Endocrine disease

Clinical examination in endocrine disease

Endocrine disease causes clinical syndromes with symptoms and signs involving many organ systems, reflecting the diverse effects of hormone deficiency and excess. 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.

6 Examination of the visual fields by confrontation

6 Examination in Graves’ ophthalmopathy

7 Examination of the thyroid gland

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 deficiency, such as the Himalayas, and 4% of women aged 20–50 years in the UK. Some endocrine diseases are becoming more common in association with emerging diseases; HIV infection is associated in particular with adrenal insufficiency. 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 (for example, with levothyroxine) has obvious clinical benefits and placebo-controlled trials would be unethical, and in part because many endocrine diseases are rare, making trials difficult to perform. Recommendations for ‘evidence-based medicine’ are, therefore, relatively scarce. They relate mainly to use of therapy that is ‘optional’ and/or recently available, such as oestrogen replacement in post-menopausal women, androgen therapy in older men and growth hormone replacement.

An overview of endocrinology

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.

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.

A wide variety of molecules can act as hormones, including peptides such as insulin and growth hormone, glycoproteins such as thyroid-stimulating 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 (p. 48). Some hormones, most notably steroids, triiodothyronine and vitamin D, bind to specific intracellular receptors, which directly bind to response elements on DNA to regulate gene expression (p. 42).

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 pro-hormones. 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 classified as shown in Box 20.1. Pathology arising within the gland is often called ‘primary’ disease (for example, primary hypothyroidism in Hashimoto’s thyroiditis), while abnormal stimulation of the gland is often called ‘secondary’ disease (for example, secondary hypothyroidism in patients with a pituitary tumour and thyroid-stimulating hormone deficiency). Some pathological processes can affect multiple endocrine glands (p. 795); these may have a genetic basis (such as organ-specific autoimmune endocrine disorders and the multiple endocrine neoplasia (MEN) syndromes) or be a consequence of therapy for another disease (for example, following treatment of childhood cancer with chemotherapy and/or radiotherapy).

20.1 Classification of endocrine disease

Hormone excess

• Primary gland over-production

• Secondary to excess trophic substance

Hormone deficiency

• Primary gland failure

• Secondary to deficient trophic hormone

Hormone hypersensitivity

• Failure of inactivation of hormone

• Target organ over-activity/hypersensitivity

Hormone resistance

• Failure of activation of hormone

• Target organ resistance

Non-functioning tumours

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 diurnal variation, such as cortisol; or those that demonstrate monthly variation, such as oestrogen or progesterone. 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.

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 tests

• Abnormalities are often characterised by loss of normal regulation of hormone secretion

• If hormone deficiency 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

• Secretory cells also take up substrates, which can be labelled

• Most endocrine glands have a high prevalence of ‘incidentalomas’, so do not scan unless the biochemistry confirms endocrine dysfunction or the primary problem is a tumour

Biopsy

• Many endocrine tumours are difficult to classify histologically (e.g. adrenal carcinoma and adenoma)

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-specific 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. 16), hypertension (Ch. 18), obesity (Ch. 5) and osteoporosis (Ch. 25). 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-specific complaints, so it is important that clinicians are familiar with their key features.

20.3 Examples of non-specific presentations of endocrine disease

Symptom	Most likely endocrine disorder(s)
Lethargy and depression	Hypothyroidism, diabetes mellitus, hyperparathyroidism, hypogonadism, adrenal insufficiency, Cushing’s syndrome
Weight gain	Hypothyroidism, Cushing’s syndrome
Weight loss	Thyrotoxicosis, adrenal insufficiency, diabetes mellitus
Polyuria and polydipsia	Diabetes mellitus, diabetes insipidus, hyperparathyroidism, hypokalaemia (Conn’s syndrome)
Heat intolerance	Thyrotoxicosis, menopause
Palpitations	Thyrotoxicosis, phaeochromocytoma
Headache	Acromegaly, pituitary tumour, phaeochromocytoma
Muscle weakness (usually proximal)	Thyrotoxicosis, Cushing’s syndrome, hypokalaemia (e.g. Conn’s syndrome), hyperparathyroidism, hypogonadism
Coarsening of features	Acromegaly, hypothyroidism

The thyroid gland

Diseases of the thyroid 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. Diseases of the thyroid are summarised in Box 20.4.

20.4 Classification of thyroid disease

	Primary	Secondary
Hormone excess	Graves’ disease Multinodular goitre Adenoma Subacute thyroiditis	TSHoma
Hormone deficiency	Hashimoto’s thyroiditis Atrophic hypothyroidism	Hypopituitarism
Hormone hypersensitivity	–
Hormone resistance	Thyroid hormone resistance syndrome 5′-monodeiodinase deficiency
Non-functioning tumours	Differentiated carcinoma Medullary carcinoma Lymphoma

Functional anatomy, physiology and investigations

Thyroid physiology is illustrated in Figure 20.3. The parafollicular C cells secrete calcitonin, which is of no apparent physiological significance 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 (T₄) and only a small amount of triiodothyronine (T₃); approximately 85% of T₃ in blood is produced from T₄ by a family of monodeiodinase enzymes which are active in many tissues, including liver, muscle, heart and kidney. Selenium is an integral component of these monodeiodinases. T₄ can be regarded as a pro-hormone, since it has a longer half-life in blood than T₃ (approximately 1 week compared with approximately 18 hours), and binds and activates thyroid hormone receptors less effectively than T₃. T₄ can also be converted to the inactive metabolite, reverse T₃.

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’s syndrome) and ‘organified’ 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 T₃ and 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) T₄ is converted to T₃ by 5′-monodeiodinase.

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 which diffuse into tissues and exert diverse metabolic actions. Some laboratories use assays which measure total T₄ and T₃ in plasma, but it is increasingly common to measure free T₄ and free T₃. The advantage of the free hormone measurements is that they are not influenced by changes in the concentration of binding proteins; in pregnancy, for example, TBG levels are increased and total T₃ and T₄ may be raised, but 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 T₃ 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 anterior pituitary is very sensitive to minor changes in thyroid hormone levels within the reference range. Although the reference range for free T₄ is 9–21 pmol/L (700–1632 pg/dL), a rise or fall of 5 pmol/L in an individual in whom the level is usually 15 pmol/L 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 in patients with pituitary disease (see Box 20.58, p. 787). Moreover, TSH may take several weeks to ‘catch up’ with T₄ and T₃ levels, for example, when prolonged suppression of TSH in thyrotoxicosis is relieved by antithyroid therapy. Heterophilic antibodies can also interfere with the TSH assay and cause a spuriously high measurement. Common patterns of abnormal thyroid function test results and their interpretation are shown in Box 20.5.

20.5 How to interpret thyroid function test results

TSH	T₄	T₃	Most likely interpretation(s)
U.D.	Raised	Raised	Primary thyrotoxicosis
U.D.	Normal¹	Raised	Primary T₃-toxicosis
U.D.	Normal¹	Normal¹	Subclinical thyrotoxicosis
U.D. or low	Raised	Low or normal	Non-thyroidal illness, amiodarone therapy
U.D.	Low	Low	Secondary hypothyroidism⁴ Transient thyroiditis in evolution
Normal	Low	Low²	Secondary hypothyroidism⁴
Mildly elevated 5–20 mU/L	Low	Low²	Primary hypothyroidism Secondary hypothyroidism⁴
Elevated > 20 mU/L	Low	Low²	Primary hypothyroidism
Mildly elevated 5–20 mU/L	Normal³	Normal²	Subclinical hypothyroidism
Elevated 20–500 mU/L	Normal	Normal	Artefact Endogenous IgG antibodies which interfere with TSH assay
Elevated	Raised	Raised	Non-compliance with T₄ replacement – recent ‘loading’ dose Secondary thyrotoxicosis⁴ Thyroid hormone resistance

(U.D. = undetectable)

¹ Usually upper part of reference range.

² T₃ is not a sensitive indicator of hypothyroidism and should not be requested.

³ Usually lower part of reference range.

⁴ i.e. Secondary to pituitary or hypothalamic disease. Note that TSH assays may report detectable TSH.

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, p. 741), radioisotope imaging, fine 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 identification of patients with abnormal results who are either asymptomatic or have non-specific 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 and autonomously functioning thyroid nodules (toxic adenoma) (Box 20.6). Thyroiditis is more common in parts of the world where relevant viral infections occur, such as North America.

20.6 Causes of thyrotoxicosis and their relative frequencies

Cause	Frequency¹ (%)
Graves’ disease	76
Multinodular goitre	14
Solitary thyroid adenoma	5
Thyroiditis
Subacute (de Quervain’s)²	3
Post-partum²	0.5
Iodide-induced
Drugs (amiodarone)²	1
Radiographic contrast media²	–
Iodine prophylaxis programme²	–
Extrathyroidal source of thyroid hormone
Factitious thyrotoxicosis²	0.2
Struma ovarii^2,³	–
TSH-induced
TSH-secreting pituitary adenoma	0.2
Choriocarcinoma and hydatidiform mole⁴	–
Follicular carcinoma ± metastases	0.1

¹ ln a series of 2087 patients presenting to the Royal Infirmary of Edinburgh over a 10-year period.

² Characterised by negligible radio-isotope uptake.

³ i.e. Ovarian teratoma containing thyroid tissue.

⁴ Human chorionic gonadotrophin has thyroid-stimulating activity.

Clinical assessment

The clinical manifestations of thyrotoxicosis are shown in Box 20.7 and an approach to differential diagnosis is given in Figure 20.4. 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 and diplopia. Pretibial myxoedema (p. 751) and the rare thyroid acropachy (a periosteal hypertrophy, indistinguishable from finger clubbing) are also specific to Graves’ disease.

20.7 Clinical features of thyroid dysfunction

Thyrotoxicosis		Hypothyroidism
Symptoms	Signs	Symptoms	Signs
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
Less common
Osteoporosis (fracture, loss of height) Diarrhoea, steatorrhoea Angina Ankle swelling Anxiety, psychosis Muscle weakness Periodic paralysis (predominantly in Chinese) Pruritus, alopecia Amenorrhoea/oligomenorrhoea Infertility, spontaneous abortion Loss of libido, impotence Excessive lacrimation	Goitre with bruit ¹ Atrial fibrillation ² Systolic hypertension/increased pulse pressure Cardiac failure ² Hyper-reflexia Ill-sustained clonus Proximal myopathy Bulbar myopathy ²	Constipation Hoarseness Carpal tunnel syndrome Alopecia Aches and pains Muscle stiffness Deafness Depression Infertility	Hoarse voice Facial features: Purplish lips Malar flush Periorbital oedema Loss of lateral eyebrows Anaemia Carotenaemia Erythema ab igne Bradycardia hypertension Delayed relaxation of reflexes Dermal myxoedema
Rare
Vomiting Apathy Anorexia Exacerbation of asthma	Gynaecomastia Spider naevi Onycholysis Pigmentation	Psychosis (myxoedema madness) Galactorrhoea Impotence	Ileus, ascites Pericardial and pleural effusions Cerebellar ataxia Myotonia

¹ ln Graves’ disease only.

² Features found particularly in elderly patients.

Investigations

The first-line investigations are serum T₃, T₄ and TSH. If abnormal values are found, the tests should be repeated and the abnormality confirmed in view of the likely need for prolonged medical treatment or destructive therapy. In most patients, serum T₃ and T₄ are both elevated, but T₄ is in the upper part of the reference range and T₃ 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 confirmed, further investigations should be undertaken to determine the underlying cause, including measurement of TSH receptor antibodies (TRAb, elevated in Graves’ disease, Box 20.8) and isotope scanning, as shown in Figure 20.4. Other non-specific abnormalities are common (Box 20.9). An ECG may demonstrate sinus tachycardia or atrial fibrillation.

20.8 Prevalence of thyroid autoantibodies (%)

	Antibodies to:
	Thyroid peroxidase¹	Thyroglobulin	TSH receptor²
Normal population	8–27	5–20	0
Graves’ disease	50–80	50–70	80–95
Autoimmune hypothyroidism	90–100	80–90	10–20
Multinodular goitre	∼30–40	∼30–40	0
Transient thyroiditis	∼30–40	∼30–40	0

¹ Thyroid peroxidase (TPO) antibodies are the principal component of what was previously measured as thyroid ‘microsomal’ antibodies.

² TSH receptor antibodies (TRAb) can be agonists (stimulatory, causing Graves’ thyrotoxicosis) or antagonists (‘blocking’, causing hypothyroidism)

20.9 Non-specific 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.

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 (p. 751). Occasionally, patients induce ‘factitious thyrotoxicosis’ by consuming excessive amounts of a thyroid hormone preparation, most often levothyroxine. The exogenous thyroxine suppresses pituitary TSH secretion and hence iodine uptake, serum thyroglobulin and release of endogenous thyroid hormones. The T₄: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 of negligible iodine uptake, high T₄:T₃ ratio and a low or undetectable thyroglobulin is diagnostic.

Management

Definitive 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) or nadolol (40–80 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, whilst patients are awaiting hospital consultation or following ¹³¹I therapy.

Atrial fibrillation in thyrotoxicosis

Atrial fibrillation occurs in about 10% of patients with thyrotoxicosis. The incidence increases with age, so that almost half of all males with thyrotoxicosis over the age of 60 are affected. Moreover, subclinical thyrotoxicosis (p. 745) is a risk factor for atrial fibrillation. Characteristically, the ventricular rate is little influenced by digoxin, but responds to the addition of a β-blocker. Thromboembolic vascular complications are particularly common in thyrotoxic atrial fibrillation so that anticoagulation with warfarin is required, unless contraindicated. Once thyroid hormone and TSH concentrations have been returned to normal, atrial fibrillation 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, confusion, tachycardia or atrial fibrillation and, in the older patient, cardiac failure. It is a medical emergency, which has a mortality of 10% despite early recognition and treatment. Thyrotoxic crisis is most commonly precipitated by infection in a patient with previously unrecognised or inadequately treated thyrotoxicosis. It may also develop shortly after subtotal thyroidectomy in an ill-prepared patient or within a few days of ¹³¹I therapy, when acute irradiation damage may lead to a transient rise in serum thyroid hormone levels.

Patients should be rehydrated and given propranolol, either orally (80 mg 4 times daily) or intravenously (1–5 mg 4 times daily). Sodium ipodate (500 mg per day orally) will restore serum T₃ levels to normal in 48–72 hours. This is a radiographic contrast medium which not only inhibits the release of thyroid hormones, but also reduces the conversion of T₄ to T₃ and is, therefore, more effective than potassium iodide or Lugol’s solution. Dexamethasone (2 mg 4 times daily) and amiodarone have similar effects. Oral carbimazole 40–60 mg daily (p. 748) should be given to inhibit the synthesis of new thyroid hormone. If the patient is unconscious or uncooperative, carbimazole can be administered rectally with good effect, but no preparation is available for parenteral use. After 10–14 days the patient can usually be maintained on carbimazole alone.

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 deficiency is endemic. Women are affected approximately six times more frequently than men.

20.10 Causes of hypothyroidism

Causes	Anti-TPO antibodies¹	Goitre²
Autoimmune
Hashimoto’s thyroiditis	++	±
Spontaneous atrophic hypothyroidism	–	–
Graves’ disease with TSH receptor-blocking antibodies	+	±
Iatrogenic
Radioactive iodine ablation	+	±
Thyroidectomy	+	–
Drugs
Carbimazole, methimazole, propylthiouracil	+	±
Amiodarone	+	±
Lithium	–	±
Transient thyroiditis
Subacute (de Quervain’s) thyroiditis	+	±
Post-partum thyroiditis	+	±
Iodine deficiency, e.g. in mountainous regions	–	++
Congenital
Dyshormonogenesis	–	++
Thyroid aplasia	–	–
Infiltrative
Amyloidosis, Riedel’s thyroiditis, sarcoidosis etc.	+	++
Secondary hypothyroidism
TSH deficiency	–	–

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.

² Goitre: – absent; ± may be present; ++ characteristic.