原发性醛固酮增多症肾上腺皮质腺瘤的 分子机制研究进展

Research Progress on the Molecular Mechanisms of Aldosterone-Producing Adrenocortical Adenomas in Primary Aldosteronism

摘要: 原发性醛固酮增多症(PA)是一种因肾上腺皮质自主分泌过量醛固酮导致的内分泌性高血压疾病，其中心亚型——分泌醛固酮的肾上腺皮质腺瘤(APA)具有高度异质性和复杂分子机制。近年来，随着高通量测序技术的发展，APA的分子机制研究取得重要进展。本文系统综述了APA在流行病学、诊断挑战、基因表达特征及分子分型等方面的最新研究。流行病学数据显示PA在高血压人群中患病率可达5%~20%，且与心血管风险显著相关。分子机制上，约90%的APA存在体细胞突变，涉及KCNJ5、CACNA1D、ATP1A1、ATP2B3等基因，这些突变通过影响离子通道功能导致细胞内钙信号异常激活，进而驱动醛固酮合成限速酶CYP11B2高表达。全转录组分析进一步揭示了基于不同驱动突变的分子亚型(如KCNJ5突变型、CACNA1D突变型和CTNNB1突变型)，各亚型具有独特的转录特征与临床表型。这些机制研究已逐步转化为临床实践，包括CYP11B2免疫组化病理诊断、基因分型指导治疗决策以及新型PET示踪剂的开发。未来，通过多组学整合与空间转录组学等技术，有望实现APA的精准分型与个体化治疗，改善患者预后。

Abstract: Primary aldosteronism (PA) is an endocrine hypertensive disorder caused by autonomous excessive secretion of aldosterone from the adrenal cortex. Its central subtype, the aldosterone-producing adrenocortical adenoma (APA), exhibits high heterogeneity and complex molecular mechanisms. In recent years, significant progress has been made in understanding APA pathology with the advancement of high-throughput sequencing technologies. This review systematically summarizes the latest research on APA regarding epidemiology, diagnostic challenges, gene expression characteristics, and molecular classification. Epidemiological data indicate that PA affects 5%~20% of hypertensive populations and is significantly associated with increased cardiovascular risk. At the molecular level, approximately 90% of APAs harbor somatic mutations involving genes such as KCNJ5, CACNA1D, ATP1A1, and ATP2B3. These mutations impair ion channel function, leading to aberrant activation of intracellular calcium signaling, which in turn drives the overexpression of CYP11B2 (the rate-limiting enzyme in aldosterone synthesis). Whole-transcriptome analyses have further identified molecular subtypes based on distinct driver mutations (e.g., KCNJ5-mutant, CACNA1D-mutant, and CTNNB1-mutant subtypes), each characterized by unique transcriptional signatures and clinical phenotypes. These mechanistic insights have gradually translated into clinical practice, including CYP11B2 immunohistochemistry for pathological diagnosis, genetic profiling to guide therapeutic decisions, and the development of novel PET tracers. Future integration of multi-omics approaches and spatial transcriptomics is expected to enable precise molecular subtyping and personalized treatment of APA, ultimately improving patient outcomes.