Primary Aldosteronism Subtypes: Pathophysiology and Steroid Signatures

摘要 原发性醛固酮增多症(PA)是最常见的肾上腺疾病，也是 内分泌性高血压。PA与心血管发病率和死亡率相关，这是不成比例的 与同等程度的高血压病患者相比更高。两大 PA的类型是单侧PA(典型的产生醛固酮的腺瘤，APA，约40%的PA病例)，它可以 通过手术和双侧醛固酮增多症(BHA，约占PA病例的60%)治愈，这需要终生 有针对性的药物治疗。尽管PA的发病率很高，而且有严重的心脏和肾脏并发症，但它是 诊断不足，部分原因是诊断和分型的步骤复杂、昂贵和侵入性。 肾上腺显像不能准确地确定醛固酮过量产生的来源(S)。因此， 目前对PA亚型的标准护理是肾上腺静脉采样(AVS)，从技术上讲，这是一种侵入性的 具有挑战性且标准化程度低的程序，仅限于三级转诊中心。 本申请的总体目标是：1)确定各种APA的类固醇合成能力 通过对APA组织进行全面的组织学、基因组和类固醇图谱分析；2)结合 基线和动态血液测试，以确定外周血中PA亚型的类固醇特征。这 该方法将在超过60%的PA患者(BHA)中消除对AVS的需求。制定了两个具体目标 以解决PA患者护理方面的严重差距。·在目标1中，我们将探讨APAS的工作假设 与不同的潜在的醛固酮驱动的体细胞突变有特定的类固醇指纹。我们将实施 细胞色素P11B2免疫组织化学引导下一代测序(NGS)鉴定体细胞 APA的潜在突变。同时，我们将使用最先进的质谱学来定义类固醇 来自：(A)最佳切割温度(OCT)包埋的APA组织；(B)来自肾上腺的血液 引流这些肿瘤的静脉；以及(C)外周血。·在目标2中，我们将测试面板的工作假设 外周血中类固醇生物标志物的含量可以区分APA与BHA和Essential 高血压。我们将实施基线和动态测试(ACTH刺激和地塞米松 抑制)，以确定PA亚型的类固醇信号之间的差异。质谱学将是 用于量化PA和原发性高血压患者的类固醇。这种方法将直接解决 临床上迫切需要简化PA的诊断和分型，并将采取必要的步骤来实现我们的长期 目的：扩大PA个体化治疗，最大限度地提高PA治愈病例数。

ABSTRACT Primary aldosteronism (PA) is the most common adrenal disorder and the most common cause of endocrine hypertension. PA is associated with cardiovascular morbidity and mortality that are disproportionately higher compared to those observed in patients with similar degree of essential hypertension. The two major types of PA are unilateral PA (typically an aldosterone producing adenoma, APA, ~40% of PA cases), which can be cured with surgery, and bilateral hyperaldosteronism (BHA, ~60% of PA cases), which requires life-long targeted medical therapy. Despite its high prevalence and serious cardio-renal complications, PA is underdiagnosed, in part because the steps for diagnosis and subtyping are complicated, costly, and invasive. Adrenal imaging is inaccurate in identifying the source(s) of excessive aldosterone production. Consequently, the current standard-of-care for PA subtyping is adrenal vein sampling (AVS), which is an invasive, technically challenging, and poorly standardized procedure, with availability limited to tertiary referral centers. The overall objectives of this application are: 1) to define the steroid synthetic capacity of various APAs by implementing comprehensive histologic, genomic and steroid profiling analyses of APA tissue; 2) combine baseline and dynamic blood tests to define the steroid signatures of PA subtypes in peripheral blood. This approach will eliminate the need for AVS in over 60% PA patients (BHA). Two specific aims have been designed to address critical gaps in the care of PA patients. • In Aim 1, we will probe the working hypothesis that APAs with distinct underlying aldosterone-driver somatic mutations have specific steroid fingerprints. We will implement CYP11B2 immunohistochemistry-guided next-generation sequencing (NGS) to characterize the somatic mutations underlying APAs. In parallel, we will use state-of-the-art mass spectrometry to define the steroid profiles of APAs from: (a) optimal cutting temperature (OCT)-embedded APA tissue; (b) blood from the adrenal veins draining these tumors; and (c) peripheral blood. • In Aim 2, we will test the working hypothesis that panels of steroid biomarkers measured in peripheral blood can distinguish APAs from both BHA and essential hypertension. We will implement baseline and dynamic testing (ACTH stimulation and Dexamethasone suppression) to identify differences between the steroid signatures of PA subtypes. Mass spectrometry will be used to quantify steroids in patients with PA and essential hypertension. This approach will directly address the critical clinical need to simplify PA diagnosis and subtyping and will take essential steps towards our long-term goal, of expanding personalized PA treatment and maximizing the number of cured PA cases.