Platelet aggregation and coagulation and fibrinolysis parameters in both portal and systemic circulations in patients with cirrhosis and hepatocellular carcinoma.

A tendency to bleed and local vasodilation in the portal circulation are exacerbatory clinical factors in patients with liver cirrhosis. Esophageal variceal bleeding, in particular, is a frequent complication in these patients. Cirrhotic patients have been reported to show impairment of platelet aggregation and an activated fibrinolytic state, possibly with consequential lengthening of the bleeding time. Our previous study has demonstrated enhanced generation of PGI(2), a vasodilating and anti-platelet aggregating hormone, in the portal circulation of cirrhotic patients. In the present study, we compared the platelet aggregation and coagulation and fibrinolytic profiles in portal circulation with those in systemic circulation in twenty cirrhotic patients complicated with hepatocellular carcinoma. A portal blood sample was collected through a fine needle inserted percutaneously and guided ultrasonographically to the intrahepatic portal vein. Simultaneously, venous blood was drawn from a forearm vein as the systemic blood sample. Coagulation and fibrinolytic profiles were assessed by examining the extrinsic fibrinolytic system (tissue plasminogen activator (tPA), t-PA-plasminogen activator inhibitor complex), fibrinogen degeneration product, fibrinogen euglobulin lysis time, platelet count, and platelet aggregation elicited by ADP and collagen. Although fibrinolytic factors were activated in patients in the present study, there were no significant differences between the portal and systemic blood samples in all the coagulation and fibrinolytic parameters examined except for platelet aggregation. The curve of platelet aggregation response to collagen (1, 2, 10 µg/ml), but not that to ADP, shifted significantly more to the right in the portal blood compared to the systemic blood (P<0.05). This result suggested that the difference in prostaglandin generation reported previously, may cause the dissociation between collagen and ADP elicitation of platelet response in portal blood while there is no effect on other parameters in the coagulation and fibrinolytic profiles.

Genotype analysis of the CYP2C19 gene in HCV-seropositive patients with cirrhosis and hepatocellular carcinoma.

This study was conducted to assess whether the genotypic frequency of Smephenytoin 4'-hydroxylase CYP2C19 gene differs in Japanese cirrhotic patients who developed hepatocellular carcinoma. Thirty-eight patients with cirrhosis were studied. The wild-type allele CYP2C19*1 and the two mutated alleles, CYP2C19*2 and CYP2C19*3, were identified by PCR-RFLP method. Individuals with homozygous CYP2C19*2 or CYP2C19*3 mutation and those with CYP2C19*2 and CYP2C19*3 heterozygous mutation were predicted to be the poor metabolizer (PM) phenotype. The overall frequency of PM predicted from the genotyping analysis was 29% (11 of the 38 patients), consisting of 5 patients homozygous for CYP2C19*2, two homozygous for CYP2C19*3 and four heterozygous for the two defects. Among 24 HCV-seropositive patients with cirrhosis and hepatocellular carcinoma, the frequency of PM was 41.7% and significantly higher than that observed in 186 healthy controls. We postulate that the PM phenotype caused by the mutation of CYP2C19 gene in cirrhotic patients with HCV infection is associated with a high risk for developing hepatocellular carcinoma.

Therapeutic and diagnostic potential of a vasopressin-2 antagonist for impaired water handling in cirrhosis.

OBJECTIVE: Progressive cirrhosis is associated with increasing difficulty to handle free water. We examined the therapeutic potential of an orally active nonpeptide vasopressin-2 receptor antagonist (OPC-31260) in the management of edema and ascites in patients with cirrhosis. By means of its chemical blockade of the vasopressin-2 receptor in the kidney, we also assessed the ability of renal water handling in the early stage of cirrhosis. METHODS: A single 30 mg dose of OPC-31260 was administered orally to eight biopsy-proven patients with cirrhosis who had ascites or peripheral edema. The aquaretic responses were compared with those in six healthy subjects. RESULTS: In the patients with cirrhosis, OPC-31260 significantly (p < 0.01) increased the urinary excretion rate at 0 to 2 hours, and significantly (p < 0.01) lowered urine osmolality at 2 to 4 hours after administration. Free water clearance increased from -0.48 +/- 0.14 to +0.19 +/- 0.21 ml/min (p < 0.05) at 0 to 4 hours after administration. However, these aquaretic responses in the patients with cirrhosis were only approximately half the responses observed in the healthy subjects. A significant (p < 0.05) inverse relationship was observed between indocyanine green retention at 15 minutes after administration and the maximal free water clearance after administration to the patients with cirrhosis. Urinary sodium excretion did not change significantly in the patients, whereas it increased twofold in the healthy subjects. Urinary vasopressin excretion tended to increase in the patients, whereas it increased twofold to threefold (p < 0.01 to 0.05) from the baseline in the healthy subjects. Urinary prostaglandin E2 excretion was not increased, and serum sodium and plasma vasopressin levels were elevated only slightly in both groups. CONCLUSIONS: Even though a hyporesponsiveness was observed in the group of patients with cirrhosis compared with the healthy group, the novel vasopressin-2 antagonist induced hypotonic diuresis in patients with cirrhosis, suggesting a therapeutic potential in managing water excess. This drug response may be a new index to assess impairment of water handling in patients with cirrhosis.

Hepatic denervation ameliorates sodium and water retention in experimental cirrhosis in rats.

Increased activity in the hepatic sympathetic nervous system may exacerbate salt and water retention in patients with liver cirrhosis. The aim of this study was to evaluate sodium and water homeostasis in rats with cirrhosis induced by diethylnitrosamine and to investigate the influence of hepatic denervation in this model. Animals were randomized into three groups: diethylnitrosamine-treated rats with (N = 13) and without (N = 8) hepatic denervation and control rats (N = 8). Rats were fed a normal salt diet (0.23% sodium ad libitum). The 24-hr measurements for sodium balance, water balance, and creatinine clearance were performed every two weeks for 12 weeks after surgery. Diethylnitrosamine-induced cirrhosis was confirmed histologically. The cumulative change in sodium balance in the innervated diethylnitrosamine-treated rat increased progressively and was significantly higher than the control during the last four weeks of the study. Meanwhile, rats with hepatic denervation showed significantly smaller changes in cumulative sodium balance at week 12 than those in the innervated group. The cumulative changes in water balance in the innervated group were significantly greater at weeks 10 and 12 than those of the denervated and control group, which remained unchanged throughout the study. Creatinine clearance in the innervated group decreased at weeks 10 and 12 by approximately 70% from baseline (P < 0.05); in contrast, it did not change significantly in the denervated group and control group throughout the study. These results demonstrated that hepatic denervation ameliorates sodium and water retention as well as glomerular function in cirrhosis model in rats.