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, 1 decompensation of cirrhosis,2 , 3 and hepatocellular carcinoma.4 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. KeywordsPortal hypertension; Cirrhosis; Varices; Variceal hemorrhage; Hepatic venous pressure gradient; Portal pressure Pathophysiology of Portal HypertensionAnatomically, 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. 5 This is caused by the activation of stellate cells with active contraction of myofibroblasts and vascular smooth muscle cells in portal venules,6 which in turn is caused by increased endogenous vasoconstrictors, such as endothelin, and reduced nitric oxide bioavailability.7 , 8

Background & Aims Large-volume paracentesis (LVP) is the treatment of choice for patients with cirrhosis and refractory ascites. However, LVP can lead to post-paracentesis circulatory dysfunction (PCD), which is associated with faster ascites recurrence and renal failure. PCD results from vasodilatation, which reduces effective blood volume, and is prevented by intravenous administration of albumin. Vasoconstrictors could be used instead of albumin and, with longer use, prevent PCD and delay ascites recurrence. Methods We performed a multicenter, randomized, double-blind, placebo controlled trial to compare albumin with the vasoconstrictor combination of octreotide and midodrine in patients with refractory ascites who underwent LVP. Patients in the albumin group received a single intravenous dose of albumin at the time of LVP plus placebos for midodrine and octreotide (n=13). Patients in the vasoconstrictor group received saline solution (as a placebo for albumin), 10 mg of oral midodrine (3 times daily), and a monthly, 20 mcg intra-muscular injection of long-acting octreotide (n=12). Patients were followed until recurrence of ascites. Results The median times to recurrence of ascites were 10 days in the albumin group and 8 days in the vasoconstrictor group (P=.318). There were no significant differences in PCD between the albumin group (18%) and the vasoconstrictor group (25%, P=.574). When ascites recurred, serum levels of creatinine were higher in the vasoconstrictor group (1.2 vs 0.9 mg/dL in the albumin group, P=.051). Conclusions The combination of midodrine and octreotide after LVP is not superior to albumin in delaying recurrence of ascites or preventing PCD in patients with cirrhosis. Outcomes appear to be worse in patients given octreotide and midodrine.

Since Helicobacter pylori persist for decades in the human stomach, the aim of this study was to examine the long-term course in H. pylori-specific serum IgG responses with respect to subclass and antigenic target. We studied paired serum samples obtained in 1973 and in 1994 in Vammala, Finland from 64 healthy H. pylori-positive adults and from other healthy controls. H. pylori serum IgA, IgG, and IgG subclass responses were determined by antigen-specific ELISAs. H. pylori-specific IgG1 and IgG4 subtype responses from 47 subjects were similar in 1973 and 1994, but not when compared to unrelated persons. H. pylori-specific IgG1/IgG4 ratios amongst the participants varied > 1000-fold; however, 89.4% had an IgG1/IgG4 ratio >1.0, consistent with a predominant IgG1 (Th1) response. Furthermore, ratios in individual hosts were stable over the 21-year period (r=0.56, p< 0.001). The immune response to heat shock protein HspA was unchanged in 49 (77%) of the 64 subjects tested; of the 15 who changed serostatus, all seroconverted and were significantly younger than those who did not change status. These findings indicate that H. pylori-specific antibody responses are host-specific with IgG1/IgG4 ratios stable over 21 years, IgG1 responses predominating, and HspA seroconversion with aging.

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