Mrs A, a 65-year-old woman presented with a three-month history of a persistent cough, lethargy and polyuria. Her husband had died six months earlier and she was finding life difficult.

She noticed she was bruising more easily than usual. She had a history of AF and hypertension, both were controlled. She was taking warfarin, simvastatin, lisinopril and digoxin.

She admitted that she had been drinking a bit more alcohol recently, mainly to help her sleep. She was drinking about two bottles of wine a week and smoked about 25 cigarettes a day.

Although she had been overweight for years, her weight had recently reduced despite still having a good appetite.

Clinical examination revealed Mrs A was slightly plethoric and I wondered if this was due to her increased alcohol intake. Respiratory examination was unremarkable.

Hilar mass
Routine blood tests showed that she had type-2 diabetes; her fasting glucose was 12.1mmol/l. Her INR was stable and other blood tests were normal, except her potassium was marginally reduced at 3.4mmol/l.

I also arranged a chest X-ray, which showed a large hilar mass, raising suspicion of a lung cancer. Her diabetes was initially managed with diet and lifestyle modification. She was referred urgently to the local respiratory clinic.

Mrs A came to see me a month later with two diagnoses - small cell lung cancer and Cushing's syndrome. The Cushing's syndrome was due to ectopic adrenocorticotrophic hormone (ACTH) secretion by her lung cancer.

She had also been seen by the local oncologist and was receiving chemotherapy.

Cushing's syndrome
Cushing's syndrome is the term used to describe the clinical state of increased free circulating glucocorticoid. Causes of Cushing's syndrome are divided into two groups, ACTH-dependent and non-ACTH-dependent (see box).

Causes of Cushing's Syndrome

ACTH-dependent disease: Pituitary adenoma (Cushing's disease): 65 per cent of cases Ectopic ACTH-producing tumours: 10 per cent of cases ACTH administration Non-ACTH-dependent causes: Adrenal adenomas or hyperplasia: 25 per cent of cases Adrenal carcinomas Glucocorticoid administration

Ectopic ACTH production usually arises from malignancy, especially small cell carcinoma of the lung and also carcinoid tumours, especially of the lung.

Random cortisol measurements are of no value in the diagnosis of Cushing's syndrome. The three main investigations to confirm the diagnosis are a low-dose dexamethasone suppression test, midnight plasma or salivary cortisol and a 24-hour urinary free cortisol.

Following confirmation of Cushing's syndrome, the next step in diagnosing the underlying cause is usually measurement of plasma ACTH.

If plasma ACTH levels are lower than 5pg/ml, a primary adrenal cause is likely. Imaging of the adrenal glands with CT or MRI is the most appropriate next step. However, if levels of ACTH are persistently higher than 15pg/ml (as was the case for Mrs A) then an ACTH-dependent pathology is likely and the patient will require further investigations.

A high-dose dexamethasone suppression test is performed. Tumours causing Cushing's disease (pituitary pathology) typically retain some responsiveness to the suppressive effects of glucocorticoids, whereas tumours causing ectopic ACTH secretion usually do not.

Ectopic ACTH secretion
ACTH is the most commonly produced ectopic hormone in lung cancer. Increased serum levels of ACTH may be detectable in up to 50 per cent of lung cancer patients.

However, despite the presence of increased levels of ACTH, Cushing's syndrome is rarely seen. This is due partly to the rapid progression of small cell lung cancer and also the release of a biologically inactive form of the hormone.

Typical features of ectopic ACTH production include pigmentation, weight loss, metabolic alkalosis and hyperglycaemia.

Impaired glucose tolerance or even diabetes mellitus are common in ectopic ACTH syndrome.

The prognosis is poor for many patients with small cell lung carcinoma and ectopic ACTH secretion. Management includes treating the underlying tumour, which may in itself improve the Cushing's syndrome.

Correction of hypokalaemia, where appropriate, and control of diabetes mellitus is also very important.

A laparoscopic bilateral adrenalectomy may even be performed for some patients who are resistant to treatment.

• Dr Newson is a GP in the West Midlands.