Hypoadrenalism



adrenal histology
Cortex zona glomerulosa mineralocorticoids
zona fasciculata glucocorticoids
zona reticularis sex steroids
Medulla catecholamines


During severe illness

1µg corticotrophin test is recommended, with 30-minute cortisol <690 nmol/l or increment <250 nmol/l being inadequate. An 'inadequate' response occurs in around 60% of patients with severe sepsis, though CBG is also reduced and free cortisol is likely to be higher than indicated by total cortisol levels.


Causes of adrenocortical insufficiency
Drugs Inhibition of cortisol synthesis
  • P450 aromatase (CYP19A1) - aminglutethimide
  • 3βHSD 2 - trilostane
  • Mitochondrial P450 dependent enzymes - ketoconazole, fluconazole, etomidate
Activation of cortisol metabolism NB may cause adrenal insufficiency in patients already taking glucocorticoids
P450 cytochromes - phenobarbital, phenytoin, rifampicin, topiramate
Suppression of CRH and ACTH Glucocorticoids, opioids, ketoroloac, medyroxyprogesterone
Peripheral resistance to glucocorticoids
  • Interaction with GC receptor - mifepristone
  • Inhibition of GC-induced gene transcription - chlorpromazine, imipramine
Polyglandular syndromes Autoimmune polyglandular syndrome type 1 Autoimmune regulator (AIRE) - autosomal recessive - also hypoparathyroidism and mucocutaneous candidiasis
Autoimmune polyglandular syndrome type 2 Gene not identified - autosomal dominant with variable penetrance - also Hashimoto's, Graves', T1DM, pernicious anaemia, coeliac, hypogonadism, myasthenia, seronegative arthritis
Disorders of steroid synthesis and cholesterol metabolism Classical 21-OH deficient CAH Cannot mount stress response and should receive standard 'sick day' advice
Non-classical 21-OH deficient CAH Should not require stress dosing unless rendered iatrogenically hypoadrenal. White (2000) states unaware of any such patient rendered hypoadrenal, as usually ACTH will be elevated, but prudence suggests stress dosing in extreme situations.
3β-hydroxysteroid dehydrogenase type II Ambiguous genitalia, hirsutism, with or without salt-wasting - more
Steroid 11β-hydroxylase Virilization, cortisol deficiency, hypertension due to excess DOC - more
Steroid 17α-hydroxylase Hypertension, amenorrhoea, sexual infantilism
P450 oxidoreductase
Steroidogenic acute regulatory protein (STAR) Severe glucocorticoid and mineralocorticoid deficiency
Lipid storage disorders X-linked adrenoleucodystrophy X-linked recessive lipid storage disease, with impaired capacity to degrade very long chain fatty acids. Various clinical presentations, most with some (clinical or subclinical) adrenal involvement:
  • Childhood cerebral - onset usually <10years, inflammatory demyelination, rapid cognitive & behavioural decline and disability.
  • Adult adrenomyeloneuropathy - onset usually 20-40 years, paraparesis over decades, late cognitive decline.
  • Adrenal failure only.
  • Carrier without clinical penetrance.
Hypothalamic and pituitary failure PROP1 mutation Pituitary transcription factor paired-like homeobox 1: typically ACTH deficiency requiring steroid replacement at about 18 years
Prader-Willi syndrome Secondary adrenal insufficiency in 60% of cases - 'sick day' steroid replacement recommended unless known normal adrenal function.
Pro-opiomelanocortin (POMC) Early onset obesity, red hair, pigmentation
ACTH receptor and signalling Familial glucocorticoid deficiency 1 Melanocortin 2 receptor MC2R (ACTH) - hyperpigmentation, facial features, tall, lethargy, normal BP
Familial glucocorticoid deficiency 2 Melanocortin 2 receptor accessory protein (MRAP) - hyperpigmentation, facial features, tall, lethargy, normal BP