Disorder

Cushings Syndrome/ Hypercortisolism

Risk factors

Prevalence & Demographics

Spontaneous Secondary- following therapeutic admin of synthetic steroids/ACTH caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids. degree of cortisol overproduction is very variable. Spontaneous-rare : ~<5/million/year Exogenous steoids is the #1 cause 2-5% prevalence for obese patients with type 2 diabetes, especially those with poor glucose control and hypertension For Cushings syndrome due to an adrenal/pituitary tumour- Female:Male=5:1 Peak incidence of cushings syndrome caused by an adrenal or pituitary adenoma- between 25-40 years Ectopic ACTH production due to lung cancer- later in life

Causes & Pathogenesis

Exogenous use of glucocorticoids- Corticosteroid medications such as prednisolone, Eg. For asthma, SLE, Rheumatoid arthritis Tumours of the adrenal gland Cushings disease Tumour elsewhere in the body which causes an increased cortisol Tumours which cause increased ACTH (eg pancreas, lung, thyroid) Can be divided into two groups: ACTH-Dependent disease Non-ACTH dependent disease - Excessive ACTH from the pituitary (Cushings disease) - Adrenal adenomas (65% of cases) - Adrenal carcinomas - Ectopic ACTH-producing tumours - Excess glucocorticoid administration - ACTH administration Others: Alcohol-induced pseudo-Cushings syndrome

Presentation

Pigmentation occurs only with ACTH-dependent causes. A Cushingoid appearance can be caused by excess alcohol consumption (pseudo-Cushing's syndrome) - the pathophysiology is poorly understood. Impaired glucose tolerance or frank diabetes is common, especially in the ectopic ACTH syndrome. Hypokalaemia due to the mineralocorticoid activity of cortisol is common with ectopic ACTH secretion.

QuickTime and a decompressor are needed to see this picture.

QuickTime and a decompressor are needed to see this picture.

Differential diagnosis

-Pseudo-Cushing's syndrome: all or some of the clinical features of Cushing's syndrome, combined with biochemical evidence of hypercortisolism (but not caused by pituitary-adrenal axis problems). Causes include: Chronic severe anxiety and/or depression Prolonged excess alcohol consumption can cause a cushingoid appearance Obesity Poorly controlled diabetes HIV infection

Investigation

Full blood count: raised white cell count. Electrolytes and acid-base balance: hypokalemia (common with ectopic ACTH secretion as a result of
mineralocorticoid activity),metabolic alkalosis.

QuickTime and a decompressor are needed to see this picture.

Q u ic k T im e a n d a d e c o m p re s s o r a re n e e d e d to s e e t h is p ic t u re .

Treatment & Management

tissue fragility, poor wound healing, hypertension, and diabetes mellitus, increase the risks of surgery. Drug therapy remains very important for normalising cortisol levels while awaiting the impact of more definitive treatment. Cortisol hypersecretion must be controlled prior to surgery or radiotherapy if at all possible. Drugs Metyrapone, ketoconazole, and mitotane can all be used to lower cortisol by directly inhibiting synthesis and secretion in the adrenal gland. Metyrapone and ketoconazole are enzyme inhibitors and have rapid onset of action, but control of hypercortisolism is often lost with corticotropin oversecretion in Cushing's disease. These drugs are not usually effective as long-term treatment and are used mainly for preparation for surgery or as adjunctive treatment

The treatment of choice in most patients is surgical, but the metabolic consequences, including increased

after surgery or pituitary radiotherapy. Mitotane acts as an adrenolytic drug with delayed onset but long-lasting action, but control of corticotropin oversecretion in Cushing's disease is maintained. Medical treatment can also be used in patients who are unwilling or unfit for surgery. Treatment can be used long term for patients with ectopic corticotropin secretion, but adrenalectomy may be preferred. Etomidate can be used for acute control of severe hypercortisolaemia. Surgical treatment Treatment of choice for: Pituitary tumours: trans-sphenoidal microsurgery. Radiation therapy may be used as an adjunct for patients who are not cured. Bilateral adrenalectomy may be necessary to control toxic cortisol levels. Adrenocortical tumours: require surgical removal. Laparoscopic surgery is now the treatment of choice for unilateral adrenal adenomas. Removal of neoplastic tissue is indicated for ectopic ACTH production. Metastatic spread makes a surgical cure unlikely or impossible. Bilateral adrenalectomy is indicated if necessary to control toxic cortisol levels. Pituitary radiotherapy Persisting hypercortisolaemia after trans-sphenoidal surgery can be treated with pituitary radiotherapy. Conventional fractionated radiotherapy is very effective but is associated with longterm hypopituitarism and can be very delayed in effectiveness. Prognosis

Incompletely controlled Cushing's syndrome - five-fold excess mortality Most common causes of Cushing's-associated mortality- hypertension, myocardial infarction, infection and
heart failure. The prognosis is guardedly favorable with surgery. The rare adrenocortical carcinomas have a 5-year survival rate of 30% or less. Complications Metabolic syndrome Hypertension Impaired glucose tolerance and diabetes Obesity Hyperlipidaemia: raised LDL cholesterol and triglycerides Coagulopathy: thrombophilia Osteoporosis Perforated viscera Impaired immunity, including opportunistic fungal infections Nelson's syndrome: may follow bilateral adrenalectomy for Cushing's disease

 A primary pituitary tumour may cause pan-hypopituitarism and visual loss

Social
http://www.netterimages.com/image/19567.htm http://www.sciencedirect.com/science/article/pii/S0140673606686996 http://www.patient.co.uk/doctor/Cushing's-Syndrome.htm