11-beta-hydroxysteroid dehydrogenase inactivates cortisol in mineralocorticoid target tissues
Expansion
The mineralocorticoid receptor has equal affinity for cortisol and aldosterone, and cortisol circulates at concentrations 100 to 1000 times higher. Specificity is created enzymatically, not by the receptor.
11-beta-hydroxysteroid dehydrogenase type 2 in the distal nephron converts cortisol to cortisone, which does not bind the receptor. Aldosterone is protected from this enzyme by its structure.
Failure of this system causes apparent mineralocorticoid excess: hypertension, hypokalaemia and metabolic alkalosis with low aldosterone and low renin.
Causes:
- Liquorice, whose glycyrrhetinic acid inhibits the enzyme
- Congenital deficiency of the enzyme
- Ectopic ACTH syndrome, where cortisol concentrations are so high that the enzyme is overwhelmed, which is why hypokalaemic alkalosis is far more prominent there than in pituitary-dependent Cushing disease
Conversely, 11-beta-HSD type 1 in liver and fat converts inactive cortisone back to cortisol, which is why prednisone and cortisone acetate require hepatic activation and are ineffective in severe liver failure.