Cushing's syndrome

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Cushing's syndrome

In the second part of our endocrinology series, H S Randeva and P M G Bouloux explain a complicated multisystem disorder

Cushing's syndrome is a multisystem disorder resulting from chronic exposure to inappropriately elevated concentrations of free circulating glucocorticoids.

Physiology of glucocorticoid secretion

Cortisol secretion from the zona fasciculata of the adrenal cortex is regulated by pituitary adrenocorticotrophic hormone (ACTH). ACTH - and therefore cortisol - has a diurnal rhythm, with peak secretion at 7-9 am and a nadir at midnight. Its secretion is regulated by hypothalamic corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP). There is synergism between CRH and AVP in ACTH release.

A number of physical and psychological factors (box 1) increase secretion of both ACTH and cortisol. Inhibition of CRH and AVP synthesis and release in the hypothalamus is a classic example of regulation of negative feedback by hormones. Cortisol is largely bound to cortisol-binding globulin (CBG) in the circulation; only 20% is free. CBG concentrations are regulated by oestrogen (for example, the oral contraceptive pill, pregnancy).

Aetiology of Cushing's syndrome

Although the commonest cause of Cushing's syndrome is exogenous administration of glucocorticoid, this article considers only the endogenous causes of Cushing's syndrome (box 1). In contrast to iatrogenic causes, Cushing's syndrome is rare, with four to six new cases per 1 million population per year. It is four to eight times commoner in women.

Box 1-Aetiology of Cushing's syndrome Endogenous ACTH dependent 85% Cushing's disease (pituitary) Ectopic ACTH syndrome Ectopic CRH syndrome ACTH independent 15% Common Adrenal adenoma Adrenal carcinoma Less common Micronodular hyperplasia Macronodular hyperplasia Rare McCune-Albright syndrome Gastric inhibitory polypeptide Exogenous ACTH treatment Glucocorticoid treatment Pseudo-Cushing's syndrome Major depressive disorder Alcoholism Obesity

ACTH dependent causes

Cushing's disease
Cushing's disease is a specific form of Cushing's syndrome caused by autonomous ACTH secretion by pituitary corticotroph tumours. These are usually microadenomas (less than 1 cm in diameter) and account for 80% of ACTH dependent causes of Cushing's syndrome. The specific abnormalities underlying the development of corticotroph adenomas are unknown.

Ectopic ACTH syndrome
Ectopic ACTH syndrome, which accounts for about 15-20% of patients with Cushing's syndrome, occurs two to three times more frequently in male patients, unlike Cushing's disease (female preponderance 8:1). Small cell lung carcinoma accounts for about 50-75% of all cases of ectopic ACTH secretion.

Ectopic CRH syndrome
This is rare and is clinically indistinguishable from Cushing's disease or ectopic ACTH syndrome associated with comparatively benign tumours. Most cases of ectopic CRH (CRH-41) secretion have been associated with bronchial carcinoid tumours.

ACTH independent causes

Adrenocortical tumours
Adrenal adenomas and carcinomas account for 15% of all cases of Cushing's syndrome, with approximately equal frequencies of adenoma and carcinoma in adults. These tumours are more common in women than in men (2:1). Carcinomas, unlike adenomas, are usually large (>6 cm) and show clinical evidence of glucocorticoid excess and excess androgen production, the latter in the form of virilisation.

Micronodular hyperplasia
This is a very rare cause of Cushing's syndrome and has also been termed primary pigmented nodular adrenal dysplasia. Bilaterally, the adrenal glands show multiple, small, deeply pigmented adrenal nodules probably caused by autoantibodies stimulating adrenal cortical growth. About half of these cases are inherited (Carney's syndrome); the other half occur sporadically in children and young adults.

Macronodular hyperplasia
This is a rare cause of Cushing's syndrome characterised by bilateral, large, hyper-functioning adrenal nodules. In most patients plasma concentrations of ACTH tend to be low, but they can vary from undetectable to high.

McCune-Albright syndrome

This syndrome is characterised by polyostotic fibrous dysplasia, cutaneous pigmentation, and multiple endocrinopathies; autonomous adrenal hyperfunction may produce Cushing's syndrome.

Pseudo-Cushing's syndrome

Around 80% of patients with severe depression have abnormally regulated cor- tisol secretion which is thought to be medi- ated by increased hypothalamic secretion of CRH. The hormonal abnormalities described disappear with the remission of depression. Chronic alcoholism is an even more uncommon cause of pseudo-Cushing's syndrome. The mechanism of hormonal abnormality may entail either increased CRH secretion or impaired hepatic metabolism of cortisol. Hormonal abnormalities disappear rapidly during abstinence from alcohol.

Clinical features of Cushing's syndrome

The most common presenting symptom is the relatively sudden onset of weight gain, which is usually centripetal (truncal). Fat deposits may appear in the cheeks (moon facies), in the dorsocervical area (buffalo hump), and the supraclavicular area.

Muscle wasting and weakness affect the proximal muscles of leg and shoulder girdle. Easy bruising of the skin is an important physical sign, and the presence of multiple purple striae with a diameter >1 cm on the abdomen or proximal extremities is virtually diagnostic of the condition. Hyperpigmentation (palmar creases and pressure points) in a patient with Cushing's syndrome strongly suggests an ACTH cause. Patients may have mild hirsutism and acne, but severe hirsutism and especially virilisation strongly suggest an adrenal carcinoma. Depression, lethargy, and insomnia often occur at the same time as other symptoms. In children the dominant clinical features are cessation of linear growth and weight gain; the clinical course is more aggressive than in adults.

In ectopic ACTH syndrome the clinical picture is variable. In the acute ACTH syndrome, which occurs in patients with rapidly progressive cancer, the physical features of Cushing's syndrome may not have time to develop; instead they may present with weight loss, severe proximal myopathy, thirst, and polydipsia. The chronic syndrome, which is associated with indolent tumours such as the bronchial carcinoids, is clinically indistinguishable from Cushing's disease. Finally, features best discriminating Cushing's syndrome from simple obesity have been shown to be easy bruising and myopathy, followed by hypertension, plethora, hirsutism, red-purple striae, menstrual irregularity, and truncal obesity.

Investigation of Cushing's syndrome

Diagnosis of Cushing's syndrome

Firstly, the syndrome must be confirmed biochemically, and, secondly, the precise aetiology of the syndrome must be established.

Screening tests (outpatient)

Urinary free cortisol
The measurement of 24 hour excretion of cortisol in urine integrates the variations in plasma free cortisol concentrations seen during the entire day; three consecutive 24 hour urine specimens. There is a false negative rate of 5.6%, with false positives of 1% in normal people and 5% in obese individuals; false positive results may, however, be obtained in several non-Cushing's hypercortisolaemic states (box 2).

Box 2-Causes of hypercortisolism

Physiological states
   Pregnancy
   Stress
   Chronic excessive exercise
   Malnutrition
Pathological states
   Cushing's syndrome
   Diabetes mellitus
   Hyperthyroidism
   Severe chronic disease
   Glucocorticoid resistance
Psychological states
   Anorexia nervosa
   Panic disorder
   Melancholic depression
   Obsessive-compulsive disorder

Dexamethasone suppression tests
In normal subjects, administration of a supraphysiological dose of glucocorticoid results in suppression of ACTH and hence of cortisol secretion (cortisol <50 nmol/l). This is the basis of dexamethasone suppression tests, of which there are several types.

The 48 hour low dose test, which is the most sensitive and specific screening test, entails the administration of 0.5 mg dexamethasone at intervals of exactly 6 hours from 9 am on day one for eight doses, and measurement of serum concentrations of cortisol at 9 am on day three, exactly 6 hours after the last dose of dexamethasone. A negative result is indicated when the serum concentration of cortisol at 9 am on day three is suppressed to <50 nmol/l. Both false negatives and false positives are rare (<2%). In other words, over 98% of patients with Cushing's syndrome fail to "suppress" serum cortisol on the low dose test.

With the overnight test, dexamethasone is administered at midnight and serum concentrations of cortisol measured 8 or 9 hours later. If 2 mg of dexamethasone is used, there is a high false-positive rate (30%). More commonly, 1 mg dexamethasone is used, which has a false negative rate of 2% and a false positive rate of 12.5%.

Confirmatory tests

Low dose dexamethasone suppression tests Circadian rhythm (diurnal)
In normal subjects, the cortisol concentration begins to rise at 2 am, peaking at 5 30-9 30 am. Concentrations drop during the morning and reach a nadir at around midnight (cortisol <50 nmol/l). Blood is taken for ACTH and cortisol at 9 am and midnight. The patient must have been in hospital for at least 48 hours, have an indwelling intravenous cannula, and be asleep before blood taking at midnight. The finding of a normal circadian rhythm virtually rules out the presence of active Cushing's syndrome.

Insulin tolerance test
In normal subjects and those with pseudo-Cushing's, insulin induced hypoglycaemia (blood glucose concentration <2.2 mmol/l) results in a rise of ACTH and cortisol concentrations. This response to hypoglycaemia is lost in most cases of Cushing's syndrome (90%). This test is contraindicated in anyone with a history of epilepsy or cardiac disease and in those with hypothyroidism and hypoadrenalism.

Problems in diagnosis

The biochemical and clinical changes caused by Cushing's syndrome can be closely mimicked in other pathological states namely - depression and chronic alcoholism (pseudo-Cushing's). In the latter, a high concentration of g-glutamyl-transferase and macrocytosis may suggest the diagnosis, and the biochemical abnormalities revert to normal on cessation of alcohol consumption. In pseudo-Cushing's, the cortisol response to hypo-glycaemia is usually intact, which may be of value diagnostically.

Many non-endocrine illnesses such as heart failure and infection can increase the production of cortisol with loss of normal circadian rhythm. Treatment with oestrogen may cause a modest increase in plasma concentrations of cortisol and no suppressibility in the 1 mg overnight dexamethasone test owing to an increase in the plasma concentration of cortisol binding globulin. In liver disease, corticosteroid metabolism is decreased, and in patients with advanced renal failure, urinary free cortisol may give falsely low values.

More importantly, drugs that induce liver enzymes - for example, certain anti- convulsants - increase the clearance rate of dexamethasone, consequently producing false positive or uninterpretable results.

Differential diagnosis of Cushing's syndrome

Once the diagnosis of Cushing's syndrome has been established, the main step is to decide whether the condition is ACTH dependent or not. A combination of biochemical and radiological investigations is often required.

Biochemical investigations

Plasma concentrations of ACTH
Plasma concentrations of ACTH (9-9 30 am) are normal or elevated in Cushing's disease (pituitary) and in the ectopic ACTH syndrome. Patients with ectopic ACTH syndrome, however, frequently have higher plasma concentrations of ACTH than those with Cushing's disease and often secrete various ACTH precursors ("big ACTH").

Plasma concentrations of potassium and glucose
Hypokalaemic alkalosis is a characteristic finding in ectopic ACTH syndrome (70-100%). The hypokalaemia is in part the result of the very high cortisol concentration, which has a mineralocorticoid action. This biochemical picture is also seen in 10% of patients with Cushing's disease.

Diabetes mellitus is more common in patients with ectopic production of ACTH (75%) than in patients with Cushing's disease (35%).

High dose dexamethasone suppression test
The high dose dexamethasone suppression test is performed in an identical manner to the 48 hour low dose test (see above), except that 2 mg of dexamethasone is administered in place of 0.5 mg. Patients with Cushing's disease generally suppress their cortisol to <50% of the baseline plasma concentration of cortisol. Between 80% and 90% of patients with Cushing's disease show the expected suppression of plasma cortisol in comparison to 10-30% of patients with ectopic ACTH syndrome.

Corticotrophin releasing hormone test
The test entails the administration of 100 mg of synthetic corticotrophin releasing hormone intravenously, with measurement of cortisol and ACTH concentrations every 15 minutes for 2 hours. In normal subjects, this test produces a rise in the concentrations of cortisol and ACTH, a response exaggerated in patients with Cushing's disease and typically absent in the ectopic ACTH syndrome and in patients with adrenal tumours.

Inferior petrosal sinus sampling
Inferior petrosal sinus sampling, an invasive procedure with potential complications, is reserved for patients with biochemically proved Cushing's disease but negative or equivocal results of pituitary magnetic resonance imaging, or patients with positive results of pituitary magnetic resonance imaging but equivocal suppression and stimulation tests. A petrosal to peripheral ACTH ratio of >3 after this test gives a sensitivity, specificity, and diagnostic accuracy of 100% in differentiating pituitary from ectopic sources of Cushing's syndrome.

Tumour markers
Some 70% of patients with ectopic ACTH syndrome cosecrete at least one other peptide: somatostatin, gastrin, pancreatic polypeptide, vasoactive intestinal peptide, glucagon, ß human chorionic gonadotrophin, plasma carcinoembryonic antigen, calcitonin, or bombesin.

Radiological investigation

Imaging procedures are useful only for determining the location of a tumour.

Adrenals
If a patient has ACTH independent Cushing's syndrome, thin section computed tomography of the adrenal glands is usually the next procedure. Autonomously functioning adrenal adenomas are unilateral and usually >1.5 cm in diameter. Tumours with diameters >6 cm should raise the suspicion of adrenal carcinoma. Magnetic resonance imaging is as sensitive as computed tomography scanning, and there is no diagnostic advantage. The presence of bilateral hyperplasia suggests an ACTH effect secondary to Cushing's disease or ectopic ACTH production.

Pituitary
About 90% of ACTH secreting pituitary tumours are microadenomas with a diameter <10 mm. Magnetic resonance imaging is the imaging technique of choice.

Ectopic tumours
All patients with suspected ectopic ACTH syndrome will need simple investigations such as a plain chest x ray film and sputum cytology. A computed tomography scan of the chest and abdomen should be undertaken and, if the findings are negative, magnetic resonance imaging of the chest and abdomen should be performed. Arteriography and bronchoscopy may be indicated. In detecting occult carcinoids, a body scan after the injection of radiolabelled somatostatin analogue octreotide may offer greater sensitivity.

Treatment of Cushing's syndrome

If left untreated, 50% of patients with Cushing's syndrome are dead within five years, usually from cardiovascular disease and susceptibility to infections. Children may be affected by permanent stunting of growth.

Cushing's disease
Cushing's disease may be treated by transsphenoidal surgery, pituitary radio-therapy, or bilateral adrenalectomy, or with medical therapy. Selective microadenomectomy using transsphenoidal pituitary microsurgery is currently the treatment of choice in patients with Cushing's disease; the cure rate is about 80%. Patients not cured by initial or repeat transsphenoidal surgery receive pituitary irradiation. This may be offered as primary treatment in those unfit or unwilling to have surgery. As the effects of radiotherapy may take several months or even years, hypercortisolism can be controlled with medical treatment (see below).

If patients are not cured, bilateral adrenalectomy is offered and the pituitary irradiated to reduce the incidence of Nelson's syndrome (post-adrenalectomy hyperpigmentation with an enlarged, locally invasive, ACTH secreting pituitary tumour). After bilateral adrenalectomy, patients require life long replacement of glucocorticoids and mineralocorticoids, and they must carry a steroid card and MedicAlert bracelet.

Primary adrenal disease
Bilateral total adrenalectomy, with or without pituitary irradiation, is required in patients with bilateral micronodular or macronodular adrenal hyperplasia. Unilateral adrenalectomy is reserved for adrenal adenomas or carcinomas, usually with 100% cure rate for the former. Patients with adrenal carcinoma almost invariably have recurrences that are not amenable to either irradiation or chemotherapy. Mitotane, a specific adrenocorticolytic agent, may be offered to these patients who are not cured.

Ectopic ACTH syndrome
Once the source of ectopic ACTH is identified, the appropriate therapeutic intervention is surgical ablation. Many ectopic ACTH secreting tumours, however, escape detection by imaging; in such cases adrenocortico-hypersecretion may be reduced by "medical adrenalectomy." Repeat search for tumour should be undertaken every 6-12 months.

Medical treatment
The aim of medical treatment is to render a patient normocortisolaemic. Metyrapone and ketoconazole are commonly used. Metyrapone blocks the 11-ß hydroxylase enzyme involved in the final step in cortisol synthesis, whereas ketoconazole acts at several levels and inhibits cortisol synthesis by a direct action on the P450 cytochrome enzyme. The adrenolytic agent, op-DDD (mitotane), has a cytotoxic effect on both normal and malignant adrenocorticol tissue. Its use is mainly in the management of adrenal carcinoma and rarely in Cushing's disease.

Summary

Cushing's syndrome results from chronic exposure to glucocorticoids; easy bruising, muscle weakness, hypertension, and redpurple striae have the greatest discriminatory value in its diagnosis. Biochemical diagnosis is based on elevated urinary concentrations of free cortisol and the failure to suppress cortisol (<50 nmol/l) after the 48 hour low dose dexamethasone suppression test, the most sensitive and specific confirmatory test for Cushing's syndrome.

An appropriate first step is to scan the adrenals immediately the diagnosis of Cushing's syndrome is made, as the identification of an adrenal mass will alter the diagnostic algorithm.

Surgical ablation is the treatment of choice for all types of Cushing's syndrome. In cases of Cushing's disease in which transsphenoidal surgery fails or disease recurs, radiation in association with medical treatment are indicated. Bilateral adrenalectomy may be indicated if surgery is unsuccessful and radiation or medical treatment fails.

H S Randeva senior registrar in endocrinology
P M G Bouloux reader in endocrinology
Centre for Neuroendocrinology, Royal Free Hospital, London NW3 2QG