A large number of frequent and rare causes of adrenal insufficiency are summarized in Tables 1 and 2, and in the following sections more detailed information on some of the more frequent causes is provided. Two reviews have given an excellent overview of causes of adrenal insufficiency including citation of all original literature which cannot be provided here because of space constraints.
Table1. Causes of primary adrenal insufficiency
Table1. Continued
Table2. Causes of secondary adrenal insufficiency
causes of Primary Adrenal Insufficiency
During the times of Thomas Addison, tuberculous adrenalitis was by far the most prevalent cause of adrenal insufficiency. In the developing world, tuberculosis still remains a major cause of ad renal insufficiency. In active tuberculosis, the incidence of adrenal involvement is 5%.
In North American and European countries, autoimmune adrenalitis accounts for more than 90% of cases with primary adrenal insufficiency; in 40% adrenal insufficiency is isolated while in 60% it arises as part of an autoimmune polyendocrine syndrome (APS). APS type 1, also termed autoimmune polyendocrinopathy– candidiasis– ectodermal dystrophy, accounts for 15% of cases and is characterized by adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous candidiasis, the latter being the primary manifestation in most cases and already apparent in childhood. APS 1 is caused by mutations in the autoimmune regulator gene (AIRE) while APS 2 is thought to be inherited as a complex trait, associated with loci within the major histocompatibility complex and distinct susceptibility genes. APS 2 is much more common than APS 1 and in addition to adrenal insufficiency most frequently comprises autoimmune thyroid disease, albeit more often autoimmune hypothyroidism than Graves’ disease.
X- linked adrenoleukodystrophy (ALD) is caused by a mutation in the X- ALD gene, which encodes a peroxisomal membrane protein (adrenoleukodystrophy protein), leading to accumulation of very long chain fatty acids (>24 carbon atoms). The clinical picture comprises adrenal insufficiency and neurological impairment due to white matter demyelination. The two major forms are cerebral ALD (50% of cases; early childhood manifestation, rapid progression) and adrenomyeloneuropathy (35% of cases; onset in early adult hood, slow progression) with restriction of demyelination to spinal cord and peripheral nerves. Adrenal insufficiency may precede the onset of neurological symptoms and is the sole manifestation of dis ease in 15% of cases.
Other causes of primary adrenal insufficiency (Table 1), e.g. adrenal infiltration or haemorrhage, are rare. Congenital or neonatal primary adrenal insufficiency accounts for only 1% of all cases. However, the recent elucidation of the genetic basis of underlying diseases has highlighted the importance of specific genes for adrenal development and steroidogenesis (see Chapter 5.8.1).
causes of Secondary Adrenal Insufficiency
The most common cause of secondary adrenal insufficiency is a tumour of the hypothalamic– pituitary region, usually associated with panhypopituitarism as a result of tumour growth or treatment with surgery and/ or irradiation (Table 2). Autoimmune lymphocytic hypophysitis is less frequent, mostly affecting women during or shortly after pregnancy. Isolated ACTH deficiency may also be of autoimmune origin as some patients concurrently suffer from other autoimmune disorders, most frequently thy roid disease. The differential diagnosis of postpartal autoimmune hypophysitis includes Sheehan’s syndrome, which results from pituitary apoplexy, mostly due to pronounced blood loss during delivery. Very rarely mutations of genes important for pituitary development or for synthesis and processing of the corticotropin precursor proopiomelanocortin cause secondary adrenal insufficiency (Table 2).
