Adrenal insufficiency: Physiology, clinical presentation and diagnostic challenges

Adrenal insufficiency (AI) is a serious condition, which can arise from pathology affecting the adrenal gland itself (primary adrenal insufficiency, PAI), hypothalamic or pituitary pathology (secondary adrenal insufficiency, SAI), or as a result of suppression of the hypothalamic-pituitaryadrenal (HPA) axis by exogenous glucocorticoid therapy (tertiary adrenal insufficiency, TAI). AI is associated with an increase in morbidity and mortality and a reduction in quality of life. In addition, the most common cause of PAI, autoimmune adrenalitis, may be associated with a variety of other autoimmune disorders. Untreated AI can present with chronic fatigue, weight loss and vulnerability to infection. The inability to cope with acute illness or infection can precipitate life-threatening adrenal crisis. It is therefore a critical diagnosis to make in a timely fashion, in order to institute appropriate management, aimed at reversing chronic ill health, preventing acute crises, and restoring quality of life. In this review, we will describe the normal physiology of the HPA axis and explain how knowledge of the physiology of this axis helps us understand the clinical presentation of AI, and forms the basis for the biochemical investigations which lead to the diagnosis of AI.