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Home > 2 SYSTEM-BASED DISEASES > 16 Endocrine disease > FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
MAJOR ENDOCRINE FUNCTIONS AND ANATOMY
Although some endocrine glands (e.g. parathyroid glands and pancreas) respond directly to metabolic signals, 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 (see Fig. 16.1). 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 of nervous, metabolic, physical or hormonal origin, in particular 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 16.2. The characteristics of each axis are described in relation to individual glands later in this chapter.
Figure 16.1 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 act as hormones. Peptides (e.g. insulin), glycoproteins (e.g. thyroid-stimulating hormone, TSH) and amines (e.g. noradrenaline) act on specific cell surface receptors which signal through G-proteins and/or enzymes on the cytosolic side of the plasma membrane. Other hormones (e.g. steroids, thyroid hormones and vitamin D) bind to specific intracellular receptors which in turn bind to response elements on DNA to regulate gene transcription.
The classical model of endocrine function involves hormones which are synthesised in endocrine glands, released into the circulation, and act at sites distant from those of secretion (as in Fig. 16.1). However, additional levels of complex regulation have now been recognised. Thus, most major organs also secrete hormones or contribute to the peripheral metabolism and activation of prohormones; many hormones act on adjacent cells (paracrine system, e.g. neurotransmitters), or even back on the cell of origin (autocrine system); and the sensitivity of target tissues is regulated in a tissue-specific fashion. The clinical implications of this complexity of hormone action are only now being appreciated.
ENDOCRINE PATHOLOGY
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Figure 16.2 The principal endocrine 'axes' and glands. A Endocrine axes. Some major endocrine glands are not controlled by the pituitary. These include the parathyroid glands (regulated by calcium concentrations-see p. 714), the adrenal zona glomerulosa (regulated by the renin-angiotensin system-see p. 720) and the endocrine pancreas (see Ch. 15 and p. 732). Italics show negative regulation. (ACTH = adrenocorticotrophic hormone; ADH = antidiuretic hormone, arginine vasopressin; CRH = corticotrophin-releasing hormone; FSH = follicle-stimulating hormone; GH = growth hormone; GHRH = growth hormone-releasing 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) B Endocrine glands.
16.1 CLASSIFICATION OF ENDOCRINE DISEASE
Non-functioning tumours
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
For each endocrine axis or major gland in this chapter, diseases can be classified as shown in
AUTOIMMUNE DISEASE
From an endocrinology perspective, autoimmune disorders cluster into two syndromes, as shown in
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16.2 AUTOIMMUNE 'POLYGLANDULAR' SYNDROMES
Type 1
Addison's disease
Chronic mucocutaneous candidiasis
Hypoparathyroidism
Type 2
Primary hypothyroidism
Primary hypogonadism
Diabetes mellitus type 1
Pernicious anaemia
Addison's disease
Vitiligo
MULTIPLE ENDOCRINE NEOPLASIA (MEN)
These are rare autosomal dominant syndromes characterised by hyperplasia and formation of adenomas or malignant tumours in multiple glands. They fall into two groups, as shown in
MEN syndromes should be considered in all patients with two or more of the relevant disorders (e.g. hypercalcaemia and pituitary tumour) and in patients with solitary tumours who report other endocrine tumours in their family.
Important advances have been made in recent years to establish the genetic causes of these syndromes. MEN I results from inactivating mutations in 'menin', a tumour suppressor gene. In MEN II, mutations in the RET protooncogene cause constitutive activation of a membrane-associated tyrosine kinase. RET controls the development of cells which migrate from the neural crest, and different mutations causing loss of function of the RET kinase are associated with Hirschsprung's disease. Somatic mutations of these genes have been described in sporadic tumours, e.g. menin mutations in parathyroid adenomas and RET mutations in papillary thyroid carcinomas.
16.3 MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROMES
In addition, in MEN IIb syndrome there are phenotypic changes (including marfanoid habitus, skeletal abnormalities, abnormal dental enamel, multiple mucosal neuromata)
MEN I (Werner's syndrome)
Primary hyperparathyroidism
Pituitary tumours
Pancreatic tumours (e.g. insulinoma, gastrinoma)
MEN II (Sipple's syndrome)
Primary hyperparathyroidism
Medullary carcinoma of thyroid
Phaeochromocytoma
As these are autosomal dominant disorders with full penetrance, there is a 50% chance that first-degree relatives of patients with MEN will carry the affected gene. Previously, relatives of index cases had to be screened using biochemical tests (MEN I: plasma calcium, prolactin and gastrin; MEN II: plasma calcium, urinary metanephrines, and calcium-pentagastrin test with calcitonin measurements). Tumours could occur at any time of life so that these tests had to be repeated, usually annually. Now, accurate genetic diagnosis is available for both syndromes. Genetic counselling is required (see p. 349). Unaffected relatives not only avoid biochemical screening, but also know that they will not pass the condition to their children. In affected relatives with MEN II, prophylactic thyroidectomy is recommended at an early age to prevent medullary carcinoma of thyroid, and biochemical screening for other manifestations is performed.
INVESTIGATION OF ENDOCRINE DISEASE
An understanding of biochemical investigations is important 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 (e.g. growth hormone) or marked physiological variation (e.g. diurnal variation of cortisol, or monthly variation of sex steroids in pre-menopausal women). Other investigations (e.g. imaging and biopsy) are usually reserved for patients who present with a tumour (e.g. in thyroid or pituitary) or in whom the biochemical diagnosis has already been made. The principles of investigation are shown on page 685. The choice of test is often pragmatic; some tests are intellectually attractive, but clinical studies have shown them to have poor predictive value (e.g. the metyrapone test in Cushing's syndrome); local access to reliable sampling facilities and laboratory measurements is an important consideration. Specific tests are described in relation to individual glands in the following sections. Approximate adult reference values for hormone concentrations in plasma are given in the Appendix.
MAJOR MANIFESTATIONS OF ENDOCRINE DISEASE
As described above (see p. 685), endocrine diseases present in many different ways. Classical syndromes are described in relation to individual glands in the following sections. The most common classical presentations are of thyroid disease, reproductive disorders and hypercalcaemia. In addition, endocrine diseases are often part of the differential diagnosis of common complaints discussed in other chapters of this book, including electrolyte abnormalities (see Ch. 9), hypertension (see Ch. 12), obesity (see Ch. 10) and osteoporosis (see Ch. 20). 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 that it is important that clinicians are familiar with their key features.
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Home > 2 SYSTEM-BASED DISEASES > 16 Endocrine disease > THE THYROID GLAND
THE THYROID GLAND
The thyroid axis is involved in the regulation of metabolism. Thyroid disease in its various forms is common, affecting some 5% of the population, predominantly females.
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
Figure 16.3 Thyroid hormone synthesis and secretion, and sites of inhibition by antithyroid drugs. Sites of action of antithyroid drugs are as follows: 1. Potassium perchlorate; 2. and 3. Carbimazole, propylthiouracil; 4. Lithium, iodide; 5. Iodide; 6. Propylthiouracil. (Tg = thyroglobulin; MIT = monoiodotyrosine; DIT = diiodotyrosine; TRH = thyrotrophin-releasing hormone; TRAb = TSH-receptor antibody present in patients with Graves' disease)
16.4 CLASSIFICATION OF THYROID DISEASE
Primary Secondary
Hormone excess Graves' disease
Multinodular goitre
Adenoma
Subacute thyroiditis Pituitary 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
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Thyroid physiology is illustrated in Figure 16.3 and diseases are classified in
The thyroid secretes predominantly thyroxine (T4), and only a small amount of triiodothyronine (T3); approximately 85% of T3 is produced by monodeiodination of T4 in other tissues such as liver, muscle and kidney. T4 is probably not metabolically active until converted to T3, and may be regarded as a prohormone. T3 and T4 circulate in plasma almost entirely (>99.9%) bound to transport proteins, mainly thyroxine-binding globulin (TBG). It is the minute fraction of unbound or free hormone which diffuses into tissues and exerts its metabolic action. While it is possible to measure the concentration of total or free T3 and T4 in plasma, 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; see p. 687). 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 and does not influence the timing of blood sampling when assessing thyroid function.
There is a negative feedback of thyroid hormones on the thyrotrophs such that in hyperthyroidism, when plasma concentrations of T3 and T4 are raised, TSH secretion is suppressed, and 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 normal range. Although the reference range for total T4 is 60-150 nmol/l, a rise or fall of 20 nmol/l in an individual in whom the level is usually 100 nmol/l would be associated on the one hand with undetectable TSH, and on the other hand with a raised TSH. The combination of 'normal' T3 and T4 and suppressed or raised TSH is known as subclinical hyperthyroidism and subclinical hypothyroidism respectively (see
16.5 PATTERNS OF THYROID FUNCTION TEST RESULTS IN PATIENTS WITH THYROID DISEASE
Type of disease T4 T3 TSH
Conventional hyperthyroidism (95% of cases) Raised Raised Undetectable
T3 -hyperthyroidism (5% of cases) Normal1 Raised Undetectable
Subclinical hyperthyroidism Normal1 Normal1 Undetectable
Primary hypothyroidism Low Not indicated2 Raised (usually > 20 mU/I)
Subclinical hypothyroidism Normal3 Not indicated2 Raised
Secondary hypothyroidism i.e. pituitary or hypothalamic disease Low Not indicated2 Usually undetectable4
Non-thyroidal illness Raised Low, normal or raised5 Usually undetectable
1Usually upper part of reference range.
2Measurement of T3 is not a sensitive indicator of hypothyroidism and should not be requested.
3Usually lower part of reference range.
4May be normal or even slightly raised due to the production of immunoreactive forms of TSH which have no biological activity.
5Depending on the assay system.
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Home > 2 SYSTEM-BASED DISEASES > 16 Endocrine disease > MAJOR MANIFESTATIONS OF THYROID DISEASE
MAJOR MANIFESTATIONS OF THYROID DISEASE
The major manifestations of thyroid disease are hyperthyroidism, hypothyroidism and goitre. Although no age group is exempt, the patient is likely to be a middle-aged female, and collectively these disorders affect some 5% of the population. In addition, ready access to accurate tests of thyroid function and an increasing tendency to screen certain populations (e.g. elderly, hospitalised) have led to the identification of patients with abnormal results who are either asymptomatic or with non-specific complaints such as tiredness and weight gain.
HYPERTHYROIDISM
Aetiology
Causes of hyperthyroidism are outlined in
16.6 CAUSES OF HYPERTHYROIDISM AND THEIR RELATIVE FREQUENCIES
Cause Frequency1 (%)
Graves' disease 76
Multinodular goitre 14
Autonomously functioning solitary thyroid nodule 5
Thyroiditis
Subacute (de Quervain's)2 3
Post-partum2 0.5
Iodide-induced
Drugs (e.g. amiodarone)2 1
Radiographic contrast media2 -
Iodine prophylaxis programme2 -
Extrathyroidal source of thyroid hormone excess
Factitious hyperthyroidism2 0.2
TSH-induced
Inappropriate TSH secretion by pituitary 0.2
Choriocarcinoma and hydatidiform mole -
Follicular carcinoma ± metastases 0.1
1In a series of 2087 patients presenting to the Royal Infirmary, Edinburgh, over a 10-year period.
2Characterised by a negligible radio-iodine uptake test result.
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16.7 CLINICAL FEATURES OF HYPERTHYROIDISM
Goitre
Diffuse ± bruit
Nodular (see p. 684)
Gastrointestinal
Weight loss despite normal or increased appetite
Hyperdefaecation
Diarrhoea and steatorrhoea
Anorexia
Vomiting
Cardiorespiratory
Palpitations, sinus tachycardia, atrial fibrillation
Increased pulse pressure
Ankle oedema in absence of cardiac failure
Angina, cardiomyopathy and cardiac failure
Dyspnoea on exertion
Exacerbation of asthma
Neuromuscular
Nervousness, irritability, emotional lability, psychosis
Tremor
Hyper-reflexia, ill-sustained clonus
Muscle weakness, proximal myopathy, bulbar myopathy
Periodic paralysis (predominantly Chinese)
Dermatological
Increased sweating, pruritus
Palmar erythema, spider naevi
Onycholysis
Alopecia
Pigmentation, vitiligo
Digital clubbing
Pretibial myxoedema (see p. 684)
Reproductive
Amenorrhoea/oligomenorrhoea
Infertility, spontaneous abortion
Loss of libido, impotence
Ocular
Lid retraction, lid lag (see p. 694)
Grittiness, excessive lacrimation
Chemosis
Exophthalmos, corneal ulceration
Ophthalmoplegia, diplopia
Papilloedema, loss of visual acuity
Other
Heat intolerance
Fatigue, apathy
Gynaecomastia
Lymphadenopathy
Thirst
Osteoporosis
Clinical features
These are shown in
Investigations
Serum T3 and T4 are elevated in the majority, but T4 is in the upper part of the normal range and T3 raised (T3-thyrotoxicosis) in 5% of patients, particularly those with recurrent hyperthyroidism, following surgery or a course of antithyroid drugs. In primary hyperthyroidism serum TSH is undetectable at less than 0.1 mU/l (see
16.8 NON-SPECIFIC BIOCHEMICAL ABNORMALITIES IN HYPERTHYROIDISM
Hepatic dysfunction
-Slightly raised concentrations of bilirubin, alanine aminotransferase and gamma-glutamyl transferase; elevated alkaline phosphatase derived from bone and liver
Mild hypercalcaemia (5%)
Glycosuria
-Associated diabetes mellitus
-'Lag storage' (see p. 648)
HYPOTHYROIDISM
Aetiology
The prevalence of primary hypothyroidism is 1:100 but increases to 5:100 if patients with subclinical hypothyroidism (normal T4, raised TSH) are included. The female:male ratio is approximately 6:1. There are various causes of primary hypothyroidism (see Box 16.9), but spontaneous atrophic hypothyroidism, thyroid failure following 131I or surgical treatment of hyperthyroidism, and the hypothyroidism of Hashimoto's thyroiditis account for over 90% of cases in those parts of the world which are not significantly iodine-deficient.
16.9 CLASSIFICATION OF PRIMARY HYPOTHYROIDISM
¨ Spontaneous atrophic
¨ Post-ablative (post-131I)
¨ Subclinical
¨ Transient
¨ Congenital
¨ Goitrous
o Hashimoto's thyroiditis
o Drug-induced
o Iodine deficiency
o Dyshormonogenesis
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16.10 CLINICAL FEATURES OF HYPOTHYROIDISM
General
§ Tiredness, somnolence
§ Weight gain
§ Cold intolerance
§ Hoarseness
§ Goitre
Cardiorespiratory
§ Bradycardia, hypertension, angina, cardiac failure
§ Xanthelasma
§ Pericardial and pleural effusion
Neuromuscular
§ Aches and pains, muscle stiffness
§ Delayed relaxation of tendon reflexes
§ Carpal tunnel syndrome, deafness
§ Depression, psychosis
§ Cerebellar ataxia
§ Myotonia
Haematological
§ Macrocytosis
§ Anaemia
§ Iron deficiency (pre-menopausal women)
§ Normochromic
§ Pernicious
Dermatological
§ Dry, flaky skin and hair, alopecia
§ Purplish lips and malar flush, carotenaemia
§ Vitiligo
§ Erythema ab igne (Granny's tartan)
§ Myxoedema
Reproductive
§ Menorrhagia
§ Infertility
§ Galactorrhoea
§ Impotence
§ Gastrointestinal
§ Constipation
§ Ileus
§ Ascites
Clinical features
These depend on the duration and severity of the hypothyroidism. In the patient in whom complete thyroid failure has developed insidiously over months or even years many of the clinical features listed in
Investigations
In the most common form of hypothyroidism, namely primary hypothyroidism resulting from an intrinsic disorder of the thyroid gland, serum T4 is low and TSH elevated, usually in excess of 20 mU/l. Serum T3 concentrations do not discriminate reliably between euthyroid and hypothyroid patients and should not be measured. Other non-specific abnormalities include elevation of the enzymes lactate dehydrogenase (LDH) and creatine kinase, raised cholesterol and triglyceride concentrations, and low serum sodium. In severe prolonged hypothyroidism the electrocardiogram classically demonstrates sinus bradycardia with low voltage complexes and ST segment and T wave abnormalities. In the rare secondary hypothyroidism there is atrophy of an inherently normal thyroid gland caused by failure of TSH secretion in a patient with hypothalamic or anterior pituitary disease, e.g. pituitary macroadenoma. Serum T4 is low but TSH may be low, normal or even slightly elevated. It follows therefore that screening for thyroid disease by measurement of TSH alone, an increasingly common laboratory policy, will result in missing cases of secondary hypothyroidism with potentially serious consequences. Antibodies against thyroid peroxidase suggest spontaneous atrophic hypothyroidism or, in the presence of goitre, Hashimoto's thyroiditis (see pp. 699-701). Further investigations are rarely required, provided there is no suspicion of transient hypothyroidism (see pp. 699 and 701).
THYROID ENLARGEMENT
Palpable thyroid enlargement is common, affecting about 5% of the population, although it is the minority who seek medical attention, often because a friend or relative has noticed a lump in the neck. There are several causes, ranging from the soft diffuse goitre of puberty and youth to the multinodular goitre of middle age and beyond (see p. 702) which may progress to hyperthyroidism, and the solitary nodule which can present at any age. Whereas diffuse and multinodular goitre are almost invariably benign, there is a
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ABNORMAL THYROID FUNCTION TEST RESULTS
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. For practical purposes these can be divided into three categories.
Subclinical hyperthyroidism
Here the serum TSH is undetectable and the serum T3 and T4 lie in the upper parts of their respective reference ranges. This combination is most often found in patients with nodular goitre. These patients are at increased risk of atrial fibrillation and osteoporosis and hence the consensus view is that such patients have mild hyperthyroidism and require therapy, usually with 131I. Otherwise annual review is essential as the conversion rate to overt hyperthyroidism with elevated T4 and/or T3 concentrations is 5% each year.
Subclinical hypothyroidism
EBM
SUBCLINICAL HYPOTHYROIDISM-progression to overt hypothyroidism
'The annual risk of developing overt hypothyroidism for asymptomatic patients with raised serum TSH but normal T3 and T4 concentrations increases from 2.1% to 4.6% if thyroid peroxidase antibodies are detected.'
Vanderpump MJ, Tunbridge WG, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol 1995; 43:55-68.
The serum TSH is raised and the serum T3 and T4 concentrations are usually in the lower part of their respective reference ranges. It is most often encountered after 131I or surgical treatment of hyperthyroidism and may persist for many years, although there is an inexorable progression to overt thyroid failure, particularly if antibodies are present in the serum directed against thyroid peroxidase. The view is that these patients are mildly hypothyroid, however asymptomatic, and it is better to treat the thyroid failure early rather than risk loss to follow-up and subsequent presentation with profound hypothyroidism. Thyroxine should be given in a dose of 50-150 µg daily, sufficient to restore the serum TSH concentration to normal.
Non-thyroidal illness
In ill patients (e.g. myocardial infarction, pneumonia) not only is there a decreased peripheral conversion of T4 to T3, but also alterations of binding proteins and their affinity for thyroid hormones. In addition, serum TSH concentrations may be subnormal as a result of the illness itself or the use of drugs such as dopamine or corticosteroids. The most common combination is a low serum TSH, raised T4 and normal or low T3, but many patterns of thyroid function tests can be seen, dependent upon the type of assay used. During convalescence serum TSH concentrations may increase to levels found in primary hypothyroidism. It follows that biochemical assessment of thyroid function should not be undertaken in patients with non-thyroidal illness, unless there is good evidence of concomitant thyroid disease, e.g. goitre, exophthalmos. If an abnormal result is found, no treatment should be given and the tests repeated after recovery.
HYPERTHYROIDISM
GRAVES' DISEASE
Graves' disease is distinguished clinically from other forms of hyperthyroidism by the presence of diffuse thyroid enlargement, ophthalmopathy and rarely pretibial myxoedema (see p. 684). It can occur at any age but is unusual before puberty and most commonly affects the 30-50-year-old age group.
Pathogenesis
Graves' disease is the major immunologically mediated form of hyperthyroidism, the other being post-partum thyroiditis (see p. 697). The hyperthyroidism results from the production of IgG antibodies directed against the TSH-receptor on the thyroid follicular cell which stimulates thyroid hormone production and, in the majority, goitre formation. These antibodies are termed thyroid-stimulating immunoglobulins or TSH-receptor antibodies (TRAb) and can be detected in the serum of most patients with Graves' disease.
In Caucasians there is an association of Graves' disease with HLA-B8, DR3 and DR2, and with inability to secrete the water-soluble glycoprotein form of the ABO blood group antigens coded for on chromosomes 6 and 19 respectively. Family studies show that 50% of monozygotic twins are concordant for hyperthyroidism as opposed to 5% of dizygotic twins.
The trigger for the development of hyperthyroidism in genetically susceptible individuals may be infection with viruses or bacteria, although there is no proof. However, certain strains of the gut organisms Escherichia coli and Yersinia enterocolitica possess cell membrane TSH-receptors. The production of antibodies to these microbial antigens which might cross-react with the TSH-receptor on the host thyroid follicular cell could result in the development of hyperthyroidism. Stress is usually dismissed as aetiologically unimportant but many experienced endocrinologists are impressed from time to time by the temporal relationship between the onset of hyperthyroidism and a major life event such as the death of a close relative. In regions of iodine deficiency, iodine supplementation may result in the development of hyperthyroidism, but only in those with pre-existing subclinical Graves' disease. Smoking is weakly associated with
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Figure 16.4 Natural history of the hyperthyroidism of Graves' disease. A and B The majority (60%) of patients have either prolonged periods of hyperthyroidism of fluctuating severity, or periods of alternating relapse and remission. C It is the minority who experience a single short-lived episode followed by prolonged remission and, in some cases, by the eventual onset of hypothyroidism.
The concentration of TRAb in the serum is presumed to fluctuate because of the natural history of Graves' disease (see Fig. 16.4). The ultimate thyroid failure seen in some patients is thought to result from the presence of yet another immunoglobulin, a blocking antibody against the TSH-receptor, and from tissue destruction by cytotoxic antibodies and cell-mediated immunity.
The pathogenesis of the ophthalmopathy and dermopathy is less well understood. Both are immunologically mediated but the autoantigen(s) which causes the local accumulation of lymphocytes has not been identified. Within the orbit (and the dermis) there is cytokine-mediated proliferation of fibroblasts which secrete hydrophilic glycosaminoglycans. The resulting increased interstitial fluid content, combined with a chronic inflammatory cell infiltrate, causes marked swelling of the extraocular muscles (see Fig. 16.5) and a rise in retrobulbar pressure. The eye is displaced forwards (proptosis, exophthalmos) and in more severe cases there is optic nerve compression. Ultimately, there is fibrosis of the extraocular muscles.
Clinical features
Goitre
The diffusely enlarged gland is usually 2-3 times the normal volume, and increased blood flow may be manifest by a thrill or bruit. In some patients, particularly the elderly, no thyroid enlargement is palpable or the gland may be nodular. The largest goitres tend to occur in young men.
Ophthalmopathy
This is only present in 50% of patients when first seen but may develop after successful treatment of the hyperthyroidism of Graves' disease, or precede its development by many years (exophthalmic Graves' disease). As noted, it is more common in cigarette smokers. 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, and pain due to conjunctivitis or corneal ulceration. In addition, there may be loss of visual acuity and/or visual field resulting from corneal oedema or optic nerve compression. If the extraocular muscles are involved and do not act in concert, diplopia will result.
Pretibial myxoedema
Figure 16.5 Graves' disease. A Bilateral ophthalmopathy in a 42-year-old man, developing 2 years after successful treatment of hyperthyroidism with 131I. The main symptoms were those of 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 fluid as a result of raised intraorbital pressure.
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This infiltrative dermopathy 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. 684). 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 may be affected.
Management of hyperthyroidism of Graves' disease
The different treatment options are compared in
Antithyroid drugs
The most commonly used are carbimazole (see
16.11 COMPARISON OF THE DIFFERENT TREATMENTS FOR THE HYPERTHYROIDISM OF GRAVES' DISEASE
Management Indications Contraindications Disadvantages/complications
Antithyroid drugs e.g. carbimazole First episode in patients <40>
Breastfeeding (propylthiouracil suitable) >50% relapse rate usually within 2 years of stopping drug
Recurrent hyperthyroidism after course of antithyroid drugs in patients <40>
Initial treatment in males with large goitres and in those with severe hyperthyroidism, i.e. total T3 >9.0 nmol/l
Poor drug compliance
Subtotal thyroidectomy Previous thyroid surgery
Dependence upon voice, e.g. opera singer, lecturer1 Transient hypocalcaemia (10%)
Hypoparathyroidism (1%)
Recurrent laryngeal nerve palsy1 (1%)
Patients >40 yrs2
Recurrence following surgery irrespective of age
Other serious comorbidity
Radio-iodinePregnancy or planned pregnancy within 6 months of treatmentHypothyroidism, approx. 40% in first year, 80% after 15 years
Most likely treatment to result in exacerbation of exophthalmos
1It is not only vocal cord palsy due to recurrent laryngeal nerve damage which alters the voice following thyroid surgery; the superior laryngeal nerves are frequently transected and result in minor changes in voice quality.
2In certain parts of the world, 131I is used more liberally and prescribed for young women in the 20-40 age group.
16.12 CARBIMAZOLE carbimazole
Dosage
§ 0-3 weeks: 40-60 mg daily
§ 4-8 weeks: 20-40 mg daily
§ Maintenance: 5-20 mg daily for 18-24 months
Adverse effects
§ Rash (2%)
§ Agranulocytosis (0.2%)
§ Jaundice (extremely rare)
There is subjective improvement within 10-14 days of starting carbimazole and the patient is usually clinically and biochemically euthyroid at 3-4 weeks. The maintenance dose is determined by measurement of T4 and TSH, attempting to keep both hormones within their respective reference ranges. In most patients it can be taken as a single daily dose and is continued for 18-24 months in the hope that during this period permanent remission will occur. Unfortunately, hyperthyroidism recurs in at least 50%, usually within 2 years of stopping treatment. Rarely, despite good drug compliance, T4 and TSH levels fluctuate between those of hyperthyroidism and hypothyroidism at successive review appointments, presumably due to rapidly changing concentrations of TRAb. In such patients satisfactory control can be achieved by blocking thyroid hormone synthesis with carbimazole 30 mg daily and adding T4 150 µg daily as replacement therapy when the patient is euthyroid.
The adverse effects of the antithyroid drugs develop within 7-28 days of starting treatment. Agranulocytosis cannot be predicted by routine measurement of white blood cell count, and is fortunately reversible. Patients should be warned to stop the drug and contact their medical attendant immediately should a severe sore throat or fever develop. Cross-sensitivity between the antithyroid drugs is relatively unusual and another member of the group can be substituted with good effect.
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EBM
GRAVES' DISEASE-antithyroid drug therapy
'Remission rates in patients with Graves' disease are not improved by combining thyroxine with antithyroid drugs (block and replace therapy).'
McIver B, Rae P, Beckett GJ, et al. Lack of effect of thyroxine in patients with
Further information: www.endocrinology.org
Subtotal thyroidectomy
Patients must be rendered euthyroid before operation. The antithyroid drug is stopped 2 weeks before surgery and replaced by potassium iodide (Lugol's solution) 60 mg 8-hourly orally. This maintains euthyroidism in the short term by inhibiting thyroid hormone release and reduces the size and vascularity of the gland, making surgery technically easier. Complications of surgery are rare (see
Radioactive iodine
131I acts either by destroying functioning thyroid cells or by inhibiting their ability to replicate. The variable radiosensitivity of the gland means that the choice of dose is empirical. In most centres 185-370 MBq (5-10 mCi) is given orally, the dose depending upon clinical assessment of goitre size. This regimen is effective in 75% of patients within 4-12 weeks. During the lag period symptoms can be controlled by a ß-adrenoceptor antagonist (ß-blocker) or, in more severe cases, by carbimazole starting 48 hours after radio-iodine administration. If hyperthyroidism persists after 12-24 weeks, a further dose of 131I should be employed. The disadvantage of 131I treatment is that the majority of patients eventually develop hypothyroidism and long-term follow-up is therefore necessary.
Beta-blockers
A non-selective ß-blocker, such as propranolol (160 mg daily) or nadolol (40-80 mg daily), will alleviate but not abolish symptoms of hyperthyroidism within 24-48 hours. Beta-blockers cannot be recommended for long-term treatment, but they are extremely useful in the short term, e.g. for patients awaiting hospital consultation or following 131I therapy. Propranolol alone or in combination with iodine has been used in the preparation of patients for subtotal thyroidectomy, but this treatment cannot be recommended as standard practice.
Management of ophthalmopathy
The majority of patients require no treatment other than reassurance. Lid retraction will usually resolve when the patient becomes euthyroid, and exophthalmos usually lessens gradually over a period of 2-3 years. For those with symptomatic ophthalmopathy, methylcellulose eye drops will counter the gritty discomfort of dry eyes, and tinted glasses or side shields attached to spectacle frames will reduce the excessive lacrimation triggered by sun or wind. Corneal ulceration is an indication for a lid-lengthening procedure. Persistent diplopia can be corrected by extraocular muscle surgery but this should be delayed until the degree of diplopia is stable.
Papilloedema, loss of visual acuity or visual field defect requires urgent treatment with prednisolone 60 mg daily if blindness is to be prevented. Close cooperation between the endocrinologist and ophthalmologist is necessary and, if significant improvement is not evident within 7-10 days, orbital decompression is indicated. Radiotherapy to the orbits in association with prednisolone may be effective in some patients.
EBM
'Development or worsening of mild ophthalmopathy in patients with Graves' disease is more common following 131I administration than with surgery or antithyroid drugs.'
Tallstedt L, Lundell G, Torring O, et al. Occurrence of ophthalmopathy after treatment for
Bartelena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of
Further information: www.endocrinology.org
Management of dermopathy
The pretibial myxoedema of Graves' disease rarely requires to be treated. Local injections of triamcinolone or the application of betamethasone ointment under occlusive dressings may be effective.
TOXIC MULTINODULAR GOITRE
Like Graves' disease, this form of hyperthyroidism is more common in women. The mean age of presentation is 60 years. Thyroid hormone levels are usually only slightly elevated but, as an older age group is affected, cardiovascular features such as atrial fibrillation or cardiac failure tend to predominate. Treatment is usually with a large dose of 131I (555-1850 MBq, 15-50 mCi), as the gland is relatively resistant to radiation. Hypothyroidism is less common than after treatment of Graves' disease. If there is tracheal compression or retrosternal extension of the goitre, partial thyroidectomy is indicated. Long-term treatment with antithyroid drugs is not appropriate as relapse is invariable after drug withdrawal.
TOXIC ADENOMA
The presence of a toxic solitary nodule is the cause of less than 5% of all cases of hyperthyroidism. 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. In some cases spontaneous resolution of hyperthyroidism has occurred as a result of infarction of the adenoma.
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Figure 16.6 99mTechnetium scans of patients with hyperthyroidism. A Graves' disease, showing diffuse uptake of isotope. B Multinodular goitre with maximum activity confined to individual nodules; such an appearance is not always associated with a palpable thyroid. C Right-sided toxic adenoma with lack of uptake of isotope by normal dormant gland due to suppression of serum TSH. Isotope thyroid scanning is of value in determining the cause of hyperthyroidism in patients with no palpable goitre or other indicators such as exophthalmos or pretibial myxoedema.
Most patients are female and over 40 years of age. Although most nodules are palpable, the diagnosis can be made with certainty only by isotope scanning (see Fig. 16.6C). The hyperthyroidism is usually mild and in almost 50% of patients the plasma T3 alone is elevated (T3-thyrotoxicosis). Treatment is by hemithyroidectomy or by 131I (555-1110 MBq, 15-30 mCi). Permanent hypothyroidism does not occur following surgery and is unusual after treatment with 131I, since the atrophic cells surrounding the nodule will have received little or no irradiation.
HYPERTHYROIDISM ASSOCIATED WITH A LOW IODINE UPTAKE
In patients with hyperthyroidism the thyroid uptake of 131I is usually high but a low or negligible uptake of iodine occurs in some rarer causes (see
Subacute (de Quervain's) thyroiditis
Subacute thyroiditis is a virus-induced (Coxsackie, mumps or adenovirus) inflammation of the thyroid gland which results in release of colloid and its constituents into the circulation.
This form of hyperthyroidism is characterised by pain in the region of the thyroid gland which 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.
Thyroid hormone levels are raised for 4-6 weeks until the pre-formed colloid is depleted. The iodine uptake is low because the damaged follicular cells are unable to trap iodine and because endogenous TSH secretion is suppressed. Low-titre thyroid autoantibodies appear transiently in the serum, and the erythrocyte sedimentation rate (ESR) is usually raised. The hyperthyroidism is followed by a period of hypothyroidism which is usually asymptomatic, and finally by full recovery of thyroid function within 4-6 months. The pain and systemic upset usually respond to simple measures such as aspirin or other non-steroidal anti-inflammatory drugs. Occasionally, however, it may be necessary to prescribe prednisolone 40 mg daily for 3-4 weeks. The hyperthyroidism is mild and treatment with propranolol 160 mg daily is usually adequate. Antithyroid drugs are of no benefit.
Post-partum thyroiditis
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The maternal immune response which is modified during pregnancy to allow survival of the fetal homograft is enhanced after delivery and may unmask previously unrecognised subclinical autoimmune thyroid disease. Surveys have shown that transient biochemical disturbances of thyroid function, i.e. hyperthyroidism, hypothyroidism, and hyperthyroidism followed by hypothyroidism, lasting a few weeks occur in 5-10% of women within 6 months of delivery. Those affected are likely to possess antithyroid peroxidase (microsomal) antibodies in the serum in early pregnancy. Thyroid biopsy shows a lymphocytic thyroiditis. Symptoms of thyroid dysfunction are rare and there is no association between postnatal depression and abnormal thyroid function tests. However, symptomatic hyperthyroidism presenting for the first time within 6 months of childbirth is unlikely to be due to Graves' disease, and the diagnosis of post-partum thyroiditis can be confirmed by a negligible radio-iodine uptake.
If treatment of the hyperthyroid phase is necessary, a ß-blocker should be prescribed and not an antithyroid drug. Post-partum thyroiditis tends to recur after subsequent pregnancies and eventually patients progress over a period of years to permanent hypothyroidism.
A similar painless form of thyroiditis, unrelated to pregnancy, has been increasingly recognised in North America and Japan, and accounts in these countries for up to 20% of all cases of hyperthyroidism.
Iodine-induced hyperthyroidism
The administration of iodine, either in prophylactic iodinisation programmes in iodine-deficient parts of the world or as a radiographic contrast medium, may result in the development of hyperthyroidism which is usually mild and self-limiting. Affected individuals are thought to have underlying thyroid autonomy, such as nodular goitre or Graves' disease in remission. This form of hyperthyroidism is now most often seen as a result of treatment with the anti-arrhythmic agent, amiodarone, which contains significant amounts of iodine. In some patients amiodarone causes a thyroiditis-like picture and mild transient hyperthyroidism which may require treatment with ß-blockers. Most patients have underlying thyroid autonomy where severe thyrotoxicosis may be precipitated. Such patients may even present for the first time up to 6 months after the drug has been stopped, due to its slow release from adipose tissue. Treatment of thyroid autonomy is with an antithyroid drug for as long as amiodarone is prescribed.
Assessment of thyroid function may be difficult in patients taking amiodarone, as the drug inhibits the peripheral conversion of T4 to T3. As a result, in euthyroid individuals it is not uncommon to record markedly elevated serum T4 concentrations and even suppressed serum TSH, but serum T3 is usually in the lower part of the normal range. In those developing hyperthyroidism, serum T3 is clearly elevated but, if the value is equivocal, the decision to treat will depend upon the presence of other features of thyroid disease, such as goitre and ophthalmopathy.
Factitious hyperthyroidism
This uncommon condition occurs when someone takes excessive amounts of a thyroid hormone preparation, most often thyroxine. The exogenous T4 suppresses pituitary TSH secretion and hence iodine uptake, serum thyroglobulin and release of endogenous thyroid hormones. As a result the T4:T3 ratio (approximately 30:1 in conventional hyperthyroidism) is increased to approximately 70:1 because circulating T3 in factitious thyrotoxicosis is derived exclusively from the peripheral monodeiodination of T4. The combination of negligible iodine uptake, high T4:T3 ratio and a low or undetectable thyroglobulin is diagnostic and has made what was often a difficult diagnosis much simpler. The condition often reflects underlying psychological or psychiatric illness that may require specialist help (see p. 268).
SPECIAL PROBLEMS OF HYPERTHYROIDISM
Hyperthyroidism in pregnancy
The coexistence of pregnancy and hyperthyroidism is unusual as anovulatory cycles are common in thyrotoxic patients and autoimmune disease tends to remit during pregnancy. The hyperthyroidism is almost always caused by Graves' disease.
The hyperthyroidism is treated with carbimazole or propylthiouracil, which crosses the placenta and also treats the fetus, whose thyroid gland is exposed to the action of maternal TRAb. It is important to use the smallest dose of antithyroid drug (optimally less than 15 mg carbimazole per day) which will maintain maternal (and presumably fetal) free hormones and TSH within their respective normal ranges in order to avoid fetal hypothyroidism and goitre. An association has been claimed between the use of carbimazole in pregnancy and a skin defect in the child known as aplasia cutis. For this reason some physicians prefer to advise propylthiouracil before and during any planned pregnancy.
The patient should be reviewed every 4 weeks and it is a wise precaution to discontinue the drug 4 weeks before the expected date of delivery to avoid any possibility of fetal hypothyroidism at the time of maximum brain development. If the assay is available, measurement of TRAb in the maternal serum at this stage is valuable; a high titre identifies those fetuses at particular risk of developing neonatal hyperthyroidism.
If maternal hyperthyroidism occurs after delivery and the patient wishes to continue breastfeeding, propylthiouracil (see p. 695) is the drug of choice as it is excreted in the milk to a much lesser extent than carbimazole.
If subtotal thyroidectomy is necessary because of poor drug compliance or hypersensitivity, it is most safely performed in the middle trimester. Radioactive iodine is absolutely contraindicated as it invariably induces fetal hypothyroidism.
Hyperthyroidism in childhood
Graves' disease is almost invariably the cause of thyrotoxicosis in childhood and usually presents in the second decade. Medical attention may be sought because of behaviour disorders, deteriorating academic performance or a premature growth spurt. Treatment should be with carbimazole until the patient is about 18 years of age in an attempt to guarantee the important stages in the physical and educational development of the child.
Atrial fibrillation
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Figure 16.7 Age-related incidence of atrial fibrillation in patients with hyperthyroidism.
Hyperthyroidism is an important cause of atrial fibrillation. Characteristically, the ventricular rate is little influenced by digoxin but responds to the addition of a ß-blocker. The dysrhythmia is present in about 10% of all patients with thyrotoxicosis but the incidence increases with age so that almost half of all males over the age of 60 are affected (see Fig. 16.7). It is increasingly recognised that subclinical hyperthyroidism may be a risk factor for atrial fibrillation. Cardioversion will establish stable sinus rhythm in up to 50% of patients but should not be contemplated until serum thyroid hormone and TSH concentrations have been restored to normal. Anticoagulation is required with warfarin unless contraindicated, in which case aspirin should be used (see p. 402).
Hyperthyroid crisis
This is a rare and life-threatening increase in the severity of the clinical features of hyperthyroidism. The most prominent signs are fever, agitation, confusion, tachycardia or atrial fibrillation and, in the older patient, cardiac failure. It is a medical emergency and, despite early recognition and treatment, the mortality rate is 10%. Thyrotoxic crisis is most commonly precipitated by infection in a patient with previously unrecognised or inadequately treated hyperthyroidism. 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 a broad-spectrum antibiotic. Propranolol is rapidly effective orally (80 mg 6-hourly) or intravenously (1-5 mg 6-hourly). Sodium iopodate 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. Oral carbimazole 40-60 mg daily inhibits 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. Sodium iopodate and propranolol can be withdrawn after 10-14 days and the patient maintained on carbimazole.
Subclinical hyperthyroidism
See page 693.
HYPOTHYROIDISM
SPONTANEOUS ATROPHIC HYPOTHYROIDISM
This form of primary hypothyroidism increases in incidence with age and, like Graves' disease and Hashimoto's thyroiditis, is an organ-specific autoimmune disorder. There is destructive lymphoid infiltration of the thyroid, ultimately leading to fibrosis and atrophy. There is also evidence for the presence of TSH-receptor antibodies which block the effects of endogenous TSH. In some patients there is a history of Graves' disease treated with antithyroid drugs 10-20 years earlier and, very occasionally, patients with this form of hypothyroidism develop Graves' disease. As with any of the immunologically mediated thyroid disorders, patients are at risk of developing other organ-specific autoimmune conditions such as type 1 diabetes mellitus, pernicious anaemia and Addison's disease, and autoimmune disease is not uncommon in first- and second-degree relatives (see p. 687).
Investigations
Serum T4 is low and TSH raised (see pp. 691-692). Antibodies against thyroid peroxidase may be detected. In symptomatic patients no further investigation is necessary. If the clinical features suggest a transient cause of hypothyroidism (such as non-thyroidal illness, neck pain suggesting subacute thyroiditis or recent pregnancy), repeat measurements after a few weeks may be required before embarking on long-term thyroxine therapy.
Management
Hypothyroidism should be treated with thyroxine; it is customary to start slowly and a dose of 50 µg per day should be given for 3 weeks, increasing thereafter to 100 µg per day for a further 3 weeks and finally to 150 µg per day. Thyroxine should always be taken as a single daily dose as it has a plasma half-life of approximately 7 days.
Patients feel better within 2-3 weeks. Reduction in weight and periorbital puffiness occurs quickly, but the restoration of skin and hair texture and resolution of any effusions may take 3-6 months.
EBM
HYPOTHYROIDISM-thyroid hormone therapy
'Neuropsychological testing has shown that some patients with primary hypothyroidism benefit from treatment with a combination of T4 and T3 when compared to T4 alone. However, no satisfactory synthetic combination preparation currently exists and animal thyroid extract has too variable a potency to be recommended.'
Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ. Comparative effects of thyroxine versus thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999; 340:424-429.
Toft AD. Thyroid hormone replacement-one hormone or two? N Engl J Med 1999; 340:469-470.
Further information: www.endocrinology.org
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Monitoring therapy
The correct dose of thyroxine in most patients is that which restores serum TSH to the lower part of the reference range when serum T4 will be normal or even slightly raised. In some patients a sense of well-being is only achieved by taking an extra 25-50 µg of thyroxine, resulting in a suppressed serum TSH concentration. This is acceptable only if serum T3 is unequivocally normal.
Patients often fail to take long-term medication in the recommended dose and thyroxine is no exception. It is, therefore, important to measure thyroid function every 1-2 years once the dose of thyroxine is stabilised and at each visit to reinforce the need for regular medication. In some poorly compliant patients thyroxine 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 T4 and high TSH.
Occasionally, patients who have been taking the same dose of thyroxine for some time show biochemical evidence of over-treatment or under-treatment. The various causes of a change in requirements are shown in
16.13 SITUATIONS IN WHICH AN ADJUSTMENT OF THE DOSE OF THYROXINE MAY BE NECESSARY
Increased dose required
Use of other medication
Phenobarbital
Phenytoin
Carbamazepine
Rifampicin
Sertraline*
Chloroquine* Increase thyroxine clearance
Colestyramine
Sucralfate
Aluminium hydroxide
Ferrous sulphate
Dietary fibre supplements
Calcium carbonate Interfere with intestinal absorption
Pregnancy or oestrogen therapy Increases concentration of serum thyroxine-binding globulin
After surgical or 131I ablation of Graves' disease Reduces thyroidal secretion with time
Malabsorption, e.g. coeliac disease
Decreased dose required
Ageing Decreases thyroxine clearance
Graves' disease developing in patient with long-standing primary hypothyroidism Switch from production of blocking to stimulating
TSH-receptor antibodies
*Mechanism not fully established.
SPECIAL PROBLEMS OF HYPOTHYROIDISM
Ischaemic heart disease
Around 5% of patients with long-standing hypothyroidism complain of angina at presentation or develop it during treatment with thyroxine. Although angina may remain unchanged in severity or paradoxically disappear with restoration of metabolic rate, exacerbation of myocardial ischaemia, infarction and sudden death are well-recognised complications, even using doses of thyroxine as low as 25 µg per day. Approximately 40% of patients with angina cannot tolerate full replacement therapy despite the use of ß-blockers and vasodilators. Although there is still reluctance to operate on patients with untreated or partially treated hypothyroidism, coronary artery surgery and balloon angioplasty can safely be performed in such patients and, if successful, allow full replacement dosage of thyroxine in the majority.
Hypothyroidism in pregnancy
Until recently it was thought that the dose of thyroxine did not need to be changed during pregnancy. However, on the basis of serum TSH measurements most pregnant women with primary hypothyroidism require an increase in the dose of thyroxine of some 50 µg daily. One explanation for this phenomenon is the well-recognised increase in serum thyroxine-binding globulin concentration during pregnancy, resulting in a decrease in serum free thyroid hormone concentrations which cannot be compensated for by thyroidal secretion. Serum TSH and free T4 should be measured during each trimester and the dose of thyroxine adjusted to maintain a normal TSH.
Myxoedema coma
This is a rare presentation of hypothyroidism in which there is a depressed level of consciousness, usually in an elderly patient who appears myxoedematous. Body temperature may be as low as 25°C, convulsions are not uncommon and cerebrospinal fluid (CSF) pressure and protein content are raised. The mortality rate is 50% and survival depends upon early recognition and treatment of hypothyroidism and other factors contributing to the altered consciousness level, e.g. drugs such as phenothiazines, cardiac failure, pneumonia, dilutional hyponatraemia, hypoxaemia and hypercapnia due to hypoventilation.
Myxoedema coma is a medical emergency and treatment must begin before biochemical confirmation of the diagnosis. Thyroxine is not usually available for parenteral use and triiodothyronine is given as an intravenous bolus of 20 µg followed by 20 µg 8-hourly 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 substitute oral thyroxine in a dose of 50 µg per day. Unless it is apparent that the patient has primary hypothyroidism, e.g. thyroidectomy scar or goitre, the thyroid failure should be assumed to be secondary to hypothalamic or pituitary disease and treatment given with hydrocortisone sodium succinate 100 mg i.m. 8-hourly, pending the results of T4, TSH and cortisol concentrations (see p. 727). Other measures include slow rewarming (see p. 332), cautious use of intravenous fluids, broad-spectrum antibiotics and high-flow oxygen. Occasionally, assisted ventilation may be necessary.
Inappropriate thyroxine therapy
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In some patients treatment with thyroxine may have been started in the past, without biochemical confirmation of the diagnosis, for a variety of complaints such as obesity, tiredness or alopecia, or may have been given for many years to patients in whom thyroid failure could have been short-lived, e.g. post-partum thyroiditis. Thyroxine should be stopped and serum T4 and TSH concentrations measured 4-6 weeks later. This period allows for any thyroxine-induced suppression of pituitary thyrotrophs to recover and a biochemical distinction to be made between primary and secondary hypothyroidism.
GOITROUS HYPOTHYROIDISM
The following conditions are not always associated with hypothyroidism and should therefore be included in the differential diagnosis of a euthyroid patient with goitre.
Hashimoto's thyroiditis
This is the most common cause of goitrous hypothyroidism. It typically affects 20-60-year-old women who present with a small or moderately sized diffuse goitre which is characteristically firm or rubbery in consistency. The goitre may be soft, however, and impossible to differentiate from simple goitre by palpation alone. Thyroid status depends upon the relative degrees of lymphocytic infiltration, fibrosis and follicular cell hyperplasia within the gland but 25% of patients are hypothyroid at presentation. In the remainder, serum T4 is normal and TSH normal or raised but these patients are at risk of developing overt hypothyroidism in future years. In 90% of patients with Hashimoto's thyroiditis thyroid peroxidase antibodies are present in the serum. In those under the age of 20 years the antinuclear factor (ANF) may also be positive.
Thyroxine therapy is indicated not only for hypothyroidism but also for goitre shrinkage. In this context the dose of thyroxine should be sufficient to suppress serum TSH to undetectable levels without inducing hyperthyroidism (usually 150-200 µg daily).
Drug-induced hypothyroidism
Lithium carbonate
This is widely used for the treatment of bipolar affective disorder (see p. 263). Like iodide, lithium inhibits the release of thyroid hormones (see Fig. 16.3, p. 689). Although the most common evidence of thyroid dysfunction is a raised serum TSH, some (usually those with underlying autoimmune thyroiditis) develop goitre and hypothyroidism.
Iodine
When taken for prolonged periods iodine may cause goitrous hypothyroidism in patients with underlying autoimmune thyroiditis. This is usually seen in patients with chronic respiratory diseases given expectorants containing potassium iodide, or in those receiving amiodarone, which contains a significant amount of iodine.
Iodine deficiency
In certain parts of the world, such as the
Dyshormonogenesis
Dyshormonogenesis is an unusual genetically determined defect in thyroid hormone synthesis. The mode of inheritance is autosomal recessive. Although several forms have been described, the most common results from deficiency of the intrathyroidal peroxidase enzyme. Homozygous individuals present with congenital hypothyroidism; heterozygotes present in the first two decades of life with goitre, normal thyroid hormone levels and a raised TSH. The combination of dyshormonogenetic goitre and nerve deafness is known as Pendred's syndrome.
TRANSIENT HYPOTHYROIDISM
This is often observed during the first 6 months after subtotal thyroidectomy or 131I treatment of Graves' disease, in the post-thyrotoxic phase of subacute thyroiditis and in post-partum thyroiditis (see Fig. 16.8). In these conditions thyroxine treatment should not be necessary as the patient is usually asymptomatic during the short period of thyroid failure. In some neonates transplacental passage of TSH-receptor-blocking antibodies from a mother with autoimmune thyroid disease is a cause of hypothyroidism which, like neonatal thyrotoxicosis, is temporary.
Figure 16.8 Total T4 and TSH levels before and after subtotal thyroidectomy in a series of patients with temporary hypothyroidism.
CONGENITAL HYPOTHYROIDISM
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It has long been recognised that early treatment with thyroxine is essential to prevent irreversible brain damage in children with congenital hypothyroidism. Thyroid failure, however, is difficult to diagnose clinically in the first few weeks of life. Routine screening of TSH levels in blood spot samples obtained 5-7 days after birth has revealed an incidence of approximately 1 in 3000, resulting either from thyroid agenesis, ectopic or hypoplastic glands, or from dyshormonogenesis. Congenital hypothyroidism is thus six times more common than phenylketonuria. It is now possible to start thyroid replacement therapy within 2 weeks of birth. Developmental assessment of infants treated at this early stage has revealed no differences between cases and controls in most children.
SIMPLE GOITRE
This is the term used to describe diffuse or multinodular enlargement of the thyroid which occurs sporadically and is of unknown aetiology. It is likely, however, that suboptimal dietary iodine intake, minor degrees of dyshormonogenesis and stimuli such as epidermal growth factor and growth-stimulating immunoglobulins are important in the development of simple goitre. Affected patients are euthyroid, are usually female and often have a family history of goitre.
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 not by the patient but by friends and relatives. Occasionally, there is a tight sensation in the neck, particularly when swallowing. The goitre is soft and symmetrical and the thyroid is enlarged to two or three times its normal size. There is no tenderness, lymphadenopathy or overlying bruit. Concentrations of T3, T4 and TSH are normal and no thyroid autoantibodies are detected in the serum. No treatment is necessary and in most cases the goitre 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 (simple multinodular goitre; see Fig. 16.9).
SIMPLE MULTINODULAR GOITRE
Figure 16.9 Natural history of simple goitre.
Presentation is rare before middle age. The patient may have been aware of a goitre for many years, perhaps slowly increasing in size. Rarely, medical advice may have been sought because of painful swelling lasting a few days caused by haemorrhage into a nodule or cyst. The goitre is nodular or lobulated on palpation and may extend retrosternally. Very large goitres may cause mediastinal compression with stridor, 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. Serum T3 and T4 are normal and in the majority are associated with normal TSH. In approximately 25%, thyroid hormone levels are in the upper part of their respective normal ranges and TSH is undetectable (subclinical hyperthyroidism, see p. 693). CT of the thoracic inlet will show tracheal displacement or compression, intrathyroidal calcification and the extent of retrosternal extension. A flow-volume loop (see p. 493) will detect cases with significant tracheal compression.
If the goitre is small, no treatment is necessary other than annual review, as the natural history is progression to a toxic multinodular goitre. Partial thyroidectomy is indicated for large goitres which cause mediastinal compression or which are cosmetically unattractive. 131I can result in a significant reduction in thyroid size after 1-2 years and may be of value in elderly patients. Unfortunately, recurrence 10-20 years later is not uncommon and is not prevented by thyroxine, which may serve only to aggravate any associated hyperthyroidism.
SOLITARY THYROID NODULE
In those who seek medical attention it is important to determine whether the nodule is benign, e.g. cyst or colloid nodule, or malignant. With the exception of haemorrhage into a cyst when thyroid enlargement is of rapid onset and painful, or the presence of cervical lymphadenopathy which is highly suggestive of carcinoma, it is rarely possible to make this distinction on clinical grounds alone. However, a solitary nodule presenting in childhood or adolescence, particularly if there is a past history of head and neck irradiation, or presenting in the elderly should raise the suspicion of malignancy. Very occasionally, a secondary deposit from a renal, breast or lung carcinoma presents as a painful, rapidly growing solitary thyroid nodule.
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Investigations
The most useful is fine-needle aspiration of the nodule. This is performed in the outpatient clinic using a standard 21-gauge venepuncture needle and a 20 ml syringe. Aspiration may be therapeutic in the small proportion of patients in whom the swelling is a pure cyst, although recurrence on more than one occasion is an indication for surgery. Usually, two to three aspirates are taken from the nodule. Cytological examination will differentiate benign (80%) from suspicious or definitely malignant nodules (20%), of which half are confirmed as cancer at surgery. The advantage of fine-needle aspiration over long-established tests such as isotope and ultrasound scanning is that a much higher proportion of patients avoid surgery. The limitation of the method is that it cannot differentiate between follicular adenoma and carcinoma.
It is important to measure serum T3, T4 and TSH in all patients with a solitary thyroid nodule. The finding of undetectable TSH is very suggestive of an autonomously functioning thyroid adenoma which can only be confirmed by thyroid isotope scanning (see Fig. 16.6, p. 697), and is for practical purposes always benign.
MALIGNANT TUMOURS
Primary thyroid malignancy is rare, accounting for less than 1% of all carcinomas, and has a prevalence of 25 per million. As shown in
DIFFERENTIATED CARCINOMA
In most patients, presentation is with a palpable solitary nodule.
Papillary carcinoma
16.14 MALIGNANT THYROID TUMOURS
Origin of tumour Type of tumour Frequency (%) Usual age of presentation (years) Approximate 20-year survival (%)
Follicular cells Differentiated carcinoma
Papillary 70 20-40 95
Follicular 10 40-60 60
Undifferentiated carcinoma
Anaplastic 5 > 60 <>
Parafollicular C cells Medullary carcinoma 5-10 > 40* 50
Lymphocytes Lymphoma 5-10 > 60 10
*Patients with medullary carcinoma as part of multiple endocrine neoplasia type II (see p. 688) may present in childhood.
This is the most common of the malignant thyroid tumours and accounts for 90% of irradiation-induced thyroid cancer. It may be multifocal, and spread is to regional lymph nodes. Some patients present with cervical lymphadenopathy and no apparent thyroid enlargement, and the primary lesion may be less than 10 mm in diameter.
Follicular carcinoma
This is always a single encapsulated lesion. Spread to cervical lymph nodes is rare. Metastases are blood-borne and are most often found in bone, lungs and brain.
Management
EBM
DIFFERENTIATED THYROID CANCER-identifying recurrent or metastatic disease
'Recombinant human TSH administration is a safe and effective means of stimulating radio-iodine uptake in patients undergoing evaluation for thyroid cancer persistence and recurrence, and compares favourably with thyroid hormone withdrawal.'
Haugen BK, Pacini F, Reiners C, et al. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999; 84:3877-3885.
Further information: www.endocrinology.org
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This is usually by total thyroidectomy followed by a large dose of 131I (3000 MBq, ~80 mCi) in order to ablate any remaining thyroid tissue, normal or malignant. Thereafter, long-term treatment with thyroxine in a dose sufficient to suppress TSH (usually 150-200 µg daily) is important, as there is some evidence that differentiated thyroid carcinomas may be TSH-dependent. Follow-up is by measurement of serum thyroglobulin which should be low or undetectable in patients taking a suppressive dose of thyroxine. A level in excess of 15 µg/l is strongly suggestive of tumour recurrence or metastases which may be detected by whole-body scanning with 131I and may respond to further radio-iodine therapy. For meaningful results, isotope scanning requires serum TSH concentrations to be elevated (> 20 mU/l). In the past this has been achieved by stopping thyroxine for 4-6 weeks. By using recombinant human TSH to stimulate radio-iodine uptake, thyroxine does not need to be discontinued and therefore symptomatic hypothyroidism is avoided.
Prognosis
Most patients have an excellent prognosis when treated appropriately. Those under 50 years of age with papillary carcinoma can anticipate a near-normal life expectancy if the tumour is less than 2 cm in diameter, confined to the thyroid and cervical nodes, and of low-grade malignancy histologically. Even for patients with distant metastases at presentation, the 10-year survival is approximately 40%.
ANAPLASTIC CARCINOMA AND LYMPHOMA
These two conditions are difficult to distinguish clinically but this is made easier with cytological examination or cutting needle biopsy. Patients are usually elderly women in whom there is rapid thyroid enlargement over 2-3 months. The goitre is hard and symmetrical. There is usually stridor due to tracheal compression and hoarseness due to recurrent laryngeal nerve palsy. There is no effective treatment of anaplastic carcinoma although radiotherapy may afford temporary relief of mediastinal compression. The prognosis for lymphoma, which may arise from pre-existing Hashimoto's thyroiditis, is better. External irradiation often produces dramatic goitre shrinkage and, when combined with chemotherapy, may result in survival for 5 years or more.
MEDULLARY CARCINOMA
This tumour arises from the parafollicular C cells of the thyroid. In addition to calcitonin, the tumour may secrete 5-hydroxytryptamine (5-HT, serotonin), various peptides of the tachykinin family, ACTH and prostaglandins. As a consequence carcinoid syndrome (see p. 801) and Cushing's syndrome (see p. 722) have been described in association with medullary carcinoma.
Patients usually present in middle age with a firm thyroid mass. Cervical lymphadenopathy is common, but distant metastases are rare initially. Serum calcitonin levels are raised and are useful in monitoring response to treatment. Despite the very high levels of calcitonin found in some patients, hypocalcaemia is extremely rare.
Treatment is by total thyroidectomy with removal of affected cervical nodes. Since the C cells do not concentrate iodine there is no role for 131I therapy. Prognosis is very variable, some patients surviving 20 years or more and others less than 1 year.
Medullary carcinoma of the thyroid may be part of the multiple endocrine neoplasia type II syndrome (see p. 688).
RIEDEL'S THYROIDITIS
This is not a form of thyroid cancer but the presentation is similar and the differentiation can usually only be made by thyroid biopsy. It is an exceptionally rare condition of unknown aetiology in which there is extensive infiltration of the thyroid and surrounding structures with fibrous tissue. There may be associated mediastinal and retroperitoneal fibrosis. Presentation is with a slow-growing goitre which is irregular and stony-hard. There is usually tracheal and oesophageal compression necessitating partial thyroidectomy. Other recognised complications include recurrent laryngeal nerve palsy, hypoparathyroidism and eventually hypothyroidism.
ISSUES IN OLDER PEOPLE
THE THYROID GLAND
Hyperthyroidism
Hyperthyroidism is commonly due to nodular goitre and those with Graves' disease often have no thyroid enlargement.
Symptoms may be significantly different from those in younger patients, with apathy, anorexia, proximal myopathy, atrial fibrillation and cardiac failure predominating.
Presentation may be late as patients equate weight loss with malignant disease and, not wishing their worst fears to be confirmed, avoid seeking medical attention.
Interpretation of thyroid function tests may be difficult due to the effects of other non-thyroidal illnesses.
Hypothyroidism
Some of the clinical features such as constipation, dry skin and slowing down both mentally and physically are often attributed to increasing age and the diagnosis is delayed for months or even years.
Because of the possibility of exacerbating latent or established heart disease, the starting dose of thyroxine should be 25 µg daily.
Thyroxine requirements fall with increasing age and few patients will need more than 100 µg daily.
Other medication (see
pages 690 - 704
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Home > 2 SYSTEM-BASED DISEASES > 16 Endocrine disease > THE REPRODUCTIVE SYSTEM
THE REPRODUCTIVE SYSTEM
Clinical practice in reproductive medicine is shared between several specialties, including gynaecology, urology, psychiatry and endocrinology. The following section focuses on aspects that are commonly managed by endocrinologists.
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
Integration link: Origin of the gonads
Taken from Human Embryology & Developmental Biology 3e
page 704
page 705
Figure 16.10 Male reproductive physiology.
Figure 16.11 Female reproductive physiology and the normal menstrual cycle.
The physiology of male and female reproductive function is illustrated in Figures 16.10 and 16.11. Pathways of synthesis of sex steroids are shown in Figure 16.16 on page 721. In the male, the testis subserves two principal functions: synthesis of testosterone by the interstitial Leydig cells under the control of luteinising hormone (LH), and spermatogenesis by Sertoli cells under the control of follicle-stimulating hormone (FSH) (but also requiring adequate testosterone). Negative feedback suppression of LH and FSH secretion is mediated principally by testosterone and another hormone from the testis, inhibin, respectively. The axis can be assessed easily by a random blood sample for testosterone, LH and FSH. Testosterone is largely bound in plasma to sex hormone-binding globulin, and this can also be measured to calculate the 'free androgen index'. Testicular function can also be tested by semen analysis.
Integration link: Functions of Sertoli cells in male sexual differentiation
Taken from Human Embryology & Developmental Biology 3e
In the female, physiology is complicated by variations in function during the normal menstrual cycle. FSH produces growth and development of ovarian follicles during the first 14 days after the menses. This leads to a gradual increase in oestradiol production from granulosa cells, which initially suppresses FSH secretion (negative feedback) but then, above a certain level, stimulates an increase in both the frequency and amplitude of gonadotrophin-releasing hormone (GnRH) pulses, resulting in a marked increase in LH secretion (positive feedback). The mid-cycle 'surge' of LH induces ovulation. After release of the ovum the follicle differentiates into a corpus luteum which secretes progesterone. Withdrawal of progesterone results in menstrual bleeding. Circulating levels of oestrogen and progesterone in pre-menopausal women are, therefore, critically dependent on the time of the cycle. The most useful 'test' of ovarian function is a careful menstrual history. In addition, ovulation can be confirmed by measuring progesterone levels during the luteal phase.
Integration link: Ovulation
Taken from Essentials of Obstetrics & Gynecology 4e
The pathophysiology of male and female reproductive function is summarised in
page 705
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16.15 CLASSIFICATION OF DISEASES OF THE REPRODUCTIVE SYSTEM
Primary Secondary
Hormone excess Polycystic ovarian syndrome Pituitary gonadotrophinoma
Granulosa cell tumour
Leydig cell tumour
Hormone deficiency Menopause Hypopituitarism
Hypogonadism (see
Turner's syndrome (45, XO female) Severe systemic illness, including anorexia nervosa
Klinefelter's syndrome (47, XXY male)
Hormone hypersensitivity -
Hormone resistance Androgen resistance syndrome ('testicular feminisation' or Reifenstein's syndrome)
5a-reductase deficiency
Non-functioning tumours Ovarian cysts
Carcinoma
pages 704 - 706
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Home > 2 SYSTEM-BASED DISEASES > 16 Endocrine disease > MAJOR MANIFESTATIONS OF REPRODUCTIVE DISEASE
MAJOR MANIFESTATIONS OF REPRODUCTIVE DISEASE
MALE HYPOGONADISM
Causes of hypogonadism are listed in
Male hypogonadism is confirmed by demonstrating a low serum testosterone level. The distinction between primary and secondary hypogonadism is made by measurement of random LH and FSH. Patients with hypogonadotrophic hypogonadism (i.e. secondary hypogonadism) should be investigated as described for pituitary disease on pages 735-736. Patients with hypergonadotrophic hypogonadism (i.e. primary hypogonadism) should have the testes examined for cryptorchidism (see p. 709) or tumours, measurement of serum ferritin (to exclude haemochromatosis) and a karyotype (to identify Klinefelter's syndrome, i.e. 47, XXY). If there is no obvious cause, then no further investigations are necessary.
Treatment of men with testosterone deficiency is described on page 713.
GYNAECOMASTIA
Gynaecomastia is the presence of glandular breast tissue in males. Normal breast development in women is oestrogen-dependent but androgens oppose this effect. Gynaecomastia results from an imbalance between androgen and oestrogen activity, which may reflect androgen deficiency or oestrogen excess. Causes are listed in
16.16 CAUSES OF GYNAECOMASTIA
Idiopathic
Physiological/peripubertal
Drug-induced
Cimetidine
Digoxin
Spironolactone
Anti-androgen therapies for prostatic carcinoma
Some exogenous anabolic steroids, e.g. diethylstilbestrol
Hypogonadism
Primary
Klinefelter's syndrome
Autoimmune gonadal failure
Mumps orchitis
Haemochromatosis
Tuberculosis
Chemotherapy or irradiation
Rare forms of congenital adrenal hyperplasia
Cryptorchidism
Secondary
Hypopituitarism
Kallmann's syndrome (GnRH deficiency)
Hyperprolactinaemia
Androgen resistance syndromes
Testicular feminisation syndrome
5a-reductase deficiency
Oestrogen excess
Liver failure (impaired steroid metabolism)
Oestrogen-secreting tumour, e.g. of testis
Human chorionic gonadotrophin (hCG)-secreting tumour, e.g. of testis
page 706
page 707
Clinical assessment
A drug history is important. Palpation allows gynaecomastia to be distinguished from the prominent adipose tissue around the nipple often seen in obesity. Unilateral gynaecomastia should be considered to be breast carcinoma unless proved otherwise. Features of hypogonadism should be sought (see above).
Investigations and management
A random blood sample should be taken for testosterone, LH, FSH, oestradiol, prolactin and human chorionic gonadotrophin. If these tests are normal, and no drug is responsible, then there is no useful endocrine therapy. Surgical excision may be justified for cosmetic reasons, except in young boys with a short history in whom gynaecomastia may resolve. The surgical approach should be through a small incision around the nipple, and is best performed by a specialist in plastic surgery.
ERECTILE IMPOTENCE
Causes of erectile failure are shown in
16.17 CAUSES OF IMPOTENCE
With reduced libido
Hypogonadism (see
Depression
With intact libido
Psychological problems, including anxiety
Vascular insufficiency (atheroma)
Neuropathic (e.g. diabetes mellitus, alcohol excess, multiple sclerosis)
Drugs (e.g. ß-blockers, thiazide diuretics)
Investigations
Blood should be taken for glucose, glycated haemoglobin, prolactin, testosterone, LH and FSH. A number of further tests are available but are rarely employed because they do not usually influence management. These tests include nocturnal tumescence monitoring (using a plethysmograph placed around the shaft of the penis overnight) to establish whether blood supply and nerve function are sufficient to allow erections to occur during sleep; intracavernosal injection of papaverine or prostaglandin E1 to test the adequacy of blood supply; internal pudendal artery angiography; and tests of autonomic and peripheral sensory nerve conduction.
Management
Hypogonadism should be treated as described on page 713. Psychotherapy which includes the sexual partner is most useful for psychological problems. Neuropathy and vascular disease are unlikely to improve, but several treatments are available. First-line therapy is usually with oral sildenafil, a phosphodiesterase inhibitor which potentiates the vasodilator action of nitric oxide on cyclic guanosine monophosphate (cGMP). Coadministration of sildenafil with nitric oxide donors ('nitrate' drugs) is contraindicated because of the risk of severe hypotension. Caution should also be exercised in patients with chronic disease including ischaemic heart disease, principally because the unaccustomed stress of sexual activity may precipitate cardiac ischaemia or dysrhythmia. Other treatments for impotence include self-administered intracavernosal injection or urethral gel administration of prostaglandin E1; vacuum devices which achieve an erection which is maintained by a tourniquet around the base of the penis; and prosthetic implants, either of a fixed rod or of an inflatable reservoir. Many patients elect not to use these methods, but unfortunately even more are unaware of their availability.
SHORT STATURE AND DE L A Y E D PUBERTY
16.18 CAUSES OF SHORT STATURE
With delayed puberty
Constitutional/familial
Systemic illness (e.g. asthma, malabsorption, coeliac disease, cystic fibrosis, renal failure)
Psychological stress
Anorexia nervosa
Excessive physical exercise
Hypogonadism (see
Other endocrine disease (e.g. Cushing's syndrome, primary hypothyroidism, pseudohypoparathyroidism)
Without delayed puberty
Isolated growth hormone deficiency
Previous precocious puberty with closure of epiphyses (e.g. congenital adrenal hyperplasia, Langerhans cell histiocytosis, McCune-Albright syndrome)
Prior problem restricting growth now resolved (e.g. intrauterine growth restriction, congenital heart disease)
Skeletal abnormality (e.g. achondroplasia, mucopolysaccharidoses)
page 707
page 708
Patients with short stature usually present during their teenage years. In most, failure to grow is associated with delayed puberty, although there are exceptions (see
Clinical assessment
Figure 16.12 Differential diagnosis of short stature from growth charts. The dots mark height measured at the chronological age shown. The mother's and father's heights are shown. Corresponding bone ages from wrist radiographs are plotted as arrowheads. Typical patterns are shown for childhood short stature (in green; due to congenital growth hormone deficiency); early accelerated growth with premature fusion of the epiphyses (in blue; due to precocious puberty, e.g. in congenital adrenal hyperplasia); late short stature with delayed puberty (in red; due to constitutional pubertal delay, but also consistent with hypogonadism or other causes shown in Box 16.18); and interrupted puberty (in light brown, where M marks the onset of periods at menarche, e.g. due to acquired hypopituitarism in craniopharyngioma, but also consistent with another severe systemic illness, e.g. anorexia nervosa).
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Patients with short stature and delayed puberty require a general history and examination. Current weight and height and assessment of pubertal development should be charted against centiles for normals (see Fig. 16.12). The heights of the parents and older siblings and the age of their pubertal development may support a diagnosis of constitutional pubertal delay. In 95% of normal children final height is within 8.5 cm of the mean parental height. Previous growth measurements in childhood, which can usually be obtained from the school health records, are useful since growth hormone-deficient children usually have always been small, whereas a change in growth velocity resulting in 'crossing the centiles' is more likely to reflect recent pathology. Patients with growth hormone deficiency are characteristically 'chubby', with increased subcutaneous fat, and so are short but not underweight. The presence of anosmia suggests possible Kallmann's syndrome due to isolated GnRH deficiency. Some light axillary and pubic hair may develop because of adrenal androgen production, even though the patient is hypogonadal.
The psychological impact of short stature and sexual immaturity on the young patient needs careful consideration since this is the principal determinant of whether specific treatment is appropriate.
Investigations
Before blood sampling, ask the patient to exercise (e.g. by running up and down the stairs or round the car park until breathless) to stimulate growth hormone secretion (normal >15 mU/l). Measure growth hormone, testosterone (in boys), oestradiol (in girls), LH and FSH, and perform screening tests for systemic illness, including haematology, renal function, liver function and thyroid function. Antigliadin and antimyosin antibodies are a useful screen for coeliac disease. A plain radiograph of the wrist should be compared with a set of standard films to obtain a bone age. Bone age is delayed in pubertal delay and hypogonadism and is advanced in other conditions, e.g. following precocious puberty.
Further tests if growth hormone deficiency or hypogonadotrophic hypogonadism is suspected are described on pages 735-736. Note that normal growth hormone responses to stimulation in peripubertal children require priming of the pituitary with sex steroids for a few days beforehand, and that growth hormone secretion is impaired by any other systemic illness. The demonstration of hypergonadotrophic hypogonadism should be followed by chromosomal analysis to establish Turner's (45, XO with female phenotype) or Klinefelter's (47, XXY with male phenotype) syndrome.
Management
Treatments of specific endocrine abnormalities are discussed elsewhere. In patients with constitutional delay, puberty can be induced using low doses of oral oestrogen in girls (e.g. ethinylestradiol 2 µg daily) or testosterone in boys (e.g. depot testosterone ester injections 50 mg i.m. each month). Higher doses carry a risk of early fusion of epiphyses. This therapy should be given in a specialist clinic and progress monitored until endogenous puberty is established and priming therapy can be discontinued, usually in less than a year.
Isolated growth hormone deficiency is treated by daily subcutaneous injection of growth hormone. Growth hormone also has an established role in Turner's syndrome and in chronic renal failure. Its use in short children without a demonstrable endocrine abnormality is controversial; although it accelerates current growth, it does not result in an increase in final height.
Patients who have already gone through puberty and whose epiphyses have fused cannot be induced to grow further.
CRYPTORCHIDISM
Cryptorchidism (undescended testis) usually occurs in otherwise normal boys but may be the presenting feature of hypogonadotrophic hypogonadism. Highly retractile testes, particularly in an obese boy, may be mistaken for cryptorchidism. If the testes remain in the inguinal canal, they are more liable to trauma than if situated in the scrotum. The seminiferous tubules will fail to develop in an undescended gland and, if the condition is bilateral, sterility will follow. However, even in testes which remain undescended into adult life, the interstitial cells can function normally, so that secondary sex characteristics may develop in the usual way. In a minority of patients with cryptorchidism, the testis has taken an abnormal route of descent during development and lies ectopically either retroperitoneally or within the pelvis. This is called 'maldescent' and carries a significant risk of testicular malignancy, so maldescended testes need to be located by cross-sectional imaging or ultrasound, and excised.
Human chorionic gonadotrophin or intranasal GnRH can induce descent in about 40% of children but, if this fails or the condition is discovered in adulthood, then the testis or testes should be either removed or placed in the scrotum surgically.
HIRSUTISM
Hirsutism refers to the excessive growth of thick terminal hair in an androgen-dependent distribution in women (upper lip, chin, chest, back, lower abdomen, thigh, forearm) and is one of the most common presentations of endocrine disease. It should be distinguished from hypertrichosis, which is generalised excessive growth of vellus hair. The aetiology of androgen excess is shown in
Clinical assessment
The severity of hirsutism is subjective. Some women suffer profound embarrassment from a degree of hair growth which others would not consider remarkable. Other important observations are a drug and menstrual history, calculation of body mass index, measurement of blood pressure, examination for virilisation (clitoromegaly, deep voice, balding, breast atrophy), and associated features including acne vulgaris or Cushing's syndrome (see p. 723). Hirsutism of recent onset associated with virilisation is suggestive of an androgen-secreting tumour, but these are rare.
Investigations
A random blood sample should be taken for testosterone, prolactin, LH and FSH. If there are clinical features of Cushing's syndrome, an overnight 1 mg dexamethasone suppression test should be performed (see p. 724).
page 709
page 710
16.19 CAUSES OF HIRSUTISM
Cause Clinical features Investigation findings Treatment
Idiopathic Often familial Normal Cosmetic measures
Mediterranean or Asian background Anti-androgens
Polycystic ovarian syndrome (see
Oligomenorrhoea or secondary amenorrhoea
Infertility LH:FSH ratio > 2.5:1
Minor elevation of androgens*
Mild hyperprolactinaemia Weight loss
Cosmetic measures
Anti-androgens (Insulin sensitising drugs
may be useful)
Congenital adrenal hyperplasia (95% 21-hydroxylase deficiency) Pigmented
History of salt-wasting in childhood, ambiguous genitalia, or adrenal crisis when stressed
Jewish background Elevated androgens* which suppress with dexamethasone
Abnormal rise in 17OH-progesterone with ACTH Glucocorticoid replacement administered in reverse rhythm to suppress early morning ACTH
Exogenous androgen administration Athletes
Virilised Low LH and FSH
Androgens depend on which steroid is being taken Stop steroid misuse
Androgen-secreting tumour of ovary or adrenal cortex Rapid onset
Virilisation: clitoromegaly, deep voice, balding, breast atrophy High androgens* which do not suppress with dexamethasone or oestrogen
Low LH and FSH
CT demonstrates a tumour Surgical excision
Cushing's syndrome Clinical features of Cushing's syndrome (see p. 723)
See investigations, page 724 Treat the cause (see p. 725)
*E.g. serum testosterone levels in women: <> 5 nM is high and requires further investigation.
If testosterone levels are elevated above twice the upper limit of the normal female range, especially if this is associated with low LH and FSH, then causes other than idiopathic hirsutism and polycystic ovarian syndrome are more likely, and the source of the androgen excess should be established. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is diagnosed by a short ACTH stimulation test with measurement of 17OH-progesterone (see p. 731). In patients with androgen-secreting tumours, serum testosterone does not suppress following dexamethasone (either as an overnight or a 48-hour low-dose suppression test) or oestrogen (30 µg daily for 7 days). The tumour should then be sought by CT or MRI of the adrenals and ovaries.
Management
This depends on the cause (see
SECONDARY AMENORRHOEA
Primary amenorrhoea describes a patient who has never menstruated, i.e. who has not had a menarche. Secondary amenorrhoea describes the cessation of menstruation. The causes of this common problem are shown in
Clinical assessment
Associated clinical features depend on the age of the patient and the underlying cause. Women of menopausal age (see p. 711) are unlikely to present unless they are considering hormone replacement therapy or are troubled by 'menopausal' symptoms such as flushing (see
Investigations
Blood should be taken for LH, FSH, oestradiol, prolactin and TSH. In the absence of a menstrual cycle these can be taken at any time. High levels of LH and FSH with low or low to normal oestradiol suggest primary ovarian failure, including the menopause. Elevated LH with normal oestradiol is common in the polycystic ovarian syndrome. Investigation of hyperprolactinaemia is described on page 740. Low levels of LH, FSH and oestradiol suggest hypothalamic or pituitary disease. Assessment of bone mineral density, e.g. by DXA scan (see p. 972), is appropriate in patients with low androgen and oestrogen levels.
page 710
page 711
16.20 CAUSES OF SECONDARY AMENORRHOEA
Hypothalamic dysfunction
See page 737; also anorexia nervosa, excessive exercise, psychogenic
Pituitary disease
See page 737; especially hyperprolactinaemia
Ovarian dysfunction
Polycystic ovarian syndrome
Androgen-secreting tumours
Autoimmune (premature menopause)
Turner mosaic
Menopause (see below)
Adrenal disease
Cushing's syndrome, congenital adrenal hyperplasia, androgen-secreting tumours
Thyroid disease
Hypo- and hyperthyroidism
Other conditions
Severe systemic disease, e.g. renal failure, endometrial tuberculosis
16.21 MENOPAUSAL SYMPTOMS
Vasomotor effects
Hot flushes
Sweating
Psychological
Anxiety
Irritability
Emotional lability
Genitourinary
Dyspareunia ('senile vaginitis')
Urgency of micturition
Vaginal infections ?
Management
This depends on the cause. In oestrogen-deficient patients it is usually appropriate to offer hormone replacement therapy for symptomatic improvement and/or to prevent osteoporosis (see p. 713).
INFERTILITY
Around 10% of couples have difficulty in conceiving children. This is attributable in roughly equal thirds to infertility in the female, infertility in the male, and idiopathic cases. So, although it is common for women to present with this problem, early assessment of both partners is essential to avoid unnecessary investigations and delay. This should include establishing that the couple are having intercourse when the woman is likely to be fertile.
Further assessment of women includes a menstrual history. Oligomenorrhoea suggests that the cycles are anovulatory. This can be confirmed by measurement of serum progesterone 21 days after the start of the last menstrual period (ovulation indicated by level >15 nmol/l). Subsequent tests are similar to those for secondary amenorrhoea above. If the woman has regular menses, and no abnormality is found in the man, then further gynaecological investigation may be required.
Integration link: Endometriosis - common sites and pathology
Taken from Robbins Basic Pathology 7e
Integration link: Pathology of endometriosis
Taken from Robbins & Cotran's Pathologic Basis of Disease 7e
The male should be examined for a varicocele or other testicular abnormality. A semen analysis should be performed. If he has oligospermia, then blood should be taken for prolactin, testosterone, FSH and LH and these interpreted as described for male hypogonadism above. If the only biochemical abnormality is a high FSH, then an irreversible failure of spermatogenesis is likely (the FSH rises because of lack of ß-inhibin). Testicular biopsy is rarely indicated.
In patients with gonadotrophin deficiency, fertility can be induced over several months, as described on page 714. This is usually performed once, and sperm stored for subsequent artificial insemination.
THE MENOPAUSE
The cessation of menstruation in women in most developed countries occurs at a median age of 50.8 years. In the 5 years before there is a gradual increase in the number of anovulatory cycles. This period is referred to as the climacteric. Oestrogen and inhibin secretion falls and negative feedback results in increased pituitary secretion of LH and FSH. Levels of serum LH and FSH >30 U/l in the presence of low oestradiol confirm the diagnosis.
Clinical features
Clinical features are listed in
Management
Many women seek explanation and reassurance rather than treatment.
page 711
page 712
Oestrogen replacement therapy (usually called HRT) is discussed on page 713. In patients who decide against such therapy (e.g. strong family history of breast cancer) vasomotor symptoms may respond to clonidine. Vaginal and urinary symptoms may be helped by topical oestrogen cream. If anxiety or emotional problems associated with the menopause do not respond to HRT, they may need treatment in their own right.
POLYCYSTIC OVARIAN SYNDROME (PCOS)
Clinical features
16.22 FEATURES OF POLYCYSTIC OVARIAN SYNDROME
Mechanisms* Manifestations
Pituitary dysfunction High serum LH
High serum prolactin
Anovulatory menstrual cycles Oligomenorrhoea
Secondary amenorrhoea
Cystic ovaries
Infertility
Androgen excess Hirsutism
Acne
Obesity Hyperglycaemia
Insulin resistance Dyslipidaemia
Hypertension
*These mechanisms are interrelated-it is not known which, if any, is primary. PCOS probably represents the common endpoint of several different pathologies.
PCOS describes a constellation of clinical and biochemical features, for which the aetiology remains poorly understood. It is probably the common endpoint of a heterogeneous group of pathologies, characterised by loss of coordinate control of the menstrual cycle. PCOS often affects several family members and is aggravated by obesity. Clinical and biochemical features are shown in
Management
This depends on the clinical problem. Infertility may be treated under specialist supervision with clomifene or exogenous gonadotrophins. Although patients with PCOS may have amenorrhoea, hormone replacement therapy is not required to prevent osteoporosis since they have elevated, rather than low, circulating levels of oestrogens and androgens.
16.23 ANTI-ANDROGEN THERAPY
Mechanism of action Drug Dose Hazards
Androgen receptor antagonists Cyproterone acetate 2, 50 or 100 mg on days 1-11 of 28-day cycle with ethinylestradiol 30 µg on days 1-21 Hepatic dysfunction
Feminisation of male fetus
Progesterone receptor agonist
Dysfunctional uterine bleeding
Spironolactone 100-200 mg daily Electrolyte disturbance
Carcinogenic in rats
Flutamide Not recommended Hepatic dysfunction
5a-reductase inhibitors (prevent conversion of testosterone to active dihydrotestosterone) Finasteride Not recommended Unproven efficacy
Suppression of ovarian steroid production Oestrogen See combination with cyproterone acetate above
or
Conventional oestrogen-containing contraceptive Venous thromboembolism
Hypertension
Weight gain
Dyslipidaemia
Increased breast and endometrial carcinoma
Suppression of adrenal androgen production Exogenous glucocorticoid to suppress ACTH e.g. Hydrocortisone 5 mg at 0900 hrs and dexamethasone 0.5 mg at 2200 hrs Cushing's syndrome
page 712
page 713
For hirsutism, most patients will have used cosmetic measures such as bleaching and waxing before consulting a doctor. Electrolysis is effective for small areas, e.g. upper lip and chest hair, but is expensive. The pathophysiology of the common causes of hirsutism is poorly understood, but insulin resistance may be an important factor in PCOS. Weight loss is a vital step to enhance insulin sensitivity and reduce the peripheral conversion of androgens to oestrogens by the aromatase enzyme in adipose tissue. If these conservative measures have been tried and have failed, then anti-androgen therapy may be employed, as shown in
SEX HORMONE REPLACEMENT THERAPY
In males
Testosterone replacement is indicated in hypogonadal adults to prevent osteoporosis, and restore muscle power and libido. It is also sometimes used in adolescents with pubertal delay (see p. 709). Routes of testosterone administration are shown in
In females
Oestrogen replacement is indicated in women with pituitary disease or premature ovarian failure to prevent osteoporosis (see EBM panel). In pre-menopausal females the treatment is cyclical oestrogen therapy on days 1-21 and progestogen on days 14-21. This is administered most conveniently as an oral contraceptive pill. If oestrogenic side-effects (fluid retention, weight gain, hypertension, thrombosis and family history of breast cancer) are a concern, then a lower-dose oral or transdermal cyclical HRT is appropriate.
16.24 OPTIONS FOR ANDROGEN REPLACEMENT THERAPY
Preparation
Depot testosterone esters 250-500 mg I.m. injection Every 2-4 weeks Tends to wear off before next dose is due
Transdermal patches 5-10 mg To skin Daily Consistent circulating testosterone levels but 10% incidence of skin hypersensitivity
Testosterone undecanoate 40-120 mg Oral 12-hourly Variable blood levels and risk of liver dysfunction
Testosterone implant 600-800 mg Subcutaneous Every 3-6 months Effective but causes scarring at site of implantation
EBM
MENOPAUSE-use of hormone replacement therapy (HRT)
'RCTs show that conventional oestrogen therapy (combined with progestogen in women with an intact uterus) is effective in preventing loss of bone mineral density and osteoporotic fractures. HRT also reduces menopausal symptoms. However, RCTs also show that combined HRT also increases the risk of breast cancer, endometrial cancer, coronary heart disease, stroke and venous thromboembolism. The risks are small; the Women's Health Initiative study predicts that 5 years of continuous combined HRT to 10 000 unselected women aged 50-79 years results in 8 extra cases of breast cancer, 8 extra cases of pulmonary embolus, 7 extra episodes of coronary heart disease and 8 extra strokes while preventing 5 hip fractures and 6 cases of colorectal cancer.'
Turgerson DJ, Bell-Syer SE. Hormone replacement therapy and prevention of nonvertebral fractures: a meta-analysis of randomized trials. JAMA 2001; 285:2891-2897.
Hulley SB, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280:605-613.
Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288:321-333.
Further information: www.cochrane.co.uk
In post-menopausal females HRT is effective for menopausal symptoms and prevents osteoporotic fractures (see EBM panel). Initial observations suggested that HRT prevents cardiovascular disease, but randomised controlled trials show that combined HRT increases the risk of coronary events and stroke. HRT also increases the risk of breast and endometrial cancer and of venous thromboembolism. Unlike the higher doses of oestrogen used for contraception, HRT probably has no adverse effect on blood pressure. The decision on whether to use HRT must be made on an individual basis, weighing up risk factors for these various benefits and complications, especially family history. Patients with a menopause before the age of 45 years should be encouraged to take HRT.
Oestrogen should not be given 'unopposed' (i.e. without progesterone) in women who have not had a hysterectomy as there is then a high risk of endometrial cancer. However, although theoretically better, it is no longer considered essential to induce withdrawal bleeds, and combined oestrogen and progesterone can be given continuously. Both oestrogen and progesterone can be given either orally or as dermal patches.
In addition to conventional oestrogen/progestogen combinations, selective oestrogen receptor modulators (SERMs) are available. These drugs interact with sites on the oestrogen receptor which are involved in interactions with tissue-specific transcription factors. As a result, they are oestrogen agonists in some sites and antagonists in others. Examples include tamoxifen (antagonist in breast, partial agonist in bone) and raloxifene (antagonist in breast and uterus, full agonist in bone). Unlike conventional HRT, these agents reduce rather than enhance the risk of breast cancer. Raloxifene is likely to be used increasingly in the prevention and treatment of osteoporosis. However, it does not relieve menopausal symptoms.
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It is often difficult to say how long to continue HRT, since the benefits regress after discontinuing therapy, but the risks are proportional to the duration of therapy. As a rough guide, patients presenting with oestrogen deficiency before the age of 45 years should be encouraged to take HRT until at least the age of 50 years, and may continue if they wish until the age of 60 years. Patients with a normal menopause may be offered treatment for 10 years or until the age of 60 years, whichever comes sooner.
EBM
MENOPAUSE-role of raloxifene
'RCTs show that raloxifene, a selective oestrogen receptor modulator, prevents loss of bone mass, prevents osteoporotic fracture, and reduces the risk of oestrogen receptor-positive breast cancer. Raloxifene does not affect the risk of developing endometrial cancer. However, it is ineffective for menopausal symptoms, and-like combined HRT-does increase the risk of thromboembolic disease.'
Ettinger B, Black D, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene. JAMA 1999; 282:637-645.
Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. JAMA 1999; 281:2189-2197.
Further information: www.endocrinology.org
In patients desiring fertility
ISSUES IN OLDER PEOPLE
REPRODUCTIVE MEDICINE
The major physiological change with ageing is the menopause in women. Although testosterone levels do fall with age, no qualitative 'male menopause' exists.
Many older people remain sexually active, so problems such as dyspareunia (due to post-menopausal vaginal dryness) or erectile dysfunction should receive careful attention.
Post-menopausal osteoporosis is a major public health problem in old age. Appropriate use of HRT after the menopause is an important preventative measure.
Preliminary evidence suggests that oestrogen therapy prevents cognitive dysfunction in elderly women. Further trials may establish the value of HRT in preventing dementia.
The risks of oestrogen therapy are increased by prolonged use and increasing age. Hence HRT should not usually be prescribed beyond the age of 60 years.
There is no evidence that replacement of testosterone in mildly hypogonadal elderly men is of benefit, and it may induce prostatic hyperplasia and cancer.
Some common disorders of reproductive function become less troublesome after the menopause, including hirsutism in polycystic ovarian syndrome. However, very old women may suffer idiopathic hirsutism and balding which, if very severe or rapidly progressive, may represent significant pathological androgen excess, e.g. from an ovarian tumour.
Sex steroid replacement does not stimulate ovulation or spermatogenesis. Patients wishing fertility are usually given injections of gonadotrophins several times a week (hCG for LH action and human or equine extracted FSH). If there is a hypothalamic cause for the hypopituitarism, then pulsatile GnRH therapy with a portable infusion pump is an alternative. Note that the pituitary GnRH receptors respond to pulsatile stimulation; continuous administration of GnRH or its analogues will suppress rather than stimulate LH/FSH secretion. The duration of gonadotrophin therapy depends on the duration and cause of hypogonadism. In both sexes the treatment requires specialist supervision, especially in females in whom there is a risk of multiple ovulation and the hyperstimulation syndrome, characterised by capillary leak with circulatory shock, pleural effusions and ascites.
pages 706 - 714
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THE PARATHYROID GLANDS
Parathyroid hormone (PTH) is a key controller of calcium metabolism which interacts with vitamin D in kidney and bone. Consequences of altered vitamin D in gut and renal disease are discussed in Chapters 17 and 14, respectively. Other metabolic bone disease is discussed in Chapter 20. Here, we address primary disorders of the parathyroid glands. The most common is hyperparathyroidism resulting in hypercalcaemia, which can be mimicked by release of PTH-like peptides, e.g. in malignancies.
Integration link: Structure and processing of preproparathyroid hormone
Taken from Physiology 5e
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
The four parathyroid glands lie behind the lobes of the thyroid. The parathyroid glands are not regulated by the pituitary gland, but respond directly to changes in ionised calcium concentrations. PTH is a single-chain polypeptide of 84 amino acids which is synthesised by the chief cells and released in response to a fall in serum ionised calcium concentration. This hormone interacts with vitamin D and its metabolites in regulating calcium absorption and excretion. Its actions are shown in Figure 16.13.
In summary, PTH has direct effects which promote reabsorption of calcium from renal tubules and bone. PTH also has indirect effects, mediated by increasing conversion of 25-hydroxycholecalciferol (i.e. 25-hydroxy-vitamin D) to the more potent hormone 1,25-dihydroxycholecalciferol, which results in increased calcium absorption from food and enhanced mobilisation of calcium from bone. PTH plays a central role in regulating calcium homeostasis because vitamin D and dietary calcium are rarely deficient. Moreover, 99% of total body calcium is in bone, but this pool is in dynamic equilibrium with the extracellular fluid by processes of bone resorption and deposition. The initial effect of PTH on bone is to stimulate osteolysis, returning calcium from bone to the extracellular fluid. Prolonged exposure of bone to PTH is associated with increased osteoclastic activity, extensive bone remodelling and osteoblastic repair.
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Integration link: Overall action of PTH - hyperparathyroidism
Taken from Physiology 5e
Figure 16.13 Outline of calcium homeostasis showing interactions between parathyroid hormone (PTH) and vitamin D. * Calcium in serum exists as 50% ionised (Ca++), 10% non-ionised or complexed with organic ions such as citrate and phosphate, and 40% protein-bound, mainly to albumin. It is the ionised calcium concentration which regulates PTH production.
Investigation of calcium metabolism is usually straightforward. Most laboratories measure total calcium in serum. About 50% of circulating calcium is bound to organic ions such as citrate or phosphate and to proteins. Total calcium measurements need to be corrected if the serum albumin is low, by adjusting the value for calcium upwards by 0.1 mmol/l for each 6 g/l reduction in albumin. Differential diagnosis of disorders of calcium metabolism requires measurement of phosphate, alkaline phosphatase and sometimes PTH (for which the blood sample has to be taken to the laboratory 'on ice' and centrifuged rapidly).
In some species calcitonin, a hormone secreted from the parafollicular C cells of the thyroid gland, also regulates calcium metabolism. However, although calcitonin is a useful tumour marker in medullary carcinoma of thyroid (see p. 704) and can be administered therapeutically in Paget's disease of bone (see p. 1031), its release from the thyroid is of no clinical relevance to calcium homeostasis in humans.
Disorders of the parathyroid glands are summarised in
16.25 CLASSIFICATION OF DISEASES OF THE PARATHYROID GLANDS
Primary Secondary
Hormone excess Primary hyperparathyroidism (adenoma, hyperplasia, occasionally carcinoma)
Tertiary hyperparathyroidism Secondary hyperparathyroidism
Hormone deficiency Post-surgical
Autoimmune
Hormone hypersensitivity -
Hormone resistance Pseudohypoparathyroidism
Non-functioning tumours Parathyroid carcinoma
pages 714 - 715
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Home > 2 SYSTEM-BASED DISEASES > 16 Endocrine disease > MAJOR MANIFESTATIONS OF DISEASES OF THE PARATHYROID GLANDS
MAJOR MANIFESTATIONS OF DISEASES OF THE PARATHYROID GLANDS
HYPERCALCAEMIA
Hypercalcaemia is one of the most common biochemical abnormalities. (For other electrolyte disturbances, see Ch. 9.) It is detected most frequently during routine biochemical analysis in asymptomatic patients. However, it can present with chronic symptoms as described below, and occasionally patients present as acute emergencies with severe hypercalcaemia and dehydration.
Causes of hypercalcaemia are listed in
Clinical assessment
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16.26 CAUSES OF HYPERCALCAEMIA
With normal or elevated (i.e. inappropriate) PTH levels
Primary or tertiary hyperparathyroidism
Lithium-induced hyperparathyroidism
Familial hypocalciuric hypercalcaemia
With low (i.e. suppressed) PTH levels
Malignancy (e.g. lung, breast, renal, ovarian, colonic and thyroid carcinoma)
Multiple myeloma
Elevated 1,25(OH)2 vitamin D3 (e.g. intoxication or sarcoidosis)
Thyrotoxicosis
Paget's disease with immobilisation
Milk-alkali syndrome
Thiazide diuretics
Addison's disease
Symptoms and signs of hypercalcaemia include polyuria and polydipsia, renal colic, lethargy, anorexia, nausea, dyspepsia and peptic ulceration, constipation, depression, drowsiness and impaired cognition. Patients with malignant hypercalcaemia can have a rapid onset of symptoms and may have clinical features which help to localise their tumour.
Patients with primary hyperparathyroidism may have a chronic, non-specific history. Their symptoms are brought to mind by the adage 'bones, stones and abdominal groans'. However, about 50% of patients with primary hyperparathyroidism are asymptomatic. In others, symptoms may go unrecognised until patients present with renal calculi (5% of first stone formers and 15% of recurrent stone formers have primary hyperparathyroidism), with or without impaired renal function, or acute dehydration and profound hypercalcaemia. Hypertension is common in hyperparathyroidism. Parathyroid tumours are almost never palpable.
A family history of renal tract stones and/or neck surgery raises the possibility of multiple endocrine neoplasia (see p. 688). Familial hypocalciuric hypercalcaemia is a rare but important catch for the unwary. This autosomal dominant disorder is associated with a defective calcium receptor in the parathyroid gland, but is almost always asymptomatic and uncomplicated. Occasionally, these patients have had their parathyroid glands removed unnecessarily.
Investigations
Low plasma phosphate and elevated alkaline phosphatase support a diagnosis of primary hyperparathyroidism or malignancy. High plasma phosphate and alkaline phosphatase accompanied by renal impairment suggest tertiary hyperparathyroidism (see p. 601). Hypercalcaemia may cause nephrocalcinosis and renal tubular impairment resulting in hyperuricaemia and hyperchloraemia.
The most discriminant investigation is the measurement of PTH using a specific immunoradiometric assay. Older assays were not able to distinguish PTH from PTH-related peptide. If PTH is normal or elevated and urinary calcium is elevated, then hyperparathyroidism is confirmed. If PTH is low and no other cause is apparent, then malignancy with or without bony metastases is likely. PTH-related peptide can be measured, but this is not generally necessary. Unless the source is obvious, the patient should be screened for malignancy with a chest radiograph, isotope bone scan, myeloma screen (ESR, serum protein electrophoresis, immunoglobulins and urinary Bence Jones protein), serum angiotensin-converting enzyme (elevated in sarcoidosis), and further imaging as appropriate.
Management
Treatment of malignant hypercalcaemia and primary hyperparathyroidism is described in
16.27 TREATMENT OF MALIGNANT HYPERCALCAEMIA
Rehydration with normal saline
To replace as much as a 4-6 l deficit
May need monitoring with central venous pressure in old age or renal impairment
Bisphosphonates, e.g. pamidronate 90 mg i.v. over 4 hours
Causes a fall in calcium which is maximal at 2-3 days and lasts a few weeks
Unless the cause is removed, follow up with an oral bisphosphonate
Additional rapid therapy may be required in very ill patients
Forced diuresis with saline and furosemide (frusemide)
Glucocorticoids, e.g. prednisolone 40 mg daily
Calcitonin
Haemodialysis
Treat the cause
HYPOCALCAEMIA
Aetiology
Hypocalcaemia is much less common than hypercalcaemia. Its differential diagnosis is shown in
The most common cause of hypoparathyroidism is damage to the parathyroid glands (or their blood supply) during thyroid surgery, although this complication is only permanent in 1% of thyroidectomies. Transient hypocalcaemia develops in 10% of patients 12-36 hours following subtotal thyroidectomy for Graves' disease.
Idiopathic hypoparathyroidism may develop at any age, and is sometimes associated with autoimmune disease of the adrenal, thyroid or ovary, especially in young people (see
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16.28 DIFFERENTIAL DIAGNOSIS OF HYPOCALCAEMIA
Total serum calcium concentration Ionised serum calcium concentration Serum phosphate concentration Serum PTH concentration Comments
Hypoalbuminaemia ? ? ? ? Adjust calcium upwards by 0.1 mmol/l for each 6 g/l reduction in albumin
Alkalosis
Respiratory, e.g. hyperventilation
Metabolic, e.g.
Vitamin D deficiency ? ? ? ? See Chapter 20
Chronic renal failure ? ? ? ? Due to impaired vitamin D hydroxylation
Serum creatinine ?
Hypoparathyroidism
Post-surgical
Idiopathic
Infantile ? ? ? ? See text
Pseudohypoparathyroidism ? ? ? ? Characteristic phenotype
Acute pancreatitis ? ? ? or ? ? Usually clinically obvious
Serum amylase ?
Pseudohypoparathyroidism is usually an autosomal dominant syndrome in which there is tissue resistance to the effects of PTH. The PTH-receptor is normal but there is a defective post-receptor mechanism.
Clinical features
Tetany occurs in all syndromes in which ionised calcium concentrations are low. Additional features are specific to different aetiologies.
Tetany
Low ionised calcium concentrations cause increased excitability of peripheral nerves. In the absence of alkalosis, tetany usually occurs in adults only if total serum calcium is <2.0 style="mso-spacerun:yes">
In children a characteristic triad of carpopedal spasm, stridor and convulsions occurs, though one or more of these may be found independently of the others. The hands in carpal spasm adopt a characteristic position. The metacarpophalangeal joints are flexed, the interphalangeal joints of the fingers and thumb are extended, and there is opposition of the thumb ('main d'accoucheur'). Pedal spasm is much less frequent. Stridor is caused by spasm of the glottis. Adults complain of tingling in the hands and feet and around the mouth. Less often there is painful carpopedal spasm, while stridor and fits are rare.
Latent tetany may be present when signs of overt tetany are lacking. It is best recognised by eliciting Trousseau's sign. Inflation of a sphygmomanometer cuff on the upper arm to more than the systolic blood pressure is followed by carpal spasm within 3 minutes. A less specific sign of hypocalcaemia is that described by Chvostek, in which tapping over the branches of the facial nerve as they emerge from the parotid gland produces twitching of the facial muscles.
Other features
Prolonged hypocalcaemia in hypoparathyroidism may cause grand mal epilepsy, psychosis, cataracts, calcification of basal ganglia and papilloedema. In addition, there is an association with mucocutaneous candidiasis. In pseudo-hypoparathyroidism there is no associated mucocutaneous candidiasis, but patients may have mental retardation and characteristically there are skeletal abnormalities such as short stature and short 4th and 5th metacarpals and metatarsals. The term 'pseudo-pseudohypoparathyroidism' is used in connection with patients exhibiting the above skeletal abnormalities but in whom serum calcium concentration and other biochemistry are normal.
Management
To control tetany, alkalosis can be reversed acutely if arterial PCO2 is increased by rebreathing expired air in a paper bag or administering 5% CO2 in oxygen. Injection of 20 ml of a 10% solution of calcium gluconate slowly into a vein will raise the serum calcium concentration immediately. An intramuscular injection of 10 ml may also be given to obtain a more prolonged effect. In severe cases of alkalotic tetany, intravenous calcium gluconate often relieves the spasm, while specific treatment of the alkalosis, which will vary with the cause, is being applied (see Ch. 9). If tetany is not relieved by giving calcium, the administration of magnesium may be required.
For chronic control of hypocalcaemia, commercial preparations of PTH are unsatisfactory because they have to be given by frequent injections, and soon become ineffective due to antibody formation. Substitution therapy for persistent hypoparathyroidism and for pseudohypoparathyroidism is provided by 1a-hydroxycholecalciferol (alfacalcidol) which is hydroxylated in the liver to 1,25-dihydroxycholecalciferol (calcitriol).
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HYPERPARATHYROIDISM
It is customary to distinguish three categories of hyperparathyroidism, as shown in
Primary hyperparathyroidism is the most common of the parathyroid disorders with a prevalence of about 1 in 800. It is two to three times more common in women than men and 90% of patients are over 50 years of age. It also occurs in all of the familial multiple endocrine neoplasia syndromes, as described on page 688, when hyperplasia rather than adenoma is more likely. Its clinical presentation is described under hypercalcaemia on page 715.
Skeletal and radiological changes in primary hyperparathyroidism
These features are rarer with earlier use of surgical parathyroidectomy (see below). Osteitis fibrosa results from increased bone resorption by osteoclasts with fibrous replacement in the lacunae. This may present as bone pain and tenderness, fracture and deformity. Chondrocalcinosis is due to deposition of calcium pyrophosphate crystals within articular cartilage. This typically affects the menisci at the knees and can result in secondary degenerative arthritis or predispose to attacks of acute pseudogout.
There are characteristic changes on plain radiographs. In the early stages there may be demineralisation, with subperiosteal erosions and terminal resorption in the phalanges (see Fig. 16.14). A 'pepper-pot' appearance may be seen on lateral radiographs of the skull. In nephrocalcinosis, scattered opacities may be visible within the renal outline. There may be soft tissue calcification in arterial walls, in soft tissues of the hands, and in the cornea. However, changes on plain radiographs are features of long-standing hyperparathyroidism, and these investigations are not required either to confirm the diagnosis or as a criterion for surgery.
Localisation of parathyroid tumours
16.29 HYPERPARATHYROIDISM
Type Serum calcium PTH
Primary Raised Not suppressed
Single adenoma (90%)
Multiple adenomata (4%)
Nodular hyperplasia (5%)
Carcinoma (1%)
Secondary Low Raised
Chronic renal failure
Malabsorption
Osteomalacia and rickets
Tertiary Raised Not suppressed
Figure 16.14 Radiograph of subperiosteal erosions (lower arrows) in a phalanx with terminal resorption (top arrow) in a patient with primary hyperparathyroidism.
If primary hyperparathyroidism is confirmed biochemically, imaging to locate the adenoma or differentiate adenomas from hyperplasia is not necessary. In over 90% of patients an experienced surgeon will locate the adenoma without difficulty. If surgical exploration has been unsuccessful, however, ultrasonography, selective neck vein catheterisation with PTH measurements, CT and subtraction imaging may prove useful. In this last technique the neck is imaged during the successive injections of two short-lived isotopes: 201thallium (taken up by thyroid and parathyroid), followed by 99mtechnetium (taken up by thyroid only). Computer subtraction of the two images leaves a solitary parathyroid image if an adenoma is present.
Treatment of primary hyperparathyroidism
Treatment of severe hypercalcaemia in hyperparathyroidism is as for malignant hypercalcaemia (see
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Most patients do not require urgent treatment. The only long-term therapy is surgery, with excision of a solitary parathyroid adenoma or debulking of hyperplastic glands. In hyperplasia, all four glands may be removed and some of the excised tissue transplanted to the forearm. If hypercalcaemia returns, part of the transplant can be removed under local anaesthetic. Post-operative hypocalcaemia is not uncommon during the first 2 weeks while residual suppressed parathyroid tissue recovers.
As detailed in the EBM panel, the selection of patients with primary hyperparathyroidism that require surgery is not always straightforward. Surgery is indicated for those with clear-cut symptoms or documented complications such as peptic ulceration, renal stones, renal impairment or osteopenia. However, a large number of patients have only vague symptoms or are asymptomatic. Younger patients are being operated on more frequently, but older patients with contraindications to surgery can be reviewed every 6-12 months, with assessment of symptoms, renal function, serum calcium and bone mineral density. They should be encouraged to maintain a high oral fluid intake to avoid renal stones.
EBM
PRIMARY HYPERPARATHYROIDISM-role of parathyroidectomy in asymptomatic patients
'In asymptomatic patients, primary hyperparathyroidism is progressive in fewer than 25% of cases over a 10-year period. Parathyroid surgery is therefore reserved for patients who either are symptomatic; are younger than 50 years; have a serum calcium > 0.4 mM above the normal range; have a creatinine clearance <>
Silverberg SJ, Shane E, Jacobs TP, et al. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999; 341:1249-1255.
NIH conference: diagnosis and management of asymptomatic primary hyperparathyroidism; consensus development conference statement. Ann Intern Med 1991; 114:593-597.
Further information: www.endocrinology.org
ISSUES IN OLDER PEOPLE
THE PARATHYROID GLANDS
Primary hyperparathyroidism becomes more common with increasing age. Most elderly patients can be observed and surgical intervention avoided.
However, hypercalcaemia causes confusion in older people. In a patient with otherwise asymptomatic primary hyperparathyroidism, confusional states may improve following parathyroidectomy.
Vitamin D deficiency is a common cause of hypocalcaemia in older patients, because of poor diet and limited exposure to the sun.
In patients with osteoporotic fractures, metabolic bone disease including osteomalacia and hyperparathyroidism should be excluded by biochemical screening.
pages 715 - 719
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Home > 2 SYSTEM-BASED DISEASES > 16 Endocrine disease > THE ADRENAL GLANDS
THE ADRENAL GLANDS
The adrenals function as several separate endocrine glands within one anatomical structure. The adrenal medulla is an extension of the sympathetic nervous system which secretes catecholamines. Most of the adrenal cortex is made up of cells which secrete cortisol and adrenal androgens, and form part of the hypothalamic-pituitary-adrenal axis. The small outer glomerulosa of the cortex secretes aldosterone under the control of the renin-angiotensin system. These functions are important in the integrated control of cardiovascular, metabolic and immune responses to stress.
Subtle alterations in adrenal function may be important in common diseases, including hypertension, obesity and type 2 diabetes mellitus. However, classical syndromes of adrenal hormone deficiency and excess are relatively rare.
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
Adrenal anatomy and function are shown in Figure 16.15. Histologically, the cortex is divided into three zones, but these function as two units (zona glomerulosa and zonae fasciculata/reticularis) which produce corticosteroids in response to humoral stimuli. Pathways for the biosynthesis of corticosteroids are shown in Figure 16.16. Investigation of adrenal function is described under specific diseases below. Pathologies are classified in
Glucocorticoids
Cortisol is the major glucocorticoid in humans. Levels are highest in the morning on waking and lowest in the middle of the night. Cortisol rises dramatically during stress, including any illness. This elevation protects key metabolic functions at the expense of others (e.g. maintaining cerebral glucose supply during starvation) and puts an important 'brake' on potentially damaging inflammatory responses to infection and injury. The clinical importance of cortisol deficiency is therefore most obvious at times of stress.
16.30 CLASSIFICATION OF DISEASES OF THE ADRENAL GLANDS
Primary Secondary
Hormone excess Non-ACTH-dependent Cushing's syndrome (see
Primary hyperaldosteronism (see
Phaeochromocytoma Secondary hyperaldosteronism
Hormone deficiency Addison's disease (see
Congenital adrenal hyperplasia Hypopituitarism
Hormone hypersensitivity 11ß-hydroxysteroid dehydrogenase deficiency
Liddle's syndrome
Hormone resistance Pseudohypoaldosteronism
Glucocorticoid resistance syndrome
Non-functioning tumours Carcinoma (usually functioning)
Metastatic tumours
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Figure 16.15 Structure and function of the adrenal glands. (ACE = angiotensin-converting enzyme; JGA = juxtaglomerular apparatus; MR = mineralocorticoid receptor; ß-LPH = ß-lipotrophic hormone, a fragment of the ACTH precursor peptide pro-opiomelanocortin which contains melanocyte-stimulating hormone activity)
In the circulation more than 95% of cortisol is bound to protein, principally cortisol-binding globulin. It is the free fraction which is biologically active via glucocorticoid receptors which regulate the transcription of many genes in many cells. Cortisol can also activate mineralocorticoid receptors, but it does not normally do so because most cells containing mineralocorticoid receptors also express an enzyme, 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD), which converts cortisol to its inactive metabolite, cortisone. Loss of this protection of mineralocorticoid receptors by inhibition of 11ß-HSD (e.g. by liquorice) results in cortisol acting like aldosterone as a potent sodium-retaining steroid.
Mineralocorticoids
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Figure 16.16 The major pathways of synthesis of steroid hormones. (DHEA = dehydroepiandrosterone; OHase = hydroxylase; HSD = hydroxysteroid dehydrogenase)
Aldosterone is the body's most important sodium-retaining hormone, which acts via mineralocorticoid receptors. Sodium is retained at the expense of increased excretion of potassium. Increased potassium in the lumen of the distal nephron also results in increased exchange with protons and metabolic alkalosis. The principal stimulus to aldosterone secretion is angiotensin II, a peptide produced by activation of the renin-angiotensin system (see Fig. 16.15). Renin secretion from the juxtaglomerular apparatus in the kidney is stimulated by low perfusion pressure in the afferent arteriole, low sodium filtration leading to low sodium concentrations at the macula densa, or increased sympathetic nerve activity. As a result, renin is increased in hypovolaemia and renal artery stenosis, and standing levels of renin are about double those when lying down.
Catecholamines
In humans, only a small proportion of circulating noradrenaline is derived from the adrenal medulla; much more is released from other nerve endings. However, the methyltransferase enzyme responsible for the conversion of noradrenaline to adrenaline is induced by glucocorticoids. Blood flow in the adrenal is centripetal so that the medulla is bathed in high concentrations of cortisol and is the major source of circulating adrenaline. However, in the absence of functioning adrenal medullae, e.g. after bilateral adrenalectomy, there appear to be no clinical consequences attributable to deficiency of circulating catecholamines.
Adrenal androgens
Adrenal androgens are secreted in response to ACTH and are the most abundant steroids in the blood stream. They are probably important in the initiation of puberty (the adrenarche). The adrenals are also the major source of androgens in adult females, and may be important in female libido.
pages 719 - 721
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MAJOR MANIFESTATIONS OF ADRENAL DISEASE
Adrenal diseases are rare but they often need to be considered because they are encountered in the context of common complaints (see p. 685). Classical syndromes of adrenal disease are described below. Disorders of the adrenal glands are also diagnosed in childhood (congenital adrenal hyperplasias), in patients presenting with hypertension (see Ch. 12; primary hyperaldosteronism, phaeochromocytoma), or in women with hirsutism (see p. 709; late-onset congenital adrenal hyperplasia).
THE 'CUSHINGOID' PATIENT
Cushing's syndrome is caused by excessive activation of glucocorticoid receptors. By far the most common cause is iatrogenic, due to prolonged administration of synthetic glucocorticoids such as prednisolone. Non-iatrogenic Cushing's syndrome is rare, although it presents by many diverse routes and is often a 'spot diagnosis' made by an astute clinician.
Iatrogenic Cushing's syndrome
The remarkable anti-inflammatory properties of glucocorticoids have led to their use in a wide variety of clinical conditions, but the hazards are significant. Equivalent doses of commonly used glucocorticoids are listed in
16.31 EQUIVALENT DOSES OF GLUCOCORTICOIDS: ANTI-INFLAMMATORY POTENCY
Hydrocortisone: 20 mg
Cortisone acetate: 25 mg
Prednisolone: 5 mg
Dexamethasone: 0.75 mg
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Side-effects of glucocorticoid therapy
The side-effects of glucocorticoid therapy are illustrated in Figure 16.17 and listed below. These effects are related to dose which should therefore be kept to a minimum. Some patients will have pre-existing disease which is exacerbated by glucocorticoid therapy; particular care is required in patients with diabetes mellitus or glucose intolerance, to avoid symptomatic hyperglycaemia. Rapid changes in cortisol levels can also lead to marked mood disturbance, either depression or mania (see pp. 262-263), and insomnia.
Even though the drug is being used for its anti-inflammatory effect, this may produce problems. Thus signs of perforation of a viscus may be masked and the patient may show no febrile response to an infection. Gastric erosions are more common, probably because of impaired prostaglandin synthesis. Hence the combination of corticosteroid with analgesic drugs such as aspirin may lead to haemorrhage from the stomach or duodenum. Latent tuberculosis may be reactivated and patients on corticosteroids should be advised to avoid contact with varicella zoster if they are not immune.
Osteoporosis is a particularly difficult problem in post-menopausal women who require long-term corticosteroids. There is evidence that both sex hormone replacement therapy and bisphosphonates protect the bones in this setting (see p. 1028).
EBM
PROLONGED GLUCOCORTICOID THERAPY-prevention of osteoporosis
'Patients receiving prolonged courses of immunosuppressive glucocorticoid therapy (i.e. > 6 months) should be considered for primary prevention of osteoporotic fractures with either calcium and vitamin D or bisphosphonate drugs. This is especially important in post-menopausal women and in patients with pre-existing osteopenia. Calcitonin is an effective but less practical alternative therapy.'
Homik J, Cranney A, Shea B, et al. Bisphosphonates for steroid-induced osteoporosis (Cochrane Review). Cochrane Library, issue 1, 2001.
Homik J, Suarez-Almazor ME, Shea B, et al. Calcium and vitamin D for corticosteroid-induced osteoporosis (Cochrane Review). Cochrane Library, issue 1, 2001.
Further information: www.cochrane.co.uk
Withdrawal of glucocorticoid therapy
16.32 ADVICE TO PATIENTS ON GLUCOCORTICOID REPLACEMENT
Intercurrent stress
e.g. Febrile illness-double dose of hydrocortisone
Surgery
Minor operation-hydrocortisone 100 mg i.m. with premedication
Major operation-hydrocortisone 100 mg 6-hourly for 24 hours, then 50 mg i.m. 6-hourly until ready to take tablets
Vomiting
Must have parenteral hydrocortisone if unable to take by mouth
Steroid card
Patient should carry this at all times. Should give information regarding diagnosis, steroid, dose and doctor
Bracelet
Patients should be encouraged to buy one of these and have it engraved with the diagnosis and a reference and phone number for a centrally held database
All glucocorticoid therapy, even if inhaled or applied topically, can suppress the hypothalamic-pituitary-adrenal axis (HPA). In practice, this is only likely to result in a crisis due to adrenal insufficiency if glucocorticoids have been administered orally or systemically for longer than 3 weeks, if repeated courses have been prescribed within the previous year, or if the dose is higher than the equivalent of 40 mg prednisolone per day. In these circumstances, the drug, when it is no longer required for the underlying condition, must be withdrawn slowly with the rate dictated by the duration of treatment. If glucocorticoid therapy has been prolonged, then it may take many months for the HPA to recover. All patients must be advised to avoid sudden drug withdrawal. They should be issued with a steroid card and/or wear an engraved bracelet (see
It should help the axis to recover if there is no exogenous glucocorticoid present during the nocturnal surge in ACTH secretion, i.e. if the glucocorticoid is given in the morning or even on alternate days. Giving ACTH to stimulate adrenal recovery is of no value as the pituitary remains suppressed.
In patients who have received glucocorticoids for longer than a few weeks, it is often valuable to confirm that the HPA is recovering during glucocorticoid withdrawal. Once the dose of glucocorticoid is reduced to a minimum (e.g. 4 mg prednisolone or 0.5 mg dexamethasone per day), then measure plasma cortisol at 0900 hrs before the next dose. If this is detectable, then perform an ACTH stimulation test (see p. 727) to confirm that glucocorticoids can be withdrawn completely.
Spontaneous, non-iatrogenic Cushing's syndrome
Aetiology
Causes are shown in
Clinical features
page 722
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16.33 CLASSIFICATION OF CUSHING'S SYNDROME
ACTH-dependent
Pituitary-dependent bilateral adrenal hyperplasia (i.e. Cushing's disease)
Ectopic ACTH syndrome (e.g. bronchial carcinoid, small-cell lung carcinoma, pancreatic carcinoma)
latrogenic (ACTH therapy)
Non-ACTH-dependent
latrogenic (chronic glucocorticoid therapy, e.g. for asthma)
Adrenal adenoma
Adrenal carcinoma
Pseudo-Cushing's syndrome, i.e. cortisol excess as part of another illness
Alcohol excess (biochemical and clinical features)
Major depressive illness (biochemical features only, some clinical overlap-see p. 262)
Primary obesity (mild biochemical features, some clinical overlap)
The diverse manifestations of glucocorticoid excess are indicated in Figure 16.17. Many of these are not specific to Cushing's syndrome and, because spontaneous Cushing's syndrome is rare, the positive predictive value of any one feature alone is low. Moreover, some common disorders can be confused with Cushing's syndrome because they are associated with alterations in cortisol secretion: for example, obesity and depression (see
Some clinical features are more common in ectopic ACTH syndrome. Unlike pituitary tumours secreting ACTH, ectopic tumours have no residual negative feedback sensitivity to cortisol, and both ACTH and cortisol levels are usually higher than with other causes. Very high ACTH levels are associated with marked pigmentation. Very high cortisol levels overcome the barrier of 11ß-HSD in the kidney (see p. 720) and cause hypokalaemic alkalosis. Hypokalaemia aggravates both myopathy and hyperglycaemia (by inhibiting insulin secretion). When the tumour secreting ACTH is malignant (e.g. pancreatic or small-cell lung carcinomas), then the onset is usually rapid and may be associated with cachexia. For these reasons, the classical features of Cushing's syndrome are less common in ectopic ACTH syndrome, and if present suggest that a benign tumour (e.g. bronchial carcinoid) is responsible.
In Cushing's disease the pituitary tumour is almost always a microadenoma (< style="mso-spacerun:yes">
Figure 16.17 Cushing's syndrome. A Clinical features common to all causes. B A patient with Cushing's disease before treatment. C The same patient 1 year after the successful removal of an ACTH-secreting pituitary microadenoma by trans-sphenoidal surgery.
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Investigations
The large number of tests available for Cushing's syndrome reflects the fact that no single test is infallible and several are needed to establish the diagnosis. It is useful to divide investigations into those which establish whether the patient has Cushing's syndrome, and those which are used subsequently to elucidate the aetiology.
A recommended sequence of investigations is shown in Figure 16.18 and the interpretation of these tests is shown in
Figure 16.18 Sequence of investigations in suspected spontaneous Cushing's syndrome. (CRH = corticotrophin-releasing hormone)
Does the patient have Cushing's syndrome?
Plasma cortisol levels are highly variable in healthy subjects so that patients with Cushing's syndrome often have daytime values within the normal range. For this reason, there is no place for a random measurement of daytime plasma cortisol in the clinic in either supporting or refuting a diagnosis of Cushing's syndrome. Cushing's syndrome is confirmed by the demonstration of increased secretion of cortisol (measured in urine) which fails to suppress with relatively low doses of dexamethasone (measured in plasma or urine) (see
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16.34 TESTS FOR CUSHING'S SYNDROME
Test Protocol Interpretation
Urine free cortisol 24-hr timed collection (some centres use overnight collections corrected for creatinine)
Overnight dexamethasone suppression test 1 mg orally at
Diurnal rhythm of plasma cortisol Sample for cortisol at 0900 hrs and at 2300 hrs (requires acclimatisation to ward for at least 48 hrs) Evening level > 75% of morning level in Cushing's
Low-dose dexamethasone suppression test 0.5 mg 6-hourly for 48 hrs; sample 24-hr urine cortisol during second day and 0900-hr plasma cortisol after 48 hrs Urine cortisol <>
Insulin tolerance test See Box 16.47, page 738 Peak plasma cortisol > 120% of baseline excludes Cushing's
High-dose dexamethasone suppression test 2 mg 6-hourly for 48 hrs; sample 24-hr urine cortisol at baseline and during second day Urine cortisol <> 50% basal suggests ectopic ACTH syndrome
Corticotrophin-releasing hormone test 100 µg ovine CRH i.v. and monitor plasma ACTH and cortisol for 2 hrs Peak plasma cortisol > 120% and/or ACTH > 150% of basal values suggests pituitary-dependent disease; lesser responses suggest ectopic ACTH syndrome
Inferior petrosal sinus sampling Catheters placed in both inferior petrosal sinuses and simultaneous sampling from these and peripheral blood for ACTH; may be repeated 10 minutes after peripheral CRH injection ACTH in either petrosal sinus > 200% peripheral
ACTH suggests pituitary-dependent disease;
<>
Dexamethasone is used for suppression testing because, unlike prednisolone, it does not cross-react in radioimmunoassays for cortisol. However, metabolism of dexamethasone may be altered by drugs, e.g. enzyme-inducers such as oestrogen or phenytoin. Also, the hypothalamic-pituitary-adrenal axis may 'escape' from suppression by dexamethasone if a more potent influence such as psychological stress supervenes.
There is a rare syndrome of cyclical Cushing's syndrome in which the excessive secretion of cortisol is episodic. If there is a strong clinical suspicion of Cushing's syndrome but initial screening tests are normal, then weekly 24-hour urine cortisol measurements for up to 3 months are sometimes justified.
What is the cause of the Cushing's syndrome?
Once the presence of Cushing's syndrome is established, measurement of plasma ACTH is key in establishing the differential diagnosis. In the presence of excess cortisol secretion, an undetectable ACTH indicates an adrenal tumour while any detectable ACTH is pathological. Tests to discriminate pituitary from ectopic sources of ACTH rely on the fact that pituitary tumours, but not ectopic tumours, retain some features of normal regulation of ACTH secretion. Thus, in Cushing's disease ACTH secretion is suppressed by dexamethasone, albeit at a higher dose than in health, and ACTH is stimulated by corticotrophin-releasing hormone (CRH).
Techniques for localisation of tumours secreting ACTH or cortisol are listed in Figure 16.18. MRI with gadolinium contrast enhancement detects around 70% of pituitary microadenomas secreting ACTH. Venous catheterisation with measurement of inferior petrosal sinus ACTH (i.e. draining directly from the pituitary) may be helpful in confirming Cushing's disease if the MRI does not show a microadenoma. CT or MRI detects most adrenal adenomas. Adrenal carcinomas are usually large (> 5 cm). If CT does not demonstrate a unilateral tumour, then lateralisation may be possible either with selective adrenal vein catheterisation and sampling for cortisol, or by functional adrenal scanning using 75selenium-labelled cholesterol.
Management
This is essential, as untreated Cushing's syndrome has a 50% 5-year mortality. Most patients are treated surgically with medical therapy given for a few weeks prior to operation. The type of surgery depends on the cause.
Medical therapy. A number of drugs are used to inhibit corticosteroid biosynthesis, including metyrapone, aminoglutethimide and ketoconazole. The dose of these agents is best titrated against 24-hour urine free cortisol.
Cushing's disease. Trans-sphenoidal surgery with selective removal of the adenoma is the treatment of choice. Experienced surgeons can identify microadenomas which were not detected by MRI and cure about 80% of patients. If the operation is unsuccessful or the diagnosis is not certain, then bilateral adrenalectomy is an alternative.
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If bilateral adrenalectomy is used in patients with pituitary-dependent Cushing's syndrome, then there is a risk that the pituitary tumour will grow in the absence of the negative feedback suppression previously provided by the elevated cortisol levels. This can result in Nelson's syndrome, with an aggressive pituitary macroadenoma and very high ACTH levels causing pigmentation. Nelson's syndrome can be prevented by pituitary irradiation.
External pituitary irradiation alone is of little value in adults but is surprisingly effective in children with Cushing's disease.
Adrenal tumours. Adrenal adenomas are removed via laparoscopy or a loin incision. Adrenal carcinomas are resected if possible, the tumour bed irradiated and the patient given the adrenolytic drug o',p'-DDD (mitotane).
Ectopic ACTH syndrome. Benign tumours causing this syndrome (e.g. bronchial carcinoid) should be removed. During treatment or palliation of other malignancies, it is important to reduce the severity of the Cushing's syndrome using medical therapy (see above).
ADRENAL INSUFFICIENCY
Adrenal insufficiency results from inadequate secretion of cortisol and/or aldosterone. It is potentially fatal and notoriously variable in its presentation. A high index of suspicion is therefore required in patients with unexplained fatigue, hyponatraemia or hypotension.
Aetiology
Causes are shown in
16.35 CAUSES OF ADRENOCORTICAL INSUFFICIENCY
Secondary (?ACTH)
Withdrawal of suppressive glucocorticoid therapy
Hypothalamic or pituitary disease
Primary (?ACTH)
Addison's disease
Common causes
Autoimmune
Sporadic
Polyglandular syndromes (see p. 687)
Tuberculosis
HIV/AIDS
Metastatic carcinomas
Bilateral adrenalectomy
Rare causes
Lymphoma
Intra-adrenal haemorrhage (Waterhouse-Friedrichsen syndrome following meningococcal septicaemia)
Amyloidosis
Haemochromatosis
Corticosteroid biosynthetic enzyme defects
Congenital adrenal hyperplasias
Drugs
Aminoglutethimide, metyrapone, ketoconazole, etomidate etc.
Clinical features
Features of adrenal insufficiency are shown in
16.36 CLINICAL AND BIOCHEMICAL FEATURES OF ADRENAL INSUFFICIENCY
Glucocorticoid insufficiency Mineralocorticoid insufficiency ACTH excess Adrenal androgen insufficiency
Withdrawal of exogenous glucocorticoid v X X v
Hypopituitarism v X X v
Addison's disease v v v v
Congenital adrenal hyperplasia (21-OHase deficiency) v v v X
Clinical features Weight loss
Malaise
Weakness
Anorexia
Nausea
Vomiting
Gastrointestinal-diarrhoea or constipation
Postural hypotension
Shock
Hypoglycaemia
Hyponatraemia
Hypercalcaemia Hypotension
Shock
Hyponatraemia
Hyperkalaemia Pigmentation
Sun-exposed areas
Pressure areas, e.g. elbows, knees
Palmar creases,
knuckles
Mucous membranes
Conjunctivae
Recent scars Decreased body hair and loss of libido, especially in female
page 726
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Patients may present with chronic features and/or in acute circulatory shock. With a chronic presentation, initial symptoms are often misdiagnosed (e.g. as chronic fatigue syndrome or depression). Adrenocortical insufficiency should also be considered in patients with hyponatraemia, even in the absence of symptoms (see Ch. 9). Vitiligo occurs in 10-20% of patients with autoimmune Addison's disease (see p. 684).
Features of an acute adrenal crisis include circulatory shock with severe hypotension, hyponatraemia, hyperkalaemia and, in some instances, hypoglycaemia and hypercalcaemia. Muscle cramps, nausea, vomiting, diarrhoea and unexplained fever may be present. The crisis is often precipitated by intercurrent disease, surgery or infection.
Investigations
In patients presenting with chronic illness the investigations below should be performed before any treatment. In patients with suspected acute adrenal crisis treatment should not be delayed pending results. A random blood sample should be stored for measurement of cortisol, and it may be appropriate to spend 30 minutes performing a short ACTH stimulation test (see Box 16.37), but investigations may need to be performed after recovery.
Assessment of glucocorticoids
Random plasma cortisol is usually low in patients with adrenal insufficiency, but it may be within the normal reference range yet inappropriately low for a seriously ill patient. Random measurement of plasma cortisol cannot therefore be used to confirm or refute the diagnosis unless the value is high, i.e. > 550 nmol/l.
16.37 ACTH STIMULATION TEST
Use
Diagnosis of primary or secondary adrenal insufficiency
Assessment of hypothalamic-pituitary-adrenal axis in patients taking suppressive glucocorticoid therapy
Relies on ACTH-dependent adrenal atrophy in secondary adrenal insufficiency, so may not detect acute ACTH deficiency (e.g. in pituitary apoplexy, see p. 736)
Dose
250 µg ACTH1-24 (Synacthen) by i.m. injection at any time of day
Blood samples
0 and 30 minutes for plasma cortisol
0 minutes also for ACTH (on ice) if Addison's disease is being considered (i.e. patient not known to have pituitary disease or to be taking exogenous glucocorticoids)
Results
Normal subjects plasma cortisol > 550 nmol/l either at baseline or at 30 minutes
Incremental change in cortisol is not a criterion
More useful is the short ACTH stimulation test (also called the tetracosactide or short Synacthen test) described in
In a patient who is already receiving glucocorticoids, the short ACTH stimulation test can be performed first thing in the morning > 12 hours after the last dose of glucocorticoid, or the treatment can be changed to a synthetic steroid such as dexamethasone (0.75 mg daily), which does not cross-react in the plasma cortisol radioimmunoassay.
Assessment of mineralocorticoids
Plasma electrolyte measurements are insufficient to assess mineralocorticoid secretion in patients with suspected Addison's disease. Hyponatraemia occurs in both aldosterone and cortisol deficiency (see
Other tests to establish the cause
Patients with unexplained secondary adrenocortical insufficiency should be investigated as described in the section on pituitary disease on page 736. In patients with elevated ACTH, further tests are required to establish the cause of Addison's disease. In those who have autoimmune adrenal failure, antibodies can often be measured against steroid-secreting cells (adrenal and gonad), thyroid antigens, pancreatic ß cells and parietal cells. Thyroid function tests, full blood count (to screen for pernicious anaemia), plasma glucose, and tests of gonadal function (see p. 705) and serum calcium should be performed. Other causes of adrenocortical disease are usually obvious clinically, particularly if health is not fully restored by corticosteroid replacement therapy. Tuberculosis causes adrenal calcification, visible on plain radiograph or ultrasound scan. A chest radiograph and early morning urine for culture should also be taken. An HIV test may be appropriate if risk factors for infection are present. Imaging of the adrenals by CT or MRI to identify metastatic malignancy may also be appropriate.
Management
page 727
page 728
Patients with adrenocortical insufficiency always need glucocorticoid replacement therapy and usually, but not always, mineralocorticoid. Other treatments depend on the underlying cause.
Glucocorticoid replacement
Cortisol (hydrocortisone) is the drug of choice. In the past, cortisone acetate was given but this has to be converted to cortisol in the liver and in some patients this process may be impaired. In someone who is not critically ill cortisol should be given by mouth, 15 mg on waking and 5 mg at ~1800 hrs. The precise dose may need to be adjusted for the individual patient, but this is subjective. Excess weight gain usually indicates over-replacement, whilst persistent lethargy may be due to an inadequate dose. Measurement of plasma cortisol levels is unhelpful, because the dynamic interaction between cortisol and glucocorticoid receptors is not predicted by measurements such as the maximum or minimum plasma cortisol level after each dose. Advice to patients dependent on glucocorticoid replacement is given in
An adrenal crisis is a medical emergency and requires intravenous hydrocortisone succinate 100 mg and intravenous fluid (normal saline and 10% dextrose for hypoglycaemia). Parenteral hydrocortisone should be continued (100 mg i.m. 6-hourly) until gastrointestinal symptoms abate before starting oral therapy. The precipitating cause should be sought and, if possible, treated.
Mineralocorticoid replacement
Aldosterone is not readily available and fludrocortisone (i.e. 9a-fluoro-hydrocortisone) is the mineralocorticoid used. The halogen group prevents fludrocortisone from being metabolised by 11ß-HSD and thereby confers a longer half-life and access to mineralocorticoid receptors. The usual dose is 0.05-0.1 mg daily. Adequacy of replacement can be assessed objectively by measurement of blood pressure, plasma electrolytes and plasma renin activity.
In adrenal crisis, however, rapid replacement of sodium deficiency is more important than administration of fludrocortisone. Intravenous saline should be infused as required to normalise haemodynamic indices. In severe hyponatraemia (< style="mso-spacerun:yes">
EBM
HRT IN ADRENOCORTICAL INSUFFICIENCY-use of adrenal androgens
'Glucocorticoid and mineralocorticoid replacement therapy have not been studied in RCTs. One RCT in 39 patients shows that replacement therapy with the adrenal androgen dehydroepiandrosterone (DHEA) improves mood and fatigue in patients with Addison's disease.'
Hunt PJ, Gurnell EM, Huppert FA, et al. Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison's disease in a randomized, double blind trial. J Clin Endocrinol Metab 2000; 85:4650-4656.
MINERALOCORTICOID EXCESS AND PRIMARY HYPERALDOSTERONISM
Aetiology
Causes of excessive activation of mineralocorticoid receptors are shown in
The prevalence of primary hyperaldosteronism is controversial. If only hypertensive patients with hypokalaemia are investigated, then fewer than 1% of patients with hypertension will be found to have primary hyperaldosteronism. Around half of these have an adrenal adenoma secreting aldosterone (
16.38 CAUSES OF MINERALOCORTICOID EXCESS
With renin high and aldosterone high (secondary hyperaldosteronism)
E.g. diuretic therapy, cardiac failure, liver failure, nephrotic syndrome, renal artery stenosis
With renin low and aldosterone high (primary hyperaldosteronism)
Adrenal adenoma secreting aldosterone (
Idiopathic bilateral adrenal hyperplasia
Glucocorticoid suppressible hyperaldosteronism (rare)
With renin low and aldosterone low (rare)
Ectopic ACTH syndrome
Liquorice misuse (inhibition of 11ß-HSD)
Liddle's syndrome
11-deoxycorticosterone-secreting adrenal tumour
Rare forms of congenital adrenal hyperplasia and 11ß-HSD deficiency
page 728
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Glucocorticoid suppressible hyperaldosteronism is a rare autosomal dominant disorder caused by translocation of two homologous genes, such that the ACTH-regulated promoter of one gene (11ß-hydroxylase) is linked with the coding exons of another (aldosterone synthase-see Fig. 16.16, p. 721). The result is inappropriate secretion of aldosterone from the adrenal in response to normal levels of ACTH, despite suppression of renin and angiotensin II levels. Treatment is by suppression of ACTH, e.g. with dexamethasone.
In a few conditions, the mineralocorticoid receptor pathway in the distal nephron is activated even though aldosterone levels are low. Either the receptors are activated by cortisol (ectopic ACTH syndrome or 11ß-HSD deficiency) or 11-deoxycorticosterone (rare congenital adrenal hyperplasias or tumours), or post-receptor mechanisms are inappropriately activated (e.g. the epithelial sodium channel in Liddle's syndrome).
Clinical features
Many patients are asymptomatic, but they may have features of sodium retention or potassium loss. Sodium retention causes oedema, while hypokalaemia causes muscle weakness (or even paralysis, especially in Chinese), polyuria (secondary to renal tubular damage which produces nephrogenic diabetes insipidus), and occasionally tetany (because of associated metabolic alkalosis and low ionised calcium). Hypertension is almost invariable in primary hyperaldosteronism.
Investigations
Biochemical
Plasma electrolytes may show hypokalaemia and elevated bicarbonate. Plasma sodium is usually towards the upper end of the normal range in primary hyperaldosteronism but is characteristically low in secondary hyperaldosteronism (because low plasma volume stimulates ADH release and high angiotensin II levels stimulate thirst).
The key measurements are plasma renin activity and aldosterone (see
If renin is low and aldosterone levels are high, then
Localisation
The only cause of primary hyperaldosteronism which is usually treated by surgery is
Figure 16.19
page 729
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Management
The mineralocorticoid receptor antagonist spironolactone is valuable in treating both hypokalaemia and hypertension in all forms of mineralocorticoid excess. High doses (up to 400 mg/day) may be required. Up to 20% of males develop gynaecomastia on spironolactone. Amiloride (10-40 mg/day), which blocks the epithelial sodium channel regulated by aldosterone, can be used when such problems arise.
In patients with
PHAEOCHROMOCYTOMA
This is a rare tumour of chromaffin tissue which secretes catecholamines and is responsible for less than 0.1% of cases of hypertension. There is a useful 'rule of tens' in this condition: ~10% are malignant; ~10% are extra-adrenal (i.e. elsewhere in the sympathetic chain); and ~10% are familial.
Clinical features
These depend on the pattern of catecholamine secretion and are listed in
Some patients may present with a complication of the hypertension, e.g. accelerated phase hypertension, stroke, myocardial infarction, left ventricular failure or hypertensive retinopathy. Occasionally, patients are hypotensive (especially those with dopamine-secreting tumours). There may be features of the familial syndromes associated with phaeochromocytoma including neurofibromatosis, von Hippel-Lindau syndrome and multiple endocrine neoplasia type II (see p. 688).
Investigations
Biochemical
16.39 CLINICAL FEATURES OF PHAEOCHROMOCYTOMA
Hypertension (usually paroxysmal; often postural drop of blood pressure)
Attacks with
Pallor (occasionally flushing)
Palpitations
Sweating
Headache
Anxiety (fear of death-angor animi)
Abdominal pain, vomiting
Constipation
Weight loss
Glucose intolerance
Excessive secretion of catecholamines can be confirmed by measuring the hormones (adrenaline, noradrenaline and dopamine) in plasma or their metabolites (e.g. vallinylmandelic acid, VMA; conjugated metanephrine and normetanephrine) in urine. However, catecholamine secretion is usually paroxysmal and sometimes the paroxysms are infrequent; in a patient with classical symptoms, phaeochromocytoma can only be excluded if the 24-hour urinary catecholamine excretion is normal on a day on which symptoms have occurred.
Increased urinary catecholamine excretion occurs in stressed patients (e.g. after myocardial infarction or major surgery) and is induced by some drugs (notably ß-blockers and antidepressants). For this reason, a suppression test may be valuable. Normal adrenomedullary secretion is suppressed by administration of drugs which interfere with sympathetic outflow, such as clonidine or pentolinium. In phaeochromocytoma these drugs do not suppress plasma catecholamines. Provocative tests of catecholamine release should not be used.
Localisation
Phaeochromocytomas are usually identified by abdominal CT (see Fig. 16.20). Difficulty can arise with the localisation of extra-adrenal tumours. Scintigraphy using meta-iodobenzyl guanidine (MIBG) can be useful; MIBG labelled with radioactive iodine is taken up by both benign and malignant phaeochromocytomas. If the tumour cannot be localised, then selective venous sampling with measurement of plasma noradrenaline may be required.
Figure 16.20 CT of abdomen showing large right phaeochromocytoma (arrows).
Management
Medical therapy is required to prepare the patient for surgery, preferably for a minimum of 6 weeks to allow restoration of normal plasma volume. The most useful drug in the face of very high circulating catecholamines is the a-blocker phenoxybenzamine (10-20 mg orally 6-8-hourly) because it is a non-competitive antagonist, unlike prazosin or doxazosin. If a-blockade produces a marked tachycardia, then a ß-blocker (e.g. propranolol) or combined a- and ß-antagonist (e.g. labetalol) can be added. On no account should the ß-antagonist be given before the a-antagonist, as vasoconstriction due to unopposed a-adrenoceptor activity may occur with a further increase in blood pressure.
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During surgery sodium nitroprusside and the short-acting a-antagonist phentolamine are useful in controlling hypertensive episodes which may result from anaesthetic induction or tumour mobilisation. Post-operative hypotension may occur and require volume expansion and, very occasionally, noradrenaline infusion. This is uncommon if the patient has been prepared with phenoxybenzamine for at least 6 weeks.
CONGENITAL ADRENAL HYPERPLASIA
Aetiology and clinical features
Defects in the cortisol biosynthetic pathway result in impaired negative feedback and increased ACTH secretion. ACTH then stimulates the production of steroids up to the enzyme block. This produces adrenal hyperplasia and a combination of clinical features which depend on the severity and site of the defect in biosynthesis. All of these enzyme abnormalities are inherited as autosomal recessive traits. There is therefore a 1:4 chance that the sibling of an affected child will also have the disease, but a low risk of passing the disease to the next generation.
Figure 16.21 Manifestations of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The enzyme block leads to insufficiency of hormones 'distal' to the block (glucocorticoids and mineralocorticoids; see Box 16.36, p. 726), and impaired negative feedback suppression of ACTH leading to accumulation of precursor hormones 'proximal' to the block which 'spill over' into the adrenal androgen biosynthetic pathway. The severity of the mutation in the 21-hydroxylase (21 OHase) gene determines which features are present. The most severely affected 'classical' patients present in infancy (salt-wasting in boys; ambiguous genitalia in girls). The least severely affected 'late-onset' patients present as adults (hirsutism in women). (DHEA = dehydroepiandrosterone)
The most common enzyme defect is 21-hydroxylase deficiency. In about one-third of cases this defect is severe, producing all of the features outlined in Figure 16.21. In the other two-thirds, mineralocorticoid secretion is not affected but there may be features of cortisol insufficiency and/or androgen excess. Sometimes the mildest enzyme defects are not apparent until adult life, when females may present with amenorrhoea and/or hirsutism (see p. 709). This is called 'non-classical' or 'late-onset' congenital adrenal hyperplasia.
Defects of all the other enzymes have been described but are much rarer. Both 17-hydroxylase and 11ß-hydroxylase deficiency may produce hypertension due to excess production of 11-deoxycorticosterone, a mineralocorticoid.
Investigations
High levels of plasma 17OH-progesterone are found in 21-hydroxylase deficiency. In late-onset cases this may only be demonstrated after ACTH administration. To avoid salt-wasting crises in infancy, 17OH-progesterone is routinely measured in heel prick blood spot samples taken from all infants in the first week of life. Assessment is otherwise as described for adrenal insufficiency on page 726.
In siblings of affected children, antenatal genetic diagnosis can be made by amniocentesis or chorionic villous sampling. This allows prevention of virilisation of affected female fetuses by administration of dexamethasone to the mother.
Management
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ISSUES IN OLDER PEOPLE
THE ADRENAL GLANDS
Presentation of adrenal disease is often insidious, and may be especially difficult to spot in elderly patients with multiple pathology.
Anti-inflammatory glucocorticoid therapy is especially hazardous in older patients, who are relatively immunocompromised and susceptible to osteoporosis, hyperglycaemia etc.
Poor compliance with glucocorticoid therapy, combined with increased prevalence of 'stressful' illness in the elderly, increases the risk of adrenal crisis. Careful explanation of the treatment, and provision of a steroid card and/or 'medicalert' bracelet are important.
The aim is to replace deficient corticosteroids, and also suppress ACTH and hence adrenal androgen production. In contrast with glucocorticoid replacement therapy in other forms of cortisol deficiency (see p. 728), it is usual to give 'reverse' treatment, i.e. a larger dose of a long-acting synthetic glucocorticoid just before going to bed to suppress the early morning ACTH peak, and a smaller dose in the morning. A careful balance is required between adequate suppression of adrenal androgen excess and excessive glucocorticoid replacement resulting in features of Cushing's syndrome. In children, growth velocity is the most useful measurement since either under- or over-replacement with glucocorticoids suppresses growth. In adults, clinical features (menstrual cycle, hirsutism, weight gain, blood pressure) and biochemical profiles (plasma renin activity and 17OH-progesterone levels) provide a guide.
Patients with late-onset 21-hydroxylase deficiency may not require corticosteroid replacement. If hirsutism is the main problem, anti-androgen therapy may be just as effective (see p. 712).
pages 721 - 732
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Home > 2 SYSTEM-BASED DISEASES > 16 Endocrine disease > THE ENDOCRINE PANCREAS AND GASTROINTESTINAL TRACT
THE ENDOCRINE PANCREAS AND GASTROINTESTINAL TRACT
A series of hormones are secreted from cells distributed throughout the gastrointestinal tract and pancreas. Functional anatomy is described in Chapters 15 and 17. Pathology of these hormones is listed in
16.40 CLASSIFICATION OF ENDOCRINE DISEASES OF THE PANCREAS AND GASTROINTESTINAL TRACT
Primary Secondary
Hormone excess Insulinoma
Gastrinoma (Zollinger-Ellison syndrome)
Carcinoid syndrome (secretion of 5-hydroxytryptamine (5-HT, serotonin) etc.)
Glucagonoma
VIPoma
Somatostatinoma Hypergastrinaemia of achlorhydria
Hormone deficiency Diabetes mellitus
Hormone hypersensitivity Rare, e.g. pseudoacromegaly
Hormone resistance Insulin resistance syndromes (e.g. type 2 diabetes mellitus, lipodystrophy, leprechaunism)
Non-functioning tumours Pancreatic carcinoma
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Home > 2 SYSTEM-BASED DISEASES > 16 Endocrine disease > MAJOR MANIFESTATIONS OF DISEASE OF THE ENDOCRINE PANCREAS
MAJOR MANIFESTATIONS OF DISEASE OF THE ENDOCRINE PANCREAS
SPONTANEOUS HYPOGLYCAEMIA
Hypoglycaemia is most commonly seen as a side-effect of treatment with insulin or sulphonylurea drugs in patients with diabetes mellitus. In a diabetic patient it is most usefully defined as a plasma glucose < style="mso-spacerun:yes">
Causes of spontaneous hypoglycaemia are shown in Figure 16.22. In all these conditions, hypoglycaemia is aggravated by fasting. Causes can be classified according to the circulating insulin and/or C-peptide concentrations. The detection of insulin in plasma in the presence of plasma glucose < style="mso-spacerun:yes">
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Figure 16.22 Differential diagnosis of spontaneous hypoglycaemia. * Plasma glucose 2.2-2.5 mmol/l with undetectable insulin and no symptoms is likely to be normal, but with detectable insulin and/or symptoms is likely to be pathological as for plasma glucose <>
Hypoglycaemia may also occur without fasting as part of a dumping syndrome in patients with previous gastric surgery, in whom rapid small bowel absorption of oral carbohydrate is thought to induce an inappropriately brisk secretion of insulin. However, it is now thought that a more important mechanism for symptoms of dumping is the osmotic effect of rapid delivery of oral carbohydrate to the small bowel (see p. 786). Indeed, whether hypoglycaemia occurs at all in the dumping syndrome has been questioned. Similarly, at one time, 'reactive' hypoglycaemia was commonly diagnosed in patients reporting post-prandial symptoms including sweating, light-headedness and lethargy. In some of these patients, plasma glucose falls below 3.0 mmol/l during a glucose tolerance test. However, this is also an occasional finding in healthy subjects undergoing glucose tolerance tests and is poorly predictive of symptoms.
Clinical features
Patients usually present either in the outpatient clinic with a history of unexplained 'attacks' or as an acute emergency with convulsions, collapse or confusion.
Clinical features are described in the section on insulin-induced hypoglycaemia on page 652. Like insulin-treated diabetic patients with recurrent hypoglycaemia, patients with chronic spontaneous hypoglycaemia often have attenuated autonomic responses, and may present with a wide variety of features of neuroglycopenia, including odd behaviour and convulsions. Symptoms are almost always episodic, and key questions include whether they are more frequent on fasting or exercise, and whether they are relieved by consumption of refined carbohydrate.
Investigations
Establishing the diagnosis
Hypoglycaemia is confirmed by a venous plasma glucose concentration < style="mso-spacerun:yes">
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In an acute presentation, suspected hypoglycaemia is usually tested first of all with capillary blood glucose strips and automated meters, used for monitoring glycaemic control in diabetic patients. However, while these tests are sufficient to exclude hypoglycaemia in the presence of symptoms, they do not confirm it as they are not sufficiently accurate in the hypoglycaemic range. Also, whole capillary blood glucose concentrations are 15% lower than plasma glucose concentrations. In patients not known to be receiving insulin or sulphonylurea therapy, hypoglycaemia must always be confirmed before treatment is administered by formal laboratory glucose measurement in a venous or capillary sample. At the same time, a blood sample should be immediately chilled on ice and centrifuged promptly for later measurement of insulin, C-peptide and, if appropriate, sulphonylurea levels. Taking these samples during an acute presentation prevents subsequent unnecessary dynamic tests and is of medicolegal importance in cases where poisoning is suspected.
In patients with a chronic history, the same blood samples must be obtained during an episode of typical symptoms. Hypoglycaemia can be provoked by fasting (either overnight or, rarely, for up to 72 hours). In suspected insulinoma, a C-peptide suppression test (involving measurement of C-peptide during insulin-induced hypoglycaemia) may be helpful.
In patients with suspected dumping syndrome or reactive hypoglycaemia, oral glucose tolerance tests are no longer considered helpful (see above). It is sometimes appropriate to measure plasma glucose following a standard meal test.
Further tests
These depend on the suspected cause (see Fig. 16.22). Insulinomas in the pancreas are usually small (< style="mso-spacerun:yes">
Management
In acute hypoglycaemia, treatment should be administered as soon as blood samples have been obtained. Intravenous 50% dextrose 30-50 ml is effective in the short term, and should be followed on recovery with oral carbohydrate. Continuous dextrose infusion may be necessary, especially in sulphonylurea poisoning. Intramuscular glucagon (1 mg) stimulates hepatic glucose release but is ineffective in low-insulin hypoglycaemia.
Chronic recurrent hypoglycaemia in insulin-secreting tumours can be treated by diet (regular oral carbohydrate consumption) combined with inhibitors of insulin secretion (diazoxide, thiazide diuretics or somatostatin analogues). Insulinomas are usually resected.
pages 732 - 734
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Home > 2 SYSTEM-BASED DISEASES > 16 Endocrine disease > THE HYPOTHALAMUS AND THE PITUITARY GLAND
THE HYPOTHALAMUS AND THE PITUITARY GLAND
Diseases of the hypothalamus and pituitary are rare, with an annual incidence of ~
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
Figure 16.23 Anatomical relationships and function of the pituitary and hypothalamus. See also Figure 16.2, page 687. A MRI. (SS = sphenoid sinus; AP = anterior pituitary; OC = optic chiasm; TV = third ventricle; H = hypothalamus; PP = posterior pituitary) B Close-up of the central area of the MRI.
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The anatomy of the pituitary is shown in Figure 16.23 and its numerous functions are shown in Figure 16.2 on page 687. The pituitary gland is enclosed in the sella turcica and bridged over by a fold of dura mater called the diaphragma sellae, with the sphenoidal air sinuses below and the optic chiasm above. The cavernous sinuses are lateral to the pituitary fossa and contain the 3rd, 4th and 6th cranial nerves and the internal carotid arteries. The gland is composed of two lobes, anterior and posterior, and is connected to the hypothalamus by the infundibular stalk, which has portal vessels carrying blood from the median eminence of the hypothalamus to the anterior lobe and nerve fibres to the posterior lobe.
Diseases of the hypothalamus and pituitary are classified in
16.41 CLASSIFICATION OF DISEASES OF THE PITUITARY AND HYPOTHALAMUS
Primary Secondary
Hormone excess
Anterior pituitary Prolactinoma
Acromegaly
Cushing's syndrome
Rare TSH-, LH- and FSHomas Disconnection hyperprolactinaemia
Hypothalamus and posterior pituitary Syndrome of inappropriate antidiuretic hormone (SIADH; see Ch. 9)
Hormone deficiency
Anterior pituitary Hypopituitarism e.g. GnRH deficiency (Kallmann's syndrome)
Hypothalamus and posterior pituitary Cranial diabetes insipidus
Hormone hypersensitivity - -
Hormone resistance Growth hormone resistance (Laron dwarfism)
Nephrogenic diabetes insipidus
Non-functioning tumours Pituitary adenoma
Craniopharyngioma
Metastatic tumours
16.42 INVESTIGATION OF PATIENTS WITH PITUITARY AND HYPOTHALAMIC DISEASE
Identify hypopituitarism
ACTH deficiency
Short ACTH stimulation test (see
Only if uncertainty in interpretation of short ACTH stimulation test (e.g. acute presentation) then insulin tolerance test (see
LH/FSH deficiency
In the male, measure random serum testosterone, LH and FSH
In the pre-menopausal female, ask if she has regular menses
In the post-menopausal female, measure random serum LH and FSH (which would normally be > 30 mU/l)
TSH deficiency
Measure random serum thyroxine
Note that TSH is often detectable in pituitary disease, due to inactive isoforms in the blood
Growth hormone deficiency
(Only investigate if growth hormone replacement therapy is being contemplated; see p. 738)
Measure immediately after exercise
Consider other stimulatory tests (see
Cranial diabetes insipidus
(Only investigate if patient complains of polyuria/polydipsia, which may be masked by ACTH or TSH deficiency)
Exclude other causes with blood glucose, potassium and calcium measurements
Water deprivation test (see
Identify hormone excess
Measure random serum prolactin
Investigate for acromegaly (glucose tolerance test) or Cushing's syndrome (see p. 724) if there are clinical features
Establish the anatomy and diagnosis
Consider visual field testing
Image the pituitary and hypothalamus by MRI or CT
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Investigations
Although pituitary disease presents with diverse manifestations (see below), the approach to the patient is similar in all cases. Clinical assessment is described below. Investigations follow the outline in
Anterior pituitary gland
Tests for hormone excess vary according to the hormone in question. For example, prolactin is not secreted in pulsatile fashion, although it rises with significant mental stress. Assuming that the patient was not distressed by venepuncture, a random measurement of serum prolactin is sufficient to diagnose hyperprolactinaemia. In contrast, growth hormone is secreted in a pulsatile fashion. A high random level does not confirm acromegaly; the diagnosis is only confirmed by failure of growth hormone to be suppressed (by the insulin-induced rise in insulin-like growth factor-1) during an oral glucose tolerance test. Similarly, in suspected ACTH-dependent Cushing's disease (see p. 724), random measurement of plasma cortisol is unreliable and the diagnosis is usually made by a dexamethasone suppression test.
The means of testing for hypopituitarism also differs between hormones. A common test, which is still employed in some centres, involves the simultaneous administration of thyrotrophin-releasing hormone (TRH), gonadotrophin-releasing hormone (GnRH) and insulin (to induce hypoglycaemic stress and stimulate ACTH and growth hormone). However, this is a potentially hazardous procedure and there is evidence that assessment of the target glands for most of these hormones provides equally reliable results. Details of each test are given in the sections on individual glands above and in
Local compression by a large pituitary tumour most commonly results in compression of the optic pathway. The resulting visual field defect can be documented by formal charting (e.g. a Goldman's perimetry chart). Viewing the pituitary gland by MRI reveals 'abnormalities' of the pituitary fossa in as many as 10% of middle-aged patients. It should therefore be performed only if there is a clear biochemical abnormality or in a patient who presents with clinical features of pituitary tumour (see below). Functional imaging (e.g. with radio-labelled octreotide, a somatostatin analogue) is rarely used.
Surgical biopsy is usually only performed as part of a therapeutic operation. Conventional staining identifies pituitary tumours as either chromophobe, acidophil or basophil. Classically, acidophil tumours are associated with growth hormone or prolactin excess, basophil tumours are associated with ACTH hypersecretion, and chromophobe tumours are non-functioning. However, many chromophobe tumours are associated with hormonal excess. Immunohistochemistry using specific antisera against the pituitary hormones is more valuable in identifying the hormone(s) secreted by specific pituitary cells. It is not possible for histology to identify the rare pituitary tumours which regrow rapidly and invade local structures.
Posterior pituitary and hypothalamus
Patients with hypothalamic disease are at risk of anterior pituitary dysfunction and require assessment as above. In addition, these patients may have posterior pituitary dysfunction. Note that the posterior pituitary is rarely affected by pituitary tumours, and dysfunction most commonly occurs following pituitary surgery. In practice, the only posterior pituitary function requiring investigation is deficiency of vasopressin resulting in diabetes insipidus (see p. 744).
pages 734 - 736
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Home > 2 SYSTEM-BASED DISEASES > 16 Endocrine disease > MAJOR MANIFESTATIONS OF HYPOTHALAMIC AND PITUITARY DISEASE
MAJOR MANIFESTATIONS OF HYPOTHALAMIC AND PITUITARY DISEASE
Routes of presentation of pituitary and hypothalamic disease are shown in
HYPOPITUITARISM
Hypopituitarism describes combined deficiency of any of the anterior pituitary hormones. Causes include any pathology of the hypothalamus and pituitary gland, as shown in
Clinical features
16.43 COMMON PRESENTING COMPLAINTS IN HYPOTHALAMIC/PITUITARY DISEASE
(See Fig. 16.24)
Chronic presentations
Secondary amenorrhoea
Galactorrhoea
Visual field defect
Incidental finding on skull radiograph or CT performed for another reason
'Spot' diagnosis of acromegaly or Cushing's syndrome
Short stature
Sexual dysfunction/infertility
Unexplained fatigue (hypopituitarism)
Acute presentations
Pituitary apoplexy (headache, cavernous sinus involvement with diplopia, visual dysfunction, hypopituitarism)
Adrenal insufficiency (shock precipitated by intercurrent illness)
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Figure 16.24 Common symptoms and signs to consider in a patient with suspected pituitary disease.
16.44 CAUSES OF HYPOPITUITARISM
Site of lesion Common deficiencies/causes Rare deficiencies/causes
Hypothalamus
Acquired Craniopharyngioma Sarcoidosis
Head injury Tuberculosis
Surgery
Radiotherapy Langerhans cell histiocytosis
Primary or secondary tumour
Syphilis
Encephalitis
Congenital GnRH (Kallmann's syndrome)
GHRH TRH
CRH
Pituitary
Structural Pituitary tumour Secondary tumour
Surgery
Radiotherapy Post-partum necrosis (Sheehan's syndrome)
Head injury Autoimmune
Local meningioma Haemorrhage (apoplexy)
Haemochromatosis
Functional Anorexia nervosa
Malnutrition
The presentation is highly variable and depends on the underlying lesion. Congenital defects of the hypothalamus usually present with short stature (see p. 707). With progressive lesions of the pituitary there is a characteristic sequence of loss of pituitary hormone secretion. Growth hormone secretion is often the earliest to be lost. In adults, this produces lethargy, muscle weakness and increased fat mass but these features are not obvious in isolation. Next, gonadotrophin (LH and FSH) secretion becomes impaired with, in the male, loss of libido and impotence and, in the female, oligomenorrhoea or amenorrhoea. Later, in the male there may be gynaecomastia and decreased frequency of shaving. In both sexes axillary and pubic hair eventually become sparse or even absent. The skin becomes characteristically finer and wrinkled.
The next hormone to be lost is usually ACTH, resulting in symptoms of cortisol insufficiency. In contrast to primary adrenal insufficiency (see p. 726), angiotensin II-dependent zona glomerulosa function is not lost and hence aldosterone secretion maintains normal plasma potassium. However, there may be postural hypotension and a dilutional hyponatraemia for three reasons:
Failure of vasoconstriction in the absence of cortisol results in pooling of blood in the legs on standing.
Antidiuretic hormone (ADH) release is enhanced by hypotension and cortisol deficiency.
Cortisol is required for normal water excretion by the kidney.
In contrast to the pigmentation of Addison's disease a striking degree of pallor is usually present, principally because of lack of stimulation of melanocytes by ß-lipotrophic hormone (ß-LPH, a fragment of the ACTH precursor peptide) in the skin.
Finally, TSH secretion is lost with consequent secondary hypothyroidism. This contributes further to apathy and cold intolerance. In contrast to primary hypothyroidism frank myxoedema is not seen.
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16.45 COMA IN A PATIENT WITH HYPOPITUITARISM
Possible cause Measure Mechanism
Hypoglycaemia Blood glucose, insulin, cortisol and growth hormone Lack of growth hormone and cortisol causing increased sensitivity to insulin
Water intoxication Plasma Na+, K+ and urea-all low Cortisol and thyroxine required for renal water excretion
Hypothermia Rectal temperature Hypothyroidism
The onset of all of the above symptoms is notoriously insidious. Sometimes, patients present acutely unwell with adrenocortical insufficiency, often precipitated by some mild infection or injury. Untreated severe hypopituitarism eventually results in coma (see
Investigations
The strategy of investigation of pituitary disease is described in
Management
Treatment of acutely ill patients is similar to that described for adrenocortical insufficiency on page 728, except that sodium depletion is not an important component to correct. Chronic hormone replacement therapies are described below. Once the cause of hypopituitarism is established, specific treatment-of a pituitary macroadenoma, for example-may be required.
Cortisol replacement
16.46 TESTS OF GROWTH HORMONE SECRETION
GH levels are commonly undetectable, so a choice from the range of stimulation tests is required:
1 hour after going to sleep
Frequent sampling during sleep
Post-exercise
Insulin-induced hypoglycaemia
Arginine
Note that in pre-pubertal patients, priming with sex steroid is required before stimulation tests are performed.
16.47 INSULIN TOLERANCE TEST
Use
Assessment of the hypothalamic-pituitary-adrenal axis
Assessment of growth hormone deficiency
Indicated when there is doubt from other tests above
Usually performed in specialist centres, especially in children
I.v. glucose and hydrocortisone must be available for resuscitation
Contraindications
Ischaemic heart disease
Epilepsy
Severe hypopituitarism (0800 hrs plasma cortisol <>
Dose
0.15 U/kg body weight soluble insulin i.v.
Aim
To produce adequate hypoglycaemia (signs of neuroglycopenia-tachycardia and sweating-with blood glucose <>
Blood samples
0, 30, 45, 60, 90, 120 minutes for blood glucose, plasma cortisol and growth hormone
Results
Normal subjects cortisol > 550 nmol/l
Hydrocortisone (another name for cortisol) should be given if there is ACTH deficiency. Suitable doses are described in the section on adrenal disease (see p. 727). Mineralocorticoid replacement is not required.
Thyroid hormone replacement
Thyroxine 0.1-0.15 mg once daily should be given. Unlike in primary hypothyroidism, measuring TSH is not helpful in adjusting the replacement dose, because patients with hypopituitarism often secrete glycoproteins which are measured in the TSH assays but are not bioactive. The aim is to maintain serum T4 in the upper part of the reference range. This is required to ensure adequate levels of triiodothyronine (T3), the active hormone, in target tissues, since all T3 in these patients is derived from circulating T4 and not secreted by the thyroid gland. It is dangerous to give thyroid replacement to patients with adrenal insufficiency without first giving glucocorticoid therapy, since this may precipitate adrenal crisis.
Sex hormone replacement
This is indicated if there is gonadotrophin deficiency in men of any age and in pre-menopausal women to restore normal sexual function and to prevent osteoporosis. See page 713.
Growth hormone replacement
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Growth hormone (GH) is administered, by daily subcutaneous self-injection, to young patients with GH deficiency, renal failure or Turner's syndrome to assist them in attaining their growth potential. Until recently, GH was discontinued once the epiphyses had fused, and was not given to adults. However, although hypopituitary adults receiving 'full' replacement with hydrocortisone, thyroxine and sex steroids are usually much improved by these therapies, they often remain lethargic and unwell compared with a healthy population. Recent studies suggest that some of these patients feel better, and have objective improvements in their fat/muscle mass ratios and other metabolic parameters, if they are also given GH replacement. The principal side-effect is sodium retention, manifest as peripheral oedema or carpal tunnel syndrome. For this reason, GH replacement is started at a low dose, with monitoring of the response by measurement of serum insulin-like growth factor-1 (IGF-1) levels.
EBM
ADULT HYPOPITUITARISM-use of growth hormone (GH) replacement therapy
'Short-term (6-12-month) RCTs show that GH improves quality of life and exercise capacity, and reduces central obesity and low-density lipoprotein-cholesterol levels. Beneficial effects on bone mineral density may occur after prolonged therapy but these results could be confounded by "selection bias". Longer-term studies are required to establish effects of GH therapy on cardiovascular disease, fracture, pituitary tumour recurrence and other malignancies. GH therapy is appropriate in patients who are incapacitated by lethargy and whose quality of life improves substantially with such treatment.'
Carroll PV, Christ ER and the members of the Growth Hormone Research Society Scientific Committee. Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. J Clin Endocrinol Metab 1998; 83:382-395.
Further information: www.endocrinology.org
VISUAL FIELD DEFECT
Compression of the neural connections between the retina and occipital cortex by a pituitary tumour leads to impaired visual fields. Although the classical visual field abnormalities associated with compression of the optic chiasm are bitemporal hemianopia or upper quadrantanopia, any type of visual field defect can result from suprasellar extension of a pituitary tumour because it may compress the optic nerve (unilateral loss of acuity or scotoma), the optic chiasm or the optic tract (homonymous hemianopia). Optic atrophy may be apparent on ophthalmoscopy. Diplopia and strabismus may follow pressure on the 3rd, 4th or 6th cranial nerves.
The differential diagnosis of visual field defects is wide, and includes neurological (see p. 1152) and orbital (e.g. glaucoma) disease. In the absence of any other clear explanation for a field defect, however, MRI or CT of the pituitary fossa should be performed to identify a pituitary tumour (see Fig. 16.25).
In patients with radiological evidence of a pituitary tumour, further clinical assessment and investigation should be performed as in
Tumours causing visual field defects require urgent treatment, as described on page 741.
GALACTORRHOEA
Figure 16.25 Pituitary macroadenoma in a patient presenting with a visual field defect. A Bitemporal hemianopia visual field defect to red (red line) and white (black line) light. B Suprasellar extension of large pituitary tumour (sagittal view). C Coronal view of pituitary tumour showing compression of the optic chiasm.
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Galactorrhoea describes lactation without breastfeeding. Some women exhibit physiological galactorrhoea, e.g. failing to stop lactation after ceasing breastfeeding or in response to a new baby in the house. The quantity of milk produced is variable, and it may be observed only by manual expression or in certain circumstances (e.g. in the heat or with nipple stimulation). Pathological galactorrhoea is caused by hyperprolactinaemia. The differential diagnosis is shown in
Clinical assessment
Important points in the history include drug use, recent pregnancy and menstrual history. Significant hyperprolactinaemia usually results in amenorrhoea or irregular menses. Unilateral galactorrhoea may be confused with nipple discharge, and careful breast examination to exclude a malignancy is important. Further assessment follows the principles in Figure 16.24, page 737. Most prolactinomas are, however, microadenomas so that hypopituitarism is relatively uncommon.
Investigations
The upper limit of normal for many assays of serum prolactin is ~500 mU/l. During pregnancy and lactation physiological levels may reach 20 000 mU/l. In non-pregnant and non-lactating patients, levels of 500-1000 mU/l are likely to be induced by stress or drugs, and a repeat measurement is indicated. Levels between 1000 and 5000 mU/l are likely to be due to drugs, a microprolactinoma or disconnection hyperprolactinaemia (due to pressure on the infundibular stalk and loss of dopamine inhibition of prolactin secretion). Levels above 5000 mU/l are highly suggestive of a prolactinoma, and the higher the level, the bigger the tumour. Some macroprolactinomas cause levels as high as 100 000 mU/l.
Patients with prolactin excess should have tests of gonadal function (see p. 705), and T4 and TSH measured to exclude primary hypothyroidism causing TRH-induced prolactin excess. Unless the prolactin falls after withdrawal of relevant drug therapy, a serum prolactin of >1000 mU/l is an indication for an MRI or a CT of the hypothalamus and pituitary. Patients with macroadenomas also need tests for hypopituitarism (see
16.48 CAUSES OF ELEVATED PLASMA PROLACTIN
Drugs
Pathological
Physiological
Stress
Pregnancy
Lactation
Chest wall reflex (e.g. nipple stimulation)
Wet nursing reflex (e.g. baby crying)
Dopamine antagonists
Antipsychotics (phenothiazines and butyrophenones)
Antidepressants
Antiemetics (e.g. metoclopramide, domperidone)
Dopamine-depleting drugs
Reserpine
Methyldopa
Oestrogens
Oral contraceptive pill
Common
Disconnection hyperprolactinaemia (e.g. non-functioning pituitary macroadenoma)
Prolactinoma (usually microadenoma)
Primary hypothyroidism
Polycystic ovarian syndrome
Uncommon
Hypothalamic disease
Pituitary tumour secreting prolactin and growth hormone
Renal failure
Rare
Post-herpes zoster
Ectopic source
MRI will detect all macroadenomas and around 70% of microadenomas. In patients with a normal scan and no other cause of prolactin excess, the presumptive diagnosis is a small microadenoma.
Management
Treatment of prolactinomas is described on page 742. Galactorrhoea will resolve on specific treatment of other causes of prolactin excess or withdrawal of the offending drug. Troublesome physiological galactorrhoea can be treated with dopamine agonists (see
PITUITARY AND HYPOTHALAMIC TUMOURS
NON-FUNCTIONING PITUITARY TUMOURS
Aetiology
Pituitary tumours are usually benign adenomas. Interpretation of their pathology is described on page 736. Primary carcinoma of the pituitary gland is rare, but a metastatic tumour from a primary in the breast, lung, kidney or elsewhere may occur in the hypothalamus and reduce pituitary function. Other tumours-for example, pinealoma, ependymoma or meningioma-may be associated with damage to the pituitary or hypothalamus. Conditions such as sarcoidosis or syphilis may mimic pituitary tumours.
Clinical features
See the approach in Figure 16.24, page 737. Clinical features vary, depending on the type of lesion in the pituitary gland and the effect of that lesion on surrounding structures. Tumours which do not secrete excess hormones-non-functioning adenomas-present with hypopituitarism or features resulting from local expansion of the tumour. Headache is the most common but least specific symptom. Pituitary tumours only cause features of hypothalamic or posterior pituitary dysfunction if they expand sufficiently to impinge on the hypothalamus, since pressure on the posterior pituitary does not interfere with its function. Visual field defects are common (see p. 739).
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Although hydrocephalus is described with pituitary tumours, it is important to recognise that these do not behave like 'brain tumours', in that they are usually slowly progressive, and exceedingly rarely cause neurological impairment or raised intracranial pressure. This is an important concept to get across to patients at an early stage.
Investigations
All patients with pituitary tumours should have the tests described in
Management
Modalities of treatment for pituitary tumours are shown in
If there is evidence of pressure on visual pathways, then urgent treatment is required. The chances of recovery of a visual field defect are proportional to the duration of symptoms; full recovery is unlikely if the defect has been present for longer than 4 months. The only medical therapy which reliably shrinks macroadenomas is dopamine agonists for macroprolactinomas (see below). It is crucial that serum prolactin is measured before emergency surgery is performed. If the prolactin is > 4000 mU/l, then a therapeutic trial of a dopamine agonist for just a few days may successfully shrink the tumour and make surgery unnecessary.
Most operations on the pituitary are performed by the trans-sphenoidal approach. The pituitary fossa is approached via the sphenoid sinus from an incision under the upper lip or through the nose. Transfrontal surgery via a craniotomy is reserved for very large tumours and craniopharyngiomas. It is uncommon to be able to resect a macroadenoma completely.
16.49 THERAPEUTIC MODALITIES FOR HYPOTHALAMIC AND PITUITARY TUMOURS
Surgery Radiotherapy Medical Comment
Non-functioning pituitary macroadenoma 1st line 2nd line -
Prolactinoma 2nd line 2nd line 1st line:
Dopamine agonists Dopamine agonists usually cause macroadenomas to shrink
Acromegaly 1st line 2nd line 2nd line:
Somatostatin analogues
Dopamine agonists
GH receptor antagonists Medical therapy does not reliably cause macroadenomas to shrink
Cushing's disease 1st line 2nd line - Radiotherapy is used in children and to prevent Nelson's syndrome
Craniopharyngioma 1st line 2nd line -
Following decompression, imaging is repeated after a few months and, if there is any residual tumour, external radiotherapy is given to reduce the risk of recurrence. Radiation therapy is not useful in patients requiring urgent therapy because it takes many months or years to be effective and there is a risk of acute swelling of the tumour.
All operations on the pituitary carry a risk of damaging normal endocrine function; this risk increases with the size of the primary tumour. Radiation therapy carries a life-long risk of hypopituitarism (50-70% in the first 10 years) and annual pituitary function tests are required. There is also concern that radiotherapy, which is delivered through the temporal lobes, might impair cognitive function and even induce primary brain tumours, but these side-effects have not been quantified and are likely to be rare.
Non-functioning tumours are followed up by repeated imaging at intervals which depend on the size of the tumour and on whether or not radiotherapy has been administered.
PROLACTINOMA
Aetiology
Elevation of plasma prolactin levels is a common finding and may arise from a variety of causes, as listed in
Clinical features
Hippocrates was one of the first to observe that milk secretion was associated with decreased gonadal function. The cardinal features of hyperprolactinaemia are galactorrhoea (see p. 739) and hypogonadism. In women hypogonadism causes secondary amenorrhoea, oligomenorrhoea or menorrhagia, and anovulation with infertility. In men there is decreased libido, erectile impotence, reduced shaving frequency and lethargy. Men usually present with symptoms at a later stage than women and are more likely to have a macroadenoma.
Patients with macroadenomas may also have any of the clinical features of non-functioning pituitary tumours (see Fig. 16.24, p. 737).
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page 742
Investigations
These are described under galactorrhoea on page 740 and the principles are outlined in
Management
Medical
In almost all cases of hyperprolactinaemia dopamine agonist therapy will normalise prolactin levels with return of gonadal function. If gonadal function does not return despite effective lowering of prolactin, then there may be associated gonadotrophin deficiency or, in the female, the onset of the menopause. Several dopamine agonists are now available, as shown in
Dopamine agonist therapy is likely to be long-term in the majority of patients. However, it has been possible to withdraw bromocriptine without recurrence of hyperprolactinaemia after 10 years' treatment in some patients with microadenoma. Also, after the menopause suppression of prolactin is only required in microadenomas if galactorrhoea is troublesome, since hypogonadism is then physiological and tumour growth highly unlikely. In patients with macroadenomas drugs can only be withdrawn after curative surgery or radiotherapy and under close supervision.
In general, patients with prolactin excess should avoid drugs which stimulate prolactin, including oestrogens.
Surgical
Dopamine agonists not only lower prolactin levels but shrink the majority of prolactin-secreting macroadenomas. Thus, surgical decompression is not usually necessary unless the macroadenoma is cystic. However, in patients who are intolerant of dopamine agonists, microadenomas can be removed selectively by trans-sphenoidal surgery with a cure rate of about 80%. The cure rate for surgery in macroadenomas is substantially lower.
Radiotherapy
External irradiation may be required for some macroadenomas to prevent regrowth if dopamine agonists are stopped.
Pregnancy
16.50 DOPAMINE AGONIST THERAPY: DRUGS USED TO TREAT PROLACTINOMAS
Oral dose* Advantages Disadvantages
Bromocriptine 2.5-15 mg/day
8-12-hourly Available for parenteral use
Short half-life; useful in treating infertility Ergotamine-like side-effects (nausea, headache, postural hypotension, constipation)
Proven long-term efficacy Frequent dosing so poor compliance
Cabergoline 250-1000 µg/week Long-acting, so missed doses less important Unsuitable for treating infertility
2 doses/week Reported to have fewer ergotamine-like side-effects
Quinagolide 50-150µg/day
Once daily A non-ergot with few side-effects in patients intolerant of the above Untested in pregnancy
Pergolide An older drug with bromocriptine-like side-effects; no longer used
* Tolerance develops for the side-effects. All of these agents, especially bromocriptine, must be introduced at low dose and increased slowly. If several doses of bromocriptine are missed, the process must start again.
Hyperprolactinaemia often presents with infertility so dopamine agonist therapy is often followed by pregnancy. Patients with microadenomas are advised to withdraw bromocriptine as soon as pregnancy is confirmed (e.g. by urinary human chorionic gonadotrophin (hCG) test on the third day after a missed period). In contrast, macroprolactinomas may enlarge rapidly under oestrogen stimulation and these patients continue dopamine agonist therapy and need measurement of prolactin levels and visual fields during pregnancy. All patients are advised to report headache or visual disturbance promptly.
ACROMEGALY
Acromegaly is caused by growth hormone (GH) secretion from a pituitary tumour, usually a macroadenoma.
Clinical features
If GH hypersecretion occurs before epiphyses have fused, then gigantism will result. More commonly, GH excess occurs in adult life, after epiphyseal closure, and acromegaly ensues. If hypersecretion starts in adolescence and persists into adult life, then the two conditions may be combined. The clinical features are listed in
Further assessment follows the strategy in Figure 16.24. Macroadenomas may be associated with local complications of tumour expansion and with hypopituitarism.
Investigations
The clinical diagnosis must be confirmed by measuring GH levels during an oral glucose tolerance test (see Fig. 16.26). In normal subjects plasma GH suppresses to below 2 mU/l. In acromegaly it does not suppress and in about 50% of patients there is a paradoxical rise. The rest of pituitary function should be investigated as described in
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16.51 CLINICAL FEATURES OF ACROMEGALY
Soft tissue changes
Skin thickening
Increased sweating
Headache
Increased sebum production
Enlargement of lips, nose and tongue
Increased heel pad thickness
'Acromegalic arthropathy'
Myopathy
Carpal tunnel syndrome
Late-onset Raynaud's phenomenon
Visceromegaly (e.g. thyroid, heart, liver)
Acral enlargement
Large hands (difficult to remove rings-see p. 684)
Large feet (increasing shoe size)
Other bone changes
Growth of lower jaw-prognathism
Skull growth-prominent supraorbital ridges with large frontal sinuses
Kyphosis
Osteoarthritis
Metabolic effects
Glucose intolerance (25%)
Diabetes mellitus (10%)
Hypertension (25% associated with increased body sodium)
Long-term complications
Atheromatous disease (two- to threefold relative risk)
Colonic cancer (two- to threefold relative risk)
Figure 16.26 Oral glucose tolerance tests in a normal subject and a patient with acromegaly with measurement of blood glucose and plasma growth hormone. Note the suppression of growth hormone secretion of <>
The diagnosis of acromegaly is more difficult in patients with insulin deficiency, either type 1 or long-standing type 2 diabetes mellitus. GH may fail to suppress following a glucose load in these patients because inadequate insulin secretion results in failure of glucose to stimulate IGF-1 from the liver. It is IGF-1 which in turn suppresses GH secretion. This is important because acromegaly can cause diabetes mellitus by exacerbating insulin resistance. However, in diabetic patients without acromegaly, IGF-1 levels are low, while in acromegalic patients they are high.
Additional tests in acromegaly may include screening for colonic neoplasms with colonoscopy.
Management
Therapeutic modalities are described in
Surgical
Trans-sphenoidal surgery is usually the first line of treatment and may result in cure of GH excess, especially in patients with microadenomas. More often, surgery serves to debulk the tumour and further second-line therapy is required, according to post-operative imaging and glucose tolerance test results.
Radiotherapy
External radiotherapy is usually employed as second-line treatment if acromegaly persists after surgery to stop tumour growth and lower GH levels. However, GH levels fall slowly (over many years) and there is a risk of hypopituitarism.
Medical
In patients with persisting acromegaly after surgery, most centres employ medical therapy to lower GH levels to < style="mso-spacerun:yes">
EBM
ACROMEGALY-therapeutic targets
'Observational data in 1362 acromegalic patients show a linear relationship between mean growth hormone (GH) levels during follow-up after surgery and radiotherapy, and mortality from colon cancer and cardiovascular disease. Attainment of GH <>
Orme SM, McNally RJQ, Cartwright RA, Belchetz PE for the United Kingdom Acromegaly Study Group. Mortality and cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol Metab 1998; 83:2730-2734.
Further information: www.endocrinology.org
CRANIOPHARYNGIOMA
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Figure 16.27 Craniopharyngioma. A This hypothalamic tumour characteristically presents in younger patients. B and C It is often cystic and calcified, as shown in the MRI (arrows) and pathology specimen. D Hypothalamic damage is manifest as diabetes insipidus and loss of satiety leading to relentless weight gain. (For DDAVP, see text)
Craniopharyngiomas are benign tumours which develop in cell rests of Rathke's pouch, and may be located within the sella turcica, or commonly in the suprasellar space. They are often cystic and/or calcified (see Fig. 16.27). They occur more commonly in young people than do pituitary adenomas. They may present with pressure effects on adjacent structures, hypopituitarism or a hypothalamic syndrome, as described below. Craniopharyngiomas can rarely be reached by the trans-sphenoidal route, and surgery involves a craniotomy, with a relatively high risk of hypothalamic damage and other complications. Surgery is unlikely to be curative, and radiotherapy is usually given, although there is uncertainty about its efficacy. Unfortunately, craniopharyngiomas often recur, requiring repeated surgery and inevitably causing considerable morbidity, usually from hypothalamic obesity and/or visual failure.
HYPOTHALAMIC AND POSTERIOR PITUITARY DISEASE
Causes of hypothalamic disease are shown in
DIABETES INSIPIDUS
This uncommon disease is characterised by the persistent excretion of excessive quantities of dilute urine, and by thirst. Diabetes insipidus can be divided into cranial diabetes insipidus, in which there is deficient production of ADH, and nephrogenic diabetes insipidus, in which the renal tubules are unresponsive to ADH.
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16.52 CAUSES OF DIABETES INSIPIDUS
Cranial
Hypothalamic or high stalk lesion
E.g. craniopharyngioma, head injury, surgery, Langerhans cell histiocytosis, sarcoidosis, pituitary tumour with suprasellar extension, basal meningitis, encephalitis
Idiopathic
Genetic defect
Dominant
Recessive (DIDMOAD syndrome-association of diabetes insipidus with diabetes mellitus, optic atrophy, deafness)
Nephrogenic
Genetic defect
Sex-linked recessive
Cystinosis
Metabolic abnormality
Hypokalaemia
Hypercalcaemia
Drug therapy
Lithium
Demeclocycline
Poisoning
Heavy metals
Aetiology
Causes of diabetes insipidus are listed in
Clinical features
The most marked symptoms are polyuria and polydipsia. The patient may pass 5-20 litres or more of urine in 24 hours. This is of low specific gravity and osmolality. If the patient has an intact thirst mechanism, is conscious and has access to oral fluids, then he or she can maintain adequate fluid intake. However, in the unconscious patient or one with damage to the hypothalamic thirst centre, diabetes insipidus is potentially lethal. If there is associated cortisol deficiency, then diabetes insipidus may not be manifest until glucocorticoid replacement therapy is given. The differential diagnosis includes diabetes mellitus and primary polydipsia, a condition which is seen most often in patients with established psychiatric disease.
Investigations
16.53 WATER DEPRIVATION TEST
Use
To establish a diagnosis of diabetes insipidus, and differentiate cranial from nephrogenic causes
Protocol
No coffee, tea or smoking on the test day
Free fluids until 0730 hrs on the morning of the test, but discourage patients from 'stocking up' with extra fluid in anticipation of fluid deprivation
No fluids from 0730 hrs
Attend at 0830 hrs for body weight, plasma and urine osmolality
Record body weight, urine volume, urine and plasma osmolality and thirst score on a visual analogue scale every 2 hours for up to 8 hours
Stop the test if the patient loses 3% of body weight
If plasma osmolality reaches > 300 mOsm/kg and urine osmolality <>
Interpretation
Diabetes insipidus is confirmed by a plasma osmolality > 300 mOsm/kg with a urine osmolality <>
Cranial diabetes insipidus is confirmed if urine osmolality rises to > 660 mOsm/kg after DDAVP
Nephrogenic diabetes insipidus is confirmed if DDAVP does not concentrate the urine
Diabetes insipidus is confirmed if, in the face of elevated plasma osmolality (i.e. > 300 mOsm/kg), either ADH is not measurable in serum or the urine is not maximally concentrated (i.e. is <> 660 mOsm/kg. More often, a dynamic test is required. Most centres use a water deprivation test, described in
In primary polydipsia the urine may be excessively dilute because of chronic diuresis which 'washes out' the solute gradient across the loop of Henle, but plasma osmolality is low rather than high. DDAVP (see below) should not be administered to patients with primary polydipsia, since it will prevent excretion of water and risks severe water intoxication if the patient continues to drink fluid to excess.
In nephrogenic diabetes insipidus appropriate further tests include plasma electrolytes, calcium and investigation of the renal tract (see Chs 9 and 14).
Management
Treatment of cranial diabetes insipidus is with des-amino-des-aspartate-arginine vasopressin (desmopressin, DDAVP), an analogue of ADH with a longer half-life. Polyuria in nephrogenic diabetes insipidus is improved by thiazide diuretics (e.g. bendroflumethiazide (bendrofluazide) 2.5-5 mg/day), amiloride (5-10 mg/day) and non-steroidal anti-inflammatory drugs (e.g. indometacin 15 mg 8-hourly), although the last of these carries a risk of reducing glomerular filtration rate.
DDAVP
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ISSUES IN OLDER PEOPLE
THE PITUITARY AND HYPOTHALAMUS
Pituitary tumours are slow-growing. In patients without visual dysfunction, treatment may not be necessary.
Older patients may not recognise the usual early features of pituitary disease (e.g. amenorrhoea, galactorrhoea, sexual dysfunction) and are likely to present late with large pituitary tumours and visual dysfunction.
Hyperprolactinaemia due to microadenoma is less hazardous after the menopause, when 'physiological hypogonadism' occurs anyway. However, macroadenomas should be actively treated at all ages.
Growth hormone secretion falls with age, sometimes resulting in apparent biochemical GH deficiency. This should only be tested when clinically indicated (see
DDAVP is usually administered via the mucous membrane of the nose, either as a metered dose spray or using a manual aerosol device. It is also available as tablets, although bioavailability of peptides after oral administration is very low and rather unpredictable. In sick patients, DDAVP is given by intramuscular injection. The dose of DDAVP required to keep the patient in water balance must be determined by measuring plasma sodium concentrations and/or osmolality. The principal hazard is excessive treatment resulting in water intoxication and hyponatraemia. Inadequate treatment results in thirst and a compensatory increase in fluid intake in the conscious patient. The ideal dose prevents nocturia but allows a degree of polyuria from time to time before the next dose (e.g. DDAVP nasal dose 5 µg in the morning and 10 µg at night).
FURTHER INFORMATION
deGroot L, Jameson JL. Endocrinology. 4th edn.
Trainer PJ, Besser GM. The Bart's endocrine protocols.
Wilson JD, Foster DW, Kronenberg HM, Larson PR. Williams textbook of endocrinology. 9th edn.
www.endocrinology.org Website of the British Society for Endocrinology; useful links to other resources.
www.endo-society.org Website of the American Endocrine Society; useful links to other resources.
pages 736 - 746
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