Davidson's Principles and Practice of Internal Medicine 24th Edition PDF

JDC Newell-Price FW Gibb 20 Endocrinology Clinical examination in endocrine disease 648 An overview of endocrinology 650 Functional anatomy and physiology 650 Endocrine pathology 650 Investigation of endocrine disease 650 Presenting problems in endocrine disease 651 The thyroid gland 651 Functional anatomy, physiology and investigations 651 Presenting problems in thyroid disease 652 Thyrotoxicosis 652 Hypothyroidism 655 Asymptomatic abnormal thyroid function tests 659 Thyroid lump or swelling 659 Autoimmune thyroid disease 660 Transient thyroiditis 663 Iodine-associated thyroid disease 663 Simple and multinodular goitre 664 Thyroid neoplasia 665 Congenital thyroid disease 667 The reproductive system 667 Functional anatomy, physiology and investigations 667 Presenting problems in reproductive disease 668 Delayed puberty 668 Amenorrhoea 669 Male hypogonadism 670 Infertility 671 Gynaecomastia 672 Hirsutism 672 Polycystic ovary syndrome 673 Turner syndrome 674 Klinefelter syndrome 674 The adrenal glands 679 Functional anatomy and physiology 679 Presenting problems in adrenal disease 679 Cushing’s syndrome 679 Therapeutic use of glucocorticoids 684 Adrenal insufciency 685 Incidental adrenal mass 687 Primary hyperaldosteronism 687 Phaeochromocytoma and paraganglioma 688 Congenital adrenal hyperplasia 689 The endocrine pancreas and gastrointestinal tract 689 Presenting problems in endocrine pancreas disease 689 Spontaneous hypoglycaemia 689 Gastroenteropancreatic neuro-endocrine tumours 691 The hypothalamus and the pituitary gland 691 Functional anatomy, physiology and investigations 692 Presenting problems in hypothalamic and pituitary disease 693 Hypopituitarism 694 Pituitary tumour 695 Hyperprolactinaemia/galactorrhoea 696 Prolactinoma 697 Acromegaly 698 Craniopharyngioma 699 Diabetes insipidus 699 Disorders affecting multiple endocrine glands 700 Multiple endocrine neoplasia 700 Autoimmune polyendocrine syndromes 701 Endocrine effects of cancer immunotherapy 701 Late effects of childhood cancer therapy 701 Opioid-induced endocrine dysfunction 701 The parathyroid glands 675 Functional anatomy, physiology and investigations 675 Presenting problems in parathyroid disease 676 Hypercalcaemia 676 Hypocalcaemia 677 Primary hyperparathyroidism 677 Familial hypocalciuric hypercalcaemia 678 Hypoparathyroidism 678 ALGRAWANY 648  ENDOCRINOLOGY Clinical examination in endocrine disease Endocrine disease causes clinical syndromes with symptoms and signs involving many organ systems. The emphasis of the clinical examination depends on the gland or hormone that is thought to be abnormal. Diabetes mellitus (described in detail in Ch. 21) and thyroid disease are the most common endocrine disorders. 5 Head Blood pressure Hypertension in Cushing’s and Conn syndromes, phaeochromocytoma Hypotension in adrenal insufficiency 6 4 Pulse Atrial fibrillation Sinus tachycardia Bradycardia Prognathism in acromegaly 6 3 Skin Hair distribution Dry/greasy Pigmentation/pallor Bruising Vitiligo Striae Thickness Eyes Graves’ disease (see opposite) Diplopia Visual field defect (see opposite) Hair Alopecia Frontal balding 7 Neck Voice Hoarse, e.g. hypothyroid Virilised Thyroid gland (see opposite) Goitre Nodules 5 Multinodular goitre 8 8 Breasts Galactorrhoea Gynaecomastia Vitiligo in organ-specific autoimmune disease Palmar erythema Tremor Acromegaly Carpal tunnel syndrome Mental state Lethargy Depression Delirium Libido 7 4 2 Hands Facial features Hypothyroid Hirsutism Acromegaly Cushing’s 9 Body fat 3 9 10 2 11 Central obesity in Cushing's syndrome and growth hormone deficiency 10 Bones Fragility fractures (e.g. of vertebrae, neck of femur or distal radius) 11 Genitalia 12 Pigmentation of creases due to high ACTH levels in Addison’s disease Acromegalic hands. Note soft tissue enlargement causing ‘spade-like’ changes 1 Height and weight Virilisation Pubertal development Testicular volume 12 Legs 1 Proximal myopathy Myxoedema Observation  Most examination in endocrinology is by observation  Astute observation can often yield ‘spot’ diagnosis of endocrine disorders  The emphasis of examination varies depending on which gland or hormone is thought to be involved Pretibial myxoedema in Graves' disease Clinical examination in endocrine disease  649 Examination of the visual elds by confrontation Examination in Graves’ ophthalmopathy  Sit opposite patient  You and patient cover opposite eyes  Bring red pin (or wiggling finger) slowly into view from extreme of your vision, as shown  Ask patient to say ‘now’ when it comes into view  Continue to move pin into centre of vision and ask patient to tell you if it disappears  Repeat in each of four quadrants  Repeat in other eye A bitemporal hemianopia is the classical finding in pituitary macroadenomas (p. 695)  Inspect from front and side Periorbital oedema (Fig. 20.9) Conjunctival inflammation (chemosis) Corneal ulceration Proptosis (exophthalmos)* Lid retraction* Normal Proptosis Lid retraction  Range of eye movements Lid lag on descending gaze* Diplopia on lateral gaze Normal Normal descent Lid lag descent  Pupillary reflexes Afferent defect (pupils constrict further on swinging light to unaffected eye, Box 28.21)  Vision Visual acuity impaired Loss of colour vision Visual field defects Right proptosis and afferent pupillary defect  Ophthalmoscopy Optic disc pallor Papilloedema *Note position of eyelids relative to iris. 20 Examination of the thyroid gland  Inspect from front to side  Palpate from behind Thyroid moves on swallowing Check if lower margin is palpable Cervical lymph nodes Tracheal deviation Abnormal findings Diffuse soft goitre with bruit Graves’ disease (p. 660) Diffuse firm goitre Hashimoto’s thyroiditis (p. 663) Diffuse tender goitre Subacute thyroiditis (p. 663)  Auscultate for bruit Ask patient to hold breath If present, check for radiating murmur  Percuss for retrosternal thyroid Multinodular goitre (p. 664) ± Retrosternal extension, tracheal compression  Consider systemic signs of thyroid dysfunction (Box 20.7) incl. tremor, palmar erythema, warm peripheries, tachycardia, lid lag  Consider signs of Graves’ disease incl. ophthalmopathy, pretibial myxoedema Solitary nodule (p. 659) Adenoma, cyst or carcinoma Cervical lymphadenopathy Suggests carcinoma  Check for Pemberton’s sign, i.e. facial engorgement when arms raised above head ALGRAWANY 650  ENDOCRINOLOGY Endocrinology concerns the synthesis, secretion and action of hormones. These are chemical messengers released from endocrine glands that coordinate the activities of many different cells. Endocrine diseases can therefore affect multiple organs and systems. This chapter describes the principles of endocrinology before dealing with the function and diseases of each gland in turn. Some endocrine disorders are common, particularly those of the thyroid, parathyroid glands, reproductive system and β cells of the pancreas (Ch. 21). For example, thyroid dysfunction occurs in more than 10% of the population in areas with iodine deciency, such as the Himalayas, and 4% of women aged 20–50 years in the UK. Less common endocrine syndromes are described later in the chapter. Few endocrine therapies have been evaluated by randomised controlled trials, in part because hormone replacement therapy (e.g. with levothyroxine) has obvious clinical benets and placebo-controlled trials would be unethical. Where trials have been performed, they relate mainly to use of therapy that is ‘optional’ and/or more recently available, such as oestrogen replacement in post-menopausal women, androgen therapy in older men and growth hormone replacement. Neural control Feedback regulation Pituitary Trophic hormone Endocrine gland Metabolism Direct regulation Hormone Binding protein An overview of endocrinology Target organ Functional anatomy and physiology Some endocrine glands, such as the parathyroids and pancreas, respond directly to metabolic signals, but most are controlled by hormones released from the pituitary gland. Anterior pituitary hormone secretion is controlled in turn by substances produced in the hypothalamus and released into portal blood, which drains directly down the pituitary stalk (Fig. 20.1). Posterior pituitary hormones are synthesised in the hypothalamus and transported down nerve axons, to be released from the posterior pituitary. Hormone release in the hypothalamus and pituitary is regulated by numerous stimuli and through feedback control by hormones produced by the target glands (thyroid, adrenal cortex and gonads). These integrated endocrine systems are called ‘axes’ and are listed in Figure 20.2. A wide variety of molecules can act as hormones, including peptides such as insulin and growth hormone, glycoproteins such as thyroidstimulating hormone, and amines such as noradrenaline (norepinephrine). The biological effects of hormones are mediated by binding to receptors. Many receptors are located on the cell surface. These interact with various intracellular signalling molecules on the cytosolic side of the plasma membrane to affect cell function, usually through changes in gene expression. Some hormones, most notably steroids, bind to specic intracellular receptors. The hormone/receptor complex forms a ligand-activated transcription factor, which regulates gene expression directly. The classical model of endocrine function involves hormones synthesised in endocrine glands, which are released into the circulation and act at sites distant from those of secretion (as in Fig. 20.1). However, additional levels of regulation are now recognised. Many other organs secrete hormones or contribute to the peripheral metabolism and activation of prohormones. A notable example is the production of oestrogens from adrenal androgens in adipose tissue by the enzyme aromatase. Some hormones, such as neurotransmitters, act in a paracrine fashion to affect adjacent cells, or act in an autocrine way to affect behaviour of the cell that produces the hormone. Endocrine pathology For each endocrine axis or major gland, diseases can be classied as shown in Box 20.1. Pathology arising within the gland is often called ‘primary’ disease (e.g. primary hypothyroidism in Hashimoto’s thyroiditis), while abnormal stimulation of the gland is often called ‘secondary’ disease (e.g. secondary hypothyroidism in patients with a pituitary tumour Receptor Action Fig. 20.1 An archetypal endocrine axis. Regulation by negative feedback and direct control is shown, along with the equilibrium between active circulating free hormone and bound or metabolised hormone. 20.1 Classication of endocrine disease Hormone excess  Primary gland over-production  Secondary to excess trophic substance Hormone deciency  Primary gland failure  Secondary to decient trophic hormone Hormone hypersensitivity  Failure of inactivation of hormone  Target organ over-activity/hypersensitivity Hormone resistance  Failure of activation by hormone  Target organ resistance Non-functioning tumours  Benign  Malignant and thyroid-stimulating hormone deciency). Some pathological processes can affect multiple endocrine glands; these may have a genetic basis (such as organ-specic autoimmune endocrine disorders and the multiple endocrine neoplasia (MEN) syndromes) or be a consequence of therapy for another disease (e.g. following treatment of childhood cancer with chemotherapy and/or radiotherapy). Investigation of endocrine disease Biochemical investigations play a central role in endocrinology. Most hormones can be measured in blood but the circumstances in which the sample is taken are often crucial, especially for hormones with pulsatile secretion, such as growth hormone; those that show circadian variation, The thyroid gland  651 Regulation Hypothalamus Pituitary Circadian rhythm Stress Cortisol Osmolality Intravascular volume GHRH Somatostatin CRH Vasopressin GH ACTH Oestrogen Progesterone Androgen Prolactin Inhibin T3 Oestrogen Stress IGF-1 GnRH TRH Dopamine LH FSH TSH Prolactin Posterior Anterior Glands/targets Target hormones Function Gonads: testes or ovaries Thyroid Oestrogen Progesterone Androgen T4 T3 Reproduction Metabolism Breast Lactation Oxytocin Liver Adrenal cortex IGF-1 IGF-BP3 Cortisol Androgen Growth Stress Metabolism Distal nephron Uterus Breast Water balance Parturition Lactation Fig. 20.2 The principal endocrine ‘axes’. Some major endocrine glands are not controlled by the pituitary. These include the parathyroid glands (regulated by calcium concentrations, p. 675), the adrenal zona glomerulosa (regulated by the renin–angiotensin system, p.679) and the endocrine pancreas (p. 689). Italics show negative regulation. (ACTH = adrenocorticotrophic hormone; CRH = corticotrophin-releasing hormone; FSH = follicle-stimulating hormone; GH = growth hormone; GHRH = growth hormonereleasing hormone; GnRH = gonadotrophin-releasing hormone; IGF-1 = insulin-like growth factor-1; IGF-BP3 = IGF-binding protein-3; LH = luteinising hormone: T3 = triiodothyronine; T4 = thyroxine; TRH = thyrotrophin-releasing hormone; TSH = thyroid-stimulating hormone; vasopressin = antidiuretic hormone (ADH)) such as cortisol; or those that demonstrate monthly variation, such as oestrogen or progesterone. Some hormones are labile and need special collection, handling and processing requirements, e.g. collection in a special tube and/or rapid transportation to the laboratory on ice. Local protocols for hormone measurement should be carefully followed. Other investigations, such as imaging and biopsy, are more frequently reserved for patients who present with a tumour. The principles of investigation are shown in Box 20.2. The choice of test is often pragmatic, taking local access to reliable sampling facilities and laboratory measurements into account. Presenting problems in endocrine disease Endocrine diseases present in many different ways and to clinicians in many different disciplines. Classical syndromes are described in relation to individual glands in the following sections. Often, however, the presentation is with non-specic symptoms (Box 20.3) or with asymptomatic biochemical abnormalities. In addition, endocrine diseases are encountered in the differential diagnosis of common complaints discussed in other chapters of this book, including electrolyte abnormalities (Ch. 19, hypertension (Ch. 16), obesity (Ch. 22) and osteoporosis (Ch. 26). Although diseases of the adrenal glands, hypothalamus and pituitary are relatively rare, their diagnosis often relies on astute clinical observation in a patient with non-specic complaints, so it is important that clinicians are familiar with their key features. 20.2 Principles of endocrine investigation Timing of measurement  Release of many hormones is rhythmical (pulsatile, circadian or monthly), so random measurement may be invalid and sequential or dynamic tests may be required Choice of dynamic biochemical test  Abnormalities are often characterised by loss of normal regulation of hormone secretion  If hormone deciency is suspected, choose a stimulation test  If hormone excess is suspected, choose a suppression test  The more tests there are to choose from, the less likely it is that any single test is infallible, so avoid interpreting one result in isolation Imaging  ‘Functional’ as well as conventional ‘structural’ imaging can be performed as secretory endocrine cells can also take up labelled substrates, e.g. radiolabelled iodine or octreotide  Most endocrine glands have a high prevalence of ‘incidentalomas’, so do not scan unless the biochemistry conrms endocrine dysfunction or the primary problem is a tumour Biopsy  Many endocrine tumours are difcult to classify histologically (e.g. adrenal carcinoma and adenoma) Functional anatomy, physiology and investigations The thyroid gland Diseases of the thyroid, summarised in Box 20.4, predominantly affect females and are common, occurring in about 5% of the population. The thyroid axis is involved in the regulation of cellular differentiation and metabolism in virtually all nucleated cells, so that disorders of thyroid function have diverse manifestations. Structural diseases of the thyroid gland, such as goitre, commonly occur in patients with normal thyroid function. Thyroid physiology is illustrated in Figure 20.3. The parafollicular C cells secrete calcitonin, which is of no apparent physiological signicance in humans. The follicular epithelial cells synthesise thyroid hormones by incorporating iodine into the amino acid tyrosine on the surface of thyroglobulin (Tg), a protein secreted into the colloid of the follicle. Iodide is a key substrate for thyroid hormone synthesis; a dietary intake in excess of 100 µg/day is required to maintain thyroid function in adults. The thyroid secretes predominantly thyroxine (T 4) and only a small amount of ALGRAWANY 20 652  ENDOCRINOLOGY 20.3 Examples of non-specic presentations of endocrine disease* Symptom Most likely endocrine disorder(s) Lethargy and depression Hypothyroidism, diabetes mellitus, hyperparathyroidism, hypogonadism, adrenal insufciency, Cushing’s syndrome Weight gain Hypothyroidism, Cushing’s syndrome Weight loss Thyrotoxicosis, adrenal insufciency, diabetes mellitus Polyuria and polydipsia Diabetes mellitus, diabetes insipidus, hyperparathyroidism, hypokalaemia (Conn syndrome) Heat intolerance* Thyrotoxicosis Palpitation Thyrotoxicosis, phaeochromocytoma Headache Acromegaly, pituitary tumour, phaeochromocytoma Muscle weakness (usually proximal) Thyrotoxicosis, Cushing’s syndrome, hypokalaemia (e.g. Conn syndrome), hyperparathyroidism, hypogonadism Coarsening of features Acromegaly, hypothyroidism *Heat intolerance is a common feature of menopause. triiodothyronine (T3); approximately 85% of T3 in blood is produced from T4 by a family of monodeiodinase enzymes that are active in many tissues, including liver, muscle, heart and kidney. Selenium is an integral component of these monodeiodinases. T 4 can be regarded as a prohormone, since it has a longer half-life in blood than T 3 (approximately 1 week compared with approximately 18 hours), and binds and activates thyroid hormone receptors less effectively than T 3. T4 can also be converted to the inactive metabolite, reverse T 3 T3 and T4 circulate in plasma almost entirely (>99%) bound to transport proteins, mainly thyroxine-binding globulin (TBG). It is the unbound or free hormones that diffuse into tissues and exert diverse metabolic actions. Some laboratories use assays that measure total T 4 and T3 in plasma but it is increasingly common to measure free T 4 and free T3. The theoretical advantage of the free hormone measurements is that they are not inuenced by changes in the concentration of binding proteins. For example, TBG levels are increased by oestrogen (such as in the combined oral contraceptive pill) and this will result in raised total T 3 and T4, although free thyroid hormone levels are normal. Production of T3 and T4 in the thyroid is stimulated by thyrotrophin (thyroid-stimulating hormone, TSH), a glycoprotein released from the thyrotroph cells of the anterior pituitary in response to the hypothalamic tripeptide, thyrotrophin-releasing hormone (TRH). A circadian rhythm of TSH secretion can be demonstrated with a peak at 0100 hrs and trough at 1100 hrs, but the variation is small so that thyroid function can be assessed reliably from a single blood sample taken at any time of day and does not usually require any dynamic stimulation or suppression tests. There is a negative feedback of thyroid hormones on the hypothalamus and pituitary such that in thyrotoxicosis, when plasma concentrations of T 3 and T4 are raised, TSH secretion is suppressed. Conversely, in hypothyroidism due to disease of the thyroid gland, low T3 and T4 are associated with high circulating TSH levels. The relationship between TSH and T 4 is classically described as inverse log-linear (Fig. 20.4). The anterior pituitary is, though, very sensitive to minor changes in thyroid hormone levels within the reference range. For example, in an individual whose free T 4 level is usually 15 pmol/L (1.17 ng/dL), a rise or fall of 5 pmol/L (0.39 ng/dL) would be associated on the one hand with undetectable TSH, and on the other hand with a raised TSH. For this reason, TSH is usually regarded as the most useful investigation of thyroid function. However, interpretation of TSH values without considering thyroid hormone levels may be misleading 20.4 Classication of thyroid disease Primary Secondary Hormone excess Graves’ disease Multinodular goitre Adenoma Subacute thyroiditis TSHoma Hormone deciency Hashimoto’s thyroiditis Atrophic hypothyroidism Hypopituitarism Hormone hypersensitivity Hormone resistance Thyroid hormone resistance syndrome 5 -monodeiodinase deciency Non-functioning tumours Differentiated carcinoma Medullary carcinoma Lymphoma in patients with pituitary disease; for example, TSH is inappropriately low or ‘normal’ in secondary hypothyroidism (see Box 20.5 and Box 20.51). Moreover, TSH may take several weeks to ‘catch up’ with T 4 and T3 levels; for example, levothyroxine therapy will raise T 4 and T3 levels within approximately 2 weeks but it may take 4–6 weeks for the TSH to reach a steady state. Heterophilic antibodies (host antibodies with afnity to the animal antibodies used in biological assays) can also interfere with the TSH assay and cause a spurious high or low measurement. Common patterns of abnormal thyroid function test results and their interpretation are shown in Box 20.5 Other modalities commonly employed in the investigation of thyroid disease include measurement of antibodies against the TSH receptor or other thyroid antigens (see Box 20.8), radioisotope imaging, ne needle aspiration biopsy and ultrasound. Their use is described below. Presenting problems in thyroid disease The most common presentations are hyperthyroidism (thyrotoxicosis), hypothyroidism and enlargement of the thyroid (goitre or thyroid nodule). Widespread availability of thyroid function tests has led to the increasingly frequent identication of patients with abnormal results who either are asymptomatic or have non-specic complaints such as tiredness and weight gain. Thyrotoxicosis Thyrotoxicosis describes a constellation of clinical features arising from elevated circulating levels of thyroid hormone. The most common causes are Graves’ disease, multinodular goitre, autonomously functioning thyroid nodules (toxic adenoma) and thyroiditis (Box 20.6). Clinical assessment The clinical manifestations of thyrotoxicosis are shown in Box 20.7 and an approach to differential diagnosis is given in Figure 20.5. The most common symptoms are weight loss with a normal or increased appetite, heat intolerance, palpitations, tremor and irritability. Tachycardia, palmar erythema and lid lag are common signs. Not all patients have a palpable goitre, but experienced clinicians can discriminate the diffuse soft goitre of Graves’ disease from the irregular enlargement of a multinodular goitre. All causes of thyrotoxicosis can cause lid retraction and lid lag, due to potentiation of sympathetic innervation of the levator palpebrae muscles, but only Graves’ disease causes other features of ophthalmopathy, including periorbital oedema, conjunctival irritation, exophthalmos The thyroid gland  653 NH2 CH2 HO MIT Tg CH COOH T4 3 CH COOH NH2 CH2 HO CH COOH 5 Follicular cell NH2 Diiodotyrosine (DIT) Stimulates all 8 steps 1 + hyperplasia 6 Iodide MIT DIT 7 8 Triiodothyronine (T3) O CH2 Thyroxine (T4) O HO CH COOH TSH Extracellular Iodide fluid T3 T 4 Target tissues NH2 CH2 Reverse T3 (rT3) O Red blood cells 2 NH2 CH COOH rT3 Blood HO T4 T3 4 HO Colloid Follicular epithelium 1 Monoiodotyrosine (MIT) CH2 4 MIT Tg T3 Tg 3 HO Parafollicular (C) cells DIT DIT Colloid Tyrosine NH2 CH2 Negative feedback CH COOH Free T4,T3 ( < 1%) T4 8 T3 Increased metabolic rate Mimic -adrenergic action, e.g. on heart rate, gut motility CNS activation Bone demineralisation Cellular differentiation etc. Protein-bound T4, T3 ( > 99%) Fig. 20.3 Structure and function of the thyroid gland. (1) Thyroglobulin (Tg) is synthesised and secreted into the colloid of the follicle. (2) Inorganic iodide (I ) is actively transported into the follicular cell (‘trapping’). (3) Iodide is transported on to the colloidal surface by a transporter (pendrin, defective in Pendred syndrome, p. 667) and ‘organied’ by the thyroid peroxidase enzyme, which incorporates it into the amino acid tyrosine on the surface of Tg to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). (4) Iodinated tyrosines couple to form triiodothyronine (T 3) and thyroxine (T4). (5) Tg is endocytosed. (6) Tg is cleaved by proteolysis to free the iodinated tyrosine and thyroid hormones. (7) Iodinated tyrosine is dehalogenated to recycle the iodide. (8) T 4 is converted to T3 by 5 -monodeiodinase. (CNS = central nervous system; TSH = thyroidstimulating hormone) 20 and diplopia. Pretibial myxoedema (see p. 663) and the rare thyroid acropachy (a periosteal hypertrophy, indistinguishable from nger clubbing) are also specic to Graves’ disease. 2.5 2.0 Investigations 1.5 LogTSH (mlU/L) 1.0 0.5 0 -0.5 5 10 15 20 25 30 35 40 45 50 55 Free T4 (pmol/L) -1.0 -1.5 -2.0 -2.5 Fig. 20.4 The relationship between serum thyroid-stimulating hormone (TSH) and free T4. Due to the classic negative feedback loop between T 4 and TSH, there is an inverse relationship between serum free T 4 and the log of serum TSH. To convert pmol/L to ng/dL, divide by 12.87. The rst-line investigations are serum T 3, T4 and TSH. If abnormal values are found, the tests should be repeated and the abnormality conrmed in view of the likely need for prolonged medical treatment or destructive therapy. In most patients, serum T 3 and T4 are both elevated, but T4 is in the upper part of the reference range and T 3 is raised (T3 toxicosis) in about 5%. Serum TSH is undetectable in primary thyrotoxicosis, but values can be raised in the very rare syndrome of secondary thyrotoxicosis caused by a TSH-producing pituitary adenoma. When biochemical thyrotoxicosis has been conrmed, measurement of TSH receptor antibodies (TRAb, elevated in Graves’ disease; Box 20.8) is recommended. Where TRAb is not available, radioisotope scanning is an alternative diagnostic approach, as shown in Figure 20.5. Other non-specic abnormalities are common (Box 20.9). An electrocardiogram (ECG) may demonstrate sinus tachycardia or atrial brillation. Radio-iodine uptake tests measure the proportion of isotope that is trapped in the whole gland but have been largely superseded by 99mtechnetium scintigraphy scans, which also indicate trapping, are quicker to perform with a lower dose of radioactivity, and provide a higher-resolution image. In low-uptake thyrotoxicosis, the cause is usually a transient thyroiditis. Occasionally, patients induce ‘factitious thyrotoxicosis’ by consuming excessive amounts of a thyroid hormone preparation, most often levothyroxine. The exogenous levothyroxine suppresses pituitary TSH secretion and hence iodine uptake, serum thyroglobulin and release ALGRAWANY 654  ENDOCRINOLOGY 20.5 How to interpret thyroid function test results TSH T4 T3 Most likely interpretation(s) Undetectable Raised Raised Primary thyrotoxicosis Undetectable or low Raised Normal Over-treatment of hypothyroidism with levothyroxine Factitious thyrotoxicosis Undetectable Normal1 Raised Primary T3 toxicosis Undetectable Normal1 Normal1 Subclinical thyrotoxicosis Undetectable or low Raised Low or normal Non-thyroidal illness Amiodarone therapy Undetectable or low Low Raised Over-treatment of hypothyroidism with liothyronine (T3) Undetectable Low Low Secondary hypothyroidism4 Transient thyroiditis in evolution Normal Low Low2 Secondary hypothyroidism4 Mildly elevated 5–20 mIU/L Low 2 Low Primary hypothyroidism Secondary hypothyroidism4 Elevated >20 mIU/L Low Low2 Primary hypothyroidism Mildly elevated 5–20 mIU/L Normal3 Normal2 Subclinical hypothyroidism Elevated 20–500 mIU/L Normal Normal Artefact Heterophilic antibodies (host antibodies with afnity to the animal antibodies used in TSH assays) Elevated Raised Raised Non-adherence to levothyroxine replacement – recent ‘loading’ dose Secondary thyrotoxicosis4 Thyroid hormone resistance 1 Usually upper part of reference range. 2T3 is not a sensitive indicator of hypothyroidism and should not be requested. 3Usually lower part of reference range. 4i.e. Secondary to pituitary or hypothalamic disease. Note that TSH assays may report detectable TSH. (TSH = thyroid-stimulating hormone) 20.6 Causes of thyrotoxicosis and their relative frequencies of negligible iodine uptake, high T 4:T3 ratio and a low or undetectable thyroglobulin is diagnostic. Cause Frequency 1 (%) Management Graves’ disease 76 Multinodular goitre 14 Solitary thyroid adenoma 5 Thyroiditis Subacute (de Quervain’s)2 Post-partum2 3 0.5 Denitive treatment of thyrotoxicosis depends on the underlying cause and may include antithyroid drugs, radioactive iodine or surgery. A non-selective β-adrenoceptor antagonist (β-blocker), such as propranolol (160 mg daily), will alleviate but not abolish symptoms in most patients within 24–48 hours. Beta-blockers should not be used for long-term treatment of thyrotoxicosis but are extremely useful in the short term, while patients are awaiting hospital consultation or following 131 I therapy. Verapamil may be used as an alternative to β-blockers, e.g. in patients with asthma, but usually is only effective in improving tachycardia and has little effect on the other systemic manifestations of thyrotoxicosis. Iodide-induced Drugs (amiodarone)2 Radiographic contrast media2 Iodine supplementation programme2 Extrathyroidal source of thyroid hormone Factitious thyrotoxicosis2 Struma ovarii2,3 TSH-induced TSH-secreting pituitary adenoma Choriocarcinoma and hydatidiform mole4 Follicular carcinoma±metastases 1 0.2 0.2 0.1 1 ln a series of 2087 patients presenting to the Royal Inrmary of Edinburgh over a 10-year period. 2Characterised by negligible radioisotope uptake. 3i.e. Ovarian teratoma containing thyroid tissue. 4Human chorionic gonadotrophin has thyroid-stimulating activity. (TSH = thyroid-stimulating hormone) of endogenous thyroid hormones. The T 4:T3 ratio (typically 30:1 in conventional thyrotoxicosis) is increased to above 70:1 because circulating T3 in factitious thyrotoxicosis is derived exclusively from the peripheral monodeiodination of T4 and not from thyroid secretion. The combination Atrial brillation in thyrotoxicosis Atrial brillation occurs in about 10% of patients with thyrotoxicosis. The incidence is higher in men and increases with age, so that almost half of all males with thyrotoxicosis over the age of 60 are affected. Moreover, subclinical thyrotoxicosis (see p. 659) is a risk factor for atrial brillation. Characteristically, the ventricular rate is little inuenced by digoxin but responds to the addition of a β-blocker. Thromboembolic vascular complications are particularly common in thyrotoxic atrial brillation so that anticoagulation is required, unless contraindicated. Once thyroid hormone and TSH concentrations have been returned to normal, atrial brillation will spontaneously revert to sinus rhythm in about 50% of patients but cardioversion may be required in the remainder. Thyrotoxic crisis (‘thyroid storm’) This is a rare but life-threatening complication of thyrotoxicosis. The most prominent signs are fever, agitation, delirium, tachycardia or atrial brillation and, in the older patient, cardiac failure. Thyrotoxic crisis is a The thyroid gland  655 20.7 Clinical features of thyroid dysfunction Common Weight loss despite normal or increased appetite Heat intolerance, sweating Palpitations, tremor Dyspnoea, fatigue Irritability, emotional lability Weight loss Tremor Palmar erythema Sinus tachycardia Lid retraction, lid lag Weight gain Cold intolerance Fatigue, somnolence Dry skin Dry hair Menorrhagia Weight gain Goitre with bruit1 Atrial brillation2 Systolic hypertension/increased pulse pressure Cardiac failure2 Hyper-reexia Ill-sustained clonus Proximal myopathy Bulbar myopathy2 Constipation Hoarseness Carpal tunnel syndrome Alopecia Aches and pains Muscle stiffness Deafness Depression Infertility Hoarse voice Facial features: Purplish lips Malar ush Periorbital oedema Loss of lateral eyebrows Anaemia Carotenaemia Erythema ab igne Bradycardia hypertension Delayed relaxation of reexes Dermal myxoedema Gynaecomastia Spider naevi Onycholysis Pigmentation Psychosis (myxoedema madness) Galactorrhoea Impotence Ileus, ascites Pericardial and pleural effusions Cerebellar ataxia Myotonia Less common Osteoporosis (fracture, loss of height) Diarrhoea, steatorrhoea Angina Ankle swelling Anxiety, psychosis Muscle weakness Periodic paralysis (predominantly in Chinese and other Asian groups) Pruritus, alopecia Amenorrhoea/oligomenorrhoea Infertility, spontaneous abortion Loss of libido, impotence Excessive lacrimation Rare Vomiting Apathy Anorexia Exacerbation of asthma 1 ln Graves’ disease only. 2Features found particularly in older patients. 20.8 Prevalence of thyroid autoantibodies (%) 20 Antibodies to: Thyroid peroxidase1 Thyroglobulin Normal population 8–27 5–20 0 Graves’ disease 50–80 50–70 >95 Autoimmune hypothyroidism 90–100 80–90 10–20 Multinodular goitre ~30–40 ~30–40 0 Transient thyroiditis ~30–40 ~30–40 1 TSH receptor 2 0 2 Thyroid peroxidase (TPO) antibodies are the principal component of what was previously measured as thyroid ‘microsomal’ antibodies. Thyroid-stimulating hormone receptor antibodies (TRAb) can be agonists (stimulatory, causing Graves’ thyrotoxicosis) or antagonists (‘blocking’, causing hypothyroidism). medical emergency and has a mortality of 10% despite early recognition and treatment. It is most commonly precipitated by infection in a patient with previously unrecognised or inadequately treated thyrotoxicosis. It may also develop in known thyrotoxicosis shortly after thyroidectomy in an ill-prepared patient or within a few days of 131I therapy, when acute radiation damage may lead to a transient rise in serum thyroid hormone levels. Urgent specialist endocrine input should be sought in cases of suspected ‘thyroid storm’, both to conrm the diagnosis and provide advice on appropriate treatment. Patients should be rehydrated and given propranolol, either orally (80 mg 4 times daily) or intravenously (1–5 mg 4 times daily). Both glucocorticoids (hydrocortisone 100 mg IV every 8 hours) and iodine are important in reducing the conversion of T 4 to active T3. Sodium ipodate, a radiographic contrast medium (500 mg per day orally), will restore serum T3 levels to normal in 48–72 hours. Where sodium ipodate is not available, potassium iodide or Lugol’s solution are reasonable alternatives. Oral propylthiouracil (PTU) (200 mg every 4 hours) should be given to inhibit the synthesis of new thyroid hormone. PTU is preferred to carbimazole (20 mg every 6 hours) as it also inhibits the conversion of T 4 to T3. If the patient is unconscious or uncooperative, PTU and propranolol can be administered by nasogastric tube. After 10–14 days the patient can usually be maintained on carbimazole alone. Hyperthyroidism in old age Some of the diagnostic and management challenges of hyperthyroidism in older people are highlighted in Box 20.12 Hypothyroidism Hypothyroidism is a common condition with various causes (Box 20.10), but autoimmune disease (Hashimoto’s thyroiditis) and thyroid failure following 131I or surgical treatment of thyrotoxicosis account for over 90% of cases, except in areas where iodine deciency is endemic. Women are affected approximately six times more frequently than men. ALGRAWANY 656  ENDOCRINOLOGY TSH and T3 ± T4 Scenario? Possible non-thyroidal illness Repeat when acute illness has resolved Clinically thyrotoxic TSH receptor antibodies1 Not available Positive Negative Any features of Graves’ disease?  Diffuse goitre with bruit  Ophthalmopathy2  Pretibial myxoedema Any features of non-Graves’ thyrotoxicosis?  Recent (< 6 months) pregnancy  Neck pain/flu-like illness  Drugs (amiodarone, T4)3  Palpable multinodular goitre or solitary nodule Yes No Thyroid scintigraphy4 No Low-uptake thyrotoxicosis  Transient thyroiditis  Extrathyroidal T4 source Toxic adenoma Toxic multinodular goitre Graves’ disease Fig. 20.5 Establishing the differential diagnosis in thyrotoxicosis. 1Thyroid-stimulating hormone (TSH) receptor antibodies are very rare in patients without autoimmune thyroid disease but occur in only 80%–95% of patients with Graves’ disease; a positive test is therefore conrmatory but a negative test does not exclude Graves’ disease. Other thyroid antibodies (e.g. anti-peroxidase and anti-thyroglobulin antibodies) are unhelpful in the differential diagnosis since they occur frequently in the population and are found with several of the disorders that cause thyrotoxicosis. 2Graves’ ophthalmopathy refers to clinical features of exophthalmos and periorbital and conjunctival oedema, not simply the lid lag and lid retraction that can occur in all forms of thyrotoxicosis. 3Scintigraphy is not necessary in most cases of drug-induced thyrotoxicosis. 4 99mTechnetium pertechnetate scans of patients with thyrotoxicosis. In low-uptake thyrotoxicosis, most commonly due to a viral, post-partum or iodine-induced thyroiditis, there is negligible isotope detected in the region of the thyroid, although uptake is apparent in nearby salivary glands (not shown here). In a toxic adenoma there is lack of uptake of isotope by the rest of the thyroid gland due to suppression of serum TSH. In multinodular goitre there is relatively low, patchy uptake within the nodules; such an appearance is not always associated with a palpable thyroid. In Graves’ disease there is diffuse uptake of isotope. 20.9 Non-specic laboratory abnormalities in thyroid dysfunction* Thyrotoxicosis  Serum enzymes: raised alanine aminotransferase, γ-glutamyl transferase (GGT), and alkaline phosphatase from liver and bone  Raised bilirubin  Mild hypercalcaemia  Glycosuria: associated diabetes mellitus, ‘lag storage’ glycosuria Hypothyroidism  Serum enzymes: raised creatine kinase, aspartate aminotransferase, lactate dehydrogenase (LDH)  Hypercholesterolaemia  Anaemia: normochromic normocytic or macrocytic  Hyponatraemia *These abnormalities are not useful in differential diagnosis, so the tests should be avoided and any further investigation undertaken only if abnormalities persist when the patient is euthyroid. Clinical assessment The clinical presentation depends on the duration and severity of the hypothyroidism. Those in whom complete thyroid failure has developed insidiously over months or years may present with many of the clinical features listed in Box 20.7. A consequence of prolonged hypothyroidism is the inltration of many body tissues by the mucopolysaccharides hyaluronic acid and chondroitin sulphate, resulting in a low-pitched voice, poor hearing, slurred speech due to a large tongue, and compression of the median nerve at the wrist (carpal tunnel syndrome). Inltration of the dermis gives rise to non-pitting oedema (myxoedema), which is most marked in the skin of the hands, feet and eyelids. The resultant periorbital pufness is often striking and may be combined with facial pallor due to vasoconstriction and anaemia, or a lemon-yellow tint to the skin caused by carotenaemia, along with purplish lips and malar ush. Most cases of hypothyroidism are not clinically obvious, however, and a high index of suspicion needs to be maintained so that the diagnosis is not overlooked in individuals complaining of non-specic symptoms such as tiredness, weight gain, depression or carpal tunnel syndrome. The thyroid gland  657 The key discriminatory features in the history and examination are highlighted in Figure 20.6. Care must be taken to identify patients with transient hypothyroidism, in whom life-long levothyroxine therapy is inappropriate. This can be observed during the rst 6 months after 131I treatment of Graves’ disease, in the post-thyrotoxic phase of subacute thyroiditis and in post-partum thyroiditis. In these conditions, levothyroxine treatment is not always necessary, as the patient may be asymptomatic during the short period of thyroid failure. 20.10 Causes of hypothyroidism Causes Anti-TPO antibodies1 Goitre2 ++ ± + ± + + ± + + ± ± ± + + ± ± – ++ Autoimmune Hashimoto’s thyroiditis Spontaneous atrophic hypothyroidism Graves’ disease with TSH receptor-blocking antibodies Investigations In the vast majority of cases, hypothyroidism results from an intrinsic disorder of the thyroid gland (primary hypothyroidism). In this situation, serum T4 is low and TSH is elevated, usually in excess of 20 mIU/L. Measurements of serum T3 are unhelpful since they do not discriminate reliably between euthyroidism and hypothyroidism. Measurement of thyroid peroxidase antibodies is helpful but further investigations are rarely required (Fig. 20.6). Secondary hypothyroidism is rare and is caused by failure of TSH secretion in an individual with hypothalamic or anterior pituitary disease. Other non-specic abnormalities are shown in Box 20.9. In severe, prolonged hypothyroidism, the ECG classically demonstrates sinus bradycardia with low-voltage complexes and ST-segment and T-wave abnormalities. Iatrogenic Radioactive iodine ablation Thyroidectomy Drugs Carbimazole, methimazole, propylthiouracil Amiodarone Lithium Transient thyroiditis Subacute (de Quervain’s) thyroiditis Post-partum thyroiditis Iodine deciency e.g. In mountainous regions Management Congenital Dyshormonogenesis Thyroid aplasia ++ Inltrative Amyloidosis, Riedel’s thyroiditis, sarcoidosis etc. + ++ – – Secondary hypothyroidism TSH deciency 1 As shown in Box 20.8, thyroid autoantibodies are common in the healthy population, so might be present in anyone. ++ high titre; + more likely to be detected than in the healthy population; – not especially likely. 2Goitre: – absent; ± may be present; ++ characteristic. (TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone) Treatment is with levothyroxine replacement. The average replacement dose of levothyroxine is 1.6 μg/kg, which equates to around 100 μg in a 70 kg adult. In healthy younger adults it is safe to commence an estimated full dose. In older individuals, and those with a history of cardiovascular disease, it is customary to start with a low dose of 50 µg per day for 3 weeks before increasing to the estimated full dose. Levothyroxine has a half-life of 7 days so it should always be taken as a single daily dose and at least 10 weeks should pass before repeating thyroid function tests (as TSH takes several weeks to reach a steady state) and adjusting the dose. Patients feel better within 2–3 weeks. Reduction in weight and periorbital pufness occurs quickly but the restoration of skin 20  TSH and  T4 Any features of secondary hypothyroidism? 4 TSH < 20 mlU/L1 Scenario? Possible non-thyroidal illness 2 Repeat when acute illness has resolved TSH > 20 mlU/L No Any features of transient thyroiditis?  Neck pain  < 12 months post-partum  Recent symptoms of thyrotoxicosis No Relevant drugs?  Amiodarone  Lithium No Thyroid ablation? Positive antithyroid No peroxidase antibodies?3 Yes Yes Yes Temporary T4 replacement4  After 4 months with normal TSH, reduce to 50 g/day for 6 weeks and repeat TSH  If normal, stop T4 for 6 weeks and repeat No T4 replacement for as long as other drug is required Yes Hashimoto’s thyroiditis Goitre? No Yes Spontaneous atrophic hypothyroidism Permanent T4 replacement Consider rare causes and refer to specialist4 Fig. 20.6 An approach to adults with suspected primary hypothyroidism. This scheme ignores congenital causes of hypothyroidism (see Box 20.10), such as thyroid aplasia and dyshormonogenesis (associated with nerve deafness in Pendred syndrome, p. 667), which are usually diagnosed in childhood. 1Immunoreactive thyroid-stimulating hormone (TSH) may be detected at normal or even modestly elevated levels in patients with pituitary failure; unless T 4 is only marginally low, TSH should be >20 mIU/L to conrm the diagnosis of primary hypothyroidism. 2The usual abnormality in sick euthyroidism is a low TSH but any pattern can occur. 3Thyroid peroxidase (TPO) antibodies are highly sensitive but not very specic for autoimmune thyroid disease (see Boxes 20.8 and 20.10). 4Specialist advice is most appropriate where indicated. Secondary hypothyroidism is rare, but is suggested by deciency of pituitary hormones or by clinical features of pituitary tumour such as headache or visual eld defect (p. 695). Rare causes of hypothyroidism with goitre include dyshormonogenesis and inltration of the thyroid (see Box 20.10). ALGRAWANY 658  ENDOCRINOLOGY and hair texture and resolution of any effusions may take 3–6 months. As illustrated in Figure 20.6, most patients do not require specialist review but will need life-long levothyroxine therapy. The dose of levothyroxine should be adjusted to maintain serum TSH within the reference range. To achieve this, serum T 4 often needs to be in the upper part of the reference range because the T 3 required for receptor activation is derived exclusively from conversion of T 4 within the target tissues, without the usual contribution from thyroid secretion. Some physicians advocate combined replacement with T 4 (levothyroxine) and T3 (liothyronine) or preparations of animal thyroid extract but this approach remains controversial and is not supported by robust evidence. Some patients remain symptomatic despite normalisation of TSH and may wish to take extra levothyroxine, which suppresses TSH. However, suppressed TSH is a risk factor for osteoporosis and atrial brillation (see below; subclinical thyrotoxicosis), so this approach cannot be recommended. It is important to measure thyroid function every 1–2 years once the dose of levothyroxine is stabilised. This encourages adherence to therapy and allows adjustment for variable underlying thyroid activity and other changes in levothyroxine requirements (Box 20.11). Some patients have a persistent elevation of serum TSH despite an ostensibly adequate replacement dose of levothyroxine; most commonly, this is a consequence of suboptimal concordance. There may be differences in bioavailability between the numerous generic preparations of levothyroxine and so, if an individual is experiencing marked changes in serum TSH despite optimal adherence, the prescription of a branded preparation of levothyroxine could be considered. There is some limited evidence that suggests levothyroxine absorption may be better when the drug is taken before bed. In some individuals with variable concordance, levothyroxine is taken diligently or even in excess for a few days prior to a clinic visit, resulting in the seemingly anomalous combination of a high serum T 4 and high TSH (see Box 20.5). dose and increased very slowly under specialist supervision. Coronary intervention may be required if angina is exacerbated by levothyroxine replacement therapy. Hypothyroidism in old age Box 20.12 illustrates some of the diagnostic and management challenges of hypothyroidism in older people. Hypothyroidism in pregnancy Women with hypothyroidism usually require an increased dose of levothyroxine in pregnancy; inadequately treated hypothyroidism in pregnancy has been associated with impaired cognitive development in the fetus. This is discussed in more detail on page 1273 (see also Box 20.13). 20.12 The thyroid gland in old age Thyrotoxicosis  Causes: commonly due to multinodular goitre.  Clinical features: apathy, anorexia, proximal myopathy, atrial brillation and cardiac failure predominate.  Non-thyroidal illness: thyroid function tests are performed more frequently in older patients but interpretation may be altered by intercurrent illness. Hypothyroidism  Clinical features: non-specic features, such as physical and mental slowing, are often attributed to increasing age and the diagnosis is delayed.  Myxoedema coma: more likely in older people.  Levothyroxine dose: to avoid exacerbating latent or established heart disease, the starting dose should be 25–50 µg daily. Levothyroxine requirements fall with increasing age and few patients need more than 100 µg daily.  Other medication (see Box 20.10): may interfere with absorption or metabolism of levothyroxine, necessitating an increase in dose. Levothyroxine replacement in ischaemic heart disease Hypothyroidism and ischaemic heart disease are common conditions that often occur together. Although angina may remain unchanged in severity or paradoxically disappear with restoration of metabolic rate, exacerbation of myocardial ischaemia, infarction and sudden death are recognised complications of levothyroxine replacement, even using doses as low as 25 µg per day. In patients with known ischaemic heart disease, thyroid hormone replacement should be introduced at low 20.11 Situations in which an adjustment of the dose of levothyroxine may be necessary 20.13 Thyroid disease in pregnancy Normal pregnancy  Trimester-specic reference ranges: should be used to interpret thyroid function test results in pregnancy. Iodine deciency  Iodine requirements: increased in pregnancy. The World Health Organization (WHO) recommends a minimum intake of 250 µg/day.  Iodine deciency: the major cause of preventable impaired cognitive development in children worldwide. Increased dose required Hypothyroidism Pregnancy or oestrogen therapy  Impaired cognitive development in the offspring: may be associated with hypothyroidism that is not adequately treated.  Levothyroxine replacement therapy dose requirements: increase by 30%–50% from early in pregnancy. Monitoring to maintain TSH results within the trimester-specic reference range is recommended in early pregnancy and at least once in each trimester.  Increases concentration of serum thyroxine-binding globulin Use of other medication  Increase T4 clearance: phenobarbital, phenytoin, carbamazepine, rifampicin, sertraline*, chloroquine*  Interfere with intestinal T4 absorption: colestyramine, sucralfate, aluminium hydroxide, ferrous sulphate, dietary bre supplements, calcium carbonate Thyrotoxicosis Ageing  Gestational thyrotoxicosis: associated with multiple pregnancies and hyperemesis gravidarum. Transient and usually does not require antithyroid drug treatment.  Graves’ disease: the most common cause of sustained thyrotoxicosis in pregnancy.  Antithyroid drugs: propylthiouracil should be used in the rst trimester, with carbimazole substituted in the second and third trimesters.  Decreases T4 clearance Post-partum thyroiditis Graves’ disease developing in patient with long-standing primary hypothyroidism  Screening: not recommended for every woman, but thyroid function should be tested 4–6 weeks post partum in those with a personal history of thyroid disease, goitre or other autoimmune disease including type 1 diabetes, in those known to have positive antithyroid peroxidase antibodies, or when there is clinical suspicion of thyroid dysfunction. After surgical or 131I ablation of Graves’ disease  Reduces thyroidal secretion with time Malabsorption Decreased dose required  Switch from production of blocking to stimulating TSH receptor antibodies *Mechanism not fully established. The thyroid gland  659 Myxoedema coma This is a very rare presentation of hypothyroidism in which there is a depressed level of consciousness, usually in an older patient who appears myxoedematous. Body temperature may be as low as 25°C, convulsions are not uncommon, and cerebrospinal uid (CSF) pressure and protein content are raised. The mortality rate is 50% and survival depends on early recognition and treatment of hypothyroidism and other factors contributing to the altered consciousness level, such as medication, cardiac failure, pneumonia, dilutional hyponatraemia and respiratory failure. Myxoedema coma is a medical emergency and treatment must begin before biochemical conrmation of the diagnosis. Suspected cases should be treated with an intravenous injection of 20 µg liothyronine, followed by further injections of 20 µg 3 times daily until there is sustained clinical improvement. In survivors, there is a rise in body temperature within 24 hours and, after 48–72 hours, it is usually possible to switch patients to oral levothyroxine in a dose of 50 µg daily. Unless it is apparent that the patient has primary hypothyroidism, the thyroid failure should also be assumed to be secondary to hypothalamic or pituitary disease and treatment given with hydrocortisone 100 mg intramuscularly 3 times daily, pending the results of T 4, TSH and cortisol measurement. Other measures include slow rewarming, cautious use of intravenous uids, broad-spectrum antibiotics and high-ow oxygen. Symptoms of hypothyroidism with normal thyroid function tests The classic symptoms of hypothyroidism are, by their very nature, non-specic (see Box 20.3). There is a wide differential diagnosis for symptoms such as ‘fatigue’, ‘weight gain’ and ‘low mood’. As has been noted, outside the context of pituitary and hypothalamic disease, serum TSH is an excellent measure of an individual’s thyroid hormone status. However, some individuals believe that they have hypothyroidism despite normal serum TSH concentrations. There are a large number of websites that claim that serum TSH is not a good measure of thyroid hormone status and suggest that other factors, such as abnormalities of T 4 to T3 conversion, may lead to low tissue levels of active thyroid hormones. Such websites often advocate a variety of tests of thyroid function of dubious scientic validity, including measurement of serum reverse T 3, 24-hour urine T3, basal body temperature, skin iodine absorption, and levels of selenium in blood and urine. Individuals who believe they have hypothyroidism, despite normal conventional tests of thyroid function, can be difcult to manage. They require reassurance that their symptoms are being taken seriously and that organic disease has been carefully considered; if their symptoms persist, referral to a team specialising in medically unexplained symptoms should be considered. there is a risk of progression to overt thyroid failure, particularly if antibodies to thyroid peroxidase are present or if the TSH rises above 10 mIU/L. In patients with non-specic symptoms, a trial of levothyroxine therapy may be appropriate. In those with positive autoantibodies or a TSH greater than 10 mIU/L, it is better to treat the thyroid failure early rather than risk loss to follow-up and subsequent presentation with profound hypothyroidism. Levothyroxine should be given in a dose sufcient to restore the serum TSH concentration to normal. Non-thyroidal illness (‘sick euthyroidism’) This typically presents with a low serum TSH, raised T 4 and normal or low T3 in a patient with systemic illness who does not have clinical evidence of thyroid disease. These abnormalities are caused by decreased peripheral conversion of T4 to T3 (with conversion instead to reverse T 3), altered levels of binding proteins and their afnity for thyroid hormones, and often reduced secretion of TSH. During convalescence, serum TSH concentrations may increase to levels found in primary hypothyroidism. As thyroid function tests are difcult to interpret in patients with non-thyroidal illness, it is wise to avoid performing thyroid function tests unless there is clinical evidence of concomitant thyroid disease. If an abnormal result is found, treatment should only be given with specialist advice and the diagnosis should be re-evaluated after recovery. Thyroid lump or swelling A lump or swelling in the thyroid gland can be a source of considerable anxiety for patients. There are numerous causes but, broadly speaking, a thyroid swelling is either a solitary nodule, a multinodular goitre or a diffuse goitre (Box 20.14). Nodular thyroid disease is more common in women and occurs in approximately 30% of the adult female population. The majority of thyroid nodules are impalpable but may be identied when imaging of the neck is performed for another reason, such as during Doppler ultrasonography of the carotid arteries or computed tomographic pulmonary angiography. Increasingly, thyroid nodules are identied during staging of patients with cancer with computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET) scans. Palpable thyroid nodules occur in 4%–8% of adult women and 1%–2% of adult men, and classically present when the individual (or a friend or relative) notices a lump in the neck. Multinodular goitre and solitary nodules sometimes present with acute painful enlargement due to haemorrhage into a nodule. Patients with thyroid nodules often worry that they have cancer but the reality is that only 5%–10% of thyroid nodules are malignant. A nodule presenting in childhood or adolescence, particularly if there is a past history of head and neck irradiation, or one presenting in an older patient should heighten suspicion of a primary thyroid malignancy. The presence of cervical lymphadenopathy also increases the likelihood of malignancy. Asymptomatic abnormal thyroid function tests One of the most common problems in medical practice is how to manage patients with abnormal thyroid function tests who have no obvious signs or symptoms of thyroid disease. These can be divided into three categories. Subclinical thyrotoxicosis Serum TSH is undetectable and serum T 3 and T4 are at the upper end of the reference range. This combination is most often found in older patients with multinodular goitre. These patients are at increased risk of atrial brillation and osteoporosis, and hence the consensus view is that they have mild thyrotoxicosis and require therapy, either with 131I or low dose thionamide. Otherwise, annual review is essential, as the conversion rate to overt thyrotoxicosis with elevated T 4 and/or T3 concentrations is 5% each year. Subclinical hypothyroidism Serum TSH is raised and serum T 3 and T4 concentrations are at the lower end of the reference range. This may persist for many years, although 20.14 Causes of thyroid enlargement Diffuse goitre  Simple goitre  Hashimoto’s thyroiditis1  Graves’ disease  Drugs: iodine, amiodarone, lithium  Iodine deciency (endemic goitre)1  Suppurative thyroiditis2  Transient thyroiditis2  Dyshormonogenesis1  Inltrative: amyloidosis, sarcoidosis etc.  Riedel’s thyroiditis2 Multinodular goitre Solitary nodule  Colloid cyst  Hyperplastic nodule  Follicular adenoma  Papillary carcinoma  Follicular carcinoma 1     Medullary cell carcinoma Anaplastic carcinoma Lymphoma Metastasis Goitre likely to shrink with levothyroxine therapy. 2Usually tender. ALGRAWANY 20 660  ENDOCRINOLOGY Rarely, a secondary deposit from a renal, breast or lung carcinoma presents as a painful, rapidly growing, solitary thyroid nodule. Thyroid nodules identied on PET scanning have an approximately 33% chance of being malignant. Clinical assessment and investigations Swellings in the anterior part of the neck most commonly originate in the thyroid and this can be conrmed by demonstrating that the swelling moves on swallowing. It is often possible to distinguish clinically between the three main causes of thyroid swelling. There is a broad differential diagnosis of anterior neck swellings, which includes lymphadenopathy, branchial cysts, dermoid cysts and thyroglossal duct cysts (the latter are classically located in the midline and move on protrusion of the tongue). An ultrasound scan should be performed urgently, if there is any doubt as to the aetiology of an anterior neck swelling. Serum T3, T4 and TSH should be measured in all patients with a goitre or solitary thyroid nodule. The nding of biochemical thyrotoxicosis or hypothyroidism (both of which may be subclinical) should lead to investigations, as already described in Box 20.5 and on page 657. Thyroid scintigraphy Thyroid scintigraphy with 99mtechnetium should be performed in an individual with a low serum TSH and a nodular thyroid to conrm the presence of an autonomously functioning (‘hot’) nodule (see Fig. 20.5). In such circumstances, further evaluation is not necessary. ‘Cold’ nodules on scintigraphy have a much higher likelihood of malignancy, but the majority are benign and so scintigraphy is not routinely used in the evaluation of thyroid nodules when TSH is normal. Thyroid ultrasound If thyroid function tests are normal, an ultrasound scan will often determine the nature of the thyroid swelling. Ultrasound can establish whether there is generalised or localised swelling of the thyroid. Inammatory disorders causing a diffuse goitre, such as Graves’ disease and Hashimoto’s thyroiditis, demonstrate a diffuse pattern of hypoechogenicity and, in the case of Graves’ disease, increased thyroid blood ow may be seen on colour-ow Doppler (although ultrasound should not form part of the routine investigation of Graves’ disease). The presence of thyroid autoantibodies will support the diagnosis of Graves’ disease or Hashimoto’s thyroiditis, while their absence in a younger patient with a diffuse goitre and normal thyroid function suggests a diagnosis of ‘simple goitre’. Ultrasound can readily determine the size and number of nodules within the thyroid and can distinguish solid nodules from those with a cystic element. Ultrasound is used increasingly as the key investigation in dening the risk of malignancy in a nodule. Size of the nodule is not a predictor of the risk of malignancy but there are other ultrasound characteristics that are associated with a higher likelihood of malignancy. These include hypoechogenicity, intranodular vascularity, the presence of microcalcication and irregular or lobulated margins. A purely cystic nodule is highly unlikely to be malignant and a ‘spongiform’ appearance is also highly predictive of a benign aetiology. Each individual nodule within a multinodular goitre has the same risk of malignancy as a solitary nodule. Thyroid ultrasonography is a highly specialised investigation and the accurate stratication of risk of malignancy of a thyroid nodule requires skill and expertise. Fine needle aspiration cytology Fine needle aspiration cytology is recommended for thyroid nodules that are suspicious for malignancy or are radiologically indeterminate. Fine needle aspiration of a thyroid nodule can be performed in the outpatient clinic, usually under ultrasound guidance. Aspiration may be therapeutic for a cyst, although recurrence on more than one occasion is an indication for surgery or alcohol ablation. Fine needle aspiration cytology cannot differentiate between a follicular adenoma and a follicular carcinoma, and in 10%–20% of cases an inadequate specimen is obtained. Management Nodules with a benign appearance on ultrasound may be observed in an ultrasound surveillance programme; when the suspicion of malignancy is very low, the patient may be reassured and discharged. In regions with borderline low iodine intake, there is evidence that levothyroxine therapy, in doses that suppress serum TSH, may reduce the size of some nodules. This should not be routine practice in iodine-sufcient populations. Nodules that are suspicious for malignancy are treated by surgical excision, by either lobectomy or thyroidectomy. Nodules that are radiologically and/or cytologically indeterminate are more of a management challenge and often end up being surgically excised. Molecular techniques may, in the future, improve the diagnostic accuracy of thyroid cytology and allow a more conservative strategy for individuals with an indeterminate biopsy. Nodules in which malignancy is conrmed by formal histology are treated as described on page 665. A diffuse or multinodular goitre may also require surgical treatment for cosmetic reasons or if there is compression of local structures (resulting in stridor or dysphagia). 131I therapy may also cause some reduction in size of a multinodular goitre. Levothyroxine therapy may shrink the goitre of Hashimoto’s disease, particularly if serum TSH is elevated. Autoimmune thyroid disease Thyroid diseases are amongst the most prevalent antibody-mediated autoimmune diseases and are associated with other organ-specic autoimmune diseases. Autoantibodies may produce inammation and destruction of thyroid tissue, resulting in hypothyroidism, goitre (in Hashimoto’s thyroiditis) or sometimes even transient thyrotoxicosis (‘Hashitoxicosis’), or they may stimulate the TSH receptor to cause thyrotoxicosis (in Graves’ disease). There is overlap between these conditions, since some patients have multiple autoantibodies. Graves’ disease Graves’ disease can occur at any age but is unusual before puberty and most commonly affects women aged 30–50 years. The most common manifestation is thyrotoxicosis with or without a diffuse goitre. The clinical features and differential diagnosis are described on page 652. Graves’ disease also causes ophthalmopathy and, rarely, pretibial myxoedema (p. 663). These extrathyroidal features usually occur in thyrotoxic patients but can arise in the absence of thyroid dysfunction. Graves’ thyrotoxicosis Pathophysiology The thyrotoxicosis results from the production of IgG antibodies directed against the TSH receptor on the thyroid follicular cell, which stimulate thyroid hormone production and proliferation of follicular cells, leading to goitre in the majority of patients. These antibodies are termed thyroid-stimulating immunoglobulins or TSH receptor antibodies (TRAb) and can be detected in the serum of >95% of patients with Graves’ disease. The concentration of TRAb in the serum is presumed to uctuate to account for the natural history of Graves’ thyrotoxicosis (Fig. 20.7). Thyroid failure seen in some patients may result from the presence of blocking antibodies against the TSH receptor, and from tissue destruction by cytotoxic antibodies and cell-mediated immunity. Graves’ disease has a strong genetic component. There is 20%–40% concordance for thyrotoxicosis between monozygotic twins but only 5% concordance between dizygotic twins. Genome-wide association studies have identied several genes associated with susceptibility. These include HLA-DRß-Arg74, CTLA4, PTPN22, TSHR1, CD25 and CD40. Many of these loci have been implicated in the pathogenesis of other autoimmune diseases. A suggested trigger for the development of thyrotoxicosis in genetically susceptible individuals may be infection with viruses or bacteria. The thyroid gland  661 In regions of iodine deciency, iodine supplementation can precipitate thyrotoxicosis, but only in those with pre-existing subclinical Graves’ disease. Smoking is associated with Graves’ thyrotoxicosis and strongly linked with the development of ophthalmopathy. Management Symptoms of thyrotoxicosis respond to β-blockade but denitive treatment requires control of thyroid hormone secretion. The different options are compared in Box 20.15. Some clinicians adopt an empirical approach of prescribing a course of antithyroid drug therapy and then recommending 131I or surgery if relapse occurs. In many centres, however, 131I is used extensively as a rst-line therapy, given the high risk of relapse following a course of antithyroid drugs (>60%). A number of observational studies have linked therapeutic 131I with increased incidence of some malignancies, particularly of the thyroid and gastrointestinal tract, but the results have been inconsistent; the association may be with Graves’ disease rather than its therapy, and the magnitude of the effect, if any, is small. Experience from the disaster at the Chernobyl nuclear power plant in 1986 suggests that younger people are more sensitive to radiationinduced thyroid cancer. A B C 0 1 Thyrotoxic 2 3 Time in years Euthyroid 4 5 Hypothyroid Antithyroid drugs The most commonly used are carbimazole and its active metabolite, methimazole (not available in the UK). Propylthiouracil is equally effective. These drugs reduce the synthesis of new thyroid hormones by inhibiting the iodination of tyrosine (see Fig. 20.3). Carbimazole may also have an immunosuppressive action, leading to a reduction in serum TRAb concentrations, but this is not enough to inuence the natural history of the thyrotoxicosis signicantly. Antithyroid drugs are typically introduced at high doses (carbimazole 40–60 mg daily or propylthiouracil 400–600 mg daily), although lower doses are reasonable in individuals with only modest elevation of T 4 and T3. Usually, this results in subjective improvement within 10–14 days and renders the patient clinically and biochemically euthyroid at 6–8 weeks. At this point, the dose can be reduced and titrated to maintain T 4 and TSH within their reference range. In most patients, carbimazole is continued at 5–20 mg per day for 12–18 months in the hope that remission will occur. Between 50% and 70% of patients with Graves’ disease will subsequently relapse, usually within 2 years of stopping treatment. Risk factors for relapse include younger age, male sex, presence of a goitre and higher TRAb titres at both diagnosis and cessation of antithyroid therapy. Rarely, T4 and TSH levels uctuate between those of thyrotoxicosis and hypothyroidism at successive review appointments, despite good drug adherence, presumably due to rapidly changing concentrations of TRAb. In these patients, satisfactory control can be achieved by blocking thyroid hormone synthesis with carbimazole 30–40 mg daily and adding levothyroxine 100–150 µg daily as replacement therapy (a ‘block and replace’ regimen). Antithyroid drugs can have adverse effects. The most common is a rash. Agranulocytosis is a rare but potentially serious complication (0.2%–0.5%) that cannot be predicted by routine measurement of white blood cell count but which is reversible on stopping treatment. Patients should be warned to stop the drug and seek medical advice immediately, should a severe sore throat or fever develop while on treatment. Propylthiouracil is associated with a small but denite risk of hepatotoxicity, which, in some instances, has resulted in liver failure requiring liver transplantation, and even in death. It should therefore be considered second-line therapy to carbimazole and be used only during pregnancy or breastfeeding, or if an adverse reaction to carbimazole has occurred. Thyroid surgery Patients should be rendered euthyroid with antithyroid Fig. 20.7 Natural history of the thyrotoxicosis of Graves’ disease. minority who experience a single short-lived episode followed by prolonged remission and, in some cases, by the eventual onset of hypothyroidism. drugs before operation. Oral potassium iodide, 60 mg three times daily, is often added for 10 days before surgery to inhibit thyroid hormone release and reduce the size and vascularity of the gland, making surgery technically easier. The optimal surgical approach is a ‘near-total’ 20.15 Comparison of treatments for the thyrotoxicosis of Graves’ disease Management Common indications Contraindications Disadvantages/complications Antithyroid drugs (carbimazole, propylthiouracil) First episode in patients 50% relapse rate usually within 2 years of stopping drug Thyroidectomy Large goitre Poor drug adherence, especially in young patients Recurrent thyrotoxicosis after course of antithyroid drugs in young patients Previous thyroid surgery Dependence on voice, e.g. singer, lecturer1 Hypothyroidism (~25%) Transient hypocalcaemia (10%) Permanent hypoparathyroidism (1%) Recurrent laryngeal nerve palsy1 (1%) Radio-iodine Patients >40 years2 Recurrence following surgery irrespective of age Other serious comorbidity Pregnancy or planned pregnancy within 6 months of treatment Active Graves’ ophthalmopathy3 Hypothyroidism: ~40% in rst year, 80% after 15 years Most likely treatment to result in exacerbation of ophthalmopathy3 1 lt is not only vocal cord palsy due to recurrent laryngeal nerve damage that alters the voice following thyroid surgery; the superior laryngeal nerves are frequently transected and this results in minor changes in voice quality. 2ln many institutions, 131I is used more liberally and is prescribed for much younger patients. 3The extent to which radio-iodine exacerbates ophthalmopathy is controversial and practice varies; some use prednisolone to reduce this risk. ALGRAWANY 20 662  ENDOCRINOLOGY thyroidectomy, leaving behind only a small portion of gland adjacent to the recurrent laryngeal nerves. This strategy invariably results in permanent hypothyroidism and is probably associated with a higher risk of hypoparathyroidism, compared to ‘subtotal’ thyroidectomy, but maximises the potential for cure of thyrotoxicosis. A Radioactive iodine 131 I is administered orally as a single dose and is trapped and organied in the thyroid (see Fig. 20.3). 131I emits both β and γ radiation and, although it decays within a few weeks, it has long-lasting inhibitory effects on survival and replication of follicular cells. The variable radio-iodine uptake and radiosensitivity of the gland means that the choice of dose is empirical; in most centres, approximately 400–600 MBq (approximately 10–15 mCi) is administered. This regimen is effective in 75% of patients within 4–12 weeks. During the lag period, symptoms can be controlled by a β-blocker or, in more severe cases, by carbimazole. However, carbimazole reduces the efcacy of 131I therapy because it prevents organication of 131I in the gland, and so should be avoided until 48 hours after radio-iodine administration. If thyrotoxicosis persists after 6 months, a further dose of 131I can be given. The disadvantage of 131I treatment is that the majority of patients eventually develop hypothyroidism. 131I is usually avoided in patients with Graves’ ophthalmopathy and evidence of signicant active orbital inammation. It can be administered with caution in those with mild or ‘burnt-out’ eye disease, when it is customary to cover the treatment with a 6-week tapering course of oral prednisolone. In women of reproductive age, pregnancy must be excluded before administration of 131I and avoided for at least 6 months thereafter; men are also advised to use strict contraceptive measures for at least 4 months after receiving 131I, to avoid the possibility of conceiving with sperm that have been exposed to radioactive iodine. Thyrotoxicosis in pregnancy Thyrotoxicosis in pregnancy may be asso- B Fig. 20.8 Graves’ disease. The main symptoms were diplopia in all directions of gaze and reduced visual acuity in the left eye. The periorbital swelling is due to retrobulbar fat prolapsing into the eyelids, and increased interstitial uid as a result of raised intraorbital pressure. most obvious at the apex of the left orbit (arrow), where compression of the optic nerve caused reduced visual acuity. ciated with signicant maternal and fetal morbidity. Management is very specialised and is discussed on page 1273 (see also Box 20.13). Thyrotoxicosis in adolescence Thyrotoxicosis can occasionally occur in adolescence and is almost always due to Graves’ disease. The presentation may be atypical and management challenging, as summarised in Box 20.16 Graves’ ophthalmopathy This condition is immunologically mediated with the TSH receptor identied as the main autoantigen. Within the orbit (and the dermis) there is cytokine-mediated proliferation of broblasts that secrete hydrophilic glycosaminoglycans. The resulting increase in interstitial uid content, combined with a chronic inammatory cell inltrate, causes marked swelling and ultimately brosis of the extraocular muscles (Fig. 20.8) and a rise in retrobulbar pressure. The eye is displaced forwards (proptosis, exophthalmos) and in severe cases there is optic nerve compression. Ophthalmopathy, like thyrotoxicosis (see Fig. 20.7), typically follows an episodic course and it is helpful to distinguish patients with active inammation (periorbital oedema and conjunctival inammation with changing orbital signs) from those in whom the inammation has ‘burnt out’. Eye disease is detectable in up to 50% of thyrotoxic patients at 20.16 Thyrotoxicosis in adolescence  Presentation: may present with a deterioration in school performance or symptoms suggestive of attention decit hyperactivity disorder.  Antithyroid drug therapy: prolonged courses may be required because remission rates following an 18-month course of therapy are much lower than in adults.  Adherence: adherence to antithyroid drug therapy is often suboptimal, resulting in poor disease control that may adversely affect performance at school.  Radio-iodine therapy: usually avoided in adolescents because of concerns about risk of future malignancy. presentation (although moderate to severe in only 5%), but active ocular inammation may occur before or after thyrotoxic episodes (exophthalmic Graves’ disease). Ophthalmopathy is more common in men and cigarette smokers. It may be exacerbated by radioiodine therapy and poor control of thyroid function, especially hypothyroidism. The most frequent presenting symptoms are related to increased exposure of the cornea, resulting from proptosis and lid retraction. There may be excessive lacrimation made worse by wind and bright light, a ‘gritty’ sensation in the eye and pain due to conjunctivitis or corneal ulceration. In addition, there may be reduction of visual acuity and/or visual elds as a consequence of corneal oedema or optic nerve compression. Other signs of optic nerve compression include reduced colour vision and a relative afferent pupillary defect (see page 649, Fig. 30.6 and Box 30.8). If the extraocular muscles are involved and do not act in concert, diplopia results. The majority of patients require no treatment other than reassurance. Smoking cessation should be actively encouraged. Methylcellulose eye drops and gel counter the gritty discomfort of dry eyes, and tinted glasses or side shields attached to spectacle frames reduce the excessive lacrimation triggered by sun or wind. In patients with mild Graves’ ophthalmopathy, oral selenium (100 µg twice daily for 6 months) improves quality of life, reduces ocular involvement and slows progression of disease; the mechanism of action is not known but may relate to an antioxidant effect. Moderate to severe ophthalmopathy is optimally managed by an expert multidisciplinary service. More severe inammatory episodes are treated with glucocorticoids (e.g. pulsed intravenous methylprednisolone) and sometimes orbital radiotherapy. In recent years evidence has emerged to support the use of immunosuppressive therapies (e.g. rituximab and tocilizumab) and the IGF-1 receptor inhibitor teprotumumab in moderate to severe ophthalmopathy. Loss of visual acuity is an indication for urgent surgical decompression of the orbit. In ‘burnt-out’ disease, surgery to the extraocular muscles, The thyroid gland  663 and later the eyelids, may improve diplopia, conjunctival exposure and cosmetic appearance. Thyrotoxic Hypothyroid Euthyroid Pretibial myxoedema This inltrative dermopathy occurs in fewer than 5% of patients with Graves’ disease and has similar pathological features as occur in the orbit. It takes the form of raised pink-coloured or purplish plaques on the anterior aspect of the leg, extending on to the dorsum of the foot (see p. 648). The lesions may be itchy and the skin may have a ‘peau d’orange’ appearance with growth of coarse hair; less commonly, the face and arms are affected. Treatment is rarely required but in severe cases topical glucocorticoids may be helpful. Reference range T4, T3 TSH 0 2 4 6 Months Hashimoto’s thyroiditis Fig. 20.9 Thyroid function tests in an episode of transient thyroiditis. This Hashimoto’s thyroiditis (or ‘chronic autoimmune thyroiditis’) is characterised by destructive lymphocytic inltration of the thyroid, ultimately leading to a varying degree of brosis and thyroid enlargement. It has atrophic and goitrous variants. Hashimoto’s thyroiditis increases in incidence with age and affects approximately 3.5 per 1000 women and 0.8 per 1000 men each year. Many present with a small or moderately sized diffuse goitre, which is characteristically rm or rubbery in consistency. Around 25% of patients are hypothyroid at presentation. In the remainder, serum T 4 is normal and TSH normal or raised, but these patients are at risk of developing overt hypothyroidism in future years. Antithyroid peroxidase antibodies are present in the serum in more than 90% of patients with Hashimoto’s thyroiditis. There is an increased risk of thyroid lymphoma, although this is exceedingly rare. Levothyroxine therapy is indicated as treatment for hypothyroidism and also to shrink an associated goitre. In this context, the dose of levothyroxine should be sufcient to suppress serum TSH to low but detectable levels. Transient thyroiditis Subacute (de Quervain’s) thyroiditis In its classical painful form, subacute thyroiditis is a transient inammation of the thyroid gland occurring after infection with Coxsackie, mumps or adenoviruses. There is pain in the region of the thyroid that may radiate to the angle of the jaw and the ears, and is made worse by swallowing, coughing and movement of the neck. The thyroid is usually palpably enlarged and tender. Systemic upset is common. Affected patients are usually females aged 20–40 years. Painless transient thyroiditis can also occur after viral infection and in patients with underlying autoimmune disease. The condition can also be precipitated by drugs, including interferon-α and lithium. Irrespective of the clinical presentation, inammation in the thyroid gland occurs and is associated with release of colloid and stored thyroid hormones, but also with damage to follicular cells and impaired synthesis of new thyroid hormones. As a result, T 4 and T3 levels are raised for 4–6 weeks until the pre-formed colloid is depleted. Thereafter, there is usually a period of hypothyroidism of variable severity before the follicular cells recover and normal thyroid function is restored within 4–6 months (Fig. 20.9). In the thyrotoxic phase, the iodine uptake is low because the damaged follicular cells are unable to trap iodine and because TSH secretion is suppressed. Low-titre thyroid autoantibodies appear transiently in the serum, and the erythrocyte sedimentation rate (ESR) is usually raised. High-titre autoantibodies suggest an underlying autoimmune pathology and greater risk of recurrence and ultimate progression to hypothyroidism. The pain and systemic upset usually respond to simple measures such as non-steroidal anti-inammatory drugs (NSAIDs). Occasionally, however, it may be necessary to prescribe prednisolone 40 mg daily for 3–4 weeks. The thyrotoxicosis is mild and treatment with a β-blocker is pattern might be observed in classical subacute (de Quervain’s) thyroiditis, painless thyroiditis or post-partum thyroiditis. The duration of each phase varies between patients. (T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone) usually adequate. Antithyroid drugs are of no benet because thyroid hormone synthesis is impaired rather than enhanced. Careful monitoring of thyroid function and symptoms is required so that levothyroxine can be prescribed temporarily in the hypothyroid phase. Care must be taken to identify patients presenting with hypothyroidism who are in the later stages of a transient thyroiditis, since they are unlikely to require life-long levothyroxine therapy (see Fig. 20.6). Post-partum thyroiditis The maternal immune response, which is modied during pregnancy to allow survival of the fetus, is enhanced after delivery and may unmask previously unrecognised subclinical autoimmune thyroid disease. Surveys have shown that transient biochemical disturbances of thyroid function occur in 5%–10% of women within 6 months of delivery (see Box 20.13). Those affected are likely to have antithyroid peroxidase antibodies in the serum in early pregnancy. Symptoms of thyroid dysfunction are rare and there is no association between postnatal depression and abnormal thyroid function tests. However, symptomatic thyrotoxicosis presenting for the rst time within 12 months of childbirth is likely to be due to post-partum thyroiditis and the diagnosis is conrmed by a negligible radio-isotope uptake. The clinical course and treatment are similar to those of painless subacute thyroiditis (see above). Post-partum thyroiditis tends to recur after subsequent pregnancies, and eventually patients progress over a period of years to permanent hypothyroidism (see also Box 20.13). Iodine-associated thyroid disease Iodine deciency Iodine is an essential micronutrient and is a key component of T 4 and T3. The World Health Organization (WHO) recommends a daily intake of iodine of 150 µg/day for adult men and women; higher levels are recommended for pregnant women (see p. 1273) as iodine deciency is associated with impaired fetal brain development, and severe deciency can cause cretinism. Dietary sources of iodine include seafood, dairy products, eggs and grains. Dietary iodine deciency is a major worldwide public health issue, with an estimated one-third of the world population living in areas of iodine insufciency. Iodine deciency is particularly common in Central Africa, South-east Asia and the Western Pacic. It is associated with the development of thyroid nodules and goitre (endemic goitre); the reduced substrate available for thyroid hormone production increases thyroid activity to maximise iodine uptake and recycling, and this acts as a potent stimulus for enlargement of the thyroid and nodule formation. Most affected patients are euthyroid with normal or raised TSH levels, although hypothyroidism can occur with severe iodine ALGRAWANY 20 664  ENDOCRINOLOGY deciency. Suspected iodine deciency can be assessed by measuring iodine in urine (either a 24-hour collection or a spot sample). Endemic goitre can be treated by iodine supplementation, and a reduction in nodule and goitre size can be seen, particularly if it is commenced in childhood. Iodine deciency is not associated with an increased risk of Graves’ disease or thyroid cancer, but the high prevalence of nodular autonomy does result in an increased risk of thyrotoxicosis and this risk may be further increased by iodine supplementation. Conversely, iodine supplementation may also increase the prevalence of subclinical hypothyroidism and autoimmune hypothyroidism. These complex effects of iodine supplementation are further discussed below.  type II: thyroiditis due to a direct cytotoxic effect of amiodarone administration. These patterns can overlap and may be difcult to distinguish clinically, as iodine uptake is low in both. There is no widely accepted management algorithm, although the iodine excess renders the gland resistant to 131I. Antithyroid drugs may be effective in patients with the type I form but are ineffective in type II thyrotoxicosis. Prednisolone is benecial in the type II form. A pragmatic approach is to commence combination therapy with an antithyroid drug and glucocorticoid in patients with signicant thyrotoxicosis. A rapid response (within 1–2 weeks) usually indicates a type II picture and permits withdrawal of the antithyroid therapy; a slower response suggests a type I picture, in which case antithyroid drugs may be continued and prednisolone withdrawn. If the cardiac state allows, amiodarone should be discontinued, but it has a long half-life (50–60 days) and so its effects are long-lasting. To minimise the risk of type I thyrotoxicosis, thyroid function should be measured in all patients prior to commencement of amiodarone therapy, and amiodarone should be avoided if TSH is suppressed. Hypothyroidism should be treated with levothyroxine, which can be given while amiodarone is continued. Iodine-induced thyroid dysfunction Iodine has complex effects on thyroid function. Very high concentrations of iodine inhibit thyroid hormone synthesis and release (known as the Wolff–Chaikoff effect) and this forms the rationale for iodine treatment in thyroid crisis and prior to thyroid surgery for thyrotoxicosis. This is an autoregulatory response to protect the body from the sudden release of large amounts of thyroid hormone in response to the ingestion of a substantial load of iodine. This effect only lasts for about 10 days, after which it is followed by an ‘escape phenomenon’: essentially, the return to normal organication of iodine and thyroid peroxidase action (see Fig. 20.3). Therefore, if iodine is given to prepare an individual with Graves’ disease for surgery, the operation must happen within 10–14 days; otherwise, a signicant relapse of the thyrotoxicosis could occur. Iodine deciency and underlying thyroid disease can both moderate the effects of iodine on thyroid function. In iodine-decient parts of the world, transient thyrotoxicosis may be precipitated by prophylactic iodinisation programmes. In iodine-sufcient areas, thyrotoxicosis can be precipitated by iodine-containing radiographic contrast medium or expectorants in individuals who have underlying thyroid disease predisposing to thyrotoxicosis, such as multinodular goitre or Graves’ disease in remission. Induction of thyrotoxicosis by iodine is called the Jod–Basedow effect. Chronic excess iodine administration can also result in hypothyroidism; this is, in effect, a failure to escape from the Wolff–Chaikoff effect and usually occurs in the context of prior insult to the thyroid by, for example, autoimmune disease, thyroiditis, lithium, antithyroid drugs or surgery. Simple and multinodular goitre These terms describe diffuse or multinodular enlargement of the thyroid, which occurs sporadically and is of unknown aetiology. Simple diffuse goitre This form of goitre usually presents between the ages of 15 and 25 years, often during pregnancy, and tends to be noticed by friends and relatives rather than the patient. Occasionally, there is a tight sensation in the neck, particularly when swallowing. The goitre is soft and symmetrical, and the thyroid enlarged to two or three times normal. There is no tenderness, lymphadenopathy or overlying bruit. Concentrations of T 3, T4 and TSH are normal and no thyroid autoantibodies are detected in the serum. No treatment is necessary and the goitre usually regresses. In some, however, the unknown stimulus to thyroid enlargement persists and, as a result of recurrent episodes of hyperplasia and involution during the following 10–20 years, the gland becomes multinodular with areas of autonomous function. Amiodarone The anti-arrhythmic agent amiodarone has a structure that is analogous to that of T4 (Fig. 20.10) and contains huge amounts of iodine; a 200 mg dose contains 75 mg iodine. Amiodarone also has a cytotoxic effect on thyroid follicular cells and inhibits conversion of T 4 to T3 (increasing the ratio of T4: T3). Most patients receiving amiodarone have normal thyroid function but up to 20% develop hypothyroidism or thyrotoxicosis, and so thyroid function should be monitored regularly. TSH provides the best indicator of thyroid function. The thyrotoxicosis can be classied as either:  type I: iodine-induced excess thyroid hormone synthesis in patients with an underlying thyroid disorder, such as nodular goitre or latent Graves’ disease (an example of the Jod–Basedow effect), or I C2H5 CH2 CH2 O C4H9 > 55 Goitre Diffuse Nodular Nodular No Minimal Yes T3, T4 Normal Normal Raised TSH Normal I Fig. 20.10 The structure of amiodarone. Note the similarities to thyroxine (T4) (see Fig. 20.3). 26–55 N C2H5 O 15–25 Tracheal compression/ deviation O C Age (in years) Normal or undetectable Undetectable Fig. 20.11 Natural history of simple goitre. (T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone) The thyroid gland  665 Multinodular goitre The natural history is shown in Figure 20.11. Patients with thyroid enlargement in the absence of thyroid dysfunction or positive autoantibodies (i.e. with ‘simple goitre’; see above) as young adults may progress to develop nodules. These nodules grow at varying rates and secrete thyroid hormone ‘autonomously’, thereby suppressing TSH-dependent growth and function in the rest of the gland. Ultimately, complete suppression of TSH occurs in about 25% of cases, with T 4 and T3 levels often within the reference range (subclinical thyrotoxicosis), but sometimes elevated (toxic multinodular goitre; see Fig. 20.5). Clinical features and investigations Multinodular goitre is usually diagnosed in patients presenting with thyrotoxicosis, a large goitre with or without tracheal compression, or sudden painful swelling caused by haemorrhage into a nodule or cyst. The goitre is nodular or lobulated on palpation and may extend retrosternally; however, not all multinodular goitres causing thyrotoxicosis are easily palpable. Very large goitres can cause mediastinal compression with stridor (Fig. 20.12), dysphagia and obstruction of the superior vena cava. Hoarseness due to recurrent laryngeal nerve palsy can occur but is far more suggestive of thyroid carcinoma. The diagnosis can be confirmed by ultrasonography and/or thyroid scintigraphy (see Fig. 20.5). In patients with large goitres, a flow-volume loop is a good screening test for significant tracheal compression (see Fig. 17.7). If intervention is contemplated, a CT or MRI of the thoracic inlet should be performed to quantify the degree of tracheal displacement or compression and the extent of retrosternal extension. Nodules should be evaluated for the possibility of thyroid neoplasia. Management If the goitre is small, no treatment is necessary but annual thyroid function testing should be arranged, as the natural history is progression to a toxic multinodular goitre. Thyroid surgery is indicated for large goitres that cause mediastinal compression or that are cosmetically unattractive. 131 I can result in a signicant reduction in thyroid size and may be of value in older patients. Levothyroxine therapy is of no benet in shrinking multinodular goitres in iodine-sufcient countries and may simply aggravate any associated thyrotoxicosis. In toxic multinodular goitre, treatment is usually with 131I. The iodine uptake is lower than in Graves’ disease, so a higher dose may be administered (up to 800 Mbq (approximately 20 mCi)) and hypothyroidism is less common. In thyrotoxic patients with a large goitre, thyroid surgery may be indicated. Long-term treatment with antithyroid drugs is not usually employed, as relapse is invariable after drug withdrawal; drug therapy is normally reserved for frail older patients in whom surgery or 131I is not an appropriate option. Asymptomatic patients with subclinical thyrotoxicosis are increasingly being treated with 131I on the grounds that a suppressed TSH is a risk factor for atrial brillation and, particularly in post-menopausal women, osteoporosis. Thyroid neoplasia Patients with thyroid tumours usually present with a solitary nodule. Most are benign and a few of these, called ‘toxic adenomas’, secrete excess thyroid hormones. Primary thyroid malignancy is rare, accounting for less than 1% of all carcinomas, and has an incidence of 25 per million per annum. As shown in Box 20.17, it can be classied according to the cell type of origin. With the exception of medullary carcinoma, thyroid cancer is more common in females. Toxic adenoma A solitary toxic nodule is the cause of less than 5% of all cases of thyrotoxicosis. The nodule is a follicular adenoma, which autonomously secretes excess thyroid hormones and inhibits endogenous TSH secretion, with subsequent atrophy of the rest of the thyroid gland. The adenoma is usually greater than 3 cm in diameter. Most patients are female and over 40 years of age. Although many nodules are palpable, the diagnosis can be made with certainty only by thyroid scintigraphy (see Fig. 20.5). The thyrotoxicosis is usually mild and in almost 50% of patients the plasma T 3 alone is elevated (T3 thyrotoxicosis). 131I (400–800 MBq (10–20 mCi)) is highly effective and is an ideal treatment since the atrophic cells surrounding the nodule do not take up iodine and so receive little or no radiation. For this reason, permanent hypothyroidism is unusual. Hemithyroidectomy is an alternative management option. Differentiated carcinoma The incidence of thyroid carcinoma has increased signicantly since the early 1990s although this has not been paralleled by any signicant increase in thyroid carcinoma deaths over the same period (Fig. 20.13). Increasing incidence of thyroid carcinoma is, at least in part, explained by an increased rate of incidental detection, which tracks greater use of neck imaging. Papillary carcinoma This is the most common of the malignant thyroid tumours and accounts for 90% of radiation-induced thyroid cancer. It may be multifocal and 20.17 Malignant thyroid tumours Type of tumour R Frequency (%) Age at presentation (years) 10-year survival (%) 75–85 10–20 60 98 94 9 5–8 >40* 78 60 45 Follicular cells Differentiated carcinoma: Papillary Follicular Anaplastic Parafollicular C cells Medullary carcinoma Lymphocytes Lymphoma Fig. 20.12 Computed tomogram showing retrosternal multinodular goitre. The goitre (black arrow) is causing acute severe breathlessness and stridor due to tracheal compression (white arrow). *Patients with medullary carcinoma as part of multiple endocrine neoplasia (MEN) types 2a and 2b (p. 700) may present in childhood. ALGRAWANY 20 Rate per 100,000 persons 666  ENDOCRINOLOGY 16 Prognosis 14 12 Most patients with papillary and follicular thyroid cancer will be cured with appropriate treatment. Adverse prognostic factors include older age at presentation, the presence of distant metastases, male sex and certain histological subtypes. However, 131I therapy can be effective in treating those with distant metastases, particularly small-volume disease in the lungs, and so prolonged survival is quite common. 10 8 6 4 2 0 1992 Anaplastic carcinoma and lymphoma 1996 2000 2004 Rate of new cases 2008 2012 2018 Death rate Fig. 20.13 Incidence and death rates of thyroid cancer. Although the incidence has increased from 1990

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