Current strategies for the treatment of severe Cushing’s syndrome

Abstract

Severe Cushing’s syndrome may present an acute emergency in patients diagnosed with Cushing’s syndrome with recent onset of at least one of the following: sepsis, opportunistic infection; intractable hypokalaemia, uncontrolled hypertension; heart failure; gastrointestinal hemorrhage; acute psychosis; progressive debilitating myopathy; thromboembolism; uncontrolled hyperglycemia and ketoacidosis. The biochemical definition includes serum cortisol ≥41μg/dl (1100 nmol/l) and/or severe hypokalemia (<3.0 mmol/l) or urine free cortisol fivefold the upper limit of normal. Treatment focuses on the management of severe metabolic disturbances followed by rapid resolution of the hypercortisolemia and subsequent confirmation of the cause. We emphasize the control of the hypokalemia, hypertension, diabetes and any psychotic state, anti-coagulation, monitoring and vigorous therapy of opportunistic infections. The ideal first-line therapies include metyrapone and ketoconazole, followed by parenteral etomidate; if all else fails life-saving bilateral adrenalectomy should be considered.

KEYWORDS:

• severe hypercortisolemia
• etomidate
• metyrapone
• ketoconazole
• pasireotide
• cabergoline

Key issues

• Urgent treatment to prevent life-threatening complications of hypercortisolism should be instituted within 24–72 –h.

• The clinical definition for severe Cushing’s syndrome is a patient with Cushing’s syndrome and recent onset of one or more of the following: sepsis, opportunistic infection, intractable hypokalemia, uncontrolled hypertension, heart failure, gastrointestinal hemorrhage, glucocorticoid-induced acute psychosis, progressive debilitating myopathy, thromboembolism, uncontrolled hyperglycemia and ketoacidosis.

• The therapeutic arrangements should be addressed to correct the metabolic derangements urgently and then measures taken to lower the cortisol levels.

• The current initial therapies are based on the use of metyrapone and ketoconazole, plus consideration of parenteral etomidate.

• Mifepristone may also rapidly reduce the symptoms and signs of CS with dose adjustment based on clinical parameters, but monitoring this glucocorticoid antagonist may present problems.

Financial & competing interests disclosure

AB Grossman has received consulting and lecture fees from Novartis, Ipsen and HRA Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.