Cushings diseaseCushings syndrome

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Cushing's disease is the excess production of glucocorticoids secondary to over-stimulation of the adrenal cortex by a pituitary tumour producing excess ACTH. Cushing's syndrome is the excess presence of glucocorticoids secondary to an autonomous glucocorticoid adenoma, adrenal carcinoma, ectopic ACTH production or the administration of large doses of steroids as medical therapy.

Clinically the patient presents with truncal obesity, moon face, hypertension, diabetes, abdominal striae, acne and a buffalo hump, and experiences profound weakness. Pituitary ACTH-producing tumours tend also to produce skin pigmentation as ACTH has a similar molecular structure to melanocyte-stimulating hormone (MSH). Because patients have a tendency to bruise easily with delicate skin which is easily damaged, and have an increased risk of infection, post-operative problems are increased.

Diagnosis

Diagnosis is by detection of an elevated plasma cortisol with lack of diurnal variation. Because other conditions can produce a similar pattern (e.g. excess alcohol production), a low dose Dexamethasone suppression test should be performed to confirm the diagnosis. Dexamethasone suppresses ACTH production but does not interfere with cortisol assay. Therefore, in a patient who does not have Cushing's syndrome, Dexamethasone, by suppressing ACTH, will suppress cortisol.

If cortisol levels are not suppressed, the next step is to measure plasma ACTH (by a radio-immunoassay) and to perform a high dose Dexamethasone suppression test to determine suppression of urinary 17-hydroxy-corticosteroids.

• Undetectable ACTH indicates a primary adrenal tumour.

• Elevated ACTH may be due to either pituitary or ectopic ACTH production.

- Pituitary ACTH hypersecretion (Cushing's disease) is partially suppressed by a high dose Dexamethsone suppression test with 17-hydroxy corticosteroids being reduced to <50% of baseline.

- Ectopic ACTH production is unaffected by a high dose Dexamethasone suppression test in which case 17-hydroxycorticosteroids will not be suppressed.

If the diagnosis is adrenal Cushing's syndrome, the tumour can normally be localised by a CT scan or an iodo-cholesterol scan. Failure to localise with the isotope scan raises the suspicion of malignancy. Adrenal tumours <5cm in diameter are usually benign but tumours >8 cm have a high incidence of malignancy.

Management

Symptoms of Cushing's syndrome can be reduced by metyrapone or aminoglutethamide but effects are usually temporary. However the use of these drugs may reduce the incidence of post-operative complications outlined above, especially risk of sepsis.

Most centres would now accept that a unilateral adrenalectomy for a tumour <5 cm should be performed by laparoscopy in all cases. The long-term side effects and complications of a large incision which would otherwise be necessary are unacceptable. The technique is not easy and patients should be referred into a main centre where the expertise for this exists. As experience is obtained, larger tumours and bilateral surgery is now being carried out by more centres.

Because of suppression of the contralateral gland, unilateral adrenalectomy will result in hypo-adrenalism which may last for several months before the contralateral gland regains function. Glucocorticoids will be necessary throughout this time. Bilateral adrenalectomy will require not only glucocorticoid replacement but also life-long mineralocorticoid.

Patients with bilateral adrenal hyperplasia due to Cushing's disease may be treated by excision of the pituitary adenoma or by bilateral adrenalectomy. In those cases treated by adrenalectomy, the pituitary tumour will tend to enlarge and in 20% of patients will cause symptoms (Nelson's syndrome). This causes hyperpigmentation, headache, increased levels of sex hormones and optic chiasma compression resulting in bi-temporal hemianopia and ultimate blindness. To prevent this, the pituitary should therefore be irradiated.

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