Differential Diagnosis of Hyperthyroidism [1 ed.] 9781616688028, 9781616682422

Citation preview

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

ENDOCRINOLOGY RESEARCH AND CLINICAL DEVELOPMENTS SERIES

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

DIFFERENTIAL DIAGNOSIS OF HYPERTHYROIDISM

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

ENDOCRINOLOGY RESEARCH AND CLINICAL DEVELOPMENTS SERIES Thyroid Hormones: Functions, Related Diseases and Uses Francis S. Kuehn and Mauris P. Lozada (Editors) 2009. ISBN: 978-1-60741-080-5 Estrogens: Production, Functions and Applications James R. Bartos (Editor) 2009. ISBN: 978-1-60741-086-7

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Estrogens: Production, Functions and Applications James R. Bartos (Editor) 2009. ISBN: 978-1-60876-220-0 (Online) Melatonin, Sleep and Insomnia Yolanda E. Soriento (Editor) 2009. ISBN: 978-1-60741-859-7 Thyroid Hormones: Functions, Related Diseases and Uses Francis S. Kuehn and Mauris P. Lozada (Editors) 2009. ISBN: 978-1-60876-647-5 (Online) Handbook of Oxytocin Research: Synthesis, Storage and Release, Actions and Drug Forms Hugo Jastrow and Daniela Feuerbach (Editors) 2009. ISBN: 978-1-60876-023-7

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Foot Ulcers: Causes, Diagnosis, and Treatments Petr E. Overhaussen (Editor) 2009. ISBN: 978-1-60741-799-6 Neuroendocrinology Research Developments Nejc S. Penkava and Logan R. Haight (Editors) 2010. ISBN: 978-1-60876-983-4

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Nervous, Immune, Endocrine Regulatory Systems and Diseases Associated with Nerve Growth Factor Co-Secretion Ildikó Molnár 2010. ISBN: 978-1-60876-780-9 Handbook of Hyperthyroidism: Etiology, Diagnosis and Treatment Lionel Mertens and Jeremy Bogaert (Editors) 2010. ISBN: 978-1-60876-441-9 The Pineal Gland and Melatonin: Recent Advances in Development, Imaging, Disease and Treatment Mehmet Turgut, Raj Kumar and Paul Steinbok (Editors) 2010. ISBN: 978-1-60876-717-5 Differential Diagnosis of Hyperthyroidism Mehtap Cakir 2010. ISBN: 978-1-61668-242-2

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

ENDOCRINOLOGY RESEARCH AND CLINICAL DEVELOPMENTS SERIES

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

DIFFERENTIAL DIAGNOSIS OF HYPERTHYROIDISM

MEHTAP CAKIR

Nova Science Publishers, Inc. New York

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‘ use of, or reliance upon, this material.

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA Cakir, Mehtap. Differential diagnosis of hyperthyroidism / Mehtap Cakir. p. ; cm. Includes bibliographical references and index. ISBN:  (eBook) 1. Hyperthyroidism--Diagnosis. 2. Diagnosis, Differential. I. Title. [DNLM: 1. Hyperthyroidism--diagnosis. 2. Diagnosis, Differential. WK 265 C139d 2009] RC656.3.C35 2009 616.4'43075--dc22 2009050563

Published by Nova Science Publishers, Inc.  New York

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

CONTENTS Preface

ix

Introduction

xi

Chapter 1

Graves‘ Disease

Chapter 2

Toxic Adenoma and Toxic Multinodular Goiter

17

Chapter 3

TSH-Secreting Pituitary Adenoma

27

Chapter 4

Syndromes of Reduced Sensitivity to Thyroid Hormones

33

Trophoblastic Tumors and Hyperemesis Gravidarum

37

Autosomal-Dominant Non-Autoimmune Hyperthyroidism

45

Chapter 7

Thyroid Carcinoma

47

Chapter 8

Struma Ovarii

49

Chapter 9

Iodine Excess and Hyperthyroidism

51

Chapter 5 Chapter 6

1

References

53

Index

89

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

PREFACE

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

I hope that this book will provide the readers straightforward and current information on hyperthyroidism. As differential diagnosis of the hyperthyroid patient is the topic of this book, I have focused particularly on the clinical presentation and laboratory studies of hyperthyroid states. I would like to acknowledge the mentors who shared their clinical observations and valuable experience with me. Special thanks to my family for their perpetual encouragement and unyielding support. Mehtap Cakir, MD

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

INTRODUCTION Thyrotoxicosis is the term given to any condition that causes exposure of the tissues to high serum concentrations of free thyroxine [T4], free triiodothyronine [T3], or both that results with hypermetabolism and hyperactivity. Hyperthyroidism is the term given to the subgroup of diseases in which the reason of thyrotoxicosis is increased thyroid hormone synthesis and secretion by the thyroid gland. Once a patient presents with symptoms of hyperthyroidism (Table 1) [1] and high thyroid hormone levels have been detected, the physician faces with a list of possible causes of hyperthyroidism which should be included in the differential diagnosis (Table 2). As some of these causes like Graves‘ disease, toxic adenoma [TA] and toxic multinodular goiter [TMNG] are more common, they should be regarded in the first place. Uncommon causes are, TSH-secreting tumors, thyroid hormone resistance syndromes, trophoblastic tumors, hyperemesis gravidarum, autosomal-dominant non-autoimmune hyperthyroidism, thyroid carcinoma, struma ovarii and drug-induced [iodine and iodine-containing drugs and radiographic contrast agents] hyperthyroidism. Once elevated thyroid hormone levels have been detected, differential diagnosis is made with patient and family histories, physical examination and laboratory and imaging studies. On patient‘s history, iodine exposure [e.g. from radiocontrast agents], pregnancy, previously detected thyroid disorders, drug use like lithium and amiodaron should be asked for and on family history existence of thyroid diseases is important. On physical examination, besides the classical features of hyperthyroidism [tachycardia, tremor, sweating, elevated systolic blood pressure], thyroid should be palpated [to evaluate the consistency of the gland, presence of tenderness, diffuse or nodular goiter] and signs related to specific types of hyperthyroidism like Graves‘ ophthalmopathy, dermopathy and thyroid acropachy should be looked for. In

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Mehtap Cakır

xii

laboratory evaluation presence of serum thyroid autoantibodies [antithyroglobulin, anti-thyroid peroxidase and TSH receptor antibodies], TSH and if neccesary HCG levels should be measured. Imaging studies include thyroid scintiscan and thyroid ultrasonography. Scintiscan can be made with technetium pertechnetate [99mTcO4] or 123I to evaluate tracer uptake levels, obtain intensity and distribution pattern of tracer activity and establish activity of nodules if there are any. With thyroid ultrasonography the echogenicity of the gland parenchyma and grade of vascularization will be evaluated and the type of goiter [diffuse or nodular] will be determined. Table 1- Symptom and signs of hyperthyroidism (1).

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

SYMPTOMS Nervousness, emotional lability Fatigue Weakness Increased perspiration Heat intolerance Tremor (at rest and with movement) Palpitation Exercise intolerance Dyspnea on exertion Appetite change (usually increase) Weight change (usually weight loss) Hyperdefecation (increased frequency of semi-formed stools) Menstrual disturbances SIGNS Anxiety, irritability Smooth, moist, warm skin Fine hair Alopecia Shiny, soft, friable nails (onycholysis) Hyperhydrosis Stare and eyelid retraction Sinus tachycardia or atrial arrhythmia Systolic hypertension

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Introduction

xiii

Widened pulse pressure Tremor Pitting edema Hyperreflexia Muscle weakness Table 2- Causes of hyperthyroidism. Graves‘ disease Toxic adenoma Toxic multinodular goiter TSH-secreting adenoma Trophoblastic tumors (hydatiform mole, choriocarcinoma, hyperplacentosis) Hyperemesis gravidarum

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Syndromes of reduced sensitivity to thyroid hormone Autosomal-dominant non-autoimmune hyperthyroidism Thyroid carcinoma Struma ovarii Iodine induced hyperthyroidism As a conclusion, differential diagnosis of hyperthyroidism demands careful evaluation of the patient combined with proper interpretation of laboratory and imaging studies.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Chapter 1

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

GRAVES’ DISEASE Graves‘ disease is caused by an activating autoantibody that targets the TSH receptor [2]. Graves‘ disease is more common in women, with a female-to-male incidence ratio of approximately 5:1 to 10:1 [3]. The peak age-specific incidence of Graves‘ disease was previously reported between 20 and 49 years in two studies [4,5], but increased incidence with age in Iceland [6] and peak incidence between 60 to 69 years in Malmö, Sweden have also been noted [7]. Graves‘ disease is the most common cause of thyrotoxicosis in iodine-sufficient populations. In patient history, existence of other autoimmune endocrine diseases is important, as in recent years it has become apparent that genetic susceptibility is shared between several autoimmune diseases [8]. There are two major types of autoimmune polyglandular syndromes [APS], type 1 and type 2 [9]. APS type 2, which is the coexistence of adrenal failure with either autoimmune thyroid disease and/or type 1 diabetes mellitus is called Schmidt‘s or Carpenter‘s syndrome. Up to 50% of type 1 diabetes mellitus patients have been reported to be positive for thyroid antibodies [10], and approximately 50% of them progress to develop clinical autoimmune thyroid disease [11]. However there is a long time interval between the manifestations of the first and second components of APS type 2 to appear which may comprise years to decades. In one series, most frequent disease combinations were type 1 diabetes mellitus/autoimmune thyroid disease [41%], followed by autoimmune thyroid disease/Addison‘s disease [14.6%], autoimmune thyroid disease/vitiligo [9.9%] and type 1 diabetes mellitus/autoimmune thyroid disease/pernicious anemia [5.3%] [12]. When type 1 diabetes mellitus and autoimmune thyroid disease occur in the same individual and adrenal cortex is spared, the phenotype is classified as autoimmune polyglandular syndrome type 3

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

2

Mehtap Cakır

[APS3 variant] [13]. An increased incidence of Graves‘ disease and a younger age at onset can be expected, when there is a family history of thyroid disease, especially in maternal relatives [14]. The concordance rate is reported to be 35% in monozygotic twins and a statistical model based on these data suggested that 79% of the predisposition to Graves‘ disease is due to genetic factors, with only 21% due to nongenetic [environmental and hormonal] factors, confirming the dominant role of heredity in the pathogenesis of the disease [15]. On physical examination, thyroid may be nonpalpable or diffusely enlarged, but it is usually soft and symmetrical (Figure 1). Notwithstanding the patient may also have thyroid nodule[s], thus accompanying nodular goiter [2]. In some cases the gland is firmer and have an irregular surface [16]. Due to increased vascularity a bruit may also be heard on auscultation over the gland. The physical examination findings of Graves‘ disease are not limited to the thyroid gland. Graves‘ ophthalmopathy is a well-known and bothersome complication of the disease and is noted roughly in 30 to 50% of patients with Graves‘ disease but it is detected in more than 80% of patients who undergo assessment by orbital imaging [3,16]. The pathophysiology of Graves‘ ophthalmopathy is not clearly known. However, it is thought that orbital fibroblasts are activated possibly by Graves‘ disease–related thyroid autoantibodies. These fibroblasts release T cell chemoattractants, initiating an interaction in which these cells activate each other [17]. These interactions ultimately result in fibroblasts expressing extracellular matrix molecules, proliferating and differentiating into myofibroblasts or lipofibroblasts [17]. Graves‘ ophthalmopathy is usually bilateral but may be asymmetric and has a diverse presentation. The onset can be rapid or insidious to develop gradually over weeks to months and its course is independent of the thyroid disease. The initial symptoms of the patient relate most commonly to discomfort of the surfaces of the eyes and may include redness, tearing, grittiness, diplopia, ocular pain and abnormal sensitivity to light [18]. Although itching is absent, misdiagnosis as allergy is common in Graves‘ ophthalmopathy [19]. In 3 to 5% of cases ophthalmopathy may be sight-threatening due to optic neuropathy or corneal breakdown [20]. On physical examination, swelling of periorbital tissues, exophthalmos and limitation of eye movements may be noted. Proptosis may ensue as a result of a mass effect due to increased glycosaminoglycan production by stimulated fibroblasts. Some patients may describe slight diplopia as ―blurring‖; however, the blurring clears with monocular occlusion [21]. Extraocular muscle involvement relates to the failure of relaxation, thus interferes with the function of ipsilateral antagonist muscles [19].

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Graves‘ Disease

3

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Figure 1. Asymmetrical enlargement of the thyroid gland due to Graves‘ disease.

Most commonly affected muscles are inferior and medial rectus muscles, thus upward gaze and abduction are commonly restricted [19]. The type of diplopia may change between patients. Intermittent diplopia is an important symptom which may be ignored by the physicians because of its changing nature. It may be apparent on waking and then resolve or become apparent only when tired [19]. Inconstant diplopia is always present in certain directions of gaze. On the other hand, diplopia may also be constant in certain head postures or may be regardless of head posture. It should be kept in mind that, if the patient has symmetric involvement of both eyes, diplopia may be absent although the patient has Graves‘ ophthalmopathy. Optic neuropathy is uncommon, but in these patients blurred vision which is not affected by blinking or closing one eye can occur. In optic neuropathy color appreciation is reduced, and an awareness of gray areas of field loss may occur [21]. Older men with diabetes and vascular disease have the highest risk for optic neuropathy [21]. Another important point to emphasize in Graves‘ ophthalmopathy is, less than 10% of patients with Graves‘ ophthalmopathy are euthyroid or hypothyroid [22,23]. Most of these patients have onset of thyrotoxicosis within 18 months [19,24], but hyperthyroidism may also develop years later. Most patients with euthyroid Graves‘ ophthalmopathy have

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

4

Mehtap Cakır

evidence of autoimmune thyroid disease, such as presence of thyroid autoantibodies [see below]. There are also cases reported who do not have positive antibodies but this may well be due to the sensitivity of the detection method and assay used [23]. The severity of Graves‘ ophthalmopathy follows a phasic pattern: the first phase follows a progressive deterioration lasting for several months. After a short period of peak severity, a phase of spontaneous improvement comes which lasts up to a year or longer. In the end, ophthalmopathy reaches a quiescent phase when inflammatory signs disappear and clinical features stabilize, although they do not usually resolve completely [25]. Graves‘ ophthalmopathy rarely becomes active again once it has become quiescent, but the activity and course may vary in individual eyes. An important point that is related with ophthalmopathy is disease activity, which relates to the presence of an acute inflammatory process within the orbit. Inasmuch as the severity of Graves‘ ophthalmopathy and activity does not go in parallel, a treatment planning should not be postponed once the diagnosis have been made. There are several scoring systems that has been proposed for evaluating clinical activity in Graves‘ ophthalmopathy like Clinical Activity Score [26] and NOSPECS [19]. European Group on Graves‘ ophthalmopathy [EUGOGO] has recently published a consensus report and has made suggestions for detailed clinical evaluation and treatment of these patients [27]. Patients with Graves‘ ophthalmopathy should be evaluated and treated by a team including an endocrinologist and ophthalmologist with expertise in this disorder. Pretibial myxedema is another finding that can be identified on physical examination in Graves‘ patients [28](Figure 2). Localized dermal myxedema can occur in 0.5% to 4.3% of patients with Graves‘ disease [2]. Up to 13% of patients with severe Graves‘ ophthalmopathy may develop myxedema [29]. Myxedema development almost always occurs with preexisting Graves‘ ophthalmopathy. There are very rare cases in the literature having euthyroid myxedema [30,31]. Myxedema generally occurs in the anterior leg so it has been called ―pretibial myxedema‖. It also tends to occur in areas under trauma or dependent areas. The lesions are asymmetric, raised, firm, pink-to-purple plaques of non-pitting edema. In myxedema the involved dermis contains an increased content of hyaluronic acid and chondroitin sulfates. Myxedema may present with several types. The most common form, diffuse nonpitting edema occurs in up to 43 % of Graves‘ dermopathy cases, which is thought to occur secondary to lymphatic compression and obstruction by dermal deposition of glycosaminoglycans [2]. Second type is seen as raised plaques occuring on a background of nonpitting edema and occurs in up to 27% of Graves‘ dermopathy.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Graves‘ Disease

5

Figure 2. Pretibial myxedema in a patient with Graves‘ disease. This patient also had Graves‘ ophthalmopathy and acropachy.

Nodular myxedema is a third type which presents with sharply circumscribed tubular or nodular lesions and is seen in 18% of patients with myxedema. Least common form is elephantiasic form occuring in 5% of myxedema patients. Another presenting feature of Graves‘ disease may be thyroid acropachy. Thyroid acropachy consists of digital clubbing, soft tissue swelling and periostal bone formation which may cause changes in fingers, toes and lower extremities [32]. Thyroid acropachy occurs in 0.1% to 1% of patients with Graves‘ disease and almost always occurs in patients with ophthalmopathy and myxedema [2]. The most common manifestation of acropachy is clubbing of the distal fingers and toes [2]. Very rare cases having acropachy of long bones such as cortical areas of femur and tibia have been reported [32,33,34,35].

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

6

Mehtap Cakır

There are also a number of clinical manifestations which are uniquely associated with Graves‘ disease and not with other types of hyperthyroidism, implying they are in some way related to immune activation rather than to elevated thyroid hormone levels. These are chronic idipathic urticaria, splenomegaly, lymphadenopathy and thymic enlargement [16,36]. It has been postulated that there is a relationship between Graves‘ disease and pulmonary hypertension [37,38]. This is further supported by the high prevalence of autoimmune thyroid disorders in patients with primary pulmonary hypertension [39]. However, pulmonary hypertension in hyperthyroidism does not occur only in subjects with Graves‘ disease but is also observed in patients with toxic multinodular goiter [40,41,42,43]. Additionally, pulmonary hypertension related to hyperthyroidism resolves after successful antithyroid treatment regardless of the underlying etiology of hyperthyroidism. Hence, findings do not suggest that the underlying autoimmune process contributes to the pathogenesis of pulmonary hypertension related to hyperthyroidism [43]. Takotsubo cardiomyopathy is a type of non-ischemic cardiomyopathy in which there is a sudden temporary weakening of the myocardium and reversible apical ballooning [44]. In English literature so far there are seven reported cases of Takotsubo cardiomyopathy with thyrotoxicosis. When evaluated in detail, five of these cases had Graves‘ disease [45,46,47,48,49] and one case had Hashimoto thyroiditis [50]. There is also a single case report in which Takotsubo cardiomyopathy was attributed to iatrogenic hyperthyroidism however, this case was also positive for TSH receptor antibodies which strongly raises the possibility that there was an underlying Graves‘ disease [44]. Thus with current data it seems that, Takotsubo cardiomyopathy is a complication unique to autoimmune thyroid disease-related hyperthyroidism however more cases need to be evaluated to be sure that it is not a complication of thyrotoxicosis per se. Regarding rheumatologic complications, frozen shoulder with thyrotoxicosis was reported by a few authors [51,52]. Also in English literature to date, there are two reported cases of carpal tunnel syndrome and Graves‘ disease [53,54]. In our study, we have investigated musculoskeletal complications of thyroid disease and no significantly increased prevalance of musculoskeletal complications [Dupuytren‘s contracture, adhesive capsulitis, trigger finger, limited joint mobility, carpal tunnel syndrome, fibromyalgia syndrome] were noted in the hyperthyroid group compared to hypothyroid or euthyroid groups [55]. However, trigger finger was found more frequently among patients who had positive thyroid autoantibodies compared to the patients who were negative for thyroid autoantibodies [55]. It is important to note at this point that, autoimmune thyroid disease and autoimmune rheumatic disease occur mainly in the same demographic

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Graves‘ Disease

7

population-namely adult women [56]. Thus autoimmune thyroid disease is found together with autoimmune rheumatic disease like SLE, Sjögren‘s syndrome, rheumatoid arthritis and scleroderma in many subjects [56]. However convincing data that the degree of thyroid disease is above than expected by chance alone is scant [56]. Neuromuscular complications of thyrotoxicosis have been reported as myopathy, mononeuropathy, myasthenia gravis, thyrotoxic periodic paralysis, movement disorders [including choreoathetosis, ataxia and myoclonus], corticospinal tract disease, encephalopathy and seizures [57]. Some of these complications need special emphasis regarding their known or possible association with Graves‘ disease. Myasthenia gravis occurs in 0.1% of patients with Graves‘ disease, which is a 30-fold increase over the prevalence in the general population [57]. The prevalence of Graves‘ disease in patients with myasthenia gravis ranges from 3% to 10% [58,59]. The overall prevalence of autoimmune thyroid disease in patients with ocular involvement was 62% compared with only 29% in those with generalized myasthenia [60,61]. It may be difficult to differentiate the ophthalmoplegia of myasthenia gravis and that of Graves‘ ophthalmopathy [62]. In a small study of patients with Graves‘ ophthalmopathy, 8% had acetylcholine receptor antibodies, but none had any signs or symptoms of myasthenia gravis after 4 ½ years of follow-up [63]. Some patients have both and the common ocular symptom is diplopia. Nonetheless, the extraocular muscles are weak in patients with myasthenia gravis and become weaker with repetitive activity. In addition, there is a positive response to edrophonium and amelioration of symptoms with anticholinesterase drugs [62]. Thyrotoxic periodic paralysis is a sporadic disorder characterized by episodic attacks of muscle weakness concomitant with hypokalemia and thyrotoxicosis. Most cases of hyperthyroidism associated with thyrotoxic periodic paralysis are due to Graves‘ disease [62]. Thyrotoxic periodic paralysis may be the presenting feature of Graves‘ disease, or occur during relapse or following radioactive iodine therapy. However there are several cases in the literature reported to develop the condition and who did not have autoimmune thyroid disease [64-67]. Corticospinal tract disease is quite rare in Graves‘ disease. There are five case reports in English literature regarding focal neurological deficits and bilateral or unilateral pyramidal signs in Graves‘ disease so far [68-72]. There are also some case reports about patients who developed pyramidal tract signs concurrent with thyrotoxicosis in which the etiology of thyrotoxicosis was not mentioned [73-77]. Regarding movement disorders; chorea and choreoathetosis [78-98], choreaballism [99], paroxysmal kinesigenic dyskinesia [100-102], myoclonus [103,104],

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

8

Mehtap Cakır

idiopathic torsion dystonia [105], ataxia [106-108] have been reported in thyrotoxicosis. Either diagnosis of Graves‘ disease or thyroid autoantibody positivity was mentioned in some of these reported cases [79,80, 82, 85, 90, 99, 100, 104, 105, 106, 108], while thyroid autoantibodies were reported to be negative in some [78, 93, 103]. Encephalopathy is another reported neurological complication of thyrotoxicosis [109-120]. Among these there are reported cases about concomitant Graves‘ disease and encephalopathy [109-113]. However it should be emphasized here that, encephalopathy can occur not only in Graves‘ disease but also in euthyroid or hypothyroid Hashimoto‘s thyroiditis thus, in patients with any type of autoimmune thyroid disease [121]. Hence the term Hashimoto encephalopathy may be a misnomer and according to author‘s view should not be used [121]. The term ―autoimmune thyroid disease-associated encephalopathy‖ may be a broader term covering all these cases. Seizures in thyrotoxicosis have been reported in less than ten cases in English literature up to date [122-129]. Some of these cases were diagnosed as Graves‘ disease [122-124]. Basedow‘s paraplegia is another extremely rare manifestation of thyrotoxicosis. This is an acute neuropathy associated with paraplegia or quadriplegia [57]. It bears a close resemblance to the Guillain-Barre syndrome, in terms of its clinical presentation with profound lower extremity weakness and areflexia. Electrophysiologic studies in these patients reveal a mixed axonal and demyelinating sensorimotor neuropathy, and electromyographic findings are consistent with denervation [130,131]. In these patients symptoms and signs usually resolve with the correction of thyrotoxicosis. In English literature search, the term Basedow‘s paraplegia reveals four cases [130-133]. Although its name is Basedow‘s paraplegia, this manifestation may not be not unique to Graves‘ disease and actually in these case reports, in one case thyroid autoantibodies were not checked and differential diagnosis of thyrotoxicosis was not made [130], one case had TMNG [131] and one case had Graves‘ disease [132]. As a note for the neuromuscular and rhematologic complications of Graves‘ disease the author would like to emphasize that, it seems that some of these may just be related to autoimmunity, hence not to thyrotoxicosis per se. However, it is quite difficult to make this distinction due to following two main reasons. First the problem is, in the literature not in all case reports the differential diagnosis of thyrotoxicosis have been made properly. Second, in the past there were not sensitive assays used to detect thyroid autoantibody positivity and eventually it is not possible to say if these cases also had an autoimmune basis.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Graves‘ Disease

9

In the laboratory studies, the patient may have subclinical hyperthyroidism with normal free T4 and free T3 levels and suppressed TSH levels or overt hyperthyroidism with high free T4 and/or T3 levels and suppressed TSH levels. Some patients with Graves‘ disease may present with predominantly elevated free T3 and suppressed TSH levels which is called isolated T3 toxicosis [134]. In these cases the serum T3:T4 [ng/dL:µg/dL] ratio is higher than 20 [135]. In complete blood count, patients with Graves‘ disease generally have normal granulocyte counts, but some may have granulocytopenia [136-138]. The exact cause is unknown, but existence of antineutrophil antibodies have been reported in Graves‘ disease [139]. Occasionally patients with Graves‘ disease, may have clinically important thrombocytopenia [platelet count < 100,000/mm3] [140], and many [42% in one study [141]] have platelet counts of less than 150,000/mm3 [142]. The reasons in these cases are thought to be both antiplatelet antibodies and thyrotoxicosis itself [136]. In a study evaluating eosinophil and monocyte counts between Graves‘ disease and destruction-induced thyroiditis eosinophil counts were found significantly higher and monocyte counts were found significantly lower in patients with Graves‘ disease compared to destruction-induced thyrotoxicosis [143]. In a recent study anemia due to Graves‘ disease was noted in 22% of cases which resembled the anemia of chronic disease, and was associated with markers of inflammation [144]. There are also cases with Graves‘ disease who present with pancytopenia [145,146]. Factor VIII deficiency due to an acquired circulating antibody that inhibited factor VIII coagulant activity was reported in two patients with Graves‘ thyrotoxicosis who presented with spontaneous bleeding [147,148]. Anticardiolipin antibodies which decreases after antithyroidal drug therapy have been found in the serum of patients with Graves‘ disease, especially those with coexisting ophthalmopathy [149,150]. However, as primary antiphospholipid syndrome and thromboembolic events are rare in Graves‘ disease, the existence of these antibodies may be just a marker for immune system activation. In general although limited the published studies suggest that patients with hyperthyroidism have an increased thrombotic risk [151]. In biochemical evaluation, patients may have elevated liver enzymes [AST, ALT, alkaline phosphatase-ALP, GGT] and bilirubin levels. However this may also be seen in other types of thyrotoxicosis and it is not related to Graves‘ disease itself [152-155]. On the other hand, not all abnormal liver function tests should be attributed to thyrotoxicosis as there are rare cases in the literature, reporting concomitant autoimmune hepatitis with Graves‘ disease [156,157]. Additionally, although rare persistently elevated ALP should alert the physician for Graves‘ acropachy [33]. In these cases bone spesific ALP measurement may be helpful for

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

10

Mehtap Cakır

differential diagnosis between liver and bone associated ALP elevations [33]. Regarding accompanying renal disease, there are rare case reports in the literature about coexisting Graves‘ disease and minimal change glomerulopathy [158-160] and a case of concomitant membranous nephropathy [161]. In two of these cases, simultaneous relapse of Graves‘ disease and minimal change glomerulopathy were noted which raises the possibility of an autoimmune basis for this coexistence but not elevated thyroid hormones [159,160]. TSH receptor antibodies [TRAb] can be detected in virtually all untreated Graves‘ disease patients using third generation immunometric receptor assays [162]. There are three types of TRAb in Graves‘ disease [163]. Thyroid stimulating antibodies [TSAb] bind to the TSH receptor and can exactly behave like TSH in stimulating adenylyl cyclase activity, iodide uptake, TPO and Tg synthesis, and T4 and T3 release by thyrocytes, growth of thyroid gland and can cause increased gland vascularity [164]. Patients with Graves‘ disease may also have thyroid blocking antibodies [TBAb]. These antibodies contrary to TSAb may block thyroid hormone synthesis. Neutral TRAb do not have any effect on TSH binding and intracellular cAMP levels. Changes in TRAb activity and functionality occur and can impact on thyroid status directly. As would be expected depending on the ratio between these stimulating and blocking antibodies the patient may present with a hyperthyroid or hypothyroid status at different times [described as having a thyroid yo-yo] [165,166]. Furthermore, the nature of most TRAb activity is complex. A weak agonist can act as an antagonist and thus both TSAb and TBAb activity may reside in the same immunoglobulin molecule [167]. It is noteworthy to take assay type into consideration when TRAb positivity is being measured. In a recent study by Massart and colleagues comparing 4 different TRAb assays [3 porcine thyroid receptor antibody [TRAb] methods [1 second- and 2 new third-generation systems] with the conventional TRAb assay based on the human recombinant TSH receptor [hTRAK]] high intermethod variability was noted in TRAb assay results [168]. With regard to thyroid autoantibodies other than TRAb, it is known that among normal adults about 10% have high serum anti-thyroglobulin [anti-Tg] antibody concentrations, and among women age 60 years and older 15% may have high anti-Tg concentrations [169-171]. Anti-Tg concentrations are high in 50% to 60% of patients with hyperthyroidism caused by Graves‘ disease [172,173]. About 10% of normal adults have high serum anti-thyroperoxidase [anti-TPO] antibody concentrations, and the prevalence increases to up to 30% in the elderly [171,174,175]. About 75% of patients with Graves‘ disease have high serum anti-TPO concentrations [174]. Serum thyroglobulin [Tg] levels will be elevated in Graves‘ disease.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Graves‘ Disease

11

In imaging studies of the thyroid gland, a baseline thyroid ultrasonography can be performed. In patients with Graves‘ disease, the thyroid is usually enlarged and the echo pattern is homogeneous [176]. Echogenicity is normal to markedly decreased. In color-Doppler ultrasonography rich vascularity and increased flow may be noted, which correlates with the degree of thyroid hyperfunction [177]. In terms of radionuclide imaging, if ophthalmopathy and thyrotoxicosis are present and the patient does not have nodule[s] the diagnosis of Graves‘ disease is straightforward and thyroid scan is not essential. However, in cases without extrathyroidal manifestations of Graves‘ disease or in subjects with coexisting nodular goiter to make a differential diagnosis between Graves‘ disease, destruction-induced thyrotoxicosis and toxic nodular goiter, a thyroid scan preferably with technetium pertechnetate [99mTcO4] should be performed. In Graves‘ disease there is diffuse uptake and compared with a normal thyroid, the thyroid lobes are larger in all dimensions, the early and late uptakes are higher and there is less background activity (Figure 3,4,5,6,7). If the patient has a recent history of high iodine intake or iodine-containing contrast media exposure or if he/she is under antithyroidal drug treatment, decreased uptake on thyroid scan may be noted. In occasional patients, the patient may also have accompanying active nodule[s] in the thyroid gland. In these cases hyperthyroidism is due to both Graves‘ disease and toxic nodular goiter and the diagnosis is called MarineLenhart syndrome [178,179]. In patients with Graves‘ disease and hypoactive thyroid nodule[s] the usual procedure should be followed and a fine needle aspiration biopsy of the nodule should be performed. In patients who have Graves‘ ophthalmopathy, if the diagnosis is uncertain, orbital CT or MRI can be used to eliminate the other causes of exophthalmos especially orbital tumors. MRI is superior to CT in identifying active ophthalmic disease and detection of optic neuropathy [19]. Somatostatin receptor scintigraphy may be used to identify active disease, but it is not routinely used [19,180]. In thyroid acropachy on radiography of the affected bones, soft tissue swelling and periostal reaction may be noted. Technetium-99m hydroxymethylene diphosphonate [HDP] or technetium-99m pyrophosphate bone scans may be used to confirm the preliminary diagnosis which will show increased uptake in the cortical areas of the affected bones [32,33]. Hyperthyroidism due to Graves‘ disease may develop in 5% of patients taking radioiodine treatment for euthyroid nodular goiter [181]. The risk is reported to increase to 22% in those who are anti-TPO positive prior to treatment [182]. The incidence of Graves‘ disease following radioiodine treatment for toxic nodular goiter is reported to be 1 to 5% [183-185], with an increased risk of 10% for those who are anti-TPO positive [183,184].

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

12

Mehtap Cakır

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Figure 3.

Figure 4.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Graves‘ Disease

13

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Figure 3, 4, 5 Diffusely increased uptake of technetium pertechnetate (99mTcO4) on thyroid scan in Graves‘ disease.

Figure 6. Diffusely increased uptake of technetium pertechnetate (99mTcO4) on thyroid scan in Graves‘ disease. Note decreased uptake in the right lower lobe due to a coexisting hypoactive nodule.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

14

Mehtap Cakır

Figure 7. Diffusely increased uptake of technetium pertechnetate (99mTcO4) on thyroid scan in Graves‘ disease. Note the prominent pyramidal lobe.

Even Graves‘ ophthalmopathy has been reported to develop in 0.07 to 0.7% in subjects with toxic nodular goiter who have received radioiodine treatment [183,184]. Likewise although rare, development of Graves‘ ophthalmopathy after radioiodine treatment for euthyroid nodular goiter [181,186] and after radioiodine ablation in a total thyroidectomized non-metastatic thyroid cancer patient [187] have been reported. Regarding the natural course of the disease, cases with transient Graves‘ disease have been reported in the literature in patients with positive TRAb [188]. These patients had mild thyrotoxicosis and on follow-up they became TRAb negative and euthyroid in months time [188].

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Graves‘ Disease

15

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Hashitoxicosis is a term used to describe patients who present with hyperthyroidism, goiter, and an elevated radioiodine uptake, and in whom hypothyroidism spontaneously develops with pathologic findings consistent with Hashimoto‘s thyroiditis [189] . In contrast to subacute lymphocytic thyroiditis, the hyperthyroid phase of this illness is presumably mediated by thyroid-stimulating immunoglobulins rather than destruction-mediated release of hormone, and the hypothyroidism caused by Hashimoto‘s thyroiditis is usually permanent. The thyrotoxic phase in Hashitoxicosis is transient compared to the sustained nature of Graves‘ hyperthyroidism. There are also rare cases of Hashimoto‘s thyroiditis in which no radioiodine tracer uptake on thyroid scan is noted in the thyrotoxic phase which may suggest that a form of destructive thyrotoxicosis may also occur in these subjects (author‘s observation).

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Chapter 2

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

TOXIC ADENOMA AND TOXIC MULTINODULAR GOITER TA and TMNG are the leading causes of thyrotoxicosis in populations with iodine insufficiency [2,190]. Accordingly, in iodine-deficient areas, TMNG accounts for up to 50% and TA accounts for up to 10% of cases of thyrotoxicosis [191,192]. In contrast, thyroid autonomy comprises about 3% to 10% of cases of thyrotoxicosis in regions with sufficient iodine supply [191,193]. In the pathogenesis, around 60% percent of TA and TMNG are caused by constitutive TSH receptor activation and upregulation of cAMP receptor signalling mostly secondary to somatic mutations in the TSH receptor gene [194-198]. In TA, mutations in adenylate cyclase-stimulating G alpha protein [GNAS] gene as well as the TSH receptor gene have been reported [199,200]. In TA there is a solitary nodule that is autonomously functioning and producing excess thyroid hormone. TMNG generally arises in a multinodular thyroid gland that subsequently develops autonomously functioning nodules over time. The autonomous secretion of thyroid hormones leads to TSH suppression and nonautonomous thyroid tissue is quiescent. As with all thyroid diseases, TA and TMNG are more frequent in women [~4 to 10:1] [201,202]. TMNG tends to occur in individuals older than 50 years of age with a history of multinodular goiter while TA usually occurs in a younger age group than does TMNG, typically in patients in their 30s or 40s [203]. Unlike Graves‘ disease which has many unique extrathyroidal manifestations due to its autoimmune basis, in TA and TMNG the patient only has symptoms and signs of hyperthyroidism [Table 1] and signs of a nodular and [if present] enlarged thyroid gland. So the patient may present with a lump of the neck, and

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

18

Mehtap Cakır

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

dysphagia or breathing difficulties due to esophageal or tracheal compression may be apparent, especially with large TMNG. On physical examination, the presence of the nodule[s] and their size, texture, tenderness and consistency should be noted (Figure 8,9). In laboratory studies, the patient may present with subclinical hyperthyroidism or overt hyperthyroidism as in Graves‘ disease. On the other hand, solitary TA is one of the most frequent causes of isolated T3 toxicosis [2]. There are some laboratory abnormalities which are related to high thyroid hormone levels and common to all types of thyrotoxicosis. On complete blood count and biochemical results these may also be noted in TMNG and TA (Table 3). Measurement of thyroid autoantibodies is not routinely performed in thyroid autonomy. However, in iodine-deficient areas, distinction between Graves‘ disease and TMNG can be difficult if extrathyroidal manifestations of the former are absent or diagnostic findings are not typical like additional presence of thyroid nodules in suspected Graves‘ disease patients or noting a patchy rather than diffuse uptake on thyroid scan [204,205].

Figure 8. Nodular goiter easily noticed on inspection.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Graves‘ Disease

19

Figure 9. Multinodular goiter noted on inspection.

Table 3. Changes in complete blood count and biochemical tests due to thyrotoxicosis Anemia (normocytic, microcytic, or macrocytic) Thrombocytopenia Hypercalcemia Hyperuricemia Elevated serum alkaline phosphatase Elevated serum aminotransferases In imaging studies, a routine chest radiograph is rarely indicated for evaluation of patients with thyroid disease. But if there is mediastinal extension of a goiter or deviation or compression of the trachea caused by a goiter in the neck

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

.

20

Mehtap Cakır

or mediastinum, it can be seen on a chest radiograph (Figure 10). If tracheal compression is suspected, it should be confirmed with a CT scan (Figure 11).

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Figure 10. Mediastinal goiter causing significant deviation of the trachea to the left.

Figure 11. Nodular goiter causing tracheal compression, seen on CT scan.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Graves‘ Disease

21

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Notably, thyroid ultrasonography is the gold standard technique in diagnosis and evaluation of thyroid nodules [206-208]. In patients who have a palpable nodule a diagnostic thyroid ultrasonography should be done, to confirm the existence of thyroid nodule[s]. Additionally in a patient who do not have a palpable nodule but have a pathcy uptake on thyroid scan, in which case a distinction between Graves‘ disease and TMNG would be difficult, a thyroid ultrasonography should be performed to clarify the diagnosis. On thyroid scan there will be an active nodule with suppressed surrounding tissue in TA (Figure 12,13,14,15).

Figure 12.

Figure 13.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

22

Mehtap Cakır

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Figure 12, 13, 14. Toxic adenoma causing suppression in the surrounding thyroid tissue.

Figure 15. Toxic adenoma causing suppression in the surrounding thyroid tissue. Note decreased uptake in the central part of the nodule due to possible necrosis.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Graves‘ Disease

23

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

In TMNG, it is important to confirm the activity of all established nodules with a thyroid scan. Some of the nodules can show normal or decreased uptake [cold nodules] on thyroid scan (Figure 16,17,18,19,20). In TMNG there may be two types of scintigraphic patterns; first includes circumscript areas of increased uptake with suppression of the surrounding thyroid tissue, second an uneven [patchy] increase in uptake combined with areas of decreased and/or normal uptake. Fine needle aspiration biopsy of hot functioning nodules is not recommended in TA and TMNG [209]. But all cold nodules confirmed by thyroid scan should be biopsied before a treatment type is chosen.

Figure 16. Toxic multinodular goiter. Thyroid scan with technetium pertechnetate (99mTcO4) showing increased uptake in multiple nodules and partial suppression in the rest of the gland. Note the hypoactive regions in the right upper pole, isthmus and middle of the left lobe which were due to hypoactive (cold) nodules.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

24

Mehtap Cakır

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Figure 17.

Figure 17, 18. Toxic multinodular goiter with complete suppression in the rest of the gland. Note in figure 18 that the nodule in the right lobe is more active compared to the one in the left lobe.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Graves‘ Disease

25

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Figure 19. Toxic multinodular goiter with multiple hyperactive and hypoactive nodules in the thyroid gland.

Figure 20. Toxic multinodular goiter with hyperactive nodules in the right lobe and partial suppression in the left lobe.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Chapter 3

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

TSH-SECRETING PITUITARY ADENOMA TSH-secreting pituitary adenomas are infrequent pituitary adenomas [0.5% to 1% of all pituitary adenomas] and extremely rare causes of hyperthyroidism [210212]. Most patients have a long history of thyroid dysfunction, often misdiagnosed as Graves‘ disease, and about one third had an inappropriate thyroidectomy or radioiodine ablation [213-215]. However, the diagnosis of these rare tumors have evolved considerably in the last two decades due to routine use of ultrasensitive immunometric assays for TSH measurement. The great majority of TSH-secreting tumors are macroadenomas which have a diameter of more than 10 mm at the time of diagnosis and around 15-20% are microadenomas [211,216]. Extrasellar extension is present in more than two thirds of cases [211,216]. These tumors are nearly always benign, and transformation into a TSH-secreting carcinoma has been reported in only two patients [217,218]. Female/male ratio is reported as 1.3 [210,211]. Although most patients are diagnosed between the third and the sixth decade of life [211], the presence of a TSH-secreting tumor has been observed in patients of any age, from 8 to 84 years [211]. Symptoms of thyrotoxicosis may change in a spectrum of nil to severe [216]. In contrast to what is observed in patients with primary thyroid disorders, atrial fibrillation and/or cardiac failure are rare events [211,219]. Alternatively, patients with TSH-secreting tumors may present with symptoms and signs related to the pressure effects of the pituitary adenomas, causing loss of vision, visual field defects, headache and/or loss of other anterior pituitary functions [211]. Given that in approximately 25% of patients with a TSH-secreting tumor a concomitant secretion of other pituitary hormones can be found, the patient may also present with symptoms of the corresponding pituitary hormone‘s excess [210,216]. This will be most commonly acromegalic features due to concomitant

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

28

Mehtap Cakır

GH secretion [210,216] but amenorrhea and galactorrhea in female patients and impotence and reduced libido in males due to prolactin hypersecretion have also been reported [210,216]. Although mixed TSH-gonadotrophin secreting tumors have been reported as well, there is only a 7-month old baby who had mixed TSHACTH adenoma in the literature [220]. Recently a case of thyrotropinoma cosecreting GH and FSH with low alpha-glycoprotein has been reported [221]. Regarding family history, familial presentation has been reported only as part of the multiple endocrine neoplasia type 1 syndrome [210,216]. On physical examination, more than 90% have goiter due to consistent TSH stimulation [210]. In essence, coexisting thyroid nodules have been reported in around 70% of cases [210]. Bilateral exophthalmos have been reported in a few patients who subsequently developed autoimmune thyroiditis, while unilateral exophthalmos due to orbital invasion by a pituitary tumor was reported in three patients [213]. There are also rare cases of TSH-secreting tumors in the literature, presenting with hypokalemic periodic paralysis [222,223]. In laboratory studies, typically high free T4 and T3 levels have been reported with accompanying normal or high, but not ―suppressed‖ TSH values [210,212]. Certain situations which leads to spuriously high levels of thyroid hormones or TSH must be eliminated [see below]. Hyperthyroxinemia associated with measurable TSH may also be found in patients treated with the iodine-containing drug, amiodarone [224]. In rare cases patient may be euthyroid or even hypothyroid in the existence of accompanying Hashimoto‘s thyroiditis [225,226]. Studies indicate that TSH molecules secreted by pituitary tumors may have normal, reduced, or increased biological activity relative to immunological activity, presumably secondary to alterations of the posttranslational processing of the hormone within tumor cells [227,228]. Thyroid hormones are transported in serum almost entirely reversibly bound to protein [229]. Seventy to 80% of the T4 and T3 in serum is bound to thyroxinebinding globulin [TBG], and the remainder is bound to transthyretin [TTR-also known as thyroxine-binding prealbumin] and albumin. Approximately 0.05% of the T4 and 0.2% of the T3 in serum are free [i.e., not bound to any protein]. Genetic alterations or treatment with certain drugs may cause quantitative/qualitative alterations of the major thyroid hormone carriers, TBG, albumin, or TTR which may lead to increases in serum T4 [211]. Among thyroid hormone carriers TBG is the major one, and pregnancy, contraceptive pills, estrogen receptor modulators, 5-fluorouracil, liver diseases, acute intermittent porphyria, and inherited TBG excess increase serum TBG, while androgens, corticosteroids, hyperthyroidism, terminal illnesses, and inherited TBG deficiency decrease or tend to decrease serum TBG [230]. In addition to androgen

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

TSH-Secreting Pituitary Adenoma

29

administration, TTR excess has been reported in pancreatic endocrine tumors, chronic renal failure, and as a compensatory mechanism in analbuminemia [inherited deficiency of albumin] [231,232]. Serum TTR decreases in severe nonthyroid illnesses, protein-calorie malnutrition, and inherited α1-AT deficiency [233]. Causes of proteinuria decrease serum TBG, TTR and albumin. Dominantly inherited genetic variants of albumin [e.g. familial dysalbuminemic hyperthyroxinemia, FDH] or TTR with altered affinity for iodothyronines, can cause free T4, and less frequently free T3 to be overestimated, particularly in ―onestep‖ analogue hormone assays [see below]. Even some ―two-step‖ assays are prone to interference and hormone measurement by equilibrium dialysis can prevent this. Nevertheless, diagnosis with total thyroid hormone measurements are not advised, as total hormone values may change with changing carrier protein levels and misguide the physician [234,235]. Meanwhile it is clear that, laboratory artifacts may cause falsely high levels of either thyroid hormones or TSH. Circulating anti-T4 and/or anti-T3 autoantibodies can interfere in the immunometric assay, leading to an overestimation of both total and free thyroid hormone levels [236]. As far as the free T4 and T3 measurements are concerned, such overestimation is frequently observed when ―one-step‖ analog methods are employed [237]. Competition assays are commonly used in which labeled T4 [the tracer] competes with serum T4 for binding sites. The presence of antiiodothyronine antibodies which can bind the tracer or anti-animal Igs which block the assay antibody will confound hormone measurement. The interference of the above autoantibodies may be counteracted by measuring free T4 and free T3 concentrations by direct ―two-step‖ methods, that is, methods able to avoid contact between serum proteins and tracer at the time of the assay. Assay of free thyroid hormones by equilibrium dialysis is the gold-standard method for eliminating interference. The factors interfering in TSH measurement are heterophilic antibodies directed against or cross-reacting with mouse IgG [238], and anti-TSH antibodies in patients previously treated with contaminated pituitary extracts. The majority of commercially available TSH assays use a non-competitive or ―sandwich‖ format with two antibodies- capture and [labelled] detection – directed against different epitopes on TSH, with the TSH moiety essentially acting as a bridge between the two. The presence of antianimal immunoglobulins [Igs] in a patient‘s serum has the potential to cause interference with the TSH assay if directed against the same species as the capture or detection antibodies will result in negative interference causing a falsely low TSH. On the contrary, the presence of an Ig that is capable of cross-linking the capture and detection antibodies may cause positive interference, leading to a falsely high TSH. The occurrence of antithyroid autoantibodies in patients with

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

30

Mehtap Cakır

TSH-secreting tumors is similar to that found in the general population, being about 8% [211]. When the possibility of a laboratory artifact has been eliminated and the patient is not on any drugs that will effect thyroid hormone levels, a finding of elevated free T4 and free T3 levels with accompanying normal or high TSH values leads to two possible diagnoses: TSH-secreting pituitary tumor or resistance to thyroid hormone [RTH]. Both diseases occur in patients of a similar age range and either gender. As will be expected, the main difference between the two entities is the familial occurence of RTH. A similar pattern of abnormal thyroid function tests in first-degree relatives of the index case strongly suggests RTH. A subset of patients with RTH may exhibit thyrotoxic signs and symptoms. With regard to using markers of thyroid hormone action and other laboratory tests in differential diagnosis of TSH-secreting tumors from RTH a number of parameters may be useful [210]. A significant difference in thyroid function tests is not expected, while a significantly higher sex hormone binding globulin [SHBG] and α-subunit levels [see below] and higher α-subunit/TSH ratio is expected in TSH-secreting pituitary tumors [210]. Among various markers, basal levels of SHBG have the greatest capacity to discriminate, which will be elevated in TSH-secreting tumors and be normal in RTH [239]. However, age and gender specific reference ranges should be used and falsely low levels of SHBG can occur in mixed GH/TSH secreting tumors due to inhibiton of synthesis by growth hormone. On the other hand, synthetic estrogens or hypogonadism can falsely elevate SHBG in RTH. Bone carboxyterminal cross-linked telopeptide of type I collagen [ICTP] is another parameter of peripheral thyroid hormone action and a marker for quantifying the degree of tissue hyperthyroidism. ICTP is found to be high in TSH-secreting tumors like common causes of hyperthyroidism, but levels are found in the normal range in patients who have RTH [240]. Additionally, in differential diagnosis of TSH-secreting pituitary adenomas and RTH two dynamic tests have been used. One is called Werner‘s test or L-T3 suppression test. In this test 100 μg per day L-T3 is given for 10 days and even in subjects who had previous thyroid ablation a complete inhibition of TSH secretion of L-T3 suppression test has never been recorded in subjects with TSH-secreting tumors [210]. This test is contraindicated in elderly patients and in those who have coronary heart disease [210]. In subjects with RTH there is a TSH inhibition but TSH suppression does not occur. Thus this test may not be helpful in differential diagnosis in terms of TSH response. Another protocol for L-T3 suppression test gives L-T3 with incremental doses, 50 μg/day, 100 μg/day and 200 μg/day each for three days [241]. While in normal subjects a suppression in cholesterol and creatine kinase and stimulation of ferritin and SHBG are expected

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

TSH-Secreting Pituitary Adenoma

31

to occur, in subjects with RTH these peripheral hormone action responses are either blunted or paradoxal [239]. Therefore, a stimulatory TRH test has been used in differential diagnosis of TSH-secreting tumors [214,242]. In the majority of patients with a TSH-secreting tumor, TSH levels show a failed response [400.000 IU/L were invariably reported to be associated with suppressed TSH concentrations [306]. There is a correlation between the biochemical severity of hyperthyroidism and the serum hCG in these patients [305]. However, not all patients with trophoblastic tumors with high serum hCG concentrations have hyperthyroidism. Absence of TRAb will enable differential diagnosis from Graves‘ disease in these subjects. In thyroid imaging, thyroid radioiodine uptake is diffusely increased [307]. In imaging studies of the tumor, ultrasonography of the uterus reveals a characteristic ‗snowstorm‘ pattern in women with a hydatidiform mole, and it also provides an accurate indication of tumor volume within the uterus [283]. The definitive diagnosis of hydatidiform mole or choriocarcinoma is based on the histopathology of the tissue removed by curettage or surgery.

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

40

Mehtap Cakır

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

HYPEREMESIS GRAVIDARUM HG occurs in 0.3% to 2% of pregnant women, and is said to be higher in multiple pregnancies [308-310]. Nausea and vomiting of pregnancy itself affects approximately 75% of pregnant women, with 25% reporting nausea alone and 50% reporting both nausea and vomiting [308]. In clinical practice, HG is identified by otherwise unexplained intractable vomiting and dehydration and it represents the far end of the spectrum of nausea and vomiting of pregnancy [308]. A criterion of weight loss, usually more than 5% of prepregnancy weight, confirms the diagnosis [308]. The International Statistical Classification of Disease and Related Health Problems ICD-9 Code 643 defines HG as persistent and excessive vomiting starting before the end of the 22nd week of gestation, and further subdivides the condition into mild and severe [311]. According to several studies comparing pregnant subjects with and without HG the only difference between these subjects were serum levels of hCG and estradiol [308]. Thus evidence points toward a role of these hormones. Although the mechanism is not yet fully understood, the combination of high hCG and estradiol levels, as well as increased free T4 concentrations transiently promotes emesis near the period of peak hCG [312]. It is known that there is a strong association between hCG concentrations and the time of peak symptoms of nausea and vomiting of pregnancy [313,314]. It has been difficult, however, to link total hCG concentrations directly with the severity of nausea and vomiting of pregnancy and with HG, because concentrations vary widely in the normal and sick population. As mentioned previously in the section of trophoblastic tumors, ‗‗hCG‘‘ actually is a family of isoforms that differ in half-life and potency at the luteinizing hormone [hCG] and TSH receptors, and differences in the isoforms may explain some of the variation in the relationship between total hCG concentrations and thyroid stimulation. Interestingly, a mother and a daughter who both had two miscarriages and then two succesful pregnancies which were all complicated with HG and hyperthyroidism have been reported [315,316]. When the TSH receptor of the proband and her mother was studied, an adenine to guanine substitution at codon 183 in exon 7 in one allele, resulting in substitution of arginine for lysine in the middle portion of the extracellular domain of the TSH receptor was revealed [315]. When the mutant TSH receptor was transfected into COS cells and the cells were incubated with hCG, it was seen that these cells were more sensitive to hCG than cells transfected with wild-type receptors, as measured by the cyclic adenosine monophosphate responses to hCG [283]. Thus, the gestational thyrotoxicosis in these two women was due to an exaggerated thyroid-stimulating

Differential Diagnosis of Hyperthyroidism, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved.

Trophoblastic Tumors and Hyperemesis Gravidarum

41

action of hCG. No other family with a TSH receptor mutation of this type has been reported to date. The symptoms of thyrotoxicosis like fatigue, palpitations, anxiety, heat intolerance, and diaphoresis are quite similar with symptoms of normal pregnancy so the clinical features of thyrotoxicosis are usually overlooked in these patients. However, in addition to nausea and vomiting, some women with HG may have clinically evident thyrotoxicosis [283]. Excess salivation [ptyalism] has been reported in up to 60% of cases of HG [317]. Although it is believed that women who have severe nausea and vomiting are more sensitive to olfactory stimuli, this belief has not been documented in objective studies [308]. On physical examination, classical signs of hyperthyroidism may be found but thyroid enlargement is rare. In laboratory evaluation, at the time of the peak hCG levels in normal pregnancy, serum TSH levels fall and bear a mirror image to the hCG peak [318,319]. In the first trimester, serum TSH may be transiently suppressed [< 0.2 mU/L] at the time of peak hCG levels in up to 20% of euthyroid women [320]. High serum free T4 and T3 concentrations are a common finding in women with HG, having been reported in 25% to 75% of patients in various series [321-327] and several reports show that free T3 or T4 levels are significantly elevated at the time when hCG levels are maximal [318,319,328,329]. Women with HG and high serum free T4 and T3 concentrations have higher serum hCG concentrations than normal pregnant women [323,327]. Additionally, HG results in hyponatremia, hypokalemia and hypochloremic metabolic alkalosis in 15% to 25% of cases [285,323]. Ketonuria and increased specific gravity of the urine may be detected [311]. Mild elevations of liver enzymes and serum bilirubin [