Old and New Concepts in the Molecular Pathogenesis of Primary Aldosteronism

Primary aldosteronism (PA) was first reported by Jerome Conn from the University of Michigan and is characterized by hypertension with excessive, autonomous production of aldosterone relative to suppressed renin levels. Once thought to be a rare condition, it is now known to be the most common form of endocrine hypertension. The overall prevalence in the general hypertensive population was recently demonstrated to be 5.9% increasing with the severity of hypertension (3.9-11.8%, grade I-III hypertension) to as much as 20% in patients with resistant hypertension. An early diagnosis followed by correct treatment has an important impact on clinical outcome because it can reverse the increased risk of cardiovascular and cerebrovascular complications associated with PA. PA can be familial caused by either of the 4 currently recognized subtypes (Familial Hyperaldosteronism types I-IV) or arise sporadically in which the aldosterone excess is unilateral [usually caused by an aldosterone-producing adenoma (APA)] or bilateral [usually caused by bilateral adrenal hyperplasia (BAH)]. The unilateral and bilateral forms of PA should be differentiated because a patient with unilateral APA is most appropriately treated by adrenalectomy, which normalizes or improves blood pressure in 84% of cases, and a patient with BAH is treated in almost all cases with a mineralocorticoid antagonist. Until 2011, the genetic basis of PA was largely unknown when in an unprecedented development germline mutations causing new familial forms of PA and somatic mutations driving aldosterone excess in the majority of sporadic unilateral APAs were uncovered. The development of specific monoclonal antibodies to the highly homologous human CYP11B2 and CYP11B1 enzymes identified novel histological structures and evolved our understanding of the pathophysiology of aldosterone overproduction. Herein we comprehensively cover what is old and what is new in the rapidly developing field of the pathogenesis of PA and focus on discoveries from genetics to histopathology of the last 3 years.