Portal hypertension is an increase in pressure in the portal vein and its tributaries. It is defined as a portal pressure gradient (the difference in pressure between the portal vein and the hepatic veins) greater than 5 mm Hg. Although this gradient defines portal hypertension, a gradient of 10 mm Hg or greater defines clinically significant portal hypertension, because this pressure gradient predicts the development of varices, decompensation of cirrhosis, and hepatocellular carcinoma. The most direct consequence of portal hypertension is the development of gastroesophageal varices that may rupture and lead to the development of variceal hemorrhage. This article reviews the pathophysiologic bases of the different pharmacologic treatments for portal hypertension in patients with cirrhosis and places them in the context of the natural history of varices and variceal hemorrhage.
Portal hypertension is an increase in pressure in the portal vein and its tributaries. It is defined as a portal pressure gradient (the difference in pressure between the portal vein and the hepatic veins) greater than 5 mm Hg. Although this gradient defines portal hypertension, a gradient of 10 mm Hg or greater defines clinically significant portal hypertension, because this pressure gradient predicts the development of varices, decompensation of cirrhosis, and hepatocellular carcinoma. The most direct consequence of portal hypertension is the development of gastroesophageal varices that may rupture and lead to the development of variceal hemorrhage. This article reviews the pathophysiologic bases of the different pharmacologic treatments for portal hypertension in patients with cirrhosis and places them in the context of the natural history of varices and variceal hemorrhage.
Pathophysiology of portal hypertension
Anatomically, the portal vein is formed by the union of the superior mesenteric vein and the splenic vein. The mesenteric vein collects blood from the splanchnic circulation. Thus, portal venous inflow is determined by the state of constriction or dilatation of splanchnic arterioles.
The initial mechanism in the genesis of portal hypertension is an increase in vascular resistance that can occur at any level within the portal venous system. Portal hypertension is therefore classified as prehepatic (portal or splenic vein thrombosis); intrahepatic (cirrhosis), and posthepatic (Budd-Chiari syndrome). The most common cause of portal hypertension is cirrhosis. In cirrhosis, the increased resistance is mostly caused by hepatic architectural distortion (fibrosis and regenerative nodules) but about a third of the increased resistance is caused by intrahepatic vasoconstriction, amenable to vasodilators. This is caused by the activation of stellate cells with active contraction of myofibroblasts and vascular smooth muscle cells in portal venules, which in turn is caused by increased endogenous vasoconstrictors, such as endothelin, and reduced nitric oxide bioavailability.
Portosystemic collaterals develop as a consequence of the high pressure in the portal vein and ameliorate the increased resistance. However, even when portal blood flow is entirely diverted through collaterals, portal hypertension persists because of a concomitant increase in portal venous inflow, which in turn is caused by splanchnic vasodilatation, mostly mediated by an increase in nitric oxide.
The most important collaterals are those that constitute gastroesophageal varices. Although the formation of collaterals had been assumed to be the result of dilatation of preexisting vascular channels, recent studies have implicated a process of neoangiogenesis. This process has been shown to contribute not only to portal-systemic collaterals but also to increased splanchnic blood flow (arteriolar-capillary network).
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