Adrenal Insufficiency

Adrenal insufficiency is a disorder in which the adrenal glands fail to produce adequate amounts of cortisol, and often of aldosterone, leading to the systemic consequences of glucocorticoid and sometimes mineralocorticoid deficiency. It may be primary, arising from disease of the adrenal cortex itself, or secondary, arising from deficient pituitary or hypothalamic stimulation, and untreated it can culminate in a life-threatening adrenal crisis.

Definition

Adrenal insufficiency is a state of deficient adrenocortical hormone production, principally of cortisol, classified as primary when the adrenal cortex is at fault and secondary when the defect lies in pituitary or hypothalamic stimulation of the gland.

Scope

The entry covers adrenal insufficiency as a pathological and laboratory-defined entity: the distinction between primary and secondary forms, the hormone deficiencies involved, the regulatory axis whose failure produces the disease, and its biochemical characterisation. It does not provide replacement regimens or individualised management advice.

Key concepts

• Cortisol deficiency
• Aldosterone (mineralocorticoid) deficiency
• Hypothalamic-pituitary-adrenal axis
• Primary versus secondary insufficiency
• Autoimmune adrenalitis (Addison disease)
• ACTH and feedback regulation
• Adrenal crisis

Mechanisms

Adrenocortical hormone output is controlled by the hypothalamic-pituitary-adrenal axis, in which adrenocorticotropic hormone (ACTH) drives cortisol production and cortisol feeds back to restrain ACTH. In primary adrenal insufficiency the cortex itself is destroyed or impaired, most often by autoimmune adrenalitis, so cortisol and usually aldosterone fall while ACTH rises in compensation; the resulting loss of mineralocorticoid contributes to salt wasting and circulatory effects, and high ACTH can cause skin hyperpigmentation. In secondary adrenal insufficiency the pituitary or hypothalamus fails to provide adequate ACTH, so cortisol is low with low or inappropriately normal ACTH, while aldosterone, governed largely by the renin-angiotensin system, is typically preserved. Because cortisol is essential to the stress response, any form can decompensate into an acute adrenal crisis.

Clinical relevance

Adrenal insufficiency is an uncommon but clinically critical endocrine disorder, defined and characterised through measurement of cortisol, ACTH, and dynamic testing of the adrenal axis, and its recognition matters because an unrecognised adrenal crisis can be fatal. This entry describes how the disorder is conceptualised and classified for reference and is not a guide to diagnosis or treatment of any individual.

Epidemiology

Primary adrenal insufficiency is rare, with autoimmune adrenalitis the leading cause in regions where tuberculosis is uncommon, and it may occur as part of autoimmune polyendocrine syndromes. Secondary adrenal insufficiency is more frequent overall, commonly related to disorders of the pituitary or to suppression of the axis by exogenous glucocorticoids.

Evidence & guidelines

The pathophysiology and clinical features are summarised in a major disease review, and the diagnostic approach to primary adrenal insufficiency is addressed in an Endocrine Society clinical practice guideline; these sources are cited for orientation rather than as prescriptive instructions.

History

Thomas Addison's mid-nineteenth-century description of the clinical syndrome of adrenal destruction gave the eponym Addison disease to primary adrenal insufficiency. Once tuberculosis was the dominant cause; in much of the world autoimmune adrenalitis later became the leading aetiology. The identification of the adrenal steroids and of the regulatory ACTH axis established the modern, biochemically grounded understanding of the disorder.

Seminal works

• charmandari-2014
• bornstein-2016

Frequently asked questions

What is the difference between primary and secondary adrenal insufficiency?

Primary adrenal insufficiency results from disease of the adrenal cortex itself, with low cortisol and aldosterone and a compensatory rise in ACTH, whereas secondary adrenal insufficiency results from inadequate pituitary or hypothalamic ACTH, with low cortisol but generally preserved aldosterone.

Why is adrenal insufficiency potentially dangerous?

Because cortisol is essential to the body's response to physiological stress, severe or unrecognised deficiency can precipitate an adrenal crisis, an acute and potentially life-threatening state, which is why prompt biochemical recognition of the disorder is important.