Nitric oxide derived from vascular endothelium is a potent vasodilator that plays a key role in the homeostasis of blood pressure. Because cirrhotic patients tend to have low arterial pressure, we measured in 51 patients and 10 control subjects serum nitrite and nitrate levels as an index of in vivo nitric oxide generation. We also measured plasma endotoxin, a substance frequently increased in cirrhotic patients and known to induce nitric oxide synthesis. Cirrhotic patients showed significant increases in serum nitrite/nitrate and plasma endotoxin compared with controls. Values were particularly increased in patients with decompensated cirrhosis, as manifested by ascites with or without functional kidney failure. High serum nitrite/nitrate levels were associated with high plasma renin activity, high aldosterone and antidiuretic hormone levels and low urinary excretion of sodium. In addition, serum nitrite/nitrate levels significantly correlated with endotoxemia. Oral administration of colistin to 15 cirrhotic patients reduced significantly plasma endotoxin levels (p < 0.01) and serum nitrite/nitrate levels (p < 0.05). Because endotoxin enhances the expression of inducible nitric oxide synthase, our results suggest that circulating endotoxin in cirrhosis is responsible for excessive synthesis and release of nitric oxide by the vasculature. These findings might explain the hemodynamic dysfunction seen in cirrhotic patients.

Nonselective ␤-blockers are very effective in preventing first variceal bleeding in patients with cirrhosis. Treatment with isosorbide-5-mononitrate (IS-MN) plus propranolol achieves a greater reduction in portal pressure than propranolol alone. The present multicenter, prospective, double-blind, randomized, controlled trial evaluated whether combined drug therapy could be more effective than propranolol alone in preventing variceal bleeding. A total of 349 consecutive cirrhotic patients with gastroesophageal varices were randomized to receive propranolol ؉ placebo (n ‫؍‬ 174) or propranolol ؉ IS-MN (n ‫؍‬ 175). There were no significant differences in the 1-and 2-year actuarial probability of variceal bleeding between the 2 groups (propranolol ؉ placebo, 8.3% and 10.6%; propranolol ؉ IS-MN, 5% and 12.5%). The only independent predictor of variceal bleeding was a variceal size greater than 5 mm. However, among patients with varices greater than 5 mm (n ‫؍‬ 196), there were no significant differences in the incidence of variceal bleeding between the 2 groups. Survival was also similar. Adverse effects were significantly more frequent in the propranolol ؉ IS-MN group due to a greater incidence of headache. There were no significant differences in the incidence of new-onset or worsening ascites or in impairment of renal function. V ariceal bleeding is one of the more severe complications of patients with cirrhosis and portal hypertension. More than 40% of cirrhotic patients already have esophageal varices at diagnosis. Nearly 30% of those patients with large esophageal varices will bleed at 2 years. 1 Nonselective ␤-blockers are an effective therapy for the prophylaxis of first variceal bleeding in patients with cirrhosis. [2][3][4] This beneficial effect of ␤-blockers is mainly due to its ability to reduce portal pressure. 5,6 Complete protection from variceal bleeding is achieved when the portal pressure gradient is reduced to less than 12 mm Abbreviation:

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B acterial translocation (BT) is considered a key event in the pathogenesis of bacterial infections in patients with advanced cirrhosis, 1 and spontaneous bacterial peritonitis is probably the most relevant infection in this setting. 2 BT is considered to be present either in patients or in animal models of cirrhosis when the culture of mesenteric lymph nodes (MLN) shows the growth of at least one bacterial species. 3 The genetic identity of bacteria isolated in ileal content, MLNs, and infected ascitic fluid (AF) in rats with experimental cirrhosis 4 has been shown, which supports the contention of a continuum among intestinal lumen, translocation to MLN, and eventual induction of spontaneous bacterial peritonitis. However, the study of BT is logically difficult in patients with cirrhosis.We have shown that roughly 30% of patients with advanced cirrhosis and AF show the simultaneous presence in blood and AF of fragments of bacterial DNA (bactDNA), mostly from the same type of bacteria, 5 and that these fragments may last in blood during variable periods. 6 The identity of the nucleotide sequences detected in a given patient during the study period, together with the fact that bactDNA may disappear and then reAbbreviations: BT, bacterial translocation; MLN, mesenteric lymph nodes; AF, ascitic fluid; PCR, polymerase chain reaction; TNF-␣, tumor necrosis factor alpha; NOx sum of NO metabolites, nitrite and nitrate. From the

Patients with cirrhosis show increased signal intensity in the globus pallidus on T1-weighted magnetic resonance imaging of the brain. This abnormal appearance of the basal ganglia has been related to the severity of liver failure and to the presence of portal-systemic shunting, although its cause and clinical significance remain unknown. We prospectively assessed the metabolic, neurological and neuropsychological statuses of 30 stable cirrhotic patients and correlated these clinical variables with computed measurements of globus pallidus signals. Some metabolic variables denoting disease severity appeared to be significantly related to image changes, although the strongest association was found with plasma ammonia levels. After adjustment for ammonia level, on multiple regression analysis, the other variables were not significant. Furthermore, pallidal changes were associated with specific neurological symptoms and neurological functions, symptoms and functions that also had a significant correlation with ammonia levels. Our findings suggest that globus pallidus signal abnormality could arise as a marker of brain impairment related to hyperammonemia.