Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia.
School of Molecular Science, College of Science, Health and Engineering, La Trobe University, Bundoora, VIC 3086, Australia.
World J Gastroenterol. 2020 Oct 28;26(40):6111-6140. doi: 10.3748/wjg.v26.i40.6111.
Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, which target the components of the classical renin angiotensin system (RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant off-target effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective -blockers (NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs. Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.
门静脉高压症和食管胃静脉曲张出血是肝硬化患者发病率和死亡率的主要原因。门静脉高压症是由肝内血管阻力增加和高动力循环状态引起的。后者的特征是心输出量高、总血容量增加和内脏血管扩张，导致肠系膜血流量增加。对肝硬化门静脉高压症的药理学干预针对内脏和肝血管床。血管紧张素转换酶抑制剂和血管紧张素 II 型受体 1 阻滞剂等药物针对经典肾素血管紧张素系统（RAS）的成分，预计通过减少细胞外基质沉积和收缩性细胞的血管活性来降低肝内血管张力，从而改善门静脉高压症。然而，这些药物已显示出显著的脱靶效应，如全身低血压和肾功能衰竭。因此，目前临床实践中预防静脉曲张出血和通过降低门静脉压改善患者生存的药理学主要手段是非选择性β受体阻滞剂（NSBBs）。这些 NSBB 通过降低心输出量和内脏血管扩张起作用，但大多数患者无法获得最佳治疗反应，而且相当一部分患者无法耐受这些药物。尽管他汀类药物单独使用或与 NSBB 联合使用已被证明可改善肝硬化患者的门静脉压力和总体死亡率，但仍需要进行涉及更大患者人群和明确临床终点的随机临床试验。另一方面，最近对研究替代 RAS 成分潜在用途的研究结果提供了令人信服的证据，这可能导致开发针对内脏血管床的药物，以抑制门静脉高压症中的内脏血管扩张。这篇综述概述了与门静脉高压症发病机制相关的机制，并尝试提供目前可用的治疗方法的最新信息，特别强调如何操纵替代 RAS，以寻找安全、特异和有效的新型疗法来治疗肝硬化中的门静脉高压症。
