Basics: Pathophysiology

基础知识：病理生理学

In all forms of PA, aldosterone production is excessive to the body's requirements and relatively autonomous with regard to its normal chronic regulator, the renin-angiotensin II system. This results in excessive sodium re-absorption through amiloride-sensitive epithelial sodium channels within the distal nephron, leading to HTN and suppression of renin-angiotensin II. Urinary loss of potassium and hydrogen ions, exchanged for sodium at the distal nephron, may result in hypokalaemia and metabolic alkalosis if severe and prolonged enough. The exact causes of excessive, autonomous aldosterone production in aldosterone-producing adenoma and bilateral adrenal hyperplasia are unknown, but genetic factors related to adrenal cortical  ellular growth regulation and/or steroid biosynthesis are likely to be involved.

在各种形式的假性醛固酮增多症中，醛固酮的合成大于身体的需要。它的合成相对自主，不受其慢性调节因子—肾素-血管紧张素II系统—的影响。过多的醛固酮导致远端肾单位上皮细胞阿米洛利敏感钠通道的钠离子再吸收显著增加，进而促进原发性高血压的产生并抑制肾素-血管紧张素II系统。远端肾单位钾-钠和氢-钠交换的增加直接导致钾离子和氢离子从尿液的排出增加。病情严重或持久迁延的情况下可能会出现低钾血症和代谢性碱中毒。自主性醛固酮合成过多、醛固酮瘤及双侧肾上腺皮质增生症的确切原因不明。但一些遗传性因素—如肾上腺皮质细胞生长失调和/或类固醇生物合成失调—很可能参与其中。

In FH-I, the causative hybrid gene encodes a hybrid enzyme of unique structure that synthesises aldosterone but, unlike CYP11B2, is regulated by adrenocorticotrophic hormone (ACTH) and not by angiotensin II. Aldosterone production in FH-I is therefore regulated by ACTH rather than by angiotensin II, and can be suppressed and managed by administering small doses of glucocorticoids such as dexamethasone.

家族性醛固酮增多症I型患者的杂合基因编码生成一种分子结构独特的杂合酶。由此酶催化生成的醛固酮与CYP11B2型不同，它受促肾上腺皮质激素（ACTH）的调节，不受血管紧张素II的调节。家族性醛固酮增多症I型患者的醛固酮合成也因此受ACTH的调节而不是受血管紧张素II的调节，并可通过小剂量糖皮质激素（如地塞米松）进行干预治疗。

Mutations in KCNJ5 (which encodes an inwardly-rectifying potassium channel) lead to reduced potassium/sodium channel selectivity and sodium influx, predisposing to cell membrane depolarisation, increased calcium influx, increased expression of genes promoting aldosterone synthesis, and increased aldosterone production by adrenocortical cells. How these effects lead to adrenal cell proliferation and tumour development remains uncertain.

编码内向整流钾离子通道的KCNJ5基因的突变导致钾/钠离子通道的选择性降低、钠离子内流增加、诱发细胞膜去极化、钙离子内流增加、醛固酮合成基因的表达增加以及肾上腺皮质细胞醛固酮合成的增加。但这些效应引发肾上腺细胞增殖和肿瘤的机制仍不明确。

Although morbidity in PA mainly results from HTN, experimental and clinical evidence strongly suggests that aldosterone excess can bring about adverse cardiovascular sequelae (including remodelling and fibrosis) independently of its hypertensive effects. In animal studies, both aldosterone excess and a high salt intake appear to be necessary for induction of cardiac fibrosis, and coronary vasculitis has been observed to be an early manifestation. These effects were preventable by the administration of mineralocorticoid receptor antagonists. The doses of aldosterone used in experimental studies have been very large, and the results of these studies may, therefore, have limited applicability to clinical situations. Nevertheless, several groups have convincingly demonstrated abnormalities in cardiovascular morphology or function in patients with PA that appear to be out of proportion to the

elevation in BP. These have included:

假性醛固酮增多症的病症主要由原发性高血压引起，但是实验和临床证据充分表明醛固酮过多所导致的心血管不良后遗症（包括重塑和纤维化）与它的升压作用无关。动物研究表明醛固酮过量和高盐摄入似乎是心脏纤维化的两个必要条件。研究同时发现冠状动脉炎是心脏纤维化的早期表现之一。盐皮质激素受体拮抗剂治疗可以预防上述病理改变的发生。实验研究中所用的醛固酮剂量总是很大，因此，其研究结果在临床上的适用性可能有限。虽说如此，有些研究团体的结果清晰地表明假性醛固酮增多症患者的心血管形态和功能的改变与血压升高的状况似乎是不相称的。此类研究结果列举如下:

·        Increased left ventricular mass index and reduced diastolic function, both of which markedly improved following specific treatment of PA

·        Reduced myocardial perfusion at rest and during exercise

·        左心室质量指数增加和舒张功能降低，经过特异性假性醛固酮增多症治疗后两项指标均明显好转

·        静止或运动时的心肌灌注减少 

·        Increased myocardial backscatter (an echo marker of myocardial fibrosis)

·        Increased proteinuria (as evidence of renal glomerular damage)

·        心肌背向散射（心肌纤维化的回声标记）增加

·        蛋白尿增加（肾小球损害的标志）

·        A greater incidence of cardiovascular events, which was reversed following specific surgical or medical treatment.

·        Evidence of left ventricular remodelling was also reported in individuals with genetically proven FH-I who had biochemical evidence of aldosterone excess but had not yet developed HTN.

·        心血管事件的发生率较高，经相关手术或药物治疗后可逆转

·        研究结果证明遗传学证实为家族性醛固酮增多症I型且生化检查显示有醛固酮过多但还没有发展成为原发性高血压的个体有左室重构现象