Surgery of the Thyroid and Parathyroid Glands E-Book
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1650 pages
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Description

Surgery of the Thyroid and Parathyroid Glands empowers the reader to diagnose benign and malignant diseases effectively, implement the latest cutting-edge techniques, and achieve optimal patient outcomes. This surgical reference book encompasses the most up to date state of the art knowledge, presented by world-renown authors in thyroid and parathyroid surgery, in one concise yet comprehensive source, offering the detailed guidance you need to produce the best results.


Sujets

Ebooks
Savoirs
Medecine
Derecho de autor
Lesión
Reino Unido
Surgical incision
Functional disorder
Nodular goiter
Oncology
Robotics
Multiple hamartoma syndrome
Parathyroid carcinoma
Parathyroid adenoma
Multiple endocrine neoplasia type 2b
Lymph node dissection
Follicular thyroid cancer
Surgical suture
Thyroid nodule
Thyroid adenoma
Neck pain
Postpartum thyroiditis
Percutaneous transhepatic cholangiography
Vandetanib
Subacute thyroiditis
Immobile
Papillary thyroid cancer
Anaplastic thyroid cancer
Thyroid function tests
Ligation
Tertiary hyperparathyroidism
Perioperative
Secondary hyperparathyroidism
Adenomatous polyposis coli
Thyroiditis
Multiple endocrine neoplasia type 1
Laryngeal paralysis
Lobectomy
Primary hyperparathyroidism
Iodine-131
Laser ablation
Recurrent laryngeal nerve
Neck dissection
Mediastinum
Lymphadenectomy
Neoplasm
Germline mutation
Thoracotomy
Familial adenomatous polyposis
Parathyroidectomy
Hyperphosphatemia
Endocrine surgery
Gardner's syndrome
Thyroglossal cyst
Chronic kidney disease
Hyperparathyroidism
Hypoparathyroidism
Hashimoto's thyroiditis
Regional anaesthesia
Cardiothoracic surgery
Eye surgery
Review
Pathogenesis
Hypercalcaemia
Adrenal medulla
Calcitonin
Triiodothyronine
Parathyroid hormone
Renal cell carcinoma
Biopsy
Lesion
Carcinoma
Parathyroid gland
Multiple endocrine neoplasia
Pheochromocytoma
Thyroidectomy
Endoscopy
Local anesthesia
Pleasure
List of surgical procedures
Embryology
Medical ultrasonography
Trachea
Hypothyroidism
X-ray computed tomography
Kidney stone
United Kingdom
Thyroid
Radiation therapy
Positron emission tomography
Physiology
Paralysis
Osteoporosis
Magnetic resonance imaging
Hyperthyroidism
General surgery
Chemotherapy
Monitoring
Lésion
Dissection
Mobilité
On Thorns I Lay
Ablation
Hormone thyroïdienne
Mutation
Larynx
Ostéoporose
Copyright
Éthanol
Royaume-Uni

Informations

Publié par
Date de parution 13 août 2012
Nombre de lectures 1
EAN13 9781455733934
Langue English
Poids de l'ouvrage 9 Mo

Informations légales : prix de location à la page 0,0736€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.

Exrait

Surgery of the Thyroid and Parathyroid Glands
Second Edition

Gregory W. Randolph, MD, FACS
Director, General, Thyroid, and Parathyroid Surgical Divisions, Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary
Member, Division of Surgical Oncology, Endocrine Surgical Service, Department of Surgery, Massachusetts General Hospital
Associate Professor, Otology and Laryngology, Harvard Medical School, Boston, Massachusetts
Saunders
Table of Contents
Instructions for online access
Cover image
Title page
Copyright
Dedication
Contributors
Foreword
Preface
Acknowledgments
Section 1: Introduction
Chapter 1: History of Thyroid and Parathyroid Surgery
The Early Years
The Surgical Revolution
Development of Modern Thyroid Surgery
Laryngeal Nerves
Parathyroid Glands
Historical Vignette Of Endocrine Surgery at the Massachusetts General Hospital
References
Chapter 2: Applied Embryology of the Thyroid and Parathyroid Glands
The Thyroid Gland
The Recurrent Laryngeal Nerve
Applied Embryology of the Parathyroid Glands
References
Chapter 3: Thyroid Physiology and Thyroid Function Testing
Introduction
Thyroid Tests
Thyroid Function Testing for Hypothyroidism
Thyroid Function Testing for Thyrotoxicosis
Thyroid Function Testing and Pregnancy
Thyroid Function Testing in Nonthyroidal Illness (Euthyroid Sick Syndrome)
Conclusions
References
Section 2: Benign Thyroid Disease
Chapter 4: Thyroiditis
Introduction
Hashimoto's Thyroiditis
Sporadic Silent and Postpartum Thyroiditis
Subacute Thyroiditis/De Quervain's Thyroiditis
Drug-Induced Thyroiditis
Acute Suppurative/Infectious Thyroiditis
Invasive Fibrous Thyroiditis/Riedel's Thyroiditis
References
Chapter 5: Hyperthyroidism: Toxic Nodular Goiter and Graves’ Disease
Introduction
Epidemiology
Pathogenesis
Diagnostic Evaluation
Treatment
References
Chapter 6: Thyroglossal Duct Cysts and Ectopic Thyroid Tissue
Embryology
Thyroglossal Duct Cysts
Ectopic Thyroid Tissue
References
Chapter 7: Surgery of Cervical and Substernal Goiter
General Considerations
Posterior Mediastinal Goiters (Substernal Goiter Type II)
Isolated Mediastinal Goiter (Substernal Goiter Type III)
Prevalence, Pathogenesis, and Natural History
Clinical Presentation
Goiter Workup
Evaluation of Upper Airway Compromise and Other Regional Symptoms
Treatment Options
Intubation of the Goiter Patient: Laryngeal Edema
Goiter Surgery
Surgical Technique for Goiter
Postoperative Complications of Goiter Surgery
Recurrent Goiter: Prevention and Treatment
Recurrent Goiter: Prevention and Treatment
References
Chapter 8: Approach to the Mediastinum: Transcervical, Transsternal, and Video-Assisted
Indications
Surgical Options for Exposure
Postoperative care
References
Chapter 9: The Surgical Management of Hyperthyroidism
Introduction
Graves' Disease
Toxic Nodular Goiter
Toxic Multinodular Goiter
Solitary Toxic Nodule
References
Chapter 10: Reoperation for Benign Disease
Introduction
Prevalence
Management of Recurrent Nodular Goiter
Presentation of Recurrent Nodular Goiter
Preoperative Workup
Operative Strategy
Postoperative Complications
Postoperative Management and Prevention of Further Recurrence
Management of Recurrent Graves’ Disease
Management of Recurrent Graves’ Disease
References
Section 3: Preoperative Evaluation
Chapter 11: The Evaluation and Management of Thyroid Nodules
Introduction
Identifying Thyroid Nodules for Evaluation
Fine-Needle Aspiration
Risk Assessment of Thyroid Nodules
Decision Analysis
Summary
References
Chapter 12: Fine-Needle Aspiration of the Thyroid Gland
Introduction
Indications for Thyroid FNA
FNA Technique
Accuracy of Thyroid FNA
Reporting Terminology: The Bethesda System
Nondiagnostic Thyroid Aspirates
Benign Conditions
Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance
Suspicious for a Follicular Neoplasm/Follicular Neoplasm: Follicular Adenomas and Follicular Carcinomas
Hurthle Cell Neoplasms
Malignant Tumors
Thyroid FNA Complications
References
Chapter 13: Ultrasound of the Thyroid and Parathyroid Glands
Introduction
Physics and Principles of Ultrasound
Thyroid Ultrasound
Role of Ultrasound in the Initial Evaluation of the Thyroid Nodule
Ultrasonography Technique and Measurements
Ultrasonography Technique and Measurements
Ultrasound Characteristics of Thyroid Nodules
Elastography
Elastography
Ultrasound Characteristics of Benign Thyroid Nodules
Ultrasound Characteristics of Benign Thyroid Nodules
Ultrasound Characteristics of Malignant Lesions
Ultrasound Characteristics of Malignant Lesions
Follicular Carcinoma
Follicular Carcinoma
Hurthle Cell Carcinoma
Hurthle Cell Carcinoma
Medullary Carcinoma
Medullary Carcinoma
Anaplastic Carcinoma
Anaplastic Carcinoma
Lymphoma
Lymphoma
Thyroid as a Site of Cancer Metastases
Thyroid as a Site of Cancer Metastases
Ultrasound Surveillance of Thyroid Nodules over Time
Ultrasound Surveillance of Thyroid Nodules over Time
Role of Ultrasound in Other Thyroid Gland Diseases
Graves’ Disease
Multinodular Goiter
Thyroiditis
Role of Ultrasound in Other Thyroid Gland Diseases
Ultrasound-Guided Thyroid Procedures
Equipment and Technique
Ultrasound Features of Malignant Nodes (Table 13-3)
Sonography of Neck Nodes
Nodal Distribution
Nodal Distribution
Contrast Enhancement
Contrast Enhancement
Elastography of Thyroid Lymph Node Metastases
Elastography of Thyroid Lymph Node Metastases
Parathyroid Ultrasound
Parathyroid Ultrasound
Embryology
Embryology
Normal Anatomy
Normal Anatomy
Ectopic Position
Chapter 14: Preoperative Radiographic Mapping of Nodal Disease for Papillary Thyroid Carcinoma
Macroscopically Positive versus Microscopically Positive LN Mets
The Importance of Radiographic Detection of Macroscopically Positive Nodes Preoperatively
Central Neck Nodes
Lateral Neck Nodes
Preoperative Radiographic Evaluation: US and CT
Physical Exam
Ultrasound
CT Scanning with Contrast
References
Chapter 15: Pre- and Postoperative Laryngeal Exam in Thyroid and Parathyroid Surgery
Introduction
Anatomy and Voice
Reported Prevalence of Recurrent Laryngeal Nerve Paralysis
Glottic Exam and Voice
Voice Symptoms with Normal Vocal Fold Mobility
Vocal Cord Paralysis without Voice Symptoms
Rationale for Preoperative Laryngeal Exam
Laryngeal Exam Guidelines
Rationale for Postoperative Laryngeal Exam
Flexible Laryngoscopy: A Standard Technique to Be Mastered by All Thyroid Surgeons
Summary
References
Chapter 16: Laser and Radiofrequency Treatment of Thyroid Nodules and Parathyroid Adenoma
Introduction
Image-Guided Tumor Ablation
Laser Ablation
Radiofrequency Ablation
Thermal Ablation Procedures in Autonomously Functioning Thyroid Nodules
Follow-up Evaluation after Thyroid Thermal Ablation Procedures
Parathyroid Thermal Ablation
Indications of Thermal Ablation Procedures in the Endocrine Neck
Conclusions
References
Section 4: Thyroid Neoplasia
Chapter 17: Molecular Pathogenesis of Thyroid Neoplasia
Introduction
Thyroid Neoplasia: An Overview
Thyroid Neoplasia: Genetic Alterations Associated with Specific Thyroid Tumors
Specific Genetic Alterations in Papillary Thyroid Carcinoma
Follicular Thyroid Carcinoma
Poorly Differentiated Thyroid Carcinoma
Anaplastic Thyroid Carcinoma
Medullary Thyroid Carcinoma
Conclusions
References
Chapter 18: Papillary Thyroid Cancer
An Overview of the Epidemiology and Initial Management of Papillary Thyroid Cancer
Initial Approach to the Patient
Epidemiology
Factors That May Contribute to Thyroid Cancer
Causes of Papillary Thyroid Cancer
Factors Influencing Prognosis
Effect of Patient Variables on Prognosis
Effect of Treatment Variables on Prognosis
Initial Treatment of Papillary Thyroid Cancer
Mortality Rates
Tumor Staging Systems
Conclusion
References
Chapter 19: Papillary Thyroid Microcarcinoma
Prevalence
An Epidemic?
Observational Data
Clinical Series of Patients with Micropapillary Cancer
Impact of Initial Surgery
Completion Thyroidectomy
Node Dissection
Radioiodine
Postoperative Surveillance
Summary and Recommendations
References
Chapter 20: Follicular Thyroid Cancer
Introduction
Epidemiology
Etiology
Diagnosis
Treatment
Prognosis
Summary
References
Chapter 21: Dynamic Risk Group Analysis for Differentiated Thyroid Cancer
Introduction
Initial Risk Stratification
Response to Therapy Assessment
Integrating Initial Risk Estimates with Response to Therapy (Dynamic Risk Assessment)
Representative Case Example
Predicting Clinical Outcomes Using Response to Therapy Variables Superimposed on Initial ATA Risk Stratification
Summary
References
Chapter 22: Hurthle Cell Tumors of the Thyroid
Introduction
Pathology
Presentation and Natural History
Pathogenesis
Pathogenesis
Ret/PTC Rearrangements
Staging and Prognostic Factors
Preoperative Evaluation
FNA
Fine-Needle Aspiration
Ultrasound and Other Imaging Modalities
Ultrasound and Other Imaging Modalities
Tumor Classification by Ret/PTC Genetic Testing
Surgery
Intraoperative Frozen Section
Preoperative or Intraoperative Ret/PTC Testing
Adjuvant Therapy
Follow-up
Follow-up
Summary
Summary
References
Chapter 23: Sporadic Medullary Thyroid Carcinoma
Introduction
Pathology
Genetics
Diagnosis
Surgical Treatment
Unilateral Surgery for MTC
Radiation Therapy
Reoperation for Residual or Recurrent Medullary Thyroid Carcinoma
Conclusions
References
Chapter 24: Syndromic Medullary Thyroid Carcinoma: MEN 2A and MEN 2B
Introduction
Clinical Presentation by Genotype
MEN 2B
Evaluation of Gene Carriers for Surgery
Surgery
References
Chapter 25: Sporadic Medullary Thyroid Microcarcinoma
Introduction
Definition and Clinical and Biochemical Characteristics of Medullary Thyroid Microcarcinoma and C-Cell Hyperplasia
Morphologic Characteristics
Medullary Thyroid Microcarcinoma
LN Compartments and LN Metastasis
Incidental Diagnosis in Final Histologic Examinations
Molecular Genetic Studies
Follow-up and Cure Rates
Recommendations for Practice
References
Chapter 26: Anaplastic Thyroid Cancer and Thyroid Lymphoma
Anaplastic Thyroid Carcinoma
Thyroid Lymphoma
Chapter 27: Pediatric Thyroid Cancer
Introduction
Etiology
Pathology
Genetics
Presentation
Treatment
Extent of Thyroidectomy
Lymph Node Dissection and Complications
Medullary Thyroid Cancer
Radioactive Iodine Ablation and Follow-up
Summary
References
Chapter 28: Chernobyl and Radiation-Induced Thyroid Cancer
Epidemiology of Radiation-Induced Thyroid Tumors
Thyroid Cancer
Pathomorphology and Mechanisms of Radiation-Induced Thyroid Cancer
Molecular Genetics of Post-Chernobyl Thyroid Tumors
Mechanisms of Chromosomal Rearrangements after Radiation Exposure
Chapter 29: Familial Nonmedullary Thyroid Cancer
Introduction
Epidemiology
Classification of Familial Disease
Clinical Features
Tumor Histology
Genetics
Treatment
Prognosis/Outcome
Summary
References
Section 5: Thyroid and Neck Surgery
Chapter 30: Principles in Thyroid Surgery
Introduction
Extent of Thyroidectomy
Extent of Surgery Based on FNA Result
Nomenclature of Thyroidectomy
Thyroidectomy Surgical Steps
References
Chapter 31: Minimally Invasive Video-Assisted Thyroidectomy
Introduction
Preoperative Evaluation and Anesthesia
Surgical Technique
Postoperative Treatment
Future Applications of Video-Assisted Approach
Conclusions
References
Chapter 32: Surgical Anatomy of the Superior Laryngeal Nerve
History
Anatomy
Physiology and Pathophysiology
Surgical Technique
Diagnosis of EBSLN Paralysis
Incidence of EBSLN Injury
Treatment of EBSLN Injury
Conclusion
References
Chapter 33: Surgical Anatomy and Monitoring of the Recurrent Laryngeal Nerve
Introduction
Surgical Anatomy
Visual Identification
SURGICAL Approaches to the RLN
RLN Surgical Dissection Tips and Pitfalls
RLN Monitoring
Chapter 34: Surgery for Locally Advanced Thyroid Cancer: Larynx
Presenting Signs and Symptoms of Invasive Thyroid Cancer
Imaging
Mechanism for Visceral Invasion by Thyroid Cancer
Mechanisms of Involvement of the Larynx in Invasive Thyroid Cancer
Surgical Management
Conclusion
Conclusion
References
Chapter 35: Surgery for Locally Advanced Thyroid Cancer: Trachea
Introduction
Biology of Thyroid Cancer
Locally Advanced Thyroid Cancer
Initial Evaluation
Staging of Tracheal Invasion
Surgical Management of Tracheal Invasion: Prognosis and Local Control
Operative Technique of Tracheal Resection
Operative Steps of Sleeve Resection of the Trachea
References
Chapter 36: Robotic and Extracervical Approaches to the Thyroid and Parathyroid Glands: A Modern Classification Scheme
Introduction
Goals of Endoscopic Thyroid Surgery
Costs and Benefits of Innovation
Recent Surgical Innovation
Classification of Surgical Techniques
Classification Factors and Definitions
Classification of Surgical Approaches
Outcomes, Concerns, and Future Directions
Conclusion
References
Chapter 37: Central Neck Dissection: Indications
Introduction
Definition
Therapeutic Lymph Node Dissection
Prophylactic Neck Dissection
Conclusion
References
Chapter 38: Central Neck Dissection: Technique
Introduction
Anatomy and Terminology
Preoperative Evaluation
Surgical Technique
Parathyroid Preservation during Paratracheal Dissection
Right Paratracheal Dissection
Left Paratracheal
Bilateral Paratracheal Dissection
The Importance of Preoperative Laryngeal Exam
Postoperative Considerations
Reoperative Considerations
References
Chapter 39: Lateral Neck Dissection: Indications
Lymphatic Drainage of the Thyroid Gland
The Patterns of Lymph Node Metastases
Risk Factors for Lymph Node Metastases
The Prognostic Significance of Lymph Node Metastases
The Management of the N0 Neck
Management of the N + Neck
Radioactive Iodine for Nodal Metastases
Adjuvant Radiation Therapy
Chapter 40: Lateral Neck Dissection: Technique
Background
Technique
Closure and Postoperative Care
Complications
References
Chapter 41: Transoral Resection of Parapharyngeal and Retropharyngeal Thyroid Carcinoma Metastases
Introduction
Operative Technique
Discussion
Conclusion
References
Chapter 42: Incisions in Thyroid and Parathyroid Surgery
Introduction
Specific Procedure Considerations
Novel Approaches
Novel Approaches
Best Practices
References
Chapter 43: Technological Innovations in Thyroid and Parathyroid Surgery
Introduction
Ultrasonic Energy (Harmonic)
Electrothermal Bipolar Vessel Sealing System (LigaSure)
Minimally Invasive Video-Assisted Thyroidectomy (MIVAT)
Other Endoscopic Techniques
References
Chapter 44: Surgical Pathology of the Thyroid Gland
Introduction
Benign Neoplasms: Adenomas and Adenomatous Nodules
Variants of Follicular Adenoma
Malignant Neoplasms
Papillary Carcinoma
Variants of Papillary Cancer
Immunohistochemistry of Papillary Carcinoma
Molecular Pathology of Papillary Carcinoma
Follicular Carcinoma
Molecular Pathology of Follicular Carcinoma
Well-Differentiated Follicular “Tumors of Undetermined/Uncertain Malignant Potential”
Oncocytic (Hurthle Cell) Tumors
Insular Carcinoma
Poorly Differentiated Carcinoma
Anaplastic Carcinoma
Follicular-Derived Familial Tumors
Medullary Carcinoma
Tumors with Thymic or Related Branchial Pouch Differentiation
Mucoepidermoid Carcinoma of Thyroid Gland
Primary Nonepithelial Tumors of Thyroid
Carcinoma in Thyroglossal Duct Cyst and Ectopic Thyroid Tissue
Pathologist and Thyroid
Intraoperative Assessment of Thyroid Nodules
Gross Examination of Thyroid Specimens
Histopathologic Reporting of Thyroid Tumors:
The Issue of Capsular or Vascular Invasion and the Diagnostic Terminology for Follicular Cancer
References
Section 6: Postoperative Considerations
Chapter 45: Pathophysiology of Recurrent Laryngeal Nerve Injury
Introduction
Variations in Symptoms
Configuration of the Paralyzed Vocal Fold
Biology of Laryngeal Nerve Injury and Regeneration
Why Are Vocal Folds Immobile Despite Reinnervation?
Muscle Compartments and Laryngeal Motion
Acute Management of the Transected Nerve
Implications of Biology for Management of Laryngeal Paralysis
Management of Bilateral Paralysis
Summary
References
Chapter 46: Management of Recurrent Laryngeal Nerve Paralysis
Introduction
Unilateral Vocal Fold Immobility
Bilateral Vocal Fold Immobility
References
Chapter 47: Non-Neural Complications of Thyroid and Parathyroid Surgery
Introduction
Hypoparathyroidism
Hypothyroidism
Thyrotoxic Storm
Hemorrhage and Hematoma
Hypertrophic Scar and Keloid
Seroma
Infection
Aerodigestive Tract Injury
Airway Complications
Methylene Blue
Rare Complications
Conclusion
References
Chapter 48: Endocrine Quality Registers: Surgical Outcome Measurement
Introduction
Measurement of Quality: The Science of Improvement
Surgical Registries
Outliers
Future Developments
Conclusion
References
Chapter 49: Ethics and Malpractice in Thyroid and Parathyroid Surgery
Malpractice Issues
Ethical Issues
The Surgeon's Responsibility: Pearls in Responsible Surgical Thyroid and Parathyroid Care
References
Section 7: Postoperative Management
Chapter 50: Postoperative Management of Differentiated Thyroid Cancer
Classification of Thyroid Tumors
Papillary Thyroid Carcinoma (PTC)
Follicular Thyroid Carcinoma (FTC)
Poorly Differentiated Carcinoma
Postoperative Management
Follow-up
Early Detection of Recurrent Disease: Methods
Distant Metastases
Side Effects of 131I Exposure for Thyroid Cancer
Treatment of Distant Metastases: Results
Molecular Targeted Therapies
References
Chapter 51: Postoperative Radioactive Iodine Ablation and Treatment of Differentiated Thyroid Cancer
Introduction
Radioiodine Remnant Ablation
RRA as a Requirement for Postoperative Surveillance in Thyroid Cancer
Adaptive Risk Stratification and Use of RRA
Dose and Modality of Radioactive Iodine Use for RRA
Radioiodine Therapy for Locally Residual Disease
Radioiodine Therapy for Distant Metastatic Disease
Risks and Side Effects of Radioactive Iodine Treatment
Summary
References
Chapter 52: External Beam Radiotherapy for Thyroid Malignancy
Differentiated Thyroid Cancer
Local or Regional Recurrence of Differentiated Thyroid Cancer
Anaplastic Thyroid Carcinoma
Medullary Thyroid Carcinoma
Lymphoma
Indolent (Low-Grade) Lymphomas
Aggressive Histology Lymphomas
Radiotherapy for Metastatic Disease
External Beam Radiation Technique
IMRT Target Volume Delineation
Toxicity from External Beam Radiotherapy
References
Chapter 53: Reoperative Thyroid Surgery
Introduction
Indications for Revision Surgery
Anatomic Changes Following Thyroidectomy
Preoperative Workup
Serum Thyroglobulin Levels
Ultrasonography
CT Axial Imaging with Contrast
Other Imaging Modalities
Preoperative Details/Documentation
Informed Consent
Surgical Therapy
Reoperative Surgery: Completion Thyroidectomy
Postoperative Management
Parathyroid Gland Preservation
Autotransplantation of Parathyroid Tissue
Adjunctive Techniques in Revision Surgery
Lateral Neck Dissection
Complications
Outcomes of Revision Thyroid Surgery for Recurrent Disease: Thyroglobulin
References
Chapter 54: Ablative Percutaneous Ultrasound-Guided Ethanol Injection for Neck Nodal Metastases in Papillary and Sporadic Medullary Thyroid Carcinoma
Neck Nodal Metastases in Differentiated Thyroid Carcinoma
Initial Management of NNM in PTC and MTC
Trends in the Management of Recurrent/Persistent NNM in PTC and MTC
First Use at Mayo of PUEI in the Management of NNM in DTC
Development of Mayo PUEI Practice 1991-2010
Initial Reporting of Mayo's PUEI Experience from 1993 through 2000
Subsequent Reports of PUEI for Treating Recurrent PTC
Future Directions for PUEI in DTC Management
References
Chapter 55: Medical Treatment for Metastatic Thyroid Cancer
Introduction
Drug Development
Thyroid Cancer Genetics
Novel Agents in Thyroid Cancer
Vandetanib (ZD-6474)
XL-184
Motesanib (AMG-706)
Sorafenib (bay 43-9006)
Sorafenib and Tipifarnib
Axitinib (AG-013736)
Pazopanib (GW-786034)
Sunitinib (SU-011248)
Thalidomide and Lenalidomide
Celecoxib
Vorinostat
Romidepsin (FK228, Depsipeptide)
Gefitinib
Bortezomib
Imatinib
Combretastatin A4 Phosphate (Fosbretabulin)
Ongoing Trials
Lessons Learned from Clinical Trials in Thyroid Cancer
Moving Forward
References
Section 8: Parathyroid Surgery
Chapter 56: Primary Hyperparathyroidism: Pathophysiology, Surgical Indications, and Preoperative Workup
Clinical Presentation
Skeleton
Bone Densitometry
Bone Histomorphometry
Fractures
Nephrolithiasis
Other Organ Involvement
Pathology
Clinical Course with and without Surgery
Surgery
Medical Management
Drug Treatment
Unusual Presentations
Normocalcemic Primary Hyperparathyroidism
References
Chapter 57: Guide to Preoperative Parathyroid Localization Testing
Introduction
Localization Studies
Unique Scenarios
Unique Scenarios
Algorithms for First-Time Operations and Recurrent/Persistent Disease
References
Chapter 58: Principles in Surgical Management of Primary Hyperparathyroidism
Preoperative Evaluation
Vitamin D and primary HPT
Normocalcemic Primary Hyperparathyroidism
Localization Testing
Localization Testing
Uniglandular versus Multiglandular Disease
Asynchronous Multiglandular Disease
Intraoperative PTH: A Functional Criteria for Uniglandular versus Multiglandular Disease
Histology
Histology
Molecular Genetics of Primary Hyperparathyroidism
Molecular Genetics of Primary Hyperparathyroidism
Parathyroid Surgical Anatomy
Parathyroid Gland Characteristics: the “Gliding Sign”
Parathyroid Gland Symmetry
Parathyroid Glands and Plane of Recurrent Laryngeal Nerve
Parathyroid Vascular Anatomy
Parathyroid Gland Position
Embryologic Variation
Locations of Missed Adenomas Based on Reoperative Series
Intrathyroidal Adenoma
Thyroidectomy during Parathyroidectomy
Parathyroid Exploration: Surgical Technique
Mediastinal Adenoma
Surgical Technique for Multiglandular Disease
Surgical Technique for Multiglandular Disease
Parathyroid Surgery Failure
Surgical Controversies
Surgical Controversies
Postoperative Assessment
Chapter 59: Standard Bilateral Parathyroid Exploration
Anatomy and Embryology Relevant for Bilateral Parathyroid Exploration
The Rationale for Bilateral Parathyroid Exploration
Preoperative Planning: Parathyroid Localization Studies
Surgical Technique of Bilateral Parathyroid Exploration
Strategy for Finding the “Missing” Parathyroid
Postoperative Management
Special Considerations in Bilateral Parathyroid Exploration
Summary
References
Chapter 60: Minimally Invasive Single Gland Parathyroid Exploration
Considerations for Performing MIP
A Standard Parathyroid Nomenclature System
Preoperative Imaging
Operative Preparation and Techniques
Postoperative and Follow-Up Care
References
Chapter 61: Minimally Invasive Video-Assisted Parathyroidectomy
Introduction
Preoperative Localization Studies
Intraoperative PTH Assay
Minimally Invasive Parathyroidectomy
Techniques for MIP
MIP: Evidence-Based Recommendations
References
Chapter 62: Local Anesthesia for Thyroid and Parathyroid Surgery
Regional Anesthesia for Thyroid Surgery
Regional Anesthesia for Parathyroid Surgery
Contraindications for Regional Anesthesia in Patients Undergoing Thyroid or Parathyroid Surgery
Regional Anesthesia for Parathyroid and Thyroid Surgery: Technique
Conclusions
References
Chapter 63: Intraoperative PTH Monitoring during Parathyroid Surgery
Introduction
History of Intraoperative PTH Monitoring
Which Patients Benefit from IPM-Guided Parathyroidectomy?
Intraoperative PTH Monitoring as an Adjunct during Parathyroidectomy
IPM Protocol for Intraoperative Blood Sampling
Intraoperative Scenarios and Troubleshooting
Intraoperative Criteria in Predicting Operative Success
Limitations of Intraoperative PTH Monitoring with the “>50% PTH Drop” Criterion
Results of Parathyroidectomy Guided by IPM
Other Applications for Intraoperative Rapid PTH Assays
Summary
References
Chapter 64: Radio-Guided Parathyroid Exploration
Introduction
Principles of Radio-Guided Parathyroid Surgery
Radio-Guided Parathyroidectomy
Radiotracer Injection
Background Counts
Finding the Hyperfunctioning Gland: In Vivo Counts
Removal of the Parathyroid Gland: Ex Vivo Counts and the “20% Rule”
Use of the Gamma Probe
Confirmation of Cure with Intraoperative PTH Monitoring
Postoperative Care
Applications of Radio-Guided Parathyroidectomy
Secondary and Tertiary Hyperparathyroidism
Parathyroid Cancer
Advantages to Radio-Guided Parathyroid Surgery
Disadvantages of Radio-Guided Parathyroid Surgery
Future Directions
Conclusions
References
Chapter 65: Surgical Management of Multiglandular Parathyroid Disease
Histopathology and Surgical Anatomy
Technique of Parathyroid Exploration
Surgical Techniques and Strategies
Cryopreservation of Parathyroid Tissue
Cryopreservation of Parathyroid Tissue
Preoperative Localization and Intraoperative PTH Measurements
References
Chapter 66: Surgical Management of Secondary and Tertiary Hyperparathyroidism
Definition
Secondary Hyperparathyroidism
Tertiary Hyperparathyroidism: Persistent Hyperparathyroidism after Successful Kidney Transplantation
Chapter 67: Parathyroid Management in the MEN Syndromes
Multiple Endocrine Neoplasia Type 1
Genetic Testing in MEN 1
MEN 1–Associated Hyperparathyroidism
Indications for Surgery
Surgical Treatment of MEN 1–Associated HPT
Treatment of Persistent or Recurrent MEN 1–Associated HPT
Multiple Endocrine Neoplasia Type 2A
Genetic Testing in MEN 2A
MEN 2A–Associated HPT
Indications for Surgery
Surgical Treatment of MEN 2–Associated HPT
Treatment of Persistent or Recurrent MEN 2A–Associated HPT
Use of Intraoperative Adjuncts during Parathyroidectomy for MEN–Associated HPT
Nonsurgical Management of Persistent or Recurrent MEN–Associated HPT
Conclusion
References
Chapter 68: Reoperation for Sporadic Primary Hyperparathyroidism
Introduction
Indications for Reoperation
Operative Planning
Operation
Postoperative Complications
Conclusion
References
Chapter 69: Parathyroid Carcinoma
Introduction
Clinical Presentation
Incidence
Etiology and Molecular Pathogenesis
Pathology
Summary
References
Chapter 70: Surgical Pathology of the Parathyroid Glands
Development and Anatomy
Hyperparathyroidism
Primary Hyperparathyroidism
Parathyroid Carcinoma
Primary Chief Cell Hyperplasia
Other Familial Hyperparathyroidism Syndromes
Other Familial Hyperparathyroidism Syndromes
Cysts
Cysts
Secondary Tumors
Secondary Tumors
Hypoparathyroidism
Hypoparathyroidism
References
Index
Copyright

1600 John F. Kennedy Blvd.
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SURGERY OF THE THYROID AND PARATHYROID GLANDS
ISBN: 978-1-4377-2227-7
Copyright © 2013, 2003 by Saunders, an imprint of Elsevier Inc.
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Notices
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With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions.
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Library of Congress Cataloging-in-Publication Data
Surgery of the thyroid and parathyroid glands / [edited by] Gregory W. Randolph. – Ed. 2.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4377-2227-7 (hardcover : alk. paper)
I. Randolph, Gregory.
[DNLM: 1. Thyroid Gland – surgery. 2. Parathyroid Glands–surgery. WK 280]
LC classification not assigned
617.5′39–dc23
2012011124
Senior Content Strategist: Stefanie Jewell-Thomas
Content Development Specialist: Roxanne Halpine Ward
Publishing Services Manager: Patricia Tannian
Senior Project Manager: Sharon Corell
Senior Book Designer: Ellen Zanolle
Printed in the United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Dedication
My wife Lorraine whose living faith and love have given me strength. Your faith, hard work, and selfless devotion to others have always been my guiding light on this our path.
Without you, Lorraine, none of this would have been worthwhile.
Gregory, Benjamin, and Madeline
Gregory, your sensitivity, artistic expertise, and hard work have gotten the job done.
Benjamin, I am so proud of the man you are, your strength, and your abiding concern for others.
Madeline, your intelligence, accomplishments, and grace through all inspire me.
My beautiful children, I could not love you more.
My mother Frances who fostered hopeful strength and a desire to learn.
Contributors

Joel T. Adler, MD
Resident, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts

Amit Agarwal, MS, FICS
Professor, Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India

Anil T. Ahuja, MD, FRCR, FHKCR, FHKAM
Professor, Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong (SAR), China

Kenneth B. Ain, MD
Director, Thyroid Clinic and Thyroid Cancer Research Laboratory, Veterans Affairs Medical Center
Professor of Medicine and The Carmen L. Buck Chair of Oncology Research, Thyroid Oncology Program, Division of Endocrinology and Molecular Medicine, University of Kentucky, Lexington, Kentucky

Göran Åkerström, MD, PhD
Professor, Department of Surgery, University Hospital, Uppsala, Sweden

Erik K. Alexander, MD, FACP
Associate Professor, Department of Medicine, Harvard Medical School
Physician, Division of Endocrinology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts

Eran E. Alon, MD
Attending Physician, Department of Otolaryngology-Head and Neck Surgery, Sheba Medical Center, Tel Hashomer, Israel

Kamal A.S. Al-Shoumer, MD, FRCP, PhD, FACE
Associate Professor, Department of Medicine Consultant, Division of Endocrinology and Metabolic Medicine, Kuwait University, Kuwait City, Kuwait

Mohammed Ahmed Alzahrani, MBBS, FACS, SSC-Surg (Hon), ABS
Clinical Fellow, Department of Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts
Associate Consultant, Department of Surgery, King Abdulaziz Medical City, Riyadh, Saudi Arabia

Carlo Enrico Ambrosini, MD, PhD
Department of Surgery, University of Pisa, Pisa, Italy

Peter Angelos, MD, PhD, FACS
Professor and Chief of Endocrine Surgery, Associate Director of the MacLean Center for Clinical Medical Ethics, Department of Surgery, University of Chicago, Chicago, Illinois

Zubair W. Baloch, MD, PhD
Professor, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

Rocco Domenico Bellantone, MD
Professor of General Surgery, Department of Surgical Science, Università Cattolica del Sacro Cuore, Rome, Italy

Anders O.J. Bergenfelz, MD, PhD
Professor, Department of Clinical Sciences, Lund University
Professor, Consultant Surgeon, Department of Surgery, Section of Endocrine and Sarcoma Surgery, Lund University Hospital, Lund, Sweden

Kunwar S.S. Bhatia, MBBS, MRCS, DLO, FRCR
Assistant Professor, Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong (SAR), China

John P. Bilezikian, MD
Professor, Department of Medicine and Endocrinology, College of Physicians and Surgeons, Columbia University, New York, New York

Giorgio Stecconi Bortolani, MD
Endocrinology Unit, IRCCS Ospedale Santa Maria Nuova, Reggio Emilia, Italy

Lenine Garcia Brandão, MD, PhD
Professor and Chairman, Department of Head and Neck Surgery, Faculdade de Medicina de Universidade de São Paulo, São Paulo, Brazil

Daniel I. Branovan, MD
Director and Chair, The New York Eye and Ear Institute, President
Project Chernobyl, Director, Rhinology Division Director, Thyroid Center Department of Otolaryngology, The New York Eye and Ear Infirmary, New York, New York

Michael Brauckhoff, MD
Consultant Surgeon, Professor, Department of Surgery, Haukeland University Hospital, Bergen, Norway

Lewis E. Braverman, MD
Professor, Department of Medicine, Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts

James D. Brierley, MBBS, FRCP, FRCR, FRCPC
Professor, Department of Radiation Oncology, University of Toronto, Radiation Oncologist, Department of Radiation Medicine, Princess Margaret Hospital, Toronto, Ontario, Canada

Miljenko Bura, MD, PhD
Chief, Special Division for Thyroid Gland Surgery, Assistant Professor, Department for Otorinolaryngology-Head and Neck Surgery, University Hospital Center Zagreb, Zagreb, Croatia

Denise Carneiro-Pla, MD
Assistant Professor, Department of Surgery, Medical University of South Carolina, Charleston, South Carolina

Claudio R. Cernea, MD
Professor of Surgery, Department of Head and Neck Surgery, University of São Paulo Medical School
Attending Surgeon, Head and Neck Service, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil

Herbert Chen, MD, FACS
Layton F. Rikkers Chair in Surgical Leadership, Professor, Department of Surgery, Section of Endocrine Surgery, University of Wisconsin
Chair of General Surgery, Department of Surgery, University of Wisconsin Hospital and Clinics
Leader of the Endocrine Disease Group, Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin

Woong Youn Chung, MD, PhD
Professor, Department of Surgery, Head, Division of Endocrine Surgery, Yonsei University College of Medicine
Director, Thyroid Cancer Clinic, Yonsei University Health System, Seoul, Korea

Edmund S. Cibas, MD
Associate Professor, Department of Pathology, Harvard Medical School
Director of Cytopathology, Brigham and Women's Hospital, Pathology Consultant, Children's Hospital Medical Center, Boston, Massachusetts

Orlo H. Clark, MD, FACS
Professor, Department of Surgery, University of California, San Francisco, Mount Zion Medical Center, San Francisco, California

Gary L. Clayman, DMD, MD, FACS
Professor and Surgeon, Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

James I. Cohen, MD, PhD, FACS
Professor, Department of Otolaryngology-Head and Neck Surgery
Chief, Otolaryngology-Assistant Chief, Surgery, Portland Veterans Affairs Medical Center, Oregon Health and Science University, Portland, Oregon

Carmela De Crea, MD
Assistant Professor of Surgery, Department of Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy

Leigh Delbridge, MD, FRACS
Head of Surgery, The University of Sydney, Sydney, Australia

Ronald A. DeLellis, MD
Professor of Pathology, Pathology and Laboratory Medicine, Alpert Medical School of Brown University
Pathologist-in-Chief, Department of Pathology, Rhode Island Hospital
Pathologist-in-Chief, Department of Pathology, The Miriam Hospital, Providence, Rhode Island

Gerard M. Doherty, MD
Utley Professor and Chair of Surgery, Professor of Surgery and Medicine (Endocrinology), Boston University
Surgeon-in-Chief, Department of Surgery, Boston Medical Center, Boston, Massachusetts

Henning Dralle, MD, FRCS, FACS
Professor and Chairman of General, Visceral, and Vascular Surgery, University Hospital and Medical Faculty, University of Halle, Halle, Germany

Quan-Yang Duh, MD
Professor in Residence, Department of Surgery, University of California, San Francisco, Attending Surgeon, Surgical Service, Veterans Affairs Medical Center, San Francisco, California

David W. Eisele, MD, FACS
Andelot Professor and Director, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland

Douglas B. Evans, MD
Professor and Chair, Department of Surgery, Medical College of Wisconsin
Surgeon-in-Chief, Department of Surgery, Froedtert Hospital, Milwaukee, Wisconsin

Guido Fadda, MD, MIAC
Assistant Professor of Pathology, Division of Anatomic Pathology and Histology, Università Cattolica–Agostino Gemelli School of Medicine, Rome, Italy

Thomas J. Fahey, III., MD
Chief, Division of Endocrine Surgery, Department of Surgery, The New York Presbyterian Hospital-Weill Cornell Medical College
Professor, Frank Glenn Faculty Scholar, Department of Surgery, Weill Cornell Medical College, New York, New York

William C. Faquin, MD, PhD
Director, Head and Neck Pathology, Department of Pathology, Massachusetts General Hospital
Chief, ENT Pathology, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary
Associate Professor of Pathology, Harvard Medical School, Boston, Massachusetts

Alan P. Farwell, MD
Associate Professor, Department of Medicine, Director, Endocrine Clinics, Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts

Robert L. Ferris, MD, PhD, FACS
Professor, Vice-Chair for Clinical Operation
Chief, Division of Head and Neck Surgery, Otolaryngology, and Immunology
Co-Leader, Cancer Immunology Program, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Ramon Arturo Franco, Jr., MD
Director, Division of Laryngology, Department of Otology and Laryngology, Harvard Medical School
Medical Director, Department of Voice and Speech Laboratory, and Otolaryngology, Massachusetts Eye and Ear Infirmary
Laryngologist, Department of Otolaryngology, Massachusetts General Hospital, Boston, Massachusetts

Jeremy L. Freeman, MD, FRCSC, FACS
Professor, Temmy Latner/Dynacare Chair of Head and Neck Oncology, Department of Otolaryngology-Head and Neck Surgery
Professor, Department of Surgery, University of Toronto
Otolaryngologist-in-Chief, Department of Otolaryngology-Head and Neck Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada

Randall D. Gaz, MD, FACS
Associate Visiting Surgeon, Department of Surgery, Massachusetts General Hospital
Assistant Professor of Surgery, Harvard Medical School
Consultant in Thyroid Surgery, Thyroid Surgical Division, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts

Hossein Gharib, MD, MACP, MACE
Professor, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine
Consultant, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota

Clive S. Grant, MD
Professor, Department of Surgery, Mayo Clinic, Rochester, Minnesota

Raymon H. Grogan, MD
Assistant Professor, Department of Surgery, Section of Endocrine Surgery, The University of Chicago Medical Center, Chicago, Illinois

Dana M. Hartl, MD, PhD
Chief, Thyroid Surgery Unit, Department of Head and Neck Oncology, Institut Gustave Roussy, Villejuif, France
Phonetics and Phonology Laboratory, University Paris III-Sorbonne Nouvelle, Paris, France

Bryan R. Haugen, MD
Professor, Departments of Medicine and Pathology, Head, Division of Endocrinology, Metabolism, and Diabetes Department of Medicine
Mary Rossick Kern and Jerome H. Kern Endowed Chair in Endocrine Neoplasms Research, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado

Ian D. Hay, MB, PhD, FACE, FACP, FRCP (Edinburgh, Glasgow, and London), FRCPI (Hon)
Professor of Medicine and the Doctor Richard F. Emslander Professor in Endocrinology and Nutrition Research, Mayo Clinic College of Medicine
Consultant in Endocrinology and Internal Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota

Avi Khafif Hefetz, MD
ARM Center for Advanced Otolaryngology Head and Neck Surgery, Assuta Medical Center, Tel Aviv, Israel

Keith S. Heller, MD
Professor, Department of Surgery, New York University School of Medicine
Chief of Endocrine Surgery, New York University Langone Medical Center, New York, New York

Abdullah N. Hisham, MS
Head and Senior Consultant Surgeon, Department of Breast Endocrine and General Surgery, Putrajaya Hospital
Deputy Director General of Health (Medical), Ministry of Health Malaysia, Putrajaya, Malaysia

F. Christopher Holsinger, MD, FACS
Associate Professor, Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Yariv Houvras, MD, PhD
Assistant Professor, Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York

Dipti Kamani, MD
Clinical Research Specialist, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts

Edwin L. Kaplan, MD
Professor, Department of Surgery, The University of Chicago, Chicago, Illinois

Electron Kebebew, MD, FACS
Head of Endocrine Oncology, Tenured Senior Investigator, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland

Moosa Khalil, MBBCh, FRCPC, FCAP
Clinical Associate Professor of Pathology, Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada

Dae S. Kim, MBChB, BDS, MSc, FRCS, PhD
Consultant ENT and Thyroid Surgeon, ENT and Head and Neck Surgery, Queen Alexandra Hospital, Portsmouth, Hampshire, United Kingdom
Honorary Senior Lecturer, Cancer Sciences, CRUK Cancer Centre, University of Southampton, Southampton, United Kingdom

Samuel S. Kim, MD
Thoracic Surgery Fellow, Massachusetts General Hospital, Boston, Massachusetts

Joshua P. Klopper, MD
Assistant Professor, Medicine and Radiology, Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes University of Colorado School of Medicine, Aurora, Colorado

Michael E. Kupferman, MD
Assistant Professor, Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Ronald B. Kuppersmith, MD, MBA, FACS
Director, The Texas Institute for Thyroid and Parathyroid Surgery, College Station, Texas

Amanda M. Laird, MD
Clinical Lecturer, Department of Surgery, University of Michigan, Ann Arbor, Michigan

Stephanie L. Lee, MD, PhD
Associate Professor, Department of Medicine, Boston University School of Medicine
Director of the Thyroid Health Center, Boston Medical Center, Boston, Massachusetts

Ted H. Leem, MD, MS
Clinical Instructor, Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, California

Carol M. Lewis, MD, MPH
Assistant Professor, Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Steven K. Libutti, MD, FACS
Professor and Vice-Chairman, Department of Surgery, Albert Einstein College of Medicine
The Marvin L. Gliedman, MD, Distinguished Surgeon and Vice-Chairman, Department of Surgery
Director of Surgery, Jack D. Weiler Hospital
Montefiore Medical Center Director, Montefiore-Einstein Center for Cancer Care, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York

Virginia A. LiVolsi, MD
Professor, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Chung-Yau Lo, MBBS(HK), MS(HK), FCSHK, FHKAM(Surgery), FRCS(Edin)
Honorary Professor, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Celestino P. Lombardi, MD
Associate Professor of General Surgery, Department of Surgical Science, Università Cattolica del Sacro Cuore, Rome, Italy

Andreas Machens, MD
Associate Professor, Department of General, Visceral, and Vascular Surgery, The Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

Miran Martinac, MD
General Surgeon, Department of Surgery, CEO and Medical Director, University Hospital Sveti Duh, Zagreb, Croatia

Gabriele Materazzi, MD
Researcher, Department of Surgery, University of Pisa, Pisa, Italy

Douglas J. Mathisen, MD
Chief, Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts

Aarti Mathur, MD
Research Fellow, Surgery Branch, National Cancer Institute, Bethesda, Maryland
Resident in General Surgery, Georgetown University Hospital, Washington, District of Columbia

Ernest L. Mazzaferri, MD
Professor of Medicine, Department of Endocrinology, Ohio State University and, University of Florida, Gainesville, Florida

Robert McConnell, MD
Clinical Professor, Department of Medicine, College of Physicians and Surgeons, Columbia University, The Thyroid Center, The New York Presbyterian Hospital, New York, New York

Christopher R. McHenry, MD, FACS, FACE
Vice-Chairman, Department of Surgery, MetroHealth Medical Center, Cleveland, Ohio

Bryan McIver, MB, ChB, PhD
Consultant in Endocrinology, Division of Endocrinology and Metabolism, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota

Jesus E. Medina, MD, FACS
Paul and Ruth Jonas Professor, Department of Otorhinolaryngology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Paolo Miccoli, MD
Professor and Head, Department of Surgery, University of Pisa, Pisa, Italy

Radu Mihai, MD, PhD, FRCS
Honorary Senior Clinical Lecturer, Nuffield Department of Surgery, Oxford University
Consultant Endocrine Surgeon, Department of Endocrine Surgery, John Radcliffe Hospital, Oxford, United Kingdom

Mira Milas, MD, FACS
Associate Professor, Department of Surgery Director, The Thyroid Center Department of Endocrine Surgery Cleveland Clinic Cleveland, Ohio

Anand K. Mishra, MS, PDCC, MCh
Assistant Professor, Department of General Surgery, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India

Elliot J. Mitmaker, MD, MSc, FRCS(C)
Assistant Professor, Department of Surgery, McGill University, Montreal, Quebec, Canada

Marica Zizic Mitrecic, MD, FACS
Otolaryngologist, Head and Neck Specialist, Department of Otolaryngology-Head and Neck Surgery, University Hospital Sveti Duh, Zagreb, Croatia

Akira Miyauchi, MD, PhD
Visiting Professor, Department of Surgery, Nippon Medical School, Tokyo, Japan
Director, Department of Surgery, Kuma Hospital, Center for Excellence in Thyroid Care, Kobe, Japan

Jeffrey F. Moley, MD
Department of Endocrine and Oncologic Surgery, Washington University of Saint Louis, Saint Louis, Missouri

James L. Netterville, MD
Associate Director, Bill Wilkerson Center for Otolaryngology and Communication Sciences
Mark C. Smith Professor, Director, Division of Head and Neck Surgical Oncology, Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, Tennessee

Bruno Niederle, MD
Professor and Chief, Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria

Yuri E. Nikiforov, MD, PhD
Professor of Pathology, Director, Division of Molecular Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Lisa A. Orloff, MD
Robert K. Werbe Distinguished Professor in Head and Neck Cancer, Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, San Francisco, California

Claudio M. Pacella, MD
Past Director, Diagnostic Imaging and Interventional Radiology, Regina Apostolorum Hospital
Consultant Physician, Radiology-Tumor Laser Ablation, Jewish Hospital of Rome
Consultant Physician, Internal Medicine-Tumor Laser Ablation, Università Cattolica del Sacro Cuore, Rome, Italy

Sareh Parangi, MD, FACS
Associate Professor of Surgery, Department of Surgery, Harvard Medical School, Boston, Massachusetts

Janice L. Pasieka, MD, FRCSC, FACS
Clinical Professor of Surgery and Oncology, Department of Surgery, Division of General Surgery, University of Calgary, Foothills Medical Center
Clinical Professor, Department of Oncology, Division of Surgical Oncology, Tom Baker Cancer Center, Calgary, Alberta, Canada

Phillip K. Pellitteri, DO, FACS
Chief, Department of Otolaryngology-Head and Neck Surgery, Guthrie Health System, Sayre, Pennsylvania
Clinical Professor of Otolaryngology-Head and Neck Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania

Nancy D. Perrier, MD, FACS
Professor, Department of Surgery
Associate Director, Endocrine Center, Chief, Section of Surgical Endocrinology
Director, Surgical Endocrinology Fellowship Program, Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas

Andre Potenza, MD
Clinical Fellow in Thyroid and Parathyroid Surgery, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts

Anathea C. Powell, MD
Resident, Department of Surgery, New York University School of Medicine, New York, New York

Jason D. Prescott, MD, PhD
Department of Surgery, Yale University School of Medicine, New Haven, Connecticut

Ruth S. Prichard, FRCSI
Consultant Endocrine and Breast Surgeon, St. Vincent's University Hospital, Elm Park, Dublin, Ireland

Marco Raffaelli, MD
Assistant Professor of Surgery, Department of Surgical Science, Università Cattolica del Sacro Cuore, Rome, Italy

Anais Rameau, MD
McGill University, Montreal, Quebec, Canada

Gregory W. Randolph, MD, FACS
Director, General, Thyroid, and Parathyroid Surgical Divisions, Department of Otolarygology-Head and Neck Surgery
Massachusetts Eye and Ear Infirmary, Member, Division of Surgical Oncology, Endocrine Surgical Service, Department of Surgery, Massachusetts General Hospital
Associate Professor, Otology and Laryngology, Harvard Medical School, Boston, Massachusetts

Sara L. Richer, MD
Otolaryngologist, Head and Neck Surgeon, Department of Surgery, St. Vincent's Medical Center, Bridgeport, Connecticut

Anatoly F. Romanchishen, MD, PhD, ScD
Merit Doctor of Russian Federation, Chief, Hospital Surgery, Traumatology, Military Surgery
Professor, Department of Oncology
State Pediatric Medical Academy, Chief, Center of Endocrine Surgery and Oncology, Health Care Committee of Saint Petersburg Government, Saint Petersburg, Russian Federation

Genevieve Rondeau, MD
Endocrinologist, Department of Medicine, University of Montreal, Montreal, Quebec, Canada

Douglas S. Ross, MD
Professor of Medicine, Harvard Medical School, Co-Director, Thyroid Associates, Massachusetts General Hospital, Boston, Massachusetts

Massimo Santoro, MD, PhD
Professor, Department of Biology and Molecular and Cellular Pathology, Università Federico II, Naples, Italy

Christian Scheuba, MD
Assistant Professor, Senior Resident, Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria

Martin Schlumberger, MD
Professor of Oncology, University Paris Sud, Chair, Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, Villejuif, France

David L. Schwartz, MD
Associate Professor and Vice-Chair, Department of Radiation Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, New York

David M. Scott-Coombes, MS, FRCS
Consultant Endocrine Surgeon, Department of Endocrine Surgery, University Hospital of Wales, Cardiff, United Kingdom
Director of Audit, British Association of Endocrine and Thyroid Surgeons, United Kingdom

Melanie W. Seybt, MD
Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, Georgia Health Sciences University, Augusta, Georgia

Jatin P. Shah, MD, PhD(Hon), FACS, FRCS(Hon), FRACS(Hon), FDSRCS(Hon)
Professor, Department of Surgery, EW Strong Chair in Head and Neck Oncology
Chief, Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center
Professor, Department of Surgery, Weill Cornell Medical College, New York, New York

Manisha H. Shah, MD
Associate Professor of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio

Ashok R. Shaha, MD
Jatin Shah Professor of Surgery, Department of Surgery, Cornell University Medical Center
Attending Surgeon, Memorial Sloan-Kettering Cancer Center, New York, New York

Maisie L. Shindo, MD
Professor, Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon

Shonni J. Silverberg, MD
Professor, Department of Medicine and Endocrinology, College of Physicians and Surgeons, Columbia University, New York, New York

Allan E. Siperstein, MD
Professor, Department of Surgery, Chair, Department of Endocrine Surgery, Cleveland Clinic, Cleveland, Ohio

Jennifer A. Sipos, MD
Assistant Professor, Department of Endocrinology, The Ohio State University, Columbus, Ohio

Cristian M. Slough, MD
Willamette Valley Ear, Nose, and Throat, Willamette Valley Medical Center, McMinnville, Oregon

Robert A. Sofferman, MD
Emeritus Professor, Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Vermont School of Medicine, Burlington, Vermont

Brendan C. Stack, Jr., MD
Professor, Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas

Peter Stålberg, MD, PhD
Associate Professor, Consultant Endocrine Surgeon, Endocrine Surgical Unit Department of Surgery, University Hospital, Uppsala, Sweden

Antonia E. Stephen, MD
Endocrine Surgeon, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts

David L. Steward, MD
Professor, Department of Otolaryngology-Head and Neck Surgery, University of Cincinnati Medical Center, Cincinnati, Ohio

David J. Terris, MD, FACS
Porubsky Professor and Chairman, Surgical Director, Georgia Health Thyroid Center, Department of Otolaryngology-Head and Neck Surgery, Georgia Health Sciences University Augusta, Georgia

Geoffrey B. Thompson, MD
Professor, Department of Surgery, Mayo Clinic College of Medicine
Consultant, Section Head, Endocrine Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota

Yoshihiro Tominaga, MD, PhD
Director, Department of Endocrine Surgery, Nagoya Second Red Cross Hospital, Nagoya, Japan

Rafael O. Toro-Serra, MD
Fellow, Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Richard W. Tsang, MD, FRCP(C)
Professor, Department of Radiation Oncology, University of Toronto
Staff Radiation Oncologist, Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada

Ralph P. Tufano, MD, MBA, FACS
Director of the Johns Hopkins Hospital Multidisciplinary Thyroid Tumor Center
Director of Thyroid and, Parathyroid Surgery, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland

R. Michael Tuttle, MD
Attending Physician, Endocrinology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center
Professor of Medicine, Weill Cornell Medical College, New York, New York

Robert Udelsman, MD, MBA, FACS, FACE
William H. Carmalt Professor, Department of Surgery and Oncology, Chairman, Department of Surgery, Yale University School of Medicine
Surgeon-in-Chief, Department of Surgery, Yale New Haven Hospital, New Haven, Connecticut

Mark Lawrence Urken, MD, FACS
Director, Head and Neck Surgery, Continuum Cancer Centers of New York, Beth Israel Medical Center
Professor, Department of Otorhinolaryngology-Head and Neck Surgery, Albert Einstein College of Medicine, New York, New York

Roberto Valcavi, MD, FACE
Director, Endocrinology Unit, Santa Maria Nuova Hospital, Reggio Emilia, Italy

Joseph Valentino, MD, FACS
Professor of Surgery and Pediatrics, Department of Otolaryngology-Head and Neck Surgery, University of Kentucky
Physician, Surgical Services Veterans Affairs Medical Center Lexington, Kentucky

Erivelto Volpi, MD, PhD
Attending Physician, Department of Head and Neck Surgery, University of São Paulo Medical School, São Paulo, Brazil

Tracy S. Wang, MD, MPH
Assistant Professor, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin

Randal S. Weber, MD, FACS
Professor and Chairman, Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Gayle Woodson, MD
Professor and Chair, Division of Otolaryngology, Southern Illinois University
Director, Voice Center, St. John's Hospital, Springfield, Illinois

Tina W.F. Yen, MD, MS
Associate Professor, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin

Abdalla E. Zarroug, MD
Assistant Professor, Department of Surgery and Pediatrics, Mayo Clinic College of Medicine
Senior Associate Consultant, Department of Surgery, Mayo Clinic, Rochester, Minnesota
Foreword
I had the pleasure of reading Gregory Randolph's first edition of Surgery of the Thyroid and Parathyroid Glands from cover to cover in 2004. I was very impressed with the comprehensive coverage by an array of truly outstanding authors from multidisciplinary fields of expertise. Not only was the written content excellent and as up to date as a textbook will allow, but the illustrations by Robert Galla also were superb and enhanced each of the procedures or the description of the anatomy especially well. Obviously a great deal of thought and exceptional editing went into the creation of this text. Having had the opportunity to review most of the other surgical texts in this field for the past three decades, I considered this one the most outstanding that had been published about the thyroid and parathyroid glands.
Now that the second edition has been produced, one might wonder whether any significant improvements or additions would be made. Dr. Randolph has not disappointed us. He has both revised and added to the text in content with many new authors and produced several videos that are included on a website that accompanies the book. Because of his activities as a clinical surgeon, researcher, educator, and frequent guest speaker both in the U.S. and overseas, Dr. Randolph has been able to evaluate and select the very best individuals to contribute chapters to this edition. He has chosen well. Where there were 46 chapters in the first edition, there are 70 in this one. No areas in which new developments have occurred have been neglected. Two of the new chapters that are noteworthy are those by Angelos and Heller on “Ethics and Malpractice in Thyroid and Parathyroid Surgery” and by Scott-Coombes and Bergenfelz on “Endocrine Quality Registers: Surgical Outcome Measurement.” These topical subjects should be of interest to all readers regardless of discipline.
Once again, Dr. Randolph has achieved his goal of producing a comprehensive review of state-of-the-art knowledge in endocrine pathophysiology, surgical anatomy, techniques, preoperative and postoperative care, and the very latest technological advances provided by the very best in their areas of expertise. Although this is a second edition, considering updates, new authors, new chapters, and editing, it can almost be considered a new text on its own merits. It is a book that most endocrinologists, pathologists, radiologists, and all surgeons interested in the thyroid and parathyroid glands will want to have readily available as an authoritative reference. Dr. Randolph has shown that there is always room for improvement, even when the original was very good.

Norman W. Thompson, MD
Professor of Surgery Emeritus, University of Michigan, Ann Arbor, Michigan
In this new second edition of the classic textbook Surgery of the Thyroid and Parathyroid Glands , Dr. Gregory W. Randolph has put forth an impressive effort to build on and improve his first edition. He has expanded the content and added new chapters and authors appropriate for such a comprehensive review of diseases of and surgery for the thyroid and parathyroid glands. All previous chapters have been updated with overall improvement in the figures and tables and, of course, updated references. As quality and outcomes now define patient care, a specific chapter focusing on this topic has been added. Another excellent addition has been the discussion of medical ethics related to thyroid and parathyroid disease.
I believe the exhaustive coverage of these topics, provided by authors who cross multiple specialties, including otolaryngology, general surgery, and thoracic surgery, provides the most comprehensive text ever to address surgery of the thyroid and parathyroid glands. The book is a tribute to Dr. Randolph and his co-authors and will be a valuable addition to the library of anyone who practices endocrine surgery.

Keith D. Lillemoe, MD
W. Gerald Austen Professor of Surgery, Harvard Medical School, Surgeon-in-Chief and Chief of Surgery, Massachusetts General Hospital, Boston, Massachusetts
The first edition of this text, written by experts in a variety of specialties, including otolaryngology, general surgery, endocrinology, and pathology, was published in 2003 and has quickly become a classic. The second edition not only is an update and revision, but also contains 24 new chapters. Dr. Randolph is to be congratulated in attracting more than 140 internationally respected authors. In addition, 17 video clips illustrating surgical anatomy and technique are included with the text.
Surgery of the Thyroid and Parathyroid Glands provides a thorough treatment of benign and neoplastic disease of thyroid and parathyroid glands, surgical management, its complications, and postoperative medical considerations. The text and outstanding illustrations provide a comprehensive treatise on best practice and surgical techniques.
This text, as was the first edition, is clearly destined to be the authoritative source for disorders of the thyroid and parathyroid glands.

Joseph B. Nadol, Jr., MD
Walter Augustus LeCompte Professor and Chairman, Department of Otology and Laryngology, Harvard Medical School, Chief of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
Preface
Surgery of the Thyroid and Parathyroid Glands is a comprehensive review of state-of-the-art knowledge of endocrine pathophysiology, surgical anatomy and techniques, preoperative and postoperative evaluation, and the latest technological advances relating to the thyroid and parathyroid glands, representing a substantial update and expansion of our first edition.
Thyroid and parathyroid surgery is seen in the context of a broad head and neck surgical perspective, and therefore chapters on associated neurolaryngology, anatomy of the lateral neck, and airway considerations are included. Throughout, emphasis is given to thorough preoperative workup and informed intraoperative decision making. Recent advances within the field, including preoperative localization, genetic analysis, recurrent laryngeal nerve monitoring, intraoperative parathyroid hormone analysis, recombinant thyroid-stimulating hormone, and minimally invasive approaches, are all thoroughly reviewed. An attempt has been made throughout the text to present controversies, such as extent of nodal surgery for thyroid cancer or conservative shave procedures for invasive thyroid cancer, and also to provide clear-cut summary recommendations.
The strength of the whole relates to the quality of each part. Each contributor, drawn from the very best in the world in the fields of endocrine, head and neck, and thoracic surgery, as well as endocrinology, radiology, and pathology, was selected because of his or her clinical activity and research contributions in the medical literature within the chapter topic area. These contributors provide an over-arching unique orientation to their respective topics that goes beyond the individual disparate facts. It has been gratifying to work with such a group. In numerous chapters collaborators were paired from different areas of the world and in some circumstances different specialties to provide a blending of various heterogeneous elements.
Chapter length in the text involved necessary page limitations. However, many chapters contain additional material available online. When the reader sees the online icon, additional material can be found in the online version of Surgery of the Thyroid and Parathyroid Glands .
This book represents a comprehensive surgical text blended with a surgical atlas. Many chapters that focus on surgical anatomy and maneuvers are heavily illustrated by Robert Galla, medical illustrator. The operative realism of Mr. Galla's handsome images is impressive and represents one of the real strengths of this text.
In addition, the book now is associated with a video library, which highlights numerous complex surgical maneuvers and procedures by leaders in the field. Where the reader sees the video icon, online video material is available. The video component of this work was produced, edited, and organized by Gregory William Randolph, Jr., our surgical text video editor in chief.
The book is intended for surgeons and endocrinologists, as well as radiologists and pathologists with an interest in thyroid and parathyroid disease. It is my intention that the book be a resource to both the surgeon in training and the experienced surgeon.

Gregory W. Randolph, MD
Acknowledgments
I would like to thank the many people without whom this project would not have been possible. Substantial thought and effort went into the development of each image in this text. Virtually every image is the result of a collaborative effort. Robert Galla and I reviewed initial sketches and ideas from contributors and then revised each drawing multiple times. It has been a pleasure to work with Mr. Galla. His drawings truly represent the backbone of this text. They are as informative as they are beautiful. We are also very pleased to include and showcase the artwork of Zach Zuffante.
In addition, I would like to thank the tireless research assistance of my friend and colleague, Dr. Dipti Kamani. This book has been shaped in many ways by my time in the operating room at Massachusetts Eye and Ear Infirmary. I have been fortunate to work with operating room nurses Peggy Kelly and Nancy Kotzuba. I appreciate the editorial assistance offered by Stefanie Jewell-Thomas, Roxanne Halpine Ward, and Sharon Corell at Elsevier Inc. I would also like to thank John and Claire Bertucci and Mike and Eliz Ruane for their ongoing support through the years and for their friendship.
Finally, I would like to thank some of the physicians who have been important in the development of this book, including Dr. Joe Nadol, my chairman, friend, and mentor, who supported the initial development and continuing evolution of my thyroid surgical practice in Boston. I would like to thank Drs. Keith Lillemoe and Ken Tanabe for their belief in a true collaborative environment and commitment to modern endocrine surgery, and Dr. Randy Gaz for his guidance and friendship. I am especially indebted to Dr. Gil Daniels, whose instruction over the years has provided framework and grounding for my thyroid and parathyroid surgical practice. For your teaching and friendship, Gil, I am grateful.

Gregory W. Randolph, MD
Section 1
Introduction
Chapter 1 History of Thyroid and Parathyroid Surgery

Marica Zizic Mitrecic, Edwin L. Kaplan, Randall D. Gaz, Cristian M. Slough, Miljenko Bura, Anatoly F. Romanchishen, Miran Martinac, Gregory W. Randolph

“Only the man who is familiar with the art and science of the past is competent to aid in its progress in the future.”
—T. Billroth, 1862 1
The history of thyroid surgery documents the evolution of modern surgical techniques and the blending of these techniques with an expanded understanding of anatomy and endocrinology. The road has had many twists. Even when thyroid and parathyroid disorders were first recognized as discrete entities, they were misunderstood. Initially, Graves’ disease was felt to represent a cardiac illness, hypothyroidism a neurologic and dermatologic disorder, and hyperparathyroidism a primary bone disorder. One of the first thyroid procedures in the 1600s resulted in the imprisonment of the surgeon. 2 Fortunately, the anatomist and physiologist embraced the initial morbid surgical misadventures, ultimately rendering the applied art of thyroid surgery a safe and even triumphant treatment form. As Halsted has written, “The extirpation of the thyroid gland for goiter typifies perhaps better than any other operation the supreme triumph of the surgeon's art.” 3 The surgical story begins with the treatment of iodine deficiency.

The Early Years
Goiter has been recognized as a discrete disease entity since earliest recorded history. The first mention of goiters in China occurs as early as 2700 b.c . Although goiter has been endemic in several parts of the world throughout history, it was not until a.d. 500 that Abdul Kasan Kelebis Abis in Baghdad performed the first recorded goiter excision. The patient survived despite massive postoperative bleeding. Other early remedies included the application of toad's blood to the neck and stroking of the thyroid gland with a cadaverous hand.
Early developments in thyroid surgery came from the school of Salerno, Italy, in the 12th and 13th centuries ( Figure 1-1 ). The typical operation involved insertion of two heated iron setons at right angles into the offending mass. These were then manipulated at the skin surface twice a day until they pierced the flesh. In cases in which arterial supply of the goiter was thought not to be excessive, the surface of the goiter was cut, the tumorous tissue was grasped with a hook, and the skin was dissected away from it. Once exposed, the section of goiter with its capsule would be removed with a finger. Pedunculated goiters would be ligated en masse with a bootlace and removed. 4 During such procedures, patients were tied down to a table and held firmly. Although these procedures sometimes reduced goiter size, patients often died from sepsis or hemorrhage. 4

Figure 1-1 The assistant holds the patient as the surgeon cuts scrofula (goiter) from the patient's neck. Rogerius Salernitanus (Ruggero Frugardo): Chirurgia (1180).
(From Ignjatović M: The thyroid gland in works of famous old anatomists and great artists. Langenbecks Arch Surg 395[7]:973-985, 2010.)
The anatomy of the normal thyroid gland was not generally understood until the Renaissance, through the work of Leonardo da Vinci ( Figure 1-2 ). He drew the thyroid as two globular glands, which he speculated filled up empty spaces in the neck ( Figure 1-3 ). 5 Others pondered the function of the thyroid gland, speculating that its role was to lubricate the neck or make it more aesthetically pleasing. Caleb Hillier Parry of Bath, England, recognizing the thyroid gland's vascularity, considered the gland a blood buffer to protect the brain from sudden increases in blood flow from the heart. 6 In Roman times, increased neck girth was believed to herald the onset of puberty. 7 Bartholomeo Eustachius of Rome in the 16th century characterized the gland as “glandulam thyroideam” with two lobes connected via an isthmus. 4 The term thyroid gland (glandula thyroideois) is attributed to Thomas Wharton (described in his work Adenographia ) (1646); he gave this name because of either the gland's own shieldlike shape ( thyreos : Greek “shield”) or because of the shape of the thyroid cartilage, with which it is closely associated. 8

Figure 1-2 Leonardo da Vinci: “The Madonna of the Carnation” or “Madonna with a Rose” ca. 1478. Madonna with the goiter.
(From Ignjatović M: The thyroid gland in works of famous old anatomists and great artists. Langenbecks Arch Surg 395[7]:973-985, 2010.)

Figure 1-3 The first illustration of a thyroid is attributed to Leonardo da Vinci in 1503.
(From O'Malley CD, de CM Saunders JB: Leonardo on the human body , New York, 1983, Dover Publications, p. 169.)
In 1646, Wilhelm Fabricus reported the first thyroidectomy performed using scalpels. However, the patient, a 10-year-old girl, died and the surgeon was imprisoned. 2 In 1791, Pierre Joseph Desault performed a successful partial thyroidectomy in Paris. 2 Guillaume Dupuytren followed in Desault's footsteps and in 1808 performed the first “total” thyroidectomy. Unfortunately, despite little intraoperative blood loss, the patient died of “shock.” 2 The most successful thyroid surgeon of that time was Johann Hedenus, a German surgeon from Dresden. By 1821 he had reported on the successful removal of six large obstructing goiters. His remarkable series would not be equaled for nearly 40 years. 5 In the 1850s, a variety of incisions—longitudinal, oblique, and, occasionally, Y-shaped—were performed for thyroidectomy. Collar incision had been introduced by Jules Boeckel of Strasbourg in 1880. 2 After skin incisions, most surgeons at this time performed blunt dissection. Bleeding was generally inadequately controlled. Bloodletting was performed for postoperative complications, despite perioperative blood loss. Typically, wounds were left open, and dead spaces were either packed or left to fill with blood. 4
The progress of early thyroid surgery is intertwined with initial advances in our understanding of thyroid endocrinology. It had been known empirically for some time that seaweed kelp and marsh seawater reduced goiter size. In 1811, Bernard Courtois discovered iodine in burned seaweed. 5 By 1820, Johann Straub and Francois Coindet, both Swiss, systematically studied the use of iodine to treat goiter. Coindet went on to recommend the use of iodine preoperatively to reduce the size and vascularity of goiters and, therefore, lessen operative risks. 4 The use of iodine preparations became widespread. Considered miracle drugs, iodine medications were abused, and toxicity often resulted. 9 In the 1830s, Robert Graves' and Karl von Basedow initially described toxic diffuse goiter through recognition of the “Merseburg triad” of goiter, exophthalmos, and palpitations. 10 , 11 Interestingly, despite being attributed to Graves' and Basedow, the association of goiter and orbital disease was described already in the 11th century by two Persian physicians, Avicenna and Aj-Jurjani. 12
By the 1850s, the mortality rate following thyroid surgery was still high, approximately 40%. The French Academy of Medicine at this time condemned any operative intervention on the thyroid gland. At about this time Samuel David Gross, a prominent American surgeon, wrote in 1866:

Can the thyroid gland, when in a state of enlargement, be removed with a reasonable hope of saving the patient? Experience emphatically answers NO.… If a surgeon should be so foolhardy as to undertake it … every step of the way will be environed with difficulty, every stroke of his knife will be followed by a torrent of blood, and lucky will it be for him if his victim lives long enough to enable him to finish his horrid butchery. No honest and sensible surgeon would ever engage in it! 13

The Surgical Revolution
Landmark developments in surgery and medicine that occurred in the 1800s helped to convert surgery of the thyroid gland from a bloody and condemned procedure to a modern, safe, surgical intervention. Foremost among these developments were anesthesia, antisepsis, and surgical hemostatic instrumentation.
The surgical revolution began with the pivotal discovery of anesthesia, as it was subsequently termed by Oliver Wendell Holmes. 14 In 1842, Crawford W. Long, from Georgia, was the first to use sulfuric ether as an anesthetic during surgery. 9 The era of modern surgical anesthesia truly began with William Morton's demonstration of ether's efficacy at Massachusetts General Hospital in Boston in 1846. 9 In 1847, in Vladikavkaz, Russia, Nikolai Pirogov was the first surgeon to use general anesthesia during a thyroidectomy. 2 The patient was a 17-year-old girl with a goiter causing compression of the trachea. 15 The surgery was quite difficult since the “tumor was of a size of an apple” and “more than 30 ligatures were required.” The wound healing was complicated “with pus.” The outcome of surgery was nevertheless a success. Soon Pirogov performed three more thyroid surgeries in St. Petersburg. He never placed sutures on the wound edges fearing erysipelas and “purulent pockets.” 16
The introduction of antisepsis by Joseph Lister in 1867 was the second step in the surgical revolution. Lister's concept was quickly adopted in continental Europe but was met with some resistance in Great Britain and the United States. 5 Theodor Kocher and Albert Theodor Billroth, fathers of modern thyroid surgery, adopted Lister's antisepsis concepts in the 1870s. Gustav Neuber introduced the concept of intraoperative asepsis in 1883 when he brought the cap and gown into the operating theater. In 1886, Ernst von Bergmann of Berlin introduced steam sterilization of surgical instruments. 17
The final step in the development of modern surgery was improved hemostasis, made possible because of new surgical instrumentation introduced by Spencer Wells. He devised a simple, self-retaining arterial forceps (with one catch) in 1872 and reported on its use in 1874. 18 Additional improvements of the forceps, such as reduction in its weight and inclusion of more ratcheted catches, transformed surgical technique by reducing operative bleeding and, ultimately, mortality.
With patients’ pain and motion better controlled by anesthesia and hemostasis improved by better hemostatic forceps, surgeons had more time to attend to the underlying anatomy, allowing for more successful thyroidectomy with a safe, nonseptic postoperative course. Consequently, from 1850 to 1875, mortality from thyroid surgery was reduced by half. 2

Development of Modern Thyroid Surgery
Albert Theodor Billroth (1829-1894) is generally regarded as the most distinguished surgeon of the 19th century. He was born the son of a German clergyman in 1829 ( Figure 1-4 ). Appointed at the age of 31 to the chair at Zurich, he cautiously undertook the surgical treatment of obstructive goiters endemic to this area. During his first 6 years in Zurich, he performed 20 thyroidectomies. He courageously published the results, noting a mortality rate of approximately 40%. Mortality was primarily due to postoperative sepsis and intraoperative hemorrhage. Billroth considered this mortality rate disastrous, and he virtually abandoned the procedure for almost a decade. 13 He regained confidence in performing thyroid surgery in 1877, after the advent of antisepsis (which he was initially slow to embrace) and improved instrumentation. At that time, the mortality rate from his procedure fell to 8%. Billroth's procedure typically involved division of the sternocleidomastoid muscle and incision and drainage of any thyroid cysts. Hemostasis was achieved through arterial ligation and the use of aneurysmal needles and an Indian vegetable styptic, punghawar djambi.

Figure 1-4 Albert Theodor Billroth, 1867.
(Reproduced with permission from Institut für Medizingeschichte, Universität Bern, Buehlstrasse 26, CH 3012 Bern.)
Billroth's accomplishments were impressive. By the time he accepted the chair at Vienna in 1867, he had already published his textbook, General Surgical Pathology and Therapeutics, and had founded the Archives of Clinical Surgery. He eventually became the most experienced thyroid surgeon in the world at that time. He was also a renowned teacher and was influential in establishing a school of surgery. Many notable surgeons studied under him, including Jan Mikulicz, Anton von Eiselsberg, and Anton Wölfler. Billroth in 1880 was asked to examine Nikolai I. Pirogov, a forefather of Russian thyroid surgery. Billroth diagnosed an inoperable maxillary cancer in the 70-year-old Pirogov. His other notable contributions to head and neck surgery included performing the first successful laryngectomy in 1873 and the first esophagectomy in 1881.

Theodor Kocher (1841-1917)
It is, however, Theodor Kocher who stands alone in the annals of thyroid surgery. The work of Kocher ( Figure 1-5 ) was instrumental in the development of modern thyroidectomy. After graduation in 1865 from the University of Bern, Kocher spent a year visiting and studying at foreign clinics. He visited Glasgow, where he witnessed Lister's revolutionary antisepsis work; Paris, where he met Louis Pasteur and Verneuil; and Zurich, where he met with Billroth. He became well versed in current developments in surgery. In 1872, at the age of 31, Kocher was appointed surgical chair at the University of Bern. Halsted observed that

a greater advance was made in the operative treatment of goiter in the decade from 1873 to 1883 than any in the forgone years, and I may say in all the years that have followed … during which period the art of operating for goiter by Billroth and Kocher and men of their school had been almost perfected, relatively minor problems remain to be solved. 2

Figure 1-5 Theodor Kocher, 1912.
(Reproduced with permission from Institut für Medizingeschichte, Universität Bern, Buehlstrasse 26, CH 3012 Bern.)
At the time of Kocher's appointment to Bern, goiters were endemic in Switzerland. Kocher noted that up to 90% of schoolchildren in Bern were afflicted with goiter. 19 He quickly acquired a remarkable experience in thyroid surgery and eventually performed more than 5000 thyroidectomies over the course of his career. He was a meticulous surgeon who paid careful attention to hemostasis. He introduced initial ligation of the inferior thyroid arteries, which substantially reduced the risk of hemorrhage. His advocacy of the use of antisepsis and hemostasis, evident in his textbook of surgery, was manifest in his mortality rates. He reported a reduction in mortality from 12.6% in the 1870s to 0.2% in 1898. 20 During Kocher's tenure, Bern became the world capital of goiter surgery ( Figure 1-6 ). Kocher's surgical technique differed from Billroth's in that Kocher preserved the strap muscles and usually used a collar incision, whereas Billroth typically used an oblique and more restrictive incision. 13 Kocher also paid close attention to the anesthesia methods available. One of Kocher's few mortalities was secondary to chloroform anesthesia. From that point onward, he used only local anesthesia with cocaine. 8

Figure 1-6 Dr. Kocher in the operative theater. This unique photograph of Kocher also shows his student, Dr. William Halsted, present in the audience (fourth from the left at the head of the table facing Kocher).
(Reproduced with permission from Institut für Medizingeschichte, Universität Bern, Buehlstrasse 26, CH 3012 Bern.)
In 1867, Kocher learned that one of his early patients, 10-year-old Marie Bischel, had developed slowness of affect, stunted growth, mental retardation, thickened fingers, and other manifestations of cretinism after bilateral thyroidectomy. He called this unknown condition cachexia struma priva .
When Kocher, in 1882, became familiar with the work of Jaques-Louis Reveridin of Geneva, who described similar symptoms of myxedema after total thyroidectomy, he began a concerted effort to recall all his goiter patients. 21 Of the 18 thyroidectomy patients Kocher was able to review, 16 displayed varying degrees of myxedema. Kocher was so appalled at the outcome epitomized by Marie Bischel ( Figure 1-7 ) that he resolved never again to perform a total thyroidectomy for benign disease. This observation was the first evidence that the thyroid played a physiologic role in growth and development.

Figure 1-7 A, Marie Bichsel (right) as an 11-year-old in 1873 with her younger sister. B, Marie Bichsel (left) as a 20-year-old with her younger sister.
(Reproduced with permission from Institut für Medizingeschichte, Universität Bern, Buehlstrasse 26, CH 3012 Bern.)
In 1883, Kocher presented his historic paper to the Fifth German Surgical Congress in which he described the adverse effects of total thyroidectomy (termed cachexia strumiprivia ), evidence that the thyroid gland in fact had a function. 22 About this time, Felix Semon, a Prussian otolaryngologist, in a meeting of the Clinical Society of London, also suggested similarities between English myxedematous patients and patients who had undergone total thyroidectomy. 23, 24
An interesting comparative observation between Billroth's and Kocher's surgical technique was made by William Halsted ( Figure 1-8 ; see also Figure 1-6 ) who, as a student, visited the clinics of both. 2 Halsted noted that most of Kocher's thyroidectomy patients developed myxedema postoperatively, but rarely tetany. The reverse was true of Billroth's patients. Halsted proposed that the origin of this phenomenon lay in Kocher's and Billroth's different surgical techniques. Whereas Kocher was known for his bloodless operative field, attention to detail, and removal of most of the thyroid while preserving surrounding structures, Billroth was known for a more rapid approach, resulting in parathyroid injury and larger retained segments of thyroid. Kocher was a versatile and astute surgeon whose accomplishments extended beyond that of endocrine surgery. Kocher's achievements included the development of a method of shoulder dislocation reduction, use of the right subcostal incision in cholecystectomy, work with gunshot wounds and osteomyelitis, localization of spinal cord lesions, and development of the surgical mobilization maneuver of the duodenum that bears his name. 13 In 1908, Kocher was awarded the Nobel Prize for his work on the physiology, pathology, and surgery of the thyroid gland. He has been acclaimed “the father of modern thyroid surgery.” 3

Figure 1-8 William S. Halsted.
(From Organ CH Jr: J Am Coll Surg 191[3]:291, Fig. 11, 2000. Used with permission.)
William Halsted (1852-1922) (see Figure 1-8 ), a student and close acquaintance of Kocher, brought Kocher's surgical philosophy to the American surgical arena. Following his graduation from Yale in 1879, Halsted studied for 2 years in well-known German and Austrian clinics, where he was influenced by the work of both Billroth and Kocher. On returning from Europe, Halsted was shocked at the state of thyroid surgery in the United States. In fact, little thyroid surgery was done at all in the United States at that time. In 1881, in New York, Halsted assisted Dr. Henry Sands at Roosevelt Hospital with resection of a right thyroid mass. The patient sat awake in a dental chair with a rubber bag tied around his neck to catch the blood. The two hemostats available at the hospital at that time were both used. 3 Halsted was quick to utilize the knowledge of antisepsis and modern hemostatic forceps in the United States. 4 In 1881, he wrote that the confidence “acquired from masterfulness in controlling hemorrhage gives to the surgeon the calm which is so needed for clear thinking and orderly procedure at the operative table.” 2 His early work, however, was not without peril. While experimenting with local infiltration anesthetic agents, Halsted became addicted to cocaine. 25 His work “The Operative Story of Goiter,” published in 1920, described advances made in thyroid surgery from the earliest days to the revolutionary work of Billroth and Kocher, whose techniques he held in great esteem.
Halsted helped to found the auspicious Johns Hopkins Hospital, where he was named the first Johns Hopkins professor of surgery. There he introduced residency training and trained many surgeons, including Cushing, Dandy, and Reed, and a number of respected thyroid surgeons, including Charles Horace, Frank Lahey, and George Crile. 25 Crile's contributions extended to early studies of shock and the surgical treatment of hyperthyroidism. Roswell Park used a pneumatic antishock suit, devised by Crile, to help prevent shock in hyperthyroid patients undergoing thyroid operations ( Figure 1-9 ).

Figure 1-9 Crile's pneumatic suit used to prevent shock in thyroid operations.
(From Park R. Principles and Practice of Modern Surgery , Philadelphia: Lea and Brothers; 1907. Used with permission.)
Charles Mayo adopted Kocher's technique of partial thyroidectomy for patients with Graves’ disease. In 1913, his medical counterpart, Henry Plummer, established the value of iodine use preoperatively in Graves’ disease. Adoption of these practices at Mayo Clinic resulted in a drop in the mortality rate in surgery for Graves’ disease from 3% to 4% to under 1%. 3
Thomas Peel Dunhill adopted the technique of total lobectomy on one side and subtotal resection on the other for toxic patients. He practiced total lobectomy by a pericapsular dissection technique. Dunhill also described operation on retrosternal goiter through sternotomy. 8
Jan Mikulicz was one of the first to demonstrate the feasibility and value of partial thyroid resection; he also showed that thyroid parenchyma can be crushed, divided, and ligated without fear of uncontrollable hemorrhage or impairment of wound healing, thereby forming the basis of modern unilateral and bilateral subtotal lobectomy. 3
Once the major obstacles of hemorrhage and infection had been addressed, thyroid surgeons recognized and investigated the peculiar entity of postthyroidectomy tetany. Wölfler, while employed as Billroth's first assistant, first described postoperative tetany in 1879. 26 Eiselsberg later succeeded Wölfler as first assistant and continued the work on postoperative tetany in Billroth's clinic. The etiology of postoperative tetany, however, was unknown until 1891, when Eugéne Gley reported that the cause could be attributed to removal of the parathyroid glands, or to interference with their blood supply. 3 It was not until the 1920s, however, that it was clear that low calcium was the cause of tetany.
It is noteworthy to mention Harold Foss, who adopted the use of motion pictures to teach surgical techniques and was one of the first to show color movies—a thyroid operation in 1935—at a national meeting. 27
Our understanding of the surgical treatment of thyroid cancer has evolved over time as well. Errors have occurred both with insufficient treatment and excessive treatment. For instance, metastatic papillary carcinoma of the thyroid initially was regarded as an embryologic migration error and termed lateral aberrant thyroid. It was believed that such patients did not require thyroid surgery. However, when the high rate of cervical lymph node metastasis in papillary carcinoma was ultimately appreciated, the response was to perform radical neck dissection. 28 With time, enthusiasm for more appropriately conservative neck treatment prevailed.

Laryngeal Nerves
The history of the recurrent laryngeal nerve and its relationship to the voice is a fascinating story, for it began in antiquity. The earliest reference to the voice and structures in the neck that we discovered is found in the Sushruta Samhita written in India in the sixth century b.c. An injury in the neck near the angle of the jaw was considered critical and caused hoarseness and a change in taste. This was thought to be due to damage to the vessels of the neck. 29 By the first century a.d., Rufus the Ephesian wrote that it was nerves and not vessels that were responsible for the faculty of voice. 30 About the same time, Leonides recognized the importance of avoiding injury to the “vocal” nerves during operations of the head and neck. He warned that if the nerves were cut, the voice would be lost. 4
However, it was Galen who first described the recurrent laryngeal nerves in detail during the second century. While Greek philosophy and medicine held the heart to be most important—the seat of intellect and learning—Galen recognized the importance of the brain. He was delighted when he found a nerve from the brain on each side of the neck that went down toward the heart and then reversed course and reascended to the larynx. Nerves were thought to contract similarly to tendons and muscles. To contract the laryngeal muscles, the pull had to be from below, he thought, and here was just such a nerve that came from the brain. He called these two nerves the recurrent nerves (or reversivi). 31
He took great pride in this wonderful finding and said that he was the first to discover these nerves. He felt that the recurrent nerves gained great mechanical advantage by a pulley action, similar to a glossocomion, which was a popular device of that day for reducing fractures. He dissected these nerves in many animals—even swans, cranes, and ostriches because of their long necks—and marveled at the mechanical advantage of the pulley system that was able to open and close the muscles of the larynx.
Galen recognized in studies on the living pig that “if one compresses the nerve with the fingers or a ligature” or if one cuts the nerve, the pig stopped squealing and the muscles of the larynx on that side ceased to work. 32
He gathered the elders of Rome and, to impress them with his greatness and knowledge, operated on the neck of a live squealing pig. When he cut the recurrent laryngeal nerve, the pig stopped squealing. This was thought to be wondrous. His dissection on the living pig is depicted in a beautiful medieval illustration ( Figure 1-10 ).

Figure 1-10 Galen demonstrating the recurrent laryngeal nerve in the living pig to the elders of Rome. When the nerve was divided, the pig's squealing ceased and it became mute.
(From Galeni Librorum Quinta Classis EAM Medicinae Partem, edited by Fabius Paulinus. Published by Guinta Family of Venice, 1625. IM Rutkow, in Surgery: an Illustrated History, St. Louis, 1993, Mosby, p 40.)
Galen described two children who were operated on by surgeons ignorant of anatomy. One surgeon tore out swollen lymph nodes from the neck with his nails and apparently removed the surrounding nerves at the same time. The slave was rendered mute.
Similarly, another surgeon while performing an operation on another child rendered him “half mute,” evidently having damaged only one of the nerves. “Everybody found it strange that the voice was damaged, although the larynx and trachea remained intact. But when I demonstrated to them the phonetic nerve [i.e., the recurrent nerve], their astonishment abated.” 33
Because of Galen's fame over the ages and the spread of his teachings, the recurrent laryngeal nerve was discussed by many surgeons and anatomists thereafter. Aetius, in the sixth century, wrote that “In the case of the throat glands, the vocal nerves must be carefully avoided … (otherwise) the patient is bereft of his voice.” 34 Paulus Aeginetus, in the seventh century, again stressed that when operating in the neck, “avoiding in particular the carotid arteries and recurrent nerves” must be exercised. 35
Arabic medical literature of the ninth to twelfth centuries also contains references to the recurrent laryngeal nerve. Abul Kasim (Albucassis, 1000 a.d. ) is credited by some with the first recorded description of a thyroidectomy. He echoed the same warnings with regard to the recurrent laryngeal nerve: “Be most careful not to cut a blood-vessel or nerve.” 36 He also described a slave girl who stabbed herself in the neck. The artery and vein had not been cut, but she developed hoarseness.
In the Middle Ages, the same experiments on the recurrent laryngeal nerves in pigs that were done by Galen were repeated in the Salernitan demonstrations. During the Renaissance, in 1503, Leonardo Da Vinci drew what may be the first anatomic representation of the recurrent laryngeal nerve, possibly in an ape. The first drawing of the thyroid gland is attributed to Da Vinci as well (see Figure 1-3 ).
Vesalius, in 1543, was particularly interested in the recurrent laryngeal nerve because, as he wrote, “nothing is more delightful to contemplate than this great miracle of nature.” His drawing of Cupid operating on the neck of the pig is reminiscent of Galen's former operations. He also produced excellent anatomic drawings of the recurrent laryngeal nerves.
Other anatomists in the 16th and 17th centuries produced excellent dissections of the recurrent laryngeal nerves and of the muscles of the larynx ( Figure 1-11 ). Hence, by the 17th or 18th century, a great deal was known not only about the anatomy of the recurrent laryngeal nerves but also about the complications when one or both of them were cut or damaged, and ways to avoid these problems. Thus, in 1724 Gherli could write:

Although there are other complications more terrible and frightening, the cutting of the recurrent nerves is dangerous in the highest degree (for when) this unfortunately occurs, either the patient dies of it miserably or at least loses for the rest of his life the most beautiful prerogative given to man by God, which is (la favella) speech; but this danger can easily be avoided by that Surgeon who, with the provision of Anatomy, knows the site of these nerves. 37

Figure 1-11 Taken from the beautiful anatomic dissection of Charles Estienne, 1546. The recurrent laryngeal nerves are shown.
(From Estienne C: La dissection des parties du corps humain divisee en trios livres , 1545, Paris, Simon Colinaeus. From the Special Collections Research Center, University of Chicago Library.)
Although the 19th century brought great advances in surgery in general and in operations on the thyroid, eminent surgeons continued to have problems not only with bleeding, infection, and tetany (which some thought was due to hysteria) but also with recurrent nerve injuries. Karl von Klein of Stuttgart, for example, reported the loss of voice during removal of a goiter in 1820. 38
Billroth's group, reported by Wolfler his chief assistant in 1882, had a 40% mortality rate for thyroidectomy for goiter while he was in Zurich before 1867 and an 8.3% mortality rate for goiter during the antiseptic period, from 1877 to 1881. 39 Five patients (10.5%) required a tracheostomy. Unilateral nerve injuries were reported in 25% (11/44) and bilateral nerve injuries in 4.5% of the later group (1877-1881).
Jankowsky reported a 14% incidence (87/620 patients) of recurrent nerve injuries for goiter operations before 1885. 40 Undoubtedly, the number was far greater because laryngeal examinations were not routine.
It was Theodor Kocher of Berne who brought his operative mortality of thyroidectomy from 14.8% in 1882 to an eventual level of less than 0.18% in 1898. 41 His meticulous technique resulted in an incidence of recurrent nerve injury similar to that of surgeons today.
Billroth, Kocher, and others appreciated the need to avoid injury to the recurrent laryngeal nerve during thyroid surgery. At that time, the common practice for preserving the nerve was to identify the inferior thyroid artery, isolate it, and ligate it laterally away from the nerve, in a bloodless field. Mikulicz, in 1882, recommended leaving a posterior portion of the thyroid capsule to cover the distal course of the nerve. 21 Kocher also preferred to leave a small posterior remnant of the thyroid to avoid damage. Once he perfected this technique, hoarseness became exceptional following his operations. 38
In the early 1900s, a debate over the proper operative approach for thyroidectomy ensued. In 1904 Russia, famous surgeon Alexandr A. Bobrov (1850-1904) reported on 106 thyroid operations under recurrent laryngeal nerves visual control. 42 August Bier of Berlin (1911) preferred to expose the recurrent laryngeal nerves routinely, but most surgeons opposed this procedure. 43 George Crile, the founder of the Cleveland Clinic, wrote in 1932 that the greatest tragedies that follow thyroidectomies pertain to these nerves, not because of their anatomy but because of their specific vulnerability to trauma. 44
As compared with peripheral nerves, the recurrent nerves are exceedingly soft … and the slightest direct or even indirect pressure on the recurrent nerve interferes with nerve conduction. … And it is this extreme vulnerability that is the first and the most important factor in the production of abductor paralysis.
If the nerve trunk is directly exposed in the course of the operation, the exposed nerve will be covered with scar formation. Scar tissue is capable of producing a block in the action current, hence, causing a physiologic severance of the nerve.
Crile recommended leaving the posterior capsule of the thyroid in each thyroid resection. He called the area near the nerve no man's land .

It is not to be palpated; it is subjected to the least possible traction and no division of tissue is made. By these precautions temporary and permanent injury of the recurrent laryngeal nerve may be completely eliminated.
Prioleau wrote in 1933, “a nerve if seen is injured.” 45 This philosophy of purposely not seeing the recurrent nerves, which influenced an entire generation of surgeons and still exists today in the minds of some inexperienced surgeons.
In 1938, Lahey reported on more than 3000 thyroidectomies performed by his fellows and staff during a 3-year period. 46 The recurrent laryngeal nerve was dissected in virtually every case. Careful dissection would “not increase but definitely decrease the number of injuries to the recurrent laryngeal nerves,” he wrote. Lahey's work with its emphasis on anatomy set the course and direction for modern thyroid surgery.
Later, in 1970, Riddell wrote that when the nerve is identified and carefully followed throughout its course, a nerve injury may occur, but the paralysis is nearly always transient . When the nerve is not identified, however, permanent paralysis of the vocal cord occurs in at least a third of cases. 46
Finally, to paraphrase Professor William Halsted, thyroidectomy may be the supreme triumph of the surgeons’ art. 2 However, to perform it safely, the greatest care must be exercised to preserve the integrity of the recurrent laryngeal nerve. It is clear that our knowledge of the anatomy and physiology of this nerve began close to 2000 years ago.
Despite work on the avoidance of recurrent laryngeal nerve injury, little attention was paid to the surgical importance of the external branch of the superior laryngeal nerve (SLN). Kocher did not even mention the external branch of the superior laryngeal nerve in his book, which for many years was considered the cornerstone of thyroid surgery. It was not until 1935, after world-famous operatic soprano Amelita Galli-Curci underwent goiter surgery, with resultant loss of her upper vocal registry, that the SLN came into the limelight. The media at the time wrote, “the surprising voice is gone forever. The sad specter of a ghost replaces the velvety softness.” 47

Parathyroid Glands

Parathyroid Anatomy and Physiology
The parathyroid glands were first identified in 1850, in an Indian rhinoceros in a London zoo, by Richard Owen, then professor of anatomy at the Hunterian Museum of the Royal College of England. 26 His work, published in 1862, went unnoticed for several years.
Credit for recognition and identification of the parathyroid glands in humans went to Ivar Sandström ( Figure 1-12 ), a medical student at Uppsala University in Sweden. In 1887, Sandström came across the parathyroid glands while dissecting the neck of a dog; he subsequently identified these glands in cats, rabbits, oxen, and horses. Later, Sandström dissected 50 human cadavers, illustrating the anatomic position, blood supply, and variability of the location of the parathyroid glands. This work led to his monograph, “On a new gland in man and fellow animals.” 26 Sandström was also the first to suggest that these glands be named “glandulae parathyreoidae.” His manuscripts, initially rejected by a German journal as too long, were finally published in a Swedish medical journal. 26 In 1890, Gley, a French pathologist, came across Sandström's work in two abstracts published in a German yearbook. Unfortunately, Sandström committed suicide before his fundamental work had been rediscovered by Gley. Although the parathyroid glands were observed independently by Cresswell Baber in 1881 in England, it was not until Gley's work in the 1890s that the parathyroid glands and their function became widely appreciated. 4 Anton Wölfler observed tetany in Billroth's patients after total thyroidectomy but attributed this development to hyperemia of the brain. 26 Gley observed that animals whose parathyroid glands were removed subsequently developed tetany. 48 Two Italians, Guillio Vassale and Francesco Generali, later duplicated this work, confirming that tetany followed parathyroidectomy. 4 As a result of these observations, surgeons understood that it was vital to treat the parathyroid glands with great care during thyroidectomy.

Figure 1-12 Ivar V. Sandström, Upsaala, Sweden.
(From Organ CH Jr: J Am Coll Surg 191[3]:286, Fig. 4, 2000. Used with permission.)
McCallum, in 1905, found that he could relieve tetany that followed parathyroidectomy by injecting animals with parathyroid extract. 49 Subsequently, McCallum and Carl Voegtlin of Baltimore, in 1909, helped to elucidate the connection between the parathyroid gland and calcium regulation. They found that tetany following parathyroidectomy was accompanied by calcium deficiency in tissues and that this condition could be relieved by injections of crude parathyroid extract or of calcium. They further were able to identify the cause of tetany as hypocalcaemia resulting from insufficient parathyroid secretion. 50 Halsted, in 1907, also reported the use of parathyroid extracts to treat tetany following thyroidectomy. 26 Halsted and a Johns Hopkins medical student, Herbert Evans, together detailed human parathyroid blood supply. 51
Frederick von Recklinghausen, then professor of pathology at Strasborg, presented seven patients with bone disease in a festschrift for Virchow in 1891. However, only in 1906 was the connection between parathyroid glands and bone disease established by the work of Jakob Erdheim in Vienna. When he cauterized the parathyroid gland in rats, he noted that not only did tetany become manifest but also defective calcification in their teeth occurred. 4 He went on the examine the parathyroid glands of patients who had died of skeletal disease and in 1907 reported enlargement of the glands following bone diseases such as osteomalacia and osteitis fibrosa cystica. 26 Erdheim himself regarded this gland enlargement to be compensatory, secondary to the bone disease. This view persisted for several years. Freidrich Schlagenhaufer of Vienna was the first physician to suggest that parathyroid glandular enlargement was primary, with bone disease a secondary effect. He suggested that surgery be performed to remove the enlarged glands and therefore cure the bone condition. 4
Henry Dixon and colleagues in St. Louis, Missouri, coined the term hyperparathyroidism, describing its features, including bone disease, muscular weakness, hypercalciuria, renal stones, and a high serum calcium level. 4 However, it was only in 1963, with development of the immunoassay measurement of parathyroid hormone by Solomon Berson and Rosalyn Yalow, that a clear understanding of parathyroid hormone and calcium metabolism emerged. 52 Berson and Yalow earned the Nobel Prize for their work.

Parathyroid Surgery
Many workers in the early 1900s thought that parathyroid glandular enlargement was associated with parathyroid hypofunction, analogous to goiter and myxedema. As a result, patients with hyperparathyroidism were treated with parathyroid gland extracts in the hope of correcting a presumed parathyroid deficiency. As previously noted, it was Schlagenhaufer, in 1915, who first suggested removal of enlarged parathyroid glands as an appropriate treatment for von Recklinghausen's disease. It was not until 1925 that Felix Mandl ( Figure 1-13 ) of Vienna actually performed the first parathyroidectomy on Albert Gahne, a tram car conductor. 4 The patient had been previously treated with parathyroid extract and implantation of parathyroid glands, consistent with the current thinking. In desperation, Mandl extracted a 21-by-15-by-12 mm parathyroid gland, believed in retrospect to represent parathyroid carcinoma. The procedure was initially successful and changed the current thinking and practice of the day. Unfortunately, Gahne developed recurrent hypercalcemia and died soon after a second surgical exploration. 26

Figure 1-13 Felix Mandl, Vienna.
(From Organ CH Jr: J Am Coll Surg 191[3]:292, Fig. 12, 2000. Used with permission.)
Less than 6 months after the operation performed by Mandl, E.J. Lewis performed the first parathyroidectomy in the United States at Cook Hospital in Chicago. 53 Four months later, additional lessons in the surgical management of hyperparathyroidism were learned through the experiences of sea captain Charles Martell at Massachusetts General Hospital in Boston. In 1931, James Walton of London advocated that during parathyroid surgery “wide exposure is essential, for not only is it necessary to explore all the parathyroid glands, but also sometimes to search behind the trachea and in the mediastinum.” 54

Further Parathyroid Advances and Autotransplantation
Eiselsberg, one of Billroth's pupils, first attempted to transplant a parathyroid gland in 1892, approximately a year after Gley's report. As a professor at Allgemeines Krankenhaus, he performed autografts in cats. His technique involved transplantation of half the thyroid and parathyroid glands into the rectus fascia and the peritoneum of animals with tetany. 26 No sign of tetany was observed in these animals 1 month after the procedure.
In 1907, Pfeiffer and Mayer were the first to achieve clinical success with autografted parathyroid tissue. 4 Halsted proved, in 1909, that even the transplantation of a single parathyroid gland could be life saving. He “made the startling and hardly believable observation that the life of a dog could be maintained with a particle of tissue only 0.25 mm in diameter and distinguished by tetany after its removal.” 55 He advocated the prevention of parathyroid gland injury during thyroidectomy and experimentally injected intravenous calcium gluconate to treat tetany in postthyroidectomy animals. 56 As understanding was established of the relationship between tetany and parathyroid glands, many surgeons eventually attempted parathyroid autotransplantation during thyroidectomy. Lahey described human parathyroid autotransplantation into the sternocleidomastoid muscle in 1926. It was not until 1976 that Sam Wells developed autotransplantation following parathyroidectomy. Instead of performing a subtotal parathyroidectomy, Wells excised all glands and autografted gland sections within the muscle of the forearm. These parathyroid gland sections then could be excised later if hyperparathyroidism recurred. 57

Historical Vignette Of Endocrine Surgery at the Massachusetts General Hospital
Massachusetts General Hospital (MGH), as a teaching hospital of the Harvard Medical School, has a long tradition of excellence in the surgical care of patients with endocrine diseases. MGH has had a rare combination of surgeons and endocrinologists with a special interest in hyperparathyroidism and thyroid diseases as well as the institutional and departmental support for dedicated thyroid and calcium metabolism laboratories, endocrine clinical research units, and clinical assignments that have singled out specific problems, questions, and treatment issues. Some of the major thyroid and parathyroid contributions include the following: 1934 description of parathyroid clear cell hyperplasia by Albright, 1958 recognition by Cope of chief cell hyperplasia, 1963 development of human parathyroid hormone (PTH) immunoassay by Potts, the first two site PTH immunoassay in 1987 and the first intraoperative PTH measurements in 1988 by Nussbaum. Other significant discoveries were the use of selective venous catheterization for PTH (Potts), intraoperative parathyroid biopsy fat stains (Roth), amino acid sequence for human PTH (Keutman), DNA sequence for human PTH (Kronenberg), detailed New England Journal of Medicine (NEJM) report of ectopic PTH production by ovarian carcinoma (Gaz), confocal laser microscopy analysis of parathyroids (White), PTH pulse therapy for osteoporosis (Neer), and identification of the PRAD oncogene, monoclonality of adenoma, polyclonality of hyperplasia (Arnold), thyroid lobar ablation (Daniels) and neural monitoring.
The story of hyperparathyroidism and parathyroid physiology is a relatively short one beginning in the early 1900s. Joseph C. Aub began the MGH tradition with studies on lead poisoning and bone metabolism in 1925. Then Fuller Albright (1900-1969) concentrated on the clinical and laboratory study of parathyroid function. He wrote the first significant compendium on parathyroid physiology and pathophysiology. The dissemination of parathyroid knowledge from MGH publications attracted many of the first patients diagnosed with bone disease (osteitis fibrosa cystica) related to parathyroid dysfunction. MGH acquired the first large series of parathyroidectomy patients treated by Dr. Oliver Cope (1902-1995) and his associates. The ensuing publications included the story of the famous maritime Captain Charles Martell ( Figure 1-14 ): In 1926, Eugene Dubois, in New York, diagnosed Captain Martell with hyperparathyroidism. He was transferred for additional study to Joseph Aub, Fuller Albright, and, ultimately, Benjamin Castleman. Captain Martell underwent the first of two unsuccessful neck explorations in 1927 at the hospital under the care of then–chief of surgery Edward Richardson. It was not until the seventh operation by Edward Churchill and Oliver Cope that a 3 × 3-cm mediastinal adenoma was resected. Interestingly, it was Martell himself who insisted on a mediastinal exploration, after reading extensively at Harvard Medical School Library about the wide variation of parathyroid gland locations. Sadly, despite the success of this final operation, Martell died 6 weeks later as a result of laryngospasm following a procedure to relieve an impacted ureter stone.

Figure 1-14 Sea captain Charles Martell (left panel) as a young man, subsequent to the development of severe bone disease (right panel).
(From Organ CH Jr: J Am Coll Surg 191[3]:293, Fig. 14, 2000. Used with permission.)
By 1936, Churchill and Cope undertook a series of 30 operations with excellent results. Churchill's experience led to an appreciation that “the success of parathyroid surgery must lie in the ability of the surgeon to know a parathyroid when he sees one, to know the distribution of the glands, where they hide, and also be delicate enough in technique to be able to use this knowledge.” 37 , 38
The name “Delphian node” was born also at the MGH. The “Delphian node,” also known as the prelaryngeal node , was named after the Delphic Oracle for its perceived ability to predict advanced disease in thyroid cancer. The name was first suggested to Oliver Cope in 1948 by Raymond V. Randall, a fourth-year student from Harvard Medical School. 58 , 59
Chiu-an Wang (1914-1996), the director of endocrine surgery at the MGH for many years, was a remarkable individual. He came from Canton, China, where he studied parasitology, to begin a brilliant career. After completing his medical education Harvard Medical School in 1943, he was a general surgery resident at MGH. Then returning to China he practiced in Canton then Hong Kong, returning to MGH in 1960. Dr. Cope assigned him to focus on parathyroid and thyroid surgery. He spent years in the pathology lab dissecting cadavers in order to write a fundamental treatise on the anatomy of parathyroid glands that continues to be a standard reference for surgeons seeking an understanding of the embryologic relations and locations of these diminutive and elusive structures. Another major contribution was his description of a technique for thyroid needle biopsy. This included a movie showing his use of the 14-gauge Vim-Silverman needle to obtain a copious tissue sample from large thyroid nodules for pathologic diagnosis. Thyroid needle biopsy was rarely performed in the United States during the 1960s, so his descriptions helped spread the use of this diagnostic procedure. Dr. Wang was one of the early champions of minimally invasive parathyroidectomy. He performed ultrasound-directed unilateral parathyroid neck explorations (1981), removing the enlarged adenoma and a small snippet biopsy of the ipsilateral second gland. He performed an on-the-table sterile Mannitol density test (1978) comparing the two glands. If there was a marked difference in density based on the disparate fat content of the two glands, he was confident of the diagnosis of adenoma and terminated the procedure. If the two glands were similar in density, then he explored the contralateral side anticipating four-gland hyperplasia. With this methodology he rarely encountered recurrence with only 1% to 2% of cases requiring reoperation. Another contribution was the technique of visual anatomic identification of the recurrent laryngeal nerve using the inferior cornu of the thyroid cartilage as a landmark. Dr. Wang has trained hundreds of surgical students, residents, and fellows in his style of meticulous, function-preserving, successful operative technique.
Advances in endocrine surgery have come from prepared minds that have analyzed previous knowledge, noted new findings, and tested innovative hypotheses. MGH has brought together gifted surgical scientists, high volumes of patients with endocrine diseases, dedicated clinical research units, basic science laboratories, and teams of ancillary services that have concentrated their efforts. The result has been a continuing high standard of patient care and ongoing new discoveries in the field of endocrine surgery.

References
For a complete list of references, go to expertconsult.com .

References

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26 Organ C.H., Jr. The history of parathyroid surgery, 1850-1996: the Excelsior Surgical Society 1998 Edward D. Churchill Lecture. J Am Coll Surg . 2000;191:284.
27 Katlic M.R. Geisinger's remarkable first surgeon, Dr Harold Foss. J Am Coll Surg . 2008;207:443.
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Chapter 2 Applied Embryology of the Thyroid and Parathyroid Glands

Amit Agarwal, Anand K. Mishra, Celestino P. Lombardi, Marco Raffaelli
This chapter contains additional online-only content, available on expertconsult.com.
The modern thyroid or endocrine surgeon should have a complete understanding of the embryonic development of the thyroid and parathyroid glands as well as knowledge of the possible congenital abnormalities arising out of these glands, as they may impact the completeness of surgery as well as the complications of surgery. The modern thyroid-parathyroid surgeon comes to a more intuitive understanding of surgical anatomy through the comprehensive appreciation of the underlying formative embryology.

The Thyroid Gland

Normal Development of Thyroid
The thyroid gland has a double origin: the primitive pharynx and the neural crest ( Figure 2-1 ). The primitive pharynx is responsible for the origin of medial thyroid anlage, whereas the lateral thyroid anlage originates from neural crest, the source of parafollicular cells or C cells that secrete calcitonin. These cells derive from the ultimobranchial bodies. 1 Support for the ultimobranchial origin of C cells has come from the studies of patients with DiGeorge syndrome, a complete or partial absence of the caudal pharyngeal complex. Less than one third of these patients have C cells within their thyroid. 2

Figure 2-1 Schematic view of the primitive pharynx of an 8- to 10-mm embryo.
The primitive pharynx is the origin of the main central portion of thyroid tissue, which appears during the second and third week of fetal life ( Figure 2-2 ). This medial thyroid anlage arises on the ventral pharyngeal wall (the tuberculum impar ) at the level of second branchial arch, appearing as a single or paired diverticulum. The median anlage forms the bulk of the thyroid gland. Division of the gland into lateral lobes, if not present from the beginning, occurs so early that it is impossible to determine whether thyroid arises singly or as a paired organ. The median stalk usually has a lumen (the thyroglossal duct) that does not extend into lateral lobes. This diverticulum follows the primitive heart as it descends caudally. It becomes a solid cord of cells that will form the follicular elements. Then, it breaks in two: the proximal part retracts and disappears, leaving only the foramen cecum at the back of the tongue to mark its origin. Early during the fifth week, the attenuated duct loses its lumen and shortly afterward breaks into fragments. The caudal end develops as bilobed encapsulated thyroid gland proper and reaches its final adult orthotopic position by the seventh week and undergoes histologic differentiation into the typical follicles during weeks 10 and 11.

Figure 2-2 Schematic view of the locations of thyroid, lateral thyroid, thymic, and parathyroid tissue. At the 13- to 14-mm stage, the parathyroid III and the parathyroid IV migrate together with the thymus and ultimobranchial bodies, respectively.
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Subsequent follicle formation takes place by budding or division of primary follicles. Follicle formation is preceded by the appearance of an intracellular periodic acid-Schiff (PAS)-positive material. Bierring and Shepard have described intracellular canaliculi with microvilli, which open at the apex and are in contact with similar structures in adjacent cells. These spaces become confluent and form the lumen of the developing follicles. Desmosomes connect the cells to keep the follicular contents from escaping. During the eleventh and twelfth weeks, all stages of follicle formation may be observed simultaneously. The greatest increase in follicle number takes place during the fourth month; colloid appears in the follicles during the eleventh week. Evidence of thyroxine comes with the appearance of colloid. LiVolsi divided the histologic differentiation of the human fetal thyroid into three stages: precolloid (7 to 13 weeks); colloid (13 to 14 weeks); and follicular (after 14 weeks).
The lateral thyroid anlage develops from proliferation of pharyngeal endoderm. The ventral portion of the fourth pharyngeal pouch becomes attached to the posterior surface of the thyroid during the fifth week and contributes up to 30% of the thyroid weight. The right and left lobes of the thyroid grow caudally with growth of the fetus, taking up their final position at either side of the second to fourth tracheal rings. The line of normal embryologic thyroid descent is called a thyroglossal tract . The causes of the fusion of the median and lateral anlages are unknown. The site of the fusion of these two structures is stated to occur at the tubercle of Zuckerkandl. 3, 4 Sugiyama speculated that the migration of ultimobranchial body controls the growth of median anlage. 5 The fusion of the ultimobranchial bodies and the median thyroid anlage explains why C cells are not scattered throughout the entire thyroid but are restricted to a zone deep within the middle to upper thirds of the lateral lobes along a hypothetical central lobar axis. 6 The extreme upper and lower poles as well as the isthmic regions are generally devoid of C cells.
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Correlative studies of tissue calcitonin immunoreactivity and C-cell distribution have shown that the highest concentrations of the hormones are found in sections corresponding to the junctions of the upper and middle third of the lateral lobes, and this is why medullary carcinomas typically arise initially in the upper and middle third of the lateral thyroid lobes. This has two practical consequences for the surgical management of patients with medullary thyroid carcinomas:

1. Subtotal or even near total resections, leaving a small posterior remnant of thyroid tissue, should never be done.
2. Because lymphatic drainage of the superior poles of the lobes may flow directly into the lateral neck area, lateral neck nodes should be systematically explored, even if the central neck nodes are not involved.
The thyroglossal duct is an epithelial tube that connects the gland and the foramen cecum (see Chapter 6 , Thyroglossal Duct Cysts and Ectopic Thyroid Tissue). Early during the fifth week, the attenuated duct loses its lumen and shortly afterward breaks into fragments. During the fifth through the seventh weeks of gestation, the hyoid bone is formed by condensation of mesoderm with subsequent chondrification from the second and third branchial arches; this grows from behind forward, dividing the thyroglossal tract into suprahyoid and infrahyoid portions. 7 The attenuated thyroglossal duct tract usually atrophies and disappears by the end of the eighth week. The tract may persist as a fibrous cord or a minute epithelial tube.

Genetic Control
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Genetic Control
A number of transcription factors involved in thyroid descent and development have been identified. TTF-1 appears at the earliest stages of thyroid development and regulates expression of thyroperoxidase and thyroglobulin. Disruption of this gene in mice results in thyroid agenesis. 8 Pax-8, which has similar actions to TTF-1, is expressed in embryonic thyroid during descent, and heterogeneous mutations are associated with thyroid hemiagenesis. 9 TTF-2 regulates the above two genes, and disruption is associated with thyroid dysgenesis. 10 HoxA3 regulates diverse embryonic processes. Disruption of murine HoxA3 results in thyroid hypoplasia, whereas combined disruption with HoxB3 or HoxD3 results in failure of fusion of the ultimobranchial body with the thyroid. All of these genetic abnormalities appear to result in impaired thyroid descent or development.

Anomalous Development of the Thyroid
Various anomalies of the development of the thyroid gland involving the median or the lateral anlage (or both) have been described ( Table 2-1 ) (see Chapters 6 , Thyroglossal Duct Cysts and Ectopic Thyroid Tissue, and 10, Reoperation for Benign Disease ). Developmental variations involving the thyroid can be categorized under the following groups:

Table 2-1 Embryologic Anomalies of Median and Lateral Thyroid Anlages

1. Anomalies of median thyroid anlage
a. Thyroid ectopias: thyroid rests, lingual thyroid, midline ectopic thyroid
b. Thyroglossal duct cysts and fistulae
c. Pyramidal lobe
d. Agenesis/hemiagenesis
2. Anomalies of lateral thyroid anlage
a. Tubercle of Zuckerkandl
3. Anomalies of abnormal/continued descent
Moreover, when dealing with thyroid and parathyroid surgery, it is of utmost importance to have knowledge of normal and anomalous anatomy of the recurrent laryngeal nerve (RLN).

Thyroid Ectopias
Though ectopic thyroid tissue can be found between the foramen cecum and the normal position of the thyroid gland, the two most common sites of undescended thyroid glands are the lingual thyroid (90%) and anterior neck (10%) ( Figure 2-3 , A and B ). Most of them are detected in childhood and are often associated with hypothyroidism. Under the influence of continued thyroid-stimulating hormone (TSH) stimulation, they may enlarge and produce local symptoms. The ectopic thyroid tissue in the anterior neck may present as a midline mass and may be misdiagnosed as a thyroglossal cyst. 11 It is important to differentiate it from the thyroglossal duct cyst, in that it frequently represents the only source of thyroid tissue.

Figure 2-3 A, Schema illustrating some common sites for midline ectopic thyroid masses. B, A summary of the major medial and lateral embryologic elements of the thyroid gland and their potential adult anatomic consequences. C, Thyroid rests grades I through IV. D, Three grades of tubercle of Zuckerkandl development. Note also the potential for a ventrally placed RLN with a posteriorly situated tubercle.

Thyroid Rests
Thyroid rests are isolated rests of normal thyroid tissue lying below the lower pole of the thyroid within the line of the thyrothymic tract, or even within the upper anterior mediastinum (see Chapters 7, Surgery of Cervical and Substernal Goiter, and 10, Reoperation for Benign Disease ). They may also have an extension or prolongation of the thyroid tissue attached to the lower pole of the thyroid by a narrow pedicle or even just a fibrovascular band. These rests are presumably an extension of the normal embryologic descent of the thyroid after separation into right and left lobes. Thyroid rests are present in over 50% of patients (see Figure 2-3 , C ). They are located within the anterior mediastinum. They may be mistaken sometimes for small lymph nodes or even parathyroid glands, and mostly they cause no problems. The development of nodular change within such a rest or prolongation of thyroid tissue might be recognized as a large thyroid nodule quite separate from and caudal to the lower pole of the thyroid gland. If such a nodule lies even further caudal, within anterior mediastinum, following the descent of the heart and the great vessels, it might well give rise to the “isolated” mediastinal or “primary” intrathoracic goiter. The blood supply for these intrathoracic rests is usually from intrathoracic vessels. This explains why primary intrathoracic goiters may require a thoracic surgical approach (i.e., sternotomy) to achieve vascular control.
Sackett et al. 12 have suggested a classification for thyroid rests in relation to the thyroid gland (see Figure 2-3 , C ).

Grade I. Thyroid rests consists of a protrusion of thyroid tissue arising from the inferior aspect of the thyroid gland in the region of the thyrothymic ligament, recognizably distinct from the line of the lower border of the thyroid lobe.
Grade II. Thyroid rests include thyroid tissue lying within the thyrothymic tract and attached to the thyroid proper only by a narrow pedicle of thyroid tissue.
Grade III. Thyroid rests are similar to grade II but are attached to the thyroid gland only by a fibrovascular core.
Grade IV. Thyroid rests have no connection to the thyroid gland.
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Snook et al., 13 in their retrospective analysis of 3044 total or secondary total thyroidectomies performed for benign multinodular goiter in the previous 25 years, reported 11 recurrences and found 5 recurrences in the thyrothymic tract. They concluded that failure to remove embryologic remnants such as thyrothymic residue during total thyroidectomy is a cause of recurrence.

Lingual Thyroid
Failure of the descent of the thyroid gland anlage early in the course of embryogenesis results in a lingual thyroid near the foramen cecum (see Chapter 6, Thyroglossal Duct Cysts and Ectopic Thyroid Tissue ). Its applied importance is as follows:

1. In the majority of cases, the lingual thyroid may be the only functioning thyroid tissue.
2. An enlarging lingual thyroid located at the base of the tongue may present with symptoms of dysphagia, upper airway obstruction, or even hemorrhage.
3. Though rare (only 43 cases have been reported so far), 14 malignant transformation of the lingual thyroid tissue may occur.
The diagnosis of a lingual thyroid may be confirmed by radioiodine scan, which would typically reveal an increased uptake focus at the base of the tongue with no apparent activity in the normal pretracheal location of the thyroid gland in the neck. Regarding treatment, in children or young adults who are euthyroid and whose sole thyroid tissue is the lingual thyroid, no treatment would be necessary. However, more commonly these patients would develop obstructive symptoms secondary to hypertrophy of the lingual thyroid because of continuous TSH stimulation as a result of hypothyroidism. In such a situation, thyroxine supplementation or sometimes suppression would help to shrink the lingual thyroid, and surgical therapy may not be required. Rarely, in situations of continued growth and obstructive symptoms or hemorrhage, surgical removal of the lingual thyroid may be necessary.

Thyroglossal Duct Cyst
Early during the fifth week, the attenuated duct loses its lumen and shortly afterward breaks into fragments (see Chapter 6, Thyroglossal Duct Cysts and Ectopic Thyroid Tissue ). During the fifth through the seventh weeks of gestation, the hyoid bone is formed by condensation of mesoderm with subsequent chondrification from the second and third branchial arches, which grow from behind forward, dividing the thyroglossal duct tract into suprahyoid and infrahyoid portions. 15, 16 The attenuated thyroglossal duct tract usually atrophies and disappears by the end of the eighth week. This tract may persist as a fibrous cord or a minute epithelial tube, and this persisting tube/duct/cord is called a thyroglossal duct , which connects the gland and the foramen cecum. The thyroid gland may reach its normal position, leaving rests of cells anywhere along this embryonic path, and give rise to postnatal development of cysts; or it may leave rests at any level along the midline developmental pathway (sublingual, prelaryngeal, rarely suprasternal). A thyroglossal duct cyst (TDC) does not have a primary external opening, which are characteristic of some branchial cleft cysts, as the embryologic course of the tract never reaches the surface of the neck.
TDCs are the most common congenital cervical abnormalities, three times more common than branchial cleft remnants. The cyst usually presents as a painless, asymptomatic midline swelling below the hyoid bone and may be observed at any age. TDCs are present at birth in approximately 25% of cases, most are noted during childhood, and the final third become apparent after age 30. The gender incidence is equal. They can be found anywhere in the midline, from the submental region to the suprasternal notch, but are most commonly located halfway between these extremes, near the hyoid bone. Ward et al. 17 noted that 80% were juxtaposed to the hyoid bone (25% located in the submental region), 2% lingual, and 7% in a suprasternal location. Only 1% of TDCs were lateral to the midline. 17 On examination, cysts are round with a smooth surface and are well defined. With swallowing or protrusion of the tongue, it classically rises in the neck as a result of the cyst being anchored to the hyoid bone and muscles of the tongue. It is usually 1 to 2 cm in diameter, slightly mobile, and nontender unless there is superimposed infection. Oral bacteria may be transmitted through the foramen cecum. Thyroglossal duct sinuses are secondary to infection of the cyst as a result of spontaneous or surgical drainage and are associated with some degree of low-grade inflammation of the surrounding skin. The cutaneous opening is usually 1 to 3 mm in diameter and may intermittently express small droplets of thin mucoid fluid usually clear or yellowish.
Preoperative thyroid imaging and thyroid function assessment should be done in all patients with TDCs to see the normal thyroid gland. Thyroid scintigraphy can be performed in patients with presumed TDC to document the presence of a normal thyroid and to exclude the possibility of an ectopic thyroid. Preoperative high-resolution sonography can also identify a normal thyroid gland and excludes ectopic thyroid tissue.
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The operations to cure thyroglossal cysts include removal of cyst with a central portion of hyoid bone and the epithelium-lined tract, running from the cyst to the foramen cecum 18 and called as Sistrunk operation . The Sistrunk operation consists of en bloc cystectomy and central hyoidectomy, with tract excision up to the foramen cecum. In Sistrunk's original report, 31 TDCs were encountered among 86,000 consecutive patients examined at the Mayo Clinic. Sistrunk emphasized the need to make no attempt at isolating the suprahyoid portion of the duct. “At this point the tract usually passes through the hyoid bone, although it is sometimes found passing above or below it.” 18 The index finger of the surgeon's hand can be placed in the patient's mouth, on the foramen cecum to elevate the tongue and to guide excision of the suprahyoid tract. Sistrunk observed that the excision invariably proceeds at a 45-degree angle. Although Sistrunk recommended apposition of the cut edges of the hyoid bone, it is more recently thought to be neither necessary nor wise to attempt to repair the cut ends of the hyoid, especially in a child. Drainage of the wound is warranted in the presence of acute infection or operative disruption of the cysts.
Histologically, a TDC is lined by pseudostratified ciliated columnar epithelium, squamous epithelium, or both. The supporting wall of the cyst consists of fibrous tissue and frequently contains heterotopic thyroid tissue (20%) and accumulations of other chronic inflammatory cells. Approximately 1% of TDCs may undergo neoplastic change, 85% of which are papillary adenocarcinoma. Cases of squamous cell, anaplastic, and Hürthle cell carcinoma in TDCs have been reported. 19 Usually these malignancies are discovered following a Sistrunk procedure. Widstrom's criteria for the diagnosis of primary papillary carcinoma arising in a TDC include the following 20 :

• Histologic identification of TDC demonstrates that the cyst or duct has an epithelial lining with normal thyroid follicles in the cyst wall.
• There is normal thyroid tissue adjacent to the tumor.
• Histopathologic examination of the thyroid gland reveals no signs of primary carcinoma.

Pyramidal Lobe
The pyramidal lobe is the embryologic remnant of the thyroglossal tract. The frequency of presence of pyramidal lobe varies from 55% to 76%. 21 When present it is more commonly associated with left side of the isthmus. The pyramidal lobe contains thyroid follicular cells and must be adequately identified and excised along with any fibrous remnant. If overlooked during surgery, it may cause recurrent benign nodular goiter or recurrent hyperthyroidism or malignant disease developing as either a midline or a left-sided neck swelling.

Tubercle of Zuckerkandl
The tubercle of Zuckerkandl (TZ) is a posterolateral projection from the thyroid lobe resulting at the point where lateral and the medial components fuse (see Figure 2-3 , D ) 4, 22

Applied importance
It is classified into three grades according to size: grade I, < 0.5 cm; grade II, 0.5 to 1.0 cm; and grade III, > 1 cm. Most common is the grade II tubercle, found in 60% to 70% cases.

1. A grade III tubercle can be associated with significant pressure symptoms and may be the cause of persistent symptoms after subtotal thyroidectomy.
2. TZ is intimately associated with RLN and the superior parathyroid. Enlargement of the tubercle usually occurs lateral to the recurrent laryngeal nerve—the nerve appears to pass into a cleft medial to the enlarged tubercle. An uncommon but high-risk arrangement is where the recurrent laryngeal nerve runs ventral to an enlarged tubercle (see Figure 2-3 , D ).
3. Elevation of the TZ allows safe dissection of recurrent nerve as it passes medially through a tunnel.
4. The widened prevertebral space, as seen on plain lateral x-ray of the neck, could provide an idea of the presence of an enlarged (grade II/III) TZ. 23

The Recurrent Laryngeal Nerve
The anatomic course of the recurrent laryngeal nerve is widely variable. In most cases, variability is related to the relationship between thyroid nodules and the inferior thyroid artery, as well as to precocious and variable branching. These variations will be the topic of Chapter 33 , Surgical Anatomy and Monitoring of the Recurrent Laryngeal Nerve. However, embryology can solely explain the congenital anomaly of the RLN: the nonrecurrence. It is important for thyroid surgeons to be aware of the possibility of the presence of nonrecurrent inferior laryngeal nerve (NRILN), as it may become damaged inadvertently during a thyroidectomy, causing permanent vocal cord palsy. Several published reports have described the incidence of NRILN of 0.21% to 1.6% on the right side and 0.4% on the left side. 24, 25, 33, 34

Normal Embryology of RLN
The inferior laryngeal nerves are derived from the VI branchial arch. These originate from the vagus nerves under the VI aortic arch. Subsequently, the V and the distal portion of the VI aortic arch regress, on both the right and left side, and the two laryngeal nerves remains anchored to the structures that develop from the IV arch (i.e., the right subclavian artery and the aortic arch on the left side). When the heart descends into the thorax, these arteries take with them the nerves, which then assume their normal recurrent course ( Figure 2-4 ).

Figure 2-4 Normal embryonic development of the aortic arches. The inferior laryngeal nerves are dragged down by the lowest persisting aortic arches. On the right side the inferior laryngeal nerve recurs around the fourth arch, which is the subclavian artery. On the left side the inferior laryngeal nerve recurs around the sixth arch, which is the arterial ligament.

Anomalous Development of the RLN
When the segment of the fourth right aortic arch between the origin of the right common carotid artery and the right subclavian artery disappears, the resulting break in the primitive arterial ring leads to a left-sided aortic arch, with the right subclavian artery being the last collateral ( Figure 2-5 ). In this case, the right subclavian is formed at the expense of the dorsal aorta and the seventh intersegmental artery and runs in an oblique direction (lusoria course) to the right axillary region. This atresia has two other consequences on the vascular system: the absence of the innominate artery and of the arterial segment under which the right RLN normally forms a loop. As a result, during the embryonic lengthening of the neck, the nerve branch is not attached at the thorax level and the right RLN arises from the vagus nerve at the cervical level ( Figure 2-6 ). Therefore, nonrecurrence of the RLN always results from this vascular anomaly during embryonic development of the aortic arches. 24, 26

Figure 2-5 Vascular anomalies required to observe a nonrecurrent inferior laryngeal nerve. A, On the right side, the right retroesophageal subclavian artery arises as the fourth branch of the aortic arch, after the right and left common carotid arteries and the left subclavian artery. No innominate artery is present. B, On the left side, (1) right aortic arch, (2) the left retroesophageal subclavian artery arises as the fourth branch of the aortic arch after the left and right common carotid arteries and the right subclavian artery, and (3) the arterial ligament is on the right.

Figure 2-6 Right nonrecurrent inferior laryngeal nerve. The nerve passes behind the common carotid artery, crosses the jugulocarotid groove, making a downward curve, and enters the larynx at the usual level.

Implications of Anomalous Development
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Implications of Anomalous Development
The following observations can be made from available literature:

1. Until recently, the chance of predicting the presence of an NRILN is very low. However, some clues may be provided by the presence of impairment of swallowing, 24 the presence of abnormal right subclavian artery (arteria lusoria) on a computed tomography (CT) or the demonstration of distortion of esophagus (bayonet image) caused by the retroesophageal esophagus on a barium swallow, 24, 27 or endoscopy showing presence of pulsations behind the cervical esophagus. 24, 27 Recently, it has been demonstrated that preoperative neck ultrasonography may suggest the presence of an NRILN. 27 Indeed, normal vascular anatomy implies a so-called Y sign on the side represented by the division of the innominate artery in the common carotid artery and subclavian artery. In the absence of this Y sign, an aberrant right subclavian artery (arteria lusoria) is suspected. As a consequence, in the absence of the Y sign, an NRILN should be expected. 27
2. Because of its anatomic position, an NRILN is at great risk of being damaged during surgery. In a large series, Toniato et al. 28, 29 reported a 12.9% injury rate among 31 patients with an NRILN, which is much higher than the rates of RLN described by most authors in published reports.
3. Three anatomic variants have been recognized 29 :
Type 1. The NRILN arises from cervical vagus directly and descends into the larynx at the level of the superior thyroid pole along with vessels of the superior thyroid pedicle.
Type 2A. The NRILN assesses from the cervical vagus directly and follows a transverse path parallel to and over the trunk of the ITA, at the level of the isthmus (see Figure 2-6 ).
Type 2B. The NRILN follows a transverse path parallel to and under the trunk of ITA, marking a downward curve.
4. It is relatively easy to check for the underlying vascular anomaly simply by noting the absence of an innominate artery. The throbbing from the aberrant subclavian artery can be felt in front of the vertebral plane by slipping the index finger along the edge of the esophagus.
5. An NRILN has been reported in association with ipsilateral RLN. 30 This anomaly cannot be explained from an embryologic point of view. For this reason, the coexistence of a recurrent inferior laryngeal nerve and an NRILN has been recently questioned 31 (discussed later). Indeed, only the absence of the innominate artery and the presence of an arteria lusoria may explain the presence of an NRILN.
6. Sometimes a sympathetic to inferior laryngeal anastomotic branch (SILAB), which is an anastomotic branch between the cervical sympathetic system and the RLN, may have the same diameter as the RLN. 31 The SILAB may be mistaken for an RLN or an NRILN. A surgeon who exposes the SILAB in a case where an NRILN has been identified could erroneously believe that both an RLN and an ipsilateral NRILN exist, if the SILAB is not dissected to its origin from the sympathetic chain. As a consequence, if an NRILN is suspected, it should be dissected throughout its course to expose its origin from the vagus nerve. Large SILABs occur much more frequently than NRILNs, and thus the implications of this anatomic condition are of utmost importance during thyroid surgery in terms of correct RLN identification. Neural electric stimulation helps significantly in these visual neural dilemmas (see Chapter 33, Surgical Anatomy and Monitoring of the Recurrent Laryngeal Nerve ,).
7. The existence of an NRILN and its potential implications in cases of damage has led to the dictum “no structure passing medially from the carotid sheath except the middle thyroid veins should be divided until after the nerve is identified.” Indeed, the middle thyroid vein passes anterior to the common carotid artery, whereas the RLN merges from the vagus in a plane that is posterior to the common carotid artery.

Applied Embryology of the Parathyroid Glands
The parathyroid glands vary considerably in size, shape, number, and location. This wide variability represents a unique challenge for surgeons dealing with parathyroid diseases. Information as to their adult location resides in their embryologic development. Indeed, the developmental embryology and surgical anatomy of the parathyroids are intimately linked. For this reason, a detailed understanding and knowledge of the embryologic development, and consequently of possible anatomic variations of the parathyroid glands, are prerequisites for devising a successful surgical strategy for patients with hyperparathyroidism and preserving parathyroid glands during thyroid surgical procedures.

Generalities
The parathyroid glands develop from the third and fourth pharyngeal pouches in humans between the fifth and the twelfth week of gestation. 32
The inferior parathyroid glands originate from the third pharyngeal pouches (see Figure 2-1 ) and are named parathyroid III (PIII) to recall their origin. 33 The thymus originates from the ventral portion of the same branchial pouch. This common origin justifies indicating the PIII as the thymic parathyroid. 34 The PIII and thymus complex has also been termed the parathymus. 33 The parathymus complex has a relatively long caudal descent to reach the final anatomic position.
The superior parathyroid glands arise from the dorsal portion of the fourth branchial pouches (see Figure 2-1 ) and are thus named parathyroid IV (PIV). 33 The fate of the PIV and of the derivatives of the fourth pharyngeal pouches are related to those of the fifth pouches. 33 The fifth pouch is usually rudimentary or vestigial, is incorporated in the fourth pharyngeal pouch, and contributes to the formation of the ultimobranchial bodies (lateral thyroid). The fourth and the rudimentary fifth pharyngeal pouches together are sometimes indicated as the caudal pharyngeal complex . This includes the primordium of PIV (dorsal portion), a ventral diverticulum (which corresponds in position to the thymus portion of the third pouch), and an ultimobranchial body derived mainly from the fifth pouch. Although the fate of the ventral diverticulum is not certain in humans, it could gives rise to a small amount of thymus tissue (rudimentary thymus IV), which, soon after its formation, disappears. 35, 36 Fatty lobules, which are seldom encountered in conjunction with the PIV at their normal site, could constitute the vestigial remnants of this thymic tissue that have not completely disappeared. 37 Because of the common origin with the lateral thyroid, the PIVs are sometimes indicated as thyroid parathyroids , analogous to the thymic parathyroid of PIII. 34
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It has been “classically” retained that the parathyroid glands are endodermal in origin, arising as proliferations of the dorsal tip of the endoderm of pharyngeal complexes III and IV (or caudal pharyngeal complex). However, there were indications that at least a part of thymus rudiment is derived from the ectodermal cells of the branchial grooves. 38 Indeed, evidence has been presented that, with the contact of the endodermal with ectodermal cells at the pharyngeal membrane, ectoderm is incorporated into the epithelial primordium. 39, 40 Experimental studies in chick embryos have demonstrated that integrity of the ventral ectoderm of the third branchial arch is necessary for the development of PIII. 41 Moreover, the classical embryologic interpretation could not explain the involvement of the parathyroid glands in multiple endocrine neoplasia (MEN) type 2 syndrome, where patients present with tumors of endocrine cells of neuroectodermal origin. 42 - 44 For this reason, an origin from the ectoderm of pharyngeal clefts III and IV has been proposed, rather than from the endoderm of the third and fourth pharyngeal pouches. 42 - 46
Recent experimental findings seem to indicate that both foregut endoderm and cells originating from the neural crest of rhombomere 6 and 7 may contribute to the anlage of parathyroid glands. 47 The neural crest originates at the apposition of neuroectoderm and ectoderm during the formation of the neural tube. Therefore, neural crest cells have to migrate toward the foregut endoderm first before they can add to the anlage of the parathyroids. The neural crest of rhombomere 6 should migrate toward the third branchial arch, whereas the fourth branchial arch should be primarily invaded by neural crest cells from rhombomere 7. 47 Signals from ectomesenchymal neural crest cells populating the pharyngeal arches may be required for the differentiation, migration, and survival of pharyngeal glandular organs. 48, 49 Nonetheless, it is important to keep in mind that in mammals the transcription factor glial cell missing 2 (GCM2) (which is homologous to the human GCMB, the expression of which is essential for parathyroid gland development, as discussed later) has been located in the endoderm, whereas in fish it is expressed in the ectoderm. 33

Genetic Control and Evolutionary Model
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Genetic Control and Evolutionary Model
The development of parathyroid glands can be schematically separated into formation of the parathyroid anlage, migration toward their final destination, and differentiation into parathyroid hormone (PTH)–secreting cells. Recent researches, using human mutations and genetically modified mouse models, have partially elucidated the cascade of genes that controls these steps. These genes include a gcm2/GCMB, Pax1 and Pax9, Hoxa3, Tbx1, GATA3, TBCE, Sox3, Eya1 and Six1/4. 32 Many of these regulatory genes are expressed from fish to mammals. However, the emergence of the parathyroid gland is an evolutionary modification that is believed to have been of great importance to the emergence of the tetrapods. 50 The evolution of the tetrapods and the shift from an aquatic to a terrestrial environment were believed to have required a new control system for regulating calcium homeostasis. For this reason, the development of the parathyroid glands seem to be a key event in the evolution for facilitating this transition. 50, 51

Histogenesis
The epithelium of the dorsal portion of the third and fourth pharyngeal pouches proliferates during the fifth week and produces small nodules dorsally to each pouch. In these nodules, the proliferation of the vascular mesoderm begins and produces a network of capillaries.
Chief cells differentiate during the embryonic development. It is commonly thought that they become functionally active for the regulation of the calcium homeostasis during the fetal life. Oxyphilic cells differentiate at 5 to 7 years of life (see Chapter 70, Surgical Pathology of the Parathyroid Glands ). 52
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The first capillaries are observed in the fifth week. 53 Blood supply is increased in the middle of pregnancy and is extremely abundant at the end of gestation as well as during the first year of life. 53 Recent studies revealed the early appearance of intercellular lymph spaces (fifth week) in the parathyroid primordia.

Development Process
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Development Process
Based on the classic paper by Norris and others, 54, 55 the development of parathyroid glands in humans can be divided into five stages.
The preprimordial stage indicates the period between the formation of the pharynx and the earliest appearance of a recognizable parathyroid anlage. During this stage, at 4 to 8 mm in length, the third and fourth pharyngeal pouches show a slight dorsal extension. The third pouch, which has the form of a tubelike lateral expansion of the primitive pharynx, makes contact with the ectoderm of the pharyngeal cleft and then continues its growth in a downward and ventral direction.
During the following stage, the early primordial stage (see Figure 2-1 ), when the embryo is about 9 mm in length, the parathyroid tissue can be recognized. Proliferation and differentiation of large, clear cells occur in the third and fourth pouches, resulting in a thickening of the third and fourth pouches and formation of a budlike nodule of the fourth pouch.
During the branchial complex stage, the derivatives of the third and fourth pharyngeal pouches become separated from each other to reach independent positions. During the early phase of this stage, the pharyngeal pouches are still joined to the primitive pharynx by pharyngobranchial ducts. These latter, subsequently, narrow and finally divide, which determines the definitive separation of the third and caudal pharyngeal complexes from the primitive pharynx. At the beginning of this stage, the primordial thymus and PIII are intimately joined. Subsequently, the thymus begins a period of rapid ventral growth, until the lower pole comes in contact with the pericardium. On the other hand, the growth of the PIII is not as rapid, and it remains a budlike projection from the superior end of the thymus cord. Finally, it takes a sphere shape, intimately attaching to the upper pole of the thymus cord. The position of the caudal pharyngeal complex in relation to the median anlage of the thyroid depends on changes in form, size, and position of the rapidly growing lateral lobe of the median thyroid. During this stage, the PIV rudiment is still attached to lateral thyroid body. When the embryo is 13 to 14 mm long (see Figure 2-2 ), the PIII and PIV migrate together with the thymus and ultimobranchial bodies, respectively. Because of the extension of the cervical spine and the descent of the heart and great vessels, the complex derived from the third branchial ( parathymus ) is drawn toward the superior mediastinum and, thus, migrates in a medial and caudal direction through the entire length of the embryonic neck to reach its final position, and separation of the PIII from the thymus begins. The PIV follows the thyroid migration of the ultimobranchial bodies, which travel toward the lateral part of the main median thyroid rudiment. Their descent in the neck is thus relatively limited. They remain in contact with the posterior part of the middle third of the thyroid lobes. The complex branchial stage ends when the embryo is approximately 18 to 20 mm in length.
The isolation stage is characterized by the separation of the parathyroid rudiments (PIII and PIV) from the other elements of the third (the thymus) and of the caudal pharyngeal complexes (the ultimobranchial bodies), respectively. The isolation of the parathyroid glands is usually accomplished when the embryo is 20 mm in length. After completing the descent through the neck, the PIII increases in size and separation from the thymus occurs, because of cephalic regression of the last. PIII is thus abandoned at the level of the anterior or posterolateral region of the inferior poles of the thyroid lobes, or at the level of the thyrothymic ligaments, vestigial structures indicative of their former connections. The two elements of the caudal pharyngeal complex also grow separately and are conjoined by a connecting stalk. The interruption of this stalk, determining the isolation of the PIV, occurs once the lateral and the median thyroid become incorporated. The final position of the PIV in relation to the thyroid gland is determined by the place at which the inclusion of the ultimobranchial body ( lateral thyroid element ) occurs.
The definitive form stage indicates the period from the end of the isolation to the time when the parathyroids assume their definitive form.

Position of Normal Parathyroid Glands, Anomalies of the Embryologic Migration, and Congenital Ectopias
Because of the limited embryologic migration, the PIVs are relatively constant in their position. In more than 80% of the cases, the PIVs are located on the posterior aspect of the thyroid lobe, in an area 2 cm in diameter centered 1 cm above the intersection of the inferior thyroid artery and the recurrent laryngeal nerve, 56 - 58 in strict proximity with the cricothyroid junction (i.e., the junction of the cricoid and thyroid cartilage) 59 ( Figure 2-7 ). The PIV often has a surrounding halo of fat and is freely mobile on the thyroid capsule. The surrounding fat may represent atrophic thymic tissue originating from the ventral diverticulum. 35, 36 Occasionally, the PIVs are closely associated to the thyroid capsule. 58 In about 15% of the cases, the PIVs are located on the posterolateral surface of the superior thyroid pole, 37, 57 - 60 hidden between the layers of perithyroidal fascia. In such cases, it is bound on the posterolateral aspect of the thyroid lobe and is therefore less mobile. 59 The PIV could also be located further in a caudal position, sometimes partially obscured by the recurrent laryngeal nerve, inferior thyroid artery, or tubercle of Zuckerkandl. 58 They may be found even further down, at a considerable distance posterior to the lower thyroid pole. 58

Figure 2-7 The area of dispersal of the PIVs is limited by their short embryonic course.
In less than 1% of the cases, they may be located higher, above the upper thyroid pole. 58 Rarely (up to 3% to 4% of the cases), normal PIVs are found more posterior in the neck in a retropharyngeal or retroesophageal location, 57, 58 whereas pathologically enlarged parathyroid glands may be found in a retropharyngeal of retroesophageal position in up to one third of the cases, as the result of migration related to the parathyroid weight 60 (see the discussion of acquired ectopic localization, presented later). Major ectopic locations of PIV are rare. They may result from descent failure or laterally directed descent and may lead to a superior parathyroid gland adjacent to the common carotid artery. 59 An exceptional superior parathyroid adenoma located in the scalene fat pad lateral to the carotid has been described. 60 These locations account for less than 1% of the cases. 59 Superior parathyroid glands are sometimes found in a subcapsular position or hidden by a cleft of thyroid capsule. True intrathyroidal superior glands are rare and less frequent than PIII, even if the PIV may become included within the thyroid at the time of fusion of the ultimobranchial bodies with the median thyroid rudiment (see the discussion of intrathyroidal parathyroid glands, presented later). 57, 58, 60 If the superior parathyroid primordium fails to separate from the remaining endoderm of the fourth pharyngeal pouch, it may migrate to a retropharyngeal location with the pyriform sinus primordium. 61 A few cases of pathologic parathyroid glands localized in the pyriform sinus have been described. 62
Because of the longer embryologic migration, the territory of normally located PIII is much more widely distributed, and they are more likely to be ectopic than PIV ( Figure 2-8 ). In about half of the cases (42% to 61%), they are located at the level of the inferior pole of the thyroid lobe, on the anterior, lateral, or posterior aspect. 57, 67 The gland typically rests in a fat lobule on or adjacent to the inferior pole. In some cases, PIIIs are located high up, on the posterior surface of the thyroid lobe, closely attached to the thyroid capsule. In such a position, they can be confused with PIVs. 34, 37 A few glands are more deeply hidden in a crease of the thyroid lobe, mimicking an intrathyroidal gland. 57, 58 In about one quarter of the cases, the PIII is located in the thyrothymic ligament or in the cervical portion of the thymus. 58

Figure 2-8 The area of dispersal of the PIII extends from the angle of the mandible to the pericardium.
As the pathway of embryologic descent of the thymus extends from the angle of mandible to the pericardium, anomalies of migration of the parathymus complex , whether excessive or deficient, are responsible for high or low ectopias of PIIIs. 34, 37 When the parathymus complex fails to descend fully, the inferior parathyroid may become stranded high in the neck, typically along the carotid sheath. Thus, during parathyroid exploration if the inferior gland is missing, it is usually found with a fragment of thymic tissue above the thyroid gland and superior to the PIV. 58, 63 Often the gland is situated adjacent to the carotid bifurcation, approximately 2 to 3 cm lateral to the thyroid superior pole. 57, 59 The undescended PIII can be found even higher in the neck, above the carotid bifurcation, adjacent to the angle of the mandible, near the hyoid bone. In all these cases, the superior thyroid vessels would provide vascularization. The incidence of this high ectopia resulting from defective embryologic descent of the parathymus does not seem to exceed 1% to 2%. 37, 57, 63 On the other hand if the separation from the thymus is delayed, the PIII may be pulled down in the anterior mediastinum to a varying degree (see Figure 2-8 ). In approximately 4% to 5% of cases, the inferior parathyroid gland is situated in the chest, within the retrosternal thymus, or at the posterior aspect of its capsule or in contact with the great mediastinal vessels (the innominate vein and ascending aorta). Only a few are located outside the thymus adjacent to the aortic arch and the origin of the great vessels. An even lower position results in the inferior parathyroid being in contact with the pleura or pericardium. 64 Most of the ectopic PIIIs, which descend below the level of the innominate vein and aortic arch, develop an ectopic arterial blood supply. Generally, this is derived from the internal mammary artery. Occasionally the blood supply may come from a thymic artery or a direct branch from the aorta. 65
The inferior parathyroid gland is truly intrathyroidal within the lower pole of thyroid in 1% to 3% of individuals (see the discussion of intrathyroid parathyroid glands, presented later).

Parathyroid Symmetry
Although the location of individual glands can vary considerably, there is often marked symmetry of the parathyroid glands. 58 Symmetry of the PIV is found in approximately 80% of the cases, whereas only 70% of the inferior glands are symmetric. Relative symmetry of both PIV and PIII glands is reported in about 60% of the cases. 58 Symmetry is less marked when glands are located in an unusual site. The awareness of parathyroid symmetry may facilitate parathyroid gland identification during surgical neck exploration, and the surgeon should keep this in mind when performing thyroid and parathyroid procedures.
The most common asymmetric location is one in which only one of the PIII is located in the thymus. Another asymmetric position is when both glands on one side are located above or below the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. 58 Indeed, the PIVs are crossed by the PIII during their descent. This embryologic crossing explains why the PIII and PIV can be very closely associated at the level of the inferior thyroid artery, at the junction of the middle and inferior thirds of the thyroid lobe, depending on the extent of migration of the PIII. Because of this crossing, in some cases both homolateral parathyroids may be at the same level, corresponding to the parathyroids in the midposition of Grisoli. 34, 37 In such cases, it is sometimes virtually impossible to distinguish the PIII and PIV. 34, 37, 58 In rare cases, the two glands are adherent to each other and appear to be fused. 34, 37, 55 This condition is known as kissing pairs . 55, 57 It is possible to differentiate this condition from a bilobated gland because of the presence of a cleavage line and a separate vascular pedicle in the kissing pair. It is essential to carefully identify these pedicles during parathyroid procedures, so as not to confuse a bilobar gland with adjacent parathyroids. Such confusion may be a source of error in assessing the findings of a surgical exploration, because surgeons may erroneously conclude that they have identified all four glands.

Intrathyroidal Parathyroid Glands
Parathyroid glands may have an intrathyroidal location. A true intrathyroidal parathyroid is defined as a gland that is completely surrounded by thyroid tissue and should be differentiated by subcapsular parathyroid glands and those that are buried in a crease of thyroid capsule. 57, 58, 60
The incidence of intrathyroidal parathyroid glands is between 0.5% and 4%, 57, 58, 60, 66 and their frequency seems to be higher in case of hyperfunctioning glands. Recent reports have shown their prevalence to be on the right side and the inferior portion of the thyroid lobe. 67
The origin of this entity has not been completely elucidated yet. Indeed, based on parathyroid embryology, one should expect that the intrathyroidal gland would be represented by PIV glands included within the thyroid when the ultimobranchial bodies fuse with the median thyroid rudiment. 57 However, several authors have found that intrathyroidal glands are primarily inferior parathyroid glands. 60, 66, 68 In particular, Thompson et al. 60 carefully sliced all thyroid lobectomy specimens during a one-decade period and found truly intrathyroidal glands in 3% of the cases. Because all of these glands were located in the lower third of the thyroid lobe, they were considered inferior parathyroid glands, even if recent findings have questioned that parathyroids located in the lower third of the thyroid lobe should always be considered PIII gland by definition; but could, however, also represent excessively migrated PIVs. 67 According to Gilmour, 35 the intrathyroidal inclusion of parathyroid tissue originating from the third pharyngeal pouch may be found with the same incidence as inclusions of thymic tissue. Indeed, although the main portion of the thymus moves rapidly to its definitive position in the thorax, its tail portion becomes thin and eventually breaks into small fragments that sometimes persist embedded in the thyroid gland.
It is now accepted that intrathyroidal parathyroid glands can be either PIII or PIV and even supernumerary glands. 67 - 72 The possibility of an intrathyroid parathyroid adenoma justifies careful palpation of the thyroid parenchyma during an operation for hyperparathyroidism when a gland, both inferior and superior, is missing. Preoperative 67 or even intraoperative ultrasonography 37 may be helpful in intrathyroidal gland identification when it is pathologic. Intraoperative PTH measurement after careful thyroid lobe palpation may reveal a rise in PTH levels and thus indicate a pathologic intrathyroidal gland. Generally, subcapsular parathyroid adenomas, hidden just beneath the thyroid capsule, may be revealed by a localized discoloration of the surface of the thyroid parenchyma. Simple incision of the thyroid capsule at this site, which darkens progressively during the dissection, allows dislodgment of the adenoma. True intrathyroidal hyperfunctioning parathyroid glands require thyroidotomy. A plane of cleavage always exists between the thyroid and the parathyroid, so it is usually possible to enucleate the gland. Even if recent reports have indicated a lower incidence of the recurrence of hyperparathyroidism in patients undergoing thyroid lobectomy, 67 one should be reluctant to perform a blind thyroid lobectomy. 37, 59, 60 Nevertheless, when suspicion remains high and incision has failed to locate the lesion, thyroid lobectomy on the appropriate side is clearly indicated.

Anomalies in Parathyroid Number: Infranumerary and Supernumerary Glands
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Anomalies in Parathyroid Number: Infranumerary and Supernumerary Glands
Autopsy studies of persons without hyperparathyroidism showed that fewer than four parathyroid glands are found in 3% to 6% of the cases. 57, 58 However, one should consider that this figure could at least in part be determined by a failure to identify all the glands rather than a true alteration in parathyroid gland development. 57, 64 On the other hand, autopsy series report more than four gland in 5% to 13% of the cases. 58, 73, 74 Up to 11 parathyroids has been counted in a single subject. 57, 75
In contrast, operative series in patients with renal failure report incidences of 25% to 30%. 73, 76 A recent surgical report favors a higher rate (> 30%) of microscopic embryonic parathyroid rests in the absence of renal failure or diffuse parathyroid hyperplasia. 73 These supernumerary parathyroid glands develop from accessory parathyroid fragments arising from the pharyngotracheal duct when the pharyngeal pouches separate from the pharynx. 34 It is conceivable that in the migratory process, parathyroid cells may split from the main migratory mass, and an ectopic microscopic rest of parathyroid tissue results. 73
It is important to differentiate between the small rudimentary rests of parathyroid tissue derived from embryologic parathyroid debris and true supernumerary glands. The former weigh less than 5 mg compared with true supernumerary glands, which, on average, weigh 24 mg. 58 In addition, the continuous growth stimulation in both primary and secondary parathyroid hyperplasia may stimulate these rudiments of parathyroid glands to grow, and many of them may thus appear as proper supernumerary glands. 58, 75
Rudimentary glands may be hidden in the perithyroid fatty tissue, usually close to the main gland. True supernumerary glands only occur in 5% of cases and occupy a location completely separate from the four normally situated glands. In most cases they are located within the thymus or thyrothymic ligament below the thyroid gland, close to the inferior thyroid pole. Therefore, routine removal of the thymic tongues and careful examination and clearance of fatty tissue around the lower poles of the thyroid are important steps in the surgical treatment of patients with more virulent forms of hyperparathyroidism such as secondary hyperparathyroidism or hyperparathyroidism associated with MEN type I. 75, 77
In some individuals, a fifth gland occurs due to splitting of abnormal or bilobed glands during development. 58 The two components lie close together and are often in direct contact with each other.
Supernumerary glands may also be situated in exceptional ectopic positions. In such localizations, they are usually found when they are pathologic and responsible for hyperparathyroidism. Pathologic parathyroid glands have been found lateral to the jugular carotid complex, 78 within the piriform fossa, 79 in the aortopulmonary window 80 - 82 and deep in the thorax within the middle mediastinum. In one case, a pathologic parathyroid gland was identified between the right main bronchus and right pulmonary artery. 80 The migration of pathologic tissue seems improbable in such cases; rather, a precocious fragmentation of PIV should be suggested. 79, 80 A recent multi-institutional clinical study favored an origin of parathyroid glands in the aortopulmonary window from a precocious fragmentation of the PIV. 83
Following the initial description by Gilmour in 1941, 84 Lack et al. 85 reported cellular aggregation of intravagal parathyroid cells in 3 out 32 subjects (9%) aged less than 1 year who underwent autopsy studies. This parathyroid tissue was found in the epineurium or in the perineurium or even conglobated in the nervous tissue (6% of the cases). 85 Sporadic reports of intravagal hyperfunctioning (adenoma and hyperplasia) parathyroid tissue have been published. 86 - 92 The origin of this supernumerary or accessory parathyroid tissue has not been explained yet. Nonetheless, it has been hypothesized that this aberrant tissue may arise from the third branchial pouch, which during embryogenesis is closely related to the vagus nerve, which originates from the third and fourth pharyngeal arches. 85 - 91 Parathyroid tissue arising from the third branchial pouch may split off and become embedded in or adjacent to the vagus during embyogenesis. 91 Thus, intravagal parathyroid tissue invariably represents accessory or supernumerary tissue.
An exceptional localization of a supernumerary hyperplastic gland in the sternohyoid muscle of a patient with MEN 1 syndrome has been recently reported. 93 The embryologic explanation of this intriguing localization has not yet been offered.
The presence of ontological parathyroid rest may also explain the occurrence of parathyromatosis in absence of previous surgical exploration. 73 The term parathyromatosis refers to the finding of multiple nodules of parathyroid tissue scattered through the neck or mediastinum and can be responsible for cases of recurrent hyperparathyroidism. However, a few cases of parathyromatosis during first neck exploration for hyperparathyroidism have been reported, 94, 95 suggesting an overgrowth of parathyroid rests ( ontogenic parathyromatosis ) in response to unknown proliferation stimuli. 73

Acquired Ectopic Localization
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Acquired Ectopic Localization
Besides ectopias resulting from variability or alteration in embryologic development, in some cases pathologically enlarged glands may have an ectopic position because of the migration following enlargement. Indeed, enlarged glands may migrate under the influence of gravity and the regional dynamics, namely the movement of the larynx and pharynx during swallowing, a suction phenomenon caused by negative intrathoracic pressure and permissive cervical-mediastinal planes. 60 An enlarged gland may then leave its proper site and acquire a progressively ectopic site. These migrations depend on the initial topography of the gland before it becomes enlarged. For this reason, PIVs that are relatively constant in their site, in the cricothyroid area, frequently migrate in the superior posterior mediastinum, posterior to the trunk of the inferior thyroid artery along the prevertebral plane. They may glide more or less downward. During this course they usually remain in very close contact with the esophagus. This “acquired” ectopia explains why whereas 1% to 4% of the normal PIVs are in para- or retroesophageal positions, 40% of the PIV adenomas are found in posterior locations. 60 Usually the adenomatous glands are at the level of the inferior lobes of the thyroid just above the trunk of the inferior thyroid artery. Sometimes, the adenoma is straddled or actually embraced by the artery. In other cases, the adenoma is frankly mediastinal, either very posterior, beside or behind the esophagus, or in the tracheoesophageal angle. In all cases, these enlarged glands, even if situated very low in the posterior mediastinum, retain a cervical blood supply arising from the thyroid system. This descending cervical pedicle indicates their initial site and facilitates their excision through the cervical incision even if deeply migrated, without risk of hemorrhage. Traction over the descending pedicle allows the descended adenoma arising from the PIV to be safely lifted up.
Adenomas developed from PIII are, it is thought, less prone to this kind of migration, probably because the adjacent anatomic structures are less favorable to gravity-induced displacement. Usually migration of pathologic PIII occurs toward the anterior superior mediastinum, into and through the thyrothymic ligament and thymus. However, this descent appears limited. More rarely, if the pathologic PIII gland was initially located at the posterolateral part of the lower pole of the thyroid lobe, its enlargement may lead to descent into the posterosuperior mediastinum 96, 97 to acquire a paraesophageal position. In these cases, unlike the adenomas developed from PIV, the vascular pedicle does not cross the trunk of the inferior thyroid artery.
It is generally felt that congenital ectopias caused by abnormal embryologic migration usually affect the PIII, whereas acquired ectopias, determined by migration of pathologically enlarged glands under the influence of gravity, usually affect the PIV.

References
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63 Edis A.Y., Purnell D.C., van Heerden J.A. The undescended “parathymus.” An occasional cause of failed neck exploration for hyperparathyroidism. Ann Surg . 1979;190:64–68.
64 Wheeler M.H. Clinical anatomy, developmental aberrations and endocrinology. In: Arora A., Tolley N.S., Tuttle R.M. A practical manual of thyroid and parathyroid disease . Chichester, West Sussex, UK: Wiley-Blackwell, John Wiley & Sons Ltd; 2010:181–188.
65 Doppman J.L., Marx S.J., Brennan M.F., et al. The blood supply of mediastinal parathyroid adenomas. Ann Surg . 1977;185:488–490.
66 Wheeler M.H., Williams E.D., Path F.R., et al. The hyperfunctioning intrathyroidal parathyroid gland: a potential pitfall in parathyroid surgery. World J Surg . 1987;11:110–114.
67 Ros P.S., Sitges-Serra A., Pereira J.A., et al. Adenomas paratiroideos de localización intratiroidea: derechos y bajos. Cir Esp . 2008;84:196–200.
68 Proye C., Bizard J.P., Carnaille B., et al. Hyperparathyroidism with intrathyroidal parathyroid gland: a review of 43 cases. Ann Chir . 1994;48:501–506.
69 Bainbridge E.T., Barnes A.D. Primary hyperparathyroidism due to overactive intrathyroid parathyroid glands: a potential cause of failed exploration. Br J Surg . 1982;69:200–202.
70 Kobayashi T., Man I.M., Shin E., et al. Hyperfunctioning intrathyroid parathyroid adenoma: report of two cases. Surg Today . 1999;29:766–768.
71 Bahar G., Feinmesser R., Joshua B.Z., et al. Hyperfunctioning intrathyroid parathyroid gland: a potential cause of failure in parathyroidectomy. Surgery . 2000;139:821–826.
72 Libutti S.K., Bartlett D.L., Jaskowiak N.T., et al. The role of thyroid resection during reoperation for persistent or recurrent hyperparathyroidism. Surgery . 1997;122:1183–1187.
73 Aly A., Douglas M. Embryonic parathyroid rests occur commonly and have implications in the management of secondary hyperparathyroidism. ANZ J Surg . 2003;73:284–288.
74 Vail A.D., Coller F.C. The parathyroid glands. Clinicopathologic correlation of parathyroid disease as found in 200 unselected autopsies. Mo Med . 1967;63:234–238.
75 Numano M., Tominaga Y., Uchid K., et al. Surgical significance of supernumerary parathyroid glands in renal hyperparathyroidism. World J Surg . 1998;22:1098–1103.
76 Pattou F., Pellissier L., Noel C., et al. Supernumerary parathyroid glands: frequency and surgical significance in the treatment of renal hyperparathyroidism. World J Surg . 2000;24:1330–1334.
77 Kraimps J.L., Duh Q.Y., Demeure M., et al. Hyperparathyroidism in multiple endocrine neoplasia syndrome. Surgery . 1992;112:1080–1086.
78 Udekwu A.O., Kaplan E.L., Wu T.C., et al. Ectopic parathyroid adenoma in the lateral triangle of the neck: report of two cases. Surgery . 1987;101:114–118.
79 Joseph M.P., Nadol J.B., Goodman M.L. Ectopic parathyroid tissue in the hypopharyngeal mucosa (piriform sinus). Head Neck Surg . 1982;5:70–74.
80 Curley I.R., Wheeler M.H., Thompson N.W., et al. The challenge of the middle mediastinal parathyroid. World J Surg . 1988;12:818–824.
81 McHenry C., Walsh M., Jarosz H., et al. Resection of parathyroid tumor in the aortopulmonary window without prior neck exploration. Surgery . 1988;104:1090–1094.
82 Proye C., Lefebvre J., Bourdelle-Hego M.F., et al. Middle mediastinal parathyroid adenoma of the aorto-pulmonary window: 2 cases. Chirurgie . 1988;114:166–173.
83 Arnault V., Beaulieu A., Lifante J.C., et al. Multicenter study of 19 aortopulmonary window parathyroid tumors: the challenge of embryologic origin. World J Surg . 2010. [Epub ahead of print] DOI 10.1007/s00268-010-0622-1
84 Gilmour J.R. Some developmental abnormalities of the thymus and parathyroids. J Pathol Bacteriol . 1941;52:213–218.
85 Lack E.E., Delay S., Linnoil R.I. Ectopic parathyroid tissue within the vagus nerve: incidence and possible clinical significance. Arch Pathol Lab Med . 1988;112:304–306.
86 Doppman J.L., Shawker T.H., Fraker D.L., et al. Parathyroid adenoma within the vagus nerve. AJR . 1994;163:943–945.
87 Reiling R.B., Cady B., Clerkin E.P. Aberrant parathyroid adenoma within the vagus nerve. Lahey Clin Bull . 1972;21:158–162.
88 Takimoto T., Okabe Y., Ito M., et al. Intravagal parathyroid adenoma. J Laryngol Otol . 1989;103:704–706.
89 Buell J.F., Fraker D.L., Doppman J.L., et al. High cervical intravagal hypercellular parathyroid gland as the etiology of severe persistent primary hyperparathyroidism. Am Surg . 1995;61:943–946.
90 Raffaelli M., Defechereux T., Lubrano D., et al. L'ectopie parathyroïdienne intravagale. Ann Chir . 2000;125:961–964.
91 Pawlik T.M., Richards M., Giordano T.J., et al. Identification and management of intravagal parathyroid adenoma. World J Surg . 2001;25:419–423.
92 Hung C., Lin P., Lee P., et al. Supernumerary intravagal parathyroid hyperplasia. Surgery . 2002;131:359–361.
93 Miura D. Ectopic parathyroid tumor in the sternohyoid muscles: supernumerary gland in a patient with MEN type 1. J Bone Miner Res . 2005;20:1478–1479.
94 Reddick R.L., Costa J.C., Marx S.J. Parathyroid hyperplasia and parathyromatosis. Lancet . 1977;1:549.
95 Palmer J.A., Brown W.A., Kerr W.H., et al. The surgical aspects of hyperparathyroidism. Arch Surg . 1975;110:1004–1007.
96 Wang C.A. Parathyroid re-exploration. A clinical and pathological study of 112 cases. Ann Surg . 1977;186:140–145.
97 Wang C., Gaz R.D., Moncure A.C. Mediastinal parathyroid exploration: a clinical and pathologic study of 47 cases. World J Surg . 1986;10:687–695.
98 Adapted fromGray S.W., Skandalakis J.E. Embryology for surgeons , ed 2. Baltimore: Williams & Wilkins; 1993.
Chapter 3 Thyroid Physiology and Thyroid Function Testing

Stephanie L. Lee

Introduction
The lifetime risk of developing thyroid dysfunction is common. 1, 2 Subclinical and overt hypothyroidism 3, 4 occurs in 4.6% to 9.5%, whereas subclinical and overt hyperthyroidism 1, 3, 4 occurs in 1.3% to 2.2% of the population. Thyroid disease occurs in women two to three times more commonly than men. 1, 3 - 5 Thyroid dysfunction has a variable clinical presentation depending on the age of the patient, degree of dysfunction, concomitant disease, and duration of disease, making the clinical diagnosis difficult. Fortunately, the presence of thyroid dysfunction can be easily confirmed biochemically. Although there are many tests, including biochemical serum tests and imaging studies, the clinical picture, together with the judicious use of a limited number of the tests recommended in this chapter, can be used to diagnose most of the thyroid illnesses encountered by primary care physicians and specialists in ambulatory care. This chapter reviews the basics of thyroid testing, including imaging of the thyroid gland, and develops a straight forward approach to the diagnosis of hypothyroidism and hyperthyroidism and the laboratory tests used for monitoring the course of differentiated thyroid carcinoma.

Thyroid Physiology
The basic functional unit of the thyroid is a follicle. The follicle is a single layer of cells that forms a sphere that surrounds a protein aggregate called colloid. Thyroid follicular cells are polarized with the side toward the colloid called the apical membrane and the outer side of the cell in contact with capillaries at the basal membrane ( Figure 3-1 ). The synthesis of thyroid hormone is activated after binding of thyrotropin-stimulating hormone (TSH) to the basal membrane surface receptor, the TSH receptor. TSH stimulates all the steps of thyroid hormone synthesis and secretion, including iodide transport, synthesis of thyroglobulin, iodination of thyroglobulin, and secretion of thyroid hormones. TSH binding of the receptor activates adenylate cyclase to increase intracellular cAMP, which activates a cascade of numerous steps in the thyroid hormone synthetic pathway (see Figure 3-1 ). 6 The first step is transport of iodide across the basal membrane into the follicular cell in an energy-dependent manner by the Na + /I symporter. 7, 8 The iodide becomes covalently attached to the precursor thyroid hormone glycoprotein, thyroglobulin at the interface between the apical membrane and the colloid by the enzyme thyroperoxidase (TPO). The iodide is attached to the tyrosine molecules in the thyroglobulin molecule to form monoiodotyrosines (MITs) and diiodotyrosines (DITs) ( Figure 3-2 ). TPO enzymatically couples two iodotyrosines to create bioactive thyroid hormones, L-thyroxine (T4) and triiodothyronine (T3) (see Figure 3-2 ). The T4 and T3 remain part of the thyroglobulin molecule and is stored as colloid within the interior of the follicle. The thyroid gland is a unique endocrine organ because it stores large amounts of thyroid hormones as colloid that is released as needed through TSH stimulation. In healthy and iodine-sufficient individuals, the majority of thyroid hormone is stored as T4 with a small amount, less than 20%, stored as T3. TSH receptor stimulation leads to colloid uptake into the cytoplasm by pinocytosis to form a cytoplasmic vesicle (see Figure 3-1 ). The cytoplasmic vesicles fuse with lysosomes and proteases hydrolyze the peptide bonds of thyroglobulin to release T4 and T3 (see Figure 3-2 ) into the cytoplasm where it diffuses into the bloodstream. Approximately 90 mcg of T4 is secreted from the thyroid each day in adults. T4 and T3 travel in the circulation bound 99.97% and 99.5%, respectively, to a group of serum thyroid hormone binding proteins synthesized in the liver, which include thyroxine binding globulin (TBG), transthyretin (also known as prealbumin), and albumin. TBG has the highest affinity to bind thyroid hormone and is clinically the most important member of this group. TBG carries about 68% of the circulating T4 and 80% of the T3. Transthyretin, formally named prealbumin, binds with a lower affinity and carries 11% of the circulating T4 and 9% of T3. Albumin has the lowest affinity for thyroid hormone but the largest capacity, binding 20% of the T4 and 11% of the T3. 9 More than 99% of thyroid hormones circulate bound to these carrier proteins, and are biologically inactive. The half time of T4 in the blood is 7 to 10 days. The thyroid hormones not associated with protein, free T4 and free T3, can enter the cells and are biologically active. T4 is made exclusively by the thyroid gland, whereas T3 is made primarily in peripheral tissues by deiodination of circulating T4 by a group of enzymes called deiodinases. 10 Deiodinase enzyme activity is tightly regulated to maintain a normal T3 despite fluctuations in T4. 11 T3 binds with a much higher affinity to the thyroid hormone receptor and is more biologically active than T4. The activity of a specific 5′-deiodinase and the resulting T3 level can be reduced by hyperthyroidism, drugs (beta-blockers, ipodate, amiodarone, dexamethasone, propylthiouracil), malnutrition, and severe illness ( Figure 3-3 ). Conversely, during hypothyroidism, the 5′ deiodinase is activated to ensure that T4 is converted to the more bioactive T3. Normally, 20% of the daily T3 requirement is directly synthesized and secreted by the thyroid gland. During starvation and illness, the 5′ deiodinase converts the bioactive T4 and T3 to biologically inactive molecules, reverse T3 (rT3) and 3, 3′ diiodothyronine (see Figure 3-3 ). The small quantity of free T3 binds to its intranuclear thyroid hormone receptor to alter gene expression, which in turn alters cellular function and determines the thyroidal status ( Figure 3-4 ). The thyroid hormone receptor (TR) is a nuclear protein that is a member of a superfamily of receptors that bind steroid hormone such as retinoic acid, vitamin D, and estrogen.

Figure 3-1 Diagram of a follicular cell. The basal membrane is in contact with the circulation, and the apical membrane is in contact with the follicular lumen and colloid. Thyroid hormone synthesis and secretion are activated when thyrotropin (TSH) binds to the TSH receptor on the basal membrane. Iodide is transported into the cell via the Na + /I − symporter and flows down an electrical gradient to the apical membrane where it is raised to a higher energy state by thyroid peroxidase (TPO). Thyroglobulin (Tg) is assembled in the Golgi apparatus and is transported to the colloid in small apical vesicles. At the apical membrane, activated iodide binds to tyrosyl residues on Tg, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT). These are subsequently coupled under the influence of TPO to form the iodothyronine hormones T4 and T3. In the process of thyroid hormone secretion, Tg enters the cell by pinocytosis, forming colloid droplets. These fuse with lysosomes, forming phagolysosomes in which Tg is broken down by proteolysis, releasing T4 and T3 to diffuse into the circulation.
(From Brent G: Thyroid hormones (T4, T3). In Conn PM, Melmed S, editors: Endocrinology: basic and clinical principles, Totowa, NJ, 1997, Humana Press.)

Figure 3-2 Molecular structure of the iodotyrosines and iodothyronines. Monoiodotyrosine (MIT) and diiodotyrosine (DIT) are formed by the iodination of tyrosyl amino acids on the thyroglobulin molecule. In a subsequent step, two DITs are coupled to form tetraiodothyronine (T4), or one DIT and one MIT are coupled to create triiodothyronine (T3).

Figure 3-3 Deiodinases. 5′Deiodinase catalyzes the removal of the 5′ iodine from the outer ring of thyroxine (T4) to create metabolically more active triiodothyronine (T3) as well as further degrading metabolically inactive reverse triiodothyronine (reverse T3) to diiodothyronine (T2). 5 Deiodinase catalyzes the removal of iodine from the inner ring, converting T4 and T3 to metabolically inactive reverse T3 and T2.

Figure 3-4 Intracellular action of T3. T4 and T3 are transported into cells (red box). T4 is converted inside the cell by 5′ deiodinase to the more bioactive T3. After entering the nucleus, T3 binds to thyroid hormone receptors (TRs; green ovals), which form dimers with other T3 receptors, or with the retinoid X receptor (RXR), or with thyroid hormone auxiliary proteins (TRAPs). The dimers interact with thyroid hormone response elements (TREs) in the promoter region of thyroid hormone responsive genes, initiating or inhibiting transcription and altering the production of messenger RNA (mRNA) and protein synthesis.
(From Chin WW: Current concepts of thyroid hormone action: progress notes for the clinician. Thyroid Today 15:1, 1992. With permission.)
Thyroid hormone nuclear receptors (TRs) mediate the biologic activities of T3. Two TR genes, alpha and beta, encode four TR isoforms (alpha 1, beta 1, beta 2, and beta 3). The transcriptional activity of TRs is regulated by the binding of T3, the type of thyroid hormone response elements located on the promoters of the T3 regulated gene, by the developmental- and tissue-dependent expression of TR isoforms and by many nuclear co-factors or co-regulatory proteins (see Figure 3-4 ). There are also nongenomic actions of iodothyronine (T4) that are not mediated by intranuclear TR. Plasma membrane-initiated actions begin at a thyroid hormone receptor on integrin alphavbeta 3 that activates ERK1/2, which leads to changes in membrane ion transport, such as the Na( + )/H( + ) exchanger, and are also involved in other important cellular events such as cell proliferation. 12, 13

Thyroid Physiology and Pregnancy
Significant changes in thyroid physiology take place during pregnancy that can make the interpretation of thyroid function tests challenging. 14 - 16 TBG levels increase by 50% by the end of the first trimester of pregnancy, which greatly increases the protein-bound levels of T4 and T3, resulting in an apparent elevation of measured T4 and T3. 16 The changes in TBG are thought to be due to the direct effect of estrogen with an increase in the liver production and glycosylation of TBG. Despite the elevation of protein-bound thyroid hormones during pregnancy, the active or free levels of T4 and T3 remain normal in euthyroid patients as reflected by a normal serum TSH level. During the first trimester, the placental human chorionic gonadotropin (hCG) increases and peaks at approximately 12 to 14 weeks of pregnancy and then decreases to a lower plateau in the second and third trimesters in the euthyroid individual. 16 hCG has a weak TSH-like activity, resulting in a small increase in free T4, which usually remains in the normal range, and a concomitant decrease in TSH. 14, 15 Up to 13% of women during the first trimester have unmeasurable TSH levels (< 0.1 mud/L) with a normal or slightly elevated FT4I and are clinically euthyroid. 16, 17 This suppression of TSH usually normalizes after the first trimester of pregnancy.

Thyroid Physiology and Nonthyroidal Illness (Euthyroid Sick Syndrome)
Severe nonthyroidal illness is accompanied by major alterations in thyroid physiology that can interfere with the interpretation of thyroid tests. 18 The total T4 is decreased primarily because of a reduction in all thyroid binding proteins, whereas Free T4 measured by equilibrium dialysis is normal or slightly low. 19 Total T3 is further decreased secondary to a decrease in the function of the 5′deiodinase, which results in a reduction in the conversion of T4 to T3 (see Figure 3-3 ). Instead, T4 is metabolized to the inactive form, reverse T3 (rT3), by 5′deiodinase ( Figure 3-5 ). Measurement of rT3 does not reliably distinguish nonthyroidal illness from hypothyroidism. 20 The serum TSH may be low, normal, or high in nonthyroidal illness. 21, 22 Serum TSH is often low secondary to medications (glucocorticoids, dopamine) 23 or a form of acquired central suppression of the hypothalamus, which occurs in severe nonthyroidal illness. The degree of TSH, and especially free T3 suppression, correlates with mortality (see Figure 3-5 ), length of stay, and mechanical ventilation in the intensive care unit (ICU). 24, 25 It can be difficult to diagnose primary thyroid dysfunction in the setting of severe nonthyroidal illness. Severe nonthyroidal illness total T4, THBR, and FT4I are usually low; total T3 is relatively lower than expected for the total T4 level, but the serum TSH (measured by a third-generation assay with a sensitivity of < 0.01 mIU/L) is almost always measurable. During recovery from the acute illness with release of the central suppression, the TSH tends to rise for a short period of time prior to returning to normal. 22

Figure 3-5 Alternation in thyroid hormones during nonthyroidal illness and recovery. The degree of change in hormone concentrations relates to the severity and duration of the illness. TSH may also be suppressed during severe illness and may transiently rise moderately above the reference range prior to returning to normal with recovery. Mortality correlates inversely with the degree of reduction in total T4 concentration.
(From Nicoloff JT, LoPresti JS: Nonthyroidal illness. In De Groot LJ, editor: Endocrinology, ed 3,

Thyroid Tests

TSH Assays
Thyroxine-stimulating hormone (TSH) is produced from the pituitary after stimulation by thyrotropin-releasing hormone (TRH), a modified three-amino acid peptide produced by neurons of the paraventricular nucleus of the hypothalamus. TRH reaches the pituitary via the portal venous system in the infundibulum (pituitary stalk). Both TRH and TSH gene expression is repressed via a negative feedback inhibition by excess thyroid hormone ( Figure 3-6 ). Pituitary TSH is secreted in a pulsatile manner with an increase in pulse frequency at night. TSH concentrations have a diurnal rhythm with the peak occurring around 11 p.m. and lower levels during the day. 26 Generally, laboratory testing of TSH during work hours, between 8 a.m. and 8 p.m., is not affected by the diurnal variation of TSH secretion, but results outside the reference range may occur in euthyroid individuals outside these times. TSH stimulates the synthesis and release of thyroid hormone and growth of the thyroid gland. TSH production from the anterior pituitary is inversely regulated by the serum thyroid hormone concentration. When thyroid hormone levels in the circulation are low, the TSH level rises to stimulate thyroid hormone production by the thyroid gland to return the system to normal function or equilibrium. The relationship or negative feedback loop between serum TSH and serum-free thyroid hormone maintains thyroid levels in a tight range ( Figures 3-6 and 3-7 ). The TSH level changes by an inverse log-linear manner, such that small changes in the serum-free T3 levels result in large changes in the serum TSH concentration (see Figure 3-7 ). Small changes in a patient's thyroid hormone level that may not be clinically apparent or result in abnormal thyroid hormone levels measured in the serum will be reflected in a significant change in the serum TSH concentration. Serum TSH is the preferred initial or screening diagnostic test for evaluation of thyroid function of the ambulatory patient, whether or not the patient is taking thyroid hormone replacement medication. 27, 28 For the healthy patient in an ambulatory setting, the diagnosis of thyroid hypothyroid or hyperthyroid dysfunction may be determined with approximately 98% sensitivity and 92% specificity. 27 Another consideration is that TSH has a narrow within-person variability of +/− 0.5 mIU/L, 29 and if there are larger changes in TSH level over time in an individual, even within the reference range, it may indicate thyroid dysfunction. In certain situations, however, such as known or suspected pituitary or hypothalamic dysfunction, recent thyrotoxicosis, critical illness, starvation, use of certain medication (dopamine or high-dose glucocorticoid therapy), interference with autoantibodies, and thyroid hormone resistance syndromes, the TSH level is inaccurate for the thyroidal status and should not be used alone to determine thyroid function. 30 The presence of interfering heterophile antibodies, antibodies against the animal-derived antibodies used in the immunometric assay, may rarely cause an abnormally high or low level of reported TSH levels. 31 Fortunately, these conditions can be easily determined clinically or are very rare. Further, the peripheral hormone levels will not correspond to the expected changes that occur with elevated or suppressed TSH levels.

Figure 3-6 Schematic representation of control of TSH secretion by the thyrotroph cells in the anterior pituitary. High concentrations of T3 suppress TSH release, and low concentrations enhance the expression of TSH. Thyrotropin-releasing hormone (TRH) also stimulates TSH release, and its absence results in failure of the thyrotrophs to release TSH, resulting in hypothyroidism. TRH is secreted by cells in the paraventricular nuclei in the hypothalamus and reaches the anterior pituitary via the hypothalamic hypophyseal portal venous system. TSH travels through the circulation to stimulate the thyroid to produce thyroid hormones, T4 and T3. By negative feedback inhibition, the circulating thyroid hormones suppress the production and excretion of TRH and TSH to bring the system back into equilibrium to maintain tight control over circulating thyroid hormone levels.

Figure 3-7 The inverse log/linear relationship between free T3 and TSH. Small changes in free T4 result in amplified changes in TSH.
(From Demers LM, Spencer CA, editors: Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease, Washington, DC, The National Academy of Clinical Biochemistry [in press]. With permission.)
TSH assays have evolved considerably since the early 1980s. The normal range of TSH in most laboratories is approximately 0.3 to 4.5 mIU/L but depends on the specific assay used. The commonly used second-generation TSH assays should have a functional lower limit of 0.10 mIU/L or less. 28, 32 This TSH assay is able to differentiate between euthyroid and hyperthyroid states but does not indicate the degree of hyperthyroidism. The third-generation immunometric TSH assays utilizing a sensitive chemiluminescent detection system have a detection limit of < 0.01 mIU/ L and are capable of determining the degree of hyperthyroidism. 32 - 34 Most clinical laboratories use a second-generation TSH assay, which is adequate for routine thyroid function testing. A third-generation TSH assay is needed only in conditions such as severe nonthyroidal illness with difficult-to-interpret thyroid function tests with a suppressed TSH. 33 Spencer found that hospitalized patients with sick euthyroid syndrome or treated with high doses of glucocorticoid always had a measurable third-generation TSH > 0.01 mIU/L but the TSH was suppressed to < 0.01 mIU/L with hyperthyroidism. 33
A TSH level measured in an ambulatory population that lies within the reference range is generally considered evidence of normal thyroid function and requires no additional testing 34 ( Figures 3-8 and 3-9 ). Current guidelines recommend using an upper TSH limit that is lower than the laboratory referenced range. The American Association of Clinical Endocrinology (AACE) recommends using a TSH reference range of 0.3 to 3 mIU/L, 35 but the National Academy of Clinical Biochemistry (NACB) Guidelines recommend a TSH upper limit of 2.5 mIU/L. 36 The Endocrine Society pregnancy guideline has recommended a trimester specific range for pregnant women of < 2.5 mIU/L during the first trimester and < 3 mIU/L in the second and third trimesters or assay-specific trimester-specific reference ranges. 15 It is important to realize that these data are based on empiric and epidemiology distribution of TSH in populations, but the true upper limit is not yet definitively defined. After an abnormal TSH result has been obtained, then measurement of the circulating thyroid hormone levels should be performed (see Figures 3-8 and 3-9 ). The specific tests will depend on whether hypothyroidism, hyperthyroidism, or nonthyroidal illness is clinically suspected.

Figure 3-8 Algorithm for the evaluation of hypothyroidism. a Management of subclinical hypothyroidism (elevated TSH, normal FT4I) is controversial. The American College of Physicians (ACP) does not have an official recommendation for treatment. The American Association of Clinical Endocrinologists (AACE) favors treatment with L-thyroxine to normalize the TSH. The presence of TPO antibodies is a strong predictor of progression to overt hypothyroidism (elevated TSH, low FT4I).

Figure 3-9 Algorithm for the evaluation of thyrotoxicosis. a, Rule out other conditions such as nonthyroidal illness. The etiology of the thyrotoxicosis can be made with TPOAb and thyroid scintiscan (see Table 3-7 ). b, The treatment of Graves’ disease, toxic multinodular goiter, and toxic adenoma includes thyroid surgery, antithyroid medication such as methimazole, and radioactive iodine ablation. The treatment of subacute thyroiditis is symptomatic, as the thyroid function abnormality will spontaneously return to normal in > 90% of patients. The approach to thyrotoxicosis from metastatic thyroid carcinoma is to treat the thyroid malignancy.

Measurement of Thyroid Hormone Levels
Thyroid panel is a term commonly used and often misused. The thyroid tests that make up a thyroid panel often do not include the most important diagnostic test, a TSH level. The measurement of TSH should replace any thyroid panel as the initial step in the assessment of thyroid function in the healthy ambulatory patient. 27, 28 However, when the TSH is not believed to be sufficient by itself for diagnosis (first-trimester pregnancy, pituitary/hypothalamic dysfunction, critical illness, high-dose glucocorticoid or dopamine therapy, etc.) or to accurately access the degree of hyperthyroidism when the TSH is low, thyroid hormone levels must also be measured. 27, 28, 34

Total T4 and Total T3
The bioactive thyroid hormones include T4 and T3. rT3, which may be elevated during nonthyroidal illness, is not biologically active, and other forms of iodothyronine are not routinely measured. Serum total T4 (TT4) and total T3 (TT3) measure both bound and free hormone levels of these two hormones. Total T4 or total T3 should never be used alone as an indication of thyroid function because many clinical conditions and medications change the amounts of thyroid hormone binding proteins or compete with the binding of thyroid hormones to the binding proteins. Changes in binding to thyroid binding proteins can greatly affect the measured TT4 and TT3 levels without altering of the bioactive free levels or thyroidal status ( Table 3-1 ). Measurement of serum TT3 is not part of the initial evaluation of thyroid function if hypothyroidism is suspected (see Figure 3-8 ). During hypothyroidism, the activity of the 5′deiodinase that converts T4 to the more biologically active T3 increases, resulting in normal T3 levels until the overall thyroid levels are very low. T3 is useful in the diagnosis and management of patients with thyrotoxicosis 34 (see Figure 3-9 ) and, occasionally, to help with differentiating Graves’ disease (higher T3/T4 ratio > 20) from subacute thyroiditis (lower T3/T4 ratio < 12). 37, 38 rT3 rarely needs to be measured during the evaluation of thyroid function. The mouse-antihuman antibodies (HAMAs) that interfere with TSH testing can interfere with thyroid hormone assays. HAMA may result in artificially elevated or reduced TT4, TT3, FT4, and FT3 levels. 39 Patients who have received therapeutic monoclonal antibody treatments seem to be especially prone to develop interfering HAMA. 40

Table 3-1 Examples of Thyroid Function Tests

Equilibrium Free T4 and Estimates of Free T4
Assessment of the bioactive free T4 can be estimated using the following three assays: (1) free T4 index (FT4I), (2) freeT4 by immunoassay, and (3) free T4 detected by equilibrium dialysis. Free T4 by equilibrium dialysis is the gold standard and measures the 0.03% of T4 that is biologically active and not bound to protein. This assay is available only at specialty laboratories and is technically difficult. The measured levels of free T4 have a significant interassay variation because of the minute amount of T4 being measured. Generally, local laboratories estimate free T4 by either the analog free T4 assay or a calculated FT4I corrected to thyroid hormone binding capacity. The free T4 test that results the same day or overnight in your institution or laboratory does not measure the free T4 concentration but is based on one-step, two-step, or labeled antibody approches. 41 This type of free T4 test is especially sensitive to abnormal albumin levels and should not be used with conditions such as familial dysalbuminemic hyperthyroxinemia, 42 pregnancy 15, 43 or severe nonthyroidal illness. 18 For example, it is common to have a free T4 lower than the reference range in a euthyroid female who is pregnant. The high estrogen state of pregnancy greatly increases the TBG in the serum, making the FT4 inaccurate. FT4I is a calculated value that is the product of the total T4 and a correction factor related to the number of free thyroid hormone binding sites ( Table 3-1 ). This correction factor may be called a THBR, T3 resin uptake (T3RU), or T3 uptake (T3U). 34 Although the FT4I seems to be one of the most difficult laboratory tests for the nonendocrinologist to understand, these tests give important information about the T4 binding capacity of the serum that is necessary to make a diagnosis of thyroid dysfunction (see Table 3-1 ). The T3RU is inversely related to the free thyroid hormone binding sites. For example, a large number of free sites may occur during hypothyroidism when there is less T4 than normal to occupy the sites or when there is an excess number of free sites because of estrogen stimulation of the TBG level. Both of these situations will result in a low T3RU. The T4 binding capacity is corrected by using the equation TT4 × T3RU = FT4I. This concept is shown in Table 3-1 . Note that when true thyroid dysfunction occurs, the TT4, T3RU, and FTI all move in the same direction: higher with hyperthyroidism and lower with hypothyroidism (see Table 3-1 ). When serum thyroid hormone binding protein levels are grossly normal, the FT4I provides a reliable index of the patient's thyroid status. Occasionally the thyroid binding protein levels markedly change in various conditions 44 (pregnancy, severe illness, malnutrition, dysproteinemia; see Table 3-1 ), resulting in changes in the ratio of bound to free hormone, making the FT4I a poor estimate of the free T4 level. When there is a binding abnormality such as with hepatitis or pregnancy, generally the total T4 and T3RU move in opposite directions (see Table 3-1 ). In these cases, TSH with a T3RU and FT4I or a measurement of the free thyroid hormone level by equilibrium dialysis is required to correctly assess thyroid function. Direct measurement of the TBG level should not routinely be ordered, because its value rarely contributes to the assessment of the patient's thyroid status that cannot be otherwise predicted by the T3RU.

Thyroid Antibodies
In the adult, hyperthyroidism and hypothyroidism are often the result of autoimmune disease, where immunoglobulin G (IgG) antibodies are formed against thyroid proteins, such as thyroglobulin (TgAb), thyroid peroxidase (TPOAb, previously known as anti-microsomal antibodies), and the TSH receptor (TSHRAb). 34 The TSHRAb is a group of immunoglobulins that can either stimulate the TSH receptor (thyroid-stimulating immunoglobulins [TSI]), causing Graves’ hyperthyroidism, or less commonly inhibit the receptor from binding TSH (thyroid hormone binding inhibiting immunoglobulins [TBII]) causing hypothyroidism. Without thyroid dysfunction, thyroid antibodies should generally not be measured except in special circumstances such as a history of hyperthyroidism during pregnancy 45 or recurrent miscarriages. 46 Both the stimulating and inhibiting TSHRAb can cross the placenta to affect fetal thyroid function and promote goiter. A high level of TPOAb during pregnancy will predict a higher risk for postpartum subacute thyroiditis. 47 More than 90% patients with autoimmune thyroid disease (Graves’ disease and Hashimoto's thyroiditis) will have elevated titers of second-generation assays for TPOAb and TgAb. 48, 49 The measurement of TPOAb can be helpful clinically, as it provides additional information regarding the autoimmune nature of the thyroid dysfunction or thyroid enlargement. It is important, however, to remember that TPOAb is diagnostic of autoimmune thyroid disease 49, 50 but does not guarantee the development of autoimmune hypothyroidism or hyperthyroidism. The NHANES III study has shown that 11% of the population with a normal TSH will have elevated TPOAb, but after 4 years of follow-up only 12% of these individuals will develop an elevated TSH. 52 TPO antibodies can be used to help predict which patients with subclinical hypothyroidism will progress to overt hypothyroidism. When patients with subclinical hypothyroidism (i.e., TSH between 5 and 10 mIU/L) were followed for 3 years, 20.5% of the patients had spontaneous normalization of their TSH, 27.3% required replacement therapy with T4 because of progression to overt hypothyroidism or persistence of serum TSH > 10 mIU/L, and 52.1% continued to have a TSH ≤ 10 mIU/L. Patients with a positive TPOAb or ultrasound (US) changes of chronic thyroiditis had a threefold increased risk of developing overt hypothyroidism (31.2% versus 9.5%, respectively). 51 Elevated titers of thyroid antibodies occur in all types of autoimmune thyroid diseases, but low titers, especially TgAb, can be measured in individuals with normal thyroid function, especially the elderly and patients with other autoimmune conditions. 3 Epidemiologic studies suggest that a positive TgAb level is not highly predictive of thyroid dysfunction. 3, 52 As almost all patients with TPOAb will have TgAb, the measurement of TgAb adds little information to the characterization of thyroid dysfunction and should not be routinely measured.

Thyroglobulin
Thyroglobulin (Tg) is a protein precursor and storage form of thyroid hormone. This large glycoprotein is stored as colloid in the interior of each thyroid follicle. Tg continuously leaks into the circulation from the thyroid gland. Serum Tg reflects the mass of normal and malignant thyroid, TSH stimulation of thyroid tissue, and injury of the thyroid tissue. Its current primary use is as a tumor marker in patients with differentiated thyroid cancer to detect recurrent disease and evaluate the efficacy of treatment after thyroidectomy and radioactive iodine ( 131 I). 53 - 56 Its clinical value for evaluating thyroid function or thyroid disease (i.e., goiter) is limited in the era of modern thyroid function testing and imaging. The demonstration of suppressed serum Tg levels can be useful in differentiating factitious thyrotoxicosis (from exogenous thyroid hormone ingestion) from excessive endogenous thyroid hormone release of any etiology. 57 When excess thyroid hormone is due to ingestion of levothyroxine, the normal thyroid function is suppressed and serum thyroglobulin levels become very low. But if the excess thyroid hormone is from the thyroid, thyroglobulin levels are elevated. Measurements of Tg are used primarily as a tumor marker for tumor recurrence or persistence after thyroidectomy and 131 I therapy. 53 - 56 Detection of tumor recurrence depends on the thyroglobulin immunometric assays that currently have a less than optimal sensitivity and high between-assay variability. Virtually all immunometric methods will report an undetectable Tg in euthyroid TgAb positive controls. 54, 58 Currently, most Tg assays have only first-generation functional sensitivity between 0.5 and 1 ng/mL but second generation Tg assays have a functional sensitivity of 0.05 to 0.1 ng/mL. The Tg assay can be made more sensitive to detect persistent or recurrent tumor after stimulated by either recombinant human TSH (rhTSH) or endogenous hypothyroidism, which results in an approximate eightfold increase in Tg. Investigators have shown at a single institution that the second-generation Tg assay correlates with the recombinant human TSH (rhTSH) stimulated Tg. 53 If the basal Tg were < 0.1 ng/mL, then 99.7% of the rhTSH stimulated Tg was less than 2 ng/mL, suggesting absence of recurrent or persistent tumor.
For clinicians to know how to use the Tg level as a tumor marker for differentiated thyroid cancer, they must understand a number of important facts (see Chapter 50, Postoperative Management of Differentiated Thyroid Cancer ). TgAb interference will usually make elevated Tg levels read as unmeasurable in the commercially available immunometric Tg assays. Thyroid cancer patients have a higher prevalence of TgAb than euthyroid controls (20% versus 12%). 3, 59, 60 Commercially available TgAb assays will detect circulating antibody in only 65% of individuals with TgAb detected with a highly sensitive assay. Thus, when a node or mass is detected in a thyroid cancer patient, an unmeasurable basal or TSH-stimulated Tg with a “negative” commercial TgAb level does not exclude a thyroid cancer recurrence. 58 It is reasonable in this uncommon category of patients to measure a Tg by radioimmunoassay (RIA) available at some specialty endocrine laboratories. 58 The thyroglobulin antibody level may be used as surrogate marker of tumor recurrence. When TgAb declined by more than 50% within the first year following thyroidectomy, none of the patients had persistent disease, but when the TgAb increased in the same time period, 37% of the patients had persistent thyroid cancer. 61 Thyroid cancer patients with a rising level of thyroglobulin antibodies are at high risk for thyroid cancer recurrence and should be evaluated promptly. 61 - 63 The sensitivities and absolute values reported by different methods of measuring Tg and TgAb are highly variable. It is essential to always use the same Tg and TgAb method 58 when following an individual over time for tumor recurrence. The presence of interfering heterophile antibodies, antibodies against the animal-derived antibodies used in the immunometric assay, may rarely cause an abnormally high or low level of reported thyrogloglobulin. 63 The most common interfering antibodies are human antimouse antibodies (HAMAs). Clinically, this can be suspected when the elevated thyroglobulin level is not appropriate for the clinical situation and does not increase with TSH stimulation. When this is suspected, the clinician should repeat the test using a commercially available heterophile-blocking tube (HBT) or with an RIA for thyroglobulin. 58, 63, 64

Thyroid Imaging
Thyroid gland imaging studies with radionuclides provide structural as well as functional information and can be very useful in determining the cause of hyperthyroidism. Nuclear thyroid imaging is not recommended during the evaluation of hypothyroidism. Many thyroidologists prefer imaging with radioactive iodine because it directly reflects the active accumulation (trapping) by the thyroid follicular cell and covalent attachment (organification) of the iodine to thyroglobulin. The preferred form for diagnostic, noncancer imaging is 123 I because this isotope emits only gamma rays that pass through tissue without significant cellular damage. 131 I emits gamma rays for imaging but also beta particles, which damage tissues. 131 I is used for the therapy of hyperthyroidism and thyroid cancer to destroy iodine-avid thyroid tissue. 123 I is administered orally with a measurement of iodine uptake and gamma scintigraphy images (scintiscan) obtained 4 or 24 hours later. Measured thyroidal uptake depends on the activity of the Na/I symporter and the circulating nonradioactive iodine. When there is an excess of nonradioactive iodine, the measured radioactive iodine uptake is reduced based on the competition between the radioactive and nonradioactive iodine uptake by the thyroid follicular cells. Sources of excess iodine include foods that contain kelp, seaweed, or red food dye #3, drugs such as amiodarone, saturated solution of potassium iodide (SSKI), Lugol's solution, povidone iodine, tincture of iodine, iodoform gauze, and radiographic contrast media for computed tomography (CT) scan and gallbladder contrast (ipodate and iopanoic acid). An alternate radionuclide for radioactive iodine, Technetium 99m pertechnetate ( 99m Tc), can be administered intravenously, and images are obtained 30 to 60 minutes later. Although 99m Tc will be trapped by the thyroid follicular cells, it cannot be attached to thyroglobulin and, therefore, does not absolutely mimic the thyroidal uptake of iodine. This difference is the basis of the observation that 123 I thyroid scans have 5% to 8% fewer false negative results 65, 66 than 99m Tc scans. But because 99m Tc scans are easier, faster, more available, and less expensive to perform, they have largely replaced 123 I scans at some institutions. Studies of direct comparison of radioiodine and pertechnetate thyroid scintiscans were concordant in all patients without nodules and in those with cold nodules. In 2 of 273 patients there were nodules that appeared hot with pertechnetate and cold with radioiodine. 66 It is felt that there is a high correlation between the two types of scintiscans with only rare discrepencies. 65, 66 However, if the results of the 99m Tc scan do not match the clinical picture or if the lesion is behind bone in the anterior mediastinum, a 123 I scan should be performed. Nuclear scintiscans are useful in the differential diagnosis of hyperthyroidism and to determine the function of a thyroid nodule. Ultrasound, CT, and magnetic resonance imaging (MRI) are structural imaging modalities that provide no functional information about the thyroid gland. Although thyroid ultrasound does not have a role in the initial evaluation of thyroid dysfunction, it is recommended as part of the initial evaluation of thyroid nodules by recent guidelines from the American Thyroid Association 67 and the American Association of Clinical Endocrinologists. 68 In addition, there are ultrasound changes that can seen but are not diagnostic of chronic Hashimoto's thyroiditis (hypoechoic, hypervascularity), subacute granulomatous, and postpartum thyroiditis (ill-defined hypoechoic area without vascularity). 69, 70 Early studies suggest that US changes consistent with chronic thyroiditis in patients with subclinical hypothyroidism are at significant risk for developing overt, more severe, hypothyroidism requiring L-T4 therapy. 51

Thyroid Function Testing for Hypothyroidism
Excluding thyroidectomy and radioactive iodine ( 131 I) ablation, the most common causes of hypothyroidism in the adult are Hashimoto's thyroiditis and the hypothyroid phase of subacute thyroiditis, including postpartum thyroiditis. Because the long-term treatment is very different, the clinicians must distinguish between these conditions. The common causes of low circulating thyroid hormone levels are found in Table 3-2 .
Table 3-2 Etiologies of Hypothyroidism Primary (thyroid failure with elevated TSH) Hashimoto's thyroiditis (chronic lymphocytic thyroiditis) Hypothyroid phase of painful subacute thyroiditis (pseudo-granulomatous–De Quervain's) Hypothyroid phase of painless lymphocytic thyroiditis Hypothyroid phase of postpartum thyroiditis Radioactive iodine ablation Thyroidectomy Head and neck radiation Drugs: lithium, amiodarone, interleukin, interferon, propylthiouracil/methimazole, iodine excess in patients with thyroiditis Iodine deficiency (uncommon in the United States) Biosynthetic defects (rare and presents in childhood) Congenital hypothyroidism (rare and presents in childhood) Secondary (hypothyroidism with low or inappropriately normal TSH) Pituitary dysfunction (pituitary damage from tumor, surgery, and/or radiation) Tertiary (hypothalamic damage from tumor, radiation)

Signs and Symptoms of Hypothyroidism
Symptoms and signs of hypothyroidism are listed in Table 3-3 . These are nonspecific, and not all patients will have all the signs and symptoms. Symptoms are usual slow in onset. In the elderly and middle-aged women, these nonspecific complaints may be interpreted as signs of normal aging or depression. Symptoms depend on the degree and duration of thyroid dysfunction but most frequently include weight gain, fatigue, constipation, and menstrual irregularities/infertility.
Table 3-3 Signs and Symptoms of Hypothyroidism General Musculoskeletal Weight gain Myalgia Fatigue Muscle cramps Cold intolerance and hypothermia Carpel tunnel syndrome Hyponatremia Elevation of creatine phosphokinase Skin Nervous System Dry and coarse skin Depression Pretibial myxedema (nonpitting edema) Decreased concentration Dry and coarse hair Dementia Hair loss   Head and Neck Cardiovascular Hoarse voice Bradycardia Enlarged tongue Diastolic hypertension Periorbital edema Hypercholesterolemia Goiter Pericardial effusion   Congestive heart failure Gastrointestinal Reproductive Constipation Irregular menstrual periods/amenorrhea   Menorrhagia   Galactorrhea with elevated prolactin levels   Infertility   Increase risk of miscarriage

Thyroid Tests in the Evaluation of Hypothyroidism
The recommended initial test for hypothyroidism is a serum TSH (see Figure 3-8 ), measured by a second- or third-generation assay, if the patient has any of the symptoms or signs shown in Table 3-3 or any of the risk factors shown in Table 3-4 . The measurement of a TSH is a very sensitive and specific method to diagnose hypothyroidism. It is almost always elevated in primary hypothyroidism, and the TSH rise occurs prior to a fall in the T4 or T3 levels. Measurement of TSH is not a good initial test for secondary hypothyroidism and should not be used to assess the thyroid status of a patient with known or suspected hypothalamic or pituitary disease or severe nonthyroidal illness. Fortunately, these disorders are uncommon and often clinically apparent. It would be extremely rare to miss an unsuspected case of central hypothyroidism with a single measurement of TSH. TSH is also difficult to use when thyroid hormone levels are changing. After thyroidectomy, the TSH level rises without L-T4 supplementation to > 30 mIU/L after 22 days in more than 95% of postoperative patients. 71 It is common to treat patients postoperatively with T3 for 2 to 3 weeks, then stop the T3 for 2 weeks prior to the hypothyroid radioactive iodine treatment or diagnostic imaging. 67
Table 3-4 Risk Factors for Hypothyroidism Female, age over 45 Male, age over 60 Family history of autoimmune disease including thyroiditis Infertility, miscarriage History of thyroid disease Goiter Other autoimmune disease (type 1 diabetes mellitus, rheumatoid arthritis, vitiligo, Addison's disease, pernicious anemia) History of head and neck radiation Drugs: lithium, amiodarone, kelp supplements, iodine-containing expectorants
An algorithm for thyroid testing for the diagnosis of hypothyroidism can be followed in Figure 3-8 . If the TSH is between 0.3 and 4.5 mIU/L, the patient does not have hypothyroidism and can be followed periodically. If the TSH is over 10, treatment should be initiated with synthetic L-T4, L-thyroxine, for hypothyroidism, as most of these patients will be symptomatic or will have a low free T4 level. An exception is during recovery from an acute illness or subacute thyroiditis, when the TSH may transiently rise to slightly elevated levels prior to returning back to normal. If the TSH level is between 4.5 and 10 mIU/L, it is recommended that the clinician repeat, in approximately 1 month, laboratory tests including TSH with an estimate of free T4 level, most commonly a FT4I, and a TPOAb level. Recent studies have suggested that either positive serum TPOAb or US evidence of thyroiditis is predictive of progressive hypothyroidism and should be treated with L-T451. Measurement of total or free T3 level is not indicated because the T3 level is maintained within the reference range in mild to moderate hypothyroidism because of increased conversion of T4 to T3 by elevated levels of 5′deiodinase. If the free T4 level (or FT4I) is subnormal, it is recommended to start L-T4 therapy for the treatment for hypothyroidism.

Subclinical Hypothyroidism
Subclinical hypothyroidism is defined as an elevated TSH with a normal measure of free T4 (FT4 or FT4I). Generally, this occurs when the TSH is between 4.5 and 10 mIU/L. When the repeated TSH remains between 4.5 and 10 and the free T4 level (FT4I) is normal, the patient has subclinical hypothyroidism. About 15% of the population over age 60 will have a TSH level between 5 and 10. 60 If followed over time, approximately 27% to 33% will develop a normal TSH over a 3- to 4-year period. 51 If all patients with a TSH between 5 and 10 are treated with L-T4, then one third of patients might be treated unnecessarily.
The optimal management of subclinical hypothyroidism has been a matter of controversy. 72, 73 There are few objective physiologic data that show the benefit of treating subclinical hypothyroidism. However, small well-controlled studies have suggested a benefit in some of the study patients’ sense of well-being, a reduction in cholesterol levels, and a reversal of mild cardiac dysfunction when treated with L-thyroxine. 74, 75 In general, the decision to treat patients with subclinical hypothyroidism 76 depends on the presence of signs or symptoms of hypothyroidism ( Table 3-3 ), increased risk of progression to overt hypothyroidism as indicated by a positive risk factor ( Table 3-4 ) such as thyroiditis on US or significant titers of antithyroid antibodies, and other high-risk conditions such as cardiovascular disease, pregnancy, or infertility. Patients with low cardiovascular risk, no symptoms, or older age have not shown any proved benefit from L-T4 treatment. If the patient is asymptomatic, the most conservative approach is to follow the patient clinically and repeat the TSH in 6 to 12 months or earlier as directed by symptoms or signs. Some clinicians would obtain additional data to determine the risk of progression to overt hypothyroidism by confirming a family history of autoimmune thyroid disease, performing a thyroid US for thyroiditis, and checking for the presence of TPOAb. In a large population study, if TPOAb is present, the patient is at risk for developing clinical hypothyroidism in the future at a rate of 5%/year. 5 The more elevated the antithyroid antibody titer, the higher the risk of developing overt hypothyroidism. It is reasonable to consider treatment in a young patient who has mildly elevated TSH, elevated TPOAb, or US evidence of thyroiditis. However, patients may have progression of their subclinical hypothyroidism to overt hypothyroidism even in the absence of serum antithyroid antibodies but with thyroiditis on US. 51 Patients with subclinical hypothyroidism should be followed clinically and biochemically for progression to overt hypothyroidism with TSH levels measured every 6 to 12 months or sooner if hypothyroid signs or symptoms are detected. Finally, TSH ranges are patient specific, so if the current TSH level is more than 0.5 mIU/L higher than prior values or if the repeat TSH values show progressive increase, then this likely indicates a progression of thyroid dysfunction and should be treated.

Etiology of Hypothyroidism
Once the diagnosis of clinical or subclinical hypothyroidism is established, the etiology needs to be identified. Often the patient is found to have an elevated TSH with or without symptoms of hypothyroidism and is treated unnecessarily for life with L-thyroxine for presumed Hashimoto's thyroiditis, which is the most common cause of hypothyroidism in the adult. However, it is extremely important that Hashimoto's thyroiditis is distinguished from transient forms of hypothyroidism, such as excess iodine intake (from contrast administration and kelp/seaweed supplements) and the hypothyroid phase of subacute thyroiditis. There are three forms of subacute thyroiditis, including postpartum, painful pseudo-granulomatous, and painless lymphocytic subacute or silent thyroiditis (see Chapter 4 ). All forms of subacute thyroiditis are characterized by transient (4 to 8 weeks) thyrotoxicosis, followed by transient (2 to 4 months) hypothyroidism, with the eventual return to the euthyroid state, although not all patients will experience all phases. 77 Postpartum thyroiditis occurs 1 to 12 months following a miscarriage, therapeutic abortion, or delivery. Subacute painful thyroiditis is associated with an enlarged and very painful thyroid gland, flulike symptoms including high fever, myalgia, and a high erythrocyte sedimentation rate (ESR). Painless or silent lymphocytic subacute thyroiditis is associated with an enlarged thyroid with the typical thyroid dysfunction of subacute thyroiditis described previously. All three types of subacute thyroiditis and can be diagnosed by a very low radioactive iodine uptake (see section on Thyroid Imaging in Hyperthyroidism). The hypothyroid phase of subacute thyroiditis does not need to be treated unless the patients is symptomatic; then the patient should be placed on L-T4 treatment to normalize the TSH. After approximately 6 months, the L-T4 should be decreased by 50% or stopped, and a serum TSH should be measured 4 to 6 weeks later. Patients with Hashimoto's with permanent thyroid dysfunction will have an elevated TSH, whereas the patients who have recovered from subacute thyroiditis will have a normal TSH. This adjustment of L-T4 dose may also be performed in patients on thyroxine replacement seen for the first time when the diagnosis of hypothyroidism is not clear.

Antithyroid Antibodies in Hypothyroidism
Measurement of antithyroid antibodies in the differential diagnosis of primary hypothyroidism should be interpreted with extreme caution and always in correlation with the clinical history. TPOAb or TgAb is positive in most patients with autoimmune thyroiditis (Hashimoto's thyroiditis) but should not be measured routinely because the presence or absence of thyroid antibody titers will not alter the therapy of hypothyroidism. Low levels of TPOAb and TgAb can occur after the release of thyroid antigens in some patients with subacute thyroiditis. In particular, postpartum thyroiditis, a transient autoimmune thyroid disorder, is associated with a transient rise in thyroid antibodies levels.

Thyroid Imaging in Hypothyroidism
Although thyroid US can detect changes of thyroiditis, the changes may be subtle and subject to variable interpretation. Radionuclide imaging of the thyroid is almost never helpful for the diagnosis of hypothyroidism. Thyroid ultrasound or radionuclide imaging should be performed to evaluate suspicious structural abnormalities, such as a dominant nodule in the thyroid gland in the hypothyroid patient. 78, 79 Although controversial, there is an epidemiologic association of higher TSH values and thyroiditis with the risk of malignancy, and it has been suggested that clinicians use sonography to evaluate patients with thyroiditis, Hashimoto's thyroiditis, and Graves’ disease to detect thyroid nodules that require biopsy. 80, 81

Monitoring of Patients with Hypothyroidism
Hypothyroidism is treated with an oral supplementation with the synthetic form of L-T4 (Levoxyl, Synthroid, Tirosint). Thyroid extracts (Armor) should not be used because of the variable amount of thyroid hormone in different lots of medication. Levoxyl and Synthroid are available as a wide array of doses in tablet form, whereas Tirosint is a soft gel capsule containing liquid L-T4. Fixed doses of L-T4/triiodothyro-nine preparations (Thyrolar, liotrix) are not recommended because of the relatively excessive ratio of T3/L-T4. T3 (Cytomel) is not recommended for the routine treatment of hypothyroidism because the short half-life requires dosing multiple times daily.
In patients with primary hypothyroidism, L-T4 dose adjustments should be done based on a serum TSH measured after 6 to 8 weeks, a few weeks after the serum T4 has risen to the new steady state in approximate three half-lives (3 × 7 to 10 days = 3 to 4 weeks). The goal of treatment is to normalize the serum TSH level to 0.5 to 2.5 mIU/L. 35 The TSH target for L-T4 treatment for thyroid cancer is determined relative to risk of persistent/recurrent disease. 67, 82 Once the TSH has normalized, the patient is followed with TSH determination every 6 to 12 months.
Although very controversial, reports suggest that patients may have symptomatic improvement when the L-T4 dose is supplemented with small amounts of the short-acting and more potent T3. 83 Although some animal data may support the need for T3 supplementation 84 to normalize T3 tissue levels, there are no case-controlled clinical studies showing a significant physiologic benefit. 85, 86 These studies have demonstrated adverse effects of this combination therapy, such as an increase in bone turnover, tachycardia, and palpitations. At the present time, hypothyroidism should not be routinely treated with T3 alone or in combination with L-T4.

Thyroid Function Testing for Thyrotoxicosis
High levels of bioactive free thyroid hormones or thyrotoxicosis are almost always associated with subnormal TSH levels. Elevated total T4 or total T3 levels caused by high thyroid hormone binding proteins with a normal free T4 and TSH levels are called hyperthyroxinemia. Patients with this condition are euthyroid with a normal TSH. Specifically, thyrotoxicosis caused by an excess production of thyroid hormone from the thyroid is called hyperthyroidism. When the high free thyroid hormone levels are not produced by the thyroid, such as with excess doses of L-T4, the condition is called thyrotoxicosis. The most common cause of adult hyperthyroidism in North America is Graves’ disease, an autoimmune thyroid hyperfunction. Other common causes of hyperthyroidism include toxic multinodular goiter (MNG), toxic adenoma, and the thyrotoxic phase of subacute thyroiditis including postpartum thyroiditis. Common causes of high thyroid hormone levels can be found in Table 3-5 . The diagnosis and management of thyrotoxicosis/hyperthyroidism (see Figure 3-9 ) are somewhat more involved and time-consuming for the physician than they are for hypothyroidism. The evaluation and treatment of the patient with hyperthyroidism are often best managed by the endocrinologist.
Table 3-5 Etiologies of Hyperthyroidism Primary (thyroid hyperfunction with a low TSH) Graves’ disease Toxic multinodular goiter Toxic adenoma Thyrotoxic phase of painful subacute thyroiditis (pseudo-granulomatous–De Quervain's) Thyrotoxic phase of painless lymphocytic thyroiditis Thyrotoxic phase of postpartum thyroiditis Excessive ingestion of thyroid hormone Metastatic thyroid carcinoma Struma ovarii Iodine induced (with preexisting chronic thyroiditis) Secondary (hyperthyroidism with an elevated or inappropriately normal TSH) TSH-producing pituitary adenoma Thyroid hormone resistance syndromes

Symptoms and Signs of Thyrotoxicosis
Hyperthyroidism is approx 10 times less common than hypothyroidism. Symptoms and signs of thyrotoxicosis are listed in Table 3-6 . Hyperthyroid elderly patients often have more cardiac symptoms but less systemic manifestations of thyrotoxicosis. Patients should be evaluated for signs or symptoms of weight loss, heat intolerance, tremor, palpitations, anxiety, menstrual abnormalities, and new onset atrial fibrillation. Evaluation should be considered, especially in patients with increased risk of hyperthyroidism, including a strong family history of thyroid dysfunction (hypothyroidism and hyperthyroidism), other autoimmune conditions, and long-standing goiter, especially after contrast or amiodarone administration. Routine screening of asymptomatic patients for hyperthyroidism is not recommended.
Table 3-6 Signs and Symptoms of Thyrotoxicosis General Skin Weight loss Excess perspiration Heat intolerance Palmer erythema Anxiety/nervousness   Insomnia Nervous System Muscle weakness Tremor   Anxiety/nervousness Cardiovascular Hyperkinesis Tachycardia   Palpitations Gastrointestinal Dyspnea on exertion Frequent stools/diarrhea Bounding pulses   Atrial fibrillation Reproductive   Irregular menstrual periods/amenorrhea Head and Neck Light menstrual flow Ophthalmopathy (Graves’ disease only: proptosis and chemosis) Infertility Stare Gynecomastia (males) Goiter  

Thyroid Tests in the Evaluation of Thyrotoxicosis
Measurement of serum TSH is the most sensitive way to diagnose hyperthyroidism, as it is always suppressed in primary hyperthyroidism. Patients with hyperthyroidism will almost always have a serum TSH concentration of < 0.1 mIU/L and often under 0.05 mIU/L. The use of a second-generation TSH assay with a functional sensitivity of < 0.2 mIU/L is sufficient for the diagnosis and management of hyperthyroidism. Secondary hyperthyroidism from a TSH-secreting pituitary adenoma is extremely rare but should be suspected when the patient has symptoms suggestive of hyperthyroidism with an inappropriately “normal” TSH. This rare clinical condition should be referred to an endocrinologist for further diagnosis and management.
Certain medical conditions (severe nonthyroidal illness, acute starvation, first-trimester pregnancy) and medications (glucocorticoids, dopamine), in addition to hypothalamic or pituitary disease, can result in low TSH. If any of these conditions are suspected, the help of a specialist is invaluable for determining the thyroid status of the patient.
An algorithm for ambulatory thyroid function testing for hyperthyroidism is shown in Figure 3-9 . If the TSH is within normal limits, the patient does not have hyperthyroidism and no further workup is indicated. Thyroid function tests should be repeated as clinically indicated. If the TSH is less than 0.3, thyroid hormone levels should be determined in addition to repeat measurement of TSH. Small increases of the thyroid hormone level will cause a disproportionate suppression of TSH because of their inverse log-linear relationship. The degree of hyperthyroidism cannot be assessed by second-generation assay TSH because even very mild thyrotoxicosis will suppress the TSH to very low levels. Although a third-generation assay can better differentiate between the degrees of hyperthyroidism, routine laboratory measurements of total T4, THBR, FT4I, and total T3 can easily and accurately assess the degree of hyperthyroidism. Measurement of total T3 is needed in the evaluation of hyperthyroidism. Graves’ disease excretes a relatively high ratio of T3/T4. If serum TSH is less than 0.3 and FT4I and total T3 is low, hypothalamic or pituitary disease needs to be considered. More often, however, this constellation of values will be associated with other conditions that result in low TSH concentration, such as nonthyroidal illness (see Figure 3-9 ).

Subclinical Thyrotoxicosis
If serum TSH is less than 0.3 and FT4I and total T3 are within normal limits, the patient has subclinical hyperthyroidism. These patients may have few or no symptoms of hyperthyroidism with the exception of tachycardia. 87 If the patient is taking thyroid hormone, the dose should be adjusted to normalize the TSH. The only clinical situation in which L-T4 suppression of TSH below the normal range is acceptable is in patients with thyroid cancer, where the goal of treatment is subclinical hyperthyroidism to suppress tumor growth in patients with a moderate or high risk of tumor recurrence or progression. L-T4 suppression to prevent nodule growth is not routinely recommended. 88
Subclinical hyperthyroidism (suppressed TSH, normal FT4I, and normal total T3) must be distinguished from nonthyroidal illness and malnutrition. Generally, a careful review of systems, past medical history, medications, weight loss, supplements, history of dieting for weight loss, and a physical examination will identify patients with a systemic nonthyroidal cause of a suppressed TSH. The optimal management for subclinical hyperthyroidism has not been established. Elderly patient studies with a baseline TSH between 0.2 and 0.4 mIU/L who were followed for a medium of 41 months rarely progressed to overt hyperthyroidism (1%/year); some returned to normal TSH level but most remained with subclinical hyperthyroidism. 89 The clinical importance of subclinical hyperthyroidism is its potentially adverse effects on bone and heart. Subclinical thyroid hormone excess is associated with cortical bone loss, 90 especially in postmenopausal but not premenopausal women and atrial fibrillation in the elderly. 87, 91 A practical approach has been to treat subclinical hyperthyroidism in patient with symptoms, osteoporosis, heart disease, atrial tachyarrhythmias, and enlarged nodular goiter, especially if elderly.

Etiology of Thyrotoxicosis
If the FT4I or T3 level is high, the patient has thyrotoxicosis and the etiology needs to be determined prior to initiating treatment. As mentioned earlier, the most common cause of hyperthyroidism is Graves’ disease. The clinical history and a careful examination may suffice to establish the etiology of hyperthyroidism. A patient who has a diffuse goiter, exophthalmos, and biochemical thyroxinemia needs no further laboratory studies for the clinician to make the diagnosis of Graves’ disease. Often, however, the exophthalmos is not present and the goiter may not be evident, especially in older patients who may not have classic symptoms. If the etiology of the thyrotoxicosis is not clear, a radionuclide thyroid scan and uptake, as described in the Thyroid Imaging in Hyperthyroidism section, Figure 3-9 , and Table 3-7 , will be helpful in making the diagnosis. Measurement of Tg may help to differentiate factitious thyrotoxicosis from overactive thyroid disease of any etiology. 57 Thyrotoxicosis from ingestion of synthetic L-T4 will suppress the function of the normal thyroid gland and result in very low levels of circulating Tg.

Table 3-7 Thyrotoxicosis and Radioactive Iodine Thyroid Scan and Uptake Results

Antithyroid Antibodies in Hyperthyroidism
Measurement of antithyroid antibodies is not essential if a thyroid scan is performed. As mentioned previously, the presence of antibodies is not diagnostic for any specific etiology, as many patients will have antibodies in the absence of disease, and a few patients will have autoimmune thyroid disease in the absence of antibodies. Thyroid sonography to confirm thyroiditis or a radionuclide thyroid scan can be used to confirm the diagnosis in a patient who is suspected of having Graves’ disease. High thyroid antibody levels correlate well with clinically important autoimmune thyroid disease. 3, 92 If antibodies are measured, only anti-TPOAb should be evaluated, as their presence highly correlates with the presence of other antibodies and they are elevated at presentation in 95% of patients with Graves’ thyrotoxicosis.

Thyroid Imaging in Thyrotoxicosis
The etiology of thyrotoxicosis is often determined after a detailed past medical and family history and physical exam are performed. If the etiology remains unclear, a thyroid scan will help to determine the etiology of the hyperthyroidism. Either a 123 I scan with uptake or 99m Tc thyroid scan with trapping is the preferred diagnostic study to determine the etiology of the biochemical evidence of thyrotoxicosis, as shown in Table 3-7 . It is important to remember that the uptake depends not only on the autonomy of the thyroid gland but also on the nonradioactive iodine intake of the patient. The nonradioactive iodine can compete with the radioactive iodine tracer, resulting in a reduced iodine uptake. Thus, in patients with a very high intake of iodine, the radioactive thyroidal iodine uptake may be normal or even low despite hyperthyroidism. A spot urinary iodine can confirm an excess iodine intake. Thyroid scans are contraindicated during pregnancy and lactation.

Monitoring of Patients with Hyperthyroidism
Treatment modalities for primary hyperthyroidism include radioactive ablation, antithyroid medications, and thyroidectomy. Radioactive ablation provides definitive treatment and is the modality preferred by endocrinologists in the United States, though surgery is performed in select cases (see Chapter 9, The Surgical Management of Hyperthyroidism ). Methimazole and propylthiouracil (PTU) block thyroid hormone synthesis and are the two medications approved in the United States for treatment of hyperthyroidism. A 2010 Food and Drug Administration (FDA) black box warning of severe liver toxicity from PTU has limited its use in selected hyperthyroid patients during the first trimester of pregnancy. 93 Beta-blockers are also used initially to ameliorate the cardiovascular and neuromuscular symptoms of thyrotoxicosis. Monitoring of thyroid status is done by measurement of TSH, total T4, an estimated free T4, and T3, with an adjustment of antithyroid medication every 1 to 2 months until euthyroid. Thyroid hormone levels tend to fluctuate frequently, because of the effect of the antithyroid treatment and the inherent variability of the thyroid disease. It is recommended that the management of the patient with hyperthyroidism is done by the endocrinologist.

Thyroid Function Testing and Pregnancy
The accuracy of THBR and analog-free T4 are poor during pregnancy in the setting of an elevated TBG. Recent studies examining thyroid function testing during pregnancy suggest that the thyroid status of a pregnant woman should be assessed with measurements of a serum TSH, total T4 (below 2x the upper reference range is normal) or FT4I. 14, 15 The analog free T4 immunoassay available at local hospitals has been shown to be inaccurate during pregnancy because of the high thyroid hormone binding proteins and should not be used during pregnancy. 15, 43 Therefore, first-trimester patients with a suppressed TSH and a normal or slightly elevated FT4I should not be treated for hyperthyroidism. Thyroid testing should be repeated in 4 weeks to confirm normalization of the TSH. If at any time during the pregnancy, the FT4I is significantly elevated, the patient is thyrotoxic and should have the appropriate treatment. If the TSH remains suppressed after the first trimester of pregnancy, an endocrinologist should evaluate the patient to confirm hyperthyroidism. Radionuclide imaging with any isotope is contraindicated in pregnancy.

Pregnancy and Hypothyroidism
Hypothyroidism is associated with menstrual irregularities and infertility. Therefore, the new diagnosis of severe hypothyroidism during pregnancy is uncommon. When diagnosed, hypothyroidism is almost always mild and almost always due to Hashimoto's thyroiditis. It is very important to make the diagnosis early, as hypothyroidism has been associated with maternal and fetal morbidity. An elevated TSH level confirms a diagnosis of hypothyroidism. We recommend screening for hypothyroidism with TSH in pregnant women with risk factors for autoimmune thyroid disease including a history of thyroid disease, goiter, other autoimmune disease, recurrent miscarriage, or family history of autoimmune thyroid disease ( Table 3-4 ). During pregnancy, the thyroid hormone requirements in the majority of patients may increase up to 50% compared to the patient's prepregnancy L-thyroxine dose. Frequent monitoring and adjustment of the L-thyroxine is needed during all three trimesters of pregnancy to maintain a TSH within the normal range, which is < 2.5 mIU/L during the first trimester and < 3 mIU/L during the remainder of the pregnancy according to the Endocrine Society Guidelines. 15, 94 - 96 The presence of antithyroid antibodies in the absence of thyroid dysfunction is associated with an increased risk for miscarriage. However, it is not recommended to measure antithyroid antibodies in all euthyroid pregnant women, as no established treatment modalities exist that would prevent miscarriage.

Thyroid Function Testing in Nonthyroidal Illness (Euthyroid Sick Syndrome)
Euthyroid sick syndrome refers to the abnormalities seen in thyroid function tests in the setting of nonthyroidal illness (see the Modalities of Thyroid Evaluation in Nonthyroidal Illness: Euthyroid Sick Syndrome section). It is not considered a primary thyroid disorder, and its pathophysiology is not clear. The evaluation of a chronically ill or hospitalized patient with abnormal thyroid function tests can often be confusing. It is recommended to avoid measuring thyroid function tests during illness, unless thyroid dysfunction is thought to contribute to the illness. Serum TSH, total T4, THBR, FT4I, total T3, and free level of T4 by equilibrium dialysis should be measured. It is important that the diagnosis of primary thyroid dysfunction is not established during severe illness based on an abnormal serum TSH. Typically in nonthyroidal illness, TSH may be low, normal, or high; T4 is low or normal; and T3 is reduced proportionately more than T4. Free levels of T4 are usually normal. rT3 may be measured, although this is not routinely done. It is usually increased in nonthyroidal illness. When possible, thyroid evaluation after recovery from the acute illness is recommended in patients suspected of having actual thyroid disease.
The use of a third-generation TSH assay can be helpful in this setting, as the serum TSH will almost always be measurable even if below the normal range. 30, 33 Up to 75% of patients with nonthyroidal illness who have an undetectable third-generation serum TSH level are thyrotoxic. Severe nonthyroidal illness total T4, THBR, and FT4I are usually low; total T3 is relatively lower than expected for the total T4 level, but the serum TSH measured by a third-generation assay is almost always measurable. During recovery from the acute illness, the TSH tends to rise for a short period of time prior to returning to normal.

Conclusions
In this chapter we reviewed thyroid physiology and tests for assessing thyroid function and dysfunction, which are critical tools for the surgeon and clinicians managing patients with thyroid disease. It is important to understand the change in thyroid physiology during pregnancy and during nonthyroidal illness in order to understand thyroid testing in this population. Specific tests are different for the evaluation of hypothyroidism and hyperthyroidism and when the patient is pregnant or has a nonthyroidal illness. Based on the knowledge of the physiology and pathophysiology of the thyroid, as well as a good history and family history, a systematic approach will allow for appropriate testing and treatment of thyroid dysfunction.

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For a complete list of references, go to expertconsult.com .

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Section 2
Benign Thyroid Disease
Chapter 4 Thyroiditis

Alan P. Farwell, Lewis E. Braverman

Introduction
Thyroiditis comprises a diverse group of disorders that are among the most common endocrine abnormalities encountered in medical endocrine clinical practice as well as by surgeons managing the thyroid. These disorders range from the extremely common chronic lymphocytic thyroiditis (Hashimoto's thyroiditis) to the extremely rare invasive fibrous thyroiditis (Riedel's thyroiditis) ( Table 4-1 ). Clinical presentations are also diverse, ranging from an incidental finding of a goiter to potentially life-threatening illness, from hypothyroidism to thyrotoxicosis. The term thyroiditis implies that the disorders described in this section are inflammatory processes involving the thyroid gland, although some of the lesions are not inflammatory and are included in the thyroiditis category largely for convenience. A rational approach to such patients, including history, physical examination, laboratory evaluation, radionuclide or ultrasonographic imaging, and fine-needle aspiration biopsy, will allow the appropriate diagnosis to be made in the majority of cases. This chapter reviews the evaluation, diagnosis, and management of thyroiditis in descending order of clinical frequency.
Table 4-1 Types of Thyroiditis (most common to least common) Chronic lymphocytic thyroiditis (Hashimoto's thyroiditis) Subacute lymphocytic thyroiditis —Postpartum thyroiditis —Sporadic silent thyroiditis Subacute granulomatous thyroiditis (De Quervain's thyroiditis) Drug-induced thyroiditis Radiation thyroiditis Acute suppurative/infectious thyroiditis —Bacterial, fungal, parasitic Invasive fibrous thyroiditis (Riedel's thyroiditis) Miscellaneous —Sarcoid, amyloid, traumatic, and palpation-induced thyroiditis

Hashimoto's Thyroiditis
Autoimmune thyroiditis, also known as struma lymphomatosa, chronic lymphocytic thyroiditis , and Hashimoto's thyroiditis, was first described by Hashimoto in 1912 ( Table 4-2 ). He described four patients with goiters, the thyroid histology of which were all characterized by diffuse lymphocytic infiltration, atrophy of parenchymal cells, fibrosis, and eosinophilic change in some of the parenchymal cells. Although this condition is common, there are several variants that differ somewhat from the one initially described by Hashimoto. 1 Classically, the disorder occurs as a painless diffuse goiter (goitrous form) in a young or middle-aged woman and often presents as an incidental finding during a routine physical examination. The atrophic form of Hashimoto's thyroiditis is less common and is usually diagnosed by the presence of thyroid antibodies in the hypothyroid patient with a normal-sized or atrophic thyroid. Although high circulating titers of antibodies to thyroid peroxidase (primarily) or thyroglobulin (less often) are almost always present, some patients with Hashimoto's thyroiditis do not have antibodies but do have a heterogeneous pattern on thyroid ultrasound. 2

Table 4-2 Comparison between the Syndromes of Thyroiditis
In iodine-sufficient countries, the most common cause of goiter, hypothyroidism, and elevated thyroid antibody levels is Hashimoto's thyroiditis. The incidence of autoimmune thyroiditis has increased over the past three generations, perhaps because of the increase in iodine intake that has occurred in the Western world. 1 Elevated serum thyroid antibody concentrations are found in approximately 10% of the United States population and in up to 25% of U.S. women over the age of 60. 1 About 45% of older women will have lymphocytic infiltration within the thyroid gland. Autoimmune thyroiditis has a female predominance with reported female-to-male ratios ranging between 5 to 1 and 9 to 1.

Pathogenesis
Although it is clear that Hashimoto's thyroiditis is an autoimmune disease, the nature of the autoimmune process is still debated. These disorders tend to aggregate in families, and a genetic link has been suggested. There have been associations between human leukocyte antigen (HLA)-DR3, HLA-DR4, and HLD-DR5, and Hashimoto's thyroiditis; however, this was demonstrated only in a cohort of Caucasian individuals. 1 Although HLA genes may be critical to the development of Hashimoto's thyroiditis, this weak association makes it clear that there are other genes that have not been identified as yet which play a role in this multigenic disease. Smoking has also been interestingly identified both as a risk factor for hypothyroidism 3 and to protect against hypothyroidism. 4
The defect in immunoregulation is currently a matter of debate. Human T lymphotropic virus-1 (HTLV-1) has been reported to be associated with autoimmune diseases, and carriers of the virus have been shown to have a higher frequency of thyroid antibody positivity as well as a higher incidence of Hashimoto's thyroiditis compared to controls. 5 , 6 Other theories hold that thyrocyte expression of class I and class II genes allows the thyrocyte to present antigen and thus induce autoimmune thyroid disease; however, in contrast, available evidence indicates that thyrocyte expression of these genes promotes anergy and thus may protect against autoimmune thyroid disease. 7 The prime defect probably lies in antigen-presenting genes in antigen-presenting cells, like macrophages, such that specific regulatory T lymphocytes are not fully activated. 8 This, together with environmental factors that may serve to down-regulate the immune system, may act together to disturb immunoregulation and allow for the development of autoimmune thyroid disease.
Many antibodies are often present in patients with Hashimoto's thyroiditis. Antithyroid peroxidase antibodies are complement fixing and are detectable in about 90% of patients with Hashimoto's thyroiditis. Antithyroglobulin antibody, a non-complement-fixing antibody, is found in about 20% to 50% of patients with Hashimoto's thyroiditis. 9 Thyrotropin (TSH) receptor antibodies that block TSH binding but do not stimulate the thyroid cell function may play a role in the clinical presentation of Hashimoto's thyroiditis, producing or exacerbating hypothyroidism in the absence of significant thyroid gland destruction. 10 Such antibodies have been reported to bind to epitopes near the carboxyl end of the TSH receptor extracellular domain, in contrast to thyroid-stimulating antibodies, which bind to epitopes near the amino terminus. 11 The prevalence of TSH receptor blocking antibodies in adult hypothyroid patients has been reported to be as high as 10% 12 and a decrease in the titer of these antibodies is likely to be responsible for “remission” of hypothyroidism in some patients with Hashimoto's thyroiditis. 13 Antibodies to colloid antigen, other thyroid autoantigens, T4 and T3, as well as other growth promoting and inhibiting antibodies may also be present.
Pathologically, there is lymphocytic infiltration of equal proportions of T and B cells and the formation of germinal centers (see Chapter 44 , Surgical Pathology of the Thyroid Gland). The follicular cells undergo metaplasia into larger, eosinophilic cells known as Hurthle or Askanazy cells, which are packed with mitochondria. These cells exhibit high metabolic activity but ineffective hormonogenesis. There is progressive fibrosis and the quantity of parenchymal tissue left in the thyroid is variable, as the pathologic involvement ranges from focal regions to an entire lobe to the entire gland. Although usually clear, the pathology needs to be differentiated from lymphoma of the thyroid.

Clinical Manifestations
Hashimoto's thyroiditis occurs most frequently in middle-aged women but can occur at any age. The usual presentation is as an incidental finding of a goiter during routine physical examination. Although usually asymptomatic, some patients may complain of an awareness of fullness in the neck. The usual course is for slow enlargement of the thyroid over years; however, the thyroid occasionally may enlarge rapidly and can produce compressive symptoms of dyspnea or dysphagia. Rarely, Hashimoto's thyroiditis may be painful 1 , 14 and must be distinguished from subacute thyroiditis (discussed later). Systemic symptoms of hypothyroidism will be present in up to 20% of patients at the time of diagnosis, 15 although this incidence is a bit higher with the atrophic form of the disorder. Conversely, Hashimoto's thyroiditis is found to be the etiology in the majority of patients in the United States with hypothyroidism.
Physical examination typically reveals a firm, lobulated, nontender goiter, which is generally symmetric, often with a palpable pyramidal lobe. Regional lymph node enlargement may be observed. Although nodular thyroid disease can, and frequently does, occur in Hashimoto's thyroiditis, single nodules and dominant nodules in a multinodular gland should be evaluated with a fine-needle aspiration biopsy to rule out a coexistent malignancy. Ophthalmopathy is present in a small subset of patients with Hashimoto's thyroiditis. 16 Further, there is evidence of chronic autoimmune thyroiditis in many patients with euthyroid Graves’ ophthalmopathy.
The hallmark of Hashimoto's thyroiditis is elevated thyroid antibody levels. The majority of individuals with elevated thyroid antibody levels are biochemically euthyroid. Up to 10% of postmenopausal women with an elevated thyroid antibody level have an increased TSH, but a minority of these (~ 0.5%) will have overt hypothyroidism. 1 Women with elevated thyroid antibody levels have been reported to develop overt hypothyroidism at a rate of 2% to 4% per year. 1, 15, 17 Mild thyrotoxicosis (“Hashitoxicosis”) has been reported to be the initial manifestation in some patients with Hashimoto's thyroiditis, 18 especially in children. The clinical course in these patients follows a pattern similar to that observed in sporadic silent or postpartum thyroiditis (discussed later), suggesting that differentiation between these disorders may be largely semantic.
The diagnosis of Hashimoto's thyroiditis is confirmed by the presence of antithyroid antibodies. Serum T4 and TSH concentrations depend on the level of thyroidal dysfunction that is present and are not specific to hypothyroidism caused by Hashimoto's thyroiditis. Serum T3 concentrations are often preserved in all but the most severely hypothyroid patient and, thus, are of little clinical utility. Similarly, the radioactive iodine uptake is usually not helpful, as it may be elevated, normal, or depressed. Thyroid isotope scanning usually reveals patchy uptake and, in general, provides little useful information unless a dominant thyroid nodule is present. Ultrasound examination of the thyroid frequently reveals marked hypoechogenicity with pseudonodules. 2
When imaged, an enlarged thymus gland is frequently found in Hashimoto's thyroiditis and may be important in the pathogenesis of the condition. In both affected patients and their relatives, there is an association with other autoimmune diseases including insulin-dependent diabetes mellitus, pernicious anemia, Addison's disease, and vitiligo. Thyroid lymphoma is rare; however, the risk is increased in those individuals with Hashimoto's thyroiditis by a factor of 67. 1 , 19 In patients in whom a fine-needle aspiration biopsy is performed, lymphocyte subsets should be determined on the biopsy specimen if the more typical pathologic features of Hashimoto's thyroiditis are not present.

Clinical Management
Treatment of Hashimoto's thyroiditis consists of thyroid hormone replacement if hypothyroidism is present. Levothyroxine is the hormone of choice for thyroid hormone replacement therapy because of its consistent potency and prolonged duration of action. The average daily adult replacement dose of levothyroxine sodium in a 68-kg person is 112 μg. Institution of therapy in healthy younger individuals can begin at full replacement doses. Because of the prolonged half-life of thyroxine (7 days), new steady-state concentrations of the hormone will not be achieved until 4 to 6 weeks after a change in dose. Thus, reevaluation with determination of serum TSH concentration need not be performed at intervals less than 6 to 8 weeks. The goal of thyroxine replacement therapy is to achieve a TSH value in the normal range, as over-replacement of thyroxine suppressing TSH values to the subnormal range may induce bone loss (especially in postmenopausal women) and cardiac dysfunction, most often atrial fibrillation. 20 In noncompliant, young patients, the cumulative weekly doses of levothyroxine may be given as a single weekly dose, which is safe, effective, and well tolerated. In individuals over the age of 60, institution of therapy at a lower daily dose of levothyroxine sodium (25 μg per day) is indicated to avoid the exacerbation of underlying and undiagnosed cardiac disease. Daily doses of thyroxine may be interrupted periodically because of intercurrent medical or surgical illnesses that prohibit taking medications by mouth. A lapse of several days of hormone replacement is unlikely to have any significant metabolic consequences. However, if more prolonged interruption in oral therapy is necessary, levothyroxine may be given intravenously at a dose 25% to 50% less than the patient's daily oral requirements.
The treatment of the euthyroid, asymptomatic patient is not so clear-cut and the recommendations for treatment of a mild increase in TSH without a corresponding low T4 concentration are divided. 20 , 21 In addition to replacement therapy, thyroid hormone therapy may be considered in the patient with a serum TSH in the normal range in an attempt to decrease the size of a goiter or as a preventative measure to preclude the development of hypothyroidism. However, goiter regression with L-T4 is frequently not generally significant, even in the subset of patients early in the course of the disease and before fibrosis. The goal of such levothyroxine suppression therapy is to decrease the serum TSH into the subnormal range. Patients on levothyroxine suppression therapy should be reevaluated periodically and the suppressive levothyroxine dose should be reduced or discontinued if the goiter does not reduce significantly. Surgery is, of course, indicated for compressive goiters with local obstructive symptoms (see Chapter 7 , Surgery of Cervical and Substernal Goiter).

Sporadic Silent and Postpartum Thyroiditis
Sporadic silent thyroiditis and postpartum thyroiditis, also known as subacute lymphocystic thyroiditis , along with subacute granulomatous thyroiditis (discussed later), are a group of disorders also known as the destruction-induced thyroididities . 22 - 25 The clinical hallmarks of the destruction-induced thyroiditides begin with the abrupt onset of thyrotoxic symptoms, which is associated with a low-thyroid radioactive iodine uptake ( Table 4-3 ) and elevated serum thyroid hormone and thyroglobulin concentrations, consistent with the leakage of preformed hormone from a damaged gland. Development of a nontender goiter or enlargement of a preexisting goiter almost always accompanies this. Following a brief euthyroid phase as the thyroid hormones fall back into the normal range, hypothyroidism ensues, which is a consequence of depleted thyroid hormone stores and, possibly, recent TSH suppression during the thyrotoxic phase. Because the destructive process is self-limited, however, recovery generally occurs.
Table 4-3 Causes of Low Radioactive Iodine Uptake Thyrotoxicosis Postpartum lymphocytic thyroiditis Silent lymphocytic thyroiditis Subacute granulomatous thyroiditis Iodine-induced thyrotoxicosis Drug-induced thyroiditis Thyrotoxicosis factitia Metastatic thyroid cancer Struma ovarii

Pathogenesis
Sporadic silent thyroiditis and postpartum thyroiditis are probably variants of the same disorder, distinguished only by their relationship to pregnancy. Their histopathologies are similar, as are their clinical courses and laboratory features (see Chapter 44 , Surgical Pathology of the Thyroid Gland). Postpartum thyroiditis is more clearly defined than sporadic silent thyroiditis, because it is easier to study the disorder in a prospective fashion and it is far more common than sporadic silent thyroiditis. Both of these disorders are autoimmune in nature. Women who test positive for antithyroid antibodies at delivery or during the first trimester have a higher risk of developing postpartum thyroiditis. 22 - 25 With the onset of postpartum thyroiditis itself, antithyroid antibody titers increase further. Elevated circulating levels of antithyroid antibodies have also been reported in sporadic silent thyroiditis. In addition, postpartum thyroiditis occurs more frequently in individuals with other autoimmune diseases, particularly those with type 1 diabetes mellitus. 26 Finally, patients with postpartum thyroiditis are more likely to have a family history of autoimmune thyroid disorders. 27
Thyroid autoimmunity in sporadic silent and postpartum thyroiditis is probably inherited and it has been proposed that “numerous genetic susceptibility factors contribute to the clinical spectrum of postpartum thyroiditis,” 28 which would be consistent with the observations that postpartum thyroiditis is weakly associated with genes that regulate immune function. 29 These include, in certain populations, HLA-DR4, -DR5, and -DR3 in combination with –A1 and –B8. 24 , 29 Initial studies of an association between postpartum thyroiditis and CTLA-4 gene polymorphisms 28 have been negative; however, studies in larger populations may be needed to establish an association. CTLA-4 polymorphisms are associated with Graves’ disease and autoimmune hypothyroidism. 30 , 31 A role for fetal microchimerism has been proposed as a mechanism of immunomodulation in postpartum thyroiditis. 32
Histopathology shows extensive lymphocytic infiltration, collapsed follicles, and degeneration of follicular cells 23 - 25 , 28 , 33 (see Chapter 44 , Surgical Pathology of the Thyroid Gland). The changes can be either focal or diffuse with lymphoid follicles being present in about half of the patients. 33 However, unlike Hashimoto's thyroiditis, there is usually no stromal fibrosis, oxyphilic changes, or germinal centers. Most intrathyroidal lymphocytes have the T-cell phenotype, and the distribution of T and B cells is similar in Hashimoto's thyroiditis and sporadic silent thyroiditis. 33 There is focal or diffuse chronic thyroiditis in the early stages of this disorder; during the recovery phase follicular disruption and hyperplastic changes of the follicles are common. The inflammatory changes noted earlier are seen as hypoechogenicity on ultrasound. 34 The hypoechogenicity resolves with the resolution of the thyroiditis; persistence of hypoechogenicity is frequently observed in those individuals with permanent hypothyroidism.
Smoking increases the risk of developing postpartum thyroiditis, whereas age, parity, the sex or birth weight of the neonate, and the duration of breastfeeding has little influence in this regard. 23 - 25 Adaptations of the immune system during pregnancy and their reversal after delivery may play a role in the induction of postpartum thyroiditis. During pregnancy the maternal immune response is biased toward antibody production and away from cell-mediated immunity. Normally in pregnancy the T-cell helper/suppressor ratio falls, and there are T-cell subset changes. Women who develop postpartum thyroiditis have lesser changes in their T-cell helper suppressor ratio. 35 Environmental factors, such as iodine intake, may influence the incidence and severity of postpartum thyroiditis. 36 Recently, a role for selenium in thyroid autoimmunity has been proposed. 37 Indeed, a recent study of selenium supplementation during pregnancy and the postpartum period decreased the incidence of postpartum thyroiditis. 38

Clinical Manifestations
The incidence of postpartum thyroiditis after delivery is variable, ranging from 2% to 21% of postpartum women in different studies. 23 - 25 Sporadic silent thyroiditis accounts for less than 1% of patients with newly diagnosed thyrotoxicosis 39 and is more common in women than in men.
Sporadic silent and postpartum thyroiditis are usually transient disorders consisting of four phases ( Figure 4-1 ), although not all phases are seen in all patients. 23 - 25 Clinical presentation is similar in both sporadic silent and postpartum thyroiditis and varies from overt thyrotoxicosis to thyroid enlargement with minimal thyroid dysfunction or hypothyroidism, depending on the stage in which the diagnosis is made. A nontender goiter is usually present. The initial phase is one of thyrotoxicosis, caused by the “leak” of thyroid hormone from the regions of lymphocytic infiltration within the thyroid gland. In postpartum thyroiditis, this occurs within a few weeks to 2 months following delivery. Tachycardia, palpitations, heat intolerance, and emotional disturbances are characteristic of the thyrotoxic phase of sporadic silent thyroiditis and postpartum thyroiditis. The ratio of serum T 3 to serum T 4 is lower in sporadic silent thyroiditis and postpartum thyroiditis than it is in Graves’ disease 40 ; therefore, patients are less symptomatic. Features that develop with long-standing thyrotoxicosis, such as substantial weight loss or severe muscle weakness, are unusual.

Figure 4-1 Clinical progression of destruction-induced thyroiditis.
(Modified from Woolf OD: Transient painless thyroiditis with hyperthyroidism: a variant of lymphocytic thyroiditis? [Review]. Endocr Rev 1:411, 1980.)
A brief period of euthyroidism follows the thyrotoxic phase and may last for a few months. 41 As the gland becomes depleted of hormone, hypothyroidism ensues and may last for up to a year. Fatigue, malaise, impaired concentration, carelessness, and symptoms related to depression are common in patients in the hypothyroid phase. Indeed, positive tests for antithyroid antibodies during gestation are associated not only with the development of postpartum thyroiditis but also with postpartum depression. 42 However, postpartum depression is not related to hypothyroidism alone, as the majority of patients with postpartum depression have normal thyroid function tests. Although severe depression may occur in a small number of women with postpartum thyroiditis, this disorder is not an important contributor to most cases of postpartum depression.
In general, the duration of hypothyroidism in those patients who initially present with thyrotoxicosis is likely to be brief. Hypothyroidism tends to be more severe and prolonged if it is the presenting disorder. Most patients do return to a euthyroid state, but up to 20% remain permanently hypothyroid, 23 - 25 although some recent studies suggest a higher incidence of permanent hypothyroidism. 43 The features associated with the development of permanent hypothyroidism are multiparity, a history of spontaneous abortion, high titers of antithyroid antibodies, the lack of a detected thyrotoxic phase, more severe degrees of hypothyroidism during postpartum thyroiditis, and persistent hypoechogenicity on ultrasound. Recurrences are common, as women with postpartum thyroiditis have a 70% risk of developing the syndrome after a subsequent pregnancy. 23 - 25 Follow-up is essential in sporadic silent thyroiditis as well, as recurrences are not unusual and patients are likely to eventually develop permanent hypothyroidism. Further, these patients are susceptible to iodine-induced hypothyroidism years later as may be seen in other disorders of the thyroid. 44 , 45
Although the major clinical feature that distinguishes sporadic silent or postpartum thyroiditis from subacute thyroiditis (discussed later) is the presence of thyroid pain and tenderness, thyroidal pain has occasionally been reported in sporadic silent thyroiditis. Fine-needle aspiration biopsies consistent with chronic lymphocytic thyroiditis were described in five of eight patients presenting with destruction-induced thyrotoxicosis and thyroidal pain. 46 These patients also had high titers of antithyroid antibodies, and many of them developed permanent hypothyroidism. Conversely, painless destruction-induced thyrotoxicosis with pathologic changes characteristic of subacute thyroiditis has been reported in 10 of 12 patients in the Netherlands. 47

Differential Diagnosis
Subacute thyroiditis, sporadic silent thyroiditis, and postpartum thyroiditis are not the only forms of thyrotoxicosis in which the radioactive iodine uptake is low (see Table 4-3 ). 48 This is also the case for thyrotoxicosis of extra-thyroidal origin, such as struma ovarii and ingestion of supraphysiologic amounts of thyroid hormone. The most useful laboratory test in the diagnosis of thyrotoxicosis factitia is the serum thyroglobulin concentration. Serum thyroglobulin is low in patients who are ingesting extra thyroid hormone and is elevated in all other causes of thyrotoxicosis, including struma ovarii. 49 Additionally, thyroid enlargement is common in destruction-induced thyrotoxicosis but unusual in thyrotoxicosis of extrathyroidal origin.
Sporadic silent thyroiditis and postpartum thyroiditis can be mistaken for Graves’ disease leading to the inappropriate use of antithyroid drugs, which are contraindicated in patients with thyrotoxicosis. Radioisotope studies are recommended in thyrotoxic patients who do not have a goiter, if they have recently been pregnant, or if they have had an abrupt onset of thyrotoxicosis. However, radioiodine studies are relatively contraindicated in the nursing mother and, if performed, require pumping and discarding breast milk for two days following the study. Measurement of the thyroid-stimulating immunoglobulin (TSI) is also helpful in differentiating between these two conditions, as it is usually elevated in Graves’ disease and negative in postpartum thyroiditis. 50 It is important to measure serum TSH at the time the radioisotope test is performed because the radioactive iodine uptake may be normal or elevated as the patient recovers from the acute thyrotoxic phase. Postpartum thyroiditis is not the only autoimmune postpartum thyroid disorder. Exacerbation or relapse of Graves’ disease is prone to occur after delivery, and a few patients experience both Graves’ disease and postpartum thyroiditis. 23 - 25 Serum thyroglobulin concentrations are elevated in both conditions, but in postpartum thyroiditis the rise in serum thyroglobulin precedes the onset of thyrotoxicosis, whereas in Graves’ disease, increases in serum thyroglobulin and thyroid hormone occur together. 51 Sporadic silent thyroiditis and postpartum thyroiditis are distinguished from each other by the setting in which they occur, because postpartum thyroiditis, by definition, occurs within weeks to months after delivery.

Clinical Management
The thyrotoxic phase of sporadic silent and postpartum thyroiditis should be treated symptomatically with beta-adrenergic blocking drugs if signs and symptoms of thyrotoxicosis are moderate or severe. Antithyroid drugs have no role, as thyroid hormone biosynthesis is not increased. Although sodium ipodate and iopanoic acid have been utilized to achieve rapid control of severe thyrotoxicosis in patients with thyroiditis in the past, neither of these two valuable medications is currently available.
Treatment of hypothyroidism may be necessary in either sporadic silent or postpartum thyroiditis if symptoms are pronounced or prolonged. However, if L-thyroxine therapy is instituted, it can be withdrawn after 6 to 9 months to determine whether recovery of thyroid function has occurred. In some patients it is reasonable to continue thyroid hormone indefinitely if a goiter persists or they have prognostic features that are associated with the development of permanent hypothyroidism, such as persistent goiter and extensive hypoechogenicity on ultrasound. 2

Subacute Thyroiditis/De Quervain's Thyroiditis
Subacute thyroiditis, like painless sporadic and postpartum thyroiditis, is a spontaneous remitting inflammatory disorder of the thyroid that may last for weeks to months 1 , 52 (see Table 4-2 ). This disorder has a number of eponyms, including De Quervain's thyroiditis, giant cell thyroiditis, pseudo-granulomatous thyroiditis, subacute painful thyroiditis, subacute granulomatous thyroiditis, acute simple thyroiditis, noninfectious thyroiditis, acute diffuse thyroiditis, migratory “creeping” thyroiditis, pseudotuberculous thyroiditis, and viral thyroiditis. The first description of subacute thyroiditis was in 1895 by Mygind, who reported 18 cases of “thyroiditis akuta simplex.” 52 However, the pathology of subacute thyroiditis was first described in 1904 by Fritz De Quervain, whose name is associated with the disorder, when he showed giant cells and granulomatous-type changes in the thyroids of affected patients. Subacute thyroiditis is the most common cause of the painful thyroid and may account for up to 5% of clinical thyroid abnormalities. 1 , 52 As with other thyroid disorders, women are more frequently affected than men, with a peak incidence in the fourth and fifth decades. This disorder is rarely observed in children and the elderly. Although the term subacute thyroiditis connotes a temporal quality that could apply to any thyroidal inflammatory process of intermediate duration and severity, it is actually referring specifically to the granulomatous appearance of the thyroid found on pathologic exam. This pathologic appearance of the thyroid is specific for the disease (see Chapter 44 , Surgical Pathology of the Thyroid Gland).

Pathogenesis

Infectious Association
Although there is no clear evidence for a specific etiology, indirect evidence suggests that subacute thyroiditis may be caused by a viral infection of the thyroid. 53 , 54 The condition is often preceded by a prodromal phase of myalgia, malaise, low-grade fevers, fatigue, and frequently by an upper respiratory tract infection. It has been reported most frequently in the temperate zone, and only rarely from other parts of the world. It has been found to occur seasonally; the highest incidence is in the summer months (July through September), which coincide with the peak of enterovirus (echovirus, Coxsackie virus A and B) infection. 5 The incidence rate has been shown to vary directly with viral epidemics; during certain viral epidemics, specifically mumps, the incidence of subacute thyroiditis has been found to be higher. Interestingly, antibodies to the mumps virus have even been detected in individuals with subacute thyroiditis who do not have clinical evidence of mumps. Subacute thyroiditis has also been associated with measles, influenza, the common cold, adenovirus, infectious mononucleosis, Coxsackie virus, myocarditis, cat scratch fever, St. Louis encephalitis, hepatitis A, and the parvovirus B19 infection. Antibodies to Coxsackie virus, adenovirus, influenza, and mumps have been detected in the convalescent phase of this disease. 55 Coxsackie virus is most commonly associated with subacute thyroiditis and, in fact, Coxsackie virus antibody titers have been shown to directly follow the course of the thyroid disease. 5 Isolation of a cytopathic virus of possible pathogenic significance from the thyroids of 5 of 28 patients with subacute thyroiditis was reported in 1976. 56
Certain nonviral infections, including Q fever and malaria, have been associated with a clinical syndrome similar to subacute thyroiditis.In addition, a case of subacute thyroiditis occurring simultaneously with giant cell arteritis has been reported. 57 Another case of subacute thyroiditis developed during α-interferon treatment for hepatitis C. 58

Autoimmune Association
Unlike painless or postpartum thyroiditis, there is no clear association between subacute thyroiditis and autoimmune thyroid disease. Serum thyroid peroxidase and thyroglobulin antibodies levels are usually normal. When described, the levels of thyroid peroxidase and thyroglobulin antibodies correlated with the phase of transient hypothyroidism. Antibodies to an unpurified thyroid preparation can be detected for up to 4 years after a bout of subacute thyroiditis.
Antibodies to the thyrotropin (TSH) receptor have been rarely detected during the course of subacute thyroiditis. 59 In most studies, there was no correlation between the presence of thyrotropin-receptor-binding inhibitory immunoglobulin (TBII) or of thyrotropin-receptor-stimulating immunoglobulin and the thyrotoxic phase of the thyroiditis. On the other hand, there has been some correlation between thyroid-blocking antibodies and the development of hypothyroidism. It is thought that the appearance of the TSH-receptor antibodies results from an immune response that occurs after there is damage to the thyrocytes, specifically membrane desquamation. 53 , 54 Following recovery from the inflammatory process of subacute thyroiditis, all immunologic phenomena disappear. 59 The transitory immunologic markers that are observed during the course of subacute thyroiditis appear to occur in response to the release of antigenic material from the thyroid.

Genetic Association
There is an apparent genetic predisposition for subacute thyroiditis, with HLA-Bw 35 reported in all ethnic groups. 52 The relative risk of HLA-Bw 35 in subacute thyroiditis is high, ranging from 8 to 56. 52 Additional evidence for genetic susceptibility is the simultaneous development of subacute thyroiditis in identical twins heterozygous for the HLA-Bw 35 haplotype. 60 However, an epidemic of “atypical” subacute thyroiditis was described in a town in the Netherlands where HLA-B15/62 was found in five of eleven patients tested, whereas only one patient tested positive for HLA-Bw 35. 47 Finally, a weak association of subacute thyroiditis with HLA-DRw8 has been reported in Japanese patients. 61

Clinical Manifestations
The manifestations may be preceded by an upper respiratory tract infection, or a prodromal phase of malaise, generalized myalgia, pharyngitis, and low-grade fevers. Pain or swelling in the thyroid region develops later accompanied by higher fevers; up to 50% of patients have symptoms of thyrotoxicosis. 1 Pain may be moderate or severe; rarely symptoms are entirely lacking. Similarly, tenderness may be moderate or severe (or even exquisite) or, conversely, may rarely be lacking. One of the lobes may be involved initially and later spread to the opposite lobe (“creeping thyroiditis”), or it may involve both lobes from the outset. The systemic reaction may be minimal or severe, and fevers may reach 40°C. Rarely, subacute thyroiditis may present as a nontender solitary nodule. In these cases, the diagnosis has been made after fine-needle aspiration biopsy. Atypical presentations are often misdiagnosed as papillary cancer.
Patients can generally localize the pain to the thyroid region over one or both lobes. They may refer to their symptoms as a “sore throat,” but upon specific questioning it becomes apparent that pain is in the neck, not within the pharynx. Typically, pain radiates from the thyroid region up to the angle of the jaw or to the ear on the affected side(s). The pain may also radiate to the anterior chest or may be centered over the thyroid only. Moving the head, swallowing, or coughing may aggravate pain. Although an occasional patient may have no systemic symptoms, most complain of myalgia, fatigue, and fevers. Malaise can be extreme and can be associated with arthralgias.
On physical exam, most patients appear uncomfortable and flushed on inspection, with variable elevations in temperature. Palpation usually reveals an exquisitely tender, hard, ill-defined nodular thyroid. The tender region may encompass an entire lobe and mild tenderness may be present in the contralateral lobe. The overlying skin is occasionally warm and erythematous. Cervical lymphadenopathy is rarely present. Although the majority of patients are only mildly to moderately ill, subacute thyroiditis may have a dramatic presentation, with marked fever, severe thyrotoxicosis, and obstructive symptoms resulting from pronounced thyroid inflammation and edema.
During the active/painful phase of subacute thyroiditis, the erythrocyte sedimentation rate is usually markedly elevated. In fact, a normal erythrocyte sedimentation rate essentially rules out subacute thyroiditis as a tenable diagnosis. The white blood count is normal to mildly increased, and there is often a normochromic, normocytic anemia. There are also increases in serum ferritin, soluble intercellular adhesion molecule-1, selectin, interleukin-6 levels, and C-reactive protein during the inflammatory phase. 53 , 62 Alkaline phosphatase and other hepatic enzymes may be elevated in the early phase. It has been suggested that subacute thyroiditis may actually represent a multisystem disease also affecting the thyroid.
In the thyrotoxic phase, the serum T 4 concentration is disproportionately elevated relative to the serum T 3 concentration, reflecting the intrathyroidal T 4 :T 3 ratio. In addition, the acute illness decreases the peripheral deiodination of T 4 to T 3 , resulting in lower serum T 3 concentrations than expected. Serum TSH concentrations are low to undetectable. It is important to note in subacute thyroiditis, antibodies directed against thyroglobulin and thyroid peroxidase are either absent or present in low titer; these develop several weeks after disease onset and tend to disappear thereafter.
The radioactive iodine uptake during the thyrotoxic phase is low, most often < 2% at 24 hours. As with the erythrocyte sedimentation rate discussed earlier, a normal radioactive iodine uptake essentially rules out subacute thyroiditis as a tenable diagnosis. Ultrasound may show generalized, multiple, or single regions of hypoechogenicity. 63
The primary events in the pathology of subacute thyroiditis are destruction of the follicular epithelium and loss of follicular integrity; however the histopathologic changes are distinct from those found with Hashimoto's thyroiditis (see Chapter 44 , Surgical Pathology of the Thyroid Gland). The lesions are patchy in distribution and are of varying stages of development, with infiltration of mononuclear cells in affected regions and partial or complete loss of colloid and fragmentation and duplication of the basement membrane. Histiocytes congregate around masses of colloid, both within the follicles and in the interstitial tissues, producing “giant cells”; often these “giant cells” consist of masses of colloid surrounded by large numbers of individual histiocytes, so they more accurately should be termed pseudo-giant cells. The term granulomatous thyroiditis, a synonym for subacute thyroiditis, should likewise be changed to pseudo-granulomatous thyroiditis. However, true giant cells and granulomas do appear in this disease as well.
During recovery, the inflammation recedes and there is a variable amount of fibrosis and fibrotic band formation. In addition, follicular regeneration occurs without caseation, hemorrhage, or calcification. Recovery is generally complete. Only in the rare instance is there complete destruction of the thyroid parenchyma that leads to permanent hypothyroidism. In the few electron microscopic studies reported, viral inclusion bodies have not been demonstrated. Fine-needle aspiration biopsies often show large numbers of histiocytes, epithelioid granulomas, multinucleated giant cells, and follicular cells with intravacuolar granules. 64

Differential Diagnosis
Subacute thyroiditis must be differentiated from the other causes of anterior neck pain ( Table 4-4 ). The diagnosis should present no difficulties in patients with typical manifestations. However, because “sore throat” is a frequent complaint, many patients are initially misdiagnosed with pharyngitis. Acute hemorrhage into a nodule or cyst and nonthyroidal etiologies can be differentiated with radioiodine scanning, as there will be normal function in the nonaffected areas of the gland. Painful Hashimoto's thyroiditis, as relatively rare condition, usually involves the entire gland and antibodies directed against thyroglobulin and thyroid peroxidase are usually present in high titer. Acute suppurative thyroiditis is distinguished by a much greater leukocytosis and febrile response, a greater inflammatory reaction in surrounding tissues, and often a septic focus is evident elsewhere, such as the urinary or respiratory tracts. The radioactive iodine uptake is usually normal in acute suppurative thyroiditis, and the scan will reveal decreased uptake in the region of suppuration.
Table 4-4 Differential Diagnosis of the Painful Neck Mass Thyroidal  Subacute thyroiditis  Acute suppurative thyroiditis  Acute hemorrhage into a cyst  Acute hemorrhage into a benign or malignant nodule  Rapidly enlarging thyroid carcinoma  Painful Hashimoto's thyroiditis  Radiation thyroiditis  Painful amiodarone-induced thyroiditis Nonthyroidal  Infected thyroglossal duct cyst  Infected branchial cleft cyst  Infected cystic hygroma  Cervical adenitis  Cellulitis of the anterior neck Other  Globus hystericus
Rarely, infiltrating cancer of the thyroid can present with a clinical and laboratory picture indistinguishable from subacute thyroiditis, requiring fine-needle aspiration biopsy for the diagnosis. Amiodarone, an iodine-rich antiarrhythmic drug, may cause iodine-induced thyrotoxicosis (Jod-Basedow's disease) and, less commonly, thyroiditis, which may occasionally be painful. Both sporadic silent and postpartum thyroiditis follow a similar clinical course as subacute thyroiditis but lack the clinical feature of a painful goiter. In addition, patients with painless or postpartum thyroiditis often exhibit high titers of antithyroglobulin and antithyroid peroxidase antibodies, and the erythrocyte sedimentation rate is normal to only slightly elevated. Fine-needle aspiration biopsies may be useful but may show large numbers of histiocytes and thus may be misleading.

Clinical Management
Despite the differing etiologies, the clinical course of subacute thyroiditis is similar to that of painless and postpartum thyroiditis (discussed earlier). The initial phase is characterized by pain and thyrotoxicosis in most patients and may last up to 3 to 4 months. The thyrotoxicosis may not be clinically apparent in some instances and may be mild when it is clinically evident. As noted previously, the thyrotoxicosis is due to a disruptive process within the thyroid causing leakage of colloid material into the interstices, where it liberates thyroid hormones, thyroglobulin, and other iodoamino acids into the circulation. If present, beta-adrenergic blocking drugs such as propranolol are useful. Antithyroid drugs have no role in the management of subacute thyroiditis, as the gland is not hyperfunctioning.
Salicylates and nonsteroidal anti-inflammatory drugs are often adequate to decrease thyroidal pain in mild to moderate cases. In more severe cases, oral glucocorticoids (prednisone up to 40 mg per day) provide dramatic relief of pain and swelling, often within a few hours of administration and in most cases within 24 to 48 hours. In fact, if thyroidal/neck pain fails to begin to improve after 24 hours of corticosteroid therapy, the diagnosis of subacute thyroiditis should be questioned. Despite the clinical response to corticosteroids, the underlying inflammatory process may persist, and symptoms may recur if the dose is tapered too rapidly. Up to one third of patients will have a recurrence of thyroidal pain if prednisone is discontinued too soon, which responds to restarting the corticosteroid. In general, full-dose corticosteroids are given for a week, followed by tapering the dose over at least 4 to 6 weeks.
Determination of the radioactive iodine uptake before discontinuing prednisone may be helpful in identifying those patients at high risk for relapse. If the radioactive iodine uptake is still low, the inflammatory process is ongoing and corticosteroids should not be discontinued. If the radioactive iodine uptake has returned to normal or is elevated, then the corticosteroid can be safely withdrawn. 65 Patients with recurrent exacerbations of symptoms after withdrawal of corticosteroids usually respond to reinstitution or continuation of the corticosteroids for an additional month. Although subacute thyroiditis is a self-limited disease and the majority of patients respond to the measures discussed here, there are occasional patients who suffer from repeated exacerbations of pain and inflammation. In these patients, therapy with L-thyroxine or L-triiodothyronine has been helpful in preventing exacerbations, suggesting that endogenous TSH may contribute to their occurrence. Rarely, thyroidectomy or thyroid ablation with radioactive iodine (providing that the radioactive iodine uptake has returned to normal) may be necessary for management of patients with protracted courses of severe neck pain and malaise.
After the acute phase, a period of transient (1 to 2 months) asymptomatic euthyroidism follows. Hypothyroidism may occur after several more weeks and may last for 6 to 9 months. The final recovery phase follows, when all aspects of thyroid function return to normal, including morphology. Hypothyroidism may be permanent in up to 5% of patients and relapse of subacute thyroiditis is rare, occurring in < 2% of patients. 66 However, some patients with a history of subacute thyroiditis were found to be particularly sensitive to the inhibitory effects of exogenously administered iodides resulting in hypothyroidism, suggesting a persistent thyroid abnormality. 45 Thus, long-term follow-up of patients after an episode of subacute thyroiditis is recommended.

Drug-Induced Thyroiditis
Several drugs have been reported to cause a drug-induced thyroiditis 67 - 70 ( Table 4-5 ). In addition, lithium has been reported to cause a nondestructive thyroiditis, similar to sporadic silent thyroiditis. 71 , 72 The clinical course of the thyroiditis is similar to the other forms of destructive thyroiditis (see Figure 4-1 ). Importantly, patients on the offending drugs may also develop subacute, sporadic, or suppurative thyroiditis, so these diagnoses need to be evaluated before ascribing the thyroiditis to a drug. The thyroid abnormalities usually resolve with discontinuation of the offending drug. Two drugs that deserve special mention are amiodarone and interferon-alfa.
Table 4-5 Causes of Drug-Induced Thyroiditis Amiodarone Interferon-alfa Interleukin-2 Lithium Minocycline
Amiodarone, an iodine-rich drug used in the treatment of cardiac arrhythmias, is well recognized to produce thyrotoxicosis by two forms: (1) iodine-induced hyperthyroidism (type I) and (2) destructive thyroiditis (type II). 67 , 73 Distinguishing between the two forms is often a diagnostic dilemma, and occasionally both forms may be present in the same patient. In general, type II amiodarone-induced thyrotoxicosis occurs in a previously normal thyroid, the 24 RAIU is completely suppressed, and color flow Doppler ultrasonography shows absent vascularity. The thyrotoxicosis usually responds to high doses of prednisone (40 to 60 mg daily), consistent with the underlying inflammatory process. In all cases of amiodarone-induced thyrotoxicosis, the drug should be discontinued if at all possible.
Interferon-alpha is an immunomodulatory drug that is used in a variety of clinical conditions, most commonly in the treatment of viral hepatitis. Up to 70% of patients without previous thyroid autoimmunity will develop high serum thyroid peroxidase antibody concentrations during interferon therapy. 74 Like amiodarone, two forms of interferon-induced thyrotoxicosis have been described: (1) a Graves’-like hyperthyroidism and (2) a destructive thyroiditis. 68 Frequently, the thyrotoxicosis is mild and symptomatic therapy is often all that is necessary. Because treatment with interferon-alpha is for a defined period, the drug usually can be continued to finish the course of therapy when thyroid dysfunction develops. Thyroid function usually normalizes after the interferon is stopped; however, affected patients are at increased risk for autoimmune thyroid dysfunction in the future.

Acute Suppurative/Infectious Thyroiditis
Infectious thyroiditis is also known as acute thyroiditis , suppurative thyroiditis, bacterial thyroiditis, and pyogenic thyroiditis (see Table 4-2 ). Bacterial infections of the thyroid are rare, with only 224 cases having been reported in the literature from 1900 to 1980 75 and only 60 cases reported in the pediatric literature. 76 Bacterial infections are the etiology of most causes of infectious thyroiditis, and the infections are generally suppurative and acute. Infectious thyroiditis caused by fungal and parasitic infections are more frequently chronic and indolent. In this section, emphasis will be placed on bacterial infections. The reader is referred to other reviews for further information on the less frequent causes of infectious thyroiditis. 52

Etiology and Pathogenesis
The thyroid gland's high iodine content, significant vascularity, lymphatic drainage as well as its protective capsule provide the thyroid gland with notable resistance to infection. 52 The most common predisposing factor to infections of the thyroid appears to be preexisting thyroid disease. Simple goiter, nodular goiter, Hashimoto's thyroiditis, or thyroid carcinoma has been observed in up to two thirds of women and one half of men with infectious thyroiditis. 75 Patients with the acquired immunodeficiency syndrome (AIDS) are a population particularly at risk for bacterial thyroiditis. As with other opportunistic infections in AIDS patients, infections of the thyroid gland often are chronic and insidious in onset.
In the adult, Staphylococcus aureus and Streptococcus pyogenes are the offending pathogens in more than ~ 80% of patients and are the sole pathogen in over 70% of cases 52 ( Table 4-6 ). In children, alpha- and beta-hemolytic Streptococcus and a variety of anaerobes account for ~ 70% of cases, whereas mixed pathogens are identified in > 50% of cases. 76 Other thyroidal bacterial pathogens that have been shown to cause infectious thyroiditis include Salmonella brandenburg , Salmonella enteritidis, Actinomyces naeslundii, Actinobacillus actinomycetemcomitans, Brucella melitensis , Clostridium septicum, Eikenella corrodens , Enterobacter , Escherichia coli, Haemophilus influenzae, Klebsiella sp., Pseudomonas aeruginosa , Serratia marcescens , Acinetobacter baumannii, and Staphylococcus nonaureus . 52
Table 4-6 Pathogenesis of Acute Suppurative Thyroiditis Organism Frequency (%) Bacterial 68 Parasitic 15 Mycobacterial  9 Fungal  5 Syphilitic  3
Infection and suppuration may result from direct spread from a nearby infection or via the bloodstream or lymphatics. The seminal observation regarding the pathogenesis of bacterial thyroiditis was made in 1979 when Takai et al. reported seven cases of infectious thyroiditis caused by a fistula originating from the left pyriform sinus. 77 Subsequently, studies involving more than 100 patients with infectious thyroiditis have identified pyriform sinus fistulae, primarily left-sided, in up to 90% of these patients, especially in those with recurrent episodes. 52 Additional reports identified infected embryonic cysts from the third and fourth brachial pouches and thyroglossal duct cysts as routes of thyroidal infection (see Chapters 2 , Applied Embryology of the Thyroid and Parathyroid Glands and 6 , Thyroglossal Duct Cysts and Ectopic Thyroid Tissue). On pathologic exam, the characteristic changes of acute bacterial inflammation, including necrosis and abscess formation, are commonly found.

Clinical Manifestations
Bacterial thyroiditis is often preceded by an upper respiratory infection, which may induce inflammation of the fistula and promote the transmission of pathogens to the thyroid. Consistent with these observations, bacterial thyroiditis is more common in the late fall and late spring months. Over 90% of patients will present with thyroidal pain, tenderness, fever, and local compression resulting in dysphagia and dysphonia; the pain is often referred diffusely to adjacent structures. Systemic symptoms, such as fever, chills, tachycardia, and malaise, are seen frequently.

Laboratory Findings
Thyroid function tests are usually normal; however, cases of hypothyroidism and thyrotoxicosis have been reported. 52 A nuclear medicine thyroid scan may show the suppurative region as a “cold” area, whereas an ultrasound examination may reveal a cystic or “complex” nodule. The polymorphonuclear leukocyte count and the sedimentation rate are usually elevated. The organism frequently can be identified by Gram stain and culture of a fine-needle aspiration in the region of suppuration, although sterile cultures are seen in ~ 8% of cases. 52

Diagnosis
The diagnosis is made with a fine-needle aspiration, Gram stain, and culture. Symptomatically, infective thyroiditis may be difficult to differentiate from subacute thyroiditis in the early phases, although the characteristic thyroid function changes in the latter disease should be helpful in discriminating the two. 54 Leukocytosis and an elevated erythrocyte sedimentation rate are not discriminatory tests as they are commonly observed in both subacute thyroiditis and infectious thyroiditis. In general, patients with bacterial thyroiditis have a greater febrile response than those with subacute thyroiditis. Once abscess formation has occurred, the local redness, lymphadenopathy, hyperpyrexia, and leukocytosis should lead to the correct diagnosis. Malignant neoplasms and hemorrhages into cysts may sometimes present with manifestations that mimic this disorder.

Clinical Management
The prognosis of bacterial thyroiditis is often dependent on the prompt recognition and treatment of this disorder, as mortality may approach 100% if the diagnosis is delayed and appropriate antimicrobial therapy is not instituted. Much depends on the identification of the microorganism from needle aspirate, incision, and drainage, or occasionally from blood culture. If no organisms are seen on the Gram stain, nafcillin and gentamicin or a third-generation cephalosporin is the appropriate initial therapy in adults, whereas a second-generation cephalosporin or clindamycin is reasonable in children. If an abscess develops and prompt response to antibiotics does not occur, incision and drainage are necessary. Sometimes partial lobectomy must be performed, especially if the disease is recurrent. Usually the lesions heal with reasonable speed after initiation of the correct antimicrobial agent, and recurrences are uncommon. Mortality from acute bacterial thyroiditis has markedly improved from the 20% to 25% reported in the early 1900s, with the extensive review by Berger estimating an overall mortality of 8.6%. 75 In one review of more than 100 patients, mortality as a complication of acute bacterial thyroiditis was not listed. 78

Invasive Fibrous Thyroiditis/Riedel's Thyroiditis
Invasive fibrous thyroiditis—also known as sclerosing thyroiditis, Riedel's struma, Riedel's thyroiditis, struma fibrosa, ligneous (Eisenharte) struma, chronic fibrous thyroiditis , and chronic productive thyroiditis —is a rare disorder of unknown cause, characterized pathologically by dense fibrous tissue, which replaces the normal thyroid parenchyma and extends into adjacent tissues, such as muscles, parathyroid glands, blood vessels, and nerves 53 (see Table 4-2 and Chapter 44 , Surgical Pathology of the Thyroid Gland). The first report by Riedel's in 1896 described cases of chronic sclerosing thyroiditis primarily affecting women, which frequently caused pressure symptoms in the neck and tended to progress ultimately to complete destruction of the thyroid gland. Riedel's interesting description was that of a “specific inflammation of mysterious nature producing an iron-hard tumefaction of the thyroid.”
This condition is quite rare. 1 , 53 , 79 In thyroidectomies performed for all disorders, an incidence between 0.03% and 0.98% has been reported. At the Mayo Clinic, the operative incidence over 64 years was 0.06%, and the incidence in outpatients was 1.06 per 100,000. Because the manifestations are likely to lead to surgery, the incidence of invasive fibrous thyroiditis among patients undergoing thyroidectomy is much greater than the incidence in patients with goiters in general.

Etiology
The cause of this disorder remains unknown. Thyroid antibodies have been reported in up to 67% of patients. 80 This observation, in addition to the presence of both B and T cells in the inflammatory infiltrate, suggests a possible autoimmune mechanism, although no direct relationship has been shown. It is not uncommon for those with invasive fibrous thyroiditis to have other autoimmune diseases, such as insulin-dependent diabetes mellitus and Addison's disease. 81 - 83 One patient was reported to have both invasive fibrous thyroiditis and pernicious anemia, which is another autoimmune disease. The expression of HLA-DR, heat-shock protein (HSP-72 kDa), and soluble intercell adhesion molecule-1 (ICAM-1) receptor in invasive fibrous thyroiditis tissue suggests a role for an active cell-mediated immune response early in the evolution of this condition. 81 - 84
Marked tissue eosinophilia and eosinophil degranulation have been observed in Riedel's struma. 85 These findings may suggest that the release of eosinophil-derived products may play a role in the fibrogenic stimulus. The nature of these products is not yet known.
Whatever the ultimate etiology is, it will have to account for the extrathyroidal fibrosclerosis as well. This was first noted as early as 1885 and described as a common accompaniment of invasive fibrous thyroiditis. 53 These extrathyroidal fibroscleroses include salivary gland fibrosis, sclerosing cholangitis, pseudo-tumors of the orbits, fibrous mediastinitis, retroperitoneal fibrosis, and lachrymal gland fibrosis. Long-term follow-up of patients with invasive fibrous thyroiditis (follow-up time: 10 years) has shown that one third develop fibrosing disorders of the retroperitoneal space (often with ureteral obstruction), chest, or orbit, almost always with a single extracervical site involved. Conversely, less than 1% of patients with retroperitoneal fibrosis have invasive fibrous thyroiditis. The association of certain drugs with retroperitoneal fibrosis has not been observed with invasive fibrous thyroiditis. There does not seem to be a genetic predisposition for this condition.

Clinical Manifestations
The age of onset has varied between 23 and 78 years, although most cases are diagnosed in the fourth to sixth decades. The female:male ratio varies between 2:1 and 4:1.
The clinical presentation is one of painless goiter that is gradually or rapidly enlarging, as constitutional symptoms of inflammation are rare. The extensive fibrosis is progressive and may eventually cause compression of adjacent structures, particularly the trachea and esophagus. Local compressive symptoms include a marked sense of pressure or severe dyspnea, with symptoms out of proportion to the size of the goiter. In some patients, the fibrotic process affects the entire gland, causing hypothyroidism; the prevalence of hypothyroidism in this population is between 25% and 40%. Hypoparathyroidism can develop when parathyroid gland infiltration occurs, and tetany associated with this process has been described.
On examination, the thyroid gland is stony hard, often described as “woody” in texture, densely adherent to adjacent cervical structures (such as muscles, blood vessels, and nerves), and may move poorly on swallowing. The lesion may be limited to one lobe. It has a harder consistency than a carcinoma and is usually nontender. Although adjacent lymph nodes are only occasionally enlarged, when they are present a diagnosis of carcinoma is often suspected.

Laboratory Findings
At presentation, the majority of patients with Riedel's thyroiditis are euthyroid; however, as mentioned earlier, some patients do develop hypothyroidism. Thyroid antibodies are detected in the majority of these patients. Calcium and phosphorus levels should be evaluated at presentation to identify those patients who also have concurrent hypoparathyroidism. Thyroid radionuclide imaging can show either a heterogeneous pattern or low isotope uptake; the “cold” areas reflect the fibrosis. The extent of the fibrosis can best be determined on either computed tomography (CT) or magnetic resonance imaging (MRI); the affected regions appear homogeneous and hypointense on T1- and T2-weighted MRI images. Ultrasound examinations can be helpful, as the areas affected appear hypoechoic; on color flow Doppler, the fibrotic areas are avascular. The white blood cell count and sedimentation rate are usually normal but can be elevated.
Pathology consists of an exuberant fibrosis involving part of or the entire thyroid. Fibrotic extension beyond the capsule of the thyroid into adjacent structures such as nerves, blood vessels, muscles, parathyroid glands, trachea, and esophagus is characteristic. Pathologic diagnostic criteria for this condition includes complete destruction of involved thyroid tissue with absence of normal lobulation, lack of a granulomatous reaction, and extension of the fibrosis beyond the thyroid into adjacent muscle, nerves, blood vessels, and adipose. Histologic exam reveals almost no thyroid follicles, and few plasma cells, eosinophils, and Hürthle cells (see Chapter 44 , Surgical Pathology of the Thyroid Gland). Lymphocytes are also sparse, in contrast to the findings in Hashimoto's thyroiditis, although occasionally, a few foci of lymphocytes may be observed. An associated arteritis and phlebitis with intimal proliferation, medial destruction, adventitial inflammation, and thrombosis may also occur. Similar features are observed in the extracervical fibrosclerotic lesions, retroperitoneal and mediastinal regions, in the orbit, lachrymal glands, and in sclerosing cholangitis.

Diagnosis and Clinical Management
The diagnosis is made by biopsy of the goiter in order to differentiate this disorder from carcinoma. However, a fine-needle aspiration biopsy is usually inadequate because of the extreme hardness of the gland; thus, an open biopsy is often required.
Treatment of Riedel's thyroiditis is surgical to relieve compressive symptoms. Extensive resection is often impossible due to fibrosis of surrounding structures, but wedge resection, especially over the isthmus to relieve tracheal compression, is often extremely effective. Despite its invasive nature, recurrences of obstruction after resection are rare. Thyroid hormone therapy is indicated only if hypothyroidism is present, as suppression therapy is ineffective. Calcium and vitamin D therapy is indicated in those patients with associated hypoparathyroidism. There have been several reports of disease improvement with glucocorticoid therapy, and relapses have reversed with the reinstitution of steroids; however, it has not been helpful in all instances. Tamoxifen has been reported to cause disease regression in a few case reports; its mechanism of action is unclear, but it may play a role in fibroblastic proliferation inhibition. 86

Prognosis
Riedel's thyroiditis is usually progressive; however, it may stabilize or remit spontaneously. Following surgery, the disease can remit or be self-limiting. Repeat surgery is only rarely required. Mortality rates range from 6% to 10%, with deaths usually attributed to asphyxia secondary to tracheal compression or laryngospasm. However, these mortality rates are derived from older literature and may not reflect (the presumably lower) current rates. In many instances, the condition is self-limiting, and improvement often persists after isthmic wedge resection.

References
For a complete list of references, go to expertconsult.com .

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61 Goto H., Uno H., Tamai H., et al. Genetic analysis of subacute (de Quervain's) thyroiditis. Tissue Antigens . 1985;26:110–113.
62 Pearce E.N., Bogazzi F., Martino E., et al. The prevalence of elevated serum C-reactive protein levels in inflammatory and noninflammatory thyroid disease. Thyroid . 2003;13:643–648.
63 Omori N., Omori K., Takano K. Association of the ultrasonographic findings of subacute thyroiditis with thyroid pain and laboratory findings. Endocr J . 2008;55:583–588.
64 Lu C.P., Chang T.C., Wang C.Y., et al. Serial changes in ultrasound-guided fine needle aspiration cytology in subacute thyroiditis. Acta Cytol . 1997;41:238–243.
65 Vagenakis A.G., Abreau C.M., Braverman L.E. Prevention of recurrence in acute thyroiditis following corticosteroid withdrawal. J Clin Endocrinol Metab . 1970;31:705–708.
66 Iitaka M., Momotani N., Ishii J., et al. Incidence of subacute thyroiditis recurrences after a prolonged latency: 24-year survey. J Clin Endocrinol Metab . 1996;81:466–469.
67 Bogazzi F., Bartalena L., Martino E. Approach to the patient with amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab . 2010;95:2529–2535.
68 Tomer Y., Menconi F. Interferon induced thyroiditis. Best Pract Res Clin Endocrinol Metab . 2009;23:703–712.
69 Schuppert F., Rambusch E., Kirchner H., et al. Patients treated with interferon-alpha, interferon-beta, and interleukin-2 have a different thyroid autoantibody pattern than patients suffering from endogenous autoimmune thyroid disease. Thyroid . 1997;7:837–842.
70 Tacon L., Tan C.T., Alvarado R., et al. Drug-induced thyroiditis and papillary carcinoma in a minocycline-pigmented black thyroid gland. Thyroid . 2008;18:795–797.
71 Dang A.H., Hershman J.M. Lithium-associated thyroiditis. Endocr Pract . 2002;8:232–236.
72 Miller K.K., Daniels G.H. Association between lithium use and thyrotoxicosis caused by silent thyroiditis. Clin Endocrinol (Oxf) . 2001;55:501–508.
73 Roti E., Minelli R., Gardini E., et al. Thyrotoxicosis followed by hypothyroidism in patients treated with amiodarone. Arch Intern Med . 1993;153:886–892.
74 Marazuela M., Garcia-Buey L., Gonzalez-Fernandez B., et al. Thyroid autoimmune disorders in patients with chronic hepatitis C before and during interferon-alpha therapy. Clin Endocrinol (Oxf) . 1996;44:635–642.
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81 Heufelder A.E., Carney J.A., et al. Coexistence of Graves’ disease and Riedel's (invasive fibrous) thyroiditis: further evidence of a link between Riedel's thyroiditis and organ-specific autoimmunity. Clin Investig . 1994;72:788–793.
82 Zimmermann-Belsing T., Feldt-Rasmussen U. Riedel's thyroiditis: an autoimmune or primary fibrotic disease? J Intern Med . 1994;235:271–274.
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84 Heufelder A.E., Bahn R.S. Soluble intercellular adhesion molecule-1 (sICAM-1) in sera of patients with Graves’ ophthalmopathy and thyroid diseases. Clin Exp Immunol . 1993;92:296–302.
85 Heufelder A.E., Goellner J.R., Bahn R.S., et al. Tissue eosinophilia and eosinophil degranulation in Riedel's invasive fibrous thyroiditis. J Clin Endocrinol Metab . 1996;81:977–984.
86 Few J., Thompson N.W., Angelos P., et al. Riedel's thyroiditis: treatment with tamoxifen. Surgery . 1996;120:993–998. discussion 998–999
Chapter 5 Hyperthyroidism
Toxic Nodular Goiter and Graves’ Disease

Kamal A.S. Al-Shoumer, Hossein Gharib

Introduction
Hyperthyroidism refers to thyrotoxicosis caused by the overproduction of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). The most common type of thyrotoxicosis encountered in the United States and worldwide is Graves’ disease ; toxic nodular goiter (TNG) is the second most common type of thyrotoxicosis.
Goiter is enlargement of the thyroid gland, commonly encountered in clinical endocrine practice. It may be classified as diffuse or nodular and may be either nontoxic or toxic. Nodular goiter may include multiple nodules (i.e., multinodular goiter [MNG]) or a single nodule. Regardless of different possible mechanisms of development, diffuse thyroid enlargement eventually evolves into a nodular stage. 1
A TNG is a thyroid gland that contains autonomously functioning thyroid nodule(s), with resulting hyperthyroidism. Also called Plummer's disease , TNG was first described by Henry Plummer at Mayo Clinic in 1913. In elderly individuals and in geographic areas of endemic iodine deficiency, TNG is the most common cause of hyperthyroidism.
Graves’ disease is the most common type of thyrotoxicosis encountered in the industrialized world. Graves', disease owes its name to an Irish doctor, Robert James Graves’ who described the first case of goiter with exophthalmos in 1835. 2 Patients with Graves’ disease usually have diffuse, nontender, symmetric enlargement of the thyroid gland. Other features of Graves’ disease affecting the eyes and skin will be described in ensuing sections in this chapter.

Epidemiology
Hyperthyroidism in the United States occurs in 0.05% to 1.3% of the general population with the majority of cases consisting of subclinical disease. The prevalence of hyperthyroidism is approximately 5 to 10 times less than that of hypothyroidism. White and Hispanic populations in the United States have a slightly higher prevalence of hyperthyroidism than black populations.

Toxic Nodular Goiter
TNG is the most frequent cause of thyrotoxicosis in the elderly. It accounts for about 5% to 15% of patients with endogenous hyperthyroidism, but the proportion is higher in iodine-deficient geographic regions. 2, 3 Changes in the iodine content of salt and in the iodine supplementation of water have been linked to changes in the incidence of TNG. In Switzerland in 1980 and in Spain in 1994, the iodine content of salt was increased, and this was associated with a transient increased incidence of thyrotoxicosis followed by decreased incidence, mainly the result of reduced TNG incidence. 4, 5

Graves’ Disease
Being the most common cause of thyrotoxicosis in all age groups, Graves’ disease accounts for 70% to 80% of endogenous hyperthyroidism. The incidence of Graves’ disease is five times higher in females than in males, occurring generally during women's reproductive years, although it may occur at any age. 2

Pathogenesis

Toxic Nodular Goiter
The natural history of a nontoxic MNG involves variable growth of individual nodules; this may progress to hemorrhage and degeneration, followed by healing and fibrosis. Calcification may be found in areas of previous hemorrhage. Some nodules may develop autonomous function. Autonomous hyperactivity is conferred by somatic mutations of thyrotropin or thyroid-stimulating hormone receptor (TSHR) in 20% to 80% of toxic adenomas and some nodules of MNGs. 6 Autonomously functioning nodules may become toxic in 10% of patients. Hyperthyroidism predominantly occurs when single autonomous nodules are larger than 2.5 cm in diameter. However, in geographic areas with iodine deficiency, smaller autonomous nodules may produce systemic, clinical manifestations of hyperthyroidism. 7
The development of hyperthyroidism in MNG takes many years. The process evolves from a small gland with one small nodule or more to nodules increasing progressively in number, size, and function. Initially, most patients are euthyroid, but with enlarging goiters, autonomy develops, illustrated by low or suppressed serum thyroid-stimulating hormone (TSH) with normal serum levels of thyroid hormones. As shown in Figure 5-1 , a state of subclinical hyperthyroidism with low TSH but normal free T4 and free T3 levels may exist for years before progression to clinical hyperthyroidism.

Figure 5-1 The evolution of hyperthyroidism in multinodular goiter, a process that often takes years, associated with an increase in the number, size, and function of nodules. Transition from a euthyroid (Eu) state (normal thyroid-stimulating hormone [TSH], free thyroxine [FT4], and free triiodothyronine [FT3]) to subclinical hyperthyroidism (SCH) (low TSH, normal FT4 and FT3) to clinical hyperthyroidism (Hyp) (low TSH, elevated FT4 and FT3). NL indicates the normal range.
(Adapted from Studer H, Peter HJ, Gerber H: Toxic nodular goitre. Clin Endocrinol Metab 14:351-372, 1985.)

Graves’ Disease
Graves’ disease is a syndrome that consists of hyperthyroidism, goiter, ophthalmopathy (orbitopathy), and occasionally a dermopathy referred to as pretibial or localized myxedema. Hyperthyroidism is the most common feature of Graves’ disease, affecting nearly all patients, and is caused by autoantibodies to the TSHR (TSHR-Ab) that activate the receptor, thereby stimulating thyroid hormone synthesis and secretion as well as thyroid growth (causing a diffuse goiter).
The histology of the thyroid gland in patients with Graves’ hyperthyroidism is characterized by follicular hyperplasia, a patchy (multifocal) lymphocytic infiltration, and rare lymphoid germinal centers. The majority of intrathyroidal lymphocytes are T cells, and germinal centers (B cells) are much less common than in chronic autoimmune thyroiditis (Hashimoto's disease). Thyroid epithelial cell size correlates with the intensity of the lymphocytic infiltrate, suggesting thyroid cell stimulation by local B cells secreting TSHR-Ab. 8 The presence of these antibodies is positively correlated with active disease and with relapse of the disease. There is an underlying genetic predisposition, because of an increased frequency of haplotypes human leukocyte antigen (HLA)-B8 and HLA-DRw3 in white patients, HLA-Bw36 in Japanese patients, and HLA-Bw46 in Chinese patients with the disease. However, it is not clear what triggers the acute episodes. Some factors that may incite the immune response are pregnancy, particularly the postpartum period; iodine excess, particularly in geographic areas of iodine deficiency; lithium therapy; viral or bacterial infections; and glucocorticoid withdrawal.
The etiology and pathogenesis of Graves’ ophthalmopathy are not known. It may involve cytotoxic lymphocytes and cytotoxic antibodies sensitized to a common antigen in orbital fibroblasts, orbital muscle, and thyroid tissue, which may cause inflammation, resulting in proptosis of the globes. It has been suggested recently that TSHR-bearing circulating fibroblasts and fibrocytes may be activated directly by the TSHR-Ab. 9 The pathogenesis of dermopathy may also involve this mechanism. Patients with exophthalmos and particularly those with dermopathy almost always have high titers of circulating TSHR autoantibodies, suggesting that these two clinical manifestations represent the most severe form of this disease.

Diagnostic Evaluation
Thyrotoxicosis is the common feature of both TNG and Graves’ disease. It may be clinical or subclinical. Subclinical hyperthyroidism presents few, if any, mild symptoms in the presence of a suppressed TSH with normal free thyroid hormones (T3 and T4). Early in Graves’ disease, hyperthyroidism may be from preferential T3 secretion, so-called T3 toxicosis.

History and Physical Examination
The clinical presentation ranges from no symptoms and a suppressed sensitive serum TSH level to overt or obvious clinical hyperthyroidism. The latter includes symptoms associated with increased adrenergic tone and resting energy expenditure and other hormonal effects. Features related to increased adrenergic tone include nervousness, tremor, increased frequency of defecation, palpitations, diaphoresis, irritability, insomnia, headaches, lid retraction and lid lag, muscle weakness, tachycardia, hyperreflexia, and widened pulse pressure. Those related to increased energy expenditure include heat intolerance, unintentional weight loss without anorexia, and warm, moist skin. In elderly subjects, the presentation may be subtle, with atrial fibrillation, weight loss, weakness, and depression. 10
Goiter may be detected in patients with either TNG or Graves’ disease. Nodular irregularity is characteristic of TNG, whereas Graves’ disease is more typically diffuse, soft, and rubbery and may have an overlying thyroid region bruit. Patients with Graves’ disease often have a goiter, may present with hyperthyroidism alone, or may have one or more extrathyroidal manifestations. Clinically apparent eye disease may occur in up to a third of patients with Graves’ disease, but orbital CT may detect changes in a majority of patients. Signs of eye disease include proptosis or exophthalmos, lid lag and retraction, and impaired extraocular muscle function. Eye symptoms and signs generally begin about 6 months before or after the diagnosis of Graves’ disease. It is generally uncommon for eye involvement to develop after the thyroid disease has been successfully treated. There is great variability, however, and in some patients with eye involvement, hyperthyroidism may never develop. The severity of eye involvement is not related to the severity of hyperthyroidism. Early signs of eye involvement may be red or inflamed eyes. Ultimately, proptosis may develop from the inflammation of retro-orbital tissues. Diminished or double vision is a rare problem that usually occurs later. It is not well known why, but problems with the eyes occur much more often in people with Graves’ disease who smoke cigarettes than in those who do not smoke.
Other features of Graves’ disease include onycholysis, acropachy, and pretibial myxedema ( Figure 5-2 ). Pretibial myxedema is a rare, reddish lumpy thickening of the skin of the shins. This skin condition is usually painless and is not serious. Like the eye disorders of Graves’ disease, the skin manifestation does not necessarily begin precisely when hyperthyroidism starts. Its severity is not related to the level of thyroid hormones. It is not known why this problem is usually limited to the lower leg or why so few people have it. Occasionally symptoms related to the mass effect of a large goiter may occur. Very large goiter may extend retrosternally or substernally, resulting in symptoms and signs of tracheoesophageal pressure. These may include dysphagia, cough, and choking sensation or stridor, particularly if severe tracheal narrowing exists. The development of facial plethora, cyanosis, and distention of neck veins with raising both arms simultaneously may result from deep goiter compression of the structures located within the bony confines of the thoracic inlet (Pemberton sign).

Figure 5-2 Extrathyroidal manifestations of Graves’ disease: ophthalmopathy (A), pretibial myxedema or Graves’ dermopathy (B), and acropachy (C).
Common and important clinical differences between Graves’ disease and TNG are summarized in Table 5-1 .
Table 5-1 Clinical Differences between Graves’ Disease and Toxic Nodular Goiter Characteristic Graves’ Disease Toxic Nodular Goiter Goiter Diffuse Multinodular —Size Small Large —Growth Rapid Slow Patient age, y < 45 > 50 Hyperthyroid onset Rapid Slow Histologic features Follicles similar, intense iodine metabolism Variable follicular size, shape, and intensity of iodine metabolism
Adapted from Hurley DL, Gharib H: Thyroid nodular disease: is it toxic or nontoxic, malignant or benign? Geriatrics 50:24-26, 29-31, 1995.

Laboratory Evaluation
Diagnosis is always established by the measurement of sensitive TSH and thyroid hormone levels (free T3 and free T4). Thyrotoxicosis caused by TNG or Graves’ disease is usually characterized by a suppressed TSH level with either normal (subclinical) or elevated (overt) free thyroid hormone levels. It is insufficient to rely on the measurement of TSH or free thyroid hormones alone to diagnose TNG or Graves’ disease, because suppression of TSH or elevation of thyroid hormones can be associated with clinical conditions other than TNG and Graves’ disease ( Table 5-2 ). Other serologic findings, such as antithyroid antibodies (antithyroid peroxidase and antithyroglobulin), that support the diagnosis of autoimmune thyroid disease may be detected in patients with Graves’ disease. However, serum TSHR-Ab is occasionally helpful in the diagnosis of Graves’ disease, though there is no consensus regarding its routine measurement in Graves’ disease.
Table 5-2 Clinical Conditions Associated with Abnormal TSH and High Free Thyroid Hormone without Toxic Nodular Goiter or Graves’ Disease Low TSH High TSH Secondary hypothyroidism TSH-secreting pituitary tumor Nonthyroidal illness Thyroid hormone resistance Glucocorticoid therapy   Amiodarone use   Excessive thyroid hormone therapy  
TSH, thyroid-stimulating hormone.

Imaging

Radionuclide Imaging
Radionuclide scanning and radioactive iodine uptake (RAIU) are useful tests to elucidate the cause of hyperthyroidism. In TNG, the radioactive iodine (RAI) concentration is in the nodule(s), and uptake is inhibited in the surrounding tissue, giving the appearance of “patchy uptake” ( Figure 5-3 ). Consequently, the total RAIU may be either slightly raised or at the upper limit of normal. In Graves’ disease, because of diffuse thyroid involvement, the RAIU is always intense and increased ( Figure 5-4 ). Thyroid radionuclide imaging may not be necessary in every case when the diagnosis is obvious, but it is helpful in the differentiation of other clinical conditions associated with hyperthyroidism but with low RAIU ( Table 5-3 ).

Figure 5-3 Radionuclide scan of toxic nodular goiter demonstrating intense focal uptake of several hot nodules with different degrees of suppression of adjacent thyroid tissue (A) compared with the scan from a patient with nontoxic multinodular goiter, showing less intense patchy radioactive iodine uptake (B).

Figure 5-4 Radionuclide scan in Graves’ hyperthyroidism demonstrating the diffuse and homogeneous nature of increased uptake in both lobes of the thyroid.
Table 5-3 Clinical Conditions Associated with Low Radioactive Iodine Uptake and Hyperthyroidism Thyroiditis Iodine-induced thyrotoxicosis Exogenous thyrotoxicosis (factitia) Ectopic functional thyroid tissue

Computed Tomography
In any patient with compressive or obstructive symptoms and an MNG, chest radiography and chest computed tomography (CT) are often informative. Chest CT is particularly valuable to define the size and extent of the goiter, especially into the mediastinum ( Figure 5-5 ). Care to avoid iodinated contrast until the patient's thyroid functional status must be taken or the significant iodine load CT contrast agent may acutely induce or worsen hyperthyroidism.

Figure 5-5 A, Chest radiography showing a huge solid goiter (horizontal arrow) displacing the trachea without compression (vertical arrow). B, Neck computed tomography of the same goiter (arrows). Thyroidectomy revealed a 290-g benign thyroid gland.

Associated Metabolic Abnormalities
Altered glucose metabolism (reversible hyperglycemia, elevated C-peptide, elevated intact proinsulin, and insulin resistance) and increased bone turnover (elevated markers of bone formation and resorption) are hallmarks of untreated hyperthyroidism. 11, 12 We have demonstrated recently that untreated hyperthyroidism is associated with an elevated chromogranin A level that changes in parallel with thyroid status. 13 Other associated metabolic abnormalities are shown in Table 5-4 . 14 All these abnormalities are not essential for the diagnosis, but the possibility of their presence in hyperthyroidism should be appreciated.
Table 5-4 Metabolic Abnormalities Associated with Hyperthyroidism Mild hypercalcemia Myopathy Hypokalemic periodic paralysis 14 Pulmonary hypertension Cholestatic jaundice

Treatment

Symptomatic Relief
TNGs generally cause milder symptoms than Graves’ disease. In the absence of contraindications, beta-blockers may be used for symptomatic relief while awaiting results of definitive treatment. Beta-blockers may also be appropriate for patients with atrial fibrillation and rapid ventricular response. Propranolol has been widely used to block T4 to T3 conversion, a theoretic benefit. A selective beta-blocker such as atenolol may be used in patients who cannot tolerate propranolol. If beta-blockers are contraindicated, a calcium channel blocker may be useful.

Definitive Treatment

Toxic Nodular Goiter
RAI therapy (with 131 I) and surgery are effective options for the definitive treatment for TNG. The long-term use of thionamide antithyroid drugs (ATDs) is not favored unless either 131 I therapy or surgery is contraindicated. Thionamides, however, may be used before surgery, especially in older patients, until euthyroidism is restored.

Radioactive iodine
The clinical utility of RAI therapy in the management of TNG is well established. If RAIU is adequate and the patient is not a good surgical candidate, RAI is the treatment of choice ( Figure 5-6 ). Although the dose of 131 I may be calculated on the basis of uptake determinations and gland weight (see the discussion of Graves’ disease, presented later in the chapter), TNGs are relatively resistant to 131 I because of their larger size and relatively lower uptake of iodine. For these reasons, some clinicians increase the standard dose by 20% to 50%. Frequently, RAI doses between 15 and 50 mCi (555 and 1850 MBq) are administered. In a report from Mayo Clinic, Jensen et al. 15 treated their patients with a mean dose of 37 mCi (1370 MBq) (range, 6.3 to 150 mCi [233 to 5550 MBq]). After 1 year of follow-up, 16% of patients were hypothyroid. Danaci et al. 16 treated TNGs with a fixed dose of 16.6 mCi (631 MBq) 131 I and reported a cumulative relapse rate of 39% at 5 years and a cumulative incidence of hypothyroidism of 24% at 5 years. In a large prospective study involving 130 consecutive patients with TNGs and a mean follow-up of 6 years, 92% of patients were cured after one or two treatments with 131 I. Thyroid volume was reduced by a mean of 43%, and adverse effects were few. Patients were treated with a median dose of 10 mCi (370 MBq). 17

Figure 5-6 An 87-year-old woman with toxic nodular goiter (TNG; also called Plummer's disease). Symptoms included increased heart rate, fatigue, and poor sleep. Examination showed a huge goiter in a toxic patient. Her thyroid-stimulating hormone level was 0.06 mIU/L, free thyroxine was 2.6 ng/dL, free triiodothyronine was 3.4 pg/mL, and uptake of radioactive iodine was 20% at 6 hours. Radionuclide scan showed intense uptake (A), and computed tomography confirmed a large TNG (B). She was treated with 50 mCi of radioactive iodine.
Generally, after RAI most patients are euthyroid within 2 to 4 months, although sometimes achieving euthyroidism may take longer. 17 Although most patients treated with RAI achieve long-term euthyroidism, 10% to 24% of these patients eventually become hypothyroid, regardless of the dose used. 15, 18 RAI is associated with a 20% chance of recurrence, 10 in which case patients may receive a second dose of 131 I or opt for thyroidectomy. These patients should not be given iodide preoperatively because of the risk of exacerbating thyrotoxicosis.

Surgery
Bilateral subtotal or total thyroidectomy is recommended for patients with large goiters causing obstructive symptoms such as choking, or dyspnea, or for those who refuse RAI therapy. Surgery may also be indicated when a suspicious cold or growing nodule is identified in a TNG. Surgery is an excellent option for patients who decline RAI therapy and also for pregnant women (see Chapter 7 , Surgery of Cervical and Substernal Goiter).
Two issues deserve further comment. The extent of thyroidectomy remains somewhat controversial. In the past, some clinics have preferred subtotal thyroidectomy to minimize complications such as recurrent laryngeal nerve damage and hypoparathyroidism. In current practice, most surgeons perform a total thyroidectomy for bilateral benign nodular goiters. 19 Also, the trend in recent decades suggests that RAI is being increasingly considered as an attractive, effective alternative to surgery in TNG. For example, a study from Mayo Clinic showed that between 1950 and 1974, 83% of patients had surgical treatment and 17% had RAI treatment. Between 1990 and 1999, the figures were 53% for surgery and 47% for RAI. 20

Thionamide antithyroid drugs
Thionamide antithyroid drugs are the preferred transient treatment during pregnancy until delivery. They should also be considered for patients who are not candidates for or who decline definitive treatment. Treatment is generally indefinite with thionamide ATDs, generally because permanent remission is never achieved in TNG.

Graves’ Disease
In the management of Graves’ disease, treatment preferences vary substantially by geographic region. This was suggested by the outcome of an international survey of endocrinologists from the United States, Europe, and Japan. Among physicians in the United States, thionamide ATDs were selected as the primary form of therapy for a “typical 43-year-old healthy woman” by only approximately 30%, whereas 69% chose RAI treatment and 1% opted for surgery. 21 By contrast, 77% of European physicians and 88% of Japanese physicians selected thionamide ATDs as the preferred primary treatment, with RAI therapy as the second choice.

Thionamide antithyroid drugs
Thionamide ATDs inhibit biosynthesis of thyroid hormones, and biochemical euthyroidism is usually achieved within 6 to 8 weeks after initiation of therapy. 11 Currently, three thionamide ATDs are available: methimazole and propylthiouracil are available in the United States and carbimazole, which is metabolized to methimazole, is sometimes used in Europe and Asia. The half-life of methimazole in plasma is 3 to 5 hours, and that of propylthiouracil is 1 to 2 hours 22 ; thus, methimazole has a longer duration of action, although both drugs are effective for more than 5 hours because they accumulate in thyroid cells.
Initial daily doses 23 range from 10 to 40 mg of methimazole usually once daily, from 100 to 150 mg of propylthiouracil every 6 to 8 hours daily, and from 15 to 45 mg daily of carbimazole usually in one dose up to three divided doses. The decision to use methimazole/carbimazole or propylthiouracil is a matter of physician preference, because both agents are equally effective. However, observations over several decades have shown that methimazole and its prodrug carbimazole are better than propylthiouracil in controlling more severe hyperthyroidism, but propylthiouracil should not be routinely used because of potential fatal hepatotoxicity. This has led to the recommendation that methimazole/carbimazole be the first-line drug when ATD therapy is initiated, either for primary treatment or to prepare a patient for RAI therapy or surgery. An exception to this rule has been pregnancy, during which propylthiouracil has been preferred because of rare reports of birth defects associated with methimazole. 24 Propylthiouracil has also been used in patients with minor reactions to methimazole but who, nonetheless, prefer to continue ATD therapy. Propylthiouracil may also be preferable in patients with life-threatening thyrotoxicosis because of its additional inhibition of T4 to T3 conversion. 25
It is crucial to evaluate patients clinically and biochemically (with serum T4 and TSH measurements) regularly from 6 to 8 weeks after the initiation of ATD treatment until the patient is biochemically euthyroid and every 8 to 12 weeks thereafter. Once the patient is euthyroid, the ATD dose may be reduced. Some clinicians favor adding levothyroxine to the ATD regimen as part of a block-replacement regimen, without reducing the original ATD dose, to minimize the number of patient visits and maintain a more normal stable TSH. This addition to the regimen causes no difference in the remission outcome compared with titration of ATD alone. 26 The concern about compliance and the advantages of ATD alone have ensured that combination treatment (thyroxine and ATD) has not been widely adopted.
It has been determined from various reports that treatment with thionamide ATDs for 12 to 18 months is optimal, resulting in long-term remission in 40% to 60% of patients with Graves’ disease, with higher remission rates in women than in men. 27 - 29 The likelihood of sustained remission is greater in patients with mild hyperthyroidism, small goiter, and low or undetectable TSHR-Ab titers than in those with moderate to severe hyperthyroidism or T3 toxicosis, large goiter, and high TSHR-Ab titers. If hyperthyroidism recurs, other modes of therapy (RAI or surgery) are considered. Most relapses following cessation of thionamide ATDs occur shortly after the ATDs are discontinued, generally within the first few months, although they may occur several years later. Therefore, clinical and biochemical evaluation is necessary 2 months after ATD withdrawal and periodically at regular intervals thereafter.
As with all other drugs, thionamide ATDs may cause adverse effects as early as 2 weeks after initiation of therapy or later in the course of therapy, and it is essential to instruct patients on how to deal with these adverse reactions ( Table 5-5 ). The most serious and rare complication, agranulocytosis, should be ruled out by obtaining white blood cell and differential counts, if fever and signs of infection such as sore throat occur while the patient is on thionamide ATD therapy.
Table 5-5 Adverse Effects of Thionamide Antithyroid Drugs Adverse Effect Propylthiouracil Methimazole Minor reactions     —Fever, rash, arthralgia 5%-20% 5%-20% (dose related) Major reactions     —Agranulocytosis 0.2%-0.5% (not clearly dose related) 0.2%-0.5% (dose related) —Hepatotoxicity (hepatitis) 30% (< 1% severe) Cholestatic (usually reversible, with few deaths reported) —Vasculitis ANCA + Rare
ANCA, antineutrophil cytoplasmic antibody.

Inorganic iodide
Iodine given in pharmacologic doses (as Lugol solution or as a saturated solution of potassium iodide) inhibits the release of thyroid hormones for a few days or weeks, after which its antithyroid action is lost. 30 For this reason it is not used routinely, but short-term iodine therapy is useful in the preparation of patients for surgery, after RAI therapy to hasten the fall in serum T3 and T4 concentrations to normal (although this is not a routine indication), and in the treatment of thyrotoxic crisis. The usual dose of Lugol solution (5% iodine and 10% potassium iodide in water) is 0.1 to 0.3 mL three times daily, and that of potassium iodide is 60 mg (1 drop) three times daily.

Radioactive iodine therapy
In use for more than 60 years, RAI therapy is established as an effective, relatively inexpensive, and safe treatment option for Graves’ disease. The objective of RAI therapy is to destroy sufficient thyroid tissue to cure hyperthyroidism. The goal of treatment is to render the patient either euthyroid or hypothyroid, depending on the willingness of the physician to risk the possibility of persistent hyperthyroidism. Much attention has focused on achieving euthyroidism by adjusting the RAI dose, but there is little consensus regarding the most appropriate dose schedule. The regimens used include the traditional method of repeated low doses (2 mCi), fixed doses, and doses calculated on the basis of the size of the thyroid, the RAIU, or the turnover of 131 I. 31 - 34 Because it has proved impossible to titrate doses for individual patients accurately to guarantee a euthyroid state, the majority of physicians in the United States prefer to administer a single, relatively large dose (10 to 20 mCi) initially with the intent of inducing thyroid ablation and the development of hypothyroidism. Thyroid function is then assessed 6 to 8 weeks after RAI administration and possibly every month thereafter to monitor the development of hypothyroidism, especially during the first 6 months after RAI treatment. When hypothyroidism is detected by TSH elevations, levothyroxine treatment should be initiated to maintain the TSH level in the normal range (0.5 to 3 mIU/L). However, if hyperthyroidism persists, another RAI dose may be delivered but should not be given until at least 6 months after the first dose.
Before RAI treatment is started, patients should be informed of the precautions needed after RAI. Rarely patients may experience mild anterior neck pain after RAI or a short-lived exacerbation of hyperthyroid symptoms caused by the leakage of preformed thyroid hormones from a damaged thyroid gland. Worsening of Graves’ ophthalmopathy, especially among smokers, may be observed after 131 I treatment. 35 - 39 Risk is reduced by cessation of smoking and the administration of glucocorticoids, namely, prednisone. Different regimens are available, but most agree on the regimen of oral prednisone administration 1 to 3 days after RAI treatment at 0.3 to 0.5 mg/kg daily, and the dose is tapered until withdrawal about 3 months later. 40
Whether to pretreat patients with thionamide ATDs until they are euthyroid before 131 I administration is a matter of debate. Retrospective studies have shown that the efficacy of treatment with 131 I is decreased after propylthiouracil. It is best to discontinue ATDs a few days before RAI is given. Previously RAI was reserved for adults because of the lack of long-term data in children and adolescents. More recently, in properly administered doses, data have shown that RAI is the ideal form of therapy for Graves’ disease in children. 41 It remains absolutely contraindicated during pregnancy and lactation.

Surgery
Because of the higher relapse rates seen with subtotal thyroidectomy, near-total or even total thyroidectomy is the recommended surgical procedure for the treatment of Graves’ hyperthyroidism (see Chapter 9, The Surgical Management of Hyperthyroidism ). 42 - 44 It usually results in postoperative hypothyroidism requiring lifelong levothyroxine replacement. Thyroidectomy is preferred in patients with large goiters (especially those with tracheoesophageal compression symptoms), coincidental suspicious thyroid nodules, and contraindications to 131 I or ATDs and in those who refuse RAI treatment or are pregnant when hyperthyroidism is difficult to control (discussed next). Surgical morbidity, including permanent hypoparathyroidism, vocal cord dysfunction caused by recurrent laryngeal nerve injury, infection, and hematoma, is low in experienced centers.
Any patient with hyperthyroidism scheduled to undergo surgery should be treated with thionamide ATDs to restore euthyroidism. Alternative methods of preoperative therapy include thionamide ATDs combined with beta-blockers (propranolol, 40 to 80 mg three times a day or a longer-acting beta-adrenergic antagonist, e.g., atenolol, 50 mg/day). Potassium iodide (40 mg three times a day for 10 days) or potassium iodide (several drops per day for 10 days) in combination with propranolol (40 to 120 mg per day) may be another alternative. Any of these regimens virtually eliminates the risk of postoperative thyrotoxic crisis. 45
Indefinite follow-up is essential after thyroidectomy with an adequate replacement dose of levothyroxine that maintains TSH within the range of normal.

Pregnancy
Appropriate management of hyperthyroidism during pregnancy is important for the mother's health and for the course of the pregnancy. Moreover, the quality of management may have considerable impact on the progeny both in fetal and in neonatal life and on the long-term health of the child. The most common form of hyperthyroidism during pregnancy is mostly the result of Graves’ disease, and its adequate control is essential. Pregnant hyperthyroid women should be treated with thionamide ATDs. Most clinicians prefer propylthiouracil, although both propylthiouracil and methimazole are shown to cross the placenta equally. 46 As noted previously, rare reports of birth defects associated with methimazole exist. The minimum dose of ATD that keeps maternal thyroid function around or slightly above the upper limit of normal should be used to avoid fetal hypothyroidism and fetal goiter. 47 Therefore, frequent monitoring of the mother and the fetus is necessary. Mothers may experience exacerbation of thyrotoxicosis after delivery, and the newborn may have transient thyroid dysfunction when exposed to ATDs or may develop transient neonatal hyperthyroidism resulting from the passage of TSHR antibodies through the placenta.
Postpartum propylthiouracil is also preferred for nursing mothers, because less drug appears in breast milk than with methimazole. 48 Surgical thyroidectomy in the second trimester of a pregnant woman with Graves’ disease is performed only in the case of uncontrollable hyperthyroidism that threatens the health of the woman or when ATDs are not tolerated. If thyroidectomy is performed, this should be followed by a systematic and a careful follow-up evaluation of the thyroid state of the fetus.

References
For a complete list of references, go to expertconsult.com .

References

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2 Graves R.J. A newly observed affection of the thyroid gland in females. London Med Surg Journal (Renshaw) . 1835;7:516–517. Reprinted in Medical Classics 5:33–36, 1940
3 Vanderpump M.P., Tunbridge W.M., French J.M., et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) . 1995;43:55–68.
4 Baltisberger B.L., Minder C.E., Burgi H. Decrease of incidence of toxic nodular goitre in a region of Switzerland after full correction of mild iodine deficiency. Eur J Endocrinol . 1995;132:546–549.
5 Galofre J.C., Fernandez-Calvet L., Rios M., et al. Increased incidence of thyrotoxicosis after iodine supplementation in an iodine sufficient area. J Endocrinol Invest . 1994;17:23–27.
6 Palos-Paz F., Perez-Guerra O., Cameselle-Teijeiro J., et alGalician Group for the Study of Toxic Multinodular Goitre. Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain. Eur J Endocrinol . 2008;159:623–631.
7 Emrich D., Erlenmaier U., Pohl M., et al. Determination of the autonomously functioning volume of the thyroid. Eur J Nucl Med . 1993;20:410–414.
8 Paschke R., Bruckner N., Eck T., et al. Regional stimulation of thyroid epithelial cells in Graves’ disease by lymphocytic aggregates and plasma cells. Acta Endocrinol (Copenh) . 1991;125:459–465.
9 Kahaly G.J. The thyrocyte-fibrocyte link: closing the loop in the pathogenesis of Graves’ disease? J Clin Endocrinol Metab . 2010;95:62–65.
10 Montori V.M., Gharib H. Hyperthyroidism. In: Rakel R.E., Bope E.T. Conn's current therapy 2004: latest approved methods of treatment for the practicing physician . Philadelphia: Saunders; 2004:692–695.
11 Al-Shoumer K.A., Vasanthy B.A., Al-Zaid M.M. Effects of treatment of hyperthyroidism on glucose homeostasis, insulin secretion, and markers of bone turnover. Endocr Pract . 2006;12:121–130.
12 Potenza M., Via M.A., Yanagisawa R.T. Excess thyroid hormone and carbohydrate metabolism. Endocr Pract . 2009;15:254–262.
13 Al-Shoumer K.A., Vasanthy B.A. Serum chromogranin A concentration in hyperthyroidism before and after medical treatment. J Clin Endocrinol Metab . 2009;94:2321–2324.
14 Antonello I.C., Antonello V.S., de Los Santos C.A., et al. Thyrotoxic hypokalemic periodic paralysis: a life-threatening syndrome. Eur J Emerg Med . 2009;16:43–44.
15 Jensen M.D., Gharib H., Naessens J.M., et al. Treatment of toxic multinodular goiter (Plummer's disease): surgery or radioiodine? World J Surg . 1986;10:673–680.
16 Danaci M., Feek C.M., Notghi A., et al. 131-I radioiodine therapy for hyperthyroidism in patients with Graves’ disease, uninodular goitre and multinodular goitre. N Z Med J . 1988;101:784–786.
17 Nygaard B., Hegedus L., Ulriksen P., et al. Radioiodine therapy for multinodular toxic goiter. Arch Intern Med . 1999;159:1364–1368.
18 Franklyn J.A., Daykin J., Holder R., et al. Radioiodine therapy compared in patients with toxic nodular or Graves’ hyperthyroidism. QJM . 1995;88:175–180.
19 Phitayakorn R., Narendra D., Bell S., et al. What constitutes adequate surgical therapy for benign nodular goiter? J Surg Res . 2009;154:51–55.
20 Kang A.S., Grant C.S., Thompson G.B., et al. Current treatment of nodular goiter with hyperthyroidism (Plummer's disease): surgery versus radioiodine. Surgery . 2002;132:916–923.
21 Wartofsky L., Glinoer D., Solomon B., et al. Differences and similarities in the diagnosis and treatment of Graves’ disease in Europe, Japan, and the United States. Thyroid . 1991;1:129–135.
22 Kampmann J.P., Hansen J.M. Clinical pharmacokinetics of antithyroid drugs. Clin Pharmacokinet . 1981;6:401–428.
23 Cooper D.S. Antithyroid drugs. N Engl J Med . 2005;352:905–917.
24 Abalovich M., Amino N., Barbour L.A., et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab . 2007;92:S1–S47.
25 Cooper D.S., Rivkees S.A. Putting propylthiouracil in perspective. J Clin Endocrinol Metab . 2009;94:1881–1882.
26 McIver B., Rae P., Beckett G., et al. Lack of effect of thyroxine in patients with Graves’ hyperthyroidism who are treated with an antithyroid drug. N Engl J Med . 1996;334:220–224.
27 Wartofsky L. Low remission after therapy for Graves’ disease: possible relation of dietary iodine with antithyroid therapy results. JAMA . 1973;226:1083–1088.
28 Hedley A.J., Young R.E., Jones S.J., et alScottish Automated Follow-Up Register Group. Antithyroid drugs in the treatment of hyperthyroidism of Graves’ disease: long-term follow-up of 434 patients. Clin Endocrinol (Oxf) . 1989;31:209–218.
29 Laurberg P., Andersen S., Karmisholt J. Antithyroid drug therapy of Graves’ hyperthyroidism: realistic goals and focus on evidence. Expert Rev Endocrinol Metab . 2006;1:91–102.
30 Philippou G., Koutras D.A., Piperingos G., et al. The effect of iodide on serum thyroid hormone levels in normal persons, in hyperthyroid patients, and in hypothyroid patients on thyroxine replacement. Clin Endocrinol (Oxf) . 1992;36:573–578.
31 Franklyn J.A., Daykin J., Drolc Z., et al. Long-term follow-up of treatment of thyrotoxicosis by three different methods. Clin Endocrinol (Oxf) . 1991;34:71–76.
32 Sridama V., McCormick M., Kaplan E.L., et al. Long-term follow-up study of compensated low-dose 131I therapy for Graves’ disease. N Engl J Med . 1984;311:426–432.
33 Holm L.E., Lundell G., Israelsson A., et al. Incidence of hypothyroidism occurring long after iodine-131 therapy for hyperthyroidism. J Nucl Med . 1982;23:103–107.
34 Roudebush C.P., Hoye K.E., DeGroot L.J. Compensated low-dose 131I therapy of Graves’ disease. Ann Intern Med . 1977;87:441–443.
35 Marcocci C., Bartalena L., Tanda M.L., et al. Graves’ ophthalmopathy and 131I therapy. Q J Nucl Med . 1999;43:307–312.
36 Rasmussen A.K., Nygaard B., Feldt-Rasmussen U. (131)I and thyroid-associated ophthalmopathy. Eur J Endocrinol . 2000;143:155–160.
37 Bonnema S.J., Bartalena L., Toft A.D., et al. Controversies in radioiodine therapy: relation to ophthalmopathy, the possible radioprotective effect of antithyroid drugs, and use in large goitres. Eur J Endocrinol . 2002;147:1–11.
38 Vannucchi G., Campi I., Covelli D., et al. Graves’ orbitopathy activation after radioactive iodine therapy with and without steroid prophylaxis. J Clin Endocrinol Metab . 2009;94:3381–3386.
39 Abalkhail S., Doi S.A., Al-Shoumer K.A. The use of corticosteroids versus other treatments for Graves’ ophthalmopathy: a quantitative evaluation. Med Sci Monit . 2003;9:CR477–CR483.
40 Bartalena L., Baldeschi L., Dickinson A., et alEuropean Group on Graves’ Orbitopathy (EUGOGO). Consensus statement of the European Group on Graves’ orbitopathy (EUGOGO): on management of GO. Eur J Endocrinol . 2008;158:273–285.
41 Rivkees S.A., Dinauer C. An optimal treatment for pediatric Graves’ disease is radioiodine. J Clin Endocrinol Metab . 2007;92:797–800.
42 Lal G., Ituarte P., Kebebew E., et al. Should total thyroidectomy become the preferred procedure for surgical management of Graves’ disease? Thyroid . 2005;15:569–574.
43 Miccoli P., Vitti P., Rago T., et al. Surgical treatment of Graves’ disease: subtotal or total thyroidectomy? Surgery . 1996;120:1020–1024.
44 Altman R.P. Total thyroidectomy for the treatment of Graves’ disease in children. J Pediatr Surg . 1973;8:295–300.
45 Franklyn J.A. The management of hyperthyroidism. N Engl J Med . 1994;330:1731–1738.
46 Mortimer R.H., Cannell G.R., Addison R.S., et al. Methimazole and propylthiouracil equally cross the perfused human term placental lobule. J Clin Endocrinol Metab . 1997;82:3099–3102.
47 Laurberg P., Bournaud C., Karmisholt J., et al. Management of Graves’ hyperthyroidism in pregnancy: focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy. Eur J Endocrinol . 2009;160:1–8.
48 Kampmann J.P., Johansen K., Hansen J.M., et al. Propylthiouracil in human milk: revision of a dogma. Lancet . 1980;1:736–737.
Chapter 6 Thyroglossal Duct Cysts and Ectopic Thyroid Tissue

Maisie L. Shindo

Embryology
Embryologically, the median anlage of the thyroid originates from the endodermal segment in the floor of the primitive pharynx at the foramen cecum located in the midline at the junction of the anterior two thirds of the tongue (first branchial arch derivative) and posterior one third (third branchial arch derivative) (see Chapter 2, Applied Embryology of the Thyroid and Parathyroid Glands ). Between 5 and 7 weeks of gestation, the gland migrates caudally from the foramen cecum to its normal position below the thyroid cartilage. The path of descent is closely associated with the hyoid bone and is usually anterior to it but can also be posterior to it or within the bone. The lateral thyroid anlage is derived from the ultimobranchial body, a descending diverticulum of the fourth to fifth pharyngeal pouch. The existence of this lateral anlage has been debated, but some believe it becomes incorporated into the median thyroid anlage to contribute morphogenesis of the thyroid parenchyma (see Chapter 2, Applied Embryology of the Thyroid and Parathyroid Glands , Figure 2-3 , D ).

Thyroglossal Duct Cysts
Between 7 and 10 weeks of gestation, the thyroglossal epithelial tract obliterates. Failure of the thyroglossal duct tract to obliterate can result in formation of thyroglossal duct cysts (TGDC). In autopsy series, thyroglossal tract remnants are found in approximately 7% of the normal population. 1 It represents the most common congenital midline mass. Thyroglossal duct cysts are found mostly in children and adolescents, but they are also found in patients more than 20 years old in one third of cases. Most thyroglossal duct cysts are found between the hyoid and thyroid cartilage (61%, 2 67% 3 ), followed by hyoid/suprahyoid (24%, 2 33% 3 ), suprasternal (13% 3 ), and in the base of tongue (2%, 2 0.1% 3 ).
The standard surgical treatment for thyroglossal duct cyst is the Sistrunk procedure. The procedure involves excising the cyst, removing the thyroglossal duct tract along with the central portion of the hyoid bone, and excising a central core of the base of the tongue at the foramen cecum. This procedure has been shown to be associated with very low (less than 4%) recurrent rates. 2 - 4
The incidence of malignancy in thyroglossal duct cysts is approximately 1%. 5, 6 The majority are papillary thyroid carcinoma, and a small percentage are follicular variant of papillary carcinoma; squamous cell carcinoma is rare. 5, 7 Thyroglossal duct malignancies are clinically difficult to distinguish from benign thyroglossal duct cysts and thus are rarely suspected preoperatively. Invasion of local structures, or suspicious metastatic lymphadenopathy on computed tomography (CT) or ultrasound, or the presence of features consistent with papillary thyroid carcinoma, such as microcalcifications, on ultrasound should raise suspicion for malignancy.
The surgical management of thyroglossal duct cyst carcinoma is still controversial. Most authors believe that incidentally discovered thyroglossal duct cyst papillary carcinoma can be adequately resected by the Sistrunk procedure alone, 5, 6, 8 provided there is no clinical or sonographic suspicion of thyroid lesion or cervical adenopathy. This procedure is associated with a cure rate of 95% in reported series. 5, 6, 8 Others advocate a more aggressive approach—total thyroidectomy along with the Sistrunk procedure. 9 - 11 One argument for this aggressive approach is the possibility of papillary carcinoma in thyroglossal duct cysts coexisting with an occult primary carcinoma in the thyroid. The reported incidences of primary thyroid carcinoma concomitant with thyroglossal duct cyst papillary carcinoma is between 11% and 56%. 9, 12 - 14 The tumors in the thyroid are usually small microcarcinomas and are frequently not palpable or detectable by preoperative imaging techniques. Another rationale for concurrent thyroidectomy is to allow postoperative treatment with radioiodine because of a high risk of lymph node metastasis. Hartl et al. reported an overall 75% incidence of lymph node metastases; 40% was in the central neck and 60% in the lateral neck. 9 Mazaferri suggested that a rational approach might be to treat thyroglossal duct cyst papillary carcinomas similar to well-differentiated thyroid cancers. Thus, low-risk tumors (defined as those existing in a patient under age 45), no prior radiation, ultrasonographically normal thyroid gland, small tumors (i.e., < 1.5 cm) with negative margins, and no cyst wall invasion or metastasis are all conditions that could adequately be treated with the Sistrunk procedure alone. 15 Total thyroidectomy is indicated if there is capsular invasion of the cystic wall or if the TGDC carcinoma is greater than 1 cm, as such tumors may behave more aggressively. 12 Those who advocate total thyroidectomy in addition to the Sistrunk procedure for TGDC carcinomas also recommend postoperative radioactive iodine ablation and thyroxine suppressive therapy. 10, 12 In patients with low-risk disease treated with the Sistrunk procedure, there are no data supporting the role of thyroid suppression therapy. The prognosis of papillary carcinoma arising in thyroglossal duct cyst is excellent, with an overall survival rate of 95.6% at 10 years. 5, 13 The postsurgical follow-up of patients is limited to an annual clinical and sonographic cervical examination in low-risk patients treated with the Sistrunk procedure. In those who have also undergone total thyroidectomy, serum thyroglobulin levels can also be measured for cancer surveillance, provided the patient does not have antibodies to thyroglobulin.

Ectopic Thyroid Tissue
Ectopic thyroid tissue, the presence of functioning thyroid tissue in a location other than its normal pretracheal location, can be found anywhere along the course of descent of the thyroid gland (see Chapters 2, Applied Embryology of the Thyroid and Parathyroid Glands , and 10 , Reoperation for Benign Disease). According to autopsy studies, the prevalence of ectopic thyroid tissue varies between 7% and 10%. Most cases of ectopic thyroid are diagnosed during the first three decades of life, and they are more common in females. 16 A classification of sites of ectopic thyroid is shown in Table 6-1 . Approximately 90% of ectopic thyroid tissue is found in the base of tongue as lingual thyroid. 16 - 19 Lingual thyroid results from complete arrest of descent of the median thyroid anlage. In 75% of patients with lingual thyroid, it is the only thyroid tissue present and the sole source of thyroid hormone production. 18 Seventy percent of cases present with hypothyroidism. 17 Rarely, lingual thyroid can be present along with normal pretracheal thyroid, but only the lingual thyroid is functional. 19 Hyperthyroidism from hyperfunctioning lingual thyroid has also been reported. 20 Most patients with lingual thyroid are asymptomatic; however, some can enlarge sufficiently to cause dysphagia and dyspnea. 21 Hypertrophy of the lingual thyroid occurs as a response to thyroid-stimulating hormone (TSH) stimulation from normal physiologic demands. Thyroid hormone production from lingual thyroid tissue often cannot meet the normal physiologic needs, which can result in enlargement of gland. Kansal et al. recommended that patients with lingual thyroid, even when small, be placed on lifelong thyroxine replacement to prevent subsequent enlargement. 22 Lingual thyroid is typically benign but rarely can harbor malignancy, usually papillary thyroid carcinoma. 23
Table 6-1 Classification of Sites of Ectopic Thyroid Sites of Ectopic Thyroid Comments Lingual Thyroid Usually nonfunctional Anterior Neck Sublingual   Subhyoid   Larynx and trachea Typically functioning Lateral Neck In soft tissue or cervical nodes Benign aberrant thyroid tissue; may represent metastatic thyroid cancer Submandibular   Parapharyngeal space   Mediastinum Thymus   Aortic wall   Pericardium, heart   Abdomen Liver, gallbladder, pancreas, adrenal   Pelvis Struma ovarii  
Cervical ectopic thyroid has also been reported to occur in the anterior neck, including the sublingual space, 16 the thyrohyoid region, 24 and within the trachea and larynx. 25 - 27 Unlike lingual thyroid, 75% of intratracheal ectopic thyroids are associated with functioning thyroid gland in its normal location. 25 Imaging studies such as CT or magnetic resonance imaging (MRI) typically demonstrate a nonerosive mass in the subglottis or upper trachea that is clearly separate from a normally located thyroid gland. These are often asymptomatic and can be incidental findings on autopsies. The most common presentation is progressive dyspnea, often mistaken for asthma. Stridor and hemoptysis are rare. Primary treatment is endoscopic laser excision. Tracheotomy may be necessary initially for emergent airway control. Radioactive iodine is not recommended for treatment of this rare entity, primarily because of the usual coexistence of normal extratracheal thyroid gland. Malignancy has also been reported in intratracheal ectopic thyroid. 28, 29
Approximately 10% of ectopic thyroid is found in the lateral neck. Lateral aberrant thyroid tissue is defined as thyroid tissue found lateral to the internal jugular vein. Most of these thyroid nests are found in cervical nodes. It has long been believed that if thyroid tissue is found in a cervical node, even if it appears benign histologically, it represents metastatic papillary thyroid carcinoma, and one simply needs to look thoroughly for a primary in the thyroid. 30 However, others have challenged this belief and argue that a small amount of normal-appearing thyroid tissue found in medially located cervical lymph nodes in a subcapsular location within the node may represent an embryologic rest within the capsules of the nodes. 31 - 34 Kozol et al. reported eight cases of thyroid tissue found in cervical nodes without any identifiable malignancy in the thyroid. 32
Other locations in the lateral neck where ectopic thyroid can be found are the submandibular region 35 - 39 and the parapharyngeal space. 40 - 43 In the submandibular region, it has been reported as the only functioning thyroid tissue or in conjunction with a normal thyroid. 35, 38 There are some theories on how of ectopic thyroid tissue occurs in the lateral neck. One theory is that nodular growths on the surface of the thyroid gland progressively enlarge and ultimately lose connection to the thyroid, termed exophytic thyroid nodules. Persistence of the lateral thyroid anlage may also be another explanation for occurrence of nonmidline ectopic thyroid tissue in the neck. 44
Ectopic thyroid can also be found in the anterior mediastinum (see Chapter 7, Surgery of Cervical and Substernal Goiter ). In contrast to substernal goiters, which are extensions of neck goiters into the mediastinum, true primary ectopic mediastinal goiters are rare and occur in less than 1% of all goiters. Ectopic thyroid in the mediastinum is usually located near the thymus. Heterotopic thyroid in the mediastinum probably developed from rudiments of developing thyroid being drawn into the chest during descent of the heart and great vessels during embryogenesis (i.e., thyroid rests; see Chapters 2, Applied Embryology of the Thyroid and Parathyroid Glands [ Figure 2-3 , B ] and 10 , Reoperation for Benign Disease). This could explain its aberrant locations in the pericardium, heart, and aortic wall. 45 - 48
Ectopic thyroid has also been reported in the abdomen, such as in the liver, gallbladder, pancreas, and adrenal gland. 49 - 52 In addition, heterotopic thyroid tissue can occur in the pelvis as struma ovarii, which is a germ cell tumor in the ovary with thyroid tissue comprising more than 50% of the tissue. 53, 54 Approximately 5% of struma ovarii are malignant. 53 - 56 The most common histopathologic subtype of malignant struma ovarii is papillary carcinoma, followed by follicular carcinoma, and a follicular variant of papillary carcinoma. 57 Diagnosis of malignant struma ovarii is usually made from primary biopsy of the ovary or oophorectomy. Rarely, the diagnosis may be suspected on radioactive iodine whole-body scanning for thyroid malignancy after total thyroidectomy. In such cases oophorectomy establishes the diagnosis. Because the thyroid tissue in struma ovarii is iodine avid and produces thyroglobulin, oophorectomy in such cases facilitates subsequent radioiodine treatment and ease of cancer surveillance.
Rarely, ectopic cervical thyroid can be present at two different sites simultaneously. Lingual/sublingual thyroid was the most common ectopic location. Subhyoid was the most common site of a second ectopic thyroid. In approximately 75% of the patients, ectopic thyroid tissue is the only functioning thyroid tissue. 58 - 61
Treatment of ectopic thyroid in the neck and chest depends on its location and size and whether or not the patient has symptoms or complications from it. Thyroid function tests, neck ultrasound, and thyroid uptake scan may be useful in diagnosis and in clinical management. Small and asymptomatic ectopic thyroid can be observed, as it may be the only functioning thyroid in the patient. Patients with compressive symptoms, suspected bleeding, malignancy, and ulceration need to be treated, either with surgery or radioiodine. Patients with relatively small ectopic mediastinal goiters are usually without symptoms and present with an abnormal incidental chest radiograph. Blood supply is typically from thoracic vessels, and a surgical approach by median sternotomy may be necessary for surgical removal if the ectopic tissue extends quite inferiorly (see Chapter 7, Surgery of Cervical and Substernal Goiter ).

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36 Mace A.T., McLaughlin I., Gibson I.W., et al. Benign ectopic submandibular thyroid with a normotopic multinodular goitre. J Laryngol Otol . 2003;117(9):739–740.
37 Zieren J., Paul M., Scharfenberg M., et al. Submandibular ectopic thyroid gland. J Craniofac Surg . 2006;17(6):1194–1198.
38 Feller K.U., Mavros A., Gaertner H.J. Ectopic submandibular thyroid tissue with a coexisting active and normally located thyroid gland: case report and review of literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . 2000;90(5):618–623.
39 Gin D., Gultekin S.H., Ward R.F., et al. Clear-cell follicular adenoma of ectopic thyroid in the submandibular region. Endocr Pathol . 1998;9:339–346.
40 Rinkel R.N., Manni J.J., van der Beek J.M. Ectopic thyroid tissue manifesting as a unique cause of an oropharyngeal mass. Otolaryngol Head Neck Surg . 2001;124:340–341.
41 Chanin L.R., Greenberg L.M. Pediatric upper airway obstruction due to ectopic thyroid: classification and case reports. Laryngoscope . 1988;98:422–427.
42 Basak S., Basak O., Odabasi O., et al. Pharyngeal thyroid: a case report. Br J Oral Maxillofac Surg . 1999;37:61–63.
43 Soscia A., Guerra G., Cinelli M.P., et al. Parapharyngeal ectopic thyroid: the possible persistence of the lateral thyroid anlage. Clinical case report. Surg Radiol Anat . 2004;26:338–343.
44 Paliaga A., Bianchelli G., Balercia G., et al. Contribution of the lateral anlage to the embryogenesis of the thyroid gland: evidence of a persisting thyrocarotid duct. Eur J Surg . 1997;163:795–797.
45 Casanova J.B., Daly R.C., Edwards B.S., et al. Intracardiac ectopic thyroid. Ann Thorac Surg . 2000;70:1694–1696.
46 Chosia M., Waligorski S., Listewnik M.H., et al. Ectopic thyroid tissue as a tumour of the heart: case report and review of the literature. Pol J Pathol . 2002;53:173–175.
47 Pistono M., Occhetta F., Sarasso G., et al. Intracardial ectopic thyroid: a report of a clinical case with a long-term follow-up. Cardiologia . 1999;44:83–88.
48 Williams R.J., Lindop G., Butler J. Ectopic thyroid tissue on the ascending aorta: an operative finding. Ann Thorac Surg . 2002;73:1642–1643.
49 Gungor B., Kebat T., Ozaslan C., et al. Intra-abdominal ectopic thyroid presenting with hyperthyroidism: report of a case. Surg Today . 2002;32:148–150.
50 Eyboglu E., Kapan M., Ipek T., et al. Ectopic thyroid in the abdomen: report of a case. Surg Today . 1999;29:472–474.
51 Liang K., Liu J.F., Wang Y.H. Ectopic thyroid presenting as a gallbladder mass. Ann R Coll Surg Engl . 2010;92(4):W4–W6.
52 Takao H., Doi I., Watanabe T. Ectopic thyroid in the adrenal gland: Computed tomography findings. J Comput Assist Tomogr . 2006;30(2):221–222.
53 Willemse P.H.B., Oosterhuis J.W., Aalders J.G., et al. Malignant struma ovarii treated by ovariectomy, thyroidectomy, and 131I administration. Cancer . 1987;60:178–182.
54 DeSimone C.P., Lele S.M., Modesitt S.C. Malignant struma ovarii: a case report and analysis of cases reported in the literature with focus on survival and I131 therapy. Gynecol Oncol . 2003;89:543–548.
55 Wirtz E.D., Bothwell N., Klem C. Role of the otolaryngologist in the treatment of struma ovarii. Laryngoscope . 2010;120(2):259–260.
56 Makani S., Kim W., Gaba A. Struma ovarii with a focus of papillary thyroid cancer: a case report and review of the literature. Gynecol Oncol . 2004;94:835–839.
57 Devaney K., Snyder R., Norris H., et al. Proliferative and histologically malignant struma ovarii: a clinicopathologic study of 54 cases. Int J Gynecol Pathol . 1993;12:333–343.
58 Baik S.H., Choi J.H., Lee H.M. Dual ectopic thyroid. Eur Arch Otorhinolaryngol . 2002;259:105–107.
59 Hod N., Mindlin N., Cohenpour M., et al. Double ectopic thyroid. Pediatr Radiol . 2002;32:859–861.
60 Kumar R., Khullar S., Gupta R., et al. Dual ectopic thyroid: case report and review of the literature. Clin Nucl Med . 2000;25:253–254.
61 Chawla M., Kumar R., Malhotra A. Dual ectopic thyroid: case series and review of the literature. Clin Nucl Med . 2007;32(1):1–5.
Chapter 7 Surgery of Cervical and Substernal Goiter

Gregory W. Randolph, Anais Rameau, James L. Netterville

“Guttur homini tantum et suibus intumesit aquarum quae potantur plerumque vitio.” (Translation: Swelling of the throat occurs only in men and swine, caused mostly by the water they drink.)
—Pliny the Elder, 1st century ad 1
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The word goiter is derived from “guttur,” the Latin term for throat. 2 Surgery for goiter is as complex as it is satisfying. With goiter, the normally complex neck base anatomy is distorted in sometimes predictable and often unpredictable patterns. Size, goiter vascularity, distortion of anatomy, substernal extension, and restrictions imposed by the bony confines of the thoracic inlets can make recurrent laryngeal nerve (RLN) and parathyroid gland identification and preservation challenging. Halsted wrote that “the extirpation of the thyroid gland for goiter better typifies perhaps than other operations, the supreme triumph of the surgeon's art.” 3
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The operative story of goiter documents the evolution of modern surgical technique. Gunther in 1864 described a case emphasizing the difficulties experienced during early goiter surgery: “After several fruitless attempts at ligation of the arteries, the severe hemorrhage was controlled by compression day and night during eight days by persons alternating with each other at the task” (see Chapter 1, History of Thyroid and Parathyroid Surgery ). 4
This chapter reviews the patterns of anatomic distortion presented by both cervical and substernal goiter. Substernal goiter represents a distinct subtype of cervical goiter and is discussed separately where appropriate, given its unique challenges. After reviewing key points about goiter definition and clinical evaluation, we shall discuss treatment options, with an emphasis on the surgical approach. The chapter highlights the evaluation of upper airway compromise in patients with goiter, the relationship between the extent of surgery and the likelihood of goiter recurrence, and the predictive risk factors for surgical complications. See also Chapters 8, Approach to the Mediastinum: Transcervical, Transsternal, and Video-Assisted , 9, The Surgical Management of Hyperthyroidism , and 10, Reoperation for Benign Disease .

General Considerations

Goiter Definition
It is important first to come to an understanding regarding what a “goiter” is and to define “big.” This is not easy when one looks critically at the literature. Both greatest diameter and goiter weight have been used to define thyroid enlargement. In available studies, methods for determining goiter size range from physical examination measured in centimeters, to physical examination estimated in grams, to surgical specimen measured in centimeters or grams. Preoperative imaging diameters may also be used.
The definition of goiter varies substantially among reports. McHenry suggested 80 g and Russell 100 g, whereas Clark proposed 200 g as the threshold value. 5 - 9 Studies investigating radioiodine treatment for multinodular goiter often define significant goiter as greater than 100 g. Hegedus, Nygaard, and Hansen found that goiter surgical specimens averaged 30 g for unilateral resection and 64 g for bilateral resection. 10 In the study by Katlic, Grillo, and Wang, the average weight of substernal goiter was 104 g (range 25 to 357 g), with greatest diameter averaging 9 cm (range 5 to 19 cm). 11 In a series of more than 200 cervical and substernal goiters treated at Massachusetts Eye and Ear Infirmary and Massachusetts General Hospital, the mean weight was 143 g and the mean goiter size was 10.5 cm. 12
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The largest goiter we can find documented in the literature is reported by Manoppo, who described a benign, nontoxic goiter that was 75 × 60 × 45 cm. The patient was unable to walk or sit because of the size of the goiter. Treatment was with right hemithyroidectomy under local anesthesia, without major complications. 13
The World Health Organization (WHO) 1960 grading system for clinical assessment of goiter defines stage 0 as no enlargement; stages 1 to 3 describe progressive goiter enlargement. Stage 1A includes patients with palpable abnormalities; stage 1B includes patients with palpable and visual abnormalities with the neck in extension. Stage 2 is defined as a goiter that is visible with the neck in neutral position, and Stage 3 as a goiter that is able to be visualized at a considerable distance. 14, 15 The WHO 1994 goiter classification system is more streamlined. Grade 0 is defined as no palpable or visual abnormality. Grade 1 is defined as a palpable thyroid mass that is not visualized with the neck in neutral position, and grade 2 as a visually apparent mass with the neck in neutral position. 16

Substernal Goiter

Definition
Substernal goiter and its subtypes have been variously termed retrosternal, subclavicular, intrathoracic, mediastinal, aberrant, wandering, and spring goiter, as well as goiter mobile and goiter plongeant. Numerous definitions and classification schemes have been proposed for substernal goiter.
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Lahey and Swinton defined substernal goiter as a “gland in which the greatest diameter of the intrathoracic component by x-ray was well below the upper aperture of the thoracic inlet.” 17 Crile, in 1939, simply defined substernal goiter as a lesion extending to the aortic arch. 18 Lindskog and Goldenberg in 1957 defined substernal goiter as a goiter whose lower border radiographically reaches the transverse process of the fourth thoracic vertebra or lower. 19 Katlic, Grillo, and Wang described substernal goiter as when greater than 50% of the goiter is present substernally. 11 Sanders et al. defined substernal goiter as that which requires mediastinal exploration and dissection for removal. 20 Other definitions have been offered. 21 - 23
Several workers have offered substernal classification schemes. Higgins based his classification scheme on the percentage of goiter in the neck versus the percentage of goiter in the chest, with greater than 50% in the neck being described as substernal, greater than 50% in the chest as partially intrathoracic, and greater than 80% in the chest as completely intrathoracic. 24 Cho, Cohen, and Som offered a grading system relating grade to percentage of goiter within the chest. Grade I is defined as 0% to 25% of the goiter within the chest, grade II as 26% to 50%, grade III as 51% to 75%, and grade IV as greater than 75%. 25 Shahian offered an interesting and detailed classification scheme. In this classification scheme, type I substernal goiter is associated with the anterior mediastinal extension, type IA involves “isolated” anterior mediastinal disease, whereas type IB involves “extensive” substernal involvement. Type II involves posterior mediastinal involvement, with type IIA being isolated posterior mediastinal goiter, type IIB posterior mediastinal goiter with ipsilateral extension relative to the thyroid lobe of origin, and type IIC contralateral extension relative to the thyroid lobe of origin, with C1 being retrotracheal and C2 being retroesophageal course. 26, 27
A classification system for substernal goiters is most useful when it takes into account the features of substernal goiters that must be appreciated to extract them safely. We define substernal goiter simply as those goiters that are associated with substernal extension such that the thoracic component requires mediastinal dissection to facilitate extraction. We believe that all substernal goiters require axial computed tomographic (CT) scanning to differentiate between the various subtypes. Such differentiation provides tremendously useful surgical information. We propose the following substernal goiter classification scheme ( Table 7-1 ).

Table 7-1 Substernal Goiter Classification

Posterior Mediastinal Goiters (Substernal Goiter Type II)
Most surgical and radiographic series suggest that substernal goiters affect the anterior mediastinum in approximately 85% of patients and the posterior mediastinum in approximately 15% (see Table 7-1 ). 26 - 29 Extension into the anterior mediastinum brings the mass anterior to the subclavian and innominate vessels and anterior to the RLN. The relationship of the anterior mediastinal goiter to the RLN is as in the normal cervical gland—that is, that the nerve is deep. When substernal goiter expands to the posterior mediastinum, it excavates the region posterior to the trachea, pushing the trachea anteriorly and splaying the great vessels anteriorly. The mass then comes to rest in a space posterior to the innominate vein, carotid sheath contents, innominate and subclavian arteries, RLN, and inferior thyroid artery. 26, 27, 30 Of importance, the relationship of the mass and the RLN is reversed as compared with the normal cervical orthotopic gland-RLN relationship. The RLN is ventral to the inferior component of the mass and, if not recognized early on, can be stretched or cut by even the most meticulous thyroid surgeon. The nerve can also be entrapped between components of the posterior mediastinal goiter; even in these circumstances, a portion of the goiter will be deep to the RLN. Such posterior mediastinal goiters can come to rest in a space bounded inferiorly by the azygous vein, posteriorly by the vertebral column, laterally by the first rib, medially by the trachea and esophagus, and anteriorly by the carotid sheath, subclavian and innominate vessels, superior vena cava, and phrenic and recurrent laryngeal nerves. 26, 27
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Posterior mediastinal goiter (type IIA) can occur ipsilateral to the cervical gland of origin or may come to rest through retrotracheal extension in the contralateral thorax (substernal goiter type IIB) (see Table 7-1 ). Extension to the right thorax is more commonly seen as a result of aortic arch and associated branch vessels obstructing the left posterior mediastinal descent pathway. 31, 32 Contralateral thoracic extension in the posterior mediastinum may occur either behind the trachea and esophagus (IIB1) or between trachea and esophagus (IIB2). Axial CT scanning and barium swallow help to determine this pattern. Generally the right chest caudal extension is limited at the level of the azygous arch ( Figure 7-1 ). 33

Figure 7-1 Patient with a large cervical and substernal goiter. Substernal goiter extends into the left chest and then crosses retrotracheally into the right chest, extending between the trachea and esophagus (substernal goiter type IIB2). A, Right superior pole extends beneath the sternocleidomastoid muscle to the level of the mandible. B, At the level of the cricoid cartilage, goiter is present bilaterally in the neck. C, At the level of the thoracic inlet, the left lobe expands and extends into the left chest and retrotracheally into the right thorax. D, The mass extends substernally along the left lateral trachea and retrotracheally, abutting both left and right lung fields, splaying the great vessels. E, The distal segment of the substernal mass has several lobulations. The innominate artery is seen anterior to the trachea. A bronchus abuts the lateral aspect of the inferior-most goiter segment. The goiter posteriorly abuts the vertebral column. F, The inferior-most extent of the goiter extends retrotracheally deep to the level of the aortic arch. The mass can be seen infiltrating the region between the trachea anteriorly and the esophagus posteriorly. G, The mass extends between the trachea and esophagus, ending just above the azygous vein and right mainstem bronchus. H, Barium swallow showing substantial cervical and mediastinal esophageal deviation. The mass was resected transcervically without sternotomy, with recurrent laryngeal nerve and vagal monitoring with normal cord motion postoperatively. The specimen weighed 450 g and was 15 cm in greatest diameter.

Isolated Mediastinal Goiter (Substernal Goiter Type III)
Although rare, thyroid masses within the mediastinum may exist without connection to the normal cervical orthotopic gland. Such purely isolated mediastinal goiters represent only 0.2% to 3% of all goiters requiring surgical treatment. 11, 24, 34, 35 Such lesions are important to recognize because unlike all other types of substernal goiters, blood supply of the isolated mediastinal goiter may be through purely mediastinal arteries (including the aorta, subclavian, internal mammary, thyrocervical trunk, and innominate) and veins. This is extremely important in planning their surgical resection. 11, 24, 36 - 40 This entity is best termed isolated mediastinal goiter . Other terms have been used, including aberrant mediastinal and ectopic mediastinal goiter.
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Three explanations exist for isolated mediastinal goiter. Embryologic fragmentation of thyroid anlagen with hyperdescent, likely associated with cardiac and great vessel descent, may explain some cases of isolated mediastinal goiter (see Chapters 6, Thyroglossal Duct Cysts and Ectopic Thyroid Tissue, and 10, Reoperation for Benign Disease ). 41, 42 Alternatively, isolated mediastinal goiter may form as an exophytic nodule, through progressive attenuation of the nodule-thyroid stalk. 41, 43, 44 Finally, the isolated mediastinal goiter may form as a parasitic nodule representing a thyroid tissue fragment implant in the upper mediastinum from past goiter surgery. We have seen such implants also within the perithyroid area and posterior to the upper cervical segment of the carotid artery.

Prevalence, Pathogenesis, and Natural History

Prevalence
Multinodular goiter affects 4% of the U.S. population and up to 10% of the British population. 45 New thyroid nodular disease occurs in from 0.1% to 1.5% of the general population per year. 46, 47 Globally, iodine deficiency contributes to the vast majority of cases of multinodular goiter and is estimated to affect 1.5 billion people, or nearly 30% of the world's population in 1990. 48 Further, it is estimated that approximately 655 million people in 118 countries are affected by endemic goiter. Endemic goiter regions are defined as iodine-deficient regions in which at least 5% to 10% of the population is affected by goiter. In certain iodine-deficient regions, higher goiter rates occur. In 1994, in Bangladesh, approximately 47% of the population was affected by endemic goiter. 49 The majority of the natural iodine supply exists as iodide in the world's oceans. It is therefore mainly noncoastal mountainous and lowland regions—where iodine is leached from the soil by flooding, heavy rainfall, and deforestation—that are at risk for endemic goiter. Sporadic forms of multinodular goiter do occur in iodine-replete regions with lesser prevalence. 16, 48 Prevalence estimates of sporadic goiters vary between authors, ranging from less than 4% (clinical evaluation series) and between 16% and 67% (ultrasound series). 50, 51
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Based on tuberculosis screening radiography in Australia and in the United States, substernal goiter has been estimated to be present in 0.02% of general population and 0.05% of females older than 40. 52, 53 The incidence of substernal goiter was found to significantly increase with age, with 60% of substernal goiters occurring in patients older than age 60. 52 Rates of substernal goiter in the past several decades appear to be decreasing, perhaps related to the introduction of iodized salt, thyroid hormone suppressive therapy, radioiodine use in selective cases, and perhaps more sensitive detection and earlier intervention. 2, 54 Substernal goiter, as a percentage of patients undergoing thyroidectomy, ranges depending on the series from less than 1% to greater than 20%, with most suggesting a rate of approximately 10%. 11, 17, 18, 27, 55 - 59 Substernal goiters represent approximately 5% of all mediastinal tumors. 27, 60

Pathogenesis
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Pathogenesis
The pathogenesis of goiter formation has classically relied on the notion that iodine deficiency promotes persistent elevated thyroid-stimulating hormone (TSH) levels, inducing diffuse thyroid enlargement through thyrocyte proliferation. Nodules form in the enlarged thyroid as the patient ages, eventually giving rise to multinodular goiter. 61, 62 Since the early 2000s, this classic model has been challenged by the view that the thyroid gland has an intrinsic propensity to form nodules over time. In this new model, low iodine levels and elevated TSH are considered additional factors, exacerbating the innate process of nodule formation. 63, 64
The shift in conceptualization of goiter pathogenesis has stemmed from new cellular models, first proposed by Studer and Derwahl. 63 - 66 These authors have argued that the development of multinodular goiter, at least in the later stages, is independent of TSH levels. Nodules arise because thyroid follicles are embryologically derived from polyclonal progenitors and have thus a heterogeneous sensitivity to TSH signaling. 67 Thyroid follicles have similarly a differential growth response to continuous exposure to goitrogens, explaining the multinodular pattern of goiters. In addition, thyrocytes may undergo somatic mutations and acquire a distinct growth capacity. 68, 69 The contribution of somatic mutations in multinodular goitrogenesis remains, however, controversial. This is in contrast with rare growth-promoting germline mutations of the TSH receptor gene, which are believed to be pivotal in congenital diffuse goiter with hyperthyroidism. 70 Importantly, activating mutations in the TSH receptor gene have not been associated with an increased risk of malignancy. 71

Natural History
The natural history of untreated, sporadic, nontoxic goiter is not completely understood, but slow growth appears to be the general predictable pattern. Berghout et al. suggested a steady volume increase of up to 10% to 20% per year. 72 Pregnancy, iodine deficiency, consumption of goitrogens, and alteration in suppressive or antithyroid medical regimens can result in goiter progression. Hemorrhage into a preexisting nodule can also result in the development of acute, regional, and airway symptoms. 73 In patients presenting with diffuse goiter, there is a general tendency toward nodule formation and progressive autonomy, with hyperthyroidism ultimately developing in up to 10% of patients (see Chapters 5, Hyperthyroidism: Toxic Nodular Goiter and Graves’ Disease , and 9, The Surgical Management of Hyperthyroidism ). 74
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Most substernal goiters arise in the setting of preexisting cervical goiter. It is of note, however, that some patients with substernal goiter have no significant cervical goiter component. Substernal goiters virtually always have a connection to the cervical orthotopic gland. Lahey, in his vast experience of approximately 24,000 goiter surgeries, believed that all substernal goiters arise from the cervical gland and maintain their cervical blood supply. 75 Even in cases of extreme substernal goiter extending to the diaphragm, the mediastinal component has been found to contain connections to the cervical gland and a blood supply from the inferior thyroid artery. 76 - 78 Connection to the cervical gland may be robust or attenuated, but it virtually always exists. The work of Torre, based on an impressive series of 237 substernal goiters, suggests that substernal goiters arise 10 years after cervical goiter presentation, suggesting that substernal goiter evolves from preexisting cervical goiter in most cases. 8
The inferior extension of cervical goiter and formation of substernal goiters is poorly understood. The inferior descent relates in part to the pattern of nodular disease within the cervical gland. Inferior progression results from a limitation of the strap muscles anteriorly, trachea medially, and vertebral column posteriorly. As Lahey and Swinton have described, the neck is “a space with no bottom.” 17 The repetitive forces of deglutition, respiratory dynamics, negative intrathoracic pressure, and gravitational forces in the setting of permissive mediastinal and neck base fascial planes facilitate the downward extension of cervical goiter. Typically, anterior mediastinal extension (substernal goiter type I) occurs from the ipsilateral lobe's inferior expansion. Descent associated with significant retrotracheal posterior mediastinal extension may arise from more posterior elements of the thyroid gland such as posterior tubercles of Zuckerkandel. (see Table 7-1 ).

Clinical Presentation

Cervical Goiter

History
The history of goitrous growth and associated symptoms is critical for determining surgical candidacy. This history should be obtained not only from the patient but also from his or her family. Regional symptoms should be addressed relating to respiration, phonation, swallowing, and presence of globus (lump sensation). As Pemberton emphasized in 1921, symptoms associated with goiter may be positionally induced. 38 Positions that may provoke goiter regional symptomatology include being supine, arms raised (as when reaching for an upper cabinet), extreme neck extension, extreme neck flexion (as with reading a book in bed), and turning the head to the extreme left or right. Patients thus need to be questioned about positional provocation of regional symptoms. In addition, the family needs to be questioned about nocturnal symptoms, as symptoms may manifest initially in the setting of recumbency and upper airway relaxation during sleep. Symptoms may also be associated with exercise and increased oxygen demands. A history of preceding upper respiratory tract infection may produce dyspnea in a patient with long-standing tracheal obstruction secondary to goiter through new laryngotracheal mucosal edema. Patients with cervical or substernal goiter may present with cough, dyspnea, foreign-body sensation, neck tightness, change in collar size, or wheezing and may come to the head and neck surgeon with a misdiagnosis of asthma or chronic obstructive pulmonary disease (COPD). In our series of patients with large cervical and substernal goiter, we found that 25% of patients were preoperatively asymptomatic. 12
Symptoms of hypothyroidism and hyperthyroidism should be reviewed. Hyperthyroidism may slowly evolve in patients with multinodular goiter or may develop acutely in response to significant iodine load such as with CT scan contrast (Jod-Basedow phenomenon) or with the introduction of iodized salt in endemic goiter regions. 79 A history of migration from an area of endemic goiter should be obtained, as well as a history of exposure to known goitrogens, notably iodine and lithium. A family history of thyroid disease should be obtained.

Physical Examination
After documentation of thyroid size, the examiner should note the consistency and fixation of the mass, especially with respect to the larynx and trachea. Estimation of goiter size by physical examination is clearly an inaccurate method of assessment. Jarlov et al. found substantial errors in the clinical assessment of thyroid size as compared with ultrasonographic assessment. 80 Estimated weight based on the physical examination generally underestimates multinodular goiter weight by 25 to 50 g. 46 The larynx (landmarks include thyroid notch and cricoid anterior arch) and trachea should be examined for deviation from the midline. Typically, cervical goiter will deviate the larynx and trachea to the contralateral side. The neck must be examined for adenopathy as well as scarring from past thyroid and other neck surgery. Jugular distention and subcutaneous venous redistribution should be noted. Although this may be present with large benign cervical or substernal goiter, true superior vena cava syndrome is generally due to malignant thyroid disease and warrants careful scanning and evaluation. 11
It is imperative in all patients with goiter that the larynx be examined. In our series, we have found that 2% of patients with goiter presented with vocal cord paralysis in the setting of benign disease and no prior neck surgery, and 3.5% of preoperative patients presented with goiter overall. 12 Vocal cord paralysis without a history of past thyroid surgery implies invasive thyroid malignancy until proved otherwise. It should be noted, however, that benign goiter has also been associated with vocal cord paralysis, presumably through stretch, which may recover postoperatively (see Chapter 33, Surgical Anatomy and Monitoring of the Recurrent Laryngeal Nerve ). 81 Certainly, such a preoperative finding focuses the surgeon's attention on the extreme importance of preserving the contralateral RLN. The laryngeal examination in patients with large cervical goiter can be difficult if there is edematous or redundant supraglottic mucosa, laryngeal compression and deviation, and hypopharyngeal crowding resulting from goitrous extrinsic compression. Symptomatic assessment of the voice, like symptomatic assessment of the airway, does not predict objective findings in patients with goiter and should not replace the laryngeal exam. In our patient series, voice change was reported preoperatively in 12.8%, but vocal cord paralysis was present in only 3.5%, consistent with the work of Michel, emphasizing that glottic function cannot be predicted by voice assessment. 82, 83 Michel noted in his series of substernal goiters that although hoarseness was described in 26%, vocal cord paralysis was only found in 3%. 89 We thus reiterate our recommendation that all patients with goiter undergo preoperative laryngeal examination.

Substernal Goiter
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Substernal Goiter
In many ways the history and physical examination for patients with substernal goiter overlaps significantly with those for patients with cervical goiter. In our series, we have found that as cervical goiter progresses substernally, given the restriction of the bony confines of the thoracic inlet, it increasingly compromises the airway. In short, substernal goiter evolution is strongly correlated with tracheal deviation, the development of regional airway symptoms, and radiographic airway compression. 12 Buckley and Stark noted that although the maximum tracheal deviation with substernal goiter usually occurs at the thoracic inlet, it may occasionally occur farther inferiorly. 33 Larger surgical series of substernal goiter show 70% to 80% of substernal goiter patients are symptomatic at presentation. Cervical mass is noted in from 69% to 97%, respiratory symptoms in 42% to 96%, dysphagia in 26% to 60%, and acute airway presentation in from 1% to 5%. 2, 8, 11, 19, 20, 25, 55, 84 - 88 Interestingly, these series show that 10% to 30% of substernal goiter patients, as previously noted, have no significant palpable cervical abnormality, 3% to 7% present with vocal cord paralysis, and 4% to 50% are asymptomatic at presentation. Wax and Briant have noted that, with careful questioning, up to one third of patients who are “asymptomatic” admit to symptoms. 88
Pemberton's sign is described as the development of head and neck venous engorgement with facial congestion, plethora, and venous distention with arms raised over the head. It is sometimes expanded to include the development of transient respiratory insufficiency. Pemberton's sign is thought to indicate goiter extension into the thoracic inlet, with secondary relative venous and airway obstruction. 38, 58, 90 Our series of large cervical and substernal goiters suggests that Pemberton's sign is insensitive in the evaluation of substernal goiter, as only 4.4% of patients presented with a positive Pemberton's sign. 12 Substernal goiters can also present with neck and upper chest pain and have rarely been associated with hematemesis secondary to downhill esophageal varices (without signs of portal hypertension), abscess formation, Horner's syndrome, chylothorax (secondary to thoracic duct obstruction), transient ischemic attacks through “thyroid steal syndrome,” venous thrombosis, and intubation injuries, especially to the posterior tracheal membranous wall. 56, 91
Laryngeal shift to the side of a dominant cervical goiter suggests contralateral substernal goiter and requires axial imaging of the neck and chest. Similarly, laryngeal shift without any palpable cervical findings suggests substernal goiter and similarly requires axial neck and chest imaging. 11, 19, 79, 84, 92 Finally, substernal goiter is suspected when the clavicle intervenes before the inferior extent of the thyroid mass can be palpated.

Goiter Workup
In the workup of patients presenting with a goiter, the clinician may address the following three important issues: (1) the existence or the potential development of airway compression, (2) the risk of malignancy, and (3) the presence of hyperthyroidism ( Boxes 7-1 and 7-2 ).

Box 7-1 Airway Imaging, Flow Volume Loops, and Goiter Symptoms: Summary

• The presence of preoperative shortness of breath correlates with goiter size, but it is of limited value as a screening tool for tracheal abnormalities.
• Dysphagia correlates with radiographic findings of esophageal deviation and compression. In the absence of dysphagia, patients do not require further esophageal imaging.
• Symptomatic assessment of voice does not predict objective findings in patients with goiter and should not replace the laryngeal exam.
• Flow volume loop studies most accurately document airway obstruction in the setting of significant airway compression. However, they correlate poorly with goiter weight and upper airway symptoms. We do not recommend flow volume loop studies as part of the routine work-up for patients with goiter.
• Thus, symptomatic flow volume loop and plain film assessment of goiter is insensitive, in distinction to axial CT scanning. The finding of tracheal compression on axial CT scanning correlates significantly with the presence of shortness of breath; therefore, we consider the finding of CT scan tracheal compression to be an appropriate surgical indication given its symptomatic respiratory correlate.

Box 7-2 Workup for Benign Goiter

History and physical examination
Symptomatic *
Massive goiter *
Bilateral circumferential goiter *
Suspect substernal goiter *
Suspect cancer (vocal cord paralysis, lymphadenopathy) *
Thyroid function tests
Chest radiograph if suspect cancer
Chest radiograph showing airway deviation → axial CT or MRI
CT, Computed tomography; MRI, magnetic resonance imaging.

* Obtain CT or MRI.

Airway Assessment in Thyroid Disease
Foremost in goiter assessment is airway evaluation. The fundamental components of airway evaluation include determination of the rate and pattern of respiration, presence of sound with breathing (i.e., stridor), and voice quality. In patients with significant airway obstruction from thyroid disease, the initial assessment requires integration of a targeted but complete history and physical examination to expeditiously identify the site and magnitude of obstruction. One must always remember to keep in mind the overall global status of the patient with respect to his or her respiratory effort and signs of distress. Fatigue, restlessness, or apprehension can occur in the setting of hypoxia. The patient who is lethargic may be hypercapnic. Body position as an indicator of respiratory comfort, peripheral signs of oxygenation, and cyanosis should be carefully evaluated. Included in this assessment is the taking of vital signs and the use of pulse oximetry. One must be vigilant that a patient with a good pulse oximeter reading—or, for that matter, good arterial blood gas levels—may, a moment later, experience complete respiratory obstruction. The sound of respiration (i.e., the presence of stridor) gives an important clue as to the magnitude and location of airway obstruction. Stridor implies turbulent airflow through a stenotic airway segment. Significant extrathoracic obstruction (most commonly laryngeal, subglottic, or upper cervical trachea) typically presents with inspiratory stridor and is seen as a variable extrathoracic obstruction on flow volume loop analysis with inspiratory phase flattening. Isolated expiratory stridor is seen in intrathoracic (lower tracheal) obstruction. Here, inspiration is silent and voice is normal.

Acute Airway Compromise
Please see the Expert Consult website for more discussion of this topic, including Figure 7-2 .

Acute Airway Compromise
The frequency of development of acute airway compromise in cervical and substernal goiter varies depending on the population studied. Unfortunately, most of the information available is from surgical series. Allo and Thompson have estimated that from 1% to 3% of patients with untreated mediastinal goiter die of respiratory obstruction. 55
The airway can be affected by goiter through a number of mechanisms, including, most typically, ongoing slowly progressive airway deviation and compression. Acute events can also precipitate airway compromise, including hemorrhage into a nodule of multinodular goiter. Georgiadis has described acute stridor caused by hemorrhage within a nodule after neck trauma. 93 Pulli and Coniglio have described a patient whose goiter increased in size after a fall on ice. 2 Torres et al. have presented a number of cases showing acute life-threatening tracheal obstruction in patients with long-standing, intrathoracic goiter with subsequent histology showing multiple foci of recent hemorrhage. 94 Hemorrhage as a mechanism of goiter size increase is supported by the work of Bodon and Piccoli. 95 We have seen acute tracheal obstruction with magnetic resonance imaging (MRI) scan evidence of central nodular hemorrhage in what was ultimately found to be a large benign follicular adenoma (see Figure 7-2 ). Sudden airway symptoms may also arise as a result of cystic degeneration, malignant degeneration, upper respiratory tract infection, or pregnancy. 96 Rare mechanisms for respiratory distress in patients with large goiters include decompensated right heart failure, pleural effusion, and pulmonary hypoperfusion secondary to compression of the pulmonary arteries. 90 We agree with Cougard et al. that a patient with goiter and acute airway decompensation requiring endotracheal tube intubation should be brought to surgery when stable, while intubated. Ultimately, after thyroid surgery, laryngeal examination should be performed to rule out laryngeal edema and assess vocal cord function before extubation. 97

Figure 7-2 A, A patient with hemorrhage within a benign follicular adenoma with sudden enlargement and sudden onset airway deviation and compression with respiratory symptoms. Note that the tracheal air column is substantially deviated to the left and that on plain chest radiograph, no significant compression is appreciated. B, Magnetic resonance imaging axial scanning shows substantial airway compression. Note the density within the center of the thyroid mass that represents hemorrhage.
Miller et al., in a nonsurgical series of 400 patients with goiter, evaluated patients with pulmonary function tests and flow volume loops. Nearly one third of such patients had flow volume evidence of upper airway obstruction. 9 Gittoes et al., in a study of 153 goiter patients followed in a medical/endocrine clinic, also found that 33% of such patients had evidence of upper airway obstruction on flow volume loop analysis. 45 Thus, two large nonsurgical series suggest that up to one third of patients with large goiters followed in endocrine clinics have evidence of upper airway obstruction as defined on flow volume loops. Limited data are available within this population as to the rate of development of acute airway symptoms. Alfonso found, in a surgical series of 91 patients with benign goiters with either radiographic or symptomatic evidence of upper aerodigestive tract compression, that approximately 9% of patients presented with acute upper airway obstruction. 98 Reeve, Rubenstein, and Rundle, in a large screening radiographic study that identified patients with significant thyromegaly as defined by plain radiographs, found 7.6% of such patients presented with “profound respiratory obstruction.” 52 In a surgical series of patients with substernal goiter, reports vary, with 1.3% to 5% of such patients presenting with acute airway insufficiency. 11, 25, 55, 84, 85, 92, 99, 100 Higher rates of acute airway insufficiency have been reported in other surgical series. 86, 101
Thus, approximately one third of patients with goiter in medical series have upper airway obstruction as defined by flow volume loops, and from 1.3% to 9% of such patients may present with acute airway symptomatology. Unfortunately, a long, chronic, stable history does not preclude spontaneous acute airway insufficiency. 55 Warren has beautifully documented cases of acute respiratory failure secondary to goiter in elderly patients. All presented with acute respiratory collapse without a history of respiratory symptoms 48 hours before the respiratory failure. 100 Cho, Cohen, and Som also emphasized, in a review of 70 patients with substernal goiter, the potential for sudden and unpredictable respiratory distress. 25
There is sometimes a tendency for patients with large compressive goiters to be followed with flow volume loops and symptomatic assessment. There is no evidence to suggest this is a rational approach. It is known that flow volume loops begin to detect airway obstruction when tracheal diameter is reduced to an extremely limiting 5 mm. 102 Symptoms of acute airway insufficiency may not occur until up to 75% of the tracheal lumen is obstructed. 94, 103 At our institution, serial axial CTs are recommended to determine surgical candidacy, most typically by documenting substernal extension or tracheal compression. 12 We have found that regional signs and symptoms, such as upper airway obstruction or radiographic evidence of tracheal or esophageal compression, are more likely with masses larger than 5 cm. Also, fine-needle aspiration (FNA) represents a less accurate assessment with lesions of this size as compared with thyroid nodules between 1 and 3 cm.

Evaluation of Upper Airway Compromise and Other Regional Symptoms

Regional Symptomatic Assessment
Upper airway obstruction is a common finding in patients with goiter, highlighting the importance of optimal airway evaluation. Common presenting symptoms in our series of patients with goiter included shortness of breath (approximately 50%) and dysphagia (approximately 50%), emphasizing the effect of cervical and substernal goiter on the adjacent cervical viscera. Although earnest symptomatic assessment at presentation is crucial in patients with goiter, clinical experience suggests subjective symptomatic assessment of the upper aerodigestive tract compressive symptoms in patients with goiter can be quite problematic. Although we found that the presence of shortness of breath correlates with goiter size, shortness of breath as a screening tool for tracheal deviation or compression is of limited value. This is despite the fact that the presence of shortness of breath is significantly related to the imaging finding of tracheal compression, consistent with the work of Mackle. 104 For the airway, symptomatic assessment alone may therefore be inadequate in goiter patients. In the setting of large cervical or substernal goiter, one cannot purely rely on the presence or absence of shortness of breath to assess true tracheal compromise, without routine axial CT scanning assessment for tracheal compression. In our series there was no significant difference in the percentage of patients with airway symptoms between patients with purely cervical and patients with substernal goiter. However, in our series substernal goiter was highly associated with tracheal deviation and compression. 12
Our series also demonstrated a positive correlation between thyroid size and globus sensation and symptoms of hyperthyroidism. No correlation was established between goiter size and presence of dysphagia, local discomfort, change in voice, hemoptysis, or symptoms of hypothyroidism. There was a significant positive correlation between preoperative dysphagia and the presence of esophageal compression and deviation. 12

Flow Volume Loop Analysis
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Flow Volume Loop Analysis
Although symptomatic assessment is important in patients with cervical and substernal goiter, the relationship between such symptoms at presentation and pulmonary function evaluation is problematic. Flow volume loops have been utilized to define airway compromise in goiter patients. In our centers, flow volume loop analysis is not part of the routine workup for goiter. Goiter weight is not well correlated with flow volume loop results. 9, 45 Bonnema has also reported that overall flow volume loop results do not correlate well with tracheal caliber on axial CT. 105 Only 30% to 40% of those with flow volume loop abnormalities have symptoms, and among those with normal flow volume loops, up to 60% may have airway symptoms.
This discordance between flow volume loop results and symptoms or objective axial CT scan findings in goiter patients should not be surprising. It is well known that lung function indices are inconsistently related to tracheal size in normal subjects. 106, 107 Poiseuille's law (flow proportional to radius) implies that with a significant reduction in the tracheal airway, small changes in tracheal caliber will be reflected in significant changes in flow volume loop characteristics, but with lesser degrees of tracheal narrowing, the two variables are more weakly related. In fact, it is known clinically that tracheal compression of up to 75% of the tracheal lumen may occur without clinical manifestation. 9, 94 Flow volume loop studies can detect tracheal stenosis when tracheal diameter is less than 5 mm, but it may not be affected in less severely narrowed airways. 102 Flow volume peak inspiratory flow of less than 1.5 L has been associated with a high risk of acute respiratory failure and therefore has been used as an indication for urgent thyroidectomy. 9, 94, 98

Imaging

Radiographic Evaluation and Regional Symptomatology
A number of studies question the strength of the correlation between regional symptoms and imaging study findings. In particular, the functional impact of airway narrowing diagnosed via CT scan remains controversial. Alfonso et al. found that two thirds of surgical goiter patients had preoperative radiographic evidence of compression. Almost half of those patients with evidence of compression had no symptoms. Those patients with airway symptoms who had old radiographs available for comparison were found to have compression up to 3 to 4 months before the onset of airway symptoms. 98 Jauregui found in a series of asymptomatic euthyroid goiter patients that 25% had radiographic evidence of tracheal obstruction and 60% had evidence of airway obstruction by flow volume loops. 108 Cooper et al. found that tracheal diameter and airway symptoms are weakly related. 109 Melissant and others have found little correlation between lung function and the CT scan–defined degree of tracheal obstruction. 105, 110
Conclusions from our series stand in contrast with the above literature. As noted earlier, we found a significant correlation between the presence of shortness of breath and the objective CT scan radiographic finding of tracheal compression. 12 Barker et al. similarly noted that if CT scan showed greater than or equal to 50% tracheal diameter narrowing, symptoms should be expected. 111 We therefore consider tracheal compression to be an important radiographic finding and an appropriate surgical indication in these patients ( Boxes 7-1 and 7-2 ).
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The relationship between esophageal symptoms and abnormal barium swallows is less contested. Alfonso et al. found all 25 patients with dysphagia also had abnormal barium swallows. 98 In our series, dysphagia was significantly associated with both radiographic esophageal deviation and compression, as evaluated with barium swallow studies. The absence of dysphagia was associated in our series with a negative predictive value of 96% for esophageal compression. 12 We therefore consider that patients without dysphagia likely do not have esophageal involvement and do not require further esophageal imaging. (See Box 7-1 .)

Chest Radiography and Barium Swallow Study
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Chest Radiography and Barium Swallow Study
Chest radiography preoperatively provides limited information regarding tracheal air column and may allow detection of macronodular pulmonary metastasis in patients with thyroid enlargement. Chest radiographs may reveal cervical or mediastinal densities with or without calcification and may, with substernal extension, identify a plane of reflection of the mediastinal pleura. Chest radiograph is read as abnormal in up to 40% to 90% of patients with substernal goiter. 11, 22, 56, 83, 87, 112 Several workers have noted that tracheal diameter as estimated from plain films is significantly greater than tracheal diameter as measured on CT scan, axial studies, or in cadaveric studies. 111, 113 Melissant et al. found that plain films missed significant tracheal obstruction in 50% of patients. 110 Cooper et al. also found in review of cervical and substernal goiter patients that plain films were misleading in 48% of patients, resulting in both over- and underestimation of tracheal narrowing as compared with CT axial scanning. 109 Plain chest radiograph can be especially misleading in the rare posterior mediastinal goiter with contralateral extension retrotracheally with respect to the lobe of origin (substernal goiter type IIB). Tracheal deviation in this complex circumstance may be toward the size of the mass as seen on plain radiographs. 26, 27, 114 We have also found that chest radiograph generally gives reasonable information regarding the degree of tracheal air column deviation, but it does significantly underestimate tracheal compression (see Figure 7-2 ). 12 In addition, when a goiter is present bilaterally, it may symmetrically compress the airway without any deviation. In such circumstances, axial CT scanning may reveal a significantly compressed airway, yet plain chest radiograph may fail to show any distortion of the tracheal air column.
Barium swallow, although not generally helpful in the preoperative evaluation of patients with cervical and substernal goiter, may be helpful in posterior mediastinal goiter. Michel found that sensitivity for the identification of substernal goiter by chest radiograph was 59%, by thyroid scanning it was 77%, and with barium swallow it was 71%, emphasizing the inaccuracies of these modalities in goiter evaluation ( Box 7-2 ). 83 Our recommendation is to not perform barium swallow studies in the absence of dysphagia, as the presence of esophageal compression is unlikely in asymptomatic patients. 12

Axial CT Scanning
We have found routine CT scanning to be very helpful in preoperative assessment of patients with large cervical or substernal goiters. 12 CT can be performed safely (i.e., without the Jod-Basedow phenomenon) in patients with thyroid disease, if TSH is not found to be suppressed. CT scanning shows the margin of benign goiter to be smooth and may often delineate gross calcification (which may be punctate, linear, eggshell, amorphous, or nodular), versus the fine stippled microcalcification that may be present in papillary or medullary carcinoma (see Chapter 13, Ultrasound of the Thyroid and Parathyroid Glands ). In patients with substernal goiter, continuity of the mediastinal mass and cervical orthotopic gland can be identified. Precontrast attenuation of thyroid tissue exceeds adjacent neck musculature by at least 15 Hounsfield units or greater and by more than 25 Hounsfield units after contrast enhancement. In patients with substernal goiter, this high attenuation, which is uncharacteristic in other types of mediastinal disease such as lymphoma or thymoma, can be helpful diagnostically. 33, 115 With CT scanning, the extent of cervical and substernal extension can be accurately defined, and the exact relationship of the goiter to the trachea, esophagus, and great vessels can be determined. The presence of nodal disease can also be established through axial scanning. Generally, benign goiter shows inhomogeneous density with discrete nonenhancing low-density areas. Malignancy may be considered in the setting of the radiographic findings of irregular/infiltrative margins, vocal cord paralysis, and nodal enlargement, especially if the nodes are calcified, cystic, or enhancing. 116 - 118 Contrary to McHenry's view that preoperative radiographic evaluation does not alter intraoperative management, we believe that CT scanning is essential for all patients with large cervical and substernal goiters. 7 We are more likely to obtain CT if the clinical exam suggests that the goiter is large, symptomatic, bilateral, or substernal or if malignancy is suspected based on vocal cord paralysis or regional lymphadenopathy (see Box 7-2 ). CT scanning ideally shows the relationship of the goiter to surrounding cervical viscera, including the airway. These relationships can affect not only surgery but also approach to intubation. Axial CT provides objective, reproducible measures of tracheal caliber. A patient's surgical candidacy may derive from information obtained from axial CT scanning, especially given a lack of sensitivity of symptomatic, flow volume loop analysis, and plain radiographic assessment. At our institutions, documentation of substernal extension or tracheal compression on CT is an appropriate surgical indication. 12 CT scanning also provides helpful information to exclude invasive malignancy. It is true that CT scanning does not differentiate well between fibrosis and tumor, although this distinction is generally not a significant clinical issue for routine goiter patients. Finally, enhanced CT scanning is essential in determining the mediastinal relationships to allow safe operative management for large posterior mediastinal goiters. Identification of significant retrotracheal extension of either cervical or substernal goiter helps to preoperatively predict that the RLN will be in a ventral position. Preoperative information of ventral nerve displacement is tremendously helpful in the offering of safe cervical and substernal goiter surgery ( Box 7-3 ).

Box 7-3 Imaging: Summary

• Plain chest radiography may detect macronodular metastatic disease but generally offers limited information about the tracheal air column. Airway compression is underestimated and bilateral goiter with circumferential tracheal compression may not be well seen on plain radiographs.
• We recommend CT scanning in all patients with large cervical and substernal goiters. Axial CT scanning has the advantage of being readily available and easily interpreted by the surgeon. CT scanning is used to judge a patient's surgical candidacy by accurately defining the degree of tracheal impact. In patients with substernal goiter, CT scanning informs surgical planning regarding sternotomy and potential thoracic surgical involvement. CT scanning is helpful in identifying the radiographic correlates of malignancy. It is also of tremendous importance in accurately defining the anatomic relationships, especially in predicting when an RLN will be ventral through retrotracheal and posterior mediastinal extension. Contrast should be avoided if the patient's thyroid functional status is unknown or if the patient is subclinically hyperthyroid.
• Advantages of MRI scanning are excellent soft-tissue delineation, excellent definition of the goiter's relationship to mediastinal vessels, and sagittal and coronal display. Disadvantages of MRI scanning include cost, patient claustrophobia in nonopen MRI scanning suites, and poor definition of calcification patterns.

MRI Scanning
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MRI Scanning
We have found that CT and MRI scanning are more or less equivalent in the assessment of cervical and substernal goiter. Several workers have suggested that MRI may be superior to CT scanning with improved vascular mediastinal relationships, ability for coronal display, and potentially better detection of early tracheal and esophageal invasion with less shoulder artifact. 83, 119, 120 Disadvantages of MRI scanning include cost, patient claustrophobia in nonopen MRI scanning suites, and poor definition of calcification patterns.

Sonography and Scintigraphy
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Sonography and Scintigraphy
Sonography generally does not provide essential information in the workup of patients with large cervical or substernal goiters. Scintigraphy also is not generally necessary. I31 I and technetium scanning may be helpful in cases of mediastinal mass without connection to the cervical orthotopic gland. Also, in patients with toxic multinodular goiter, iodine scanning can be helpful in mapping out hot regions so that they can be encompassed by surgery. In toxic multinodular goiter, the sonographic nodules may not necessarily overlie the areas of scintigraphic activity. Thus, iodine scanning may be helpful if less than total thyroidectomy is planned (see Box 7-3 ).

Thyroid Function Tests and Fine-Needle Aspiration
Thyroid function tests must be checked in all patients presenting with goiter. In our series, only 8% of patients had noniatrogenic causes of abnormal thyroid function testing, reaffirming that the majority of patients with goiter if not on suppressive therapy are euthyroid. 12 Nevertheless, rates of thyroid dysfunction in patients with goiter are not negligible, and it is imperative that the clinician evaluates for any abnormality. Hyperthyroidism is the foremost concern in patients with goiter. Florid hyperthyroidism has been reported in up to 30% in patients with multinodular goiter. 74, 121 Rates of hyperthyroidism in patients with substernal goiter range from 1.3% to 7%, although rates as high as 44% have been described. 11, 56, 122 Autonomous nodules may elicit a slowly progressive increase in thyroid hormone production, independently of TSH levels. 123 Alternatively, hyperthyroidism may manifest acutely in patients with goiter exposed to high iodine, such as in CT scan contrast material or in amiodarone. 124, 125 Elderly patients notoriously do not exhibit the typical overt signs and symptoms of hyperthyroidism and are also more prone to cardiac complications. Screening for subclinical hyperthyroidism (TSH low, T3 and T4 normal) is particularly crucial in the elderly population because of the increased risks of atrial fibrillation and accelerated bone demineralization. Subclinical hyperthyroidism may also impact the issue of extent of surgery and may lead more towards total thyroidectomy if present. Iatrogenic iodine exposure should be avoided in elderly patients with subclinical hyperthyroidism to avert the increased risk for the development of overt hyperthyroidism. 126, 127 Finally, hypothyroidism (typically Hashimoto's disease) must also be excluded in patients with goiter. A fibrotic variant of Hashimoto's disease can result in a massive firm goiter.
We believe that if the history, physical examination, and CT scan evaluation of the patient with thyromegaly suggest benign goiter requiring surgery and surgical candidacy is established on that basis, then FNA is not essential. 2 Certainly, if there is any suspicion on history, physical examination, or radiographic evaluation of malignancy, then FNA should be considered. Hemorrhage into a nodule after FNA may convert a stable but compromised airway to emergency airway obstruction. FNA information infrequently contributes substantially to preoperative workup in patients with large cervical and substernal goiters.

Treatment Options

Suppressive Therapy
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Suppressive Therapy
Reports about the effectiveness of thyroid hormone suppression in nontoxic goiter suppression have varied greatly. 27, 128 - 131 In 1997, Lima et al. studied prospectively thyroxine (T 4 ) treatment at 200 μg, to suppress thyroid-stimulating hormone (TSH) to less than 0.1 μU/L in patients with nontoxic multinodular goiter. Response defined as a greater than 50% decrease in combined nodular volume occurred in only 29.1% of patients. Forty-seven percent of patients were nonresponders. 132 Berghout et al. found that in patients responding to thyroid treatment, goiter size reduction averaged only 25%. In addition, when thyroid hormone treatment was discontinued, thyroid volume was found to return to pretreatment values within a few months. 72 Hurley and Gharib found that thyroid hormone was able to reduce goiter size by 50% in only 27% of patients. 46 Ross noted that when thyroid hormone is affected, a size reduction occurs with a lag of approximately 3 months relative to initiation of therapy. 128 Zorrilla found that thyroid hormone-induced size reduction was unpredictable. 133 Generally, diffuse goiters are thought to be more thyroid hormone responsive as compared with multinodular goiters. 128 Burgi et al. found that nodules larger than 2 or 3 cm are less likely to respond to thyroid hormone therapy. 134 Other studies looking at combined nodular volume reduction show response rates ranging from 20% to 58% of patients suppressed. 135 - 138
T 4 suppression is generally not offered to patients who present with subclinical hyperthyroidism with a TSH level less than or equal to 1 μU/L or in elderly patients. 46 Thyroid hormone suppressive therapy for goiter, which must be carried out indefinitely because of the tendency for goiter to recur after cessation of therapy, risks atrial fibrillation in patients older than age 60 and those with bone loss, especially in postmenopausal women. 126, 139, 140 Overall, a review of the literature suggests that T 4 suppressive therapy has variable efficacy in reducing goiter size, is characterized by a high regrowth rate of goiter when T 4 is discontinued, and is limited in the elderly population and in patients with subclinical hyperthyroidism.

Radioiodine
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Radioiodine
Radioiodine can be used for the treatment of nontoxic multinodular goiter. Although not widely used currently in the United States, radioiodine as a treatment for large goiter with compressive symptoms has become more commonplace in Europe. Higher doses of 131 I (similar to ablative doses used in thyroid cancer patients) are required for nontoxic multinodular goiter, as compared with doses used for Graves’ disease, because of the large volume and lower uptake of nontoxic multinodular goiters. Generally, uptake is lower in nontoxic multinodular goiters than in diffuse (anodular) goiters (i.e., Graves' disease). 141 Studies looking at radioiodine as a treatment for nontoxic multinodular goiter show volume reduction of one third to two thirds occurring in more than 80% of patients, with 70% to 80% of patients having a decrease in obstructive symptomatology. Complications include radiation thyroiditis with acute worsening of airway symptoms in less than 5% of patients, the need for greater than one dose of radioiodine in up to 20% of patients, hypothyroidism in 60% of patients (increased risk if positive antithyroid peroxidase autoantibodies, family history of hypothyroidism, or in patients with small goiters), and radiation-induced Graves’ disease in up to 10% of patients. The high doses of radioiodine used increase the estimated lifetime risk of cancers outside the thyroid gland by 1.6% overall and by 0.5% for patients older than age 65. 105, 129, 130, 142 - 149
Radioiodine in the treatment of large goiter that is affecting the airway deserves special attention. Le Moli found the larger the goiter, the less responsive to radioiodine. 147 Nygaard found transient increase in goiter size in approximately 7% of patients treated. In these patients, increased size averaged 25%, with a range from 11% to 60%. 129, 144, 148 Bonnema also found that within 1 week of radioiodine treatment, the tracheal cross-sectional area decreased by 9.2% from an initial value, with 33% being the greatest reduction in tracheal caliber seen. 105 Radioiodine treatment should be considered only in patients with smaller goiters without airway impact and in patients who could not otherwise tolerate surgery. 130 The use of radioiodine is ill advised in patients with substernal goiter who have a substantial increased rate of airway compression. 55 In our goiter series, we found that one third of surgical patients had failed medical management with either T4 or radioactive iodine treatment. Failure of these medical treatments did not increase surgical complication rates. However, we appreciate that radioiodine treatment could potentially increase scarring and vascularity at the level of the thyroid capsule, which may present a challenge in subsequent surgery. 12

Surgery

Rationale and Indications
Surgery represents a rational treatment option for many patients with cervical goiter and most patients with substernal goiter. Regional compressive symptoms resolve postoperatively, faster than with suppressive or radioiodine therapy. Complication rates are low, subclinical hyperthyroidism remits, airway complications are avoided, and a pathology report is provided. Goiter surgery is most safely offered when it is not offered with undue delay. Waiting until a goiter is massive will likely increase operative complication rates. Surgery brings no risk of radioiodine-induced immediate airway complications, malignancies, or Graves’ disease. Surgery also brings no risk of thyroid hormone–induced atrial fibrillation or osteoporosis. A patient cannot be a “nonresponder” to surgery ( Box 7-4 ). Surgery is recommended in patients with multinodular goiter who present with hyperthyroidism, as they do not generally respond well to antithyroid drugs, including perchlorate and iopanoic acid. 150 Furthermore, surgery may be preferred over radioactive iodine treatment in elderly patients with goiter and subclinical or frank hyperthyroidism, to forestall the risk of radioiodine-induce Graves’ disease in this cardiac-frail population (see Box 7-4 ).

Box 7-4 Cervical and Substernal Surgery Rationale

• Natural history of goiter is of progressive growth
• Treats existent regional/compressive symptoms
• Avoids rapid and unpredictable increase in size and airway compression
• Provides pathology report; rules out malignancy
• Treats hyperthyroidism and subclinical hyperthyroidism
• Has low operative morbidity
• Thyroid hormone (suppressive) treatment is associated with a high nonresponse rate, requires lifetime treatment, cannot be offered if TSH is <1, risks atrial fibrillation and osteoporosis, and is less likely to be effective with large nodular goiters
• Radioactive iodine treatment of goiter risks acute radiation thyroiditis and airway compression and, in approximately 10% of patients, induces Graves’ disease
TSH, Thyroid-stimulating hormone.
Based on our experience, patients can be reasonably considered for cervical goiter surgery in the following situations: (1) if a patient has clear-cut regional upper aerodigestive tract symptoms without other cause, as such symptoms may first manifest with positional provocation or nocturnally; (2) if radiographic evaluation through axial CT scanning is showing evidence of tracheal compression; (3) for masses greater than 5 cm or masses with significant cosmetic issues, as our experience is that regional symptoms typically emerge when the mass is 5 cm or greater, and fine-needle aspiration is less accurate to exclude malignancy in a mass of this size or greater; (4) goiter patients with subclinical hyperthyroidism; (5) patients in whom carcinoma is suspected or proved; and (6) all patients with substernal extension. The presence of substernal goiter in general in our practice is a surgical indication because of the strong association of tracheal compression and substernal growth and because the mediastinal component is difficult to follow on physical exam or with fine-needle biopsy ( Box 7-5 ). 12 In our series, substernal extent was the surgical indication in the majority of cases (78%), as this factor is sufficient to warrant excision at our institutions. Additional surgical indications are as follows: compressive symptoms (49.5%), concern for cancer (17%), patient's desire/cosmesis (3%), nonthyroid local neoplasm (1%), and other/nonspecified (1%). 82

Box 7-5 Surgical Indications for Multinodular Goiter

1. Clear-cut significant regional aerodigestive tract symptom without other cause
2. CT with tracheal compression
3. Masses greater than 5 cm
4. Goiter with subclinical or frank hyperthyroidism
5. All patients with malignancy suspected or proved
6. All patients with substernal goiter
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Patients with goiter in whom carcinoma is suspected or proved should undergo surgical excision. The typical pathology report for substernal or surgical goiter reveals adenomatous nodules with old hemorrhage, calcification, cyst formation, fibrosis, and, sometimes, focal thyroiditis. The pathology report may also be primarily thyroiditis in some circumstances. The rate of malignancy varies in cervical and substernal goiter surgical specimens. Singh, Lucente, and Shaha, in reviewing the surgical literature, noted an average rate of 8.3%, with a range of 0% to 40%. 85 Katlic, Grillo, and Wang in 80 substernal goiters noted only a 2% rate, whereas Sanders et al. noted a rate as high as 21%. 11, 20 Certainly some, though not all, of these malignancies are occult and incidentally noted. Unfortunately, a long and stable history does not preclude malignancy. The alternative to surgical extirpation of multiple thyroid nodules is multiple fine-needle aspiration (FNA) of all sizable nodules. It is a matter of judgment as to whether this implies simply aspiration of the dominant nodule or all nodules within the goiter greater than 1 cm. Given that negative FNAs of all sizable nodules do not rule out malignancy, we believe it is reasonable to abstain from aspirating all nodules in a patient who is scheduled for goiter surgery and who is not suspected to harbor malignancy based on physical exam and CT scanning especially when total thyroidectomy is planned.

Surgery for Substernal Goiter
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Surgery for Substernal Goiter
We believe that all patients, whether symptomatic or not, with substernal goiter should be considered for surgery. Substernal extension in our series of more than 200 large cervical and substernal goiters highly correlates with airway compression. This is not surprising, considering the bony confines of the thoracic inlet. 12 The thoracic component of a substernal goiter is also unavailable for ongoing clinical examination or FNA. If the substernal component acutely enlarges, the airway is affected on a mediastinal level. Most substernal goiter series note a small but significant rate of acute airway emergency. Neither tracheotomy nor intubation may relieve an obstruction associated with mediastinal airway compression. 11 Aside from typical regional symptoms, benign substernal goiter has also been associated with superior vena cava (SVC) syndrome, downhill esophageal varices, recurrent laryngeal nerve paralysis, phrenic paralysis, Horner's syndrome, chylothorax, abscess formation, and cerebral vascular accident. 73, 91, 151 - 154 Given the propensity for regional symptomatology, the lack of other reasonable treatment options, and the low complication rate of surgery, all patients with substernal goiter should be considered for surgery, assuming their medical condition permits.

Intubation of the Goiter Patient: Laryngeal Edema
Intubation generally proceeds well in patients with large cervical and substernal goiters, but occasionally it can be difficult. When difficult, anesthesia induction and intubation can represent a dramatic and life-threatening process, given the fact that emergent or “underlocal” tracheotomies generally are not options because of the mass of the overlying goiter. In patients with goiter, there may be evidence of substantial laryngeal deviation and perhaps vocal cord paralysis at intubation. The surgeon who performs the preoperative laryngoscopy should convey all information regarding the appearance of the larynx, presence of deviation, and vocal cord paralysis to the anesthesia staff, and both the surgeon and the anesthesiologist should review the preoperative CT scans and examine the patient together before induction.
The method of intubation and the size of the tube and contingency plans can be discussed and decided upon through these discussions. Typically, a straightforward induction with transoral intubation can be performed. Laryngeal deviation generally does not represent a problem, and tracheal compression generally yields to a reasonably sized endotracheal tube. An alternative and safe method that we favor is an awake, sitting up, fiberoptic transnasal intubation. This is especially a reasonable course of action if there is any doubt as to the adequacy of a sedated mask anesthesia airway, particularly if the larynx is significantly deviated by the cervical component of the goiter. Newer video laryngoscopes are also an excellent adjunct for intubation in such patients. Maximum tracheal compression in cervical and substernal goiter usually occurs at the thoracic inlet but may be present further distally. 33 As previously noted, tracheal compression by benign goiter typically yields to a reasonably sized endotracheal tube. One exception is when there is malignant infiltration of the trachea, especially if there is intraluminal disease. In these circumstances, transoral bronchoscopic intubation with bronchoscopic core-out can lead to satisfactory airway. Once again, preoperative CT scanning empowers the surgeon. Vigilance and recognition of nonthyroid factors, such as jaw and tongue size, anteriorly positioned larynx, and available degree of head extension, are also important determinants of difficult intubation.
Our experience has shown that a significant problem in patients with large cervical or substernal goiters, especially with bilateral circumferential goiters, is the development of laryngeal edema with initial intubation attempts by anesthesia. The larynx, which represents the extreme distal end of the airway projected into the hypopharynx, likely has chronically reduced venous and lymphatic drainage as a result of a large, constricting bilateral goiter. Such a larynx is easily made edematous with multiple unsuccessful intubation attempts. This edema can last weeks postoperatively, sometimes requiring tracheotomy, which usually can be removed after such edema resolves. It is therefore best to intubate once correctly. Intubation problems, although rare, can quickly spell disaster. The propensity for laryngeal edema from intubation attempts with goiter has been emphasized in the case reports of Hassard. 155 In our series of 200 patients with goiter, we encountered difficult intubation in only four cases (2%). There were no significant predictors of difficult intubation, including size, substernal extension, preoperative compressive symptoms, or radiographic presence of tracheal deviation or compression. Tracheotomy was performed in only 3% of patients and was done electively at the time of thyroidectomy. Tracheotomy was performed either because of concern about laryngeal edema from multiple intubation attempts or in cases where vocal cord dysfunction was in question in cases without neural monitoring, especially if one vocal cord was known to be paralyzed preoperatively. With neural monitoring, greater certainty exists as to the functional status of both nerves during surgery. 82

Goiter Surgery

Extent of Surgery
Decisions regarding the extent of surgery relate to the balance between operative complications and the risk of recurrence. Some suggest total thyroidectomy for goiter, 156, 157 others recommend a more conservative initial surgical plan, 11 and some, such as Kraimps, support a selectively aggressive surgical treatment plan based on extent of disease. 158 Complication rates must be kept extremely low in the setting of treatment of benign thyroid disease. Therefore, we suggest a conservative philosophy, tailoring the extent of surgery to the initial disease with the minimum procedure being a total unilateral lobar resection, reserving bilateral surgery for significant bilateral goiter. In our series, this surgical philosophy resulted in unilateral surgery in 63% of patients and bilateral surgery in 37%. Patients undergoing initial surgery at our center experienced a 1.5% recurrence rate. 82
Please see the Expert Consult website for more discussion of this topic.
Studies looking at the extent of surgery and benign multinodular goiter recurrence are confounded by several factors: (1) variability in the initial extent of thyroid gland nodularity, (2) variability in the extent of recognition of contralateral nodularity at first surgery, (3) insufficient follow-up periods in many studies, and (4) variable definitions of recurrence. Some studies, for example, diagnose recurrence based on an asymptomatic, ultrasonographic identification of thyroid nodularity. A more reasonable definition of recurrence is the development of clinical, palpable thyroid enlargement, which again meets surgical criteria for goiter treatment. The question is, can less than total thyroidectomy and even hemithyroidectomy be performed if anodular normal tissue is left? Complication rates of bilateral surgery are expected to be higher than unilateral. Conservative initial surgery also allows a patient to avoid a lifetime of replacement therapy. However, long-term studies show the overall recurrence rate after surgery for goiter is in the range of 15% to 42%. 10, 159, 160 When recurrence occurs and requires revision goiter surgery, the complication rates are significantly higher than for first-time surgery, with RLN rates of paralysis ranging from 3% to 18% and permanent hyperparathyroidism ranging from 0% to 25% (see Chapter 10, Reoperation for Benign Disease ). 161 - 164
The literature offers conflicting conclusions on factors associated with recurrence of goiter. The duration of postoperative follow-up is important to consider when examining recurrence of goiter. The data offered by Delbridge, Guinea, and Reeve suggest recurrences may require 10 to 13 years to manifest. 156 Rojdmark and Jarhult found that the overall recurrence rate rose to 42% with 30-year postoperative follow-up. 160 Bistrup et al., in a randomized, prospective, nonplacebo, controlled study, showed rates of recurrence for nontoxic goiter between 14% and 22%. They found the extent of surgery did not relate to the likelihood of recurrence. 159 Hegedus, Nygaard, and Hansen found that the weight of thyroid tissue resected was actually greater in those patients who developed subsequent recurrence. 10 However, Berghout et al., with a 7-year follow-up, found that unilateral surgery was associated with higher recurrence rates than bilateral surgery. 165 Australian workers have shown that in patients with unilateral disease, hemithyroidectomy results in a 12% recurrence rate in the contralateral lobe. 166
Other workers have supported a philosophy of total thyroidectomy or bilateral subtotal thyroidectomy in most patients with goiter. 156, 157 Subtotal thyroidectomy is defined as total lobectomy with a contralateral remnant approximately equivalent to a small normal lobe, whereas in near total thyroidectomy, a remnant of several grams is maintained in the contralateral bed typically adjacent to the RLN entry point. In patients who require bilateral surgery, the technique of subtotal lobectomy has been both recommended and condemned. 25, 163, 167, 168 Cohen-Kerem, in a study of 124 patients with a follow-up of 7.6 years, noted that with bilateral subtotal technique, only 4% of patients required additional surgery. 167 Pappalardo found similar rates of recurrence in 69 patients treated for benign goiter randomized to total versus subtotal procedures. 164 Reeve et al., however, found subtotal thyroidectomy was associated with a 23% recurrence rate. 168 Clearly, less than lobectomy as a minimum procedure is unwise. Cohen-Kerem et al. found a recurrence rate after unilateral subtotal resection was 60%. 167 Kocher noted an 18% recurrence rate with nodule enucleation. 169 Kraimps, using a selectively aggressive surgical treatment plan based on the extent of disease, noted very low recurrence rates of 1% with lobectomy and 3% with bilateral surgery. 158 Others have supported such a selectively aggressive approach to surgery based on extent of disease. 6, 84, 170
Modern series show that in skilled hands, total thyroidectomy for goiter can be performed without significant complications, given the work of Reeve et al., Netterville et al., and others. 156, 168, 171 Delbridge, Guinea, and Reeve noted that for patients with bilateral multinodular goiter, total thyroidectomy can be associated with permanent paralysis of the RLN in 0.5% and permanent hypoparathyroidism in 0.4%. 156 They believe the policy of autotransplantation of at least one parathyroid during each total thyroidectomy is in part responsible for the low rate of hypoparathyroidism. 156 Grant, in his commentary of this article, wrote, “to consider total thyroidectomy as the only acceptable alternative would probably risk causing more cases of troublesome hypoparathyroidism than it would prevent cases of goiter recurrence… . Moreover, it seems difficult to assert total thyroidectomy as the only option for benign disease when many surgical authorities strongly disagree with its use, even in thyroid cancer.” 156 Some workers have suggested that the likelihood of identifying cancer in goiter specimens justifies total thyroidectomy. Most studies document an incidence of malignancy in such specimens of between 3% and 17%. Most are small, occult, incidentally noted malignancies within otherwise benign multinodular goiters and would not normally justify an aggressive surgical approach. 11, 20, 172
Our experience, similar to the work of Berghout et al., has suggested a greater likelihood of recurrence in females and in patients with a positive family history of thyroid disease. 82, 165 Overall, females were found to be three times more likely to require revision surgery, and those with a positive family history of thyroid disease were six times more likely to require revision surgery. 82 Others have found no such increased risk in these populations. 158 We now tend to be more aggressive in females and in those with a positive family history, especially if they are young. Further, we have treated many patients with recurrent disease and appreciate the difficulty of these cases and of the occasional need to leave at least a small thyroid tissue remnant in such revision cases. However, contrary to most reports in the literature, revision cases in our series whether unilateral or bilateral, second, third, or fourth revisions were not more likely to be associated with postoperative complications in our series of patients with goiter. 82 We have used radioactive iodine postoperatively after complex multiple revision cases to avoid the need for additional reoperation in these circumstances ( Box 7-6 ).

Box 7-6 Extent of Surgery for Goiter: Summary

• We believe that complication rates must be low in the setting of surgery for benign thyroid disease.
• Less than unilateral lobectomy leads to extremely high recurrence rates and difficult reoperations and is to be condemned.
• The extent of surgery should be rationally tailored to the extent of initial disease. Dominant goitrous enlargement should be treated with total lobectomy on that side. Preoperative assessment with imaging will help to document the extent of surgery necessary on the contralateral side.
With clear-cut unilateral disease, total lobectomy is appropriate.
With clear-cut evidence of bilateral goiter, bilateral surgery is appropriate.
• Consideration should be given for more aggressive surgery in young females and in patients with a positive family history of thyroid disease who may have a higher recurrence rate.
• In patients who have required multiple thyroid surgeries for benign recurrence and still have some remnant tissue remaining after the last revision surgery, radioactive iodine ablation can be considered.

Hashimoto's Thyroiditis
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Hashimoto's Thyroiditis
Other variables important during surgery are the degree of capsular blood vessel engorgement and friability, and goiter consistency. Goiters that are soft and compressible are more easily manipulated during surgery, whereas those that are firm can be challenging even when of small size. Generally, glands affected by Hashimoto's thyroiditis are more difficult to work on than the more typical benign adenomatous goiter. Hashimoto's glands, especially those resulting from the fibrotic variant of Hashimoto's thyroiditis, can be firm and less compressible and have a friable, “sticky” surface, which bleeds easily. Such goiters can be associated with multiple perithyroidal lymph nodes that can sometimes make a surgeon consider papillary carcinoma. Such nodes also make parathyroid identification more challenging. The rare fibrous variant of Hashimoto's thyroiditis is an especially firm variant, which makes the performance of less than total lobectomy challenging.

Surgical Technique for Goiter
Patient positioning is important. We prefer a thyroid inflatable bag under the shoulders. The surgeon and anesthesiology staff must be comfortable with the degree of head support. The patient is placed into a semisitting position to reduce venous pressure.

Incision
A generous collar incision is mandatory. Endoscopic or minimal access approaches are not appropriate here. When unilateral glandular enlargement has resulted in significant deformity of the anterior neck, that side of the incision can be curved slightly higher because after resection the skin will come to fall caudally to some extent. The incision for a large bilateral cervical goiter extends to the lateral edge of the sternocleidomastoid (SCM) muscle to allow for exposure of the bilateral carotid sheath contents. A subplatysmal upper flap is developed. A lower flap is typically not necessary. Flaps can be sutured in place or several Gelpi retractors or Beckman goiter retractors can be used.

Strap Muscles
It has been frequently recommended to routinely section the strap muscles during goiter surgery. Certainly, if there is any question that strap division would help exposure, it should be done without hesitation. This is most often necessary in revision surgery where strap muscle division had been performed during the initial surgery. The muscles in this circumstance are significantly scarred to the surface of the goiter. In first-time surgery in which superior pole exposure is limited, we recommend a “mini strap section” by an isolated incision of the cranial head of the sternothyroid muscle. Although subtle and transient voice changes may accompany strap division, they are of little consequence overall when compared with potential division of the RLN or external branch of the superior laryngeal nerve through poor exposure. In some massive cervical goiters, the SCM muscle can be sectioned as well as the strap muscles, although this is uncommon. It, like the strap muscles, can be sutured at the completion of surgery with little ill effect. If the strap muscles are sectioned, it is important during surgery to either suture or place a clamp on the divided edges, which have a tendency to retract, with a resultant loss of the perithyroidal plane they define. If the strap muscles are completely sectioned, it is best first to define their lateral edge, which can blend with tissue adjacent to the jugular vein and other carotid sheath contents. In most of the goiter surgeries that we have performed, strap muscles are preserved and retracted. This preserves a perithyroidal plane better than sectioning the muscles in some circumstances, and it helps to preserve anatomic organization to the neck base that can be substantially altered by goitrous change.

Importance of Carotid Sheath
The carotid sheath (including the carotid artery, jugular vein, and vagus nerve) is to the initial steps in goiter surgery what the lateral thyroid region (with RLN and inferior thyroid artery) is to surgery of a normal-sized thyroid gland ( Figure 7-3 ). It is extremely helpful to dissect the carotid jugular vein and identify the vagus nerve early on during the case. A lateral or inferior approach to the nerve may be used initially, with a superior approach reserved for use only when the goiter size and position prevent the more standard technique ( Figure 7-4 ). A large cervical goiter frequently extends to the carotid sheath, necessitating this dissection, and allows reflection of the jugular vein, and sometimes the carotid and vagus, off the lateral surface of the goiter. Identification of the vagus nerve allows intermittent vagal stimulation, a very helpful technique during substernal goiter surgery (see the discussion of vagal monitoring during goiter surgery below). The identification and dissection of the carotid artery, as it extends in the neck and importantly as it extends into the mediastinum, are essential if the surgeon is to understand the substernal goiter's relationship to the mediastinum and aortic arch (see Figure 7-3 ). Once the strap muscles and carotid sheath are dealt with, the procedure continues with the steps typical of routine thyroidectomy, including middle thyroid vein division, inferior thyroid vein division, and identification of the inferior thyroid artery. Because of the size of the goiter, the inferior thyroid artery may not be able to be identified during this segment of the surgery but can be identified later, after goiter delivery. The branches of the inferior thyroid artery are taken directly on the thyroid capsule to preserve parathyroid tissue.

Figure 7-3 Neural and vascular anatomy of the neck base.
(From Janfaza P, et al, editors: Surgical anatomy of the head and neck, Philadelphia, 2001, Lippincott Williams & Wilkins, with permission.)

Figure 7-4 Superior approach to the recurrent laryngeal nerve (RLN).

Goiter and Recurrent Laryngeal Nerve
Approaches to the RLN can be made laterally, inferiorly, or superiorly (see Chapter 33, Surgical Anatomy and Monitoring of the Recurrent Laryngeal Nerve ). Goiter may significantly distort the position of the RLN. In our experience with large cervical and substernal goiters, we have found that in nearly 16% of cases the RLN was entrapped on the surface through fascial band fixation or splayed over the surface of the goiter in such a way that significant traction or goiter delivery without RLN identification would have definitively injured the nerve (stretched or avulsed) ( Figure 7-5 ). 82 We found that left and right lobes were equally affected. Cases of fixation and nerve splaying were more likely with increased goiter size, substernal extension, significant tracheal compression, and intubation difficulties. In our unpublished series of 184 cases of thyroidectomy not involving goiter, we found no such cases of fixation or splaying other than in cases of malignant infiltration. It is interesting to note that Sinclair's work demonstrates that postoperative RLN paralysis in patients with substernal goiter in whom the RLN was not specifically identified during blind digital goiter delivery was 17.5%. Sinclair wrote in several cases that the nerve was associated with the thyroid gland and

was at serious risk when the retrosternal mass was mobilized into the neck [during] a maneuver usually achieved by dislocating the mass with a finger from below and behind. I believe that this hazard must be recognized by all thyroid surgeons and that every strand of tissue stretched over the retrosternal component of the goiter should be presumed to be nerve until anatomically proved otherwise. 173

Figure 7-5 Demonstration of fixation and splaying of the nerve in patients with substernal goiter. RLN, Recurrent laryngeal nerve.
Sinclair's rate of paralysis and our rate of nerves at risk are similar.
We believe that, because of the possibility of nerve fixation and splaying on the undersurface of the goiter, blunt dissection without nerve identification risks stretch injury. Identification of the RLN in such cases is a necessary initial step. The nerve that is fixed to or splayed on the undersurface of the goiter should be dissected off before delivery of the gland. The nerve can be identified through a superior approach and can be dissected retrograde off the goiter before digital delivery of the goiter (see Figure 7-4 ). This dissection is coupled with dissection of the vagus nerve in the carotid sheath laterally and allows the pathway of the vagus and recurrent laryngeal nerves to be predicted in the mediastinum. After goiter resection, the RLN so dissected can appear significantly redundant but will stimulate normally and function postoperatively, despite the intraoperative appearance of laxity (see Figure 7-6 , available on expertconsult.com). In some circumstances, if the goiter is soft and compressible, the inferior pole can be retracted cranially without delivering it out of the neck, and the RLN, despite impressive goiter size, can be identified through a normal inferior approach.

Figure 7-6 A and B, Patient 1. This computed tomography (CT) scan was obtained after the patient had two previous thyroidectomies, 10 and 20 years before presentation. This surgery represented her third revision thyroidectomy. Preoperative diagnosis at an outside institution was asthma. The mass was benign. The recurrent laryngeal nerves were identified and monitored. There was normal cord motion postoperatively. The trachea was compressed, but there was no evidence of tracheomalacia, and the patient did not require tracheotomy. Airway symptoms resolved postoperatively. C - E, Patient 2. Elderly woman with a large, multilobulated, calcified cervical goiter. The recurrent laryngeal nerve was entrapped within layers of fascia adjacent to the lateral aspect of the left thyroid lobe (see the white band on the side of the goiter in E ). Neural monitoring allowed identification and preservation of both recurrent laryngeal nerves, with normal cord function postoperatively. F and G, Patient 3. Large cervical goiter. Note the redistribution of subcutaneous veins secondary to jugular compression. The asymmetry of the goiter resulted in larynx rotation, with the left recurrent laryngeal nerve entering the rotated larynx in the midline. The recurrent laryngeal nerves were identified and preserved, with normal cord function postoperatively. F and G , Patient 3. Large cervical goiter. Note the redistribution of subcutaneous veins secondary to jugular compression. The asymmetry of the goiter resulted in larynx rotation, with the left recurrent laryngeal nerve entering the rotated larynx in the midline. The recurrent laryngeal nerves were identified and preserved, with normal cord function postoperatively. H - J, Patient 4. Patient with a large cervical and substernal goiter. The mass was resected without sterna split transcervically, with normal cord function postoperatively. K - O, Patient 5. Large cervical and substernal goiter extending to the aortic arch, resected transcervically without sternal split, with normal cord function postoperatively. The patient had undergone parathyroid exploration 17 years previously. K - O , Patient 5. Large cervical and substernal goiter extending to the aortic arch, resected transcervically without sternal split, with normal cord function postoperatively. The patient had undergone parathyroid exploration 17 years previously. P - T, Patient 6. Elderly woman with large cervical and bilateral substernal goiter. The right substernal mass extended retrotracheally. The bilateral goiter was resected, with total thyroidectomy transcervically without sternal split and with normal cord function postoperatively. P - T, Patient 6. Elderly woman with large cervical and bilateral substernal goiter. The right substernal mass extended retrotracheally. The bilateral goiter was resected, with total thyroidectomy transcervically without sternal split and with normal cord function postoperatively. U - Z, Patient 7. Elderly woman with cervical goiter with significant left substernal extension to below the aortic arch down to the azygous vein. The mass was excised transcervically without sternal split and without change to preoperative vocal cord function.
( E, H - J, P - T, Reprinted with modification, with permission from Montgomery W, editor: Surgery of the larynx, trachea, esophagus, and neck, Philadelphia, 2002, WB Saunders.) U - Z, Patient 7. Elderly woman with cervical goiter with significant left substernal extension to below the aortic arch down to the azygous vein. The mass was excised transcervically without sternal split and without change to preoperative vocal cord function.

The Special Case of Retrotracheal Cervical and Posterior Mediastinal Goiter: The Ventral Recurrent Laryngeal Nerve
Retrotracheal cervical goiter and posterior mediastinal goiters (substernal goiter type IIA, B) represent especially unique surgical challenges ( Figure 7-7 ). Approximately 9% to 15% of all substernal goiters extend into the posterior mediastinal. 11, 22, 29, 30, 83 The chief difficulty is that in these cases, thyroid tissue has excavated posteriorly and deeply to the RLN (i.e., the RLN is ventral to thyroid tissue). As the posterior mediastinal goiter descends, it pushes the trachea anteriorly and splays the great vessels. 26, 27, 174 For the surgeon, the ventral RLN is a disorienting and high-risk RLN position. The RLN in all other cases of thyroidectomy is always deep to the thyroid gland. The most complex posterior mediastinal goiters are those that descend from the left lobe and then cross, being pushed by the aortic arch and its branches to the right thorax (substernal goiter type IIB). These crossings may occur either behind both the trachea and esophagus (type IIB1) or between the trachea and esophagus (type IIB2) (see Table 7-1 , and see also Figures 7-1 , A-H , available on expertconsult.com). 26, 27, 30 Some have recommended sternotomy, 30, 174 and some advocate posterolateral right thoracotomy 22, 175, 176 along with a cervical approach. Right thoracotomy, when necessary, is performed through the right fourth and fifth intercostal space. The lung is retracted and the goiter is identified posterior to the superior vena cava, superior to the azygous vein, and anterior to the vertebral column. The pleura over the goiter is incised, and the goiter is manipulated into the thoracic inlet with the help of traction from above. 59 Katlic, Grillo, and Wang found 7 of 80 patients with substernal goiter extended into the posterior mediastinum and could be typically removed through a cervical approach. 11 DeAndrade's extensive experience with posterior mediastinal goiter found that virtually all could be extracted through a cervical incision and were vascularized by the inferior thyroid artery. 29 Certainly, these cases make clear the need for preoperative imaging and should be handled by experienced surgical teams.

Figure 7-7 Retrotracheal masses excavate the region posterior to the trachea, bringing the nerve ventral to the lesion. A, A cervical goiter with some retrotracheal extent. B, At surgery the recurrent laryngeal nerve was found to be displaced anteriorly and was adherent to the ventral surface of the mass. The nerve was identified through neural monitoring, dissected away, and functioned normally postoperatively. C, Female with large retrotracheal mass shown on computed tomography. D, The recurrent laryngeal nerve was ventral to this mass here seen on magnetic resonance imaging and was identified with neural monitoring, dissected away, and functioned normally postoperatively. E - F, Lymphangioma arising from the inferior pole of the thyroid, extending inferiorly into the mediastinum approximately 13 cm. E and F, Axial cuts in the neck base and upper chest. The mass was excised completely and was deep to the recurrent laryngeal nerve which was closely associated with it. The nerve was identified through neural monitoring, dissected away, and functioned normally postoperatively. The lymphangioma was resected completely. G, Asymmetric goiter that caused rotation of the larynx. The RLN entry point was rotated because of the laryngeal rotation such that the nerve entered the larynx in the midline. H, Cervical goiter that had a tightly adherent RLN through crossing vessels on the undersurface of the left smaller side. This RLN was dissected away and perserved. Such vessels can be seen and predicted on preop CT as shown here.

Superior Goiter Extent
Please see the Expert Consult website for more discussion of this topic, including Figure 7-8 .

Superior Goiter Extent
The superior extent of the goiter is more easily handled with good exposure of the superior pole region. As previously noted, the superior pole region can be more widely exposed through an isolated section of the head of the sternothyroid muscle along with an adequately raised superior skin flap. Right-angle clamps are very helpful in superior pole dissection. Large superior-pole vessels should be doubly tied because they can lead to troublesome bleeding and retract, if not controlled appropriately. We have seen a number of goiters with significant superior pole development extending to the retropharyngeal region and tonsil fossa ( Figure 7-8 , A and B ).

Figure 7-8 A and B, Cervical goiter can extend superiorly to the retropharyngeal region.

Parathyroid Preservation during Goiter Surgery
The distal inferior thyroid artery is taken after the RLN is identified and either before or after goiter delivery. The artery is taken directly on the thyroid capsule to reduce the risk of parathyroid ischemia. The superior parathyroid glands are more constant in position and are more frequently seen at thyroidectomy for goiter; therefore, they are more readily preserved. In their series of 80 substernal goiters, Katlic, Grillo, and Wang noted that upper glands were seen twice as often as lower glands. 11 The inferior parathyroid gland is more widely distributed and more likely to be significantly displaced by inferior pole goitrous change. Therefore, our real emphasis during goiter surgery should be on superior parathyroid preservation. Inferiorly, we must strictly adhere to capsular dissection so as to preserve displaced inferior parathyroid glands. It is important to emphasize that with goiter surgery, as with all thyroid surgery, any resected thyroid specimen must be meticulously examined for capsular parathyroid glands before being sent to pathology. Any capsular parathyroid glands that are found should be dissected off, biopsied to confirm parathyroid tissue, and then autotransplanted. These glands may be found within folds and crevices of the goiter surface.

Substernal Goiter Techniques for Delivery
As previously described, after the RLN is identified and completely dissected away from the goiter (typically allowing it to fall away posterolaterally), finger dissection in a strictly capsular plane, with an understanding of the specific goiter/mediastinal anatomy, can allow for safe goiter delivery ( Figures 7-9 and 7-10 )—one finger on a strictly capsular location medially adjacent to the trachea and one finger laterally adjacent to the carotid sheath. The goiter is slowly incrementally mobilized upward. Thin, fascial band attachments drawn up with the finger are stimulated with the nerve stimulator and cauterized or clamped. Slow, step-by-step incremental goiter delivery is achieved from the mediastinum with substernal goiter or out of the thyroid bed for cervical goiter. RLN identification and dissection before delivery are mandatory, as previously noted. The vagus may be intermittently stimulated as the goiter is mobilized or continous vagal monitoring can be used (see Chapter 33, Surgical Anatomy and Monitoring of the Recurrent Laryngeal Nerve ). In patients with large substernal goiters with a contralateral cervical component, performing surgery on the contralateral side first may be necessary to increase the mobility of the laryngotracheal complex and allow for substernal goiter delivery. If all these maneuvers are not effective, sternotomy may be considered. Despite nearly 80% of patients having substernal extension, the sternotomy rate was only 1% in our series of patients with goiter. 82 It is important that any surgeon who does not routinely perform sternotomy himself or herself review preoperative CT scans of patients with substernal goiters with thoracic surgical colleagues and arrange the surgical date when a thoracic surgeon is available, if needed.

Figure 7-9 Vascular anatomy of the neck base and upper mediastinum.
(From Janfaza P, et al, editors: Surgical anatomy of the head and neck, Philadelphia, 2001, Lippincott Williams & Wilkins, with permission.)

Figure 7-10 Substernal goiter extension on the right, with tracheal deviation in the upper mediastinum.
Substernal goiter is a product of the neck. The blood supply to substernal goiters is almost always cervical (i.e., the inferior thyroid artery). One must keep in mind that although cervical goiter and the majority of substernal goiters’ blood supply are through the inferior thyroid artery, there are rare cases of substernal and even cervical goiter with aberrant intrathoracic blood supply. 22, 79 Substernal goiters thus infrequently obtain significant blood supply from mediastinal vessels such as the thyroid ima, subclavian, or internal mammary artery or aorta. 34, 36, 25, 83 In our series of 200 thyroidectomies for goiter, we found only two cases where the blood supply to the thyroid mass was provided by vessels of intrathoracic origin. 82 With this in mind, it is best that fascial bands produced during digital dissection of the substernal goiter be cauterized only if transparent. Thicker pedicles of tissue should be clamped and securely tied only after the RLN and vagus locations are completely understood along their full course.
Morselization is a technique that has been performed in the past to help reduce goiter size and provide for delivery. It was first described by Kocher in 1889, popularized by Lahey in 1945, and has its more recent proponents. 20, 75, 169, 177 We believe that this technique should be abandoned because it risks significant and perhaps uncontrollable hemorrhage as well as the spread of carcinoma if that is ultimately found to be present. 11 Johnson and Swente have reported a case of mediastinal hematoma and death following morselization of a large posterior mediastinal goiter. 22 Allo and Thompson described a form of morselization with thyroid capsular incision and insertion of a suction. 55 Recently, a powered endoscopic debrider instrument initially designed for cartilage ablation during endoscopic knee surgery and later modified for endoscopic sinus surgery was used for goiter morselization. This new technology makes morselization no more appealing, given risks of bleeding and cancer dissemination. 178 Cysts within the thyroid, if benign, can be decompressed with a needle, although such a technique is rarely necessary. A variety of instruments have been used to facilitate substernal goiter delivery. Kocher introduced a mediastinal goiter spoon to facilitate substernal goiter delivery. The use of this blunt instrument breaks negative intrathoracic pressure and occupies less space than the surgeon's finger. 169, 179 Sanders has used a Foley catheter placed into the mediastinum and inflated to assist in the delivery of substernal goiter without sternum split. 20

Sternotomy for Substernal Goiter
Multiple substernal goiter series show sternotomy rate of between 1% and 8% (see Chapter 8, Approach to the Mediastinum: Transcervical, Transsternal, and Video-Assisted ). 11, 20, 55, 57, 83, 86, 87, 97, 180, 181 Resection of the medial one third of the clavicle can also be used to increase the bony confines of the thoracic inlet (see Figure 7-10 ). 182 Sternotomy must, in all cases, be discussed preoperatively with the patient and thoracic surgical colleagues. We believe that sternotomy must be considered in the following circumstances:

• Known or suspected malignancy extending into the mediastinum.
• Posterior mediastinal goiter if associated with contralateral extension (substernal goiter type IIB).
• Cases in which goiter blood supply is mediastinal. This information may not always be available preoperatively. Patients with isolated mediastinal goiter (substernal goiter type III) are at higher risk for having noncervical blood supply.
• Cases associated with true superior vena cava syndrome preoperatively identified, which suggests substantial neck base/mediastinal venous obstruction. True superior vena cava syndrome should raise the specter of mediastinal malignancy rather than benign substernal goiter.
• Recurrent large substernal goiters.
• Any case in which delivery maneuvers reveal an immobile substernal component or where goitrous adhesions to surrounding mediastinal vessels and pleura are identified.
• Cases in which substernal goiter delivery is associated with substantial mediastinal hemorrhage.
• Cases in which the diameter of the intrathoracic component of the goiter is substantially greater than the diameter of the thoracic inlet.
• Cases where there is a long thin stalk from the cervical to the substernal component. Such stalks may fragment with significant retraction, especially if the mediastinal component is wide and bulbous.
Sternotomy or thoracotomy, as an isolated approach to substernal goiter, is not appropriate because of the greater risk to the RLN during such a procedure and the inability to effectively control the inferior thyroid artery. 87, 92

Vagal Monitoring during Goiter Surgery
Please see the Expert Consult website for more discussion of this topic, including Figure 7-11 .

Vagal Monitoring during Goiter Surgery
We have used intermittent vagal stimulation to help preserve the vagus and recurrent laryngeal nerves during surgery of large cervical and substernal goiters. Initially, the vagus nerve can be identified during carotid sheath dissection. Vagal stimulation can be used intermittently during goiter surgery to test the entire “circuit” (i.e., the entire ipsilateral vagus and RLN) and ensure that it is intact during maneuvers that, because of goiter size or substernal extent, risk neural stretch. Such maneuvers are performed slowly with progressive incremental goiter delivery during ongoing passive neural vagal monitoring and intermittent vagal stimulation. If any change in stimulation is detected, the vagal and RLN course and surgical maneuver are reevaluated to ensure that neural stretch is not occurring.
We have seen no adverse neural, cardiopulmonary, neurologic, or cardiovascular effects with stimulation of either the left or right vagus despite repetitive, constant current pulse stimulation in the 1 to 2 mA range, 4 pulses per second, 100 μs stimulation duration. The latency is longer (average 6 to 8 ms), as one would expect, compared with RLN stimulation during thyroidectomy (see Chapter 33, Surgical Anatomy and Monitoring of the Recurrent Laryngeal Nerve ) ( Figure 7-11 ). The safety of vagal stimulation is in agreement with the works of Friedman et al., Leonetti et al., and Eisele. 183 - 185 Satoh, using penetrating electrodes, transcutaneously stimulated the human vagus nerve in the lower neck and found that ipsilateral thyroarytenoid electromyographic (EMG) activity was biphasic or triphasic, with latency of 6 to 8 ms (2 to 3 ms shorter on the right), amplitude of 0.4 to 0.7 mV, and response duration of 4 to 5 ms. 186 Friedman et al. documented the cardiac safety of vagal stimulation in dogs with stimulation in the 1 to 10 mA range, with 0.4 ms duration at 10 to 100 Hz. 183 Intermittent vagal stimulation through an implanted vagal coil electrode was introduced in 1990 as treatment for some forms of refractive epilepsy. Such stimulation has been shown to be well tolerated and safe. 187, 188 Lundy studied the laryngeal effects of vagal stimulation for epilepsy in humans. The induced position of the vocal cord is felt to depend on the amplitude and frequency of electrical stimulation (see Chapter 33, Surgical Anatomy and Monitoring of the Recurrent Laryngeal Nerve ). No adverse cardiopulmonary effects were seen with a frequency of stimulation less than 40 Hz. At 3 mA, stimulation of less than 10 Hz resulted in oscillation of the vocal cord at the rate of stimulation. Stimulation at from 10 to 30 Hz resulted in vocal cord ab duction. Stimulation at 40 Hz or greater resulted in ad duction, with progression to tetany. Others have documented vagal stimulation safety in humans. 180, 189, 190

Figure 7-11 Electromyographic activity recorded in the thyroarytenoid/vocalis muscle of the larynx during ipsilateral vagal nerve stimulation at 2 mA. Note the increased latency of the evoked response from stimulation artifact as compared with recurrent laryngeal nerve stimulation (stimulation artifact represented by the dotted line on the left).
Vagal stimulation can also be used to diagnose cases of nonrecurrent RLN. In such cases, vagal stimulation high in the neck results in laryngeal EMG activity, but stimulation low in the neck below the larynx and below the RLN branch point does not. We have used such stimulation to diagnose nonrecurrence of the right RLN before the nerve is directly visualized.

Postoperative Complications of Goiter Surgery

Recurrent Laryngeal Nerve
RLN paralysis rates vary significantly from study to study, but in general they are consistently higher when surgery is performed for goiter as compared with routine thyroidectomy. It is encouraging to note that in highly skilled hands, even recurrent substernal goiter can be treated with very low complication rates, as noted by Australian workers. 161 In our series, the rate of RLN permanent paralysis was zero and the rate of transient paralysis was 2.5% of procedures and 1.8% of nerves at risk, all resolving within 7 months. 82 Sinclair, while noting a 1.1% permanent RLN paralysis rate overall in his series of 767 thyroid surgeries, described a 17.5% rate with substernal goiter, associated with a policy of not identifying the RLN before goiter delivery. 173 Hockauf and Saylor, in treating 1713 patients with goiter, noted a 6.8% rate of permanent RLN paralysis for goiter overall and a 27% rate of RLN paralysis with substernal goiter. 191 MacIntosh described a 10% rate of RLN paralysis with substernal goiter. 192 In a German multicenter study of 7266 patients with benign goiter, Thomusch found transient RLN paralysis occurred in 2.1% of patients and permanent RLN paralysis in 1.1%. Bilateral RLN transient paralysis occurred in 0.002% and bilateral RLN permanent paralysis in 0.001%. 193 Shen, in a surgical series of 60 patients with substernal goiter, found 12% had airway complications postoperatively but did not provide information regarding postoperative laryngeal examination in these patients. 194 Rios-Zambudio, in 301 patients with goiter operated on by experienced endocrine surgeons, found RLN injury occurred in 8.6% of patients and was more likely in patients with hyperthyroidism and in those with larger and substernal goiters. Again, routine laryngoscopy was not performed. 195 In our series, laryngeal nerve monitoring was associated with a significant decreased risk of RLN paralysis by 87%. Analysis of risk factors in our series revealed that RLN paralysis during goiter surgery found that increased RLN risk was predicted by the presence of bilateral cervical goiter, but not by size, presence of revision surgery, substernal extension, or preoperative compressive symptoms. We also confirmed that retrotracheal goiter and posterior mediastinal goiter, when identified on preoperative CT scan, can help predict a ventrally displaced RLN where it is at extremely high risk during surgery. 82

Parathyroid Glands
Rates of hypoparathyroidism vary significantly between series in goiter surgery. Rates in expert hands as low as 1% to 1.5% have been reported. 84, 193 Thomusch found that transient parathyroid hypofunction occurred in 6.4% of patients, and permanent parathyroid dysfunction occurred in 1.5% of patients in his multicenter study on benign goiter. There was a correlation between long-term hypoparathyroidism and extent of thyroid resection. 193 We found permanent hypoparathyroidism in 8% of patients undergoing bilateral surgery, and in 3% of patients overall, including patients with revision surgery. 82 Hypothyroidism can be expected based on degree of thyroid resection, dietary iodine status, and presence of autoimmune thyroid antibodies.

Risk Factors for Complications during Goiter Surgery
Several series suggest an increased risk of both RLN and parathyroid complications for substernal versus cervical goiter. 173, 191 Lo, Kwok, and Yuen found increased RLN risk during goiter surgery with longer operative procedures and those associated with increased blood loss. 196 Torre et al. found increased risk if substernal goiter had a “complex endothoracic” relationship or if total thyroidectomy was performed. 8 Agerback et al. found increased RLN risk with increasing goiter size. 185 Calik et al. found increased risk to both the RLN and parathyroids with recurrent goiter, cases associated with thyroid cancer with nodal resection, and thyroiditis. 197 Judd, Beahrs, and Bowes found an increased overall complication rate in patients requiring sternotomy. 92 In our series, we identified a number of other factors that are important in the conduct of surgery, including degree of capsular blood vessel engorgement and friability, goiter consistency, and compressibility. 82
Thomusch, in a German multicenter study, provided a multivaried analysis of complications that occurred during benign goiter surgery in 7266 patients. 193 Using logistical regression analysis, RLN injury was found to be associated with (1) extent of surgery, (2) recurrent goiters, and (3) failure to identify the RLN. It is of interest that failure to identify the nerve resulted in a 9.9-fold increase of nerve paralysis for patients undergoing total thyroidectomy. Hypoparathyroid complications were found to be associated with (1) extent of resection, (2) recurrent goiters, (3) age, (4) gender (female more than male), (5) volume of thyroid surgery done in the hospital, and (6) presence of Graves’ disease. Also interesting was Thomusch's finding that, unlike RLN identification, the identification of at least one parathyroid gland during the goiter surgery did not affect the rate of postoperative hypoparathyroidism. 193

Other Complications
Please see the Expert Consult website for more discussion of this topic.

Other Complications
Very limited information is available regarding superior laryngeal nerve (SLN) paralysis during goiter surgery, though Calik et al. described a rate of 1.1%. 198 Serious intraoperative bleeding is reported in from 0.5% to 5.5% of cases of cervical and substernal goiter. 8, 20, 198 Mediastinal hematoma, in a literature review by Singh, Lucente, and Shaha, is reported in 3% of patients with substernal goiter. 85 Pneumothorax has been reported in from 1.4% to 5.3% of cases. 25, 199 Wound infection is reported in 1.8% of patients. 198 Cho, Cohen, and Som noted a single patient with esophageal laceration as a result of substernal goiter surgery. 25 Others have described low rates of atrial fibrillation, pleural effusion, and Horner's syndrome. Air embolism was reported by Pemberton in 1921. 38 Chyle fistula was reported by Lahey in 1936. 200 The rate of tracheotomy has been reported as ranging from 2.1% to 13%. 8, 20, 201, 202 Tracheotomy may be due to bilateral vocal cord paralysis or airway edema, or performed for nonairway issues (pulmonary toilette) or prophylactically. The mortality rate following goiter surgery is low. Torre et al. noted a 0.8% rate in their series of more than 200 substernal goiters. This single patient had an advanced mediastinal malignancy. 8
In our series of 200 thyroidectomies for goiter, complications other than hypoparathyroidism and RLN injury included one episode of hemorrhage requiring ligation of a bleeding vessel in the operating room and one episode of subglottic stenosis, eventually requiring tracheotomy in a multiple revision patient. We also encountered one case of atrial fibrillation postoperatively in a previously euthyroid patient and two cases of dysphagia following resection of masses causing tracheal deviation or compression. 82


Tracheomalacia
Tracheomalacia is poorly understood, extremely rare, and apparently reversible. Geelhoed and Green et al. have reported tracheomalacia after goiter surgery. 203, 204 The incidence of tracheomalacia has previously been estimated to be between 0.001% and 1.5%. 91, 204, 205 Of note, Sitges-Serra and Sancho, in reviewing six major studies, found two cases of what they believed was tracheomalacia. 91 In 72 patients with substernal goiters, Rodriguez also noted no cases of tracheomalacia. 84 McHenry and Protrowski, Mellière et al., Shaha et al., and Wade found no cases of tracheomalacia in their series. 5, 55, 101, 206 In our combined series of 200 large cervical and substernal goiters treated at Massachusetts Eye and Ear Infirmary and Massachusetts General Hospital, we have not identified a single case of tracheomalacia from benign goiter, even in the setting of chronic significant tracheal deviation, compression, and remodeling with massive and recurrent goiters. Tracheotomy was performed in only 3% of patients, and in none of these cases, was it performed for tracheomalacia. 82 In all cases the trachea can be evaluated directly through the wound to determine whether there is evidence of poor tracheal integrity or dynamic change with the respiratory cycle. We have seen cases that were referred with a presumptive diagnosis of tracheomalacia that ultimately were found to have bilateral vocal cord paralysis that had not been recognized. It is our strong clinical impression that tracheomalacia from goiter is rare and likely has arisen as a diagnostic error for underlying bilateral vocal cord paralysis. We do not advocate routine postsurgical bronchoscopy or prophylactic tracheotomy. If tracheomalacia exists as a diagnostic entity from chronic goiter compression, it is unclear how short-term intubation would make structurally intact a trachea that has been rendered significantly structurally insufficient (i.e., floppy) by chronic goiter compression. A variety of recommendations have been made regarding the treatment of tracheomalacia, including intubation, tracheotomy, Marlex mesh of the trachea, trachelopexy, and various types of tracheal grafting.

Recurrent Goiter: Prevention and Treatment
Please see the Expert Consult website for more discussion of this topic.

Recurrent Goiter: Prevention and Treatment
The administration of thyroid hormone as a preventative method against goiter recurrence is controversial. Thyroid hormone has also been used in suppressive mode to prevent goiter recurrence after less than total thyroidectomy. Several studies showing benefit to T 4 treatment were nonrandomized. 163, 207, 208 Miccoli showed benefit in a prospective randomized study but without adequate control group and follow-up of only 3 years. Recurrence in this study was defined as the sonographic reappearance of nodules, not clinical recurrence. 209 Several studies show no difference in goiter recurrence with or without T 4 treatment. 10, 159, 160, 162, 210 Bistrup, in a randomized, prospective, nonplacebo, controlled study with a 9-year follow-up, found no significant effect of T 4 in preventing postoperative goiter recurrence. 159 Hegedus, Nygaard, and Hansen, in 202 patients with a 12-year follow-up, found no statistically significant benefit to T 4 suppressive therapy in goiter recurrence. 10 Interestingly, Hegedus found increased goiter recurrence in patients who had larger goiter specimens removed, in those with larger remnants left in situ (24-mL remnant with recurrence versus 18-ml remnant without recurrence), and in those with lower postoperative TSH (TSH 1.6 μg/dL with recurrence versus 2.2 μg/dL without recurrence). Patients from iodine-deficient regions and those with a history of past radiation therapy may represent responders in terms of T 4 prevention of recurrent goiter formation. 10, 159 We believe that uncertainty regarding the efficacy of T 4 suppressive therapy coupled with the known skeletal and cardiac effects of subclinical hyperthyroidism make routine postoperative T 4 suppression unwarranted. TSH is only one of many follicular growth factors.
Recurrent goiter presentation is similar to initial goiter presentation except that past perithyroidal scarring may restrict thyroid growth and more readily result in compressive aerodigestive tract symptoms. Vocal cord paralysis and recurrent thyroid masses require consideration of malignant infiltration versus injury from past surgery. Past surgical operative notes and pathology reports should be reviewed. Operative notes may detail key information regarding location of the RLN and remaining parathyroid glands (see Chapter 10, Reoperation for Benign Disease ). The RLN, through an inferior approach, may allow identification of the nerve in a relatively undissected region, depending on the extent of past surgery (see Chapter 33, Surgical Anatomy and Monitoring of the Recurrent Laryngeal Nerve ). When operating on a contralateral lesion (relative to past thyroid surgery), one should conservatively assume, despite operative notes to the contrary, that both parathyroids from the first surgery have been removed. At the beginning of surgery, bilateral inferior jugular parathyroid hormone (PTH) sampling may provide further information regarding parathyroid function on each side of the neck. Risks of reoperative goiter surgery are emphasized in the literature, which documents RLN permanent paralysis in from 3% to 18% and permanent hypoparathyroidism in from 0% to 25% of patients. 161 - 164 , 211, 212 In our series of 200 thyroidectomies for goiter, revision surgery was, however, not more likely to be associated with postoperative complications than first-time surgery. 82

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Chapter 8 Approach to the Mediastinum
Transcervical, Transsternal, and Video-Assisted

Douglas J. Mathisen, Samuel S. Kim
Surgeons involved in the care of patients with thyroid and parathyroid disease must be familiar with the options for approaches to the mediastinum. Often the approach is anticipated in advance, but there may be occasions when the need becomes apparent only at the time of surgery. Collaboration with other specialties is optimized when anticipated in advance. All surgeons dealing with thyroid and parathyroid pathology must be aware of the indications for mediastinal exposure to allow for appropriate surgical planning.

Indications
The most common indication for mediastinal exposure is the presence of a substernal goiter or true posterior descending goiter (see Chapter 7 , Surgery of Cervical and Substernal Goiter). Although substernal goiter is a relatively common finding, the need for mediastinal exposure is infrequent but often cannot be determined until the time of surgery. Thyroid cancer that involves mediastinal structures or is associated with enlarged mediastinal nodes is another indication. Certain thyroid malignancies may involve the trachea, larynx, and esophagus, necessitating a cervical exenteration with mediastinal tracheostomy requiring extensive mediastinal exposure. Tumors may involve vascular structures requiring proximal and distal control only achieved by mediastinal exposure. Occasionally, parathyroid adenomas descend into the mediastinum and require access to the mediastinum.
Substernal goiter is the most common clinical problem requiring mediastinal exposure. The typical patient with a substernal goiter is shown in Figure 8-1 . This type of patient can almost always have the goiter removed through a low collar incision. Substernal goiters represent between 3% and 47% 1 - 6 of all goiters removed, depending on the definition of what constitutes a substernal goiter (see Chapter 7 , Surgery of Cervical and Substernal Goiter). The indications for removal of substernal goiter include actual or impending airway obstruction or threat of malignancy (about 2% to 3%). The majority of substernal goiters can be removed through a cervical incision. In our experience about 3% have required an upper or full sternotomy. 2 , 3 The only case requiring a full sternotomy in our series was a patient who had previous goiter surgery through a posterior thoracotomy ( Figure 8-2 ). A full sternotomy was required to safely remove a recurrent goiter because of massive size, location, and prior thoracotomy (see Figure 8-2 ).

Figure 8-1 Chest radiograph showing a typical substernal goiter. This type of sternal goiter can almost always be removed through a low cervical collar incision.

Figure 8-2 This chest radiograph (A) and computed tomographic scan (B) are of a patient requiring full median sternotomy for removal. The patient had previously undergone goiter surgery through a right thoracotomy many years ago.
Mediastinal exposure for substernal goiter is required infrequently in part because extension of the neck acts to migrate the gland into the neck. Conventional techniques of capsular dissection allow gradual delivery into the neck. Thyroid surgeons should be aware of additional techniques described by others for delivery of difficult substernal goiters. These techniques include the use of a spoon, 6 a Foley balloon catheter, 7 and, rarely, morcellation. 8
The true posterior descending goiter is an uncommon entity. The largest experience was reported by DeAndrade. 8 DeAndrade reported a total of 9100 patients with goiters, 1300 (14.2%) of whom were intrathoracic (substernal); only 128 were posterior mediastinal in location. Interestingly, all of these were removed through a cervical exposure. The ability to remove posterior goiters through a cervical approach is undoubtedly related to the preservation of some connection to the cervical gland and cervical blood supply, making delivery possible. The use of sternotomy, thoracotomy, or trapdoor incision advocated by some 9 , 10 is rarely indicated currently.
True ectopic thyroid masses (i.e., thyroid tissue separate from the thyroid gland) are extremely uncommon. 11 Such lesions may derive their blood supply from the mediastinum. Sternotomy or thoracotomy may be used in these cases because the preoperative diagnosis may be in doubt or concern exists about control of mediastinal vessels (see Chapter 7 , Surgery of Cervical and Substernal Goiter).

Surgical Options for Exposure

Partial Sternotomy
Positioning patients with an inflated thyroid bag under the shoulders to extend the neck brings the carina to the level of the angle of Louis. Division of the manubrium to just beyond the angle of Louis exposes the upper mediastinum and is all that is required for most circumstances. This is accomplished by making a longitudinal skin incision from the midpoint of the collar incision, carrying it down just below the angle of Louis ( Figure 8-3 ). It is important to dissect the suprasternal notch free of surrounding attachments. This allows the surgeon to insert a finger behind the manubrium and clear the areolar attachments. This maneuver is important to sweep the innominate vein and the pleura free from the back of the manubrium. Division of the innominate vein is the greatest risk to division of the upper sternum. Once the back of the manubrium has been cleared, the midline should be identified and scored with the cautery. The manubrium can be divided in a variety of ways. Some prefer the sternal saw. We rely on the Lebsche knife ( Figure 8-4 ). The Lebsche knife has a sharp edge to divide the bone, a broad surface to allow striking with a mallet, and a footplate to allow some control over the depth of division of the sternum. To use the Lebsche knife, the footplate is inserted under the sternal notch and the tip angled upward toward the back of the sternum. The Lebsche knife is vigorously pulled up, lifting the sternum as the mallet strikes it. It is important to divide the manubrium in the midline to allow for reapproximation when the operation is completed. When the manubrium is divided, it is gently spread with a right-angled retractor to allow placement of a small pediatric sternal spreader ( Figure 8-5 ). The spreader is gradually opened to prevent fracture; however, if fracture does occur, it can be reapproximated with expected good results if it is fractured on one side only. This exposure is sufficient for most problems confronting the thyroid surgeon. With the sternal spreader in place, the exposure to the mediastinum is greatly improved. This gives access to the trachea, esophagus, innominate vein, and artery. Dissection can be achieved in the tracheoesophageal groove and into the angle formed by the arch of the aorta and the innominate artery. Mediastinal exposure can be further enhanced with the addition of partial sternotomy ( Figure 8-6 ).

Figure 8-3 The low collar incision is utilized to explore patients to determine whether further exposure is needed. If additional exposure is needed, an incision is carried inferiorly from the midpoint of the collar incision to just below the angle of Louis.

Figure 8-4 The Lebsche knife is seen on the left and the mallet on the right. The handle at the top holds the knife, and the sternum is elevated in this fashion. The footplate seen at the bottom is inserted under the sternal notch. The mallet strikes the knife on the flat surface just above and posterior to the footplate.

Figure 8-5 A small pediatric sternal spreader is inserted in the divided manubrium to give additional exposure to the mediastinum.

Figure 8-6 A sternal spreader is inserted following manubrial and partial sternal division to give wide exposure to the mediastinum.
At the conclusion of the surgical procedure, we prefer sternal wires to reapproximate the sternum, and we usually use two sutures. The sutures are placed through the bone rather than around it at this level. This avoids injury to the internal mammary vessels or violation of the pleura.
The most significant complication of sternotomy is the division of the innominate vein. This almost always necessitates completing the full sternotomy to gain control of the vessel. Direct finger pressure on the divided vein to compress it against the back of the sternum is the first maneuver. Once the vein is controlled in this fashion, the two ends are identified and clamped. The vein can usually be reapproximated with no tension. A running 5-0 Prolene is used. It is important to avoid purse stringing and narrowing the vein. Intravenous infusion into the left arm should be stopped until continuity is restored. If for some reason the vein cannot be reconstructed, division is well tolerated with the only complication being left arm swelling. The arm should be elevated following surgery, and no intravenous fluids should be infused into this arm.
If the pleura are violated and a pneumothorax develops, a chest tube should be inserted anteriorly in the midclavicular line between the second and third rib. If it can be determined that the lung is not injured, a catheter attached to suction can be inserted into the pleural space. A pursestring suture is placed in the pleura around the catheter. The anesthesiologist inflates and holds the lung as suction is applied to the catheter. The catheter is quickly removed as an assistant ties the pursestring suture. A chest radiograph must be obtained to determine whether there is a pneumothorax. A small pneumothorax can be followed. The presence of a significant pneumothorax requires placement of a chest tube.
Sternal infection usually manifests itself in a delayed fashion. Symptoms can be subtle. The classic findings are fever, leukocytosis, sternal clicking, erythema, and purulent drainage. Computed tomography (CT) of the chest should be obtained if doubt exists. Telltale findings include separation of the sternum, the presence of retrosternal air, and fluid collections. If it is determined that infection exists, the wound should be opened, the sternum debrided, and the wound packed. Frequent dressing changes and debridement allow the wound to granulate and ultimately close. If a full sternotomy has been utilized, the problem is more significant. Reopening the sternum for debridement and irrigation is required. An attempt at closure with povidone-iodine (Betadine) irrigation is favored by some. If this fails, debridement and rotation of muscle flaps may be required.

Sternotomy
A complete sternotomy may be appropriate for some patients with very large goiters, extensive tumors or nodal involvement, or aberrant parathyroids. The patient is positioned as for an upper sternotomy. The skin incision extends from the collar incision inferiorly in the midline to just above the xyphoid process. The incision is carried down to the sternum. The midline of the sternum is identified and scored with electrocautery. It is essential to divide the sternum in the midline to ensure proper healing and stability of the sternum. It is important to dissect the suprasternal notch as previously described to minimize the risk of injury to the innominate vein. Inferiorly the midline fascia should be freed from the xyphoid process. A finger should be swept under the xyphoid to free the diaphragmatic and pericardial attachments from the back of the sternum to avoid entry into the pericardial sac. When the time comes to divide the sternum, the anesthesiologist deflates both lungs by disconnecting the endotracheal tube from the ventilator to minimize the risk of injury to the pleura and lungs. We prefer the sternal saw to open the entire sternum. The xyphoid is divided with heavy scissors. The footplate of the saw is insinuated between the divided ends of the xyphoid. As the saw is advanced, it should be pulled ventrally, uplifting the sternum and slightly angling the footplate upward. The edges of the sternum are cauterized. A sternal spreader is inserted and gradually opened for exposure.

Trapdoor Incision
Occasionally a trapdoor incision is required, usually for extension of the disease process into the right chest. It is usually coupled with an upper sternotomy. The sternum is transected between the second and third ribs on the right side. The internal mammary artery and vein are ligated and divided. The incision is carried laterally in the second interspace on top of the third rib. This “trapdoor” can now be elevated or spread to give excellent exposure to the right-sided mediastinal structures. The incision is closed by pericostal sutures around the second and third ribs. The sternum is approximated with sternal wires as described earlier.

Thoracoscopy
Video-assisted thoracoscopic surgery (VATS) represents a new approach in the management of mediastinal diseases, and its role has evolved over the past decade. In earlier decades, VATS was used primarily for diagnostic purposes within the mediastinum. 12 As surgeons increased their experience with techniques and instruments improved, VATS became a promising therapeutic alternative to open approaches in mediastinal surgeries, performed in excision of substernal goiters or a mediastinal parathyroid adenoma to thymectomy in surgical management of myasthenia gravis. 13 - 15 According to a growing number of reports in the literature, operative results from VATS are comparable and in some cases superior to traditional open techniques, with patients reporting less operative pain, better preserved early postoperative pulmonary function, and improved cosmesis. 16
Preoperative imaging and localization are important in planning the operation, from making a choice in using a left-sided, right-sided, or bilateral approach to determining the accessibility of the lesion from adjacent structures. Preoperative CT scans or magnetic resonance imaging (MRI) usually gives an excellent idea as to where to make incisions and which side to approach to allow direct visualization and resection. When operating on intrathoracic ectopic parathyroid adenoma, a preoperative localization using 99m Tc-sestamibi scan is helpful for identifying the lesion and planning the operation.
A thoracoscopic mediastinal operation requires collapse of the lung to allow visualization. A double lumen endotracheal tube is therefore imperative. The patient is placed on the appropriate lateral decubitus position, and the bed is flexed to allow the intercostal space to open. The laterality of surgical approach depends not only on the location of the disease but also on the surgeon's preference. In performing VATS thymectomy, advocates of the right-side approach assert that operating from the right chest is ergonomically easier on the operator, allows greater maneuverability in the wider right pleural space, and makes identification of the innominate vein easier because the superior vena cava (SVC) serves as a landmark. 15 The proponents of the left-sided approach advocate that the dissection maneuvers are safer because the superior vena cava lies out of the surgical field, thus reducing the risk of iatrogenic injury to this vessel, and it provides access to extensive removal of ectopic thymic tissue, particularly from the left cardiophrenic angle and the aortopulmonary window. 17 Some surgeons occasionally place patients in the supine position, which allows a simultaneous bilateral approach to provide a superior exposure and extended dissection. 18
The position of the trocar site is variable depending on the lesion. Usually, a 0- to 30-degree thoracoscope is inserted in the midaxillary line, and the trocar placements are triangulated in respect to the lesion. Often, a 4- to 6-cm utility thoracotomy is made anteriorly between the axillary line and the sternum, which facilitates removal of a large specimen and also insertion of conventional instruments when necessary.
Despite recent advances in techniques and instruments, there are limitations to the thoracoscopic operation, and not all mediastinal lesions should be approached thoracoscopically. There is a steep learning curve, and in general operative time is considerably longer. Large masses (typically > 4 to 5 cm) and lesions that are densely adherent to surrounding structures are especially challenging because of limited view and space to operate and proximity to vital organs and vessels. We recommend open operation in these cases. The use of a VATS approach for an anterior mediastinal neoplasm is also controversial, and the safest approach we feel remains an open operation.

Cervical Exenteration
Cervical exenteration is an uncommon operation that removes the larynx, a portion of the trachea, all or part of the esophagus, and lower pharynx and frequently requires a mediastinal tracheostomy. 19 Careful patient selection and preparation are essential. The most common indications for this radical procedure are postcricoid carcinomas of the esophagus, laryngeal cancers, extensive or recurrent thyroid malignancies, or extensive destruction of the upper aerodigestive tract from high-dose radiotherapy. If the operation goes well, it has the net effect of a laryngectomy (see also Chapters 34 , Surgery for Locally Advanced Thyroid Cancer: Larynx, and 35 , Surgery for Locally Advanced Thyroid Cancer: Trachea).
The patient is intubated either orally or through an existing tracheostomy (with the tube prepped into the operative field). The patient is placed supine on the operating table; the operating field extends from the chin to the pubis. A thigh is also prepared as a source of split-thickness skin grafts. If it is believed that a vascular graft will be required, allowance must also be made for this procedure. At least one arm is usually abducted so that it is available for arterial or venous access.
The operation is usually performed with two operating teams, one for the neck and mediastinum and the other for the abdomen to prepare the esophageal replacement. If the patient has been intubated through an existing tracheostomy, a sterile endotracheal tube is inserted during preparation and connected to the anesthesia machine with sterile tubing after completion of draping. The endotracheal tube may be moved at will on the operative field and does not hinder the surgeon.
Incisions are individualized depending on existing tracheal stomas and whether tumor or severe radiation change involves cervical tissue. In general, the initial approach is a transverse incision just above the heads of the clavicles ( Figure 8-7 ). This permits full exposure for exploration and, when extended, is adequate for the entire cervical dissection. The cervical exploration is conducted so that no irrevocable moves are made until the surgeon is certain that the procedure can indeed be completed. In the case of a bulky lesion such as recurrent thyroid carcinoma in which it is clear that exenteration will be complete, the dissection is carried out just medial and anterior to the carotid artery and internal jugular vein on both sides. On rare occasions, even if one of these vessels is involved, it may be excised and reconstructed. If the extent of mediastinal involvement cannot be determined adequately through the cervical incision described, the incision is extended laterally along the margin of the clavicles on either side and the inferior flap is raised over the pectoral fascia, especially in the midline ( Figure 8-8 ). The upper sternum is divided and then split vertically in the midline from notch to second interspace and across the second interspace transversely (see Figure 8-8 ). Occasionally, depending on the extent of the trachea involved, this procedure may be performed through the first interspace only. Once the surgeon determines that the lesion can be removed, the abdominal team begins to mobilize the portion of bowel that will be used for esophageal reconstruction. Some patients, such as those with adenoid cystic carcinoma, require only laryngotracheotomy without esophageal resection. Some require only removal of the anterior muscular layer, whereas some require resection of both muscular and mucosal layers of the esophagus.

Figure 8-7 Skin incisions used for cervical exenteration with anterior mediastinal tracheostomy. Initially, cervical exploration is performed through an extended supraclavicular collar incision, and tumor resectability is assessed.

Figure 8-8 Anterior cervical skin and platysma are elevated inferiorly over the pectoral fascia, especially in the midline. The sternocleidomastoid muscles are detached from their sternal and clavicular attachments.
Where it is clear that the tracheostomy will lie in the mediastinum, a plaque of anterior chest wall is removed at this point before the trachea is divided ( Figure 8-9 ). If, on the other hand, some question exists regarding the possibility of excising the lesion, the midtrachea is dissected further before the plaque of bone is removed, through the exposure provided by the divided sternum.

Figure 8-9 Resection of a plaque of sternum, clavicles, and first and second ribs allows the bipedicled skin flap to reach the trachea easily. The incision is made through the medial clavicles, adjacent first costal cartilages, and sternum, either above or below the sternomanubrial junction, depending on the location of tracheal division. The innominate artery may require division for very low mediastinal tracheostomies. This should be performed with intraoperative electroencephalogram (EEG) monitoring.
To remove the bony plaque to provide for the mediastinal tracheostomy, each of the clavicles is divided approximately 4 cm from its medial end by passing instruments carefully beneath the clavicle, avoiding injury to the underlying subclavian vein and dividing the bone on each side with a Gigli saw. The surgeon divides the first and second cartilages on both sides after first freeing the intercostal muscle from the junction of the sternum and ribs. The plaque of clavicle, cartilage, and sternum is removed on both sides (see Figure 8-9 ). The maneuver is greatly facilitated by previous division of the sternum as described. Ideally, the pleura will remain intact. The level of transection of the trachea is next selected, establishing an adequate margin below the level of the tumor. Particularly in thyroid carcinoma, the lymph nodes in the V-shaped space between the innominate artery and left carotid artery should be dissected with the specimen. In such patients, the strap muscles are usually included with the specimen.
When resection of the involved structures is complete, it is time to form the mediastinal tracheostomy, reconstruct the esophagus if necessary, and close the wound ( Figure 8-10 ). To construct a mediastinal tracheostomy, a second transverse incision is now made, usually in the submammary line from anterior axillary line to anterior axillary line (see Figure 8-7 ). With the previous upper transverse incision, a large bipedicled chest skin flap is now elevated from the pectoral fascia, with great care taken to spare the lateral feeding blood vessels. The large well-vascularized flap will drop into the mediastinal defect created by removal of the sternal plaque.

Figure 8-10 Sutures are placed between the subcutaneous tissues and the side of the trachea to reduce tension on the tracheocutaneous anastomosis (not shown). The divided innominate artery and the reconstructed esophagus are shown.
A short transverse incision is made in or a small transverse oval is excised from the middle of the skin flap at an appropriate spot corresponding to the end of the trachea in the mediastinum. Anastomosis is made of the end of the trachea to the opening in the skin. The traction sutures are used to draw the tracheal end through the opening. Four to six absorbable sutures are placed from the subcutaneous tissues to the tracheal walls distal to the transected end and are tied. The skin is anastomosed to the tracheal margin with 4-0 Vicryl interrupted sutures ( Figure 8-11 ). This may be done by intermittent removal and replacement of the endotracheal tube. After completion of the anastomosis, vacuum drains are placed beneath the flaps and in the neck and mediastinum, and the upper incision is closed. Although with further mobilization of the inferior margin of the inferior incision it would be possible in most cases to pull the skin together, this is avoided so that tension is not placed on the tracheal cutaneous anastomosis. Therefore, the roughly elliptical defect beneath the lower incision that overlies solid chest wall is usually skin grafted ( Figure 8-12 ).

Figure 8-11 The tracheocutaneous anastomosis is performed with absorbable sutures.

Figure 8-12 The completed anterior mediastinal tracheostomy.

Postoperative care
Ventilation in patients who require it is usually provided through the inlying Tovell tube, which is carefully taped in position. Because of the anatomic disposition of the mediastinal tracheostomy, no standard tracheostomy tube will be satisfactory. As little pressure as possible is used in the cuff to avoid injury to the stomal suture line. The greatest problem in the past in mediastinal tracheostomies has been separation of the skin from the tracheostomy, with subsequent erosion and massive hemorrhage from the innominate artery or the aortic arch. In our experience with the addition of innominate artery division and placement of the omentum over the vessels, the complication of major hemorrhage has not occurred. When tracheal-cutaneous separation has occurred (a hazard particularly when the patient has had preoperative irradiation), subsequent healing has occurred without hemorrhagic problems. In some of these patients with cutaneous tumor and extensive radiation change, the procedure was modified to include an island myocutaneous flap to provide nonradiated tissue for the stomal region reconstruction. Such problems must be foreseen and reviewed in advance with a consultant in plastic surgery. Routine use of myocutaneous flaps is not necessary to accomplish these procedures, however.

References
For a complete list of references, go to expertconsult.com .

References

1 Judd E.S., Beahrs O.H., Bowes D.E. A consideration of the proper surgical approach for substernal goiter. Surg Gynecol Obstet . 1960:90–98.
2 Katlic M.R., Wang C.A., Grillo H.C. Substernal goiter. Ann Thorac Surg . 1985;39:391.
3 Katlic M.R., Grillo H.C., Wang C.A. Substernal goiter: analysis of 80 patients from Massachusetts General Hospital. Am J Surg . 1985;149:283.
4 Rodriguez J.M., et al. Substernal goiter: clinical experience of 72 cases. Ann Otol Rhinol Laryngol . 1999;108:501.
5 Allo M.D., Thompson N.W. Rationale for the operative management of substernal goiters. Surgery . 1983;94:969.
6 Landreneau R.J., et al. Intrathoracic goiter: approaching the posterior mediastinal mass. Ann Thorac Surg . 1991;52:134.
7 Pandya S., Sanders L.E. Use of a Foley catheter in the removal of a substernal goiter. Am J Surg . 1998;175:155.
8 DeAndrade M.A. A review of 128 cases of posterior mediastinal goiter. World J Surg . 1977;1:789.
9 Michel L.A., Bradpiece H.A. Surgical management of substernal goitre. Br J Surg . 1988;75:565.
10 Gourin A., Garzon A.A., Karlson K.E. The cervicomediastinal approach to intrathoracic goiter. Surgery . 1971;69:651.
11 Hall T.S., et al. Substernal goiter versus intrathoracic aberrant thyroid: a critical difference. Ann Thorac Surg . 1988;46:684.
12 Cirino L., Milanez de Campos J., et al. Diagnosis and treatment of mediastinal tumor by thoracoscopy. Chest . 2000;117:1787–1792.
13 Shigemura N., Akashi A., et al. VATS with a supraclavicular window for huge substernal goiter: an alternative technique for preventing recurrent laryngeal nerve injury. Thorac Cardiovasc Surg . 2005;53(4):231–233.
14 Smythe W.R. Thoracoscopic removal of mediastinal parathyroid adenoma. Ann Thorac Surg . 1995;59:236–238.
15 Yim A.P.C., Kay R.L.C., Ho J.K.S. Video-assisted thoracoscopic thymectomy for myasthenia gravis. Chest . 1995;108:1440–1443.
16 Ruckert J.C., Walter M., Muller J.M. Pulmonary function after thoracoscopic thymectomy versus median sternotomy for myasthenia gravis. Ann Thorac Surg . 2000;70:1656–1661.
17 Mineo T.C., Pompeo E., et al. Thoracoscopic thymectomy in autoimmune myasthenia: results of left-sided approach. Ann Thorac Surg . 2000;69:1537–1541.
18 Pompeo E., Tacconi F., et al. Long-term outcome of thoracoscopic extended thymectomy for nonthymomatous myasthenia gravis. Euro J Cardiothorac Surg . 2009;36(1):164–169.
19 Grillo H.C., Mathisen D.J. Cervical exenteration. Ann Thorac Surg . 1990;49:401.
Chapter 9 The Surgical Management of Hyperthyroidism

Christopher R. Mchenry, Chung-yau Lo

Introduction
Primary hyperthyroidism is a syndrome manifested by signs and symptoms of hypermetabolism and excess sympathetic nervous system activity that results from excess synthesis and secretion of thyroid hormone by the thyroid gland. The overall prevalence of hyperthyroidism is 1.3% in the U.S. population. It occurs in 2% of women and 0.5% of men, and its prevalence can be as high as 5% in older women. 1 The term hyperthyroidism is distinct from thyrotoxicosis, which is a syndrome that results from excessive thyroid hormone that may come from other sources in addition to the thyroid gland. Patients with subacute, painless, or radiation-induced thyroiditis; excess thyroid hormone ingestion; struma ovarii; and functional metastatic thyroid cancer are examples of those who have thyrotoxicosis that is not attributed to hyperthyroidism. This chapter focuses on the clinical presentation, diagnosis, and surgical management of hyperthyroidism from Graves' disease, toxic multinodular goiter, and a solitary toxic nodule (see also Chapter 3 , Thyroid Physiology and Thyroid Function Testing).
The excess synthesis and secretion of thyroid hormone that occur in patients with hyperthyroidism may produce a variety of clinical manifestations and findings on physical examination ( Boxes 9-1 and 9-2 ). Elderly patients are more likely to present with subtle symptoms of thyrotoxicosis such as asthenia, fatigue, and weakness, a syndrome referred to as apathetic hyperthyroidism. Elderly patients are also more likely to have cardiovascular manifestations of hyperthyroidism such as atrial fibrillation, ischemic heart disease, and congestive heart failure.

Box 9-1 Symptoms and Manifestations of Hyperthyroidism

Palpitations
Nervousness
Restlessness
Weight loss
Increased appetite
Anxiety
Irritability
Emotional lability
Heat intolerance
Increased sweating
Fatigue
Muscle weakness
Insomnia
Thinning of the hair and hair loss
Brittle nails
Increased bowel movements
Irregular menses
Impaired fertility
Osteoporosis and increased fracture risk
Atrial fibrillation or other supraventricular arrhythmias
Congestive heart failure
Male gynecomastia and erectile dysfunction

Box 9-2 Signs of Hyperthyroidism

Stare
Lid lag
Tachycardia
Irregularly irregular pulse
Systolic hypertension
Proximal muscle weakness
Hyperreflexia
Resting tremor
Warm, moist skin
Thin, fine hair
Onycholysis
The best screening test for hyperthyroidism is a serum thyrotropin (TSH) level (see Chapter 3 , Thyroid Physiology and Thyroid Function Testing). With the rare exception of a TSH-secreting pituitary tumor, patients with hyperthyroidism will have a decreased serum TSH level. Patients with a low serum TSH level should have a free T 4 (FT 4 ) and a free T 3 (FT 3 ) level measured to help determine the degree of hyperthyroidism. Patients with a low serum TSH level and normal FT 4 and FT 3 levels are defined as having subclinical hyperthyroidism. A FT 3 level is important to make a diagnosis of “T 3 thyrotoxicosis” in a patient with a suppressed serum TSH level and a normal FT 4 level. In most patients, T 3 thyrotoxicosis is an early manifestation of Graves' disease (see also Chapter 5 , Hyperthyroidism: Toxic Nodular Goiter and Graves' Disease).
Measurement of iodine-123 uptake and thyroid scintigraphy can be helpful in establishing the cause of hyperthyroidism. Radioiodine uptake is elevated in patients with Graves' disease. Radioiodine uptake may be elevated or normal in patients with toxic multinodular goiter or a solitary toxic nodule. Radioiodine uptake is low or undetectable in patients with thyrotoxicosis from thyroiditis, excess thyroid hormone ingestion, excess iodine intake, and struma ovarii. Thyroid scintigraphy demonstrates diffuse symmetric uptake in patients with Graves' disease, heterogeneous uptake in patients with toxic multinodular goiter, and single area hyperfunction with a variable degree of suppression of the remainder of the thyroid gland in patients with a solitary toxic nodule. Measurement of thyroid stimulating immunoglobulin levels may help establish a diagnosis of Graves' disease when radioiodine scanning is contraindicated.

Graves' Disease

Pathogenesis
Graves' disease is an autoimmune disorder with familial predisposition. It is characterized by lymphocytic infiltration of the thyroid gland and antithyroid antibodies directed against the TSH receptor. The specific cause of Graves' is unknown. Thyroid receptor antibodies are primarily thyroid stimulating immunoglobulins, which activate TSH receptors in the membrane of the follicular epithelial cells of the thyroid gland, resulting in excess synthesis and secretion of thyroid hormone and growth of the thyroid gland (see Chapter 5 , Hyperthyroidism: Toxic Nodular Goiter and Graves' Disease).

Historical Perspective
The syndrome known in the Western world as Graves' disease was independently described by Dr. Caleb Hillier Parry in 1786, Sir Robert James Graves' in 1835, and Dr. Carl A. Basedow in 1840. 2 - 6 Caleb Hillier Parry, an English physician and descendant from a Welsh pedigree, first described a patient with diffuse goiter and hyperthyroidism in 1786. In 1825, after Parry's death, his report of eight patients with exophthalmic goiter and hyperthyroidism was published by his son Charles. 2 Sir Robert James Graves' a physician from Dublin, Ireland, published a monograph in 1835 titled “Newly Observed Affection of the Thyroid Gland in Females,” describing six patients with thyrotoxicosis, exophthalmos, and enlargement of the thyroid gland. 3 The first description of toxic goiter in Europe was in 1840 by Carl A. von Basedow, a German private practitioner. 4 He described exophthalmos, struma (goiter) and palpitations of the heart in three women.
Graves' disease, Parry's disease, and Basedow's disease have all been used to describe the syndrome of thyrotoxicosis, exophthalmos, and diffuse symmetric goiter. It was Armand Trousseau, professor of medicine at the Hotel-Dieu in Paris and author of the foreword of Robert Graves' book of clinical lectures, who proposed that the syndrome of exophthalmic goiter be named “Maladie de Graves.” 7 It has been suggested that the attachment of Graves' name to the syndrome is the result of Trousseau's influence. 6 A strong case can be made for renaming the syndrome “Parry's disease,” a proposal that was made by Sir William Osler. 6

Epidemiology
The annual incidence of Graves' disease in the United States is approximately 0.4%. 8 It occurs four to six times more commonly in women and usually presents between the ages of 20 and 50 years. 8 It is the most common cause of hyperthyroidism, accounting for 50% to 80% of all cases. 9 It occurs in association with other autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, chronic lymphocytic thyroiditis, Sjögren's syndrome, vitiligo, pernicious anemia, type 1 diabetes mellitus, Addison disease, myasthenia gravis, and idiopathic thrombocytopenic purpura. 10

Clinical Presentation
The clinical manifestations of Graves' disease include symptoms and signs of thyrotoxicosis (see Boxes 9-1 and 9-2 ), a diffuse symmetric goiter often with a palpable thrill or an audible bruit, and a variable degree of presence of extrathyroidal manifestations including ophthalmopathy, pretibial myxedema, and acropachy. Extrathyroidal manifestations occur as a result of cellular infiltration and glycosaminoglycan deposition in the soft tissues in response to antibody reaction to tissue antigens, which cross-react with the TSH receptor in the thyroid gland.
Clinically relevant ophthalmopathy occurs in 20% to 30% of patients with Graves' disease and is vision-threatening in 3% to 5%. 11 It is more common in cigarette smokers and patients with higher levels of thyrotropin receptor antibodies ( Figure 9-1 ). It occurs as a result of antibody-mediated inflammation of the extraocular muscles, retroorbital fat and connective tissue, and the optic nerve. Stare, lid lag, and eyelid retraction are due to excess sympathetic nervous system stimulation of the levator palpebrae superioris muscles and may occur in all patients with hyperthyroidism, but only patients with Graves' disease have ophthalmopathy. Periorbital edema, chemosis, exophthalmos, and extraocular muscle weakness are more specific manifestations of Graves' ophthalmopathy. Patients may experience a gritty feeling in the eyes, eye pain, photophobia, tearing, diplopia, and decreased visual acuity. Patients may develop corneal ulcerations as a result of proptosis and lid retraction. Severe proptosis can cause optic neuropathy and blindness.

Figure 9-1 Graves' ophthalmopathy.
Pretibial myxedema is an infiltrative dermopathy most often involving the skin of the legs. It occurs in 0.5% to 4% of patients with Graves' disease. It is manifested by painful, pruritic, raised plaquelike lesions that are violaceous and hyperpigmented in appearance with a texture of an orange peel. Acropachy occurs in less than 1% of patients with Graves' disease and is manifested by clubbing and periosteal new bone formation of the metacarpal bones and the phalanges.

Diagnosis and Evaluation
The diagnosis of Graves' disease is established by the association of hyperthyroidism, a diffuse symmetric goiter ( Figure 9-2 ) and increased radioiodine uptake. Iodine-123 thyroid scintigraphy demonstrates diffuse symmetric uptake in the thyroid gland ( Figure 9-3 ); however, it is not routinely necessary to make a diagnosis of Graves' disease. Measurement of radioiodine uptake and thyroid scintigraphy are primarily of value in helping to differentiate thyrotoxicosis caused by Graves' disease from toxic multinodular goiter, a solitary toxic adenoma or thyroiditis. In rare circumstances, documentation of elevated thyroid stimulating immunoglobulins, because of their high sensitivity and specificity, may be helpful in establishing or excluding a diagnosis of Graves' disease.

Figure 9-2 Marked diffuse symmetric thyroid enlargement of Graves' disease.

Figure 9-3 Iodine-123 thyroid scan demonstrating diffuse symmetric uptake, characteristic of Graves' disease.

Treatment
The goals of therapy for Graves' disease are rapid amelioration of symptoms and prevention of recurrent hyperthyroidism. There are three therapeutic alternatives for Graves' disease: antithyroid drugs, radioiodine ablation, and thyroidectomy. Each alternative has its own advantages and disadvantages. Patient, physician, institutional, or geographic preferences often influence the choice of therapy. In the United States, radioiodine ablation is most commonly used. 12 In Europe, Japan, and South America, prolonged antithyroid drug therapy is the preferred option 13, 14 (see Chapter 5 , Hyperthyroidism: Toxic Nodular Goiter and Graves' Disease).

Antithyroid Drugs
Most patients with Graves' disease are initially treated with an antithyroid drug. The antithyroid drugs that are used are the thionamide agents, propylthiouracil and methimazole. Both agents decrease thyroid hormone synthesis and re-establish a euthyroid state in 3 to 8 weeks. A beta-blocker is often added for the rapid amelioration of symptoms attributable to excess sympathetic nervous system activity such as palpitations, tachycardia, tremor, heat intolerance, diaphoresis, and anxiety. Permanent remission of Graves' disease occurs in 20% to 50% of patients after 12 to 18 months of therapy, typically in patients with smaller goiters and with less severe hyperthyroidism. 13
Lifelong antithyroid drug therapy is one option for the management of patients with Graves' disease who relapse after discontinuation of antithyroid drugs therapy. However, in the United States, lifelong administration of antithyroid drug is seldom used for definitive therapy for Graves' disease. Antithyroid drugs are routinely used for preoperative preparation, and propylthiouracil is preferred for the management of Graves' disease during pregnancy. Minor adverse reactions to antithyroid drugs occur in approximately 5% of patients and include rash, urticaria, arthralgia, fever, anorexia, nausea, and abnormalities of taste and smell. Major adverse effects include agranulocytosis, which occurs in approximately 0.1% to 0.3% of patients, and hepatotoxicity, an even rarer complication, which may be fatal. 9, 15

Radioiodine
Radioiodine was introduced for treatment of hyperthyroidism in the 1940s. 16 Prior to the 1940s, subtotal thyroidectomy was the standard therapy for Graves' disease. Iodine-131 gradually became the first-line treatment for Graves' disease in the United States. Iodine-131 admits beta particles, which destroy the follicular cells of the thyroid gland. At most centers, the goal of radioiodine therapy is to induce hypothyroidism in order to prevent recurrence of Graves' disease. 9 This is achieved in approximately 80% of patients with either a calculated or fixed dosage regimen. 17
Radioiodine ablation therapy takes a median of 3 months and sometimes multiple doses before hyperthyroidism is corrected. 18 Radioiodine therapy is contraindicated in women who are pregnant or who are breast-feeding. A pregnancy test should be obtained prior to radioiodine administration in all women of reproductive age. Radioiodine is excreted in the urine, exposing the pelvic viscera to radiation. Radioiodine also crosses the placenta where it can be taken up by the fetal thyroid gland. It is generally recommended that women do not become pregnant for 6 to 12 months after radioiodine treatment. 9 Side affects of radioiodine ablation include neck pain and tenderness from radiation-induced thyroiditis, transient increase in thyroid hormone levels, and worsening of Graves' ophthalmopathy. 9

Surgery
Surgical treatment of Graves' disease is indicated for (1) pregnant patients requiring high doses of an antithyroid drug or who are intolerant to antithyroid drugs, (2) patients with a concomitant thyroid nodule that is malignant or suspicious for malignancy, (3) failure of radioiodine therapy, (4) massive thyroid enlargement (see Figure 9-2 ) with compressive symptoms, (5) severe ophthalmopathy, and (6) patient preference. Patient preference is often related to the desire for the most rapid amelioration of symptoms, a reluctance to receive radioiodine because of having young children, a desire to become pregnant, and a fear of exposure to radiation. The advantages of surgical therapy are that patients experience immediate symptomatic improvement and, with total thyroidectomy, the risk of recurrent hyperthyroidism is eliminated. It also allows for treatment of concomitant thyroid nodules and incidental thyroid carcinoma. Incidental carcinoma has been reported to occur in 2.3% of patients with Graves' disease. 19 In addition, total thyroidectomy is effective in improving the eye manifestations attributable to excess adrenergic activity. 20
The disadvantage of surgical treatment of Graves' disease is the risk of complications from thyroidectomy, which include recurrent laryngeal nerve injury, hypoparathyroidism, neck hematoma, and thyroid storm. Hypothyroidism is an intended consequence of total thyroidectomy and requires lifelong thyroid hormone replacement. When total thyroidectomy is performed by a skilled surgeon, the incidence of recurrent laryngeal nerve injury and hypoparathyroidism is approximately 1% to 2%, and neck hematoma is 1% or less. 20 - 23
Thyroid storm is a life-threatening condition that can be precipitated by surgery in a patient with poorly treated hyperthyroidism. It is characterized by severe manifestations of hyperthyroidism along with fever, nausea, vomiting, diarrhea, tachyarrhythmias, congestive heart failure, agitation, and delirium. The risk of thyroid storm can be eliminated by adequate preoperative preparation. 21, 22 An antithyroid drug is used to normalize free T 4 and free T 3 levels prior to the operation. A beta-blocker is used for symptomatic treatment of adrenergic symptoms and tachycardia. Once the patient's free T 4 and free T 3 levels are normalized, a saturated solution of potassium iodide (50 mg mixed in an 8-oz glass of water daily) is administered for 10 days prior to surgery ( Box 9-3 ). Iodide treatment preoperatively reduces the rate of blood flow, thyroid vascularity, and intraoperative blood loss during thyroidectomy for Graves' disease. 24 In patients who are noncompliant or intolerant to antithyroid drugs, thyroidectomy can be performed safely using adequate beta-blockade alone. 25

Box 9-3 Two Options for Preoperative Preparation for Graves' Surgery

1. SSKI
50 mg iodide/gtt
1 to 2 gtts (0.05 to 0.1 mL)
 —tid in water or juice for 10 days preop
2. Lugol's solution
8 mg iodide/gtt
5 to 7 mg/gtt (0.25 to 0.35 mL)
 —tid in water or juice for 10 days preop
The extent of thyroidectomy for the treatment of Graves' disease is controversial. The surgical procedures most often performed for the treatment of Graves' disease are subtotal thyroidectomy with bilateral 2- to 4-gram thyroid remnants (Enderlen-Holtz procedure) or a unilateral remnant less than 7 grams (Hartley-Dunhill procedure) and a near-total thyroidectomy, with a remnant less than 1 gram, and a total thyroidectomy. The decision for subtotal thyroidectomy versus near-total or total thyroidectomy essentially balances the risk of disease recurrence with the need for lifelong thyroid hormone replacement. In many countries, subtotal thyroidectomy is the preferred surgical option because of the relatively smaller risk of inducing complications and the limited access to postoperative thyroid hormone replacement medications.
In the past, bilateral subtotal thyroidectomy was the standard treatment for Graves' disease in the United States. This most often consisted of leaving a 3-gram remnant of thyroid tissue on either side of the trachea in an attempt to establish and maintain a euthyroid state, reduce the risk of recurrent laryngeal nerve injury and hypoparathyroidism, and minimize the risk of persistent or recurrent hyperthyroidism. The problem with subtotal thyroidectomy is that it is difficult to standardize remnant sizes and to establish a reproducible relationship between remnant size and a euthyroid state postoperatively. 26 Forty percent to 60% of patients with Graves' disease treated with bilateral subtotal thyroidectomy become hypothyroid within 20 years of operation. 27 As a result, diligent long-term follow-up is necessary to prevent delay in diagnosis and treatment of hypothyroidism and development of untoward sequelae. Bilateral subtotal thyroidectomy is also associated with an approximate 8% rate of persistent or recurrent hyperthyroidism and is even as high 28% depending on the size of thyroid remnants. 28, 29
Total thyroidectomy is the preferred surgical option for treatment of Graves' disease when thyroid hormone replacement therapy is readily available. Removal of all thyroid tissue eliminates the potential for persistent or recurrent hyperthyroidism. Persistent or recurrent hyperthyroidism is a particularly bad outcome because it may subject patients to radioiodine therapy, which they may have initially declined, or reoperative surgery, which has an increased risk of morbidity. Total thyroidectomy simplifies the postoperative follow-up because all patients are started on a replacement dose of thyroid hormone. In addition, total thyroidectomy eliminates the antigen that is the source for the TSH receptor antibodies and other antibodies that cross-react with antigens in the extraocular muscles, the retroorbital connective tissue, and the optic nerve. 30

Toxic Nodular Goiter
In 1913, Henry S. Plummer first described a “nonhyperplastic goiter” as a cause for hyperthyroidism distinct from Graves' disease. 31 Since then, the term Plummer's disease has been used to describe toxic nodular goiter, which refers to hyperthyroidism resulting from either a single or multiple adenomatous nodules. Toxic nodular goiter includes two entities, toxic multinodular goiter and a solitary toxic nodule. Both disorders are characterized by abnormal thyroid function independent of TSH regulation. However, there are clear differences in their pathogenesis and clinical presentation. Together, these two disorders are the second most common cause of thyrotoxicosis, accounting for 5% to 15% of all causes. Most patients with Plummer's disease have toxic multinodular goiter, which is the most common cause of thyrotoxicosis in the elderly. 32 Hence, it is also common to refer to toxic multinodular goiter as Plummer's disease and solitary toxic nodule as toxic adenoma. These two disease entities will be considered separately.

Toxic Multinodular Goiter

Pathogenesis
Many etiologic factors are involved in the formation of a multinodular goiter. These include an inherent functional heterogeneity of thyroid follicles, the effect of growth factors and goitrogens, the presence or absence of iodine, and genetic abnormalities. 33 In contrast to Graves' disease, in which the thyroid follicular cells become hyperfunctional as a result of antithyroid immunoglobulins that bind to and activate the TSH receptor, autonomous thyroid nodules develop hyperfunction through alterations in the cellular biology of the follicular cells. Somatic activating mutations of the TSH receptor may be involved in the pathogenesis by constitutively activating the c-AMP cascade, resulting in replication and increased growth of thyroid follicular cells. It is postulated that chronic TSH stimulation associated with prolonged iodine deficiency increases the replication of follicular cells and results in the appearance and expression of mutations in the TSH receptor gene 34, 35 (see Chapter 5 , Hyperthyroidism: Toxic Nodular Goiter and Graves' Disease).
Nodular goiter occurs as a result of the hyperplasia of small groups of follicular cells with abnormal growth potential that develop at multiple sites in the thyroid gland. Toxic multinodular goiter represents the final phase in the evolution of a goiter in which nodules slowly become autonomous, progressing from a nontoxic to a toxic state. A nontoxic multinodular goiter is dependent on TSH regulation and initially may be suppressible by thyroid hormone. The goiter gradually develops autonomy and becomes independent of TSH control and is no longer suppressible with thyroxine administration. An autonomous goiter may progress to a toxic multinodular goiter, in which elevated free T 4 and free T 3 levels are associated with a low or suppressed TSH level. Hyperfunctioning nodules can be identified on iodine-123 thyroid scintigraphy. Nodule autonomy implies nodule excessive thyroid hormone production despite a suppressed TSH.
The prevalence of toxic multinodular goiter is significantly higher in areas of iodine deficiency, and in some geographic regions it is the most common cause of thyrotoxicosis. Toxic multinodular goiter generally affects older individuals with a history of a long-standing nontoxic multinodular goiter. A nontoxic multinodular goiter is present for an average of 17 years before becoming toxic. 31 In a review of 90 patients with euthyroid multinodular goiter, those with preexisting autonomous areas within the gland were more likely to become toxic. 35 Patients with nontoxic multinodular goiter have a high prevalence of subclinical hyperthyroidism (i.e., suppressed TSH with normal thyroid hormone levels). 36 Iodine-induced thyrotoxicosis or the Jod-Basedow phenomenon can be precipitated in patients with nontoxic multinodular goiter with or without autonomy and is typically precipitated by iodine-containing drugs or iodinated contrast. 37 Iodine-induced thyrotoxicosis is a self-limited condition but indicates that toxic multinodular goiter may develop in the future if not already present. 33

Clinical Presentation
Toxic multinodular goiter typically occurs in individuals over 50 years of age, who often have a preexisting history of a nontoxic multinodular goiter that has been present for many years. 38, 39 Similar to nontoxic multinodular goiter, the incidence is higher in women. Patients present with symptoms and signs of hyperthyroidism (see Boxes 9-1 and 9-2 ) and an enlarged thyroid gland with multiple nodules. The hyperthyroidism is usually less severe than in patients with Graves' disease. The severity of hyperthyroidism varies depending on the stage of the goiter's development and its degree of autonomous activity. The onset of hyperthyroidism is insidious, often preceded by a long period of subclinical hyperthyroidism; and the infiltrative ophthalmopathy and dermopathy of Graves' disease do not occur. 37, 38 Overt manifestations of thyrotoxicosis are similar to those with other types of thyrotoxicosis but are often masked in older patients. Cardiac manifestations, such as atrial fibrillation, tachycardia, congestive heart failure, and accelerated angina, are more common in patients with toxic multinodular goiter because they are older. Unexplained weight loss, anxiety, insomnia, and muscle wasting are also more likely to occur in the elderly patient with hyperthyroidism.
Patients with marked thyroid enlargement may present with symptoms attributable to mass effect ( Figure 9-4 ), particularly when there is substernal extension. Patients may complain of dysphagia related to esophageal compression ( Figure 9-5 ). Dyspnea, decreased exercise tolerance, cough, and a choking sensation may occur from tracheal compression ( Figure 9-6 ). Hoarseness and other voice changes may occur as a result of compression or stretch of the recurrent and superior laryngeal nerves.

Figure 9-4 A 60-year-old man with a long-standing goiter who complained of progressive increasing size of the goiter (A) . Symptoms of thyrotoxicosis were not apparent. He had a large multinodular goiter (B) and left eye-lid retraction (C) without infiltrative ophthalmopathy.

Figure 9-5 Esophageal displacement and compression from a substernal nodular goiter.

Figure 9-6 A, A large toxic multinodular goiter with retrosternal extension causing tracheal narrowing and deviation to the right seen on chest radiography. B, Computed tomographic image showing similar findings with calcification and fibrosis of the right lobe of the thyroid gland.

Diagnosis and Evaluation
The diagnosis of toxic multinodular goiter can usually be made on the basis of symptoms of hyperthyroidism, an enlarged nodular goiter on physical examination and a low serum TSH level with or without elevated FT 4 and FT 3 levels. The diagnosis may be difficult in 20% of such toxic multinodular patients who present without palpable thyromegaly. Ultrasound imaging and measurement of radioiodine uptake and thyroid scintiscanning are not routinely necessary to make a diagnosis, but they can be of value in helping to determine the etiology of thyrotoxicosis. Ultrasound demonstrates multiple thyroid nodules of varying size and number. Fine-needle aspiration cytology is not required unless there is a sonographically suspicious or a dominant nodule. Radioiodine uptake is usually only slightly elevated or in the high normal range and thyroid scintigraphy reveals a heterogenous pattern of iodine uptake, with focal areas of increased uptake corresponding to the hyperfunctioning nodules 38 ( Figure 9-7 ). Thyroid iodine scanning may also be of value in patients with thyrotoxicosis when it is difficult to determine whether they have diffuse or nodular thyroid enlargement.

Figure 9-7 The appearance of a toxic multinodular goiter on thyroid scintigraphy from the patient in Figure 9-4 demonstrating heterogeneous technetium uptake with a discrete hot nodule in each lobe of the thyroid gland.

Treatment
The goal of treatment in patients with toxic multinodular goiter is to eradicate all autonomously functioning thyroid tissue. The alternatives for definitive treatment are radioiodine ablation or thyroidectomy. 33, 38 - 41 Recurrent hyperthyroidism invariably occurs after initially successful treatment with propylthiouracil or methimazole. In a study comparing patients with toxic multinodular goiter and patients with Graves' disease treated with a thionamide drug for at least 1 year after becoming biochemically euthyroid, relapse occurred in 95% of patients with toxic nodular goiter compared to 34% of patients with Graves' disease after a minimum 2-year follow-up. 42 As a result, thionamide therapy is not considered an option for the definitive treatment of toxic multinodular goiter.

Radioiodine
Radioiodine treatment of toxic multinodular goiter is preferable in elderly patients with concurrent medical problems that increase their risk for surgery. The goal of radioiodine therapy is complete thyroid ablation to prevent recurrence and, as a result, permanent hypothyroidism is an accepted consequence. 38 The usual dose of 131 I varies between 15 and 30 mCi depending on the size and radioactive iodine uptake of the gland. Higher (>50 mCi) and multiple doses of 131 I are often required to control hyperthyroidism because of the typical large goiter size and lower 131 I uptake as compared to patients with Graves' disease. Patients become euthyroid within 8 weeks after the administration of 131 I, although it may take longer. 39 The recurrence rate after 131 I treatment is approximately 20%. 31, 38, 39 Because toxic multinodular goiter contains nonfunctioning nodules and areas of fibrosis and calcification ( Figure 9-8 ), 131 I treatment is varyingly effective in producing a clinically significant reduction in goiter size and in relieving compressive symptoms. However, one study using magnetic resonance imaging demonstrated a reduction in thyroid volume and an increase in the cross-sectional area of the tracheal lumen after treatment of toxic and nontoxic multinodular goiter with 131 I. 43 Another study showed goiter size was reduced by as much as 40% 1 year after 131 I treatment. 44 In some centers, patients with toxic multinodular goiter are being referred earlier for treatment and are increasingly treated with 131 I. 32, 45 - 47

Figure 9-8 Total thyroidectomy specimen from patient in Figure 9-4 with nodules of variable size and heterogeneous appearance (A) and the bisected toxic multinodular goiter with are areas of hemorrhage, fibrosis, and calcification (B) .

Surgery
Surgical resection is an excellent, and we think the preferred, method of treatment for most patients with toxic multinodular goiter because of the typically large goiter size and presence of compressive symptoms (see Figures 9-8 and 9-9 ). 42 The presence of substernal thyroid extension or airway obstruction is a relative contraindication for 131 I because of the potential for transient increase in size of the goiter and worsening of airway compromise through radioactive iodine-induced transient radiation thyroiditis. Surgical resection should consist of removal of all abnormal thyroid tissue, and this usually is best accomplished by performing a near-total or total thyroidectomy. Subtotal thyroidectomy is an option, but only when it can be performed without leaving abnormal thyroid tissue behind. One potential advantage of subtotal thyroidectomy is that, if enough thyroid tissue is left behind, a patient may not develop hypothyroidism. However, recurrence after incomplete surgery for multinodular goiter can be as high as 50% to 78%. 48 - 50 Total thyroidectomy, when it is performed by a skilled surgeon, is preferable because it eliminates the risk of recurrence without an accompanying increased risk of permanent hypoparathyroidism or recurrent nerve injury. 51 The thyroid gland in patients with toxic multinodular goiter is much less vascular than in patients with Graves' disease. In contrast to the treatment given to patients with Graves' disease, a saturated solution of potassium iodide is not given preoperatively because it may worsen the hyperthyroidism.

Figure 9-9 Surgical treatment of a large toxic multinodular goiter with retrosternal extension involved careful dissection and delivery of the retrosternal component into the wound. The capsule of the thyroid lobe and the engorged vessels are kept intact to avoid capsular bleeding.
Although it is difficult to compare surgical and 131 I therapy, a model has been developed to measure outcomes in quality-adjusted life years and compare lifetime cost for each modality. In patients less than 62 years of age, surgery, when performed by experienced surgeons with minimal morbidity, is more cost effective than 131 I therapy. 52 Surgery also has the added advantage of removing the thyroid nodules to confirm underlying histology and to cure concomitant thyroid carcinoma. Incidental or concomitant well-differentiated thyroid carcinoma occurs in 2% to 6% of patients with multinodular goiter. 19, 53 - 55 Older patients (>50 years) and cold nodules were significant risk factors for malignancy. 55

Solitary Toxic Nodule

Pathogenesis
A solitary toxic nodule is an autonomously hyperfunctioning nodule present in an otherwise normal thyroid gland that causes hyperthyroidism. A hyperfunctioning nodule accounts for 5% to 15% of all thyroid nodules, and it is defined as a nodule that takes up greater radioiodine than the surrounding thyroid tissue. Only 25% of hyperfunctioning nodules cause hyperthyroidism and are true toxic nodules. Approximately 20% of patients with a hyperfunctioning nodule ≥3 cm will develop thyrotoxicosis compared to 2% to 5% of patients with nodules <3 cm in diameter. 56
The majority of solitary toxic nodules are functioning follicular adenomas and less commonly adenomatous nodules. These follicular adenomas represent monoclonal expansion of thyroid follicular cells with a high prevalence of activating mutations in the gene for the TSH receptor. 33, 34 Development of a toxic nodule is similar to a toxic multinodular goiter. In its early phase of development, a solitary nontoxic hyperfunctioning nodule is under the regulatory control of TSH and thus can be treated with thyroid hormone suppressive therapy. Over time, the nodule gradually increases in size and function, progressing to a solitary autonomous hyperfunctioning nodule that is independent of TSH control and nonsuppressible by thyroid hormone. As a result, the nodule continues to secrete thyroid hormone despite a low serum TSH level and can suppress the radioiodine uptake of the remainder of the thyroid gland. A thyroid scan will show a single hyperfunctioning nodule with reduced or absent uptake in the remaining thyroid tissue.
Hyperthyroidism usually does not occur until a hyperfunctioning nodule is ≥3.0 cm in diameter. In 20% of patients with nontoxic autonomous nodules larger than 3 cm, thyrotoxicosis develops within 6 years of observation. 56 In addition, the development of thyrotoxicosis in patients with an autonomous nodule seems to be age related. Thyrotoxicosis develops in 57% of patients over 60 years of age but in only 13% of those younger than 60 years. 56 In one study, 15% of autonomous nodules of all sizes became toxic after a 5-year follow-up. In contrast to other studies, age, gender, nodule size, and initial scintigraphic appearance were not predictive of thyrotoxicity. 57
Thyroid hormone secretion may acutely increase, and patients may become thyrotoxic after receiving an iodine load. This is confirmed by the development of symptoms of hyperthyroidism and increased urinary iodine levels. 57 Spontaneous remission of thyrotoxicosis can occur from hemorrhage in the nodule or cystic degeneration resulting in the loss of autonomy and a decrease in the size of the nodule. 58

Clinical Presentation and Evaluation
A solitary toxic nodule can occur at any age but, in contrast to toxic multinodular goiter, usually affects younger patients ranging from 30 to 50 years of age. The signs and symptoms of hyperthyroidism (see Boxes 9-1 and 9-2 ) are milder than in patients with Graves' disease. Most patients present with a discrete nodule that is palpable on physical examination. Hyperfunctioning nodules grow to a relatively large size before the onset of hyperthyroidism; as a result, patients usually come to medical attention because of a neck mass rather than symptoms of thyrotoxicity. Serum TSH levels are low and serum FT 4 and FT 3 are normal or high depending on the stage of development of the toxic nodule. Occasionally the serum FT 3 level is elevated with a normal FT 4 level (T 3 thyrotoxicosis). Radioactive iodine uptake is overall normal to high and is concentrated in the nodule, with some degree of surrounding gland suppression.
Although fine-needle aspiration biopsy is routinely performed for a solitary nontoxic thyroid nodule, the presence of a low serum TSH level should change the diagnostic algorithm, with radionuclide imaging as the initial diagnostic test ( Figure 9-10 ). 33, 38 - 41 , 59 In patients with a thyroid nodule and a low serum TSH level, thyroid scintigraphy is important to distinguish a hyperfunctioning nodule from a hypofunctioning nodule in a patient with Graves' disease. A solitary toxic nodule may appear “warm” or “hot” on an iodine-123 or technetium 99m-pertechnetate thyroid scintigraphy with a variable degree of suppression of the surrounding thyroid tissue depending on the stage of development ( Figure 9-11 ). Fine-needle aspiration biopsy of a toxic nodule is unnecessary, but when it is performed it is often indeterminate, showing characteristics of a follicular neoplasm with varying degrees of nuclear atypia and hypercellularity. In an autonomous functioning nodule that is not toxic, the risk of malignancy varies between 2% to 6%, 33, 60, 61 and in toxic nodules, the risk is less than 1%.

Figure 9-10 Algorithm for the clinical evaluation of a thyroid nodule.
(From McHenry CR, Slusarczyk SJ, Ascari AT, et al: Refined use of scintigraphy in the evaluation of nodular thyroid disease. Surgery 124:656-662,1998. Reproduced with permission.)

Figure 9-11 Technetium scintigraphy demonstrating a solitary toxic nodule of the right thyroid lobe with suppression of the remaining thyroid gland (A) . Hemithyroidectomy was performed for cure, and the gross (B) as well as bisected specimen of the toxic nodule (C) are seen.

Treatment of Solitary Toxic Nodule

Surgery
Patients with a hyperfunctioning nodule who are asymptomatic and not thyrotoxic can be observed with no therapy. They are followed with history, physical exam, and serum TSH monitoring. The principal therapeutic alternatives for a solitary toxic nodule are radioiodine and thyroid lobectomy. Thionamide drug therapy is not curative and, as a result, is not considered as a primary therapeutic alternative. Treatment with a thionamide drug does not cause nodule regression, and hyperthyroidism recurs when the therapy is discontinued. Because an autonomous nodule usually continues to grow and secrete thyroid hormone, it is generally recommended that a patient undergo definitive therapy.
Surgical therapy for a solitary toxic nodule consists of a unilateral thyroid lobectomy. The advantages of surgery are removal of the nodule, immediate resolution of symptoms of hyperthyroidism and compressive symptoms, avoidance of radiation exposure to the normal thyroid tissue, and confirmation of tissue diagnosis in rare cases of suspected carcinoma. Persistent or recurrent hyperthyroidism is uncommon. 62, 63 The incidence of hypothyroidism is low with a reported rate of 14% compared to 22% for radioiodine therapy. 63, 64 The potential morbidity associated with unilateral thyroid lobectomy is bleeding and recurrent laryngeal nerve injury.
The preoperative preparation of the patient with a toxic solitary nodule is the same as for the patient with a toxic multinodular goiter. To reduce the risk of thyroid storm, patients are treated with a thionamide agent to normalize the FT 4 and FT 3 levels prior to operation. Beta-blockers for 1 to 2 weeks can be employed as an alternative for preoperative preparation in patients who are unable to take a thionamide agent. Iodine therapy preoperatively is not indicated.

Radioiodine
131 I administration is also effective therapy for a solitary toxic nodule. Radioiodine treatment usually requires higher doses of 131 I (25-40 mCi) than are used for the treatment of Graves' disease. Although Ross reported a cure rate of 90% with a mean dose of 10 mCi of 131 I, 65 Eyre-Brook and Talbot found a relapse rate of 73% in patients treated with doses of 1.2 to 15 mCi. 59 McCormack and Sheline found a relapse rate of 47% with doses of 6 to 14 mCi, but no relapses with doses of 28 to 56 mCi. 66 Using a median dose of 29 mCi, O'Brien found a 4.4% incidence of persistent hyperthyroidism and 0% incidence of recurrence. 60 Higher doses of 131 I are associated with a decreased incidence of persistent and recurrent hyperthyroidism but also an increased risk of hypothyroidism. Complete nodule regression occurs in 2.2% to 56.3% of cases, and higher doses of 131 I are associated with a greater likelihood of nodule regression. 63, 65 Persistent nodules require careful follow-up. 33 The disadvantages of radioiodine therapy are the persistence of the nodule, delay in symptomatic relief, and exposure of the normal thyroid tissue adjacent to the toxic nodule to radiation with the potential development of hypothyroidism in up to 36% of patients. 65, 66

Ethanol Injection
Percutaneous ethanol injection is another option for treating a solitary toxic nodule (see Chapter 16 , Laser and Radiofrequency Treatment of Thyroid Nodules and Parathyroid Adenoma). Using real-time ultrasound guidance, sterile 95% ethanol is injected into the nodule. Four to eight injections are frequently needed for satisfactory treatment, and the total amount of ethanol is usually about 50% more than the nodule volume. 67 The ultimate goal is to ablate the vascular supply of the nodule. A prospective nonrandomized multicenter Italian study evaluated 429 patients with a solitary toxic or pretoxic nodule treated with 2 to 12 ethanol injections. 68 Reported complications included neck pain (90%), fever (8%), transient dysphonia (4%), neck hematoma (4%), and internal jugular vein thrombosis (0.2%). At 1-year follow-up, 67% and 83% of patients with a toxic or “pretoxic” nodule were successfully treated. Percutaneous ethanol injection is generally considered as a third-line treatment for patients with solitary toxic nodule when patients decline or have contraindications to surgery or 131 I therapy. Ethanol injection can be used in combination with radioiodine therapy for patients with solitary toxic nodules > 4 cm when surgery is not an option. A more significant reduction in nodule size and persistent hyperthyroidism can be achieved than with 131 I alone. 69

References
For a complete list of references, go to expertconsult.com .

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