Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids (primarily cortisol), mineralocorticoids (primarily aldosterone), and androgens. These hormones are important in regulating blood pressure, electrolytes, and metabolism as a whole. This is called secondary adrenal insufficiency (when caused by lack of production of adrenocorticotropic hormone (ACTH) in the pituitary gland) or tertiary adrenal insufficiency (when caused by lack of corticotropin-releasing hormone (CRH) in the hypothalamus).

Types

There are three major types of adrenal insufficiency, depending on the affected organ.

  • Primary adrenal insufficiency is due to impairment of the adrenal glands, resulting in a lack of glucocorticoid production. Since the adrenal glands are directly affected, mineralocorticoid production is also reduced. Principal causes include:
  • Autoimmune: e.g., Addison's disease (also called autoimmune adrenalitis), which has been identified to be the cause of 80–90% of primary adrenal insufficiency cases since 1950.
  • Surgery or radiation: Pituitary gland surgery and/or radiation can lead to destruction of ACTH-producing tissue. Hyponatremia is a sign of secondary insufficiency.

Pathophysiology

thumb|660x660px|Diagram detailing the hypothalamus–pituitary–adrenal axis in the normal state, primary adrenal insufficiency, secondary adrenal insufficiency, and tertiary adrenal insufficiency

thumb|The adrenal cortex produces different hormones in different areas of the organs, called zonas.

When functioning normally, the adrenal glands secrete glucocorticoids (primarily cortisol) in the zona fasciculata and mineralocorticoids (primarily aldosterone) in the zona glomerulosa to regulate metabolism, blood pressure, and electrolyte balance. Adrenal hormone production is controlled by the hypothalamic–pituitary–adrenal axis, in which the hypothalamus produces corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to produce adrenocorticotropic hormone (ACTH), which stimulates the adrenal gland to produce cortisol. The overproduction of α-MSH leads to the characteristic hyperpigmentation of Addison's disease.

Aldosterone deficiency

Although the production of aldosterone occurs within the adrenal cortex, it is not induced by adrenocorticotropic (ACTH); instead, it is regulated by the renin–angiotensin–aldosterone system (RAAS). Renin production in the juxtaglomerular cells of the kidney is induced by decreased arterial blood pressure, decreased sodium content in the distal convoluted tubule, and increased sympathetic tone.

Causes

Causes of acute adrenal insufficiency are mainly sudden withdrawal of long-term corticosteroid therapy, Waterhouse–Friderichsen syndrome, and stress in people with underlying chronic adrenal insufficiency. The latter is termed critical illness–related corticosteroid insufficiency.

For chronic adrenal insufficiency, the major contributors are autoimmune adrenalitis (Addison's Disease), tuberculosis, AIDS, and metastatic disease.

Adrenal destruction

Autoimmune adrenalitis (Addison's disease) is the most common cause of primary adrenal insufficiency in the industrialised world, causing 80–90% of cases since 1950. This may be isolated or in the context of autoimmune polyendocrine syndrome (APS type 1 or 2), in which other hormone-producing organs, such as the thyroid and pancreas, may also be affected.

Autoimmune adrenalitis may be part of type 2 autoimmune polyglandular syndrome, which can include type 1 diabetes, hyperthyroidism, and autoimmune thyroid disease (also known as autoimmune thyroiditis, Hashimoto's thyroiditis, and Hashimoto's disease). Hypogonadism may also present with this syndrome. Other diseases that are more common in people with autoimmune adrenalitis include premature ovarian failure, celiac disease, and autoimmune gastritis with pernicious anemia.

Adrenal destruction is a feature of adrenoleukodystrophy (ALD). Destruction also occurs when the adrenal glands are involved in metastasis (seeding of cancer cells from elsewhere in the body, especially lung), hemorrhage (e.g. in Waterhouse–Friderichsen syndrome or antiphospholipid syndrome), particular infections which can spread to the adrenal cortex (tuberculosis, histoplasmosis, coccidioidomycosis), or the deposition of abnormal protein in amyloidosis.

Impaired steroidogenesis

To form cortisol, the adrenal gland requires cholesterol, which is then converted biochemically into steroid hormones. Interruptions in the delivery of cholesterol include Smith–Lemli–Opitz syndrome and abetalipoproteinemia.

Of the synthesis problems, congenital adrenal hyperplasia is the most common (in various forms: 21-hydroxylase, 17α-hydroxylase, 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase), lipoid CAH due to deficiency of StAR and mitochondrial DNA mutations. Use of steroids joint injections may also result in adrenal suppression after discontinuation.

Adrenal dysgenesis

All causes in this category are genetic and generally very rare. These include mutations to the SF1 transcription factor, congenital adrenal hypoplasia due to DAX-1 gene mutations and mutations to the ACTH receptor gene (or related genes, such as in the Triple A or Allgrove syndrome). DAX-1 mutations may cluster in a syndrome with glycerol kinase deficiency with a number of other symptoms when DAX-1 is deleted together with a number of other genes.

To confirm inappropriately low cortisol secretion, testing may include baseline morning cortisol level in the blood or morning cortisol level in the saliva.

In children, congenital adrenal hyperplasia (CAH) is the most common cause of adrenal insufficiency, with an incidence of 1 in 14,200 live births.