Knowledge on rare diseases and orphan drugs

It is a rare disease with a prevalence of about 1/ 7, 100 and an annual incidence of about 1/ 250, 000 in Western populations.

Disease onset peaks around 40 but can occur at any age. It presents insidiously with nonspecific symptoms that can be mistaken for other more prevalent conditions. Common manifestations include fatigue, loss of energy, malaise, weight loss, nausea, anorexia (failure to thrive in children), muscle and joint pain. Pigmentation of skin and mucous membranes (darkening of the skin especially in the palmar creases, knuckles, scars, oral mucosa and sites of friction) is a cardinal sign of CPAI. Symptoms of postural hypotension and hypoglycemia are late manifestations. Patients may also crave salt. Vitiligo and alopecia areata are often present when an autoimmune disorder is the cause. CPAI also causes dehydroepiandrosterone deficiency causing additional symptoms seen only in women (loss of axillary/pubic hair, absence of pubarch in children, reduced libido and dry skin). Acute adrenal insufficiency (AAI) can occur if treatment is not followed or during precipitating illnesses and is a life threatening medical emergency.

The most common cause of CPAI in the developed world is Addison disease (AD), also known as autoimmune adrenalitis , seen in 80%-90% of cases. Autoimmune adrenalitis can be isolated or seen as part of an autoimmune disorder (autoimmune polyendocrine syndrome type 1, 2 or 4). Infiltrative disorders are another cause of CPAI and include tuberculosis, fungal infections and AIDS-associated opportunistic infections. Genetic disorders (i.e. congenital adrenal hyperplasia), tumors, and treatment with certain drugs are other less common causes.

Biochemical tests are needed to diagnose CPAI. Early morning serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels are measured. Plasma ACTH is much higher in individuals with CPAI (>22 pmol/L) and morning serum cortisol levels are usually low (<83nmol/L) but can fluctuate. A stimulation test observing the cortisol response to exogenous ACTH is a useful tool in confirming a diagnosis. In healthy subjects serum cortisol concentrations increase (>500 nmol/L) after exogenous ACTH administration but no increase is seen in CPAI patients. Raised plasma ACTH levels confirm adrenal origin of the disease.

Secondary adrenal insufficiency needs to be eliminated. Causes include pituitary tumors, lymphatic hypophystitis, pituitary tuberculosis and sarcoidosis, all of which are differential diagnoses.

Management is life-long and requires a multidisciplinary team. Glucocorticoid replacement with oral hydrocortisone (10-25 mg daily taken in 2-3 doses) is given to mimic physiological cortisol secretion patterns. Oral fludrocortisone is given to replace mineralocorticoid hormones. Dehydroepiandrosterone replacement is optional. Glucocorticoid levels can be adjusted during times of stress to prevent AAI. The dose of hydrocortisone is maintained on the basis of clinical assessment and responses, taking into account a patient's well-being and presence of signs of over-replacement or under-replacement. An assessment of plasma renin activity is helpful in optimizing the dose of fludrocortisone. Growth and development in children must be monitored. Patients should carry a ready to inject hydrocortisone preparation and wear a medical alert card, in case of adrenal crisis.

There is no cure for CPAI but with proper treatment and care taken to prevent AAI there is no decrease in life expectancy. CPAI is only life threatening when ignored.

Last update: November 2012 - Expert reviewer(s): Dr Anne BACHELOT