Endocrine and metabolic disorders

Thirst and polyuria

Excessive thirst (polydipsia) and increased urine output (polyuria) are important symptoms for which careful history taking is crucial for accurate diagnosis. The word ‘excessive’ appears in almost all dictionary definitions of polydipsia and polyuria, but no accepted number of episodes of fluid intake or excretion indicate a definite abnormality, largely because individual habitual fluid intake is so variable in health. If the symptoms form the basis of a patient’s complaint, they require careful and sympathetic evaluation. Polyuria and polydipsia are common presenting symptoms of diabetes mellitus; these are discussed in detail below. These symptoms may also be caused by impairment of renal concentrating capacity as a result of a deficiency of antidiuretic hormone (ADH) or a failure of ADH action (cranial and nephrogenic diabetes insipidus, respectively). The latter may be inherited or may occur secondary to impairment of ADH action by hypercalcaemia or hypokalaemia. An important distinction must be made between frequency of urination and polyuria. Prostatic enlargement in men and childbirth-related pelvic damage in women are common causes of frequent urination, but in these situations the volumes of urine passed will usually be small and the symptoms will not be accompanied by thirst. Nocturia (the passage of urine during conventional sleeping hours) is common in men with prostatic enlargement, but is not accompanied by thirst; indeed, most men will make conscious efforts to restrict evening fluid intake in an attempt to reduce nocturia with its associated fatigue. In contrast, a patient with diabetes insipidus, characteristically, will take at least a glass, often a whole bottle, of water to bed in order to quench his nocturnal thirst. Probing the details of nocturnal symptoms is also useful in distinguishing the reported polydipsia and polyuria caused by increased fluid intake, which at its most extreme may be vastly excessive (primary, sometimes referred to as psychogenic, polydipsia). In general, nocturnal polyuria is not a feature of primary polydipsia, because the capacity of the pituitary to release ADH and of the kidney to respond to it are not disturbed. In contrast, it is often the nocturia and the associated urge to drink that most disturb patients with diabetes insipidus. However, this is not an absolute distinction and further investigation of urine concentrating capacity is sometimes required.

Weight loss

Loss of weight is a feature of decreased food intake or increased metabolic rate. Sometimes both factors may operate to reduce body weight, as in the cachexia of malignant disease. Thyroid overactivity (hyperthyroidism) is nearly always associated with a combination of unintentional or effortless weight loss and increased appetite, although occasionally the latter may be stimulated more than the former so that a paradoxical increase in weight occurs. Weight loss is rarely the sole presenting symptom of hyperthyroidism and other clinical features often predominate, particularly in younger patients ( Box 19.1 ). In the elderly, however, hyperthyroidism may be occult or may simulate the gradual weight loss of malignant disease. Cardiac arrhythmias are a frequent feature in the elderly. Anorexia nervosa, a psychogenic disorder characterized by a long history of low body weight in the absence of other features of ill health, must be considered, especially in young women. Any form of weight loss may be associated with oligo-amenorrhoea.

Other endocrine conditions in which weight loss is a major feature are listed in Box 19.2 .

Weight gain or redistribution

An increase in body weight ( Box 19.3 ) is a predictable result of a reduction in metabolic rate. Weight gain is therefore a common feature of primary hypothyroidism. However, obesity is rarely a consequence of specific endocrine dysfunction, an exception being the very rare phenomenon of leptin deficiency. In the majority of patients, ‘simple obesity’ is owing to a long-standing imbalance between energy intake and expenditure; it frequently begins in childhood and is often present in more than one family member. Glucocorticoid hormone excess (Cushing’s syndrome) results in an increase in body fat predominantly involving abdominal, omental and interscapular fat (truncal obesity), with paradoxical thinning of the limbs owing to muscle atrophy.

Muscle weakness

Symptomatic muscular weakness not caused by neurological disease is a feature of several metabolic disorders, including thyrotoxicosis, Cushing’s syndrome and vitamin D deficiency. In all these conditions, the metabolic myopathy ( Box 19.4 ) causes symmetrical proximal weakness, mainly involving the shoulder and hip girdle musculature. There is usually associated muscle wasting. The major reported symptom is difficulty in climbing stairs, boarding a bus or rising from a sitting position. Most patients with hyperthyroidism have proximal weakness. This may be subclinical; it is best demonstrated by asking the patient to rise from the squatting position. The proximal myopathy of vitamin D deficiency is often painful, in contrast to other causes. The differential diagnosis of painful proximal muscular weakness includes polymyositis and polymyalgia rheumatica, as well as spinal root or plexus disease.

Cold intolerance

An abnormal sensation of cold, out of proportion to that experienced by other individuals, may indicate underlying hypothyroidism ( Boxes 19.5 and 19.6 ). This symptom differs from the localized vasomotor symptoms in the hands found in Raynaud’s phenomenon and is rather non-specific, especially in the elderly.

Heat intolerance

The increased metabolic rate of thyrotoxicosis may be associated with heat intolerance in which, at its most extreme, the patient is comfortable at an ambient temperature that others find unpleasantly cold. This is an important symptom, highly specific for thyroid overactivity, which may partly explain some of the seasonal variation in presentation of the condition.

Increased sweating

Hyperhidrosis (excessive sweating) may be a constitutional abnormality, characterized by onset in childhood or adolescence and sometimes by a family history. A recent increase in sweat secretion, on the other hand, may be an early indication of thyroid overactivity. Paroxysmal sweating is a common feature of anxiety. Increased catecholamine secretion from a phaeochromocytoma of the adrenal medulla is a rare cause of hyperhidrosis. Intermittent sweating after meals (gustatory hyperhidrosis) may occur in patients with autonomic dysfunction. Growth hormone excess (acromegaly) also increases sweating, perhaps because of hypertrophy of the sweat glands, and this feature can be used to assess the activity of the disease in the clinic. Increased sweating should be distinguished from flushing that occurs physiologically at the time of the natural menopause. Flushing may be a presenting feature of serotonin-secreting carcinoid tumours of the gut and usually indicates extensive disease with hepatic metastases.

Tremor

A fine rapid resting tremor is one of the cardinal clinical features of thyrotoxicosis. This must be distinguished from the coarser and more irregular tremor of anxiety, which is usually associated with a cool peripheral skin temperature, in contrast to the warm skin of the thyrotoxic patient. Tremor owing to neurological disease is greater in amplitude, slower in rate and may be present at rest, as in Parkinson’s disease, or on movement, as in cerebellar tremor. It therefore rarely simulates thyrotoxic tremor. Essential tremor is not so rapid as thyrotoxic tremor; it is variable and is worse in certain postures. It often involves the head and neck.

Palpitations

Palpitations are a heightened, unpleasant awareness of the heartbeat. They may be a feature of thyrotoxicosis, but more likely are caused by anxiety. Awareness of the heartbeat while lying down is normal. Other causes of rapid heart rate include paroxysmal tachyarrhythmias. The sensation of intermittent forceful cardiac contraction, sometimes described by the patient as a missed beat, is often owing to a compensatory pause following an ectopic beat and is usually a normal phenomenon.

Postural unsteadiness

Dizziness, or a sensation of faintness on standing, should prompt measurement of lying and standing blood pressure. Postural hypotension, a fall of diastolic blood pressure on standing, occurs with reduced blood volume. In the absence of obvious bleeding or gastrointestinal fluid loss, adrenal insufficiency should be considered. Postural hypotension is frequently caused by autonomic neuropathy, especially in patients with long-standing diabetes mellitus. It is also a common complication of any drug therapy for essential hypertension. The drug history is particularly important in the elderly patient with dizziness.

Visual disturbance

Several endocrine conditions may cause visual symptoms. Blurred vision is common in uncontrolled hyperglycaemia. Decreased visual acuity may be caused by space-occupying lesions compressing the optic nerve. For example, severe dysthyroid eye disease and orbital or retro-orbital tumours may present in this way. Bitemporal hemianopia (bilateral loss of part or all of the temporal fields of vision), often asymmetrical or incongruous, is a major feature of suprasellar extension of pituitary adenomas compressing the optic chiasm, but may occur in other tumours in this location. Double vision (diplopia) on lateral or upward gaze often results from medial or lateral rectus muscle tethering in dysthyroid eye disease. Apparent magnification of vision (macropsia) can occur in hypoglycaemia.

Fasting symptoms

Tachycardia, sweating and tremor occurring intermittently, especially when fasting, are suggestive of hypoglycaemia. These symptoms resemble those associated with the increased sympathetic drive found in states of fear or with excess secretion of noradrenaline (norepinephrine), as in phaeochromocytoma. In severe persistent hypoglycaemia, these symptoms may progress to decreased consciousness. This is a serious emergency implying neuroglycopenia sufficient to impair brain function. Spontaneous or fasting hypoglycaemia may be caused by the following:

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  Autonomous insulin production owing to an insulinoma

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  Glucocorticoid deficiency, with or without thyroxine and growth hormone deficiency (e.g. primary adrenal failure or hypopituitarism)

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  Inappropriate insulin or excessive sulfonylurea drug administration in a diabetic patient

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  Rarer causes of hypoglycaemia, for example hepatic failure and rapidly growing malignant lesions, especially thoracic or retroperitoneal mesothelial tumours secreting proinsulin-like growth factor II.

Cramps and ‘pins and needles’

Intermittent cramps and ‘pins and needles’ (paraesthesiae), especially if bilateral, can be caused by a decreased level of circulating ionized calcium. This may occur in hypoparathyroidism or be associated with a fall in the ionized component of serum calcium because of an increased extracellular pH (alkalosis). The latter may occur with any alkalosis, but is particularly well recognized in hyperventilatory states (respiratory alkalosis) and hypokalaemia (metabolic alkalosis). Refractory cramping symptoms after correction of hypocalcaemia may be owing to an associated hypomagnesaemia. However, the differential diagnosis of paraesthesiae in the hands includes median nerve compression at the wrist (carpal tunnel syndrome), a syndrome usually accompanied by typical sensory and motor disturbance suggestive of a lesion in the median nerve (see Chapter 16 ). Paraesthesiae in the feet are a common symptom of diabetic peripheral sensory neuropathy.

Nausea

Nausea is a rare symptom of endocrine disease. It is an important presenting feature of adrenal insufficiency, in which typically it is maximal in the morning and may be associated with vomiting. Similar symptoms may occur with severe hypercalcaemia and may be the sole manifestation of this condition. These two conditions should be considered early in the differential diagnosis of a patient presenting with upper gastrointestinal symptoms in the absence of demonstrable structural disease. Occasionally, thyrotoxicosis may present with nausea and vomiting, although looseness of stools is the more common gastrointestinal manifestation of this condition.

Dysphagia

Difficulty in swallowing is an unusual manifestation of endocrine disease, but it may be the presenting feature of multinodular thyroid enlargement with retrosternal extension. Smaller goitres only rarely result in dysphagia. Severe hyperthyroidism with generalized weakness may be associated with a reversible myopathy of the pharyngeal musculature and consequent dysphagia.

Neck pain and swelling

Superficial discomfort in the neck may lead to the incidental finding of thyroid enlargement. Modest degrees of thyroid enlargement are very common, whereas pain arising from the thyroid is comparatively unusual. The most common cause of local discomfort and tenderness in the neck is inflammatory lymphadenopathy. Severe tenderness of the thyroid itself, especially when accompanied by fever and signs of thyrotoxicosis, suggests a diagnosis of viral subacute thyroiditis (de Quervain’s thyroiditis). Occasionally, autoimmune thyroiditis may give rise to pain and tenderness, which mimics a viral thyroiditis but is less severe. The sudden onset of localized pain and swelling in the thyroid is indicative of bleeding into a pre-existing thyroid nodule and is a recognized complication of multinodular goitre. The symptoms are self-limiting. Painless enlargement of the thyroid gland (goitre) presents either with pressure effects, resulting in dysphagia progressing to tracheal compression and stridor, or cosmetic disturbance. The underlying cause of thyroid enlargement is often difficult to establish. The family history and subsequent investigation may point to autoimmune thyroiditis or dyshormonogenesis. A history of rapid enlargement of the gland, especially in an elderly patient, suggests an anaplastic thyroid carcinoma. Coexisting severe diarrhoea points towards a diagnosis of medullary carcinoma of the thyroid. In the differential diagnosis, goitrogenic drugs, for example lithium, should be considered, as should residence in an iodine-deficient area. Previous exposure to neck irradiation or to radioactive iodine in childhood may also be important.

Impotence

Reduced erectile potency may be a consequence of primary abnormalities, such as the following:

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  Decreased blood supply to the penis (e.g. atherosclerosis)

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  Neural dysfunction (e.g. autonomic neuropathy complicating diabetes)

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  Testosterone deficiency (e.g. hypopituitarism and primary testicular failure)

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  Hyperprolactinaemia

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  Drug therapy (e.g. certain antihypertensives)

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  Psychological factors

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  A combination of several causes

It is often difficult to distinguish with certainty between impotence owing to organic factors and that which is psychological, although total erectile failure and the absence of nocturnal and morning erections suggest a physical cause. Impotence in a diabetic patient should not be assumed to be inevitably owing to autonomic neuropathy, and other causes should be considered. Most importantly, it should be recognized that male impotence is often complicated by a psychological disturbance, which may serve to exacerbate the problem.

Gynaecomastia

Gynaecomastia refers to a smooth, firm, mobile, often tender disc of breast tissue under the areola in the male. It should be distinguished from the soft, fatty enlargement often seen in obesity. Mild gynaecomastia (sometimes unilateral or asymmetrical) frequently occurs as a temporary phenomenon in normal puberty and may persist for several years or sometimes indefinitely (termed persistent pubertal gynaecomastia). In adults, gynaecomastia may result from:

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  Excess oestrogen stimulation

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  Reduction in circulating androgen

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  Antagonism of androgen action

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  Androgen insensitivity ( Box 19.7 )

  Box 19.7

  Causes of gynaecomastia

  Increased oestrogen/testosterone ratio

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    Chronic liver disease

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    Thyrotoxicosis

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    Phenytoin therapy

  Androgen receptor antagonists

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    Spironolactone, digoxin

  Inherited androgen receptor defects

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    Testicular feminization syndrome

  Testosterone deficiency or oestrogen excess

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    Primary and secondary hypogonadism

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    Tumour production of human chorionic gonadotrophin (hCG)

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    Oestrogen production by Leydig cell tumour of testis

  Congenital and hereditary

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    X-linked spinal muscular atrophy (Kennedy syndrome)

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    Klinefelter’s syndrome (karyotype XXY)

Therefore, clinical assessment of the patient with gynaecomastia should include an enquiry about any change in libido and an examination of thyroid status, the genitalia, the muscles and for stigmata of chronic liver disease.