Genetic heterogeneity of hypervariable region 1 of the hepatitis C virus (HCV) genome and sensitivity of HCV to alpha interferon therapy.

Hepatitis C virus (HCV) populations persist in vivo as a mixture of heterogeneous viruses called quasispecies. The relationship between the genetic heterogeneity of these variants and their responses to antiviral treatment remains to be elucidated. We have studied 26 virus strains to determine the influence of hypervariable region 1 (HVR-1) of the HCV genome on the effectiveness of alpha interferon (IFN-alpha) therapy. Following PCR amplification, we cloned and sequenced HVR-1. Pretreatment serum samples from 13 individuals with chronic hepatitis C whose virus was subsequently eradicated by treatment were compared with samples from 13 nonresponders matched according to the major factors known to influence the response, i.e., sex, genotype, and pretreatment serum HCV RNA concentration. The degree of virus variation was assessed by analyzing 20 clones per sample and by calculating nucleotide sequence entropy (complexity) and genetic distances (diversity). Types of mutational changes were also determined by calculating nonsynonymous substitutions per nonsynonymous site (K(a)) and synonymous substitutions per synonymous site (K(s)). The paired-comparison analysis of the nucleotide sequence entropy and genetic distance showed no statistical differences between responders and nonresponders. By contrast, nonsynonymous substitutions were more frequent than synonymous substitutions (P

Prostate-specific antigen in acute hepatitis and hepatocellular carcinoma.

BACKGROUND: Prostate-specific antigen (PSA) is the most important tumor marker in prostate cancer diagnosis and follow-up. Its catabolism by the liver has not influenced its use as a prostate marker until the recent report of a significant increase in a man and a woman with acute hepatitis. In addition, PSA was detected in liver tumor extracts, which warranted its evaluation in liver cytolysis and hepatocellular carcinoma. In this study, PSA was evaluated in a cohort of both sexes presenting either acute hepatitis or hepatocellular carcinoima. METHODS: Forty-two patients with acute hepatitis (21 male patients, 21 female patients) and 54 patients with hepatocellular carcinoma (31 male patients, 23 female patients) were tested for PSA by equimolar immunoassay (Abbott AxSYM Total PSA, Abbott Diagnostics, Rungis, France) and for relevant liver biological parameters (alpha-fetoprotein, alanine aminotransferase, aspartate aminotransferase, total bilirubin, and prothrombin rate). RESULTS: PSA was undetectable in all the female patients and was consistent with age in the males (PSA median and range in acute hepatitis, 0.36 microg/l (range, 0.05-1.3); in hepatocellular carcinoma, 0.36 microg/l (range, 0.02-3.9)). It did not correlate with alpha-fetoprotein and aminotransferases. CONCLUSIONS: Our results confirm the well-established reliability of PSA, and show that PSA remains a valid prostate marker in patients with acute hepatitis and hepatocellular carcinoma.

Better efficacy of a 12-month interferon alfa-2b retreatment in patients with chronic hepatitis C relapsing after a 6-month treatment: a multicenter, controlled, randomized trial. Le Groupe D'étude et De Traitement du Virus De L'hépatite C (Get.Vhc).

We studied the efficacy of three interferon alfa-2b (IFN-2b) regimens for the retreatment of patients with chronic hepatitis C (CHC) with prior complete response followed by relapse. Consecutive patients with CHC who had a complete biochemical response but relapse after a first course of 6 months of IFN with 3 million units (MU) given subcutaneously three times per week were enrolled in the study. Six to 24 months after the end of the first treatment, the patients were randomly assigned to receive IFN with either the same regimen (group 1), a regimen of 12 months with 3 MU (group 2), or a regimen of 6 months with 10 MU (group 3). Sustained biochemical response was defined as normal serum alanine transaminase (ALT) values during the follow-up and sustained virological response as a clearance of hepatitis C virus (HCV) RNA from the serum at the end of follow-up (6 months' posttreatment). Histological improvement was defined as a decrease of 1 point in Metavir score between the first liver biopsy and a biopsy performed at 6 months' postretreatment. Two hundred forty-seven patients were randomized: 75 to group 1, 91 to group 2, and 81 to group 3. In an intent-to-treat analysis, 12%, 36.3%, and 18.5% of patients had a sustained biochemical response after retreatment in groups 1, 2, and 3, respectively (P <.001); 13. 8%, 32.4%, and 17.2% of patients had a sustained virological response after retreatment in groups 1, 2, and 3, respectively (P <. 05). A low viral load and patients in group 2 were independently associated with a sustained biochemical response. A low Knodell score index before treatment, patients with a high level of ALT before retreatment, genotype 3, low viral load, and patients in group 2 were independently associated with sustained virological response. Younger age, a high level of ALT, a low level of gamma-glutamyl transferase before retreatment, low viral load, and patients in group 2 were independently associated with sustained biochemical and virological response. Among the 80 patients with repeated liver biopsies, 47.6% had improved histological activity scores; this improvement was associated with a sustained biochemical and virological response. In patients with CHC initially treated with 3 MU of IFN given subcutaneously three times per week over a 6-month period, and who subsequently developed a relapse after a biochemical response, retreatment with a regimen of 3 MU of IFN given three times per week for 12 months produced better biochemical and virological sustained response rates than regimens involving a higher dose or a shorter duration of retreatment. The biochemical and virological sustained response was associated with histological improvement.

Haemodynamic effects of molsidomine and propranolol in patients with cirrhosis.

Propranolol and molsidomine have both been shown to decrease the hepatic venous pressure gradient in patients with cirrhosis. The present study aimed at assessing the effects of the combination of these two drugs on splanchnic and systemic haemodynamics of cirrhotic patients. Fifteen patients with biopsy proven alcoholic cirrhosis had haemodynamic measurements under basal conditions, 60 min after oral administration of 4 mg molsidomine then 15 min after intravenous administration of 15 mg propranolol. As compared with baseline values, molsidomine was found to decrease mean arterial pressure (-7.9%, (P < 0.01), cardiac output (-7.3%, P < 0.01), pulmonary wedged pressure (-45.8%, (P < 0.05) and hepatic venous pressure gradient (-11.7%, P < 0.01). Propranolol decreased heart rate (-21%, P < 0.01), further decreased cardiac output (-20.6%, (P < 0.01) and hepatic venous pressure gradient (-10.5%, P < 0.01). As a whole, molsidomine plus propranolol decreased mean arterial pressure (-8%, P < 0.01), heart rate (-19%, P < 0.01), cardiac output (-26.5%, P < 0.01) and hepatic venous pressure gradient (-21%, P < 0.01). Pulmonary wedged pressure, liver blood flow and hepatic intrinsic clearance of indocyanine green were not significantly changed by the association of molsidomine and propranolol. We conclude that in patients with cirrhosis, molsidomine and propranolol potentiate their effects on hepatic venous pressure gradient. Such a combination could therefore prove useful in the treatment of portal hypertension.

[Enterovenous fistula. An unusual complication of Crohn disease]. / La fistule entéro-veineuse. Une complication exceptionnelle de la maladie de Crohn.

We report a case of enterovenous fistula in a young 22-year-old patient with Crohn's disease associated with jaundice. Ultrasound and computed tomography showed stationary gaz and barium in the liver. Pathological examination showed a fistula between the lumen of the inflamed segment of the ileum and the superior mesenteric venous system. This unusual finding in Crohn's disease may be a severe complication.

[Treatment of hemorrhages by rupture of cardio-tuberous varices with transjugular intrahepatic portasystemic shunt]. / Traitement des hémorragies par rupture de varices cardio-tubérositaires par anastomose porto-systémique intra-hépatique par voie trans-jugulaire.

Twelve consecutive patients admitted for bleeding from ruptured gastric varices were treated with transjugular intrahepatic portosystemic shunts and followed for a mean of 6 +/- 3 months (range: 8-293 days). The shunt was performed successfully in all 12 patients. The shunt occluded in 3 patients (respectively 19, 101 and 103 days after insertion) of whom one remained asymptomatic and two experienced rebleeding. Four patients presented with acute encephalopathy, spontaneously in two and after rebleeding in two. Three patients died, two after rebleeding and one of septic shock secondary to pneumonia. Overall, 9 patients survived a mean of 211 +/- 92 days with no rebleeding, 8 of whom have not yet experienced any complications. These results suggest that transjugular intrahepatic portosystemic shunts could be useful in treating hemorrhages from ruptured gastric varices and in preventing their recurrence.

Prophylactic treatment of esophageal varices before bleeding.

After years of effort, the treatment of an episode of bleeding from a ruptured varix remains unsatisfactory, as does prophylaxis of rebleeding. As a consequence it was logical to try to prevent bleeding before the first hemorrhage has occurred (primary prophylaxis). Shunt surgery proved to be useful in terms of bleeding rate, but side effects and operative risk made this method inapplicable for prophylaxis. Endoscopic sclerotherapy was efficient in terms of bleeding rate, but doubts about its efficacy in improving survival, together with difficulties in performing repeated endoscopies over the long term, have limited its use in primary prophylaxis. Beta-blockers have proved useful for preventing bleeding and, in some studies, for improving survival. Further studies are still necessary to accurately identify the suitable target population, the method of follow-up and the duration of treatment. Although some groups have started using beta-blockers for prophylaxis before bleeding on a routine basis, others consider this treatment only for prospective randomized trials.

Incidence of large oesophageal varices in patients with cirrhosis: application to prophylaxis of first bleeding.

Because several studies have suggested that beta blockers are effective in the prophylaxis of first variceal bleeding in cirrhosis, screening for oesophageal varices might be appropriate. We prospectively studied 84 cirrhotic patients without obvious evidence of large oesophageal varices and previous bleeding during a mean follow up of 16 months. At entry to the study 41 patients had no oesophageal varices and in 43 these were grade 1. The subsequent percentages of patients without large oesophageal varices were 74% at one year and 52% at two years. Univariate analysis showed that a longer duration of cirrhosis (p less than 0.05) and grade 1 oesophageal varices at entry (p less than 0.001) were predictive factors for the occurrence of large oesophageal varices, whereas, multivariate analysis showed that the initial size of the oesophageal varices (p less than 0.001), a high initial Child-Pugh score, and a smaller improvement in Child-Pugh score during the study were independent risk factors. Among patients with grades 0 and 1 oesophageal varices at the start of the study the proportions with large oesophageal varices at two years were 31% and 70% respectively. We have calculated that, accepting a maximum risk of first bleeding of 10% without prophylactic treatment, a patient without oesophageal varices should be screened endoscopically every other year, while a patient with grade 1 disease should benefit from one annual upper gastrointestinal endoscopy.

Gastroesophageal endoscopic features in cirrhosis. Observer variability, interassociations, and relationship to hepatic dysfunction.

Nowadays, gastroesophageal endoscopic features of portal hypertension are the recognized predictive factors for bleeding and consequently allow the selection of patients for prophylactic therapies. The aim of this prospective study was to investigate the interobserver agreement, the interassociations between these features, and the relationship between these signs and the degree of hepatic dysfunction. In 100 consecutive cirrhotic patients (84% with alcoholism) without history of digestive bleeding, gastroesophageal endoscopic examination was performed and recorded using a videoendoscope. Four independent observers evaluated the following endoscopic features: the size, extent, color, and red signs of esophageal varices, the mosaic pattern, congestive gastropathy, fundic varices, and associated lesions of the stomach. Agreement was assessed using kappa statistics (kappa) and a quantitative score. The size of esophageal varices was significantly associated with their extent and the presence of red signs, whereas no relation was found either between gastropathy or mosaic pattern and fundic varices, or between esophageal and gastric features. Agreement between observers was good for the size of esophageal varices (kappa = 0.59), the presence of red signs (kappa = 0.60), and of gastric-associated lesions (kappa = 0.68) and gastropathy (kappa = 0.50), while it was poor for the extent (kappa = 0.37) and the color (kappa = 0.28) of esophageal varices as well as for the mosaic pattern (kappa = 0.38). The Child-Pugh score significantly increased along with the presence or the size of esophageal varices as well as with the presence of red signs; no relationship could be shown between this score and the presence of gastric features. We conclude that (1) interobserver agreement was good for the main endoscopic features, especially for the size and the red signs of esophageal varices; (2) esophageal patterns were significantly associated between themselves and related to hepatic dysfunction; and (3) gastric patterns were related neither to esophageal features nor to hepatic dysfunction and were not associated between themselves.

Atrial natriuretic peptide, plasma renin activity, plasma volume, systemic vascular resistance and cardiac output in patients with cirrhosis.

The present study aimed to assess relationships between plasma levels of atrial natriuretic peptide (ANP) and plasma volume, systemic vascular resistances, cardiac output and plasma renin activity in patients with cirrhosis. Thirty patients were included: eight with no history of liver disease were used as controls; 22 patients had biopsy-proven alcoholic cirrhosis without ascites (n = 11) and with ascites (n = 11). Mean ANP plasma level was significantly higher in both groups of cirrhotic patients than in controls (P less than 0.05). In the control group, ANP and plasma renin activity were inversely correlated (P less than 0.05) but no correlation was found in cirrhotic patients. In the group of patients with ascites, ANP plasma levels were inversely correlated to plasma volume (P less than 0.05) and to cardiac output (P less than 0.01) and directly correlated to systemic vascular resistances (P less than 0.01). Using multiple regression analysis, ANP remained correlated only with systemic vascular resistances (P less than 0.05). These results suggest that cirrhotic patients have high plasma levels of ANP whether or not they have ascites. In the light of current knowledge of ANP actions, the relationships between ANP plasma levels and plasma volume, cardiac output, and systemic vascular resistances are paradoxical in cirrhotic patients with ascites. ANP does not seem to play a critical role in the pathogenesis of sodium and water retention observed in these patients.

[Computerized tomographic diagnosis of hepatocarcinoma after injection of lipiodol into the hepatic artery]. / Diagnostic scanographique des hépatocarcinomes après injection de lipiodol dans l'artère hépatique.

Iodized oil (lipiodol) injected into the hepatic artery is selectively retained by hepatocarcinomas, as demonstrated by computerized tomography (CT) performed one week after the injection. The value of this technique for the diagnosis of hepatocarcinoma was assessed in a retrospective study of 45 patients. In 39 per cent of the cases intrahepatic tumoral extension was determined by the iodized oil which showed tumoral nodules that had not been detected by conventional methods, such as ultrasonography and CT alone. The lesions revealed by the iodized oil were small nodules around the main tumour. The combined iodized oil-CT technique plays an important role in the choice of treatment, especially when surgical excision is contemplated. It might also contribute to an early diagnosis of hepatocarcinoma in patients at risk, as illustrated by four of our cases where conventional morphological examinations had been negative.

Verapamil has no effect on porto-hepatic pressure gradient, hepatic blood flow and elimination function of the liver in patients with liver cirrhosis.

This study aimed to assess the effects of verapamil, a calcium-channel blocker, on porto-hepatic pressure gradient and on hepatic function as measured by the intrinsic hepatic clearance of indocyanine green (ICG) in patients with biopsy proven alcoholic cirrhosis. Hepatic venous pressures and hepatic extraction of ICG were measured before and 60 min after intravenous injection of 10 mg of verapamil in 19 consecutive patients. Hepatic blood flow and intrinsic hepatic clearance of ICG were calculated in the 10 patients whose hepatic extraction fraction was higher than 10%. No significant difference was observed when comparing porto-hepatic pressure gradient (17.72 +/- 4.79 vs. 17.77 +/- 4.43 mmHg), hepatic blood flow (13.47 +/- 4.75 vs. 16.13 +/- 7.88 ml.min-1.kg-1) and intrinsic hepatic clearance of ICG (1.99 +/- 0.54 vs. 1.97 +/- 0.45 ml.min-1.kg-1) before and after verapamil injection. We conclude that verapamil has no beneficial effect in patients with alcoholic cirrhosis.

Effect of propranolol on metabolic activity of the liver in patients with alcoholic cirrhosis.

Many studies have been performed to investigate the haemodynamic effects of propranolol. However, little is known of its actions on the metabolic activity of the liver. This study aimed to investigate the influence of propranolol on hepatic function as assessed by the galactose elimination capacity (GEC) and the intrinsic clearance of indocyanine green (ICG). 15 patients with biopsy-proven alcoholic cirrhosis and portal hypertension were studied. 10 had GEC and ICG clearance measured before and after the i.v. injection of 15 mg of propranolol (group P) and 5 had ICG clearance measurement before and after normal saline injection (group C). Propranolol significantly reduced heart rate (P less than 0.005) and the porto-hepatic pressure gradient (P less than 0.01). Hepatic blood flow was not changed. GEC was not altered by propranolol. Propranolol decreased the intrinsic hepatic clearance of ICG as determined by the 'sinusoidal' model by 12% (P less than 0.01). This suggests that propranolol may have an inhibitory action on the hepatic elimination of ICG that is independent of any effect on total liver blood flow or drug metabolism, since intrinsic clearance is not influenced by changes in blood flow and ICG is thought not to be metabolized.

[Outcome of patients after obliteration of esophageal varices by endoscopic sclerosis. Results of a prospective study]. / Devenir des malades après éradication des varices oesophagiennes par sclérose endoscopique. Résultats d'une étude prospective.

The purpose of this prospective was study to investigate the course of patients after obliteration of bleeding esophageal varices by endoscopic sclerotherapy and to outline prognostic factors. Sixty-seven patients (45 men, 22 women, mean age: 53.3 +/- 14 years) were followed for a mean of 14 +/- 8 months median = 15 months-range: 1-33 months) from the time of obliteration. Etiology of portal hypertension was portal vein thrombosis in 3 patients and cirrhosis in 64, 44 of whom (65 p. 100) were due to alcoholism (Child-Pugh's class: A: 8 p. 100, B: 42 p. 100, C: 50 p. 100). Recurrence of varices was observed in 23 patients within 1.4 to 25 months (median: 6.6 months). The recurrence rate increased in a linear fashion with time. Reobliteration was achieved in one to three sessions of sclerotherapy. More than one bleeding episodes was observed more often, before sclerotherapy (p less than 0.05) and esophageal stenosis was seen less often during treatment (p less than 0.05) than in patients without recurrence. Variceal bleeding occurred in 14 patients (21 p. 100) within 0.1 to 23 months (median = 5.6), 6 of whom (43 p. 100) died. In the subgroup of alcoholic cirrhosis, absence of withdrawal was associated with a higher risk of rebleeding (p = 0.04). Fifteen patients (22 p. 100) died within 1 to 26 months (median = 12.3). They had a higher mean age (p less than 0.01) and a lower blood fibrinogen (p less than 0.05) than survivors.(ABSTRACT TRUNCATED AT 250 WORDS)