Thyroid Disease: Challenges and Debates [1st ed.] 9783030487744, 9783030487751

Table of contents :
Front Matter ....Pages i-xxiv
Thyroid Disease During Pregnancy (Mahmoud F. Sakr)....Pages 1-70
Hashimoto’s Disease (Mahmoud F. Sakr)....Pages 71-132
Hürthle Cell Lesions of the Thyroid (Mahmoud F. Sakr)....Pages 133-191
Solitary Thyroid Nodule (Mahmoud F. Sakr)....Pages 193-303
Retrosternal Goiter (Mahmoud F. Sakr)....Pages 305-344
Thyroid Cancer (Mahmoud F. Sakr)....Pages 345-456
Recurrent Thyroid Disease (Mahmoud F. Sakr)....Pages 457-504
Thyroidectomy Techniques (Mahmoud F. Sakr)....Pages 505-597
Post-Thyroidectomy Hypocalcemia (Mahmoud F. Sakr)....Pages 599-662
Thyroid Auto-Transplantation (Mahmoud F. Sakr)....Pages 663-699

Citation preview

Thyroid Disease Challenges and Debates Mahmoud F. Sakr

123

Thyroid Disease

Mahmoud F. Sakr

Thyroid Disease Challenges and Debates

Mahmoud F. Sakr Department of Surgery University of Alexandria Alexandria Egypt

ISBN 978-3-030-48774-4    ISBN 978-3-030-48775-1 (eBook) https://doi.org/10.1007/978-3-030-48775-1 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To my students and colleagues

Preface

In this single-author book, we aim at emphasizing established concepts, displaying the ongoing arguments, controversies, challenges, and debates on thyroid disease with a view to clarifying some uncertainties, and making suggestions, which may contribute to further resolving others. This book, with 210 images, will provide a valuable source of knowledge and reference for all specialists and trainees entrusted with the care of patients suffering from thyroid disease. It includes ten chapters, namely, thyroid disease during pregnancy, Hashimoto's disease, Hurthle cell lesions, solitary thyroid nodule, retrosternal goiter, thyroid cancer, recurrent thyroid disease, thyroidectomy techniques, post-thyroidectomy hypocalcemia, and thyroid auto-transplantation. It is my collective hope that head and neck surgeons, endocrinologists, and clinicians of other specialties will find this book to be a useful and indispensable resource. Alexandria, Egypt

Mahmoud F. Sakr

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Acknowledgments

I would like to thank all those who helped and encouraged me during the writing, editing, and revision of this book. I would like to express my appreciation and gratitude to my wife and children for their continuous support and unconditioned love.

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Contents

1 Thyroid Disease During Pregnancy����������������������������������������������������������   1 1.1 Introduction����������������������������������������������������������������������������������������   1 1.2 Physiological Changes During Pregnancy������������������������������������������   2 1.3 Thyroid Function Tests in Pregnancy ������������������������������������������������   3 1.3.1 How Do Thyroid Function Tests Change During Pregnancy?������������������������������������������������������������������   3 1.3.2 What Is the Normal Range for TSH in Each Trimester?��������   5 1.3.3 Recommendations������������������������������������������������������������������   6 1.4 Screening for Maternal Thyroid Dysfunction������������������������������������   7 1.4.1 Introduction����������������������������������������������������������������������������   7 1.4.2 Screening for Thyroid Dysfunction����������������������������������������   7 1.4.3 Efficacy of Case Finding��������������������������������������������������������   8 1.4.4 Thyroid Screening in Pregnancy: Current Practice and Cost-­Effectiveness������������������������������������������������������������   9 1.4.5 Recommendations������������������������������������������������������������������  10 1.4.6 Conclusion������������������������������������������������������������������������������  11 1.5 Iodine Deficiency During Pregnancy��������������������������������������������������  11 1.5.1 Requirement of Iodine During Pregnancy and Lactation��������������������������������������������������������������������������  11 1.5.2 Requirement of Iodine in Neonates����������������������������������������  13 1.5.3 Conclusion������������������������������������������������������������������������������  14 1.5.4 Recommendations������������������������������������������������������������������  14 1.6 Hyperthyroidism in Pregnancy ����������������������������������������������������������  15 1.6.1 Definitions������������������������������������������������������������������������������  15 1.6.2 Causes of Thyrotoxicosis��������������������������������������������������������  15 1.6.3 Diagnosis of Hyperthyroidism in Pregnancy��������������������������  16 1.6.4 Risks of Hyperthyroidism During Pregnancy on Fetal and Maternal Health��������������������������������������������������  16 1.6.5 Treatment of Hyperthyroidism During Pregnancy ����������������  18 1.6.6 Treatment of Hyperthyroidism During the Post-partum Period������������������������������������������������������������  22 1.6.7 Recommendations������������������������������������������������������������������  22

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1.7 Hypothyroidism in Pregnancy������������������������������������������������������������  24 1.7.1 Iodine Deprivation and Goiter Formation������������������������������  24 1.7.2 Overt or Subclinical Hypothyroidism? ����������������������������������  25 1.7.3 Isolated Hypothyroxinemia����������������������������������������������������  25 1.7.4 Incidence of Hypothyroidism During Pregnancy ������������������  25 1.7.5 Risks of Hypothyroidism on Fetal and Maternal Health��������  26 1.7.6 Treatment of Hypothyroidism During Pregnancy������������������  30 1.7.7 Treatment of Hypothyroidism During the Post-partum Period������������������������������������������������������������  33 1.7.8 Recommendations������������������������������������������������������������������  33 1.8 Autoimmune Thyroiditis in Pregnancy����������������������������������������������  35 1.8.1 Incidence ��������������������������������������������������������������������������������  35 1.8.2 Risks on Fetal and Maternal Health����������������������������������������  35 1.8.3 Treatment��������������������������������������������������������������������������������  37 1.8.4 Recommendations������������������������������������������������������������������  38 1.9 Infertility and Miscarriage: Impact of Thyroid Dysfunction��������������  38 1.9.1 Introduction����������������������������������������������������������������������������  38 1.9.2 Autoimmunity and Reproductive Failure�������������������������������  39 1.9.3 Impact of TAI on Infertility����������������������������������������������������  40 1.9.4 Impact of TAI on Miscarriage������������������������������������������������  42 1.9.5 Conclusions����������������������������������������������������������������������������  47 1.10 Post-partum Thyroiditis����������������������������������������������������������������������  47 1.10.1 Definition��������������������������������������������������������������������������������  47 1.10.2 Incidence ��������������������������������������������������������������������������������  48 1.10.3 Clinical Evaluation and Treatment������������������������������������������  48 1.10.4 Recommendations������������������������������������������������������������������  48 1.11 Thyroid Nodules and Thyroid Cancer During Pregnancy������������������  49 1.11.1 Pregnancy and the Risk of Thyroid Cancer����������������������������  49 1.11.2 Diagnostic Strategy for Thyroid Nodules Detected During Pregnancy����������������������������������������������������  50 1.11.3 Impact of Pregnancy on the Prognosis of Thyroid Carcinoma������������������������������������������������������������  51 1.11.4 Management of Benign Thyroid Nodules During Pregnancy ������������������������������������������������������������������  52 1.11.5 Management of Thyroid Cancer During Pregnancy ��������������  52 1.11.6 Pregnancy After Treatment of DTC����������������������������������������  54 1.11.7 Conclusions����������������������������������������������������������������������������  55 1.11.8 Recommendations������������������������������������������������������������������  55 References����������������������������������������������������������������������������������������������������  56 2 Hashimoto’s Disease����������������������������������������������������������������������������������  71 2.1 Historical Review��������������������������������������������������������������������������������  71 2.2 Epidemiology��������������������������������������������������������������������������������������  73 2.2.1 Incidence ��������������������������������������������������������������������������������  73 2.2.2 Prevalence ������������������������������������������������������������������������������  74

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2.3 Pathology��������������������������������������������������������������������������������������������  75 2.3.1 Gross Appearance ������������������������������������������������������������������  75 2.3.2 Microscopic Picture����������������������������������������������������������������  75 2.4 Etiology and Risk Factors������������������������������������������������������������������  78 2.4.1 Genetic Factors ����������������������������������������������������������������������  78 2.4.2 Nongenetic Factors ����������������������������������������������������������������  81 2.5 Pathogenesis����������������������������������������������������������������������������������������  82 2.6 Clinical Course������������������������������������������������������������������������������������  87 2.6.1 Goiter (Neck Swelling) ����������������������������������������������������������  88 2.6.2 Pain/Tenderness����������������������������������������������������������������������  88 2.6.3 Hypothyroidism����������������������������������������������������������������������  89 2.6.4 Associated “Unusual” Syndromes������������������������������������������  89 2.6.5 Neoplastic Transformation������������������������������������������������������  90 2.6.6 Remission of Hashimoto’s Thyroiditis: Pregnancy����������������  91 2.6.7 Painless (Silent) and Post-partum Thyroiditis (PPT)��������������  92 2.6.8 Hashimoto’s Encephalopathy�������������������������������������������������  93 2.6.9 Hashimoto’s Ophthalmopathy������������������������������������������������  94 2.6.10 Summary of Various Presentations of Hashimoto’s Thyroiditis������������������������������������������������������������������������������  94 2.7 Hashimoto’s Encephalopathy��������������������������������������������������������������  95 2.7.1 Introduction����������������������������������������������������������������������������  95 2.7.2 Definition and Synonyms��������������������������������������������������������  95 2.7.3 History������������������������������������������������������������������������������������  96 2.7.4 Epidemiology��������������������������������������������������������������������������  96 2.7.5 Pathogenesis����������������������������������������������������������������������������  96 2.7.6 Pathology��������������������������������������������������������������������������������  97 2.7.7 Clinical Presentation ��������������������������������������������������������������  97 2.7.8 Diagnosis��������������������������������������������������������������������������������  97 2.7.9 Differential Diagnosis ������������������������������������������������������������  98 2.7.10 Treatment��������������������������������������������������������������������������������  99 2.7.11 Prognosis��������������������������������������������������������������������������������  99 2.8 Iodine Metabolism and Effects ����������������������������������������������������������  99 2.9 Diagnosis and Differential Diagnosis ������������������������������������������������ 100 2.9.1 Clinical Evaluation������������������������������������������������������������������ 100 2.9.2 Laboratory Tests���������������������������������������������������������������������� 102 2.9.3 Histology/Cytology���������������������������������������������������������������� 103 2.9.4 Isotope Scanning�������������������������������������������������������������������� 104 2.9.5 Ultrasound Imaging���������������������������������������������������������������� 104 2.9.6 Evaluating Variations in Presentation of Hashimoto’s Thyroiditis������������������������������������������������������������������������������ 105 2.9.7 Evaluating Complications of Hypothyroidism ���������������������� 105 2.9.8 Differential Diagnosis ������������������������������������������������������������ 106 2.10 Association with Papillary Thyroid Carcinoma���������������������������������� 107 2.10.1 Introduction���������������������������������������������������������������������������� 107 2.10.2 Meta-analysis�������������������������������������������������������������������������� 108

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2.10.3 HT in PTC Versus Benign Lesions ���������������������������������������� 108 2.10.4 HT in PTC Versus Other Carcinomas ������������������������������������ 110 2.10.5 Clinico-pathological Characteristics of PTCs with HT���������� 110 2.10.6 Analysis of Survival���������������������������������������������������������������� 111 2.10.7 Significance of the Presence of Hashimoto’s Thyroiditis in PTC������������������������������������������������������������������ 111 2.10.8 Conclusions���������������������������������������������������������������������������� 112 2.11 Management���������������������������������������������������������������������������������������� 112 2.11.1 No Treatment: Observation and Monitoring�������������������������� 112 2.11.2 Medical Treatment������������������������������������������������������������������ 113 2.11.3 Surgical Treatment������������������������������������������������������������������ 118 2.11.4 Long-Term Monitoring ���������������������������������������������������������� 119 2.11.5 Patient Education�������������������������������������������������������������������� 119 2.11.6 Summary of Management of Hashimoto’s Thyroiditis���������� 119 2.12 Prognosis�������������������������������������������������������������������������������������������� 120 2.13 Summary �������������������������������������������������������������������������������������������� 121 References���������������������������������������������������������������������������������������������������� 121 3 Hürthle Cell Lesions of the Thyroid�������������������������������������������������������� 133 3.1 Introduction���������������������������������������������������������������������������������������� 133 3.2 Controversy of Nomenclature������������������������������������������������������������ 133 3.2.1 Histology: What Are Hürthle Cells (HCs)?���������������������������� 134 3.2.2 Historical Controversy: Hürthle or Ashkanazy? �������������������� 136 3.2.3 Controversy of Origin: Follicular or Para-follicular Cells?���������������������������������������������������������� 136 3.3 Controversy of Diagnosis�������������������������������������������������������������������� 136 3.3.1 Is It a Hürthle Cell Lesion (HCL)? ���������������������������������������� 136 3.3.2 Hürthle Cell Lesion: The Challenge of Neoplastic or Non-­neoplastic?������������������������������������������������������������������ 137 3.4 Controversy of Hürthle Cell Neoplasm���������������������������������������������� 142 3.4.1 The Challenge of Benign or Malignant���������������������������������� 142 3.4.2 Stratification of HCC Risk������������������������������������������������������ 150 3.4.3 Differential Diagnosis of “True” Hürthle Cell Lesions���������������������������������������������������������������������������� 151 3.5 Hürthle Cell Tumor: Controversy of Pathological Classification�������������������������������������������������������������������������������������� 151 3.6 Hürthle Cell Tumor: Controversy of Clinical Behavior���������������������� 153 3.7 Hürthle Cell Neoplasm: Debates in Management������������������������������ 155 3.7.1 First Debate���������������������������������������������������������������������������� 155 3.7.2 Second Debate������������������������������������������������������������������������ 155 3.7.3 Third Debate �������������������������������������������������������������������������� 156 3.7.4 Conclusion������������������������������������������������������������������������������ 156 3.8 Hürthle Cell Adenoma (HCA)������������������������������������������������������������ 157 3.8.1 Definition�������������������������������������������������������������������������������� 157 3.8.2 Risk Factors and Clinical Significance ���������������������������������� 157

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3.8.3 Histology�������������������������������������������������������������������������������� 157 3.8.4 Treatment�������������������������������������������������������������������������������� 158 3.8.5 Hürthle Cell Adenoma in Hashimoto’s Thyroiditis���������������� 158 3.9 Hürthle Cell Carcinoma (HCC)���������������������������������������������������������� 160 3.9.1 Background ���������������������������������������������������������������������������� 160 3.9.2 Pathophysiology���������������������������������������������������������������������� 160 3.9.3 Epidemiology�������������������������������������������������������������������������� 162 3.9.4 Etiology���������������������������������������������������������������������������������� 163 3.9.5 Clinical Presentation and Differentia Diagnosis�������������������� 163 3.9.6 Investigations (Work-Up)�������������������������������������������������������� 164 3.9.7 Staging of Hürthle Cell Carcinoma���������������������������������������� 167 3.9.8 Treatment of Hürthle Cell Carcinoma������������������������������������ 168 3.9.9 Follow-Up ������������������������������������������������������������������������������ 175 3.9.10 Complications ������������������������������������������������������������������������ 178 3.9.11 Patient Education�������������������������������������������������������������������� 179 3.10 Hürthle Cell Carcinoma: Controversy of Prognosis �������������������������� 179 3.11 Hürthle Cell Lesions: Conclusions ���������������������������������������������������� 181 References���������������������������������������������������������������������������������������������������� 182 4 Solitary Thyroid Nodule���������������������������������������������������������������������������� 193 4.1 Overview�������������������������������������������������������������������������������������������� 193 4.2 Prevalence ������������������������������������������������������������������������������������������ 194 4.2.1 Frequency of STN in the United States���������������������������������� 194 4.2.2 International Frequency of STN �������������������������������������������� 195 4.3 Pathological Classification������������������������������������������������������������������ 195 4.3.1 Benign Thyroid Nodules�������������������������������������������������������� 196 4.3.2 Benign Thyroid Nodules�������������������������������������������������������� 204 4.4 Initial Clinical Evaluation ������������������������������������������������������������������ 214 4.4.1 History-Taking (Risk Factors)������������������������������������������������ 215 4.4.2 Physical Examination (Risk Factors)�������������������������������������� 217 4.5 Laboratory Tests���������������������������������������������������������������������������������� 220 4.5.1 Thyroid Function Tests ���������������������������������������������������������� 220 4.5.2 Serum Thyroglobulin (Tg)?���������������������������������������������������� 220 4.5.3 Serum Calcitonin�������������������������������������������������������������������� 220 4.5.4 Carcinoembryonic Antigen (CEA) ���������������������������������������� 222 4.5.5 DNA Testing �������������������������������������������������������������������������� 222 4.5.6 Complete Blood Count and Serum Calcium Levels �������������� 223 4.5.7 Follow-Up Tests���������������������������������������������������������������������� 223 4.6 Imaging Studies���������������������������������������������������������������������������������� 223 4.6.1 Ultrasonography (US)������������������������������������������������������������ 223 4.6.2 Sonographic Features Suspicious of Malignancy ������������������ 224 4.6.3 Doppler Scan�������������������������������������������������������������������������� 224 4.6.4 Ultrasound-Elastography (Elasto-sonography)���������������������� 225 4.6.5 Ultrasound-Guided Fine-Needle Aspiration (FNA)���������������� 227 4.6.6 Radionuclide Imaging (Thyroid Scintigraphy)���������������������� 229

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4.6.7 Computed Tomography (CT) and Magnetic Resonance Imaging (MRI)������������������������������������������������������ 230 4.6.8 Plain Chest Radiography�������������������������������������������������������� 231 4.6.9 Positron Emission Tomography (PET)? �������������������������������� 231 4.7 Biopsy (Cytology/Histology)�������������������������������������������������������������� 232 4.7.1 Fine-Needle Aspiration Cytology (FNAC): Free-Hand or US-Guided�������������������������������������������������������� 232 4.7.2 Large-Needle Biopsy (LNB) and Core-Needle Biopsy (CNB) ������������������������������������������������������������������������ 242 4.7.3 Intra-operative Frozen-Section Biopsy? �������������������������������� 243 4.8 Staging of a Malignant Thyroid Nodule �������������������������������������������� 243 4.8.1 Well-Differentiated Thyroid Carcinoma (WDTC)������������������ 243 4.8.2 Anaplastic Thyroid Carcinoma (ATC)������������������������������������ 244 4.8.3 Medullary Thyroid Cancer (MTC) ���������������������������������������� 244 4.9 Management���������������������������������������������������������������������������������������� 245 4.9.1 Clinically Non-palpable Incidental Nodule 200,000 IU/L, TSH was suppressed (0.2 mIU/L) in 67% of women and in 100% of women if hCG concentrations were >400,000 IU/L [28]. In a small percentage of women, TSH can be very suppressed (30 years – Personal history of thyroid dysfunction – Prior head or neck irradiation – Prior thyroid surgery – Family history of thyroid dysfunction – Symptoms of thyroid dysfunction – Presence of goiter – TPO-Ab positivity – Autoimmunity or Type 1 diabetes – Infertility – History of miscarriage or preterm delivery – Iodine-deficient population (residing in an area of known moderate to severe iodine deficiency) – Medications, e.g., lithium and iodinated contrast mediaa – Morbid obesity (BMI >40 kg/m2)a a

Only for American Thyroid Association 2011 guidelines

10

1  Thyroid Disease During Pregnancy

trimester of pregnancy with TSH and TPOA-Ab. Women with TSH elevations underwent further testing, and treatment with LT4 was initiated when indicated. Their analysis showed that universal screening of pregnant women was a cost-­ effective measure compared not only to no screening at all but also when compared to screening of high-risk women alone. Importantly, universal screening remained cost-effective even when only OH, rather than SCH, was detected and treated.

1.4.5 Recommendations Screening recommendations for thyroid dysfunction encountered during pregnancy are summarized in Table 1.3. Table 1.3  Screening recommendations for thyroid disorders in pregnancy Authors American College of Obstetricians and Gynecologists (ACOG) [45]

Year 2007

The Cochrane Collaboration [43]

2010

American Thyroid Association [8]

2011

Joint guidelines from AACE and ATA [41]

2012

The Endocrine Society [42]

2012

Recommendations Thyroid testing in pregnancy should be performed on symptomatic women and those with a personal history of thyroid disease or other associated medical conditions. Without evidence that diagnosis and treatment of pregnant women with SCH improves maternal or infant outcomes, routine screening for SCH currently is not recommended Targeted thyroid function testing in pregnancy should be implemented in women with symptoms or family history or at risk of thyroid disease. Consideration could be given to screening women with a personal history of preterm birth or recurrent miscarriage. At present, universal screening would not be based on firm evidence Universal screening of healthy women for thyroid dysfunction before pregnancy is not recommended. However, caregivers should identify individuals at high risk for thyroid illness (Table 1.1) Universal screening is not recommended for patients who are pregnant or are planning pregnancy, including assisted reproduction. Aggressive case finding, rather than universal screening, should be considered for patients who are planning pregnancy The committee could not reach agreement on testing recommendations for all newly pregnant women as follows: 1. Some members recommended screening of all pregnant women for serum TSH abnormalities by the 9th week or at the first visit 2. Other recommended aggressive case finding to identify and test high-risk women for elevated TSH levels by the 9th week or at the first visit before or during pregnancy. If risk assessment is not feasible, testing of all women by week 9 of pregnancy or at the first prenatal visit is reasonable

1.5  Iodine Deficiency During Pregnancy

11

Table 1.3 (continued) Authors Society of Maternal-­ Fetal Medicine [44]

Year 2012

European Thyroid Association (ETA) [31]

2014

Recommendations Thyroid testing for pregnant women at risk, such as those with known thyroid disease, symptoms of overt thyroid disease, suspected goiter, and autoimmune medical disorders such as Type 1 diabetes mellitus Universal screening for SCH is not recommended despite the beneficial effects of LT4 treatment on obstetric outcome and the fact that targeted approach to screening thyroid function will miss a large percentage of women with thyroid dysfunction

1.4.6 Conclusion Treatment of overt maternal hyperthyroidism and OH clearly improves outcomes. To date, there is limited evidence that levothyroxine treatment of pregnant women with SCH, isolated hypothyroxinemia, or thyroid autoimmunity is beneficial. Therefore, there is ongoing debate regarding the need for universal screening for thyroid dysfunction during pregnancy. Current guidelines differ; some recommend an aggressive case-finding approach, whereas others advocate testing only symptomatic women or those with a personal history of thyroid disease or other associated medical conditions.

1.5

Iodine Deficiency During Pregnancy

1.5.1 Requirement of Iodine During Pregnancy and Lactation Iodine (I2) requirement is increased during pregnancy because of three main factors: (1) an increased requirement of thyroxin (T4) in order to maintain a normal global metabolism in the mother, (2) a transfer of T4 and iodide from the mother to the fetus, and (3) an increased loss of iodide through the kidney due to an increase in the renal clearance of iodide. Because of these factors, the recommended dietary intake of I2 during pregnancy is higher than the value of 150 μg/day recommended for non-­ pregnant adults and adolescents.[59, 60]. Below this critical threshold of 150 μg/ day, the I2 balance is negative during pregnancy [61]. The World Health Organization (WHO) recommended an I2 intake of 200 μg/day for pregnant women [59], i.e., a percentage increase of 33% over non-pregnant women. The Institute of Medicine (IOM) of the US Academy of Sciences recommended a higher intake of 220 μg/day [60], i.e., a 47% increase, and other organizations recommended 175–230 μg/day [62, 63].

1.5.1.1 Increase in T4 Requirements The daily dose of T4 required to maintain euthyroidism in hypothyroid women increases by 10–150% during pregnancy with a median increment of 40–50% [64– 66]. This represents an additional dose of 50–100 μg iodine/day.

12

1  Thyroid Disease During Pregnancy

1.5.1.2 Transfer of T4 and Iodide from Mother to Fetus The transfer of T4 from the mother to the fetus, including before the onset of fetal thyroid function, has not been quantified but has been estimated that up to 40% of the T4 measured on the cord at birth is still of maternal origin [66]. The transfer of iodide is also difficult to quantify, but considering that the iodine content of the fetal thyroid increases progressively from less than 2 μg at 17 weeks of gestation [67] up to 300 μg at term [68–71], that the T4 iodine at term probably averages 500 μg [72], and that the substitutive dose of T4 in hypothyroid neonates is 50–75 μg/day [73, 74], it can be estimated that the transfer of iodide from mother to fetus represents nearly 50 μg/day. 1.5.1.3 Increased Renal Clearance of Iodide The increase in I2 requirement during pregnancy has been attributed largely due to an increased loss of iodide through the kidney because of an increased renal clearance of iodide. This should decrease the serum concentration of plasma inorganic iodide [75–78]. However, Dworkin et  al. [61] reported that urinary excretion of iodide is almost similar in pregnant and non-pregnant women. On the other hand, the studies conducted by Smyth et al. [4, 79] in Ireland, the UK, and Sri Lanka and those conducted by Kung et al. in Hong Kong [80] and by Hess et al. in Switzerland [81] have shown a clear-cut increase in the urinary iodine excretion during pregnancy. On the contrary, several studies showed that urinary iodine decreases during gestation.[82–94]. It thus appears that the concept of systematically increased urinary loss of iodine during pregnancy is not firmly established. Taking these variables into consideration, it is conceivable that the additional requirement of I2 during pregnancy is at least 100–150 μg/day, i.e., an increment of almost 100% as compared to non-pregnant adults instead of the 33% proposed by WHO/UNICEF/ICCIDD [59]. Consequently, I2 requirement during pregnancy is at least 250 μg/day, probably in the range of 250–300 μg/day. This figure is still higher than that of 220 μg/day proposed by the IOM [60], which did not take into account the increased requirement of T4 during pregnancy. During lactation, considering that the I2 content of breast milk in conditions of iodine sufficiency is in the range of 150–180 μg/L and that the milk production is from 0.5 to 1.1 L/day up to the age of 6 months, the daily loss of iodine in human milk is estimated to be 75–200 μg/day. Thus, I2 requirement during lactation is estimated to be 225–350 μg/day. The slight difference, if any, as compared to the figure of 290  μg/day recommended by IOM [60] results from more recent data on the iodine content of breast milk.[84, 85]. 1.5.1.4 Level of Urinary I2 Indicating Optimal I2 Nutrition During Pregnancy and Lactation Since more than 90% of I2 absorbed in the body eventually appears in the urine, urinary I2 excretion is a good marker of a very recent dietary I2 intake. Thus, a median of urinary I2 in the general population varying between 100 and 199 μg/L is considered as an indicator of an adequate I2 intake and an optimal status of I2 nutrition. As the I2 requirement is increased during pregnancy, the median urinary I2

1.5  Iodine Deficiency During Pregnancy

13

during pregnancy indicating optimal I2 nutrition needs to be higher than 100 μg/L. As indicated earlier, it appears difficult to derive a reference value for urinary iodine during pregnancy and lactation from the data collected in countries with no iodine deficiency as this value varies from 800 μg/L in Chile to 138 μg/L in Switzerland, where the median urinary I2 in the general population is barely above the lower limit of normal [81]. From these different considerations, it can be concluded that the recommended median value for urinary iodine during pregnancy and lactation has to be based on theoretical grounds. If, as in non-pregnant adults, the recommended median (100–200 μg/L) corresponds to the recommended intake (150 μg/day), the median urinary iodine during pregnancy and lactation should be in the range of 225–350 μg/L. If, on the contrary, this recommended median was based on a recommended intake of 225–350 μg/day and a mean daily urinary volume of 1.5 L/day, it should be in the range of 150–230  μg/L, i.e., only slightly higher than the value recommended for non-pregnant adults. In summary, it appears that the recommended dietary intake of iodine during pregnancy (250–300  μg/L) and lactation (225–350  μg/L) should be higher than what has been proposed earlier, especially by WHO/UNICEF/ICCIDD [59], and that a median urinary iodine indicating optimal iodine nutrition during pregnancy and lactation could be in the range of 150–230 μg/L.

1.5.2 Requirement of Iodine in Neonates As underlined by the IOM [60], no functional criteria of iodine status have been demonstrated that reflect response to dietary intake in infants. Consequently, the recommended intake of iodine in neonates reflects the observed mean iodine intake of young infants exclusively fed human milk in iodine-replete areas. Up to the late 1960s, the iodine content of breast milk in such areas was usually around 50 μg/L [84–86]. Considering a daily intake of breast milk of around 0.6–1 L in the neonate and young infant, the assumption was that an infant may get 30–50 μg/day iodine in milk from an adequately fed mother [87]. However, it is well established that the iodine content of breast milk is critically influenced by the dietary intake of the pregnant and lactating mother and of the general population and that much higher figures have been recorded more recently [84, 85]. Thus, again on theoretical grounds, the requirement of iodine in neonates was evaluated from metabolic studies by determining the value which resulted in a situation of positive I2 balance, which is required in order to insure a progressively increased intra-thyroidal iodine pool in the growing young infant.

1.5.2.1 Level of Urinary I2 Indicating Optimal I2 Nutrition in Neonates The optimal urinary I2 level has to be defined on the basis of theoretical considerations. Based on an I2 requirement of 90 μg/day and a volume of urines in neonates of some 0.4–0.5  L/day [88], the median value of urinary I2 indicating optimal I2 nutrition in neonates can be evaluated to be 180–225 μg/L when ignoring the fact

14

1  Thyroid Disease During Pregnancy

that the I2 balance of the neonate should also be positive in order to constitute the I2 stores of the thyroid. This level, which is higher than the one recommended for school children and adults, is indeed observed when healthy young infants are supplemented with a daily physiological dose of 90 μg/day [89]. It is also the value reported in some parts of the USA supposed to be I2-sufficient [90, 91]. On the other hand, studies reported in the literature in which urinary I2 has been determined simultaneously in mothers at delivery and in neonates during the first days of life [82, 92, 93] indicate that these levels are almost similar in mothers and neonates. Thus, based on the considerations on optimal urinary I2 in pregnant mothers, it can be extrapolated that the level in neonates should be around 150–230 μg/L, which is almost similar to the figure derived from the I2 requirements of the neonates. In brief, the recommended dietary intake of I2 in neonates is 90 μg/day, and the median urinary I2 to be expected, when this requirement is met, ranges from 180 to 225 μg/L, which is similar to the one recommended for pregnant women.

1.5.3 Conclusion Pregnant and lactating women and neonates are the main targets to the effects of iodine deficiency because of the impact of maternal, fetal, and neonatal hypothyroxinemia on brain development of the progeny [94–100]. Therefore, any program of salt iodization in a population should pay special attention to these particular groups. Based on an extensive and critical review of the literature on thyroid physiopathology during the peri-natal period, the following proposals are made: the iodine requirements are 250–300 μg/day during pregnancy, 225–350 μg/day during lactation, and 90 μg/day during the neonatal period. The median urinary iodine indicating optimal iodine nutrition during these three periods should be in the range of 150–230 μg/L. These figures are higher than those recommended so far by international agencies. The dose of iodine supplement needs to reflect local iodine status and iodization policies and will need careful monitoring at the population level to ensure doses to prevent underdosing/excess dosing which would undermine the potential benefits. National tailored guidance is therefore essential [101].

1.5.4 Recommendations [8] 1. All pregnant and lactating women should ingest a minimum of 250 mg I2 daily. 2 . To achieve a total of 250  mg of iodine ingestion daily in North America, all women who are planning to be pregnant or are pregnant or breast-feeding should supplement their diet with a daily oral supplement that contains 150  mg of iodine. This is optimally delivered in the form of potassium iodide because kelp and other forms of seaweed do not provide a consistent delivery of daily iodide. 3. In areas of the world outside of North America, strategies for ensuring adequate iodine intake during pre-conception, pregnancy, and lactation should vary according to regional dietary patterns and availability of iodized salt.

1.6  Hyperthyroidism in Pregnancy

15

4. Pharmacologic doses of iodine exposure during pregnancy should be avoided, except in preparation for thyroid surgery for Graves’ disease. Clinicians should carefully weigh the risks and benefits when ordering medications or diagnostic tests that will result in high iodine exposure. 5. Sustained iodine intake from diet and dietary supplements exceeding 500–1100 mg daily should be avoided due to concerns about the potential for fetal hypothyroidism.

1.6

Hyperthyroidism in Pregnancy

1.6.1 Definitions The term thyrotoxicosis refers to a clinical state, which results from inappropriately high thyroid hormone action in tissues generally due to inappropriately high tissue thyroid hormone levels. The term hyperthyroidism is a form of thyrotoxicosis due to inappropriately high synthesis and secretion of thyroid hormone(s) by the thyroid. Hyperthyroidism is defined as “the clinical syndrome of hypermetabolism and hyperactivity that results when TSH concentrations are low or suppressed along with elevated free T4 (fT4) or free T3 (fT3) (in overt disease) or with normal thyroid hormone levels (in subclinical disease).” Consequently, overt hyperthyroidism is defined as a subnormal (usually undetectable) serum thyrotropin (TSH) with elevated serum levels of triiodothyronine (T3) and/or fT4 estimates. Subclinical hyperthyroidism is defined as a low or undetectable serum TSH with values within the normal reference range for both T3 and fT4 [8, 102]. Gestational hyperthyroidism is defined as “transient hyperthyroidism, limited to the first half of pregnancy and characterized by elevated fT4 or adjusted total T4 (TT4) and suppressed or undetectable serum TSH, in the absence of serum markers of thyroid autoimmunity.”

1.6.2 Causes of Thyrotoxicosis In general, thyrotoxicosis can occur if (1) the thyroid is excessively stimulated by trophic factors; (2) constitutive activation of thyroid hormone synthesis and secretion occurs, leading to autonomous release of excess thyroid hormone; (3) thyroid stores of preformed hormone are passively released in excessive amounts owing to autoimmune, infectious, chemical, or mechanical insult; or (4) there is exposure to extra-thyroidal sources of thyroid hormone, which may be either endogenous (struma ovarii, metastatic differentiated thyroid cancer) or exogenous (factitious thyrotoxicosis). Hyperthyroidism may be diagnosed for the first time in pregnancy or may present as a recurrent episode in a woman with a past history of hyperthyroidism. Graves’ disease, an autoimmune condition characterized by stimulation of the thyroid gland by TSH receptor antibodies (TRAbs), is the most common cause of autoimmune hyperthyroidism in pregnancy. Overt hyperthyroidism during pregnancy occurs in 0.2% of pregnancies, and subclinical hyperthyroidism in 1.7% [8, 16, 17,

16

1  Thyroid Disease During Pregnancy

103, 104]. A new onset of Graves’ is thought to be rare in pregnancy [8, 42]. A more common condition as the cause of thyrotoxicosis is the syndrome of transient hyperthyroidism resulting from hyperemesis gravidarum (THHG) due to the thyroid stimulation of beta-HCG [8, 105]. Gestational hyperthyroidism is diagnosed in about 1–3% of pregnancies, depending on the geographic area. It is more prevalent in Asian populations compared to Europeans [8, 42, 106–108]. It may be associated with hyperemesis gravidarum (HEG), which occurs in 0.5–10/1000 pregnancies [20, 21]. Notably, up to 50% of women with HEG have transient hyperthyroidism [8, 42]. Other conditions associated with HCG-induced thyrotoxicosis include multiple gestations, hydatidiform mole, or choriocarcinoma [20, 21]. Most of the cases present with marked elevations of serum HCG [32]. A TSH receptor mutation leading to functional hypersensitivity to HCG has also been recognized as a rare cause of gestational hyperthyroidism [22]. Distinguishing between new-onset or recurring Graves’ disease in pregnancy and gestational hyperthyroidism may be difficult. Distinctive clinical features associated with Graves’ disease (ophthalmopathy, diffuse goiter, and pretibial myxoedema) and previous history of thyroid disease help in differentiating between both conditions, as gestational hyperthyroidism is more common among women without history of thyroid diseases [8, 42]. Elevated TRAb titers are rarely present in gestational hyperthyroidism, so their presence can help confirm Graves’ disease in pregnancy [8, 42]. Less common are the non-autoimmune causes of thyrotoxicosis, which include toxic multinodular goiter (MNG), toxic adenoma, and factitious thyrotoxicosis [8, 42]. Subacute painful or silent thyroiditis and struma ovarii are rare causes of thyrotoxicosis in pregnancy.

1.6.3 Diagnosis of Hyperthyroidism in Pregnancy The diagnosis of hyperthyroidism in pregnancy can be challenging. In the vast majority of patients, the disease is caused by a primary thyroid abnormality, and the principal finding will be a suppressed serum TSH, with serum free T4 (or total T4) and/or T3 levels above the reference range (overt hyperthyroidism), or within the reference range (subclinical hyperthyroidism). A key point is that reference ranges for thyroid function tests are different during different stages of pregnancy, and these changes may be assay dependent.

1.6.4 R  isks of Hyperthyroidism During Pregnancy on Fetal and Maternal Health The natural physiological changes during pregnancy can mimic some of the signs observed in hyperthyroidism, including increased basal metabolism, heart rate, fatigue, anxiety, palpitations, heat intolerance, warm and wet skin, hand tremors, and systolic murmur; thus, diagnosis of hyperthyroidism during pregnancy could

1.6  Hyperthyroidism in Pregnancy

17

cause clinical difficulties [103, 109, 110]. Pregnant women, who suffer from hyperthyroidism, have more severe tachycardia and thyromegaly, along with exophthalmia, and lack of weight gain despite receiving adequate food [110]. It is well documented that the adverse effects of overt hyperthyroidism on pregnancy outcomes (Table  1.4) include miscarriages, preeclampsia [113], low birth weight or fetal growth restriction [113, 114], and maternal cardiac dysfunction [120], with the risks increasing with poorer hyperthyroidism control [113, 114]. Furthermore, women with Graves’ disease have antibodies that can stop or stimulate the fetal anti-TSH receptor of thyroid gland [115, 116, 121]. Even in populations with treated hyperthyroidism, the risks of some neonatal outcomes seemed to be higher [118, 122] indicating either inadequate hyperthyroidism management or intrinsic effect of hyperthyroidism that increases risk of adverse neonatal health even with adequate treatment. A large American cohort study showed that hyperthyroidism increased the risk of preeclampsia, preterm birth, labor induction, ICU admissions, neonatal respiratory disease, sepsis, cardiomyopathy, retinopathy, and neonatal thyroid diseases [119, 123]. Table 1.4  Adverse effects of overt hyperthyroidism on pregnancy and neonatal outcomes Authors (year) Davis et al. [111] (1980)

Location USA

Type of study Prospective

Number 60

Kriplani et al. [112] (1994)

India

Prospective

32

Millar et al. [113] (1994) Phoojaroenchanachai et al. [114] (2001) Peleg et al. [115] (2002) Polak et al. [116] (2004) Luton et al. [117] (2005)

USA

Retrospective

181

Thailand

Retrospective

293

Outcome Small for gestational age births, stillbirths, and possibly congenital malformations Preterm labor, pregnancy-­ induced hypertension thyroid crisis, intrauterine growth retardation. Abnormal thyroid status of neonates Low birth weight infants and severe preeclampsia Low birth weight

USA

Retrospective

29

Neonatal thyrotoxicosis

France

Prospective

72

Fetal goiter

France

prospective

72

Luewan et al. [118] (2011)

Thailand

Prospective (cohort)

180

Männistö et al. [119] (2013)

USA

Retrospective (cohort)

223,512

Goiter (11 fetuses at 32 weeks) and fetal thyroid dysfunction Fetal growth restriction, preterm birth and low birth weight, tendency to have a higher rate of pregnancy-­ induced hypertension Preeclampsia, superimposed preeclampsia, preterm birth, induction, neonatal intensive care unit admission

18

1  Thyroid Disease During Pregnancy

A recent study has also shown that already high-normal maternal fT4 levels are associated with a decrease in child IQ and gray matter and cortex volumes, similar to the effects of hypothyroidism [124]. Clinical neonatal hyperthyroidism occurs in about 1% of infants born to mothers with Graves’ disease. Rarely, it may also be seen in infants of mothers with Graves’ hyperthyroidism owing to trans-placental transfer of circulating maternal ATDs, or pituitary–thyroid axis suppression from transfer of maternal thyroxin. On the other hand, there is no consensus regarding the adverse effect of subclinical hyperthyroidism on pregnancy or neonatal outcomes. In USA, Casey et al. [109] underwent thyroid screening for a total of 25,765 women of whom 433 were considered to have subclinical hyperthyroidism. They reported no significant increase of placenta abruption, preterm labor, and low birth weight in pregnancy complicated by subclinical hyperthyroidism in comparison with euthyroid ones. Similar results were also reported by Stagnaro-Green and Pearce [125] who emphasized that subclinical hyperthyroidism was not associated with intrauterine growth retardation (IUGR).

1.6.5 Treatment of Hyperthyroidism During Pregnancy As the associations between untreated persistent hyperthyroidism and adverse pregnancy outcomes are well established, hyperthyroidism should be adequately managed before and during pregnancy [8, 42]. In non-pregnant patients, the management options for Graves’ disease include radioactive iodine (RAI) ablation, antithyroid drug (ATD) treatment, and/or surgery [29], whereas only ATDs and surgery are options in the pregnant patient [8, 42]. RAI ablation results in a long latency of 2–6 months before development of hypothyroidism as well as in an increase in TRAb titers. As such, this treatment option is not generally recommended for hyperthyroid women planning pregnancy in the near future (within 6 months of the treatment) as it is unlikely that they would have achieved a stable euthyroid state during that time [8, 124]. It is noteworthy that RAI is absolutely contraindicated in pregnancy and the puerperium. Surgery is an option for patients hoping to conceive soon after the operation, but even then, the optimal management of hypothyroidism after total or near-total thyroidectomy should be reached before conception to reduce risk of adverse pregnancy outcomes [8, 124]. In non-pregnant women with mild hyperthyroidism, ATDs are often recommended as these patients have high likelihood of remission [124]. Notably, up to 30% of patients with Graves’ disease may achieve remission without treatment [124]. Generally, ATDs are used in non-pregnant patients for up to 12–18 months, after which they are discontinued if TSH is normal at that time [124]. Other treatment approaches should be considered at that time if remission is not achieved [124]. Women who have achieved remission of hyperthyroidism before pregnancy with ATD therapy seem to have a low risk of hyperthyroidism relapse during pregnancy but a high relapse risk post-partum [124]. Still such women need to be carefully monitored during pregnancy for clinical or biochemical signs of relapse as well as be tested for TRAb positivity at mid-gestation [8]. Antithyroid drugs (ATDs) can also be used to control hyperthyroidism in women planning pregnancy or among those with newly discovered Graves’ disease during pregnancy [8, 42]. The ATD methimazole (MMI) (and its prodrug carbimazole) is

1.6  Hyperthyroidism in Pregnancy

19

associated with teratogenicity, including aplasia cutis and recto-anal or esophageal atresia [126]. However, these specific malformations are very rare on a population level. The other commonly used ATD, propylthiouracil (PTU), is not associated with teratogenicity, but in rare instances it may increase the risk of hepatotoxicity in the mother [8, 42]. Current recommendations suggest using PTU during pre-­ conception and in the first trimester of pregnancy to reduce teratogenicity and switching to MMI after the first trimester to reduce maternal hepatotoxicity [8, 42]. However, if one ATD is not available or there are tolerance issues, either PTU or MMI can be used throughout pregnancy as the neonatal and maternal risks of untreated maternal hyperthyroidism outweigh the small risks of malformations or liver toxicity [8, 42]. Both ATDs are similarly effective in treating hyperthyroidism [8, 42]. There are no studies to show if the prevalence of maternal symptoms or abnormal thyroid function tests increases after switching of ATDs during pregnancy or if the switch is related to adverse pregnancy outcomes. After switching, thyroid function should be promptly tested (within 2 weeks), with a subsequent follow-up every 4–6 weeks once euthyroid state is reached [8, 42]. Management recommendations of Graves’ disease causing overt hyperthyroidism in pregnancy are summarized in Table 1.5 according to the timing of diagnosis and specific circumstances. Table  1.6 shows the results of seven studies on Table 1.5  Management recommendations of Graves’ disease causing overt hyperthyroidism in pregnancy Timing of diagnosis Graves’ disease diagnosed during pregnancy

Specific circumstances Diagnosed during first trimester

Diagnosed after first trimester

Graves’ disease diagnosed and treated prior to pregnancy

Currently taking methimazole

In remission after stopping ATD Previous treatment with RAI or surgery

Recommendations – Begin PTU – Measure TRAb at diagnosis and, if elevated, repeat at 18–22 weeks and again at 30–34 weeks of gestation – Measure TRAb at diagnosis and, if elevated, repeat at 18–22 weeks and again at 30–34 weeks of gestation – Begin MMI – Measure TRAb at diagnosis and, if elevated, repeat at 18–22 weeks and again at 30–34 weeks of gestation (all depending on week of diagnosis) – If thyroidectomy is required, it is optimally performed during the second trimester – Switch to PTU or withdraw ATD therapy as soon as pregnancy is confirmed with early testing – Measure TRAb initially and, if elevated, again at 18–22 weeks and 30–34 weeks of gestation Perform thyroid function testing to confirm euthyroidism. TRAb measurement not necessary Measure TRAb initially during the first trimester and, if elevated, again at 18–22 weeks of gestation

20

1  Thyroid Disease During Pregnancy

Table 1.6  Congenital anomalies associated with ATD treatment of hyperthyroidism during pregnancy [127] Authors (year) Momotani et al. [128] (1984)

Study type Case– control

Study population 117 women treated with MMI

Wing et al. [129] (1994)

Case– control

135 women treated with PTU or MMI

Rosenfeld et al. [130] (2009)

Cohort

80 women treated with PTU

Chen et al. [122] (2011)

Case– control

703 women treated with PTU or MMI

Korelitz et al. [131] (2012)

Case– control

Yoshihara et al. [126] (2012)

Case– control

Andersen et al. [132] (2013)

Cohort

1023 women treated with PTU or MMI, 126 women who shifted between MMI and PTU 2630 women treated with PTU or MMI Women shifted between MMI and PTU

Controls 350 women without hyperthyroidism

Treatment MMI during the first trimester

43 women not receiving any ATD, 99 women without hyperthyroidism 1066 women without hyperthyroidism

PTU or MMI

14,150 women without hyperthyroidism, 2127 women not receiving any ATD 634,858 women without hyperthyroidism, 5932 women not receiving any ATD

1906 women not receiving any ATD

Women not receiving any ATD 1066 women without hyperthyroidism

PTU at 4–13 weeks of gestation PTU or MMI for at least 30 days PTU or MMI within the last 6 months of pregnancy

PTU or MMI during the first trimester ATD in early pregnancy

Birth anomalies Earlobe anomalies, omphalocele, imperforate anus, anencephaly, harelip, polydactyly Severe pulmonary stenosis, ventricular septal defect, patent ductus arteriosus Developmental dysplasia of the hip

Cleft lip and palate, limb defects, heart defects, Down syndrome, hypospadias Anomalies of the eye, heart (atrial and ventricular septal defects), respiratory system, and genital organs

Aplasia cutis, omphalocele, and omphalomesenteric duct anomaly Malformations in urinary system, face and neck region, atresia (anal, esophageal)

congenital malformations. Patients included were pregnant women with hyperthyroidism who required treatment with ATDs to reach a euthyroid state. All controls were pregnant women who were euthyroid or presented with hyperthyroidism that was observed late in pregnancy; the latter group of patients delivered before therapy and did not require any antithyroid medication therapy.[127].

1.6  Hyperthyroidism in Pregnancy

21

Surgery is also an option for pregnant patients where rapid control of hyperthyroidism is needed or ATDs cannot be used [124]. However, as anesthetic agents are teratogenic in the first trimester and surgery is associated with increased fetal loss in the third trimester, the late second trimester is thought to be the safest period to perform thyroidectomy in a pregnant woman [124]. As treating hyperthyroidism during pregnancy is a balance between adverse outcomes related to treatment and hyperthyroidism itself, hyperthyroidism should preferentially be already treated before conception. Women with gestational hyperthyroidism generally do not require treatment as the condition is transient and not associated with adverse pregnancy outcomes [8, 109, 133–135]. Those with hyperemesis gravidarum and gestational hyperthyroidism may require hyperemesis symptom management, but generally they do not require ATD treatment [8]. Propranolol, a beta-blocker, can be used in short-term symptom management as it has some direct antithyroid activity by blocking iodide transport to the thyroid [8, 135]. However, if women do not reach euthyroidism as pregnancy progresses or there are other symptoms, Graves’ disease should be suspected, and a treatment trial with ATDs may be useful [8].

1.6.5.1 Caveats and Goals of Antithyroid Drug Treatment All ATDs cross the placenta and may have deleterious impacts on the fetal thyroid function [8, 135]. When treating pregnant women with ATDs, the treatment goal is to maintain fT4 values at or above the upper non-pregnant reference limit or high-­ normal within the pregnant reference limit (preferred approach) using the lowest possible dose of the drug [8, 135]. Upon treatment initiation, thyroid function tests should be measured every 2–4 weeks and every 4 weeks after treatment goals are reached [8]. Maternal TSH levels may remain suppressed or low throughout pregnancy in spite of adequate ATD treatment [8]. Over-treatment with ATDs may lead to goitrogenesis and hypothyroidism in the fetus, the risk of which is thought to be lower by maintaining high-normal maternal fT4 levels [8, 135]. Graves’ disease typically exacerbates in the first trimester of pregnancy, gradually improves afterward, and subsequently relapses in the post-partum [8, 135]. Consequently, up to 20–30% of all women with hyperthyroidism may discontinue ATD therapy in late pregnancy. However, women with high TRAb titers continue to be at high risk of recurrence and require ATD treatment throughout pregnancy [8, 135]. Besides the fetal hypothyroidism risk inflicted by maternal ATD therapy, untreated maternal hyperthyroidism may lead to transient central hypothyroidism in the fetus. Maternal TRAbs pass through the placenta and can lead to fetal or neonatal hyperthyroidism. Women with past or present history of Graves’ disease should have their TRAb titers checked in mid-pregnancy to estimate this risk as fetal hyperthyroidism is associated with increased neonatal morbidity and mortality [8, 135]. Fetal surveillance with serial ultrasounds is required to diagnose fetal thyroid dysfunction and follow fetal growth and well-being if a woman has uncontrolled hyperthyroidism and/or positive TRAb during pregnancy. Similarly, evaluation for thyroid dysfunction is required in neonates of women with Graves’ disease or positive

22

1  Thyroid Disease During Pregnancy

TRAb during pregnancy [135]. LT4 and ATDs should not be used together, except in the rare cases of fetal hyperthyroidism. Administering both concurrently leads to a relative increase in maternal fT4 levels leading to increased requirements of ATDs, which in turn may lead to fetal hypothyroidism [8].

1.6.6 T  reatment of Hyperthyroidism During the Post-partum Period Women with a history of hyperthyroidism treated during pregnancy are at a higher risk of post-partum relapse [8]. The use of moderate doses of ATDs during breast-­ feeding is safe. In one study, breast-fed infants of mothers with high TSH levels after administration of high doses of MMI had normal levels of T4 and TSH [23] Furthermore, the physical and intellectual development of children, aged 48–86 months, remained unchanged in comparison with controls when assessed by the Wechsler and Good enough tests [136]. In conclusion, breast-feeding is safe in mothers on ATDs at moderate doses (PTU less than 300  mg/Dormethimazole 20–30 mg/day). It is currently recommended that breast-feeding infants of mothers taking ATDs be screened with thyroid function tests and that the mothers take their ATDs in divided doses immediately following each feeding.

1.6.7 Recommendations [116, 135, 137, 138] 1. In the presence of a suppressed serum TSH in the first trimester (TSH 170, persistent for over 10 min), intrauterine growth restriction, presence of fetal goiter (the earliest sonographic sign of fetal thyroid dysfunction), accelerated bone maturation, signs of congestive heart failure, and fetal hydrops [116]. A team approach to the management of these patients is required including an experienced obstetrician or maternal–fetal medicine specialist, neonatologist, and anesthesiologist. In most cases, the diagnosis of fetal hyperthyroidism should be made on clinical grounds based on maternal history, interpretation of serum TRAb levels, and fetal ultrasonography [137]. Monitoring may include ultrasound for heart rate, growth, amniotic fluid volume, and fetal goiter. 15. Cordocentesis should be used in extremely rare circumstances and performed in an appropriate setting. It may occasionally be of use when fetal goiter is detected in women taking ATDs to help determine whether the fetus is hyperthyroid or hypothyroid. 16. Methimazole (MMI) in doses up to 20–30 mg/day is safe for lactating mothers and their infants. PTU at doses up to 300 mg/day is a second-line agent due to concerns about severe hepatotoxicity. ATDs should be administered following a feeding and in divided doses. 17. In women developing thyrotoxicosis after delivery, selective diagnostic studies should be performed to distinguish post-partum destructive thyroiditis from post-partum Graves’ disease.

24

1  Thyroid Disease During Pregnancy

18. In women with symptomatic thyrotoxicosis from post-partum destructive thyroiditis, the judicious use of β-adrenergic blocking agents is recommended. 19. In pregnant women diagnosed with hyperthyroidism due to multinodular thyroid autonomy or a solitary thyroid adenoma (TA), special care should be taken not to induce fetal hypothyroidism by ATD therapy.

1.7

Hypothyroidism in Pregnancy

Pregnancy can imitate some of the signs that are observed in hypothyroidism, such as fatigue, anxiety, constipation, muscle cramps, and weight gain; as a result, the clinical diagnosis of hypothyroidism during pregnancy may be difficult [110, 138]. Most signs of hypothyroidism can also be hidden by a woman’s status following the increase in metabolism during pregnancy. Moreover, the thyroid hormonal profile in normal pregnancy can be mistaken for hypothyroidism, and as a result the interpretation of thyroid function tests needs trimester-specific reference intervals for a specific population [108, 121]. Applying trimester-specific reference ranges of thyroid hormones prevents misclassification of thyroid dysfunction during pregnancy.

1.7.1 Iodine Deprivation and Goiter Formation The main cause of hypothyroidism during pregnancy worldwide is iodide insufficiency; however, in iodide-sufficient areas its main cause is autoimmune thyroiditis [12]. Goiter formation is the most directly visible consequence of iodine (I2) deprivation, and pregnancy should be considered an environmental factor that triggers the glandular machinery and induces functional and anatomical abnormalities of the thyroid gland in localities with a low I2 intake. Several studies showed that pregnancy was associated with goiter formation in places with low I2 intake, with increases in thyroid volume ranging between 20% and 35% [17]. It is noteworthy that it is not only the mother but also the fetus that is at risk of developing glandular hyperplasia when an infant is born to a mother who has not been supplemented with I2 during gestation [65]. Thus, pregnancy represents a strong goitrogenic stimulus for both the mother and the fetus, even in areas where there is only a moderate I2 deficiency. Maternal goiter formation is correlated with the degree and duration of glandular stimulation that takes place during gestation. In addition, a goiter formed during gestation may only partially regress after parturition, so that pregnancy is one of the factors that may help explain the higher prevalence of goiter and thyroid disorders in women compared with men. Finally and perhaps most importantly, since goiter formation also takes place in the progeny, this emphasizes the exquisite sensitivity of the fetal thyroid gland to the consequences of maternal I2 deprivation. In conditions of I2 deficiency, the process of goiter formation may start during the earliest stages of fetal thyroid gland development.

1.7  Hypothyroidism in Pregnancy

25

1.7.2 Overt or Subclinical Hypothyroidism? In the absence of rare exceptions such as TSH-secreting pituitary tumor, thyroid hormone resistance, and a few cases of central hypothyroidism with biologically inactive TSH, primary maternal hypothyroidism is defined as the “presence of an elevated TSH concentration during gestation.” Historically, the reference range for serum TSH was derived from the serum of healthy, non-pregnant individuals. Using these data, values >4.0 mIU/L were considered abnormal. More recently, normative data from healthy pregnant women suggest the upper reference range may approximate 2.5–3.0 mIU/L [28, 137]. When maternal TSH is elevated, measurement of serum FT4 concentration is necessary to classify the patient’s status as either subclinical hypothyroidism (SCH) or overt hypothyroidism (OH). This is dependent upon whether fT4 is within or below the trimester-specific fT4 reference range. SCH is defined as “an elevated TSH level with a normal level of circulating fT4.” The distinction of OH from SCH is important because published data relating to the maternal and fetal effects attributable to OH are more consistent and easier to translate into clinical recommendations in comparison with those regarding SCH. SCH is the most common thyroid dysfunction during pregnancy [139, 140]. Its prevalence varies between 1.5 and 5% based on various definitions, different ethnicity, iodine consumption, and nutrition lifestyle as well as study designs [53]. While the adverse effects of SCH accompanied with positive TPO antibodies or OH on pregnancy outcome are well-known, there is controversy on the negative impact of SCH without autoimmunity on the outcomes of pregnancy [138, 141–143]. Pregnant women who possess TPO antibodies during the initiation of their pregnancy are subjected to SCH during their pregnancy or thyroid dysfunction after childbirth [104].

1.7.3 Isolated Hypothyroxinemia Isolated hypothyroxinemia is defined as “a normal maternal TSH concentration with fT4 concentrations in the lower 5th or 10th percentiles of the reference range.” Observational studies have not shown any adverse obstetric outcomes [143]. However, it is unclear whether isolated maternal hypothyroxinemia is associated with adverse neuro-developmental outcomes.

1.7.4 Incidence of Hypothyroidism During Pregnancy Compared to hyperthyroidism, hypothyroidism is very common during pregnancy [139, 144]. Several authors report that at least 2–3% of apparently healthy, non-­ pregnant women of childbearing age have an elevated serum TSH. Among these healthy non-pregnant women of childbearing age, it is estimated that 0.3–0.5% of them would, after having thyroid function tests, be classified as having OH and

26

1  Thyroid Disease During Pregnancy

2–2.5% as having SCH [8, 42]. When I2 nutrition is adequate, the most frequent cause of hypothyroidism is autoimmune thyroid disease (Hashimoto’s thyroiditis). Thyroid auto-antibodies were detected in 50% of pregnant women with SCH and in more than 80% with OH [38]. A smaller proportion of hypothyroidism is due to iatrogenic causes including surgery to treat thyroid cancer or nodules, or radioactive iodine ablation to treat hyperthyroidism. Pregnant women or those planning pregnancy are diagnosed with OH when they have elevated TSH levels with low fT4 concentrations, preferably defined with pregnancy-specific reference intervals [8, 42]. However, pregnant women with TSH over 10 mIU/L are always diagnosed with OH, irrespective of fT4 concentrations. SCH is diagnosed when TSH is elevated, but less than 10 mIU/L and fT4 concentrations are normal [8, 42].

1.7.5 Risks of Hypothyroidism on Fetal and Maternal Health The risks of hypothyroidism during pregnancy affect both maternal and fetal well-­ being. Furthermore, these risks extend to affect the child and adolescent as depicted in Fig. 1.3. Both, OH and SCH as well as increases in maternal TSH concentrations have been associated with increased risk of miscarriages/fetal losses [145–150], preeclampsia [24, 37, 141, 151], placental abruptions [24, 152], preterm birth [26, 149, 150, 152, 153], and poor neurological development in the offspring [146, 152, 154]. Overt hypothyroidism has also been associated with maternal anemia and post-­ partum hemorrhage [24] and SCH with cesarean sections [142], gestational diabetes [152, 155], breech presentation [156, 157], infants being small for gestational age [149], fetal distress [150], neonates needing intensive care treatment [110, 152], and respiratory distress syndrome. [110]. However, several studies have found no

Fetus

Neonate

Child and Adolescent

• Spontaneous abortion/stillbirth • Congenital anomalies • Endemic cretinism

• Hypothyroidsim • Mental retardation • Increased mortality

• Goiter • Hypothyroidsim • Neurocognitive defects • Impaired physical development • Lower intelligence quotient

Fig. 1.3  Impact of hypothyroidism on the fetus, neonate, child, and adolescent

1.7  Hypothyroidism in Pregnancy

27

association between adverse peri-natal outcomes and hypothyroidism [133, 134, 141, 143, 147, 154, 158–162]. In a large cohort study, women with diagnosed hypothyroidism or treated hypothyroidism had higher risk of pregnancy complications such as preeclampsia [119, 163, 164], gestational diabetes [119, 163], cesarean sections [119, 163], labor inductions [119, 163], preterm birth [119, 163], malformations [163], placental abruptions [119], and intensive care unit (ICU) admissions [119] and neonatal complications including need for ICU treatment, respiratory problems, sepsis, anemia, and infants being both large or small for gestational age (depending on the race/ ethnicity of the mother) [123]. Adequately treated hypothyroidism still appears to increase risk of cesarean sections [165, 166] but is not associated with other adverse outcomes [166]. A threefold risk of placental abruption and a twofold risk of preterm delivery were reported in mothers with SCH [167]. Another study showed a higher prevalence of SCH in women with preterm delivery (before 32 weeks) compared to matched controls with full-term delivery. An association with adverse obstetrics outcome has also been demonstrated in pregnant women with thyroid autoimmunity independent of thyroid function. Treatment of hypothyroidism reduces the risks of these adverse obstetric and fetal outcomes; a retrospective study of 150 pregnancies showed that treatment of hypothyroidism led to reduced rates of abortion and premature delivery. A prospective intervention trial study showed also that treatment of euthyroid antibody positive pregnant women led to fewer rates of miscarriage than non-treated controls [145]. Tables 1.7 and 1.8 summarize the studies on adverse outcomes of OH and SCH, respectively.

Table 1.7  Adverse effects of overt hyperthyroidism (OH) on pregnancy and neonatal outcomes Authors (year) Abalovich et al. [145] (2002) Wolfberg et al. [164] (2005) Idris et al. [165] (2005) Cleary Goldman et al. [142] (2008) Sahu et al. [143] (2010)

Location Argentina

USA

Type of study Randomized clinical trial (RCT) Retrospective

Study population 114 with 1ry hypothyroidism (16 OH) 482 with treated hypothyroidism

England

Retrospective

167

USA

Prospective

10,990

India

Prospective

633

Outcome Abortion, premature delivery

Preeclampsia

Low birth weight infants and cesarean sections Preterm labor , macrostomia, gestational diabetes

Pregnancy-induced hypertension, intrauterine growth restriction, intrauterine demise, gestational diabetes (continued)

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1  Thyroid Disease During Pregnancy

Table 1.7 (continued) Authors (year) Hirsch et al. [168] (2013)

Location Israel

Type of study Retrospective

Männistö et al. [119] (2013)

USA

Retrospective

Manju VK and Sathiamma PK [169] (2017)

India

Cohort

Study population 306 (101 with hypothyroidism, 205 euthyroid) 223,512 singleton pregnancies

93

Outcome Abortions and premature delivery 1ry hypothyroidism: preeclampsia, diabetes, preterm birth, induction, cesarean section, ICU admission Iatrogenic hypothyroidism:placental abruption, breech presentation, cesarean section Preeclampsia, spontaneous abortion, recurrent miscarriage, infertility, post-partum hemorrhage, and abruption

Table 1.8  Adverse effects of subclinical hyperthyroidism (SCH) (with/without thyroid autoimmunity) on pregnancy outcomes Type of study Study population Authors (year) Location Subclinical hypothyroidism without control of TPO-Ab Argentina Prospective 114 with 1ry Abalovich (RCT) hypothyroidism et al. [145] (35SCH) (2002) USA Prospective 953 Stagnaro-­ Green et al. [26] (2005) USA Prospective 25,756 Casey et al. [140] (2005) USA Prospective 10,990 Cleary Goldman et al. [143] (2008) Sahu et al. India Prospective 633 [142] (2010) Wilson et al. USA Prospective 24,883 [141] (2012) India Cohort 324 Manju and Sathiamma [169] (2017)

Outcome Abortion, premature delivery Very preterm delivery

Placental abruption Preterm birth SCH was not associated with adverse outcomes

Cesarean section rate for fetal distress Severe preeclampsia Preeclampsia, anemia, spontaneous abortion, recurrent pregnancy loss.

1.7  Hypothyroidism in Pregnancy

29

Table 1.8 (continued) Type of study Study population Outcome Authors (year) Location Subclinical hypothyroidism including negative and positive TPO-Ab Negro et al. Italy RCT 984 Those with positive [138] (2006) TPO-Ab developed impaired thyroid function, ↑ risk of abortion, and premature labor Benhadi et al. Netherlands Prospective 2497 Those without OH, the risk [147] (2009) (cohort) of child loss ↑ with higher levels of maternal TSH Greece Prospective 1170 Karakosta ↑ gestational diabetes and et al. [170] low birth weight neonates (2012) among those with high TSH and spontaneous preterm among those without elevated TSH levels

It has long been known that cretinism (i.e., gross reduction in IQ) occurs in areas of severe I2 deficiency due to the fact that the mother is unable to make T4 for transport to the fetus particularly in the first trimester. This neuro-intellectual impairment has now been shown in an I2-sufficient area (USA) where a study showed that the IQ scores of 7–9-year-old children, born to mothers with undiagnosed and untreated hypothyroidism in pregnancy, were 7 points lower than those of children of matched controls with normal thyroid function in pregnancy [146]. Another study showed that persistent hypothyroxinemia at 12 weeks of gestation was associated with an 8–10-point deficit in mental and motor function scores in infant offspring compared to children of mothers with normal thyroid function [40]. Although the long-term effect of OH on cognitive function is well documented to cause lower IQ and more developmental dysfunction [12, 15, 121, 146, 162, 168, 171–173], yet there is no consensus on the long-term cognitive effects of SCH. While some authors reported loss of motor function and intelligence in infants and children, others reported a normal motor and cognitive function [123, 161, 174, 175]. Table 1.9 summarizes the cognitive function of infants and children affected by OH or SCH during pregnancy. Maternal TPO antibodies were also shown to be associated with impaired intellectual development in the offspring of mothers with normal thyroid function [147]. Interestingly, it has been shown that it is only the maternal fT4 levels that are associated with child IQ and brain morphological outcomes, as opposed to maternal TSH levels [124]. Several observational studies have not shown any adverse outcomes of isolated hypothyroxinemia [143, 152]. Pop and colleagues [172] reported a decrease in psychomotor test scores and reduction in the IQ among offsprings born to women with isolated hypothyroxinemia. Data from a more recent study (2010) showed that children born to women with isolated hypothyroxinemia had a 1.5- to 2-fold increased risk of cognitive delays in early childhood [174].

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1  Thyroid Disease During Pregnancy

Table 1.9  The cognitive function of infants and children subjected to overt or subclinical hypothyroidism during pregnancy Authors (year) Location Overt hypothyroidism (OH) Liu et al. [176] China (1994) Haddow et al. England [146] (1999)

Type of study

Study population

Prospective (cohort) Prospective (cohort)

19 cases and 142 controls 25,216

125 (63 cases and 62 controls) 204 (108 cases and 96 control)

Pop et al. [172] (2003)

Netherlands

Prospective

Kooistra et al. [173] (2006)

Netherlands

Retrospective (case control)

Li et al. [174] (2010)

China

Prospective (cohort)

19 cases and 142 controls

Henrichs et al. [177] (2010)

Netherlands

Prospective (cohort)

3659

Chevrier et al. [178] (2011) Downing et al. [179] (2012)

USA

Prospective (cohort) Case report

287

USA

Japan Case report Momotani et al. [180] (2012) Subclinical hypothyroidism (SCH) Prospective Ghorbani Behrooz et al. [175] (2012)

3

5

62

Outcome All children showed normal IQs Adversely affect their children’s subsequent performance on neuro-­ psychological tests Delay in infant neuro-development Lower scores on the Neonatal Behavioral Assessment Scale and orientation index Lower motor and intellectual development at 25–30 months Higher risk of expressive language and non-verbal cognitive delay No adverse effect on child neuro-development Children had average or above average results on all parameters The development scores of all children were either normal or advanced No adverse effect on IQ level and cognitive performance of children

1.7.6 Treatment of Hypothyroidism During Pregnancy Levothyroxine (LT4) is the treatment of choice for hypothyroidism in pregnancy. Thyroid function should be normalized prior to conception in women with pre-­ existing thyroid disease. Due to the well-established associations between OH and adverse pregnancy outcomes, OH should be promptly treated to attempt to mitigate these known risks [8, 42]. However, there is debate about whether to treat all women with SCH. Two different strategies are proposed: to treat everyone [42] and to treat women with SCH and positive thyroid antibodies [8]. Up to 40% of women with positive thyroid antibodies develop hypothyroidism during or immediately after pregnancy [171], but most studies evaluating the association between SCH and

1.7  Hypothyroidism in Pregnancy

31

pregnancy outcomes have been cross-sectional and based on first-trimester measures of thyroid function. Therefore, more information is needed to determine whether hypothyroidism detected in the first trimester will progress, which factors predict disease progression, and if some women switch from hypothyroidism to euthyroidism as pregnancy continues. In a study evaluating treatment for SCH, 44% of women with initially high TSH had normal thyroid function tests in a repeat sample taken 1 week later [181]. A randomized placebo controlled trial of levothyroxine treatment for SCH during pregnancy with early pregnancy sampling and longitudinal follow-up will provide new information on the natural history of untreated SCH and indicate whether levothyroxine treatment is beneficial in reducing adverse outcomes [182]. The goal of LT4 treatment is normalization of serum TSH concentrations, using the pregnancy-specific reference intervals [8]. In pregnancy, treatment should be started with a dose as close to the final estimated dose as possible to minimize time with hypothyroidism [150, 183]. Pregnancy increases LT4 requirements in most women very early on among those diagnosed and treated for hypothyroidism before conception [184]. Women with LT4 treatment should have pre-conception TSH levels less than 2.5  mIU/L in order to minimize the probability of hypothyroidism during pregnancy [8]. However, even with adequate pre-conception management of hypothyroidism, up to 27% of women had elevated TSH concentrations in early pregnancy [185]. Therefore, the current recommendation is for women to increase their LT4 dose by 25–30% upon missed periods [8]. Interestingly, 5% and 17% of women with pre-pregnancy TSH levels of 1.21–2.40 and 0.1–1.2 mIU/L, respectively, needed LT4 dose increases during pregnancy [186]. This indicates that tighter hypothyroidisms control before pregnancy might reduce the risk of elevated TSH levels in pregnancy. In one trial, hypothyroid women (irrespective of cause but with baseline TSH less than 5.0 mIU/L) were randomized to receive two or three extra LT4 tablets per week once pregnancy was confirmed, resulting in 29–43% increase in their medication [185]. Under this strategy, 58–78% of women maintained euthyroidism throughout pregnancy [185]. Those requiring dose reductions were more often athyrotic or had high pre-conception LT4 doses (at least 100 μg/day) or pre-conception TSH less than 1.5 mIU/L. Most women did not need additional LT4 dose increases under this treatment strategy [185]. The etiology of thyroid disease also affects the need of LT4 dose adjustments in pregnancy. Women with post-ablative or surgical hypothyroidism required higher dose increases than those with primary hypothyroidism or thyroid cancer, irrespective of good baseline management of hypothyroidism [187]. In another study where women with SCH, OH, and post-ablative hypothyroidism were diagnosed and adequately treated before pregnancy, those with SCH required the highest absolute dose increases in LT4 [188]. These studies would suggest that an individualized approach based on baseline TSH concentrations and etiology of hypothyroidism could be utilized when counseling women treated with LT4 who are planning pregnancy, as lower baseline TSH levels could potentially reduce risks of TSH elevation in early pregnancy. However,

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1  Thyroid Disease During Pregnancy

there are no large prospective studies evaluating the effectiveness of this strategy. Given that pregnant women are at increased risk of TSH elevations, tests for thyroid function should begin early in pregnancy, continuing every 4 weeks until mid-gestation and at least once between 26 and 32 weeks among those with levothyroxine treatment to ensure euthyroidism throughout pregnancy [8, 42]. Monitoring thyroid function tests every 4 weeks during pregnancy detected over 90% of abnormal values in one study [185]. Similarly, the etiology and severity of hypothyroidism diagnosed during pregnancy affects the LT4 dose required to achieve and maintain euthyroid status. Newly diagnosed OH in pregnancy required almost double the dose of LT4 compared with those treated for SCH [183]. Among women with SCH during pregnancy, those with baseline TSH up to 4.2 mIU/L required smaller LT4 (1 μg/kg/ day) than those with baseline TSH 4.2–10  mIU/L (1.42  μg/kg/day) to achieve euthyroidism [183]. When treating women with SCH with steady LT4 doses based on their baseline TSH levels, 79, 82, and 90% of women with baseline TSH 2.5–5.0, 5.0–8.0 mIU/L, and higher than 8.0 mIU/L, respectively, reached euthyroidism with respective LT4 doses of 50, 75, and 100 μg/day [181]. Either weightbased starting dose or a steady starting dose based on the severity of newly diagnosed hypothyroidism determined by baseline TSH concentration seems to be appropriate in reaching euthyroidism.

1.7.6.1 Effectiveness of Levothyroxine Treatment There are no prospective randomized controlled trials to study the effectiveness of levothyroxine treatment to prevent adverse outcomes among women with OH, but as the association between OH and adverse outcomes is well established, such a trial would be unethical [8]. In a systematic review, treatment of SCH was shown to reduce risk of miscarriage and preterm birth [189]. There is currently insufficient evidence to show clear benefits of treating SCH [188]. In one trial randomizing women to case finding or universal screening for thyroid disease during pregnancy, 91.2% of all women with undiagnosed and untreated hypothyroidism had at least one adverse outcome, whereas the rate was 35% among those with diagnosed and treated hypothyroidism [148]. Lazarus et  al. [57] randomized mildly hypothyroid pregnant women to LT4 treatment versus no treatment. At age 3, children of women treated with LT4 (started at a median gestational age of 13 weeks) had similar IQ tests of children of untreated women. These results have been criticized on the basis that intervention began in many women following the first trimester, which is the critical time for fetal brain development. Furthermore, IQ testing may not be the most sensitive method of assessing the effect of hypothyroidism on neural development in 3-year-olds. Among women undergoing assisted reproduction, LT4 treatment of SCH has been shown to reduce miscarriages in some [190] but not all studies [191]. A randomized placebo controlled trial provided new evidence on treatment efficacy among women with SCH and the benefit in preventing adverse intellectual outcomes in the offspring and have an effect on neonatal outcomes [182].

1.7  Hypothyroidism in Pregnancy

33

1.7.6.2 Caveats of Levothyroxine (LT4) Treatment During Pregnancy Only about 62–82% of all ingested LT4 is absorbed, with concurrent ingestion of food, caffeine, and iron and calcium supplements decreasing the absorption further [192]. LT4 should be ingested in the morning at least 60 min before eating [193]. Additionally, there should be a 4- to 6-h gap between LT4 ingestion and administration of other medications that decrease LT4 absorption [193]. This includes common dietary supplements such as iron and calcium in prenatal vitamins, which are routinely administered to nearly all pregnant women. In addition, several chronic conditions including celiac disease, lactose intolerance, and atrophic gastritis decrease absorption of LT4 if untreated [193]. Compliance with medication as well as gastrointestinal conditions and medication interference should be evaluated in women with persistent hypothyroidism requiring higher than normal doses of LT4 [193]. Different LT4 are not clinically interchangeable, and there might be more than 12.5% difference in levothyroxine doses between products [194, 195]. As LT4 has a narrow therapeutic range, such differences may be clinically meaningful and lead to deviations from euthyroidism when switching from one product to another [194, 195]. Indeed, in a survey to physicians treating patients with LT4, most reports of changes in thyroid function were after switching between LT4 products [196], often by the pharmacy without the physician’s knowledge. For optimized therapy, patients are often advised to stay on the same brand of LT4. If products are switched, thyroid function tests should be performed to ensure euthyroidism [192].

1.7.7 T  reatment of Hypothyroidism During the Post-partum Period Most women with hypothyroidism can reduce their dose of LT4 post-partum, with assessment of TSH levels 6 weeks following the dose reduction to ensure euthyroidism [8, 188, 192]. Women with positive thyroid antibodies are at higher risk of exacerbation of autoimmune thyroid dysfunction post-partum, and over 50% of women with Hashimoto’s thyroiditis continued to require increased doses of LT4 in the post-partum period [196]. Women with SCH during pregnancy may not require LT4 treatment during the post-partum period, unless post-partum thyroiditis ensues or the woman is planning to conceive again soon. These women are at high risk for thyroid dysfunction in their subsequent pregnancies and require adequate pre-conception consultation and management. They are also at higher risk of developing permanent thyroid disease later in life [134].

1.7.8 Recommendations [8, 197] 1. Overt hypothyroidism (OH) should be treated in pregnancy. This includes women with a TSH concentration above the trimester-specific reference inter-

34

1  Thyroid Disease During Pregnancy

val with a decreased FT4, and all women with a TSH concentration above 10.0 mIU/L, irrespective of the level of fT4. 2. Subclinical hypothyroidism (SCH) has been associated with adverse maternal and fetal outcomes. However, due to the lack of randomized controlled trials (RCTs), there is insufficient evidence to recommend for or against universal LT4 treatment in pregnant women with SCH. 3. Women who are positive for TPO-Ab and have SCH should be treated with levothyroxine (LT4). 4. The recommended treatment of maternal hypothyroidism is with administration of oral LT4. It is strongly recommended not to use other thyroid preparations such as T3 or desiccated thyroid. 5. The goal of LT4 treatment is to normalize maternal serum TSH values within the trimester-specific pregnancy reference range (first trimester, 0.1–2.5 mIU/L; second trimester, 0.2–3.0 mIU/L; third trimester, 0.3–3.0 mIU/L). 6. Women with SCH in pregnancy who are not initially treated should be monitored for progression to OH with a serum TSH and FT4 approximately every 4 weeks until 16–20 weeks of gestation and at least once between 26 and 32 weeks of gestation. 7. Treated hypothyroid patients (receiving LT4) who are newly pregnant should independently increase their dose of LT4 by 25–30% upon a missed menstrual cycle or positive home pregnancy test and notify their caregiver promptly. One means of accomplishing this adjustment is to increase LT4 from once daily dosing to a total of nine doses per week (29% increase). 8. There exists great inter-individual variability regarding the increased amount of T4 (or LT4) necessary to maintain a normal TSH throughout pregnancy, with some women requiring only 10–20% increased dosing, while others may require as much as an 80% increase. The etiology of maternal hypothyroidism, as well as the pre-conception level of TSH, may provide insight into the magnitude of necessary LT4 increase. Clinicians should seek this information upon assessment of the patient after pregnancy is confirmed. 9. Treated hypothyroid patients (receiving LT4) who are planning pregnancy should have their dose adjusted by their provider in order to optimize serum TSH values to 80%) are 2.0 cm [29]. In another study, the incidence rate increased for tumors 4.0 cm in size but not for tumors of medium size (2.0–4.0 cm) [30]. In Spain, from 1978 to 2001, thyroid cancer incidence increased equally in microcarcinomas and in larger tumors [33]. Recently, an increased incidence for thyroid cancers of all stages has been confirmed [34]. The increased incidence of thyroid cancers of large

6.4  Incidence of Thyroid Cancer

355

volume and advanced stages, usually clinically apparent, can hardly be explained by increased detection. Moreover, the thyroid cancer increase almost exclusively occurred for papillary thyroid carcinoma (PTC), while improved detection should have affected all histotypes. We cannot exclude, therefore, that specific carcinogens might have favored the molecular abnormalities typical of PTC, a hypothesis supported by the increasing incidence of BRAF-positive papillary tumors over time [39, 40]. Finally, when increased detection is the only cause, the cancer increase is expected to occur in all age and gender categories. Indeed, the age-adjusted incidence rates of thyroid cancer have increased among females more than males (158% vs. 106%, respectively) with a clear birth cohort pattern, possibly reflecting changes in risk factors [41]. Also the age-specific trends by race do not support a detection effect as the reason for the increasing incidence.

6.4.1.3 Risk Factors that May Contribute to Increased Thyroid Cancer Incidence Radiation Exposure to ionizing radiation is a well-documented risk factor for cancer. The thyroid is very radiosensitive at a young age. Children exposed to radiation frequently develop PTC as shown by the peak of thyroid cancers observed after the Chernobyl accident, when 1.7 × 1018 Bq of 131I were released into the atmosphere. On that occasion, the thyroid received a dose 500 to 1000 times > the rest of the body, and 4000 thyroid cancer cases were reported [42]. The thyroid may be irradiated more than other tissues because of its position in the body and its ability to concentrate iodine (I2). The individual radiation dose has doubled in the USA [43], from approximately 3 mSv/year in 1980 to 6 mSv/year in 2006. This variation is mainly due to medical diagnostic procedures [43]. Medical and dental diagnostic examinations have specifically increased thyroid exposure to X-rays [44]. Although CT scans account for only 15% of all radiological diagnostic procedures in the USA, they provide >50% of the radiation dose absorbed by patients [45]. Because one third of all CT scans are performed in the head/neck region, the thyroid is particularly exposed to radiation. Moreover, the use of iodinated contrast agents increases the radiation absorbed by the thyroid by up to 35% because iodine blocks photons, increasing the local radiation energy [46]. The role of CT scans in increasing the risk of cancer in children is already documented: CT scans delivering a cumulative dose of 50–60 mGy almost triple the risk of leukemia and brain cancer [47]. Direct evidence of CT radiation effect on the incidence of thyroid cancer in children is not available. However, the increasing number of CT scans during childhood was hypothesized to increase the number of thyroid malignancies by up to 390/million exposed individuals [48], and CT scans carried out in the USA in 2007 have been estimated to potentially cause about 1000 future thyroid cancers [49]. Thyroid cancer risk in children exposed to head and neck radiation is inversely correlated to the age, decreasing to a non-statistically significant level by age 15

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6  Thyroid Cancer

[50]. However, a carcinogenic effect of radiation on the adult thyroid population cannot be excluded, as indicated by the increased incidence of thyroid cancer among female survivors of the atomic bomb that were older than 20 years at the time of the explosion [51]. Moreover, a recent report indicates that dental X-rays may increase thyroid cancer risk also in adults [52]. Thus, thyroid shielding has been recently recommended by the ATA during diagnostic dental X-rays both in children and adults. Another specific source of thyroid irradiation is thyroid imaging with 131I that has been largely used for the diagnosis of thyroid diseases. Thyroid scans reached 13% of all nuclear medicine examinations in 1973 [53] and thereafter decreased to 1 Gy [55, 56]. Finally, radiotherapy for head and neck malignancies is an additional source of thyroid irradiation. In a cohort of childhood cancer survivors, 7.5% of all secondary malignancies were thyroid cancers [57]. Increased exposure to radiation, therefore, may have contributed to the increased incidence of thyroid cancer. TSH Levels and Iodine Intake Iodine deficiency causes an increase of TSH, a major growth factor for thyroid follicular cells. Animal experiments showed a clear increase of thyroid cancer after prolonged I2 deficiency leading to increased TSH. However, this effect is not demonstrated in human residents of I2-deficient areas [58, 59]. I2 intake is known to influence the thyroid cancer histotype distribution, rather than the overall incidence, with more follicular and fewer papillary carcinomas in iodine-deficient areas [60]. When I2 prophylaxis is introduced, average serum TSH decreases and the papillary/ follicular ratio increases [61]. The I2-associated shift from a follicular to a papillary histotype may be due to the frequency of the BRAF (V600E) mutation, a typical molecular alteration in PTC. BRAF-positive PTCs were significantly more frequent in Chinese regions with a high I2 intake than in control areas [62, 63]. Although a causal relationship between I2 intake and BRAF mutation is not proven, the worldwide increase of I2 intake and the parallel increase in the prevalence of BRAF-­ positive PTCs are in agreement with a possible role of increased I2 intake in the increased PTC incidence. TSH Levels and Autoimmune Thyroiditis A major role of TSH in thyroid cancer progression is indicated by the decreased recurrence rate (RR) and improved survival in thyroid cancer patients treated with TSH-suppressive L-T4 [64]. However, a role of TSH in inducing thyroid cancer, documented in rodents, is controversial in humans. A recent study indicates that the risk to have a thyroid cancer and also to have a cancer in an advanced stage is

6.4  Incidence of Thyroid Cancer

357

increased in patients with higher TSH serum level [65]. This correlation was confirmed in FNABs in a large series of >10,000 patients with thyroid nodules: the risk of malignancy was higher in patients with a higher TSH serum level [66]. Conversely, the risk of cancer was reduced in hyperthyroid patients with autonomous thyroid nodules and a low serum TSH. A similar correlation was observed also in L-T4treated patients having serum TSH lower than untreated patients [67]. These data suggest that TSH levels, independently of the underlying mechanism, are positively correlated with thyroid cancer risk. There is no evidence that serum TSH levels have increased in the population in the last decades. However, the frequency of chronic autoimmune Hashimoto’s thyroiditis, the most common cause of primary hypothyroidism in the Westernized world, has increased in the last three decades, paralleling the increased I2 intake [68]. Autoimmune thyroiditis might influence cancer risk not only by increasing TSH levels but also because the autoimmune process per se, via the production of pro-inflammatory cytokines and oxidative stress [69], might enhance thyroid tumorigenesis. However, the PTC frequency in patients with autoimmune thyroiditis is related to serum TSH but not to the presence of antithyroid antibodies, and when these patients are treated with LT-4 to prevent a TSH increase, the risk of thyroid cancer is no longer increased [67]. Thyroid Nodules/Solitary vs. Multiple Whether the prevalence of thyroid cancer is different in thyroid glands with a solitary thyroid nodule (STN) vs. multinodular goiter (MNG) remains uncertain. The prevalence of malignancy in STN has been estimated at 5% [70]. As indicated in the recent guidelines for the management of thyroid nodules, patients with multiple thyroid nodules have the same risk of malignancy as those with solitary nodules [71–74]. Individual studies, however, provide cancer prevalence in patients with MNG that are lower (4.1%) [75] or higher (18%) [76]. A recent meta-analysis supported the inference that thyroid cancer is less frequent in MNG than in SN, although this finding appears to hold true mostly outside the USA, in I2-deficient populations [77]. Body Weight and Insulin Resistance A strong correlation between obesity and cancer risk and mortality has been demonstrated for several malignancies [78]. A pooled analysis of five prospective studies indicated that also the risk of thyroid cancer is greater in obese subjects [79]. A recent study supports the possibility that insulin resistance and hyper-insulinemia (a typical feature of obesity) rather than metabolic derangement may be a risk factor for thyroid cancer [80]. Insulin regulates thyroid gene expression and stimulates thyrocyte proliferation, differentiation, and transformation. Insulin resistance was present in 50% of PTC patients vs. 10% of matched controls [81], and BMI at the time of diagnosis was directly related to thyroid cancer risk in females [82]. The pandemia of obesity that characterizes the last decades, therefore, may have contributed to thyroid cancer increase, but whether a specific effect on the thyroid is present and what is the underlying mechanism is unknown.

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6  Thyroid Cancer

Diet, Lifestyle, and Environmental Pollutants The evidences of a possible effect of nutrient/food or environmental pollutants on thyroid cancer are weak and not confirmed [83]. Some industrialized food contaminants, for instance, nitrates, can compete with iodine uptake by the thyroid and can behave as potential thyroid function disruptors and carcinogens. Nitrate is a frequent contaminant of drinking water in areas of intense agricultural industry and is found at high levels in some vegetables and processed food [84, 85]. A high average nitrate level in water supplies is associated with an increased risk of thyroid cancer (RR = 2.9) [86]. At present, no causal correlation has been established between environmental pollutants like asbestos, benzene, formaldehyde, pesticides, and polyhalogenated aromatic hydrocarbons (PHAHs) and thyroid cancer in humans [87]. Volcanic environment may be associated with increased thyroid cancer incidence [59, 88, 89]. In the Mt. Etna volcanic area, where thyroid cancer incidence rate is >doubled in respect to the rest of Sicily [59], only the PTC is increased and both micro- and macro-carcinomas are augmented, reflecting the worldwide pattern of thyroid cancer increase.

6.4.2 Incidence in the USA While the incidence of many head and neck cancers in the USA is decreasing [90], the incidence of thyroid cancer is increasing [91–95]. This increase can be either real due an increase in risk factors for the cancer or apparent because of increased diagnostic scrutiny. Although some thyroid cancers can spread and cause death, for many people thyroid cancer has also long been recognized to exist in a subclinical form. More than 60 years ago, pathologists reported that thyroid cancer (particularly PTC) was a common autopsy finding, despite its never having caused symptoms during a person’s life [96–100]. Harach et al. [101] systematically sectioned 101 thyroid glands in 2- to 3-mm slices. They found that 36% of people not known to have thyroid cancer during their lifetime nonetheless had one or more foci of thyroid cancer. They went on to calculate that, if sectioned finely enough, virtually every person would be found to harbor a thyroid cancer. As diagnostic techniques for thyroid cancer have become more sensitive, particularly with the advent of US and FNA, it has become possible to detect this subclinical reservoir. Thus, while increasing incidence of thyroid cancer might reflect an increase in the true occurrence of disease, it might also reflect increased diagnostic scrutiny.

6.4.2.1 Incidence Trends, 1973–2002 The incidence of thyroid cancer increased from 3.6/100,000 in 1973 to 8.7/100,000 in 2002 – a 2.4-fold increase. This 5.1/100,000 increase in the incidence of thyroid cancer is virtually entirely due to an increase in papillary thyroid cancer (PTC), which increased by 5/100,000, from 2.7 to 7.7/100,000 – a 2.9-fold increase. There

6.4  Incidence of Thyroid Cancer

359

was no significant change in the incidence of the less common histological categories: follicular, medullary, and anaplastic.

6.4.2.2 Papillary Cancer Size Distribution, 1988–2002 Since SEER began recording cancer size in 1988, incidence of PTC has increased by 4.1/100,000. The bulk of this increase is the result of increased detection of small cancers since 49% of the increase consisted of cancers measuring 1 cm or less and 87% consisted of cancers measuring 2 cm or less. 6.4.2.3 Mortality, 1973–2002 Despite increasing incidence, the mortality from thyroid cancer has remained stable. Thyroid cancer-specific mortality was approximately 0.5 deaths/100,000  in both 1973 and 2002. Mortality was 0.57 in 1973, decreased to 0.48 by 1980, and was 0.47 in 2002. The proportion of deaths due to papillary type has not changed over time. 6.4.2.4 Comment The incidence of thyroid cancer in the USA more than doubled over the past 30 years, and 87% of the increase was due to the diagnosis of small papillary cancers. Mortality remained stable during this period. Increasing incidence in the face of stable mortality represents a new category of thyroid cancer – symptomatic but not lethal. Because many of these cancers would likely never have caused symptoms during life, epidemiologists have labeled the phenomenon “overdiagnosis” – a term perhaps most familiar in the setting of prostate cancer [102]. The case for overdiagnosis is strengthened because almost all the increased incidence is attributable to the detection of small cancers best discovered by use of US and FNA [11, 103, 104]. Overdiagnosis is a cause for concern because it makes it hard to identify which patients need treatment. Davies and Welch [31] reported that most patients diagnosed with thyroid cancer underwent total thyroidectomy (TT). This was the case even for PTC; 75% of those with PTCs found to measure 1–4 cm in greatest dimension PT3 Intra-thyroidal tumor, >4 cm in greatest dimension pT4 Tumor of any size, extending beyond thyroid capsule pTX Primary tumor cannot be assessed Regional LNs (cervical or upper mediastinal) N0 No nodes involved N1 Regional nodes involved N1a Ipsilateral cervical nodes N1b Bilateral, midline, or contralateral cervical nodes or mediastinal nodes NX Nodes cannot be assessed Distant metastases M0 No distant metastases M1 Distant metastases MX Distant metastases cannot be assessed

6.6  Well-Differentiated Thyroid Cancer (WDTC) Table 6.8  Papillary or follicular carcinoma staging by age [133, 134]

Stage Stage I Stage II

365 Under 45 years Any T, any N, M0 Any T, any N, M1

Stage III Stage IV

Table 6.9  10-year mortality rate (MR) for DCT [7]

Stage I II III IV

45 years and older pT1, N0, M0 pT2, N0, M0 pT3, N0, M0 pT4, N0, M0 Any pT, N1, M0 Any pT, any N, M1

10-year cancer-specific MR (%) 1.7 15.8 30 60

6.6.2 Management of DTC 6.6.2.1 Surgical Treatment Fine-needle aspiration cytology (FNAC) should be used in the planning of surgery. Patients with a PTC >1 cm or with high-risk FTC should undergo near-TT or TT, while those with PTC ≤1 cm or low-risk FTC may be treated with thyroid lobectomy alone. Serum thyroglobulin (Tg) should be checked in all post-operative patients with DTC, but not sooner than 6 weeks after surgery. Patients will normally start on l-thyroxin 100 μg daily after the operation. This should be stopped 2 weeks before 131I ablation or therapy. Most patients with a tumor >1 cm, who have undergone a near-TT/TT, should have 131I ablation. Pregnancy and breast-feeding should always be excluded before administering 131I. Breast-feeding should be stopped 4 weeks and preferably 8 weeks before 131I ablation or treatment and should not be resumed. A post-ablation scan (3–10 days after 131I ablation) should be performed. Patients treated with 131I will require l-thyroxin therapy in a dose sufficient to suppress the serum TSH to 2 high-dose 131I therapies [137]. Adequate hydration at the time of treatment and for several days afterward, regular emptying of the urinary bladder, and avoidance of constipation help to prevent a reduction in sperm count. Post-operative 131I Ablation Patients >45 years with tumors >1.5 cm should receive 131I ablation to reduce local and distant recurrence and cancer mortality [138, 139]. The benefit of 131I ablation for low-risk patients may however be questionable. Other factors such as invasion, metastases, completeness of excision, and associated disease should be considered. Benefits of 131I Ablation The reported benefits of 131I ablation in the literature include the following: 1. Eradication of all thyroid cells including residual post-operative microscopic disease and thus possible reduction of risk of local and distant tumor recurrence. 2. Reassurance to patients imparted by the knowledge that serum Tg is undetectable and I2 scan −ve, implying that all thyroid tissue was destroyed. 3. Possible prolonged survival [140]. 4. Increased sensitivity of monitoring by serum Tg measurements and possibly earlier detection of recurrent or metastatic disease [141]. Indications of Remnant Ablation with 131I There is no indication for those patients with a low risk of recurrence or cancer-­ specific mortality [142, 143]. Patients should satisfy all the following criteria for 131I ablation to be omitted: complete surgery; favorable histology; tumor unifocal, ≤1  cm, N0, M0, or minimally invasive FTCs, without vascular invasion, 10 involved LNs and >3 LNs with extra-capsular spread) [145]. • Probable indications: Any one of the following categories is a “probable” indication for 131I ablation: less than TT, status of LNs not assessed at surgery, tumor size >1  cm and 3 ECE-LNs and a tumor size of 4 cm or less, and (4) a very high risk (41–93%) in patients with either >10 metastatic LNs or >3 ECE-LNs and a tumor size >4 cm [236].

References

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Table 7.2  Risk stratification for persistent disease Low risk (0–7%) – No central LN metastases – 5 or fewer metastatic LNs

Medium risk (5–21%) – 10 or fewer metastatic LNs – 3 or fewer ECE-LNs

High risk (23–62%) – 10 metastatic LNs – 3 ECE-LNs

Very high risk (41–93%) – 10 metastatic LNs – 3 ECE-LNs

– Tumor size of 4 cm or less

– Tumor size of 4 cm or less

– Tumor size >4 cm

Table 7.3  Risk stratification for recurrent disease

Low risk (0.3–10%) – Undetectable Tg level – 3 ECE-LNs seem to have an intermediate risk of relapse, but risk group classification is limited by the low number of events [236]. These results are concordant with a study from Toubeau et al. [237], who found a 3% risk of recurrence in case of undetectable Tg level and no LN metastases and a 40% risk of recurrence in case of detectable Tg level and/or LN metastases.

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174. Choudhary C, Wartofsky L, Tefera E, Burman K. Evaluation of thyroid bed nodules on ultrasonography after total thyroidectomy: risk for loco-regional recurrence of thyroid cancer. Eur Thyroid J. 2015;4(2):106–14. 175. Tuttle RM, Tala H, Shah J, Leboeuf R, Ghossein R, Gonen M, Brokhin M, Omry G, Fagin JA, Shaha A. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid. 2010;20:1341–9. 176. Lee JH, Lee HK, Lee DH, Choi CG, Gong G, Shong YK, Kim SJ. Ultrasonographic findings of a newly detected nodule on the thyroid bed in postoperative patients for thyroid carcinoma: correlation with the results of ultrasonography-guided fine-needle aspiration biopsy. Clin Imaging. 2007;31:109–13. 177. Shin J, Han B-K, Ko E, Kang S.  Sonographic findings in the surgical bed after thyroidectomy: comparison of recurrent tumors and nonrecurrent lesions. J Ultrasound Med. 2007;26:1359–66. 178. Rondeau G, Fish S, Hann LE, Fagin JA, Tuttle RM. Ultrasonographically detected small thyroid bed nodules identified after total thyroidectomy for differentiated thyroid cancer seldom show clinically significant structural progression. Thyroid. 2011;21:845–53. 179. Schlumberger M, Berg G, Cohen O, Duntas L, Jamar F, Jarzab B, Limbert E, Lind P, Pacini F, Reiners C, Sánchez Franco F, Toft A, Wiersinga WM. Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective. Eur J Endocrinol. 2004;150:105–11. 180. Krishnamurthy S, Bedi DG, Caraway NP. Ultrasound-guided fine-needle aspiration biopsy of the thyroid bed. Cancer. 2001;93:199–205. 181. Leenhardt L, Erdogan MF, Hegedus L, Mandel SJ, Paschke R, Rago T, Russ G. 2013 European Thyroid Association guidelines for cervical ultrasound scan and ultrasound-guided techniques in the postoperative management of patients with thyroid cancer. Eur Thyroid J. 2013;2:147–59. 182. Ronga G, Fiorentino A, Paserio E, et  al. Can iodine-I 131 whole body scan be replaced by thyroglobulin measurement in the postsurgical follow-up of differentiated thyroid carcinoma? J Nucl Med. 1990;31:1766–71. 183. Maxon HR, Smith HS. Radioiodine- 131 in the diagnosis and treatment of metastatic well differentiated thyroid cancer. Clin Endocrinol Metab North Am. 1990;19:685–718. 184. Hamby LS, McGrath PC, Schwartz RW.  Management of local recurrence in well-­ differentiated thyroid carcinoma. J Surg Res. 1992;52:113–7. 185. Schneider AB, Line BR, Goldman JM, Robbins J. Sequential serum thyroglobulin determinations, 131I scans, and 131I uptakes after triiodothyronine withdrawal in patients with thyroid cancer. J Clin Endocrinol Metab. 1981;53:1199–206. 186. Ozata M, Suzuki S, Miyamoto T, Liu RT, Fierro-Renoy F, DeGroot LJ. Serum thyroglobulin in the follow-up of patients with treated differentiated thyroid cancer. J Clin Endo Metab. 1994;79:98–105. 187. Ditkoff BA, Marvin MR, Yemul S, et al. Detection of circulating thyroid cells in peripheral blood. Surgery. 1996;120:959–65. 188. Ringel MD, Ladenson PW, Levine MA. Molecular diagnosis of residual and recurrent thyroid cancer by amplification of thyroglobulin mRNA in peripheral blood. J Clin Endocrinol Metab. 1998;83:4435–42. 189. Arturi F, Russo D, Giuffrida D, et al. Early diagnosis by genetic analysis of differentiated thyroid cancer metastases in small lymph nodes. J Clin Endocrinol Metab. 1997;82:1638–41. 190. Tallini G, Ghossein RA, Emanuel J, et al. Detection of thyroglobulin, thyroid peroxidase, and RET/PTC1 mRNA transcripts in the peripheral blood of patients with thyroid disease. J Clin Oncol. 1998;16:1158–66. 191. Podnos YD, Smith D, Wagman LD, Ellenhorn JD.  Radioactive iodine offers sur vival improvement in patients with follicular carcinoma of the thyroid. Surgery. 2005;128(6):1072–6.

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192. Spies WG, Wojtowicz CH, Spies SM, et al. Value of post-therapy whole-body 1- 131 imaging in the evaluation of patients with thyroid carcinoma having undergone high-dose 1-131 therapy. Clin Nucl Med. 1989;14:793–800. 193. Michael Coburn M, Teates D, Wanebo H. Recurrent thyroid cancer: role of surgery versus radioactive iodine (131I). Ann Surg. 1994;219(6):587–95. 194. Pak H, Gourgiotis L, Chang WI, et al. Role of metastasectomy in the management of thyroid carcinoma: the NIH experience. J Surg Oncol. 2003;82(1):10–8. 195. Rosenbluth BD, Serrano V, Happersett L, et al. Intensity-modulated radiation therapy for the treatment of nonanaplastic thyroid cancer. Int J Radiat Oncol Biol Phys. 2005;63(5):1419–26. 196. De Besi P, Busnardo B, Toso S, et al. Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer. J Endocrinol Invest. 1991;14(6):475–80. 197. 2018. http://news.cancerconnect.com/targeted-therapies-show-initial-ffectiveness-subsetpapillary-thyroid-cancer/. 198. Schlumberger M, Makoto T, Wirth L, et al. N Engl J Med. 2015;372:621–30. 199. FDA approves Nexavar to treat type of thyroid cancer. [FDA News Release]. US Food and Drug Administration, 2013 website. Available at: http://www.fda.gov/NewsEvents/ Newsroom/Press Announcements/ucm376443.htm. 200. Advanced thyroid cancer responds to targeted therapy with sunitinib [press release]. Endocrine Society website. Available at: https://www.endocrine.org/news-room/current-press-releases/ advanced-thyroid-cancer-responds-to-targeted-therapy-with-sunitinib. 201. Grebe SK, Hay ID. Thyroid cancer nodal metastases: biologic significance and therapeutic considerations. Surg Oncol Clin N Am. 1996;5:43–63. 202. Maxon HR, Thomas SR, Hertzberg VS, Kereiakes JG, Chen IW, Sperling MI, Saenger EL. Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer. N Engl J Med. 1983;309:937–41. 203. Lewis BD, Hay ID, Charboneau JW, McIver B, Reading CC, Goellner JR.  Percutaneous ethanol injection for treatment of cervical lymph node metastases in patients with papillary thyroid carcinoma. AJR Am J Roentgenol. 2002;178:699–704. 204. Lim CY, Yun JS, Lee J, Nam KH, Chung WY, Park CS. Percutaneous ethanol injection therapy for locally recurrent papillary thyroid carcinoma. Thyroid. 2007;17:347–50. 205. Monchik JM, Donatini G, Iannuccilli J, Dupuy DE. Radiofrequency ablation and percutaneous ethanol injection treatment for recurrent local and distant well-differentiated thyroid carcinoma. Ann Surg. 2006;244:296–304. 206. Al-Saif O, Farrar WB, Bloomston M, Porter K, Ringel MD, Kloos RT. Long-term efficiency of lymph node re-operation for persistent papillary thyroid cancer. J Clin Endocrinol Metab. 2010;95:2187–94. 207. Ito Y, Miyauchi A, Inoue H, Fukushima M, Kihara M, Higashiyama T, Tomoda C, Takamura Y, Kobayashi K, Miya A.  An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg. 2010;34:28–35. 208. Solorzano CC, Carneiro DM, Ramirez M, Lee TM, Irvin GL III. Surgeon-performed ultrasound in the management of thyroid malignancy. Am Surg. 2004;70:576–80. 209. Stulak JM, Grant CS, Farley DR, Thompson GB, van Heerden JA, Hay ID, Reading CC, Charboneau JW. Value of preoperative ultrasonography in the surgical management of initial and reoperative papillary thyroid cancer. Arch Surg. 2006;141:489–94. 210. Tisell LE, Nilsson B, Mölne J, Hansson G, Fjälling M, Jansson S, Wingren V. Improved survival of patients with papillary thyroid cancer after surgical microdissection. World J Surg. 1996;20:854–9. 211. Carty SE, Cooper DS, Doherty GM, Duh QY, Kloos RT, Mandel SJ, Randolph GW, Stack BC Jr, Steward DL, Terris DJ, Thompson GB, Tufano RP, Tuttle RM, Udelsman R. Consensus statement on the terminology and classification of central neck dissection for thyroid cancer. Thyroid. 2009;19:1153–8. 212. Sywak M, Cornford L, Roach P, Stalberg P, Sidhu S, Delbridge L. Routine ipsilateral level VI lymphadenectomy reduces postoperative thyroglobulin levels in papillary thyroid cancer. Surgery. 2006;140:1000–7.

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213. White ML, Gauger PG, Doherty GM. Central lymph node dissection in differentiated thyroid cancer. World J Surg. 2007;31:895–904. 214. Nikiforov YE, Steward DL, Robinson-Smith TM, Haugen BR, Klopper JP, Zhu Z, Fagin JA, Falciglia M, Weber K, Nikiforova MN. Molecular testing for mutations in improving the fine-­ needle aspiration diagnosis of thyroid nodules. J Clin Endocrinol Metab. 2009;94:2092–8. 215. Noguchi S, Noguchi A, Murakami N. Papillary carcinoma of the thyroid. I. Developing pattern of metastasis. Cancer. 1970;26:1053–60. 216. Chow SM, Law SC, Chan JK, Au SK, Yau S, Lau WH.  Papillary microcarcinoma of the thyroid—prognostic significance of lymph node metastasis and multifocality. Cancer. 2003;98:31–40. 217. Mazzaferri EL, Kloos RT.  Clinical review 128: current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab. 2001;86:1447–63. 218. Hay ID, Bergstralh EJ, Grant CS, McIver B, Thompson GB, van Heerden JA, Goellner JR.  Impact of primary surgery on outcome in 300 patients with pathologic tumor-node-­ metastasis stage III papillary thyroid carcinoma treated at one institution from 1940 through 1989. Surgery. 1999;126:1173–81. 219. Tsang RW, Brierley JD, Simpson WJ, Panzarella T, Gospodarowicz MK, Sutcliffe SB. The effects of surgery, radioiodine, and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma. Cancer. 1998;82:375–88. 220. Loh KC, Greenspan FS, Gee L, Miller TR, Yeo PP.  Pathological tumor-node-metastasis (pTNM) staging for papillary and follicular thyroid carcinomas: a retrospective analysis of 700 patients. J Clin Endocrinol Metab. 1997;82:3553–62. 221. Simon D, Goretzki PE, Witte J, Roher HD. Incidence of regional recurrence guiding radicality in differentiated thyroid carcinoma. World J Surg. 1996;20:860–6. 222. Coburn MC, Wanebo HJ. Prognostic factors and management considerations in patients with cervical metastases of thyroid cancer. Am J Surg. 1992;164:671–6. 223. Samaan NA, Schultz PN, Hickey RC, Goepfert H, Haynie TP, Johnston DA, Ordonez NG. The results of various modalities of treatment of well differentiated thyroid carcinomas: a retrospective review of 1599 patients. J Clin Endocrinol Metab. 1992;75:714–20. 224. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab. 1990;71:414–24. 225. Sugitani I, Kasai N, Fujimoto Y, Yanagisawa A. A novel classification system for patients with PTC: addition of the new variables of large (3  cm or greater) nodal metastases and reclassification during the follow-up period. Surgery. 2004;135:139–48. 226. Yamashita H, Noguchi S, Murakami N, Toda M, Uchino S, Watanabe S, Kawamoto H. Extracapsular invasion of lymph node metastasis. A good indicator of disease recurrence and poor prognosis in patients with thyroid microcarcinoma. Cancer. 1999;86:842–9. 227. Sato N, Oyamatsu M, Koyama Y, Emura I, Tamiya Y, Hatakeyama K. Do the level of nodal disease according to the TNM classification and the number of involved cervical nodes reflect prognosis in patients with differentiated carcinoma of the thyroid gland? J Surg Oncol. 1998;69:151–5. 228. Scheumann GF, Gimm O, Wegener G, Hundeshagen H, Dralle H.  Prognostic significance and surgical management of locoregional lymph node metastases in papillary thyroid cancer. World J Surg. 1994;18:559–67. 229. Shah JP, Loree TR, Dharker D, Strong EW, Begg C, Vlamis V. Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg. 1992;164:658–61. 230. Soares J, Limbert E, Sobrinho-Simoes M.  Diffuse sclerosing variant of papillary thyroid carcinoma. A clinicopathologic study of 10 cases. Pathol Res Pract. 1989;185:200–6. 231. Moreno Egea A, Rodriguez Gonzalez JM, Sola Perez J, Soria Cogollos T, Parrilla Paricio P. Prognostic value of the tall cell variety of papillary cancer of the thyroid. Eur J Surg Oncol. 1993;19:517–21. 232. Akslen LA, LiVolsi VA. Prognostic significance of histologic grading compared with subclassification of papillary thyroid carcinoma. Cancer. 2000;88:1902–8.

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233. Hughes CJ, Shaha AR, Shah JP, Loree TR. Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a matched-pair analysis. Head Neck. 1996;18:127–32. 234. Shaha AR, Loree TR, Shah JP. Intermediate-risk group for differentiated carcinoma of thyroid. Surgery. 1994;116:1036–40. 235. Tubiana M, Schlumberger M, Rougier P, Laplanche A, Benhamou E, Gardet P, et al. Long-­ term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer. 1985;55:794–804. 236. Leboulleux S, Rubino C, Baudin E, Caillou B, Hartl DM, Bidart JM, et al. Prognostic factors for persistent or recurrent disease of papillary thyroid carcinoma with neck lymph node metastases and/or tumor extension beyond the thyroid capsule at initial diagnosis. J Clin Endocrinol Metab. 2005;90(10):5723–9. 237. Toubeau M, Touzery C, Arveux P, Chaplain G, Vaillant G, Berriolo A, et al. Predictive value for disease progression of serum thyroglobulin levels measured in the postoperative period and after (131)I ablation therapy in patients with differentiated thyroid cancer. J Nucl Med. 2004;45:988–94.

8

Thyroidectomy Techniques

8.1

Thyroidectomy: History

8.1.1 Introduction The earliest distinct reference of a successful attempt at surgical treatment of goiter is present in the medical writings (Al-Tasrif) by the Moorish physician Ali Ibn Abbas or Albucasis in about 952 AD. At one point of history, thyroid surgery was considered such a dreaded operation with a definite grim outcome that surgeons were fearful in performing it at all. However, surgeons like Theodor Billroth and his pupil Theodor Kocher ventured into this surgical domain and mastered it, thereby popularizing it and allaying all fears about a dreaded outcome. Thyroid surgery has travelled a long way since then, and now, attempts are being made to perform the surgery in a way so as to make it minimally invasive.

8.1.2 History of Goiter Around 2700 BC, goiter was appreciated in China, and in as early as 1600 BC, the Chinese used burnt sponge and seaweed to treat goiters. Pliny the Elder noted goiter epidemics in the Alps and also mentioned the use of burnt seaweed in their treatment, which supposedly they learnt from the Chinese. The Atharva Veda (2000 BC), an ancient Hindu collection of incantations, also contains exorcisms for goiter. It termed the swelling of the neck (goiter) as “galaganda.” The earliest anatomical picture of the thyroid gland was made by the famous Italian legend, Leonardo da Vinci (Fig. 8.1) in 1511 during his anatomical studies in Florence. The exact function of the gland was not known to him, and he presumed that its purpose was to fill in the interval produced by a deficit of muscles, in so doing holding the trachea away from the sternum [1].

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2020 M. F. Sakr, Thyroid Disease, https://doi.org/10.1007/978-3-030-48775-1_8

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Fig. 8.1  Leonardo da Vinci (1452–1519)—Italian scientist and painter

Exophthalmic goiter was first described by Caleb Hillier Parry of Bath in 1768 in his write-up in “Enlargement of the Thyroid Gland in Connection with Enlargement or Palpitation of the Heart” [2]. This subject was then further scrutinized by Robert James Graves [3] and Carl Adolf von Basedow [4] who published their observations independently in 1835 and 1840, respectively. Their publications dealt with the association of goiter, exophthalmos, palpitation, irritability, weight loss, wild hunger, hyperactivity, warmth, and sweating.

8.1.3 History of the Surgical Procedure One of thyroid surgery’s earliest references comes from the seventh century when a classical Byzantine doctor, Paul of Aegina, described struma and its operation, but it is not certain whether what was struma according to him was actually a goiter of the present day [5]. The earliest distinct reference of a successful attempt at surgical treatment of goiter is present in the medical writings (Al Tasrif) by the Moorish physician Ali Ibn Abbas or Albucasis in about 952 AD. His experience is recorded as the removal of a large goiter under sedation with opium with the use of simple ligatures along with hot cautery irons as the patient sat with a bag tied around his neck to collect the blood from the wound [6]. The Salerno school was a leading surgical center in between the ninth and the thirteenth century AD. In 1170, a prominent surgeon, Roger Frugardi, performed a

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507

thyroidectomy using setons, hot irons, ligaments, and caustic powders [7]. Frugardii wrote “Practica chirurgiae,” which became a principle of surgery in the thirteenth and fourteenth centuries. It had special importance in the schools of Bologna and Montpellier where surgery had an important place because of Ronaldo of Parma and Wilhelm von Congenis [8]. When the church  started to control University Legislation, progress started to wane. The church discouraged medical activity, especially surgery, among educated people and clerics. Libraries shunned books on surgical works and faculties stopped educating surgeons, as in the Montpellier school in 1230. An expression was coined by the church “Ecclesia abhorret e sanguine” meaning “The Church bewares of blood’.” Doctors started to avoid taking up surgery fearing a loss of position and rank. Thus, surgery was disjointed from medicine, and it began to be controlled by uneducated people, the so-called barbers. They set broken bones, drained abscesses and did blood lettings, which were a part of treatment in those times [8]. In the late Middle Ages, surgery was revived with the efforts of Guy de Chauliac and others like Henri de Mondeville or Guido and Bonetus Lanfranchi. They used the teachings of Albucasis and Roger Frugardi, but there were no references to the thyroid surgeries performed by them. The period of Renaissance saw the emergence of a great surgeon Ambrois Parre, but his contribution to the field of thyroid surgery was not very significant [8]. In 1791, Pierre Joseph Desault achieved a landmark in thyroid surgery by performing the first partial thyroidectomy [9]. Surgeons like Dupuytren in 1808, William Blizard in 1811, or Henry Earle in 1823 followed him closely. In between 1842 and 1859, Heusser is said to have performed 35 thyroidectomies with only 1 death. Victor von Bruns of Tubingen, in between 1851 and 1876, was the first surgeon to have separated the isthmus from the gland and performed 28 thyroidectomies with 6 deaths. However, Halsted in his “The operative history of goiter” scrutinized procedures done before 1850 and analyzed them to be associated with 40% mortality [9, 10]. The high mortality was mainly due to hemorrhage, asphyxia due to tracheal compression, hospital gangrene, and air embolism. These drawbacks made even the most skilled jittery, and they avoided operating on goiters. In 1846, Robert Liston  called thyroid surgery “a proceeding by no means to be thought of” after performing five thyroidectomies [11]. Two years later, Samuel Gross wrote: “Can the thyroid in the state of enlargement be removed? Emphatically, experience answers no. Should the surgeon be so foolhardy to undertake it….every stroke of the knife will be followed by a torrent of blood and lucky it would be for him if his victim lived long enough for him to finish his horrid butchery. No honest and sensible surgeon would ever engage in it” [12]. The French Academy of Medicine also banned thyroid operations in 1850 due to the high mortality associated with them. Thyroid surgery started coming out of its doldrums in the middle of the nineteenth century. This was due to the concerted improvement in anesthesia, infection prophylaxis, and better hemostasis. Oliver Wendell Holmes coined the term “anesthesia.” Crawford W. Long of Georgia used sulfuric ether as the anesthetic agent for the first time in 1842 and in 1846; WTG Morton  demonstrated the use of ether anesthesia in Massachusetts General Hospital. Three years later,

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Nikolai Oiringoff performed a successful thyroidectomy using ether anesthesia in St. Petersburg [12]. Surgery progressed further with newer methods of infection prophylaxis, such as the use of carbolic acid in antisepsis by Joseph Lister of Glasgow in 1867 [13]. The introduction of steam sterilization of instruments by Ernst von Bergmann in 1886 [14] and intra-operative antisepsis with a cap and gown by Gustav Neuber in 1883 [15] reduced the incidence of infection significantly in the post-operative period. In 1874, Spencer Wells and Jules Pear introduced the first effective hemostatic forceps. With all these advances, the surgical stage was well set for the most skilled surgeons of the nineteenth century. Theodor Billroth (Fig. 8.2) performed 36 thyroidectomies with 16 deaths, in Zurich and Vienna [16]. With the use of newer methods of antisepsis and hemostasis in between 1877 and 1881, Billroth performed 48 thyroidectomies and was able to decrease the mortality to 8.3%. Theodor Kocher (Fig. 8.3), a pupil of Billroth, carried forward the baton of thyroid surgery from his teacher. In 1872, Kocher was appointed to the chair of surgery in Berne. He became a professor of surgery at the age of 31. During his first 10 years in Berne, he had performed 101 thyroidectomies, experiencing a mortality of 2.4%. By 1895, the mortality rate improved to about 1%. He operated initially through an oblique incision along the anterior border of sternomastoid or by a vertical midline incision. He suggested a more cautious resection and a more precise technique by extra-capsular dissection.

Fig. 8.2  Albert Theodor Billroth, Austrian surgeon from Vienna (1829–1894)—the most skilled surgeon of the nineteenth century

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509

Fig. 8.3  Emil Theodor Kocher, Swiss surgeon from Berne (1841–1917)—a pupil of Billroth and Nobel Prize laureate in 1909

In 1909, Kocher was awarded the Nobel Prize for the work done by him on thyroid surgery. At the age of 76, in 1917, he presented the results of his entire work at the Swiss Surgical Congress, weeks before his demise. His presentation revealed his enormous amount of work, about 500 thyroid surgeries performed by him with a mortality rate of 0.5% [16]. The side effect of total thyroidectomy in the form of cretinoid changes was first observed by Kocher, and he called this “cachexia strumi priva.” He observed that the patients would become sluggish, cold, fat, and sometimes mentally deranged. In 1877, William Ord  named this disorder “myxedema” [17]. After this discovery Kocher stated: “In technical terms, we have certainly learned to master the operation for goiter. We can deal with bleeding and prevent loss of speech. Billroth’s tetany is so unusual that it has not made us change our methods. But something else happened… Removal of the thyroid gland has deprived my patients of what gives them human value. I have doomed people with goiter, otherwise healthy, to a vegetative existence. Many of them, I have turned to cretins, saved for a life not worth living…” [5]. His thoughts were imparted in a German Surgical Congress in Berlin and written in a report on the results of total thyroidectomies in 1883, which was published in the “Archiv für Klinische Chirurgie” [18]. He promised not to remove a thyroid gland completely and advised to perform lobectomies. One of his famous rules reads: “A surgeon is a doctor who can operate and who knows when not to” [5]. What is really interesting is the fact that Billroth had limited experience with myxedema after total thyroidectomy. He was plagued by another disorder following surgery, which is tetany. Kocher on the other hand seldom witnessed it. Halsted who had the rare opportunity of watching both the surgeons presumed that the difference of outcome was the result of their difference in temperaments. The explanation probably lies in the operative methods of the two illustrious surgeons. Kocher, neat and precise, operating in a relatively bloodless manner, scrupulously removed the entire thyroid gland, doing little damage outside the capsule. Billroth, operating more rapidly, and as I recall his manner, with less regard for tissues and less concern for hemorrhage, might easily have removed the parathyroids or at least interfered with their blood supply, and have left remnants of thyroid [10].

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In 1891, Gley opined that post-thyroidectomy tetany is caused either by removal of the parathyroid glands (PTGs) or interference of the blood supply to these glands. In 1896, Vassale and Generalim demonstrated that loss of parathyroid function may cause tetany in animals [19]. This gave an opportunity to the surgeons to further develop techniques to preserve the glands. Billroth’s pupils, Anton Wolfer and, Jan Mikulicz-Radecki, were the first to look for a solution to this problem. Anton Wolfer, the then chair of surgery of Graz, in 1886, described tetany in detail. Miculicz, the chair of surgery of Kraków, in 1882, devised a new approach to thyroidectomy. He suggested that with the preservation of the posterior aspects of both the lobes, tetany could be prevented. The parathyroid blood supply was published in 1907 by Halsted and Evans. They opined that “ultra-ligation” of the thyroid arteries was to be practiced, which was ligation distal to the points of origin of the parathyroid artery branches. They suggested avoiding inferior thyroid artery (ITA) ligation [20]. Another serious complication after total thyroidectomy was the laryngeal nerve injury. Mikulicz-Radecki was particularly interested in preventing this complication. His new technique of preservation of the posterior aspect of the lobes additionally took care of the recurrent laryngeal nerves (RLNs) and preservation of its function. It may be presumed that a significant number of RLN injuries were not diagnosed till the introduction of mirror examination of the larynx, the credit of which goes to the Spanish singer  Manuel Garcia. On his discovery, Manual Garcia had stated “I had often thought of using a mirror to observe the larynx from within while singing, but I had always considered it impossible. In September 1854, on a visit to Paris, I decided to see whether it could be done. I went to the famous instrument-­maker Charrier and asked if he had a thin mirror with a long shaft that could be used to inspect the throat. He had a small tooth-mirror, sent to the London exhibition in 1851, which nobody wanted. I bought it and took it to my sister’s, with another little pocket-mirror, impatient to begin my experiment. I warmed the mirror in hot water, dried it carefully, and placed it against the tongue. When I cast in light with the pocket-mirror against it, I saw the larynx wide open before me!” [5]. Until the case of the lead opera singer Amelita Galli-Curci, little attention was paid to the superior laryngeal nerves (SLNs) and their function. She was operated for goiter in 1936 by Arnold Kegel and G. Raphael Dunleavy. Several months after recovery, the singer returned to the stage, but her career was short-lived. She failed in her upper range and could not sustain the notes with apparent breathlessness during her performance. The complication that happened to Amelita Galli-­Curci can now be recognized to be an injury to the external branch of the SLN, which resulted in cricothyroid muscle dysfunction which, in turn, resulted in its inability to sustain maintenance of tone of the vocal cords [5]. All these years, thyroidectomies were being performed on non-toxic goiters as toxic ones were considered poor candidates for surgery. Thus, toxic goiters posed a new challenge for the surgeons. In 1884, Ludwig Rehn  of Frankfurt-am-Main reported three cases where goiters were operated upon to relieve impending obstruction but incidentally they got cured from the toxic symptoms [21]. Toxic thyroidectomies were performed by surgeons like Theodor Kocher, Frank Hartley, Cahrles Mayo, Thomas Peel Dunhill, and George Washington Crile. 

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511

To provide greater safety, Kocher practiced initial ligation of the thyroid arteries [11]. Hartley was a pioneer in removing the second lobe partially in a select number of patients [22]. Mayo practiced unilateral or bilateral pole ligation prior to partial thyroidectomy in patients with severe thyrotoxicosis [23]. A second lobectomy was suggested by Dunhill  in patients with thyrotoxicosis who failed to respond to their initial procedure. The basis of Graves’ disease was not known till 1886 when P.J. Moebius suggested that the cause was disordered function of the thyroid gland itself. From a surgical viewpoint, however, this did not make much of a difference. Although it had been known for some time that seaweed kelp reduced goiter size, it was not until 1811 that Bernard Courtois discovered iodine in burnt seaweed, which fostered the idea that this was the active ingredient in the treatments that were being successfully prescribed for goiter. Ten years later, Coindet was the first to recommend iodine in the pre-operative treatment of goiter to decrease vascularity and consequently lessen the operative risk. This was endorsed further by Marine in 1907, who proposed that iodine was necessary for normal function of the thyroid gland, and in 1911, iodine was recommended as the therapy for Graves’ disease which happened to be a landmark in the treatment of toxic goiters [24]. In 1923, Plummer published results of the 600 thyrotoxic patients that he had operated upon after using Lugol’s iodine pre-operatively. He demonstrated that the operative mortality rate dropped from 4% to 1% by using Lugol’s iodine [25]. Further progress in the management of toxic goiter happened with the introduction of radioactive iodine (RAI) and its incorporation in therapeutics in 1942 by  Means, Evans, and  Hertz. A year later, in 1943, came thiouracil, introduced by Edwin Bennet Astwood. Beta-blockers (propranolol), developed about 20 years later, were inducted into the armamentarium for treatment of toxic goiters in 1965. The incorporation of these drugs contributed significantly to the peri-operative management of toxic goiter, the group of treatment, drugs, RAI, and surgery, still followed as the basis of treatment for thyrotoxicosis. With the development of radiological procedures like ultrasound and computerized tomography (CT) scanning, the diagnosis has become even more precise. The introduction of fine-needle aspiration cytology (FNAC) in 1952, as described by Soderstorm, further improved the diagnosis of goiter [14]. Along with advances in other disciplines of medical science, viz., anesthesia, physiology, and radiology, surgical treatment of thyroid diseases improved significantly. The procedure became safer with introduction of devices like the nerve monitor for electro-identification of the RLN intra-operatively. The transplantation of accidentally removed PTGs also gave a new hope in total thyroidectomy surgeries. Apart from making the surgery safe and effective, the quest started for newer techniques of performing the procedure to achieve cosmetically better results and surpassing its other drawbacks.

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8  Thyroidectomy Techniques

8.1.4 Minimal Access Thyroid Surgery (MITS) Minimal access thyroid surgery (MITS) is a recent addition to the surgical techniques of thyroid surgery. Minimal access surgery is well accepted in other surgical specialties, but in head and neck surgery, its acceptance has been rather slow [26]. Gagner et al, in 1996, generated much interest in this field after he reported feasibility of endoscopic approach to the PTGs [27]. His focus shifted to thyroid surgery as well to the quest for less invasive techniques and better aesthetic outcome. The concept attracted the attention of patients who appreciated the prospect of a better cosmetic outcome, less hospital stay and less post-operative pain. Over a short period of time, a number of techniques simultaneously started being called as minimally invasive thyroid surgery. These can be classified as pure endoscopic techniques, video-assisted techniques, and minimally invasive open surgery. Pure endoscopic technique also differed in terms of the different routes being used to approach the thyroid compartment with or without carbon dioxide gas insufflation—the routes of access being lateral neck [28], axilla [29], anterior chest [30], and breast [31]. In all the routes, usage of a 30° endoscope is common. Minimally invasive video-assisted thyroidectomy (MIVAT) was introduced and popularized by an Italian team (Miccoli et al.) in the 1990s. It is the most widely used method. In this method, a 1.5-cm incision is made in the cervical skin crease, and it is through this incision that the excised part is delivered after video-assisted excision of the gland. “Small incision thyroidectomy” is a minimally invasive open surgical technique which does not require specialized instruments [32]. It differs from the conventional surgery only in terms of its length of incision but with advantages galore which includes decreased tissue trauma, less hospital stay, better cosmesis, less post-­ operative pain, and increased post-operative comfort. However, it has its disadvantages too—longer surgical time, steep learning curve, and the inflated expenses of the surgery. Till 2002, thyroid malignancies were considered unsuitable for endoscopic surgeries, but then Miccoli et al. [33] reported his series of endoscopic surgery done in papillary thyroid cancer (PTC) patients. They found MITS to be as effective as conventional surgery in carefully selected cases of PTC, as there was no significant difference in between the two groups in terms of iodine (I131) uptake or circulating thyroglobulin (Tg) levels. Although there is not any specific criteria for selection of cases, there seems to be a consensus in terms of patient selection for MITS in terms of size of the tumor (