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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Serie: Lecture Notes
- Sprache: Englisch
This brand new title in the Lecture Notes series covers a core element of the medical school curriculum.
It presents the basic science needed to understand mechanisms of disease and describes the clinical presentations of the disorders associated with different glands, concluding with the relevant investigations and management.
Focusing on conditions commonly encountered on the wards and in exams, with key points to aid revision and recall, this new title is perfect as a course companion and is the ideal revision tool for medical students, specialist nurses, and doctors working on endocrinology rotations. Lecture Notes: Endocrinology and Diabetes is also essential for endocrinology trainees approaching the new Knowledge Based Assessment (KBA).
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Seitenzahl: 587
Veröffentlichungsjahr: 2013
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Contents
Preface
Acknowledgements
Abbreviations
Chapter 1: Thyroid anatomy and physiology
Anatomy
Physiology
Chapter 2: Hypothyroidism
Epidemiology
Aetiology
Clinical presentations
Investigations
Treatment
Follow-up and monitoring
Special circumstances
Chapter 3: Thyrotoxicosis
Epidemiology
Aetiology
Clinical presentations
Investigations
Treatment
Special circumstances
Thyroid hormone resistance
Chapter 4: Goitre, thyroid nodules and cancer
Goitre and thyroid nodules
Thyroid cancer
Thyroid lymphoma
Chapter 5: Adrenal anatomy and physiology
Aldosterone
Cortisol
Adrenal androgens
Chapter 6: Adrenal insufficiency
Epidemiology
Aetiology
Clinical presentations of primary adrenal insufficiency
Clinical presentations of secondary adrenal insufficiency
Investigations
Treatment
Follow-up and monitoring
Chapter 7: Primary hyperaldosteronism
Epidemiology
Aetiology
Clinical presentations
Investigations
Treatment
Other causes of endocrine hypertension
Chapter 8: Phaeochromocytomas and paragangliomas
Clinical presentations
Investigations
Treatment
Malignant phaeochromocytomas
Follow-up and monitoring
Chapter 9: Congenital adrenal hyperplasia
Epidemiology
Aetiology
Clinical presentations
Investigations
Treatment
Follow-up and monitoring
chapter 10: Adrenal incidentalomas
Radiological evaluation
Clinical assessment
Biochemical a ssessment
Treatment
Follow-up
Bilateral adrenal masses
chapter 11: Pituitary anatomy and physiology
Anterior pituitary hormones
Posterior pituitary hormones
chapter 12: Pituitary tumours and other sellar disorders
Pituitary tumours
Epidemiology
Aetiology
Clinical presentations
Investigations
Treatment
Follow-up and monitoring
Other pituitary and sellar disorders
chapter 13: Hypopituitarism
Clinical presentations
Investigations
Treatment and monitoring
chapter 14: Hyperprolactinaemia
Epidemiology
Clinical presentations
Evaluation
Treatment
Prognosis
chapter 15: Acromegaly
Epidemiology
Aetiology
Clinical presentations
Treatment
Follow-up and monitoring
Prognosis
chapter 16: Cushing’s syndrome
Aetiology
Epidemiology
Clinical presentations
Investigations
Treatment
Prognosis
Follow-up and monitoring
Rare causes of ACTH-independent Cushing’s syndrome
chapter 17: Diabetes insipidus
Epidemiology
Aetiology
Diagnosis
Treatment
chapter 18: Hyponatraemia and syndrome of inappropriate ADH secretion
Epidemiology
Aetiology
Clinical presentations
Investigations
Treatment
chapter 19: Male reproductive physiology and hypogonadism
Testicular a natomy and physiology
Male hypogonadism
chapter 20: Gynaecomastia
Epidemiology
Aetiology
Clinical presentations
Investigations
Treatment, follow-up and monitoring
chapter 21: Female reproductive physiology, amenorrhoea and premature ovarian failure
The menstrual cycle
Amenorrhoea
chapter 22: Polycystic ovary syndrome
Epidemiology
Aetiology
Clinical presentations
Investigations
Treatment
Other causes of hirsutism
chapter 23: Menopause
Endocrinology of menopause
Clinical presentations
Diagnosis and differential diagnoses
Management
chapter 24: Hypocalcaemia
Aetiology
Clinical presentations
Investigations
Treatment
chapter 25: Hypercalcaemia and primary hyperparathyroidism
Calcium homeostasis
Hypercalcaemia
Primary hyperparathyroidism
Clinical presentations
Investigations
chapter 26: Osteomalacia
Aetiology
Clinical presentations
Investigations
Treatment
Follow-up and monitoring
chapter 27: Osteoporosis
Bone remodelling
Osteoporosis
Epidemiology
28Paget’s disease of bone
Epidemiology
Aetiology
Clinical presentations
Investigations
Treatment
Follow-up and monitoring
chapter 29: Disorders of puberty
Puberty
Delayed puberty
Precocious puberty
chapter 30: Growth and stature
Normal growth
Short stature
Tall stature
chapter 31: Endocrine disorders of pregnancy
Disorders of thyroid function
Prolactinomas in pregnancy
Adrenal disorders in pregnancy
Diabetes mellitus in pregnancy
chapter 32: Neuroendocrine tumours
Aetiology
Epidemiology
Clinical presentations
Investigations
Treatment
Prognosis
Multiple endocrine neoplasia
chapter 33: Obesity
Appetite regulation
Obesity
chapter 34: Insulin and diabetes mellitus: classification, pathogenesis and diagnosis
Insulin
Diabetes mellitus
chapter 35: Treatment of diabetes mellitus
Patient education
Glycaemic control in type 1 diabetes
Glycaemic control in type 2 diabetes
Screening for and treatment of complications
Screening for and treatment of cardiovascular risk factors
chapter 36: Diabetic emergencies
Diabetic ketoacidosis
Hyperosmolar hyperglycaemic state
Hypoglycaemia
chapter 37: Diabetic retinopathy
Epidemiology
Aetiology
Clinical presentations
Screening
Treatment
chapter 38: Diabetic nephropathy
Pathogenesis
Epidemiology
Diagnosis
Treatment
chapter 39: Diabetic neuropathy
Epidemiology
Pathogenesis
Clinical presentations
Diagnosis
Treatment
chapter 40: Musculoskeletal and dermatological manifestations of diabetes
Diabetic foot ulcers
Charcot arthropathy
Other musculoskeletal manifestations of diabetes
Dermatological manifestations of diabetes
Index
This edition first published 2009, © 2009 by Amir H. Sam and Karim Meeran
Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell.
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Library of Congress Cataloging-in-Publication Data
Sam, Amir H. Lecture notes. Endocrinology and diabetes / Amir Sam, Karim Meeran. p. ; cm. Includes index. ISBN 978-1-4051-5345-4 (pbk. : alk. paper) 1. Endocrinology–Outlines, syllabi, etc. 2. Diabetes–Outlines, syllabi, etc. 3. Endocrine glands–Diseases–Outlines, syllabi, etc. I. Meeran, Karim. II. Title. III. Title: Endocrinology and diabetes. [DNLM: 1. Endocrine System Diseases. 2. Diabetes Mellitus. WK 140 S187L 2009] RC649.S26 2009 616.4–dc22
2009002846
ISBN: 9781405153454
A catalogue record for this book is available from the British Library.
1 2009
Preface
In the conception of this book, we used our teaching experience to cover the main topics in endocrinology and diabetes in a simple and easy-to-understand style.
We have tried to discuss the basic anatomy and physiology of the endocrine system, which is fundamental to the understanding of pathophysiology and presentation of the endocrine diseases. Lecture Notes: Endocrinology and Diabetes also contains detailed sections on the practical management of diabetes and endocrine disorders. Therefore we believe that this book is suitable for medical students and doctors training in endocrinology, and can be used for exam revision as well as rapid consultation in the clinic.
Amir SamKarim Meeran
Acknowledgements
We are grateful to Mr Fausto Palazzo, Dr Roberto Dina, Professor Pierre-Marc Bouloux, Dr John Frank and Dr Owais Chaudhri for kindly providing some of the illustrations used in this book. Additionally, we would like to express our thanks to Dr Kevin Shotliff and John Wiley & Sons for the diabetic retinopathy images used in Chapter 37, which were taken from Practical Diabetes International, Volume 23, pages 418–20. We are also grateful to Dr Waljit Dhillo, Dr Victoria Salem and Dr Sufyan Hussain for their useful advice.
Abbreviations
5-HIAA 5-hydroxyindoleacetic acid
ABPI ankle–brachial pressure index
ACCORD Action to Control Cardiovascular Risk in Diabetes trial
ACE angiotensin-converting enzyme
ACR albumin-to-creatinine ratio
ACTH adrenocorticotrophic hormone
ADH antidiuretic hormone
ADVANCE Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation trial
AGB adjustable gastric banding
AGE advanced glycosylation end-product
AHO Albright’s hereditary osteodystrophy
AIDS acquired immune deficiency syndrome
ALT alanine transaminase
AMPK adenosine monophosphate-activated protein kinase
APS autoimmune polyglandular syndrome
ARB angiotensin receptor blocker
AVP arginine vasopressin
BFGF basic fibroblast growth factor
BMD bone mineral density
BMI body mass index
BMP-7 bone morphogenic protein-7
CAH congenital adrenal hyperplasia
CARDS Collaborative AtoRvastatin Diabetes Study
CARE Cholesterol and Recurrent Events trial
CDGP constitutional delay of growth and puberty
CEA carcinoembryonic antigen
CNS central nervous system
CPT I carnitine palmitoyltransferase-I
CRH corticotrophin-releasing hormone
CSW cerebral salt wasting
CT computed tomography
CTLA-4 cytotoxic T-lymphocyte antigen 4
CVD cardiovascular disease
DAFNE Dose Adjustment for Normal Eating
DCCT Diabetes Control and Complications Trial
DEXA dual-energy X-ray absorptiometry
DHEA dehydroepiandrosterone
DHEA-S dehydroepiandrosterone sulphate
DIEP Diabetes in Early Pregnancy study
DKA diabetic ketoacidosis
DMSA dimercaptosuccinic acid
DPP-IV dipeptidyl peptidase-IV
ECG electrocardiogram
EDIC Epidemiology of Diabetes Interventions and Complications study
eGFR estimated glomerular filtration rate
ESR erythrocyte sedimentation rate
ESRD end-stage renal disease
FIELD Fenofibrate Intervention and Event Lowering in Diabetes study
FNA fine needle aspiration
FSH follicle-stimulating hormone
GAD glutamic acid decarboxylase
GEMINI Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives
GFR glomerular filtration rate
GH growth hormone
GHRH growth hormone-releasing hormone
GLP-1 glucagon-like peptide-1
GSH glucocorticoid-suppressible hyperaldosteronism
HbA1c glycated haemoglobin
hCG human chorionic gonadotrophin
HDL high-density lipoprotein
HHS hyperosmolar hyperglycaemic state
HIF hypoxia-inducible factor
HIV human immunodeficiency virus
HPA hypothalamic–pituitary–adrenal
HRT hormone replacement therapy
ICSI intracytoplasmic sperm injection
IGF-I insulin-like growth factor-I
IGFBP-3 insulin-like growth factor-binding protein-3
IRMA intraretinal microvascular abnormality
IRS insulin receptor substrate
ITT insulin tolerance test
IVF in vitro fertilization
JNK c-Jun amino-terminal kinase
LADA latent autoimmune diabetes in adults
LDL low-density lipoprotein
LH luteinizing hormone
MAPK mitogen-activated protein kinase
MC4R melanocortin-4 receptor
MDRD Modification of Diet in Renal Disease study
MEN multiple endocrine neoplasia
MI myocardial infarction
MODY maturity-onset diabetes of the young
MRI magnetic resonance imaging
MSH melanocyte-stimulating hormone
MTC medullary thyroid carcinoma
NET neuroendocrine tumour
NF neurofibromatosis
NPH neutral protamine Hagedorn
NSAID non-steroidal anti-inflammatory drug
NSC National Screening Committee
NVD new vessels on disc
NVE new vessels elsewhere
OGTT oral glucose tolerance test
PAC plasma aldosterone concentration
PCOS polycystic ovary syndrome
POMC proopiomelanocortin
POPADAD Prevention of Progression of Arterial Disease and Diabetes study
PPAR peroxisome proliferator-activated receptor
PPNAD primary pigmented nodular adrenocortical disease
PRA plasma renin activity
PSA prostate-specific antigen
PTH parathyroid hormone
PTTG pituitary tumour transforming gene
PTU propylthiouracil
PYY peptide YY
RANK receptor activator of nuclear factor kappa B
RANKL RANK ligand
RYGB roux-en-Y gastric bypass
SD standard deviation
SDHB succinate dehydrogenase subunit B
SG specific gravity
SHBG sex hormone-binding globulin
SIADH syndrome of inappropriate antidiuretic hormone
SOS Swedish Obese Subjects study
SRS somatostatin receptor scintigraphy
StAR steroidogenic acute regulatory protein
STAT signal transduction and activators of transcription
T3 triiodothyronine
T4 thyroxine
TGF transforming growth factor
TNF tumour necrosis factor
TRAb thyroid-stimulating hormone receptor antibody
TRH thyrotrophin-releasing hormone
TSH thyroid-stimulating hormone
UKPDS United Kingdom Prospective Diabetes Study
VEGF vascular endothelial growth factor
WHI Women’s Health Initiative trials
WHO World Health Organization
Chapter 1
Thyroid anatomy and physiology
Anatomy
The thyroid gland consists of left and right lobes connected by a midline isthmus (Fig. 1.1). The isthmus lies below the cricoid cartilage, and the lobes extend upward over the lower half of the thyroid cartilage. The thyroid is covered by the strap muscles of the neck and overlapped by the sternocleidomastoids. The pretracheal fascia encloses the thyroid gland and attaches it to the larynx and the trachea. This accounts for the upward movement of the thyroid gland on swallowing.
The thyroid gland develops from the floor of the pharynx in the position of the foramen caecum of the adult tongue as a downgrowth that descends into the neck. During this descent, the thyroid gland remains connected to the tongue by the thyroglossal duct, which later disappears. However, aberrant thyroid tissue or thyroglossal cysts (cystic remnants of the thyroglossal duct) may occur anywhere along the course of the duct (Fig. 1.2). Such thyroid remnants move upward when the tongue is protruded.
The thyroid gland is composed of epithelial spheres called follicles (Fig 1.3), whose lumens are filled with a proteinaceous colloid containing thyroglobulin. Two basic cell types are present in the follicles. The follicular cells secrete thyroxine (T4) and triiodothyronine (T3) and originate from a downward growth of the endoderm of the floor of the pharynx (see above). The parafollicular or C cells secrete calcitonin and arise from neural crest cells that migrate into the developing thyroid gland. The follicles are surrounded by an extensive capillary network.
Physiology
Thyroid hormones act on many tissues. They regulate:
organogenesis, growth and development (central nervous system, bone)
energy expenditure
protein, carbohydrate and fat metabolism
gut motility
bone turnover
heart rate and contractility, and peripheral vascular resistance
beta-adrenergic receptor expression
muscle contraction and relaxation
the menstrual cycle
erythropoiesis.
Iodine is essential for normal thyroid function. It is obtained by the ingestion of foods such as seafood, seaweed, kelp, dairy products, some vegetables and iodized salt. The recommended iodine intake for adults is 150 μg per day (250 μg per day for pregnant and lactating women). Dietary iodine is absorbed as iodide. Iodide is excreted in the urine.
Figure 1.1 Thyroid gland.
Figure 1.2 Possible sites of remnants of the thyroglossal duct.
Thyroid hormone synthesis
Figure 1.4 illustrates different steps in thyroid hormone synthesis:
Thyroglobulin
is synthesized in the rough endoplasmic reticulum and is transported into the follicular lumen by exocytosis.
Iodide is transported into the thyroid follicular cells via a sodium–iodide symporter on the basolateral membrane of the follicular cells. Iodide transport requires oxidative metabolism.
Inside the follicular cells, iodide diffuses to the apical surface and is transported by pendrin (a membrane iodide–chloride transporter) into the follicular lumen.
Thyroid peroxidase
(TPO) enzyme catalyzes the process of oxidation of the iodide to iodine and its binding (organification) to the tyrosine residues of thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT).
DIT and MIT molecules are linked by TPO to form
thyroxine
(T
4
) and
triiodothyronine
(T
3
) in a process known as coupling.
Thyroglobulin containing T
4
and T
3
is resorbed into the follicular cells by endocytosis and is cleaved by lysosomal enzymes (proteases and peptidases) to release T
4
and T
3
. T
4
and T
3
are then secreted into the circulation.
Uncoupled MIT and DIT are deiodinated, and the free tyrosine and iodide are recycled.
Figure 1.3 (a) A low-power histological image of thyroid tissue showing numerous follicles filled with colloid and lined by cuboidal epithelium. (b) A high-power view of follicles lined by cuboidal epithelium. (c) Thyroid follicles (lined by follicular cells), surrounding capillaries and parafollicular cells.
The thyroid gland stores T4 and T3 incorporated in thyroglobulin, and can therefore secrete T4 and T3 more quickly than if they had to be synthesized.
Extra-thyroidal T3 production
T4 is produced entirely by the thyroid gland. The production rate of T4 is about 100 μg per day. However, only 20% of T3 is produced directly by the thyroid gland (by coupling of MIT and DIT). Around 80% of T3 is produced by the deiodination of T4 in peripheral extra-thyroidal tissues (mainly liver and kidney). The total daily production rate of T3 is about 35μg.
T4 is converted to T3 (the biologically active metabolite) by 5′-deiodination (outer-ring deiodination). 5′-Deiodination is mediated by deiodinases type 1 (D1) and type 2 (D2). D1 is the predominant deiodinating enzyme in the liver, kidney and thyroid. D2 is the predominant deiodinating enzyme in muscle, brain, pituitary, skin and placenta. Type 3 deiodinase (D3) catalyzes the conversion of T3 to reverse T3 (the inactive metabolite) by 5-deiodination (inner ring deiodination), as shown in Fig. 1.5.
Changes in T3 concentration may indicate a change in the rate of peripheral conversion and may not be an accurate measure of the change in thyroid hormone production. For example, the rate of T3 production (by 5′-deiodination of T4) is reduced in acute illness and starvation.
Total and free T4 and T3
Approximately 99.97% of circulating T4 and 99.7% of circulating T3 are bound to plasma proteins: thyroid-binding globulin (TBG), transthyretin (also known as thyroid-binding pre-albumin), albumin and lipoproteins.
Figure 1.4 Steps in thyroid hormone synthesis. (1) Thyroglobulin (TG) is synthesized in the endoplasmic reticulum (ER) in the thyroid follicular cells and is transported into the follicular lumen. The small blue squares represent the amino acid residues comprising TG. (2) Iodide is transported into the follicular cell by the sodium–iodide (Na+/I−) symporter (NIS). (3) Iodide diffuses to the apical surface and is transported into the follicular lumen by pendrin (P). (4) Iodide is oxidized and linked to tyrosine residues in TG to form diiodotyrosine (DIT) and monoiodotyrosine (MIT) molecules. (5) Within the TG, T4 is formed from two DIT molecules, and T3 is formed from one DIT and one MIT molecule. (6) TG containing T4 and T3 is resorbed into the follicular cell by endocytosis. (7) TG is degraded by lysosomal enzymes to release T4 and T3 molecules, which move across the basolateral membrane of the follicular cell into the adjacent capillaries. TPO, thyroid peroxidase.
Only the unbound thyroid hormone is available to the tissues. T3 is less strongly bound and therefore has a more rapid onset and offset of action. The binding proteins have both storage and buffer functions. They help to maintain the serum free T4 and T3 levels within narrow limits, and also ensure continuous and rapid availability of the hormones to the tissues.
Free thyroid hormone concentrations are easier to interpret than total thyroid hormone levels. This is because the level of bound hormone alters with changes in the levels of thyroid-binding proteins, even though free T4 (and T3) concentrations do not change and the patient remains euthyroid (Fig. 1.6). Box 1.1 summarizes factors that may alter TBG levels.
Figure 1.5 The conversion of T4 to T3 by 5′-deiodination and to reverse T3 by 5-deiodination.
Figure 1.6 (a) If serum thyroid-binding globulin (TBG) levels are decreased, the level of thyroid hormone bound to TBG also decreases (the dark blue part of the bar). However, homeostatic mechanisms will maintain the free thyroid hormone levels (the light blue part of the bar). Note that although free hormone levels are unchanged, the ‘total’ hormone levels measured will be lower. (b) If TBG levels are increased, the level of thyroid hormone bound to TBG also increases (the dark blue part of the bar). However, homeostatic mechanisms will maintain the free hormone levels (the light blue part of the bar). Note that although free hormone levels are unchanged, the ‘total’ hormone levels measured will be higher.
Other causes of increased serum total T4 and T3 levels include familial dysalbuminaemic hyperthyroxinaemia (due to the presence of an abnormal albumin with a higher affinity for T4) and the presence of anti-T4 antibodies. Patients with these conditions are euthyroid, have normal serum thyroid-stimulating hormone (TSH) levels, and usually have normal serum free T4 and T3 levels when measured by appropriate methods.
Thyroid hormone metabolism
T4 is degraded at a rate of 10% per day. Around 40% of the T4 is deiodinated to T3 and 40% to reverse T3. The remaining T4 is conjugated with glucuronide and sulphate, deaminated and decarboxylated, or cleaved between the two rings.
T3 is degraded (mostly by deiodination) at a rate of 75% per day. Reverse T3 is degraded even more rapidly than T3, mostly by deiodination.
Regulation of thyroid hormone production and release
T3 and T4 synthesis and secretion is stimulated by the thyroid-stimulating hormone (TSH) released from the anterior pituitary gland (Fig. 1.7). TSH production and release is increased by hypothalamic thyrotrophin-releasing hormone (TRH).
Thyrotrophin-releasing hormone
TRH is a tripeptide synthesized and released by the hypothalamus. TRH content is highest in the median eminence and paraventricular nuclei of the hypothalamus. TRH stimulates TSH secretion by activating a G-protein-coupled receptor and the phospholipase C-phosphoinositide pathway, resulting in mobilization of calcium from intracellular storage sites.
Chronic TRH stimulation also increases the synthesis and glycosylation of TSH, which increases its biological activity.
Thyroid-stimulating hormone
TSH is a glycoprotein secreted by the thyrotroph cells of the anterior pituitary. TSH is composed of alpha and beta subunits that are non-covalently bound. The alpha subunit is the same as that of luteinizing hormone, follicle-stimulating hormone and human chorionic gonadotrophin. However, the beta subunit is unique to TSH. TSH binds to specific plasma membrane receptors and activates adenylyl cyclase. TSH also stimulates phospholipase C activity.
Figure 1.7 Hypothalamic–pituitary–thyroid axis. TRH, thyrotrophin-releasing hormone; TSH, thyroid-stimulating hormone.
TSH stimulates every step in thyroid hormone synthesis and secretion. It also stimulates the expression of many genes in thyroid tissue and causes thyroid hyperplasia and hypertrophy.
T4 and T3 inhibit TSH synthesis and release both directly (by inhibiting transcription of the TSH subunit genes) and indirectly (by inhibiting TRH release). T4 and T3 also decrease the glycosylation and hence bioactivity of TSH.
TSH secretion is regulated by very small changes in serum T4 and T3 concentrations. However, an important exception is that the reduced T3 levels in patients with non-thyroidal illness have little effect on TSH secretion. This may be due to a greater contribution of serum T4 to the nuclear T3 content of the pituitary than other tissues.
Box 1.2 shows a list of the causes of increased and decreased TSH concentration.
Mechanism of action of thyroid hormones
Thyroid hormones enter cells via active membrane transporter proteins (e.g. MCT8). Inside the cells, T3 formed from the deiodination of T4 and T3 that enters the cells from the serum is transferred to the nucleus. The thyroid hormone receptors (TRs) heterodimerize with the retinoid X receptor and act as nuclear transcription factors. TRs bind thyroid hormone response elements in the promoter region of thyroid hormone-responsive genes. In the absence of T3, TRs bind co-repressor proteins that repress transcription. On T3 binding, co-repressors are displaced and co-activator proteins bind the TRs, resulting in histone acetylation, generation of a permissive chromatin structure and induction of gene transcription.
There are two T3 nuclear receptors—alpha and beta—encoded by separate genes located on chromosomes 17 and 3. Two forms of each TR are generated by alternative splicing. Only the beta-1, beta-2 and alpha-1 receptors bind T3. Liver predominantly expresses beta receptors, whereas heart and bone express alpha receptors. The hypothalamus and pituitary express beta-2 receptors which mediate the negative feedback regulation.
Chapter 2
Hypothyroidism
Hypothyroidism results from insufficient secretion of thyroid hormones.
Primary
hypothyroidism is characterized by low serum free thyroxine (T
4
) and high serum thyroid-stimulating hormone (TSH) levels (due to a reduced negative feedback effect of T
4
on TSH synthesis/secretion).
Subclinical
hypothyroidism is defined as normal serum free T
4
and T
3
levels and a high serum TSH. This reflects the sensitivity of TSH secretion to very small decreases in thyroid hormone secretion.
Central
hypothyroidism is much less common and results from reduced TSH secretion from the anterior pituitary (secondary hypothyroidism) or reduced thyrotrophin-releasing hormone (TRH) secretion from the hypothalamus (tertiary hypothyroidism).
Epidemiology
The prevalence of congenital hypothyroidism in the UK is about 1 in 4000 of the population. The frequency of hypothyroidism varies from 0.1% to 2% of adults. Hypothyroidism is 5–8 times more common in females. Primary hypothyroidism accounts for more than 95% of cases of hypothyroidism. Around 5% of adults and 15% of women over the age of 60 have subclinical hypothyroidism.
Aetiology
Box 2.1 summarizes the causes of hypothyroidism.
Subclinical hypothyroidism (see above) may result from the same causes as primary hypothyroidism or from inadequate T4 replacement in a patient with overt hypothyroidism.
Congenital hypothyroidism may be secondary to thyroid agenesis, dysgenesis or inherited defects in thyroid hormone biosynthesis.
Acquired hypothyroidism may be primary or central as mentioned above. Primary hypothyroidism may be due to chronic autoimmune (Hashimoto’s) thyroiditis, iatrogenic causes (e.g. drugs, thyroidectomy, radioiodine), iodine deficiency/excess or thyroiditis.
Chronic autoimmune (Hashimoto’s) thyroiditis is caused by cellular and antibody-mediated injury to the thyroid tissue. There are two forms, goitrous and atrophic, which have similar pathophysiology but are different in the extent of thyroid follicular cell hyperplasia, lymphocytic infiltration and fibrosis. Chronic autoimmune thyroiditis is usually but not always permanent. These patients are more likely to have a personal or family history of other autoimmune conditions, such as Addison’s disease and type 1 diabetes mellitus, vitiligo (Fig. 2.1), pernicious anaemia and premature ovarian failure. An increased incidence of Hashimoto’s thyroiditis is also found in those with Down’s or Turner’s syndrome.
Drugs such as the antithyroid drugs carbimazole and propylthiouracil (used to treat hyperthyroidism) may cause hypothyroidism. Amiodarone is an iodine-containing drug and may cause both hypothyroidism (see below) and thyrotoxicosis (see Chapter 3). Other drugs that may cause hypothyroidism include lithium, alpha-interferon and interleukin-2. Patients on these drugs should have their serum TSH checked every 6–12 months.
T4 has a half-life of 7 days, and hypothyroidism occurs about 2–4 weeks following total thyroidectomy. After subtotal thyroidectomy for the treatment of Graves’ disease, hypothyroidism occurs within the first year in the majority of patients. The annual risk of hypothyroidism in those who are euthyroid at 1 year is 0.5–1%. Some patients become transiently hypothyroid after 4–8 weeks but recover several weeks or months later.
Figure 2.1 Vitiligo in a patient with Hashimoto’s thyroiditis.
Following radioiodine therapy for the treatment of Graves’ disease, the majority of patients become hypothyroid within the first year. The rest have a 0.5–2% annual risk of hypothyroidism. Some patients with toxic multinodular goitre or thyroid adenomas who receive radioiodine therapy also become hypothyroid.
External irradiation of the neck may result in hypothyroidism with a gradual onset. Many patients develop overt hypothyroidism after several years of subclinical hypothyroidism.
Iodine deficiency and excess can both cause hypothyroidism. Iodine deficiency is the most common worldwide cause of hypothyroidism and is more prevalent in mountainous areas. Iodine excess can also result in hypothyroidism by inhibiting iodine organification and T4 and T3 synthesis (Wolff–Chaikoff effect).
In postpartum and subacute thyroiditis, transient hypothyroidism (lasting weeks to a few months) may follow transient thyrotoxicosis.
Rarer causes include infiltrative diseases, for example fibrous (Reidel’s) thyroiditis, haemochromatosis, sarcoidosis, amyloidosis, leukaemia, and consumptive hypothyroidism due to an ectopic production of the type 3 deiodinase in vascular and fibrotic tumours, which metabolizes T4 to reverse T3.
Clinical presentations
Hypothyroidism often has an insidious and non-specific onset. Patients may present with fatigue, lethargy and cold intolerance. Clinical presentations of thyroid hormone deficiency result from a generalized slowing of metabolic processes and an accumulation of hydrophilic glycosaminoglycans in the interstitial spaces of the tissues (myxoedema). Box 2.2 summarizes the clinical presentations of hypothyroidism in adults and possible explanations for these manifestations.
In secondary hypothyroidism due to hypothalamic/pituitary disease, the symptoms are usually milder than in primary hypothyroidism and may be masked by symptoms of other hormone deficiencies (see Chapter 12). For example, hot flushes secondary to hypogonadism may make the cold intolerance caused by hypothyroidism less obvious.
Investigations
The diagnosis of hypothyroidism is made by measuring serum TSH and free T4. In many developed countries, congenital hypothyroidism is diagnosed during the routine screening of all infants by measuring TSH or T4 in blood obtained from a heel prick in the first week of life.
Table 2.1 shows the results of thyroid function tests in primary, subclinical and secondary hypothyroidism. In general, younger patients presenting with primary hypothyroidism have much higher TSH levels than older patients.
Other laboratory test abnormalities in hypothyroid patients include hyperlipidaemia and hyponatraemia.
Patients with central hypothyroidism should have pituitary function tests and a magnetic resonance imaging scan of the hypothalamus and pituitary. A TRH test may occasionally be done to differentiate between pituitary and hypothalamic causes of TSH deficiency. A dose of 200 μg of TRH is given intravenously over 2 minutes. Blood samples are taken at 30 and 60 minutes. The 60-minute value exceeds the 30-minute value in hypothalamic hypothyroidism.
Pituitary enlargement may occasionally be seen in severe primary hypothyroidism owing to hypertrophy and hyperplasia of the thyrotroph cells. It is important to distinguish this entity, which is reversible with T4 replacement, from a pituitary adenoma.
Table 2.1 Thyroid function tests in various forms of hypothyroidism.
Treatment
Hypothyroidism usually requires lifelong treatment with synthetic levothyroxine. Exceptions include cases of transient hypothyroidism following subacute or postpartum thyroiditis, or reversible hypothyroidism due to a drug that can be stopped.
Treatment objectives are the resolution of symptoms, a normalization of TSH and a reduction in the size of the goitre in patients with Hashimoto’s thyroiditis.
There is no proven benefit in using a combined T3/T4 replacement.
Dose and administration of levothyroxine
Younger patients (under 50 years) can be started on levothyroxine 50 μg daily. Thyroid function tests are repeated after 6 weeks and the dose is increased by 25 μg until the TSH is in the normal range and ideally as close to 1.0 mU/L as possible.
Older patients should be started on a lower dose (25 μg daily) as they may have ischaemic heart disease, and levothyroxine increases myocardial oxygen demand. The dose may be gradually increased; however, a suboptimal replacement may have to be accepted if an optimal dose causes cardiac symptoms.
The average dose of levothyroxine in hypothyroid adults is about 100 μg per day, but the range varies from 50 to 200 μg daily. It is important to advise patients on the potential adverse effects of levothyroxine over-replacement, such as arrhythmias and osteoporosis.
Levothyroxine should be taken on an empty stomach, and medications that interfere with its absorption (e.g. ferrous salts, cholestyramine) should be taken several hours after the levothyroxine dose. Some drugs (e.g. phenytoin, carbamazepine) may increase levothyroxine metabolism.
Patients with poor compliance with levothyroxine replacement may occasionally receive their total weekly dose of levothyroxine once per week. This should probably be avoided in coronary heart disease.
Follow-up and monitoring
Levothyroxine has a half-life of 1 week and it takes about 6 weeks (six half-lives) to reach a steady-state concentration. Serum T4 increases first, and then TSH secretion starts to fall. Follow-up appointments for clinical assessment, measurements of thyroid function and adjustment of the dose should be arranged every 6 weeks. After stabilization of TSH levels and establishment of the proper maintenance dose, clinical assessment and serum TSH measurements should be carried out annually.
When levothyroxine is commenced, TSH occasionally rises further initially before it starts to fall. This may be because the pituitary itself has begun to suffer from the profound hypothyroidism and has failed to make TSH. On commencement of the levothyroxine, the pituitary starts to recover.
It is worth noting that hair loss may initially be made worse by commencing levothyroxine. This is because new hair follicles start growing and push up the old hair follicles. It may take about 9 months before this stabilizes.
Special circumstances
Myxoedema coma
Myxoedema coma should be treated aggressively as it has a high mortality of up to 80%. Patients should be monitored closely in an intensive care unit. Mechanical ventilation should be instituted for respiratory failure. Blood should be taken for culture, free T4, T3, TSH and cortisol before starting treatment. Treatment must be started before diagnosis is established.
No consensus has yet been reached about the optimal replacement regimen of
thyroid hormone
replacement. An accepted regimen includes the administration of intravenous levothyroxine 300–500 μg (depending on the patient’s age, weight and risk of myocardial ischaemia or arrhythmia) followed by daily intravenous doses of 50–100 μg until the patient can take oral levothyroxine. If there is no improvement within 24–48 hours, intravenous T
3
(10 μg, 8-hourly) is added.
Intravenous
hydrocortisone
(100 mg 6–8-hourly) must be given until coexisting adrenal insufficiency can be excluded.
Treat possible
precipitating factors
such as infection with broad-spectrum antibiotics.
Replace intravenous
fluids
(and glucose) appropriately.
Correct
hypothermia
using a heating blanket. Aim for an hourly rise of 0.5 °C in core temperature. Rapid external warming can cause inappropriate vasodilatation and cardiovascular collapse.
Suspected adrenal insufficiency
Levothyroxine replacement in patients with untreated adrenal insufficiency can precipitate an Addisonian crisis (see Chapter 6). A short Synacthen test should always be done prior to levothyroxine replacement if adrenal insufficiency or secondary hypothyroidism is suspected. Hydrocortisone must be given with the levothyroxine if adrenal insufficiency is confirmed.
Subclinical hypothyroidism
Indications for levothyroxine replacement in subclinical hypothyroidism include pregnancy, a serum TSH above 10 mU/L, goitre, symptoms of hypothyroidism such as fatigue, constipation or depression, or high serum antithyroid peroxidase (microsomal) antibody. Patients who are not treated should have periodic thyroid function tests to detect progression to overt hypothyroidism.
Oestrogen therapy
Oestrogens may increase the need for levothyroxine. In women receiving levothyroxine replacement, serum TSH should be measured about 12 weeks after starting oestrogen therapy to determine whether an increase in levothyroxine dose is needed.
Surgery
Patients on thyroxine replacement who are unable to eat or drink following surgery should receive intravenous levothyroxine (80% of oral dose) only if they have not resumed oral intake after 5–7 days.
Transient hypothyroidism
Transient hypothyroidism, for example following thyroiditis, can last from a few weeks to as long as 6 months. Patients with minimal symptoms may not require therapy. Symptomatic patients should receive levothyroxine for several months. A normal serum TSH level 6 weeks after stopping levothyroxine indicates a recovery of thyroid function.
Pregnancy
See Chapter 31.
Chapter 3
Thyrotoxicosis
Thyrotoxicosis is the syndrome resulting from an excess of circulating free thyroxine (T4) and/or free triiodothyronine (T3). Thyrotoxicosis may be due to either increased thyroid hormone synthesis (hyperthyroidism) or increased release of stored thyroid hormone from an inflamed thyroid gland (e.g. in subacute thyroiditis).
Primary
hyperthyroidism is characterized by raised free T
4
and/or T
3
and low thyroid-stimulating hormone (TSH). TSH is suppressed due to the negative feedback effect of thyroid hormones on TSH synthesis/secretion.
Secondary
hyperthyroidism is characterized by raised T
4
and T
3
due to increased TSH secretion from a pituitary tumour (‘thyrotroph adenoma’).
T3 toxicosis (high free T3, normal free T4, low TSH) tends to occur early in the course of hyperthyroidism, when patients have relatively few symptoms. T4 toxicosis (high free T4, normal free T3, low TSH) may be seen in hyperthyroid patients in whom a concurrent non-thyroidal illness reduces the conversion of T4 to T3.
Subclinical hyperthyroidism is defined as suppressed TSH in the presence of normal free T4 and T3. These patients may have few or no symptoms or signs of hyperthyroidism.
Epidemiology
Thyrotoxicosis affects 1% of females and 0.1% of males. Graves’ disease accounts for 70–80% of all cases of hyperthyroidism. Toxic multinodular goitre is the most common cause of hyperthyroidism in the elderly. Secondary hyperthyroidism is very rare.
Aetiology
Box 3.1 summarizes the causes of thyrotoxicosis.
Graves’ disease
Graves’ disease is caused by autoantibodies that stimulate the TSH receptor and hence thyroid hormone synthesis and secretion, and thyroid growth (causing a diffuse goitre). Possible precipitating and predisposing factors include genetic susceptibility (suggested by an association with certain alleles of CTLA-4 and HLA) and environmental factors such as infection.
The mechanisms that may be involved in the pathogenesis of Graves’ hyperthyroidism include molecular mimicry (similarity between some infectious/exogenous antigens and human proteins) and thyroid cell expression of HLA class II molecules (which may act as antigen-presenting cells to initiate an autoimmune response).
Patients with Graves’ disease may have a personal or family history of other autoimmune disorders such as vitiligo, alopecia areata, pernicious anaemia, type 1 diabetes mellitus, myasthenia gravis or coeliac disease.
Toxic multinodular goitre and toxic adenoma
These are the result of focal and/or diffuse hyperplasia of thyroid follicular cells whose function is independent of regulation by TSH. Between 20% and 80% of toxic adenomas and some nodules of toxic multinodular goitres have somatic mutations of the TSH receptor gene that confer autonomous hyperactivity.
Thyroiditis
Thyroiditis (e.g. subacute viral, postpartum) can result in thyrotoxicosis by the release of preformed thyroid hormones from a damaged thyroid gland into the circulation.
Subacute (de Quervain’s) viral thyroiditis presents initially with thyrotoxicosis followed by hypothyroidism several weeks later. Recovery of normal thyroid function occurs 3–6 months later, but 10% of patients may have late relapses. A similar but painless thyroiditis may occur 3–6 months after delivery (postpartum thyroiditis) possibly due to the exacerbation of a previously subclinical autoimmune thyroiditis. The thyrotoxic phase lasts for about 1–4 weeks.
Secondary hyperthyroidism
Secondary hyperthyroidism due to a TSH-secreting pituitary tumour is very rare. A similar biochemical picture (high free T4/T3 and normal or high TSH) may be seen in the uncommon ‘thyroid hormone resistance syndrome’ (see below).
Amiodarone
Amiodarone (an iodine-containing antiarrhythmic drug) may affect thyroid function in several ways. Amiodarone inhibits the conversion of T4 to T3 and results in a high or high-normal free T4, low-normal free T3 and initially high TSH that normalizes within 2–3 months. In addition, amiodarone may cause both hypothyroidism (see Chapter 2) and thyrotoxicosis.
In amiodarone-induced thyrotoxicosis, clinical manifestations are often masked by the drug’s beta-blocking activity. Patients may present with atrial arrhythmias, exacerbation of ischaemic heart disease or heart failure, unexplained weight loss, restlessness or low-grade fever. There are two types of amiodarone-induced thyrotoxicosis. However, some patients may have a mixture of both types:
Type 1
thyrotoxicosis is caused by amiodarone’s high iodine content, which provides the substrate for excessive thyroid hormone synthesis in patients with a previously silent multinodular goitre.
Type 2
thyrotoxicosis is due to a direct toxic effect of the drug on the thyroid gland, resulting in a destructive thyroiditis and the release of preformed T
4
and T
3
.
Subclinical hyperthyroidism
This condition may be endogenous (due to the same conditions that cause overt hyperthyroidism) or due to excess exogenous T4.
Clinical presentations
Clinical presentations of thyrotoxicosis are summarized in Box 3.2.
Examination of the neck may reveal a diffusely enlarged goitre (90% of patients with Graves’ disease), a multinodular goitre or a solitary nodule. A diffuse goitre may also be seen in painless thyroiditis and TSH-secreting pituitary tumours. Subacute (de Quervain’s) thyroiditis presents with a small tender goitre, and patients may have had a preceding flu-like illness.
Clinical signs specific to Graves’ disease include ophthalmopathy, pretibial myxoedema and thyroid acropachy. These are mediated by different autoantibodies that may co-exist in Graves’ disease.
Graves’ ophthalmopathy
Graves’ ophthalmopathy (Fig. 3.1) may be clinically obvious in 20–25% of patients with Graves’ hyperthyroidism at the time of diagnosis of the hyperthyroidism. It is more common in females. Many more (>90%) may have evidence of ophthalmopathy on computed tomography/magnetic resonance imaging (CT/MRI) of the orbits. Around 10% of patients with Graves’ ophthalmopathy do not have Graves’ disease; they may have autoimmune hypothyroidism or thyroid autoantibodies.
Graves’ ophthalmopathy may present with periorbital oedema, conjunctival oedema (chemosis) and injection, grittiness, corneal ulceration, proptosis (60%), ophthalmoplegia and diplopia (40%), retrobulbar pain or pain on eye movement, and optic nerve compression (6%), which may result in impaired visual acuity or visual field defects. Graves’ ophthalmopathy may be unilateral in 15% of patients.
Pathogenesis involves activated T cell cytokines and TSH receptor antibodies that activate TSH receptors on fibroblasts and adipocytes. This sets off an inflammatory process and causes the secretion of hydrophilic glycosaminoglycans, resulting in an increased retro-orbital volume.
Patients with thyrotoxicosis due to any cause may have lid retraction and lid lag (sclera visible above the iris as the patient looks downward) caused by sympathetic overactivity, possibly mediated by increased beta-adrenergic receptors.
Figure 3.1 Graves’ ophthalmopathy.
Pretibial myxoedema
Pretibial myxoedema (Fig. 3.2) is specific to Graves’ disease. It is seen in up to 2% of patients and results from an accumulation of hydrophilic glycosaminoglycans secreted by fibroblasts in the dermis. Pretibial myxoedema is characterized by raised, pigmented, orange-peel textured nodules or plaques on the anterior aspect of the leg or the dorsum of the foot. They are usually asymptomatic, but may be pruritic or painful.
Thyroid acropachy
Thyroid acropachy (Fig. 3.3) is seen in fewer than 1% of the patients with Graves’ disease and resembles clubbing. It is due to periosteal new bone formation in the phalanges.
Figure 3.2 Pretibial myxoedema.
Figure 3.3 Thyroid acropachy.
Thyroid storm
A thyroid storm (‘thyrotoxic crisis’) may present with:
fever, sweating
cardiovascular symptoms: tachyarrhythmias, cardiac failure
neurological symptoms: agitation, delirium, seizure, coma
gastrointestinal symptoms: diarrhoea, vomiting, jaundice.
It has an untreated mortality of 50%. It may be precipitated by thyroid surgery, radio-iodine, iodinated contrast agents, withdrawal of thionamides (antithyroid drugs) and acute illnesses such as infection, stroke, diabetic ketoacidosis or trauma.
Investigations
Thyroid function tests
In
primary hyperthyroidism
, thyroid function tests show suppressed serum TSH and high free T
4
and or free T
3
.
In
secondary hyperthyroidism
, TSH is either high or inappropriately normal in the presence of a raised free T
4
/T
3
. The differential diagnosis of this state includes thyroid hormone resistance (see below).
In
subclinical hyperthyroidism
, TSH is low, but free T
4
and free T
3
levels are normal. Therefore free T
3
levels should always be measured when TSH is low in the presence of a normal T
4
to differentiate between subclinical hyperthyroidism and T
3
thyrotoxicosis.
Patients on amiodarone therapy should have their thyroid function checked before starting therapy, every 3–4 months during treatment and for at least 1 year after the drug has been stopped.
Radioisotope uptake scan
A radioisotope (intravenous [i.v.] 99technetium pertechnetate or oral 123iodine) uptake scan is helpful in differentiating between different causes of thyrotoxicosis (Fig. 3.4):
Graves’ disease is characterized by a diffuse increased uptake of the radioisotope. (Normal uptake is up to 3% of the administered dose.)
Toxic multinodular goitre is characterized by multiple areas of increased radioisotope uptake (‘hot’ nodules) with suppression of uptake in the rest of the gland.
A solitary toxic adenoma is seen as a single area of increased radioisotope uptake (‘hot nodule’) with suppression of uptake in the rest of the gland.
A low or absent radioisotope uptake indicates either thyroiditis (inflammation and destruction of thyroid tissue) or an extra-thyroidal (e.g. exogenous) source of excess thyroid hormone.
The scanning time is earlier with 99technetium pertechnetate (maximum thyroid uptake occurring within 30 minutes of i.v. injection), and there is no need to stop antithyroid drugs before the scan (technetium is transported into the thyroid follicular cells, but it is not organified).
Patients must not have any iodine-containing medications, supplements or radiocontrast dyes before the radioisotope scan as they block radioisotope uptake. It is essential to make sure that the patient is not pregnant prior to the radioisotope scan.
TSH receptor-stimulating antibodies
TSH receptor-stimulating antibodies are positive in Graves’ disease. However, this test is expensive, and the aetiology of thyrotoxicosis can often be determined with a combination of thyroid function tests and a radioisotope uptake scan.
Some laboratories measure ‘TBII’ (TSH-binding inhibitor immunoglobulin). This test shows that there is an antibody that competes with TSH for the TSH receptor, but it does not differentiate between stimulating and blocking antibodies (some patients with Graves’ disease have a mixture of stimulating and blocking TSH receptor antibodies).
Antithyroglobulin and antithyroid peroxidase (microsomal) antibodies are present in up to 87% of patients with Graves’ disease. However, these have low specificity and are present in 15% of healthy females and 5% of males.
Figure 3.499Technetium pertechnetate uptake scan: (a) Graves’ disease, (b) toxic multinodular goitre, (c) solitary toxic adenoma, and (d) thyroiditis.
Other investigations
Thyroiditis
Erythrocyte sedimentation rate (ESR) is elevated in patients with subacute viral de Quervain’s thyroiditis.
Graves’ ophthalmopathy
CT or MRI (STIR sequence) of the orbits may be used in the assessment and follow-up of patients with Graves’ ophthalmopathy.
Secondary hyperthyroidism
A pituitary MRI should be requested in cases of secondary hyperthyroidism. A differential diagnosis of secondary hyperthyroidism is thyroid hormone resistance (see below).
Amiodarone-induced thyrotoxicosis
A detectable uptake on a radioisotope uptake scan suggests type 1 amiodarone-induced thyrotoxicosis (see above). Low or absent uptake may be due to either type 2 amiodarone-induced thyrotoxicosis (i.e. thyroiditis) or the iodine content of amiodarone itself in those who have recently been taking the drug. Therefore a radioisotope uptake scan is only useful in those who have not recently been on amiodarone, and even then it may be difficult to interpret given its very long half-life. Colour-flow Doppler ultrasonography may distinguish type 1 (increased vascularity) from type 2 (reduced vascularity) amiodarone-induced thyrotoxicosis. However, this test requires an experienced sonographer.
Treatment
All patients with primary hyperthyroidism should be told about the three options available for treatment (Box 3.3). For the treatment of secondary hyperthyroidism, see Chapter 12.
In patients with severe thyrotoxic symptoms, beta-blockers such as propranolol (20–80 mg three times a day) may be used temporarily (initially, for 4–8 weeks). Atenolol (100 mg daily) is an alternative.
Graves’ disease
In Europe, most patients with Graves’ disease below the age of 50 years receive antithyroid drugs as initial treatment (see below). Radio-iodine is more commonly used in North America. However, if thyrotoxicosis relapses, a second course of antithyroid drugs is unlikely to result in remission, and definitive treatment (radio-iodine or surgery) is preferred. An alternative is the indefinite use of low-dose antithyroid drugs, with the risk of recurrence if drugs are inadvertently stopped.
In patients with Graves’ disease who are over 50 years of age, radio-iodine or surgery should be encouraged as recurrent thyrotoxicosis may be dangerous in the presence of coincidental heart disease. A 12–18-month course of thionamides has a 50% relapse rate in women and a 95% relapse rate in men. Thus men tend to be offered radio-iodine as primary treatment.
Pre-treatment with antithyroid drugs prior to radio-iodine or surgery may be required in those who do not tolerate the symptoms of hyperthyroidism. Symptoms are usually controlled in 4–8 weeks with antithyroid drugs. Pre-treatment with antithyroid drugs may reduce the risk of thyroid storm and transient thyroiditis. However, pre-treatment with antithyroid drugs is associated with a higher rate of failure, and a larger dose of radio-iodine may be necessary.
Toxic multinodular goitre and toxic adenoma
Patients with multinodular goitre and toxic adenoma are ideally treated with radio-iodine or surgery depending on the patient’s preference. Surgery is preferred in those with retrosternal extension or large goitres. However, long-term antithyroid drugs may be used in those who refuse or cannot have radio-iodine or surgery.
Antithyroid drugs
The antithyroid drugs carbimazole, methimazole and propylthiouracil (PTU) reduce T4 and T3 production by inhibiting thyroid peroxidase. PTU also inhibits the peripheral conversion of T4 to T3. Carbimazole has the advantage of once-daily dosing. Up to 50% of female patients with Graves’ disease show sustained remission after treatment with thionamides. This may possibly be secondary to a decrease in TSH-stimulating antibody levels by these drugs.
In the titration regimen, the initial doses of carbimazole (30–40 mg per day) or PTU (300–400 mg per day) are gradually reduced over 4–8 weeks (depending on thyroid function tests) to a maintenance dose of 5–15 mg per day of carbimazole or 50–150 mg per day of PTU. A higher initial dose of carbimazole (60 mg per day) or PTU (200 mg three times a day) is occasionally required in severely thyrotoxic patients.
The antithyroid drug dose is titrated down at monthly follow-up visits, using the free T4/T3 levels as a guide. It takes longer (up to several months) for suppressed TSH levels to increase. Treatment is continued for 12–18 months with regular monitoring of thyroid function tests.
In the block and replacement regimen, carbimazole 40 mg per day or PTU 400 mg per day is started, and T4 (usually 100 μg) is added when free T4 is in the normal range (usually after about 4 weeks). This regimen is given for 18 months and requires fewer follow-up visits. The block and replacement regimen is contraindicated in pregnancy because levothyroxine crosses the placenta less well than antithyroid drugs, resulting in fetal hypothyroidism and goitre.
A rare but significant complication of antithyroid drugs is agranulocytosis, which usually occurs within the first 3 months of treatment in 0.1–0.5% of patients. Patients must be given written instructions to stop their antithyroid drug and tell their doctor immediately if they develop fever, a sore throat, mouth ulcers or any signs of infection. Patients should have their full blood count checked. Mild neutropenia (1–1.5 × 109/L) is common in patients on antithyroid drugs. However, in patients with a neutrophil count of less than 1 × 109/L, antithyroid drugs should be discontinued. Such patients need radio-iodine or urgent surgery. In the short term, beta-blockers may be used to control the symptoms.
The cut-off for intervention is controversial. Patients with a neutrophil count of less than 0.5 × 109/L and a sore throat may require admission and treatment with granulocyte colony-stimulating factor and antibiotics.
Rashes and pruritus are common side-effects of antithyroid drugs and may be treated with antihistamines without stopping treatment. Occasionally, one antithyroid drug may need to be substituted with another. Other side-effects include macular rash (1–5%), nausea, vomiting, abnormal taste/smell, arthralgia, pruritus, lymphadenopathy and deranged liver function tests (cholestatic or hepatitis). PTU may rarely be associated with antineutrophil cytoplasmic antibody positive vasculitis.
Follow-up
In both the regimens described above, drugs are discontinued after 18 months of treatment, and thyroid function tests are checked at intervals (e.g. 6-weekly for 6 months, 6-monthly for 2 years and then annually) or sooner if the patient develops symptoms suggestive of relapse. Around 70% of relapses occur in the first year; relapse is more likely in patients with a large goitre and high free T3 levels at the time of diagnosis. Those who relapse (50% of females, 95% of males) need further definitive treatment in the form of radio-iodine or surgery (thyroidectomy). Those who cannot have definitive treatment require lifelong antithyroid drug treatment. Autoimmune hypothyroidism may occur in 15% of patients with Graves’ disease.
Radio-iodine
Radio-iodine (131I) is given orally as a capsule or solution. It is concentrated in the thyroid, and its beta-emissions result in cell damage and death over a period of 6–18 weeks. Antithyroid drugs should be discontinued (about 3 days) before radio-iodine to allow uptake of the isotope by the thyroid gland.
Some centres use a fixed dose (370 or 555 MBq) to ablate the thyroid gland in Graves’ disease; others vary the dose (200–600 MBq) according to the size of the thyroid gland and the 24-hour radio-iodine uptake result. Higher doses of radio-iodine (e.g. 600–800 MBq) are used to treat toxic adenoma or toxic multinodular goitre. In patients with renal failure, doses of radio-iodine must be significantly reduced.
Most endocrinologists prefer to delay radio-iodine treatment in patients with moderate-to-severe ophthalmopathy until their eye disease has been stable for at least 1 year. Radio-iodine is occasionally given with prednisolone cover (25–30 mg per day withdrawn over 6–12 weeks).
Complications and advice for patients
Radio-iodine destroys fetal thyroid and is contraindicated in pregnancy and breast-feeding. Pregnancy is safe 4 months after radio-iodine. Patients must avoid close contact with small children for several weeks depending on the radio-iodine dose. Therefore radio-iodine may not be an option for those patients who cannot comply with the restrictions.
Most studies suggest that radio-iodine is associated with the appearance or exacerbation of Graves’ ophthalmopathy. Radio-iodine therapy is followed by a transient increase in serum TSH receptor antibodies, which might be important in initiating or exacerbating ophthalmopathy.
Radio-iodine may occasionally cause transient thyroiditis and sialoadenitis. Radio-iodine therapy for hyperthyroidism does not increase the overall risk of malignancy.
Follow-up
Antithyroid drugs may need to be started shortly after radio-iodine treatment in those who develop a transient thyroiditis. A total of 10% of patients develop permanent hypothyroidism during the first year and 2–3% annually thereafter. Therefore patients should be followed up with repeat thyroid function tests regularly in the first year and then annually. It is common practice to wait 4–6 months before repeating radio-iodine treatment in patients with persistent thyrotoxicosis because remission commonly occurs during this period.
Surgery
Surgery is an unpopular therapy for Graves’ hyperthyroidism, and the extent of surgery for Graves’ hyperthyroidism is controversial. More aggressive surgery (thyroid remnants < 4 g) is associated with a higher rate of hypothyroidism. Less aggressive surgery is associated with a higher rate of recurrent overt/subclinical hyperthyroidism. Surgery is more popular for patients with toxic multinodular goitre and toxic adenomas (see above).
Recurrence rates are about 2–4% in the best centres. The prevalence of hypothyroidism may be up to 80% several years after surgery. Other surgical complications (<1%) include hypoparathyroidism, recurrent laryngeal nerve damage and laryngeal oedema (due to bleeding into the neck).
Preparation of thyrotoxic patients for thyroidectomy
Preparation includes administration of a beta-blocker, antithyroid drugs and an excess of iodide/ iodine, for example potassium iodide 60 mg three times a day or Lugol’s iodine 0.3 mL three times a day. Iodide excess is given for 10 days before surgery to inhibit thyroid hormone synthesis (the Wolff–Chaikoff effect) and probably reduce perioperative blood loss. If the window at 10 days is missed, recurrent thyrotoxicosis occurs (the Jod–Basedow effect). PTU should be administered an hour before any iodide to prevent organification of the administered iodine.
Surgery is chosen over radio-iodine in:
patients with large goitres causing upper airway obstruction or dysphagia
patients who cannot take antithyroid drugs (e.g. due to allergy/agranulocytosis) and are either pregnant or have moderate/severe Graves’ ophthalmopathy (which may be exacerbated by radio-iodine).
Graves’ ophthalmopathy
Urgent ophthalmology review is needed in cases of visual impairment or corneal damage.
Patients should be reviewed by surgeons specialized in orbital, oculoplastic and strabismus surgery depending on their presentation. Patients must be advised to stop smoking. The treatment of Graves’ ophthalmopathy depends on the severity of symptoms:
for mild symptoms:
for congestive ophthalmopathy with visual impairment:
Orbital radiotherapy is contraindicated in patients with diabetic retinopathy. Surgical correction may also be performed for cases of diplopia or cosmetic disability. Hypothyroidism (e.g. after radioactive iodine, overtreatment with drugs) is a risk factor for developing or worsening eye disease and must be promptly corrected.
Pretibial myxoedema
Pruritus or discomfort may be treated with topical steroid ointment such as fluocinolone covered by an occlusive dressing. Systemic corticosteroid therapy may occasionally be given for resistant cases.
Special circumstances
Thyroid storm (thyrotoxic crisis)
General supportive treatments include:
close monitoring in the high-dependency or intensive therapy unit
i.v. fluids, paracetamol and cooling. Avoid aspirin (as it displaces T
4
from thyroid-binding globulin)
antiarrhythmics; when anticoagulation is given for atrial fibrillation, remember that thyrotoxic patients are very sensitive to warfarin
treating the precipitating cause, for example antibiotics for infection
chlorpromazine (50–100 mg intramuscularly) is useful for the treatment of agitation and hyperpyrexia
