SOMATIC MUTATIONS IN ADRENALS FROM PATIENTS WITH PRIMARY ALDOSTERONISM NOT CURED AFTER ADRENALECTOMY SUGGEST COMMON PATHOGENIC MECHANISMS BETWEEN UNILATERAL AND BILATERAL DISEASE

Abstract

Objective: Primary aldosteronism (PA) is the most common form of secondary and curable hypertension, with a prevalence of 5% in primary care and 10% in referred patients. Different germline and somatic mutations are found in aldosterone producing adenoma (APA) and familial forms of the disease, while the causes of bilateral adrenal hyperplasia (BAH) remain largely unknown. Adrenalectomy is the recommended treatment for patients with aldosterone-producing adenoma (APA); however, 6% of patients are not cured and show persistent PA after surgery suggesting BAH. The objective of this study was to analyze clinical data of patients with APA without biochemical success after adrenalectomy and the histological and genetic characteristics of their adrenal glands. Design and method: Clinical data from 16 PA patients undergoing adrenalectomy between 2008 and 2018 without biochemical success were compared to those from 39 PA patients with hormonal cure after surgery. Histological, morphological and genetic characterization of the adrenals was carried out by CYP11B2 and CYP11B1 immunostaining and by CYP11B2 guided next generation sequencing on formalin-fixed paraffin-embedded APA tissues. Results: Patients with absent hormonal cure displayed longer duration of arterial hypertension before PA diagnosis and lower index of lateralization of aldosterone production on adrenal vein sampling. In 14 patients, APA expressing CYP11B2 were identified. No difference in histological and morphological characteristics was observed between patients with our without hormonal cure. Somatic mutations in APA driver genes were identified in 13 out of 14 CYP11B2 positive APA. Mutations in the CACNA1D gene were the most frequent genetic abnormality and associated with smaller nodules. The mutational status of APA in patients without hormonal cure was not associated with differences in CYP11B1 or CYP11B2 expression. Conclusions: In conclusion, 93% of adrenals from patients with absent hormonal cure showed CYP11B2 expressing adenomas carrying somatic mutations, confirming the diagnosis of APA. However, these patients were diagnosed later and exhibited lower lateralization index of aldosterone production, suggesting asymmetric aldosterone production in the context of BAH. Somatic mutations in adrenal glands from those patients indicate common mechanisms underlying BAH and APA.