Metabolic phenotypes and fatty acid profiles associated with histopathology of primary aldosteronism

Abstract

Primary aldosteronism (PA) caused by aldosterone hypersecretion is treated by adrenalectomy or medications. Histopathologic examination of resected adrenals reveals diverse histopathologic features. This study aimed to investigate the potential association of peripheral and adrenal tissue metabolic profiles with the histopathologic features of PA. The retrospective study included 105 surgically treated and 43 medically treated patients with PA. Adrenal specimens were categorized according to the HISTALDO (HISTopathology of primary ALDOsteronism) consensus. Peripheral and adrenal tissue metabolic profiles were assessed, including adiposity, adipokines and fatty acid abundances. The distinct fatty acid, arachidonic acid, was further functionally characterized. Surgically treated patients with classical histopathologic findings (n = 71) displayed lower body mass indexes, a lower prevalence of obesity, smaller waist circumference and visceral adipose tissue areas, and lower leptin concentrations compared with operated patients with the nonclassical histopathology (n = 34). No such differences were identified between the nonclassical histopathology group and medically treated group. Distinct concentrations of 18 out of 35 peripheral venous fatty acids, including arachidonic acid, were identified among the 3 groups. Further, accumulation of arachidonic acid was demonstrated in 4 aldosterone-producing adenomas compared with paired adjacent cortex possibly linked with suppressed peroxisomal beta-oxidation. Stimulation of human adrenocortical cells with arachidonic acid or peroxisomal beta-oxidation inhibitor caused 3.8-fold (P = 0.0050) and 1.7-fold (P = 0.0328) amplification of CYP11B2 expression, respectively, which were ablated by BAPTA-AM or KN93, and induced oxidative stress and apoptosis. Our findings show metabolic heterogeneity related to histopathology and support a role for arachidonic acid in PA pathophysiology.