Pathogenesis of Primary Aldosteronism: Impact on Clinical Outcome

Abstract

Primary aldosteronism (PA) is the most common form of secondary arterial hypertension, with a prevalence of approximately 20% in patients with resistant hypertension. In the last decade, somatic pathogenic variants in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 genes, which are involved in maintaining intracellular ionic homeostasis and cell membrane potential, were described in aldosterone-producing adenomas (aldosteronomas). All variants in these genes lead to the activation of calcium signaling, the major trigger for aldosterone production. Genetic causes of familial hyperaldosteronism have been expanded through the report of germline pathogenic variants in KCNJ5, CACNA1H and CLCN2 genes. Moreover, PDE2A and PDE3B variants were associated with bilateral PA and increased the spectrum of genetic etiologies of PA. Of great importance, the genetic investigation of adrenal lesions guided by the CYP11B2 staining strongly changed the landscape of somatic genetic findings of PA. Furthermore, CYP11B2 staining allowed the better characterization of the aldosterone-producing adrenal lesions in unilateral PA. Aldosterone production may occur from multiple sources, such as solitary aldosteronoma or aldosterone-producing nodule (classical histopathology) or clusters of autonomous aldosterone-producing cells without apparent neoplasia denominated aldosterone-producing micronodules (non-classical histopathology). Interestingly, KCNJ5 mutational status and classical histopathology of unilateral PA (aldosteronoma) have emerged as relevant predictors of clinical and biochemical outcome, respectively. In this review, we summarize the most recent advances in the pathogenesis of PA and discuss their impact on clinical outcome.

Advances in Medical Treatment of Primary Aldosteronism

“…Although PA occurs mainly as sporadic disease, about 5% of PA patients are observed in families and inherited by autosomal dominant traits. Four different Mendelian forms of PA (types I to IV) familial hyperaldosteronism (FH) have been identified 7,8 .…”

The Entity of Connshing Syndrome: Primary Aldosteronism with Autonomous Cortisol Secretion

“…Adrenal tumours display a highly heterogeneous profile with respect to molecular and pathological/immunohistochemistry profile, as well as genetic background, and this field has recently seen spectacular progress [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 ].…”

“…Traditionally, PA is associated with an adrenal tumour, bilateral adrenal hyperplasia, adrenal cortex carcinoma and ectopic aldosterone production, but benign adrenal sources are described as aldosteronona (solitary tumour), aldosterone-producing nodule or multiple micronodules (non-classical type), respective bilateral adrenal disease; for instance, unilateral PA may underline a unilateral single or multiple aldosterone-producing adenoma or an aldosterone-producing cell cluster [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 127 , 128 , 129 , 130 , 131 , 135 , 136 ].…”

“…PA is caused by somatic mutations of KCNJ5 (with predictive potential), CACNA1D , CACNA1H, CLCN2, ATP1A1 and ATP2B3 genes which are found in 60–80% of sporadic aldosteronomas (mostly KCNJ5 ). They involve ion channels or pumps associated transmembrane exchange triggering calcium-related signal transducing pathways that leads to aldosterone overproduction [ 127 , 128 , 129 , 130 , 131 , 137 ]. Familial PA (bilateral glands involvement in familial PA type I, II, III and IV) is associated with germline mutations of KCNJ5, CACNA1H and CLCN2 genes, and probably PDE2A and PDE3B variants [ 128 , 129 , 130 , 131 ].…”

“…They involve ion channels or pumps associated transmembrane exchange triggering calcium-related signal transducing pathways that leads to aldosterone overproduction [ 127 , 128 , 129 , 130 , 131 , 137 ]. Familial PA (bilateral glands involvement in familial PA type I, II, III and IV) is associated with germline mutations of KCNJ5, CACNA1H and CLCN2 genes, and probably PDE2A and PDE3B variants [ 128 , 129 , 130 , 131 ]. Recently, CYP11B2 staining in addition to a genetic workup improved the characterization of PA.…”