Table 2.
Major Etiologies of PAI and Associated Features
| Etiology | Associated Features |
|---|---|
| Autoimmune | |
| Isolated | Not associated with other autoimmune disorders |
| APS type 1 (APECED) | Chronic cutaneous candidiasis, hypoparathyroidism |
| APS type 2 | Autoimmune thyroid disease, type 1 diabetes |
| Adrenal—infiltration/injury | |
| Adrenal hemorrhage | Associated with sepsis, anticoagulants, anti-cardiolipin/lupus anti-coagulant syndrome |
| Adrenal metastases | Malignancies: lung, breast, colon, melanoma, lymphoma |
| Infections: adrenalitis | Tuberculosis, HIV/AIDS, CMV, candidiasis, histoplasmosis, syphilis, African trypanosomiasis, paracoccidioidomycosis (eg, in South America) |
| Infiltration | Hemochromatosis, primary amyloidosis |
| Bilateral adrenalectomy | Procedure for intractable Cushing's syndrome or bilateral pheochromocytoma |
| CAH: most forms can cause salt loss | Commonest cause of PAI in children (80%); may be diagnosed in older individuals |
| 21-Hydroxylase deficiency | Commonest type of CAH is 21-hydroxylase deficiency, with associated hyperandrogenism |
| 11β-hydroxylase deficiency | Hyperandrogenism, hypertension (in older children and adults) |
| 3β-hydroxysteroid dehydrogenase II deficiency | Ambiguous genitalia in boys, hyperandrogenism in girls |
| P450 side-chain cleavage deficiency (CYP11A1 mutations) | XY sex reversal |
| P450 oxidoreductase deficiency | Skeletal malformations, abnormal genitalia |
| Congenital lipoid adrenal hyperplasia (StAR mutations) | XY sex reversal |
| Adrenal hypoplasia congenita | X-linked NROB1, Xp21 deletion (with Duchenne's muscular deficiency), SF-1 mutations (XY sex reversal), IMAGe syndrome |
| ACTH insensitivity syndromes | Type 1: ACTH receptor, melanocortin 2 receptor gene MC2R |
| Type 2: MRAP | |
| Familial glucocorticoid deficiency (MCM4, NNT, TXNRD2) | |
| TripleA (Allgrove's) syndrome, achalasia, Addison's disease, alacrima, AAAS gene mutation | |
| Drug-induced | Adrenal enzyme inhibitors: mitotane, ketoconazole, metyrapone, etomidate, aminoglutethimide, drugs that may accelerate cortisol metabolism and induce adrenal insufficiency |
| T4 also accelerates cortisol metabolism (at least in part through stimulation of 11β-HSD2) | |
| CTLA-4 inhibitors may enhance autoimmunity and cause PAI | |
| Other metabolic disorders | Mitochondrial disease (rare) |
| Adrenoleukodystrophy in males | |
| Wolman's disease |
Abbreviations: APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; CMV, cytomegalovirus; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CYP, cytochrome P; HSD, hydroxysteroid dehydrogenase; 11β-HSD2, 11β-hydroxysteroid dehydrogenase type 2; IMAGe, intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, genital abnormalities; MC2R, melanocortin 2 receptor gene; MCM4, minichromosome maintenance-deficient 4; MRAP, melanocortin receptor accessory protein; NNT, nicotinamide nucleotide transhydrogenase; StAR, steroidogenic acute regulatory protein; TXNRD2, thioredoxin reductase 2. [Derived from E. Charmandari E, et al: Adrenal insufficiency. Lancet. 2014;383:2152–2167 (164), with permission. © Elsevier.]