The cause of Addison’s disease is adrenal insufficiency. There are three major ways through which adrenal gland produce insufficient cortisol. The three ways are, adrenal dysgenesis (incomplete and inadequate development of adrenal glands), impaired steroidogenesis (despite presence of adrenal it is unable to produce cortisol biochemically), and adrenal destruction (due to some disease process).

Impaired steroidogenesis in causation of Addison’s disease:

For formation of cortisol in adrenal gland, cholesterol is required, which is than converted into steroid hormones biochemically. Any disruption/interruption (such as abetalipoproteinemia) in the delivery of cholesterol may result in impaired formation of hormones (steroid hormones). Some medications also interfere with steroid synthesis enzymes (e.g. ketoconazole) which synthesize steroid hormones and some medications increase breakdown of hormones (e.g. rifampicin, phenytoin) in the liver. Congenital adrenal hypoplasia results in problem in the synthesis of steroid hormones by affecting different enzymes (e.g. 21-hydroxylase, 17alpha-hydroxylase, 11beta-hydroxylase etc.) involved in synthesis of hormones.

Adrenal dysgenesis in causation of Addison’s disease:

The cause of adrenal dysgenesis is genetic and its occurrence is rare. Mutation occurs in DAX-1 gene to cause congenital adrenal hypoplasia, ACTH receptor gene, SF1 transcription factor etc. and result in interruption of synthesis of steroid hormones.

Adrenal destruction in causation of Addison’s disease:

One of the commonest causes of destruction of adrenal tissue is autoimmune destruction (autoimmune adrenalitis). Autoimmune adrenalitis results in autoimmune destruction of adrenal cortex due to immune reaction to 21-hydroxylase enzyme.

Destruction of adrenal gland tissue may also occur due to hemorrhage, due to metastasis of cancer (from lung), adrenoleukodystrophy (ALD), due to deposition of abnormal protein as seen in amyloidosis, infection such as tuberculosis, histoplasmosis, coccidioidomycosis etc.

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