Monogenic Forms of Low-Renin Hypertension

Vesna D Garovic; Anthony A Hilliard; Stephen T Turner


Nat Clin Pract Nephrol. 2006;2(11):624-630. 

In This Article

Syndrome of Apparent Mineralocorticoid Excess

Both cortisol and aldosterone are potent activators of renal MCRs. In vitro, cortisol is a tenfold more potent activator of the MCR than aldosterone. In the kidney, 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2) converts cortisol to cortisone, which does not activate the renal MCR. This mechanism thereby protects the collecting tubules from inappropriate activation of the MCR by circulating cortisol. The autosomal recessive syndrome of apparent mineralocorticoid excess causes severe hypertension through mutations in the 11β-HSD-2 gene (Figure 3B), which render the enzyme ineffective.[16] This allows cortisol, which circulates at much higher concentrations than aldosterone, to saturate the MCR and induce hypertension and hypokalemia.

This disorder typically presents in childhood with hypertension, hypokalemia, and suppressed renin and aldosterone levels. An increased ratio of cortisol-to-cortisone metabolites in the urine is the hallmark of the syndrome. Treatment consists of spironolactone, which blocks binding of both cortisol and aldosterone to the MCR. Adjunctive treatments are potassium supplementation and a low-sodium diet. Dexamethasone can sometimes correct hypokalemia by suppressing cortisol formation via feedback inhibition of ACTH, but this agent lacks a consistent antihypertensive effect.[8]

There are several acquired forms of apparent mineralocorticoid excess that are more common than congenital forms, and therefore need to be considered in the differential diagnosis. A component of black licorice, glycyrrhetinic acid, inhibits 11β-dehydrogenase, thereby increasing levels of cortisol and saturating the MCR.[17] Conditions associated with ectopic ACTH release, such as small cell lung cancer, might cause apparent mineralocorticoid excess by inducing such high cortisol levels that the capacity of the 11β-dehydrogenase enzyme to convert cortisol to cortisone is exceeded.[18] Affected individuals typically present with hypertension and hypokalemic alkalosis; cushingoid features are usually absent due to malignant cachexia. A dexamethasone suppression test might lead to the diagnosis by demonstrating nonsuppressible hypersecretion of ACTH and cortisol. The prognosis in these patients is ultimately dependent on progression of the underlying malignancy. Commonly, the prognosis is grave, as ectopic ACTH syndrome, like other paraneoplastic syndromes, is frequently associated with advanced disease.


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