, 121 122, 135 Secondary hypothyroidism, 90 91, 91t, 98, 113 114, 118 119 Selenium, 14, 46 47, 57 58 Selenocysteine, 57 58 Selenocysteine insertion sequence (SECIS), 58 Selenomethionine, 14 Selumetinib, 238 Septations, 151 Sequenced Inventory of Communication Development, 194 Serpin, 55 Serum thyroglobulin, 287 Shock, 181 182 Sialylated thyroxine-binding globulin, 55 Silent lymphocytic thyroiditis, 267 268, 268b Silent thyroiditis, 274 Silver iodate, 46

Simple cuboidal epithelium, 24 25 Simple goiter, 33 35, 73, 75 Sinus tachycardia, 179 180, 185 Sjögren syndrome, 150 151 Skeletal system, 107 hyperthyroidism, 132 hypothyroidism, 107 Sodium iodate, 46 Sodium iodide, 138 Sodium-iodide cotransporter (SLC5A) gene, 46 47 Sodium-iodide symporter (NIS) membrane protein, 46 48, 231, 281 Sodium-iodide transporter, 47 48 Sodium potassium ATPase, 33 35 Solitary thyroid nodule, 79, 207 208 Somatostatin, 98 99 Sonolucent areas, 154 155 Sorafenib, 238 Spindle cells, 219 Sporadic congenital hypothyroidism, 289 Sporadic goiter, 8 9 Star D report, 193 Sternothyroid, 24 Stippled epiphysis, 285 Stress, 196 197 Stroke, 184 Stroma, 26 Struma. See Riedel’s thyroiditis Struma ovarii, 124 Subacute lymphocytic thyroiditis, 152 Subacute thyroiditis, 9, 50, 152 155, 167, 174 175 clinical presentation, 153 154 diagnosis, 154 155, 154f epidemiology, 152 pathogenesis, 152, 153f risk factors, 153 treatment, 155 Subclinical hyperthyroidism, 15 16, 103, 140 141, 183 184, 187, 203, 249 costs of, 251t medical services for, 250t prevalence of, 125t Subclinical hypothyroidism, 92 93, 99, 115 116, 152, 245 246, 261 costs of, 248t estimated medical services for, 247t pregnancy, 265, 273 and pregnancy, 265, 273

317

318

Index

Substance dependence without physiological dependence syndrome, 199 Substance dependence with physiological dependence syndrome, 199 Subtotal thyroidectomy, 139 140 Sunitinib, 97 98, 238 Superior vena cava syndrome, 78 79 Supraventricular cardiac arrhythmias, 187 Supraventricular rhythm, 179 180 Suspected autoimmune thyroiditis, 83 Syncope, 180 Syncytiotrophoblast, 47 48

T Table salt vs. sea salt, 46b Tall-cell variant, 214 215 Tamoxifen, 158 159 Tapioca, 76 77, 94 Technetium (99mTc) pertechnetate, 29, 154 155, 267, 283 284 Telangiectasia, 130 131 Telopeptides, 132 Teratogenic potential, 270 Tertiary hypothyroidism, 98 Tetraiodothyronine. See Thyroxine (T4) Thermogenesis, 38 Thiocyanates, 94 Thionamide antithyroid drugs, 125, 137 Thiourea drugs, 48 50 Thrombectomy, 184 Thyrocalcitonin, 26 27 Thyrocytes, 91 Thyroglobulin, 29 31, 46, 50 breakdown, 31 removal of, 31 synthesis, 282 thyroxine residues, 49 50 triiodothyronine residues, 49 50 tyrosine, 32 Thyroglossal duct, 21 24 Thyroid agenesis, 92, 283 284 Thyroid anlage, 21 22 Thyroid arteries, 27 Thyroid autonomy, 208 209 Thyroid-binding globulins, 31 Thyroid cancers, 10 11, 15, 82 83, 142, 187, 207 208 benign adenomas, 208 210

clinical presentation, 209 210 diagnosis, 210 epidemiology, 208 pathogenesis, 208 209, 209f risk factors, 209 treatment, 210 clinical presentation, 226 227 complications, 17 costs for treatments, 18 diagnosis of, 227 234, 228b fine-needle aspiration, 228, 231 232 initial evaluation, 228 229 initial laboratory studies, 229 231 positron emission tomography (PET), 227 228 staging, 232 234, 233t, 235f thyroid scan, 228 global effects of, 252 253, 253b incidence of, 12, 13f, 14f malignant tumors, 211 223 classifications, 212 219, 213t epidemiology, 219 221, 220f, 222f etiology, 211 212 pathogenesis, 221 223, 223f mortality rates of, 238 239 during pregnancy, 268 271 risk factors, 223 226, 224b dietary factors, 225 exposure to radiation, 224 225 nonmalignant thyroid disorder relationships, 225 226 treatment for, 235 238 chemotherapy, 238 costs for, 239 radiation therapy, 236 238 surgery, 235 236 targeted therapy, 238 Thyroid cartilage, 23 Thyroid crisis, 181, 196 Thyroid dermopathy, 131 Thyroidectomy, 29b, 164 165, 235 236 Thyroid follicles, 24 25, 31 Thyroid function in newborn, 279 280, 280b in pregnancy, 260 261, 260f, 261b Thyroid gland, 21 embryology, 21 22, 22f functions of, 36 38

Index

imaging of, 29, 30f parathyroid glands, 38 41, 40f size of, 24 structure of, 23 29, 23f Adam’s apple, 23 alveolar gland, 23 Berry’s ligament, 23 conical pyramidal lobe, 23 convex lateral surface, 24 cricoid cartilage, 23 ectopic thyroid tissue, 23 24 foramen cecum, 23 24 histology, 24 27, 25f innervation, 29 isthmus, 24 lingual thyroid, 23 24 lobes, 23 lymphatic drainage, 27 29 thyroglossal duct cysts, 23 24 thyroid cartilage, 23 vascular supply, 27, 28f thyroid hormone synthesis and release, 32 36, 33f, 34f calcitonin, 36, 37f dietary iodide ion (I) absorption, 32 iodide ion diffusion, 32 thyroxine, 35 36 thyroxine (T4), 32 triiodothyronine, 35 triiodothyronine (T3), 32 tyrosine linkage, 32 thyroid-stimulating hormone, 29 32 Thyroid hormone replacement therapy, 143, 155, 177 178, 192, 235 236 Thyroid hormone response elements (TREs), 58 59 Thyroid hormones (THs), 26, 29 31, 107, 177, 192 and blood circulation, 54 59, 54f deiodination of iodothyronine, 57 58, 58f free thyroid hormones, 56 thyroid hormone action, 58 59, 59f thyroxine-binding globulin, 55 transmembrane thyroid hormone, 57, 57f transthyretin (TTR), 55 56 effects of, 37 38, 39t metabolism, 67f release, 31

storage and release, 50 51 synthesis and release, 32 36, 33f, 34f calcitonin, 36, 37f dietary iodide ion (I) absorption, 32 iodide ion diffusion, 32 thyroxine (T4), 32, 35 36 triiodothyronine (T3), 32, 35 tyrosine linkage, 32 Thyroid hormones (THs) deficiency, 65, 101 103 Thyroid hypoplasia, 92 Thyroiditis, 11 12, 16, 122, 225 226 and cardiovascular complications, 174 178, 178b anemia, 175 176 heart failure, 174 175 hypercholesterolemia, 176 178 definition of, 148 Hashimoto’s thyroiditis, 148 152 infectious, 155 157 Riedel’s thyroiditis, 157 159 subacute, 152 155 Thyroid lymphoma, 16 17 Thyroid nodules, 8 12, 16, 73 74, 80 83, 142, 208 Thyroid peroxidase (TPO), 49, 282 deficiency, 278 279 TPO antibody, 108 109, 112, 115 116, 265, 274 Thyroid-regulating hormone (TRH), 26, 98 99, 278 Thyroid scan, 228 Thyroid-specific transcription factor PAX8, 283 Thyroid-stimulating hormone (TSH), 26, 29 32, 36 38, 45 48, 50, 66 67, 81, 83, 90 91, 94 95, 98 99, 111 112, 132, 134, 137, 141 142, 151, 163 164, 171, 208, 227, 265, 278 trimester-specific ranges for, 266 Thyroid-stimulating hormone receptor (TSHR), 52, 54, 79, 81, 149, 208 209, 260 261 Thyroid-stimulating hormone (TSH)-secreting pituitary tumor, 121 122, 135 Thyroid storm, 16, 134, 139 140, 196 197, 236, 264 265 cardiovascular disease with, 181 182 coma, 182, 183t shock, 181 182 thyroid crisis, 181

319

320

Index

Thyroid storm (Continued) propylthiouracil, 197 symptoms of, 197 Thyroid transcription factors 1 and 2 (TTF-1 and TTF-2), 283 Thyroid uptake and scan, 280 Thyroperoxidase, 14, 29 31, 36 Thyrotoxic crisis. See Thyroid storm Thyrotoxic myopathy, 131 132 Thyrotoxicosis, 73, 83, 121 122, 129 131, 148, 159, 175, 180 182, 203 diagnosis of, 135 signs and symptoms, 128, 128t Thyrotoxicosis factitia, 122 Thyrotropin, 52 54, 53t, 186 Thyrotropin-blocking antibodies (TRBAbs), 290 Thyrotropin receptor antibody, 261 Thyrotropin-releasing hormone (TRH), 32 Thyrotropin-secreting pituitary adenomas, 98 99 Thyrotropin-stimulated thyroid cell functions, 53t Thyroxine (T4), 26, 32, 35 36, 46 47, 50 51, 60f, 114, 142 143, 151, 154f, 188, 192 193, 270 271, 277 279, 288 Thyroxine-binding globulin (TBG), 55, 260, 277 TNM staging system, 232 234, 233t Total thyroidectomy, 165, 218 Toxic diffuse goiter. See Graves’ disease Toxic multinodular goiter, 78 79, 123, 143 Toxic solitary goiter, 123 Toxic thyroid hyperplasia, 81 TRAb test, 261 Tracheoesophageal nodes, 269 270 Transient congenital hypothyroidism, 92 Transient gestational hyperthyroidism (GTT), 260 261, 271 Transient gestational thyrotoxicosis, 261 263, 263f, 271 Transient hypothyroidism, 286, 290 Transmembrane thyroid hormone, 57, 57f Transthyretin (TTR), 31, 55 56 Tremelimumab, 162 Triiodothyronine (T3), 26, 32, 35, 46 47, 54 55, 60f, 66 67, 114, 154 155, 160, 177, 188, 192 193, 279 Trophic hormones, 77 Trophoblastic disease, 262

Trophoblasts, 263 Trousseau sign, 236 T3 toxicosis, 126, 160 Turner syndrome, 148 Type 1 deiodinase (D1), 277 278 Type 1 diabetes, 93, 143, 150 151 Type I muscle fibers, 106 Type 2 deiodinase (D2), 277 278 Type 3 deiodinase (D3), 277 278 Type 2 polyglandular deficiency syndrome, 150 151 Typical ophthalmopathy, 160 Tyrosine kinase inhibitors (TKIs), 97 98 Tyrosine linkage, 32

U Ubiquitin, 279 Ultimobranchial glands, 22 Ultrasonography, 29, 84, 156, 210, 230 Ultrasound elastography (USE), 231 Undifferentiated thyroid carcinoma, 168 Urinary iodine concentration, 244 Urothelial epithelia, 277 278

V Vandetanib, 238 Vascular endothelial growth factor (VEGF), 238 Very-low-density lipoprotein (VLDL), 177 Vitiligo, 130 131, 150 151

W Warfarin, 138 Westergren scale, 154 155 Whickham Study, 124 125 Wolff Chaikoff effect, 138

X Xerostomia, 237 238

Y Years lost due to disability (YLD), 17 Years of life lost (YLL), 17 Yersinia enterocolitica,, 160 162 Yuca, 76 77