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At a glance

Progressive weakness, anemia, hypoglycemia, and skin hyperpigmentation. Acute episodes may present with vomiting, apneic spells, cyanosis cardiovascular shock, and potentially death.

Synonyms

Addison Disease; Adrenal Insufficiency; Adrenal Hypoplasia/Aplasia.

History

First described in patients suffering from tuberculosis with suprarenal involvement in 1849 by Thomas Addison, an English physician.

Incidence

Primary Addisonian Syndrome affects approximately 70-140:1,000,000 people in Caucasian populations.

Genetic inheritance

Most cases are sporadic, but depending on the etiology, X-linked recessive (with the mutations mapped to chromosome Xp21.2) and autosomal recessive forms have been described.

Pathophysiology

Complete or partial lack of mineralocorticoids and glucocorticoid hormones, excreted by the zona fasciculata (glucocorticoids) and glomerulosa (aldosterone) of the adrenal cortex, caused by different mechanisms. Autoimmune mechanisms account for approximately 80% of cases and are often associated with other autoimmune diseases (see “Clinical aspects”). Dysfunction of the adrenal cortex leads to interrupted hypothalamic and anterior pituitary gland feedback inhibition, resulting in continuous and uninhibited secretion of adrenocorticotropic hormone (ACTH). Cleavage of the prohormone proopiomelanocortin in the adenohypophysis results in simultaneous secretion of ACTH and melanocyte-stimulating hormone (MSH). The elevated MSH level is responsible for the typical bronze hyperpigmentation of skin and mucous membranes in patients with primary adrenal insufficiency.

Diagnosis

Vomiting, hypoglycemia, seizures, cyanosis, apneic spells, and vascular collapse are common presenting symptoms of an adrenal crisis. Shock with cardiovascular collapse and death may occur. Plasma and urinary concentrations of all adrenal steroids are low. Serum glucose level is usually low. Sodium plasma concentration is decreased (but rarely <120 mmol/l)="" and="" potassium="" plasma="" concentration="" is="" increased="" (but="" rarely="">7.0 mmol/L). Moderate metabolic acidosis with plasma bicarbonate levels between 15 and 20 mmol/L is common. Serum urea concentration is typically elevated. Urinary excretion of sodium and chloride is increased, whereas potassium excretion is decreased. Plasma cortisol levels—if measured before treatment—are low. However, the final diagnosis of adrenocortical insufficiency is based on the finding of decreased or absent adrenal steroid synthesis after stimulation with administration of external (intravenous or intramuscular) ACTH. A response with increased serum concentrations of cortisol and aldosterone is an indicator of a functional adrenal cortex. Under normal conditions, cortisol synthesis increases by a factor of two to five times above normal levels after administration of ACTH. Failure of aldosterone serum levels to double within 30 minutes after ACTH administration indicates a problem with mineralocorticoid synthesis. A normal ACTH-stimulation test result excludes the diagnosis of primary adrenocortical insufficiency. On an abdominal CT scan or ultrasound, the adrenal glands may appear enlarged in patients with Addison Syndrome secondary to infection, hemorrhage, or malignancies involving the adrenal glands (see below). Primary adrenal insufficiency results in atrophic adrenal glands secondary to inactivity. Idiopathic autoimmune adrenocortical insufficiency is usually the result of autoimmune lymphocytic infiltration of the adrenal cortex (autoimmune adrenalitis) and ...

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