Cushing’s syndrome

Cushing’s syndrome is a clinical disorder resulting from prolonged exposure to excess glucocorticoids and should not be confused with Cushing’s disease which refers exclusively to those cases that arise due to an adrenocorticotrophic hormone (ACTH) secreting pituitary adenoma (Table 39.1). Clinically overt Cushing’s syndrome caused by ectopic secretion of ACTH by non-endocrine-derived tumours is rare. Approximately 20% of cases of Cushing’s syndrome are caused by ectopic ACTH secretion by a tumour that is frequently occult at presentation. For this reason the differential diagnosis between pituitary adenoma and ectopic ACTH is important clinically but biochemical overlap often makes this difficult. More than half the cases of ectopic ACTH syndrome are due to small cell lung cancer, with carcinoid tumours and neural crest tumours (phaeochromocytoma, neuroblastoma, medullary cell carcinoma of the thyroid) accounting for a further 15%. The typical presentation is of a middle-aged smoker with features of severe hypercortisolism and hypokalaemic metabolic alkalosis. Patients have muscle weakness or atrophy, oedema, hypertension, mental changes, glucose intolerance and weight loss. When ectopic ACTH production arises from a more benign tumour, for example, bronchial carcinoid or thymoma, the other classic features of Cushing’s syndrome may be present including truncal obesity, moon facies and cutaneous striae (Figure 39.1).

The diagnosis of Cushing’s syndrome may be confirmed by elevated urinary free cortisol, loss of diurnal variation of plasma cortisol and failure of cortisol suppression in the low-dose dexamethasone (2 mg) test. After establishing the diagnosis, an elevated plasma ACTH supports the diagnosis of pituitary adenoma or ectopic ACTH syndrome. Failure of cortisol suppression following high-dose dexamethasone (2 mg four times daily for 2 days, or 8 mg overnight) and very high levels of ACTH (>200 pg/mL) suggest an ectopic source of ACTH. In difficult cases, a corticotrophin-releasing hormone (CRH) stimulation test, selective venous catheterization of the inferior petrosal sinus with ACTH estimations, somatostatin analogue scintigraphy and technetium-99 methoxyisobutylisonitrile (MIBI) imaging may be necessary to determine the source of ACTH.

The mainstay of palliative therapy for Cushing’s syndrome due to ectopic ACTH production is inhibition of steroid synthesis, although inhibition of ACTH release and blocking glucocorticoid receptors have also been attempted. Several steroid synthesis inhibitors are available and successful use in these circumstances has been reported with aminoglutethamide, metyrapone, mitotane, ketoconazole and octreotide. On rare occasions laparoscopic bilateral adrenalectomy or adrenal artery embolization may be necessary to control symptoms.

Syndrome of inappropriate antidiuresis

Hyponatraemia is a common finding in association with advanced malignancy and many factors may contribute including cardiac and hepatic failure, hyperglycaemia and diuretics. However, the detection of concentrated urine in conjunction with hypo-osmolar plasma suggests abnormal renal free water excretion and the presence of the syndrome of inappropriate antidiuresis (SIAD). This acronym is better than the previous term “syndrome of inappropriate antidiuretic hormone” (SIADH), since there is no vasopressin (ADH) secretion in approximately 15% of cases. In malignancy-related SIAD, tumours secrete ectopic arginine vasopressin or vasopressin-like peptides. In many respects SIAD is the opposite of diabetes insipidus; patients with SIAD are waterlogged with low plasma osmolality and sodium and high urine osmolality, whilst patients with diabetes insipidus are dehydrated with high plasma osmolality and sodium and low urine osmolality. SIAD is most frequently associated with small cell lung cancer or carcinoid tumours but has also been described in pancreatic, oesophageal, prostatic and haematological malignancies. Nonetheless many factors may contribute to SIAD (Table 39.2). Ecstasy (MDMA, methylenedioxymethamphetamine) is another cause of SIAD although over-drinking water at raves may contribute to the hyponatraemia too.

Significant symptoms of hyponatraemia appear at plasma sodium levels below 125 mmol/L, with confusion progressing to stupor, coma and seizures as levels fall. Nausea, vomiting and focal neurological deficits may also occur. The clinical features depend on both the levels of plasma sodium and the rate of decline. With gradual falls in sodium, the brain cells are able to compensate against cerebral oedema by secreting potassium and other intracellular solutes. Asymptomatic hyponatraemia therefore suggests chronic SIAD rather than acute SIAD. The division into chronic and acute SIAD is of therapeutic importance as their management differs. The diagnosis of SIAD requires the demonstration of plasma hyponatraemia and hypo-osmolality in the presence of concentrated urine and normal extracellular fluid volume (Table 39.3).

The management of SIAD depends upon the rate of onset of hyponatraemia and the presence of neurological complications. Acute SIAD with an onset over 2–3 days and falls in serum sodium in excess of 0.5 mmol/L per day are associated with neurological sequelae and require prompt correction by intravenous hypertonic saline. However, correcting the plasma sodium too fast can also lead to severe neurological consequences including central pontine myelinolysis, an osmotic demyelination that causes acute paralysis, dsyphagia, dysarthria and coma (Figure 39.2). Hyponatraemia should not be corrected faster than 10 mmol/L/24 hours. In contrast, the mainstay of therapy for chronic asymptomatic SIAD is fluid restriction and inhibition of tubular reabsorption of water with drugs including the tetracycline antibiotic demeclocycline.

Non-islet cell tumour hypoglycaemia

Enteropancreatic hormone syndromes

Carcinoid syndrome

Phaeochromocytoma