Hirsutism refers to an increased growth of body hair in women. The clinical evaluation and differential diagnosis are presented on page 315. The absence of facial hair in a man suggests hypogonadism, while temporal recession of the scalp hair in women occurs with androgen excess. The decrease in adrenal androgen production that occurs as a result of hypogonadism, hypopituitarism or adrenal insufficiency can cause loss of axillary and pubic hair in both sexes.

Lethargy

This common symptom can be due to a number of different diseases. Patients with hypothyroidism, Addison’s disease and diabetes mellitus can present with this problem. Anaemia, connective tissue diseases, chronic infection (e.g. HIV, infective endocarditis), drugs (e.g. sedatives, diuretics causing electrolyte disturbances), chronic liver disease, renal failure and occult malignancy may also result in lethargy. Importantly, depression is a common cause of this symptom (page 411).

Changes in the skin and nails

The skin becomes coarse, pale and dry in hypothyroidism, and dry and scaly in hypoparathyroidism. Flushing of the skin of the face and neck occurs in the carcinoid syndrome (due to the release of vasoactive peptides from the tumour). Soft-tissue overgrowth occurs in acromegaly and skin tags may appear in the axillae. These are called molluscum fibrinosum. Acanthosis nigricans can also occur in acromegaly and in insulin-resistant states including Cushing’s syndrome and polycystic ovarian syndrome. Xanthelasma can be present in patients with diabetes or hypothyroidism.

Onycholysis occurs in Graves’ disease and Cushing’s syndrome is associated with spontaneous ecchymoses, thin skin and purple striae.

Changes in pigmentation

Increased pigmentation may be reported in primary adrenal insufficiency, Cushing’s syndrome or acromegaly. Decreased pigmentation occurs in hypopituitarism. Localised depigmentation is characteristic of vitiligo, which may be associated with certain endocrine diseases such as Hashimoto’s ^a disease with hypothyroidism and Addison’s disease with adrenal insufficiency as well as other auto-immune conditions.

Changes in stature

Tallness may occur in children for constitutional reasons (tall parents) or, rarely, may reflect growth hormone excess (leading to gigantism), gonadotrophin deficiency, Klinefelter’s syndrome ^b, Marfan’s syndrome or generalised lipodystrophy. Short stature can also result from endocrine disease, as discussed on page 313.

Erectile dysfunction (impotence)

A persistent inability to attain or sustain penile erections may occasionally be due to primary hypogonadism or to secondary hypogonadism due to hyperprolactinaemia or hypopituitarism. More often, it is related to emotional disorders. Vascular disease, autonomic neuropathy (e.g. in diabetes mellitus or alcoholism), spinal cord disease or testicular atrophy can also cause this problem.

Galactorrhoea

Hyperprolactinaemia (usually the result of pituitary adenoma) can cause galactorrhoea in up to 80% of women and 30% of men. Galactorrhoea in men occurs from a normal-appearing male breast.

Menstruation

Failure to menstruate is termed amenorrhoea.

Primary amenorrhoea is defined as a failure to start menstruating by 17 years of age. True primary amenorrhoea may result from ovarian failure (e.g. X chromosomal abnormalities such as Turner’s syndrome) or from pituitary or hypothalamic disease (e.g. tumour, trauma or idiopathic disease). Excess androgen production or systemic disease (e.g. malabsorption, chronic renal failure, obesity) can also result in primary amenorrhoea.

Apparent primary amenorrhoea can also occur if menstrual flow cannot escape: for example, if there is an imperforate hymen.

Secondary amenorrhoea is defined as the cessation of menstruation for 6 months or more. Pregnancy and menopause are common causes. The polycystic ovarian syndrome, hyperprolactinaemia, virilising syndromes or hypothalamic or pituitary disease can also result in this problem, as can use of the contraceptive pill or psychiatric disease.

Polyuria

Polyuria is defined as a urine volume of more than 3 litres/day. Patients who report urinary frequency may find it difficult to tell if large volumes of urine are being passed. Causes include diabetes mellitus (due to excessive filtration of glucose, a poorly resorbed solute); diabetes insipidus (due to inadequate renal water conservation from a central deficiency of antidiuretic hormone, or a lack of renal responsiveness to this hormone); primary polydipsia, where a patient drinks excessive water (due to psychogenic or hypothalamic disease or drugs such as chlorpromazine or thioridazine); hypercalcaemia; and tubulointerstitial or cystic renal disease.

Past history

A previous history of any endocrine condition must be uncovered. This includes surgery on the neck for a goitre. A partial thyroidectomy or radio-iodine (¹³¹I) treatment in the past can lead to eventual hypothyroidism. The same may apply to radiation of the thyroid for carcinoma. A woman may have been diagnosed with diabetes mellitus after the birth of a large baby. There may be a past history of hypertension, which is occasionally due to an endocrine condition (e.g. phaeochromocytoma, Cushing’s syndrome or Conn’s syndrome). Previous thyroid surgery can be associated with hypoparathyroidism because of surgical damage to the parathyroid glands.

Previous treatment of a patient’s thyroid problems may have included the use of antithyroid drugs, thyroid hormone or radioactive iodine. Surgery on the adrenals or pituitary may have been performed and this may leave the patient with decreased adrenal or pituitary function.

Patients with diabetes mellitus have an important chronic condition (Questions box 10.7, page 316). Treatment may be with diet, insulin or oral hypoglycaemic agents. One must determine how well the patient understands the condition, and whether he or she understands the principles of the diabetic diet and adheres to it. Find out how the blood sugar levels are monitored and whether or not the patient adjusts the insulin dose. Most patients should now be able to monitor their own blood sugar levels at home using a glucometer. There is now good evidence that tight control of blood sugar levels reduces the incidence of diabetic complications. Patients should have records of home blood sugar measurements, and may know the results of tests such as the haemoglobin A1c (a measure of average blood sugar levels) and of tests of renal function and for protein in the urine.

The patient should be aware of the need for care of the feet and eyes to help prevent complications. Most diabetics have regular ophthalmological review, often using retinal photography. There may be a history of laser treatment for proliferative diabetic retinopathy.

Patients with hypopituitarism or hypoadrenalism may be on glucocorticoid (steroid) replacement; the latter also require mineralocorticoid replacement. Details of the patient’s dosage schedule should be obtained.

Social history

Many of these conditions are chronic and their complications serious. How well the patient copes with various problems and the conditions at home and work will have an important effect on the success of treatment.

Family history

There may be a history in the family of thyroid conditions or diabetes mellitus. Occasionally a family history of a multiple endocrine neoplasia (MEN) syndrome may be obtained. These are rare autosomal-dominant conditions. They include pituitary tumours, medullary carcinoma of the thyroid, hyperparathyroidism, phaeochromocytoma and pancreatic islet cell tumours.

The endocrine examination

A formal examination of the whole endocrine system is set out on page 322. Usually there will be some clue from the history and general inspection to indicate what specific endocrine diseases should be pursued.

The thyroid

The thyroid gland ^c

Examination anatomy

Even when it is not enlarged, the thyroid (Figure 10.2) is the largest

Figure 10.2 The anatomy of the thyroid

Figure 10.1 The endocrine glands

endocrine gland. Enlargement is common, occurring in 10% of women and 2% of men and more commonly in iodine-deficient parts of the world. The normal gland lies anterior to the larynx and trachea and below the laryngeal prominence of the thyroid cartilage. It consists of a narrow isthmus in the middle line (anterior to the second to fourth tracheal rings and 1.5 cm in size), and two larger lateral lobes each about 4 cm long. Although the position of the larynx varies, the thyroid gland is almost always about 4 cm below the larynx.

Inspection

The normal thyroid may be just visible below the cricoid cartilage in a thin young person (Table 10.2).¹^,². Usually only the isthmus is visible as a diffuse central swelling. Enlargement of the gland, called a goitre (Latin guttur, ‘throat’), should be apparent on inspection (see Good signs guide 10.1), especially if the patient extends the neck. Look at the front and sides of the neck and decide whether there is localised or general swelling of the gland. In normal people the line between the cricoid cartilage and the suprasternal notch should be straight. An outward bulge suggests the presence of a goitre (Figure 10.3). Remember that 80% of people with a goitre are biochemically euthyroid, 10% are hypothyroid and 10% are hyperthyroid.

TABLE 10.2 Causes of neck swellings

^* Aulus Celsus (page 297), the Roman medical writer who was active early in the 1st century AD, was the first to publish work distinguishing a goitre from cervical lymphadenopathy.

GOOD SIGNS GUIDE 10.1 Detection of a goitre (compared with ultrasound findings)

Sign	Positive LR	Negative LR^*
No goitre on inspection or palpation	0.4	—
Goitre palpated and visible only on neck extension	NS	—
Goitre palpated and visible with neck in normal position	26.3	—

NAS = not significant.

^* No values available.

From McGee S, Evidence-based physical diagnosis, 2nd edn. St Louis: Saunders, 2007.

Figure 10.3 The thyroid and goitre

Adapted from McGee S, Evidence-based physical diagnosis, 2nd edition, St Louis, Saunders, 2007.

The temptation to begin touching a swelling as soon as it has been detected should be resisted until a glass of water has been procured. The patient takes sips from this repeatedly so that swallowing is possible without discomfort. Ask the patient to swallow, and watch the neck swelling carefully. Only a goitre or a thyroglossal cyst, because of attachment to the larynx, will rise during swallowing. The thyroid and trachea rise about 2 cm as the patient swallows; they pause for half a second and then descend. Some non-thyroid masses may rise slightly during swallowing but move up less than the trachea and fall again without pausing. A thyroid gland fixed by neoplastic infiltration may not rise on swallowing, but this is rare. Swallowing also allows the shape of the gland to be seen better.

It should be noted whether an inferior border is visible as the gland rises. The thyroglossal cyst is a midline mass that can present at any age. It is an embryological remnant of the thyroglossal duct. Characteristically it rises when the patient protrudes the tongue.

Inspect the skin of the neck for scars. A thyroidectomy scar forms a ring around the base of the neck in the position of a high necklace. Also look for prominent veins. Dilated veins over the upper part of the chest wall, often accompanied by filling of the external jugular vein, suggest retrosternal extension of the goitre (thoracic inlet obstruction). Rarely, redness of the skin over the gland occurs in cases of suppurative thyroiditis.

Palpation

Palpation is best begun from behind (Figure 10.4) but warn the patient. Both hands are placed with the pulps of the fingers over the gland. The patient’s neck should be slightly flexed so as to relax the sternomastoid muscles. Feel systematically both lobes of the gland and its isthmus.

Figure 10.4 Palpating the thyroid from behind while the patient swallows sips of water

Consider the following:

• Size: only an approximate estimation is possible (Figure 10.5). Feel particularly carefully for a lower border, because its absence suggests retrosternal extension.

• Shape: note whether the gland is uniformly enlarged or irregular and whether the isthmus is affected. If a nodule that feels distinct from the remaining thyroid tissue is palpable, determine its location, size, consistency, tenderness and mobility. Also decide whether the whole gland feels nodular (multinodular goitre).

• Consistency: may vary in different parts of the gland. Soft is normal; the gland is often firm in simple goitre and typically rubbery hard in Hashimoto’s thyroiditis. A stony, hard node suggests carcinoma (Table 10.3), calcification in a cyst, fibrosis or Riedel’s thyroiditis.

• Tenderness: a feature of thyroiditis (subacute or rarely suppurative), or less often of a bleed into a cyst or carcinoma.

• Mobility: carcinoma may tether the gland.

Figure 10.5 Goitre: (a) large; (b) massive

TABLE 10.3 Differential diagnosis of thyroid nodules

1 Carcinoma (5% of palpable nodules)—fixed to surrounding tissues, palpable lymph nodes, vocal cord paralysis, hard, larger than 4 cm (most are, however, smaller than this)

2 Adenoma—mobile, no local associated features

3 Big nodule in a multinodular goitre—palpable multinodular goitre

Repeat the assessment while the patient swallows

Decide if a thrill is palpable over the gland, as occurs when the gland is unusually metabolically active as in thyrotoxicosis.

Palpate the cervical lymph nodes (page 228). These may be involved in carcinoma of the thyroid.

Move to the front. Palpate again. Localised swellings may be more easily defined here. Note the position of the trachea, which may be displaced by a retrosternal gland.

Percussion

The upper part of the manubrium can be percussed from one side to the other. A change from resonant to dull indicates a possible retrosternal goitre, but this is not a very reliable sign.

Auscultation

Listen over each lobe for a bruit (a swishing sound coinciding with systole). This is a sign of increased blood supply which may occur in hyperthyroidism, or occasionally from the use of antithyroid drugs. The differential diagnosis also includes a carotid bruit (louder over the carotid itself) or a venous hum (obliterated by gentle pressure over the base of the neck). If there is a goitre, apply mild compression to the lateral lobes and listen again for stridor.

Pemberton’s sign

Ask the patient to lift both arms as high as possible. Wait a few moments, then search the face eagerly for signs of congestion (plethora) and cyanosis. Associated respiratory distress and inspiratory stridor may occur. Look at the neck veins for distension (venous congestion). Ask the patient to take a deep breath in through the mouth and listen for stridor. This is a test for thoracic inlet obstruction due to a retrosternal goitre or any retrosternal mass.³ (Lifting the arms up pulls the thoracic inlet upward so that the goitre occupies more of this inflexible bony opening.)

Examination of the thyroid should be part of every routine physical examination. Causes of a goitre are listed in Table 10.4.

TABLE 10.4 Goitre

Causes of a diffuse goitre (patient often euthyroid)

Idiopathic (majority)

Puberty or pregnancy

Thyroiditis

• Hashimoto’s

• Subacute (gland usually tender)

Simple goitre (iodine deficiency)

Goitrogens—iodine excess, drugs (e.g. lithium)

Inborn errors of thyroid hormone synthesis—e.g.

Pendred’s ^* syndrome (an autosomal-recessive condition associated with nerve deafness)

Causes of a solitary thyroid nodule

Benign:

• Dominant nodule in a multinodular goitre

• Degeneration or haemorrhage into a colloid cyst or nodule

• Follicular adenoma

• Simple cyst (rare)

Malignant:

• Carcinoma—primary or secondary (rare)

• Lymphoma (rare)

^* Vaughan Pendred (b. 1869), London physician.

Hyperthyroidism (thyrotoxicosis)

This is a disease caused by excessive concentrations of thyroid hormones. The cause is usually overproduction by the gland but may sometimes be due to accidental or deliberate use of thyroid hormone (thyroxine) tablets; thyrotoxicosis factitia. Thyroxine is sometimes taken by patients as a way of losing weight. The cause may be apparent in these cases if a careful history is taken (Questions box 10.1). The anti-arrhythmic drug amiodarone which contains large quantities of iodine can cause thyrotoxicosis in up to 12% of patients in low-iodine-intake areas.

Questions box 10.1

Questions to ask the patient with suspected hyperthyroidism

! denotes symptoms for the possible diagnosis of an urgent or dangerous problem.

1. Have you any history of thyroid problems?

2. Have you a family history of thyrotoxicosis?—There is a familial incidence of Graves disease and associated auto-immune conditions such as vitiligo, Addison’s disease, pernicious anaemia, type 1 diabetes, myasthenia gravis and premature ovarian failure

3. Have you taken amiodarone or thyroxine?

4. Have you had recent exposure to iodine?—Iodinated X-ray contrast materials can precipitate thyrotoxicosis (usually in patients with an existing multinodular goitre)

5. Have you had palpitations?—Thyrotoxicosis can present with atrial fibrillation which may precipitate heart failure

6. Have you noticed insomnia, irritability or hyperactivity?

7. Have you had loss of weight, diarrhoea or increased stool frequency, increased sweating or heat intolerance?

8. Have you had muscle weakness?—Proximal muscle weakness is common and the patient may have noticed difficulty getting out of a chair

9. Have you had eye problems such as double vision, grittiness, redness or pain behind the eyes?

Many of the clinical features of thyrotoxicosis are characterised by signs of sympathetic nervous system overactivity such as tremor, tachycardia and sweating. The explanation is not entirely clear. Catecholamine secretion is usually normal in hyperthyroidism; however, thyroid hormone potentiates the effects of catecholamines, possibly by increasing the number of adrenergic receptors in the tissues.

The commonest cause of thyrotoxicosis in young people is Graves’ disease,^d an autoimmune disease where circulating immunoglobulins stimulate thyroid stimulating hormone (TSH) receptors on the surface of the thyroid follicular cells.

Examine a suspected case of thyrotoxicosis as follows (see Good signs guide 10.2).

GOOD SIGNS GUIDE 10.2 Thyrotoxicosis

Sign	Positive LR	Negative LR
Pulse
≥90/min	4.4	0.2
Skin
Moist and warm	6.7	0.7
Thyroid
Enlarged	2.3	0.1
Eyes
Eyelid retraction	31.5	0.7
Lid lag	17.6	0.8
Neurological
Fine tremor	11.4	0.3

From McGee S, Evidence-based physical diagnosis, 2nd edn. St Louis: Saunders, 2007.

General inspection

Look for signs of weight loss, anxiety and the frightened facies of thyrotoxicosis.

The hands

Ask the patient to put out his or her arms and look for a fine tremor (due to sympathetic overactivity). Laying a sheet of paper over the patient’s fingers may more clearly demonstrate this tremor, to the amazement of less-experienced colleagues.

Look at the nails for onycholysis (Plummer’s ^e nails) (Figure 10.6). Onycholysis (where there is separation of the nail from its bed) is said to occur particularly on the ring finger, but can occur on all the fingernails, and is apparently due to sympathetic overactivity. Inspect now for thyroid acropathy (acropathy is another term for clubbing), seen rarely in Graves’ disease but not with other causes of thyrotoxicosis.

Figure 10.6 Onycholysis (Plummer’s nails)

Inspect for palmar erythema and feel the palms for warmth and sweatiness (sympathetic overactivity).

Take the pulse. Note the presence of sinus tachycardia (sympathetic overdrive) or atrial fibrillation (due to a shortened refractory period of atrial cells related to sympathetic drive and hormone-induced changes). The pulse may also have a collapsing character due to a high cardiac output.

Test for proximal myopathy and tap the arm reflexes for abnormal briskness, especially in the relaxation phase.

The eyes

Examine the eyes for exophthalmos, which is protrusion of the eyeball from the orbit (Figure 10.7, Table 10.5). This may be very obvious, but if not, look carefully at the sclerae, which in exophthalmos are not covered by the lower eyelid. Next look from behind over the patient’s forehead for exophthalmos, where the eye will be visible anterior to the superior orbital margin. Now examine for the complications of proptosis, which include: (i) chemosis (oedema of the conjunctiva and injection of the sclera, particularly over the insertion of the lateral rectus); (ii) conjunctivitis; (iii) corneal ulceration (due to inability to close the eyelids); (iv) optic atrophy (rare and possibly due to optic nerve stretching); and (v) ophthalmoplegia (the inferior rectus muscle power tends to be lost first, and later convergence is weakened).

Figure 10.7 Thyrotoxicosis: thyroid stare and exophthalmos

TABLE 10.5 Causes of exophthalmos

Bilateral

Graves’ disease

Unilateral

Tumours of the orbit: e.g. dermoid, optic nerve glioma, neurofibroma, granuloma

Cavernous sinus thrombosis

Graves’ disease

Pseudotumours of the orbit

The mechanism of exophthalmos is uncertain. It occurs only in Graves’ disease. It may precede the onset of thyrotoxicosis, or may persist after the patient has become euthyroid. It is characterised by an inflammatory infiltrate of the orbital contents, but not of the globe itself. The orbital muscles are particularly affected, and an increase in their size accounts for most of the increased volume of the orbital contents and therefore for protrusion of the globe. It is probably due to an autoimmune abnormality.

Next examine for the components of thyroid ophthalmopathy, which are related to sympathetic overactivity and are not specific for Graves’ disease. Look for the thyroid stare (a frightened expression) and lid retraction (Dalrymple’s sign ^f), where there is sclera visible above the iris. Test for lid lag (von Graefe’s sign^g) by asking the patient to follow your finger as it descends at a moderate rate from the upper to the lower part of the visual field. Descent of the upper lid lags behind descent of the eyeball.

If ptosis is present, one should rule out myasthenia gravis, which can be associated with autoimmune disease.

The neck

Examine for thyroid enlargement, which is usually detectable (60%–90% of patients). In Graves’ disease the gland is classically diffusely enlarged and is smooth and firm. An associated thrill is usually present but this finding is not specific for thyrotoxicosis caused by Graves’ disease. Absence of thyroid enlargement makes Graves’ disease unlikely, but does not exclude it. Possible thyroid abnormalities in patients who are thyrotoxic but do not have Graves’ disease include a toxic multinodular goitre, a solitary nodule (toxic adenoma), and painless, postpartum or subacute (de Quervain’s ^h) thyroiditis. In de Quervain’s thyroiditis there is typically a moderately enlarged firm and tender gland. Thyrotoxicosis may occur without any goitre, particularly in elderly patients. Alternatively, in hyperthyroidism due to a rare abnormality of trophoblastic tissue (a hydatidiform mole or choriocarcinoma of the testis or uterus), or excessive thyroid hormone replacement, the thyroid gland will not usually be palpable.

If a thyroidectomy scar is present, assess for hypoparathyroidism (Chvostek’s ⁱ or Trousseau’s^j signs; page 311). These signs are most often present in the first few days after operation.

Look first for pretibial myxoedema. This takes the form of bilateral firm, elevated dermal nodules and plaques, which can be pink, brown or skin-coloured. They are caused by mucopolysaccharide accumulation. Despite the name, this occurs only in Graves’ disease and not in hypothyroidism. Test now for proximal myopathy and hyperreflexia in the legs which is present in only about a quarter of cases.

Hypothyroidism (myxoedema)

Hypothyroidism (deficiency of thyroid hormone) is due to primary disease of the thyroid or, less commonly, is secondary to pituitary or hypothalamic failure (Table 10.6). Myxoedema implies a more severe form of hypothyroidism. In myxoedema, for unknown reasons, hydrophilic mucopolysaccharides accumulate in the ground substance of tissues including the skin. This results in excessive interstitial fluid, which is relatively immobile, causing skin thickening and a doughy induration.

TABLE 10.6 Thyrotoxicosis and hypothyroidism