Endocrine Abstracts

Primary Aldosteronism (PA), due to a unilateral aldosterone-producing adenoma of the adrenal (APA), is the commonest curable cause of Hypertension, but the prospects for cure fall with age. APAs rarely increase in size, suggesting an origin much earlier than the development of resistant hypertension. Most APAs have gain-of-function somatic mutations which result in increased Ca²⁺ entry, and constitutive activation of aldosterone production. Women with larger APAs, and cells resembling zona fasciculata (ZF) cells, are likely to have KCNJ5 mutation, whilst smaller APAs in men, with resemblance to zona glomerulosa (ZG) cells, are more likely to have mutations of ATP1A1, ATP2B3, CTNNB1 or CACNA1D.^1,2 The number of different gain-of-function mutations within one gene (19 in CACNA1D), and overall frequency of APAs, suggest a common driver, which we believe may, paradoxically, be salt. A striking difference between ZG of human adrenals and other species is the sparseness of aldosterone synthase expression, and an irregular, even atrophic, ZG. A microarray of ZG cells found several genes which are many-fold upregulated in human ZG (vs ZF) that do not feature in similar analysis of rat adrenals.³ Functional analysis of some of these genes (e.g. LGR5, DACH1) showed that they inhibit aldosterone production. Since the CYP11B2^−/− mouse, and monkeys treated with a selective aldosterone synthase inhibitor, have apoptotic ZG cells, we hypothesize that aldosterone protects against apoptosis, and that the prevailing salt-induced suppression of aldosterone in human ZG selects for ZG cells with mutations causing constitutive aldosterone production. The selective advantage comes not from proliferation, but from synthesis of aldosterone. Indeed, on ¹¹C-metomidate PET CT, ZG-like APAs are often detected as small, bright hot spots within adrenals previously reported as ‘normal’, and immunohistochemistry shows an inverse correlation between size and CYP11B2 density.

References

1. Azizan EA, Poulsen H, Tuluc P, et al. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet 2013; 45: 1055–60.

2. Teo AED, Garg S, Haris Shaikh L et al. Pregnancy, Primary Aldosteronism, and Adrenal CTNNB1 Mutations. New England Journal of Medicine. 2015; 373:1429–1436.

3. Haris Shaikh L, Zhou J, Teo AE, et al. LGR5 Activates Noncanonical Wnt Signaling and Inhibits Aldosterone Production in the Human Adrenal. J Clin Endocrinol Metab 2015; 100: E836–44.