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We compared sustained virological response (SVR) in chronic hepatitis C patients with severe fibrosis treated with pegylated interferon (Peg-IFN) alpha-2b 1.5 microg/kg/week or 0.75 microg/kg/week in combination with ribavirin 800 mg/day for 48 weeks. This was a multicentre randomized controlled study. SVR was observed in 44.5% (45/101) of patients treated with the standard dose of Peg-IFN and 37.2% (38/102) of patients treated with the low dose (NS). In patients with genotypes 1, 4 and 5, SVR was observed in 25.0% of patients who received the standard dose and 16.9% of patients who received the low dose of Peg-IFN (P = NS). In patients with genotypes 1, 4 and 5 and low viraemia, SVR was obtained in 27.3% of patients treated with the standard dose and 25.8% of patients treated with the low dose (P = NS). In the high-viraemia subgroup, SVR was obtained in 24.0% and 9.1% of patients, respectively. In patients with genotypes 2 and 3, SVR was similar in both groups (73.2%vs 73.0%). Thus, (1) patients with genotypes 2 and 3 and severe fibrosis can be treated with low dose of Peg-IFN and ribavirin, (2) this study suggests that patients with genotypes 1, 4 and 5 and high viraemia could receive a standard dose of Peg-IFN associated with ribavirin for 48 weeks, (3) side effects limit the efficacy of the treatment with standard dose of Peg-IFN in patients with genotypes 1, 4 and 5 and low viraemia, (4) more studies are needed for patients with genotype 2 or 3 to define the optimal duration (24 or 48 weeks) in patients with severe fibrosis.

Noninvasive measurement of liver stiffness with transient elastography has been recently validated for the evaluation of hepatic fibrosis in chronic hepatitis C. The current study assessed the diagnostic performance of liver stiffness measurement (LSM) for the determination of fibrosis stage in chronic cholestatic diseases. One hundred one patients with primary biliary cirrhosis (PBC, n=73) or primary sclerosing cholangitis (PSC, n=28) were prospectively enrolled in a multicenter study. All patients underwent liver biopsy (LB) and LSM. Histological and fibrosis stages were assessed on LB by two pathologists. LSM was performed by transient elastography. Efficiency of LSM for the determination of histological and fibrosis stages were determined by a receiver operating characteristics (ROC) curve analysis. Analysis failed in six patients (5.9%) because of unsuitable LB (n=4) or LSM (n=2). Stiffness values ranged from 2.8 to 69.1 kPa (median, 7.8 kPa). LSM was correlated to both fibrosis (Spearman's rho= 0.84, P.0001) and histological (0.79, P.0001) stages. These correlations were still found when PBC and PSC patients were analyzed separately. Areas under ROC curves were 0.92 for fibrosis stage (F)or =2, 0.95 for For =3 and 0.96 for F=4. Optimal stiffness cutoff values of 7.3, 9.8, and 17.3 kPa showed For =2, For =3 and F=4, respectively. LSM and serum hyaluronic acid level were independent parameters associated with extensive fibrosis on LB. In conclusion, transient elastography is a simple and reliable noninvasive means for assessing biliary fibrosis. It should be a promising tool to assess antifibrotic therapies in PBC or PSC.

Congenital cystic lesions of bile ducts may affect intra or extrahepatic bile ducts. Intrahepatic lesions include five entities: congenital hepatic fibrosis, Caroli's syndrome, von Meyenburg complexes, simple cyst of the liver and polycystic liver disease. Congenital hepatic fibrosis and von Meyenburg complexes are secondary to ductal plate malformation affecting the smallest intrahepatic bile ducts. Cystic dilatations are of small size and only detected at histological examination of the liver. They have few clinical consequences. In congenital hepatic fibrosis, the main manifestations result from portal hypertension. Caroli's syndrome is secondary to ductal plate malformation affecting the largest intrahepatic bile ducts. Cystic dilatations are macroscopic and responsible for cholangitis and may lead to biliary stones and carcinoma which develop within cystic dilatations. Caroli's syndrome may be or not associated with congenital hepatic fibrosis. In case of associated congenital hepatic fibrosis, portal hypertension is present. Simple cyst of the liver and polycystic liver disease are characterized by cystic dilatations which, by contrast to the preceding entities, do not communicate with the rest of biliary tree. As a result, they have only few clinical consequences. In congenital hepatic fibrosis and polycystic liver disease, renal abnormalities are frequently observed. They correspond to renal malformations associated with biliary malformations. In congenital hepatic fibrosis, renal lesions are characterized by ectatic collecting tubules which are present in two thirds of the cases and transmitted as an autosomal recessive trait. In polycystic liver disease, renal lesions are characterized by polycystic disease which is present in half of the cases and transmitted as an autosomal dominant trait. Congenital cystic lesions of extrahepatic bile ducts consist of choledochal cyst, which is secondary to malformation of the pancreato-biliary ductal junction. The major risk of choledochal cyst is the development of intracystic cancer, the prevention of which is total surgical resection of the cyst.

The actual impact of transarterial chemoembolization before liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient survival and HCC recurrence is not known. Between 1985 and 1998, 479 patients with HCC in 14 French centers were evaluated for LT. Among these 479 patients, this case-control study included 100 patients who received transarterial chemoembolization before LT (TACE group) and 100 control patients who did not receive chemoembolization (no-TACE group). Patients and controls were matched for the pre-LT tumor characteristics, the period of transplantation, the time spent on the waiting list, and pre- and posttransplantation treatments. Kaplan-Meier estimates were calculated 5 years after LT and were compared with the log-rank test. The mean waiting time before LT was 4.2 ± 3.2 months in the TACE group and 4.3 ± 4.4 months in the no-TACE group. The median number of TACE procedures was 1 (range: 1-12). Demographic data, median alpha-fetoprotein level (21.6 ng/mL and 22.0 ng/mL, respectively), and pre- and post-LT morphologic characteristics of the tumors did not differ in the TACE and no-TACE groups. Overall 5-year survival was 59.4% with TACE and 59.3% without TACE (ns). Survival rates did not differ significantly between the two groups with respect to the time on the waiting list, the tumor diameter, or the type of TACE (selective or nonselective). In the TACE group, 30 patients had tumor necrosis ≥80% on the liver explant with a 5-year survival rate of 63.2%, compared with 54.2% among their matched controls (P = 0.9). In conclusion, with a mean waiting period of 4.2 months and 1 TACE procedure, pre-LT TACE does not influence post-LT overall survival and disease-free survival. (Liver Transpl 2005;11:767–775.)

Liver fibrosis is the main predictor of the progression of chronic hepatitis C, and its assessment by liver biopsy (LB) can help determine therapy. However, biopsy is an invasive procedure with several limitations. A new, noninvasive medical device based on transient elastography has been designed to measure liver stiffness. The aim of this study was to investigate the use of liver stiffness measurement (LSM) in the evaluation of liver fibrosis in patients with chronic hepatitis C. We prospectively enrolled 327 patients with chronic hepatitis C in a multicenter study. Patients underwent LB and LSM. METAVIR liver fibrosis stages were assessed on biopsy specimens by 2 pathologists. LSM was performed by transient elastography. Efficiency of LSM and optimal cutoff values for fibrosis stage assessment were determined by a receiver-operating characteristics (ROC) curve analysis and cross-validated by the jack-knife method. LSM was well correlated with fibrosis stage (Kendall correlation coefficient: 0.55; P.0001). The areas under ROC curves were 0.79 (95% CI, 0.73-0.84) for For =2, 0.91 (0.87-0.96) for For =3, and 0.97 (0.93-1) for F=4; for larger biopsies, these values were, respectively, 0.81, 0.95, and 0.99. Optimal stiffness cutoff values of 8.7 and 14.5 kPa showed For =2 and F=4, respectively. In conclusion, noninvasive assessment of liver stiffness with transient elastography appears as a reliable tool to detect significant fibrosis or cirrhosis in patients with chronic hepatitis C.

Summary. This study reports evidence that hepatocellular steatosis, a frequent histological feature of chronic hepatitis C, is principally metabolic in hepatitis C virus (HCV) genotype 1-infected patients, whereas it is principally virus-induced in HCV genotype 3-infected patients. Multivariate analysis of data on 176 patients with chronic hepatitis C revealed that the severity of steatosis was independently related to HCV RNA load alone in patients infected by HCV genotype 3, whereas it was independently related to the body mass index, daily alcohol intake and histological activity grade (but not viral load) in patients infected by HCV genotype 1. These findings suggest that steatosis is a cytopathic lesion induced by HCV genotype 3, whereas HCV genotype 1 is not steatogenic per se or at the usual in vivo expression levels.

This study compared the efficacy and safety of peginterferon alpha-2a 135 microg/wk, peginterferon alpha-2a 180 microg/wk and interferon alpha-2a in patients with chronic hepatitis C.A total of 639 patients received peginterferon alpha-2a 135 microg or 180 microg once weekly, or interferon alpha-2a 3 MIU thrice weekly for 48 wk.Sustained virological responses were significantly higher with peginterferon alpha-2a than with interferon alpha-2a 3 MIU (28% in the 135 microg and 180 microg peginterferon alpha-2a groups vs 11% with interferon alpha-2a, p = 0.001). The proportion of patients with clinically significant histological improvement was lower in the peginterferon alpha-2a 135 microg (48%) than the 180 microg group (58%, p = 0.035 vs peginterferon alpha-2a 135 microg), but similar to that in the interferon alpha-2a group (45%, p = 0.820 vs peginterferon alpha-2a 135 microg and p = 0.017 vs peginterferon alpha-2a 180 microg, respectively). The overall safety profiles were similar for the three treatments. In patients with chronic hepatitis C, peginterferon alpha-2a 135 microg/wk and 180 microg/wk produced similar sustained virological response rates, both of which were significantly higher than that achieved with interferon alpha-2a thrice weekly. A significantly higher proportion of patients treated with the 180 microg dose of peginterferon alpha-2a had clinically significant histological improvement.

Background & Aims : In the patients with chronic hepatitis C, the addition of ribavirin to interferon (IFN)-α significantly increases the virologic responses. Our aim was to assess the antiviral action of ribavirin on hepatitis C virus (HCV) as a function of ribavirin pharmacokinetics and to evaluate the influence of this antiviral effect on IFN-α efficacy. Methods : Forty-five patients with chronic hepatitis C (genotype 1b) received various schedules of IFN-α and/or ribavirin administration. Frequent blood sampling was performed for HCV RNA kinetics and ribavirin pharmacokinetics assessment. Results : Ribavirin monotherapy induced a significant, moderate, early, and transient viral load decrease in approximately half of the patients. The occurrence of this effect was associated with longer ribavirin clearance half-lives and higher serum ribavirin concentrations. Ribavirin antiviral effect partly reduced the rebound preceding the second IFN-α injection in patients receiving standard IFN-α 3 times per week plus ribavirin. The magnitude of the rebound was inversely related to ribavirin concentrations. These patients subsequently experienced a slow, but significant, second slope of viral decrease and cleared HCV RNA. The addition of ribavirin to daily IFN-α monotherapy did not have any impact on the second phase of viral decline. Conclusions : Ribavirin exerts a significant, moderate, and transient antiviral effect in a significant proportion of patients with chronic hepatitis C. The antiviral effect of ribavirin correlates with ribavirin pharmacokinetics and is partly responsible for the improved efficacy of the combination of standard IFN-α and ribavirin compared with IFN-α monotherapy by increasing the incidence of the initial response.

Recent studies suggest that liver steatosis in chronic hepatitis C may be the expression of a direct cytopathic effect of hepatitis C virus (HCV), particularly in patients infected with genotype 3. To investigate this hypothesis, we studied the relationship between steatosis evolution and HCV clearance after antiviral treatment in patients with chronic hepatitis C and paired liver biopsies.A total of 151 patients (37 with HCV genotype 3; 114 with HCV non-3 genotypes) were selected according to the following criteria: presence of steatosis at initial biopsy; no antiviral treatment prior to the first biopsy; antiviral treatment received between the two biopsies; body mass index (BMI)28 kg/m(2); absence of excessive alcohol intake; no serum hepatitis B surface antigen or human immunodeficiency virus antibodies; and absence of diabetes mellitus. Evolution of steatosis was examined by comparing steatosis grades between the two biopsies.Twenty five patients (16.5%) were sustained virological responders (SVR) to antiviral treatment. Steatosis evolution after antiviral treatment was as follows: improvement in 36% of cases; stability in 51%; and worsening in 13%. Steatosis improvement was significantly more frequent in SVR than in non-responders (NR) (64% v 31%; p0.004). This significant difference occurred in patients infected with genotype 3 (91% v 19%; p0.0001) but not in those infected with non-3 genotypes (43% v 34%; NS). Among the 25 SVR, improvement in steatosis was significantly more frequent in patients infected with genotype 3 than in those infected with non-3 genotypes (91% v 43%; p0.04) whereas in NR, improvement in steatosis did not differ between those infected with genotype 3 and non-3 genotypes (19% v 34%; NS). In multivariate analysis, four factors were independently associated with steatosis improvement: sustained virological response to antiviral therapy (odds ratio (OR) 6.06 (95% confidence interval (CI) 1.61-22.9); p = 0.01), severe steatosis (OR 5.50 (95% CI 1.54-19.6); p = 0.01), HCV genotype 3 (OR 2.90 (95% CI 0.85-10.0); p = 0.07), and BMI25 kg/m(2) (OR 0.24 (95% CI 0.08-0.73); p = 0.02).Our results showed significant improvement in steatosis in patients infected with HCV genotype 3, who achieved sustained viral clearance. This provides further evidence for direct involvement of HCV genotype 3 in the pathogenesis of hepatic steatosis.

The aim of this study was to assess the prevalence and prognostic value of major alterations of portal flow in patients with steroid-treated alcoholic hepatitis. Fifty patients with severe, histologically proven alcoholic hepatitis were enrolled. Clinical data, liver test results, and hepatic Doppler ultrasound findings were collected at inclusion and at month 2. Patients were followed for 1 year or until death. Major changes in portal flow were defined as reversed or alternating flow in the portal trunk and/or in intrahepatic portal branches. Changes in portal flow were observed in 24 (48.0%) of 50 and 17 (39.5%) of 43 patients at inclusion and month 2, respectively. Univariate analysis showed that age older than 50 years, steatosis less than 20% on initial liver biopsy, presence of major changes in portal flow, Child-Turcotte-Pugh score higher than 12, factor V level higher than 45%, and hepatofugal splenic blood flow were associated with a lower 1-year survival. Cox regression analysis showed that steatosis < 20% (relative hazard [RH] = 9.3, P = .0009) and major changes in portal flow (RH = 3.1, P = .04), were independently associated with poor survival. In conclusion, major changes in portal flow are frequent in patients with severe alcoholic hepatitis. Altered portal flow and steatosis < 20% are new prognostic factors in steroid-treated alcoholic hepatitis and must be taken into account in patient management. (HEPATOLOGY 2004;40:1370-1378).

Summary Aim : To evaluate the effects of minimal to moderate alcohol consumption on the severity of histological lesions in patients with chronic hepatitis C. Methods : Daily alcohol intake (none, 1–20, 21–30, 31–50 g/day) and histological activity and fibrosis were recorded in 260 patients with chronic hepatitis C. Results : The proportion of patients with moderate (A2) or marked (A3) activity increased gradually from 53.8% in abstinent patients to 86.5% for an intake between 31 and 50 g/day (P = 0.003). In multivariate analysis, age > 40 years, alcohol intake between 31 and 50 g/day and moderate or severe steatosis were independently related to histological activity. The proportion of patients with moderate (F2) or marked (F3) fibrosis or cirrhosis (F4) gradually increased from 29.0% in abstinent patients to 67.6% for an intake between 31 and 50 g/day (P

The aim of this study was to analyze the clinical impact of hepatitis C virus (HCV)-related cryoglobulinemia in patients that had received liver transplants after HCV cirrhosis. Thirty patients who had received transplants between 1990 and 1996 for HCV cirrhosis and who had a follow-up longer than 1 year were studied. Serum HCV RNA levels, HCV genotype, cryoglobulinemia, rheumatoid factor, serum C3 and C4, IgA, IgG, IgM levels, liver tests, and liver histology were studied 30 +/- 16 months post-transplant. Cryoglobulinemia was found in 9 of 30 patients (30.0%) and was symptomatic in 4 of the 9 cases (glomerulonephritis, 1 case; palpable purpura, 3 cases). Age, sex distribution, alanine aminotransferase (ALAT) activity, and Knodell score did not differ, whether cryoglobulinemia was present or not. Rheumatoid factor (209.5 +/- 70.4 IU/l vs 12.0 +/- 4.4 IU/l, P = 0.004) and IgM levels (3.2 +/- 0.5 g/l vs 1.6 +/- 0.9 g/l, P = 0.0001) were significantly higher, and C4 levels (0.16 +/- 0.16 g/l vs 0.30 +/- 0.10 g/l, P = 0.009) were significantly lower in patients with cryoglobulinemia. One patient died from cryoglobulin-related renal failure. We concluded that, after liver transplantation (LT) for HCV cirrhosis, cryoglobulinemia was frequent and often symptomatic. Cryoglobulinemia did not seem to be associated with more severe graft damage. Cryoglobulinemia-associated morbidity must be taken into account in the management of post-transplant HCV infection.

Gastric bicarbonate secretion might be modifiedin portal hypertension as a consequence of theintramucosal increase in prostaglandins and nitric oxidecontent. Therefore, we studied gastric bicarbonate secretion in control and portal hypertensiverats and investigated the role of prostaglandins andnitric oxide. Basal gastric bicarbonate secretion wasstudied in rats, using a gastric pH back-titration technique, two weeks after partial portal veinligation or a sham operation. The effects of thefollowing drugs were investigated: the prostaglandinsynthase inhibitor indomethacin (5 mg/kg intravenously), prostaglandin (PGE2) (1 mg/kgintravenously), the nitric oxide synthase inhibitorsNG-nitro-L-arginine methyl ester (LG NAME, 5mg/kg intravenously) andNG-monomethyl-L-arginine (L-NMMA, 50 mg/kgintravenously), and the nitric oxide donor nitroprusside (5mmol/liter in the gastric perfusate). Plasma leakage inthe gastric wall was also measured after Evans blue dyeinjection in portal hypertensive and sham-operated rats pretreated by indomethacin (5 mg/kg,intravenously) and L-NAME (5 mg/kg, intravenously).Basal bicarbonate secretion was significantly increasedin portal hypertensive rats as compared to controls. After indomethacin, the bicarbonate secretionwas significantly reduced to a similar level in bothgroups. PGE2 increased bicarbonate secretionsignificantly more in portal hypertensive rats than insham-operated rats. The NO synthase inhibitor L-NMMAsignificantly increased bicarbonate secretion in portalhypertensive rats only, while the other inhibitor,L-NAME, increased it significantly more in portalhypertensive than in the sham-operated rats. Plasma leakagein portal hypertensive rats, which was increased in thebasal condition as compared to control, was furtherenhanced by indomethacin but not by L-NAME pretreatment. The nitric oxide donor significantly reducedbicarbonate secretion in portal hypertensive rats toreach a similar level as in sham-operated rats. Basalgastric bicarbonate secretion is increased in portal hypertensive rats. This could be due to anenhanced prostaglandin mucosal level. Nitric oxide,which reduces bicarbonate secretion, may contribute tolimiting prostaglandin-induced bicarbonateoverproduction.

Inherited disorders of bilirubin metabolism might reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into bile. Reductions in uptake could increase levels of unconjugated or conjugated bilirubin (Rotor syndrome). Defects in bilirubin conjugation could increase levels of unconjugated bilirubin; the effects can be benign and frequent (Gilbert syndrome) or rare but severe, increasing the risk of bilirubin encephalopathy (Crigler–Najjar syndrome). Impairment of bilirubin secretion leads to accumulation of conjugated bilirubin (Dubin–Johnson syndrome). We review the genetic causes and pathophysiology of disorders of bilirubin transport and conjugation as well as clinical and therapeutic aspects. We also discuss the possible mechanisms by which hyperbilirubinemia protects against cardiovascular disease and the metabolic syndrome and the effects of specific genetic variants on drug metabolism and cancer development.

Background/Aims :Interferon therapy has been shown to have beneficial effects in chronic hepatitis C, but the optimal duration of treatment has not been clearly defined. The aims of this study were: (a) to perform a detailed histological comparison of the effects of a 6-month and a 12-month treatment using the Knodell score as well as a recently proposed grid of analysis, (b) to determine possible histological predictive factors of response to therapy, and (c) to attempt to relate histological and biochemical modifications. Methods :Liver biopsies obtained before and 18 months after beginning of treatment were therefore compared in 26 patients treated for 6 months, and in 34 patients treated for 12 months. Results :Six months of treatment induced a significant decrease in periportal ( p =0.02) and intralobular ( p =0.004) hepatocyte necrosis. The same items were improved in the 12-month-related patiens but in addition, portal inflammation ( p =0.01), bile duct lesions ( p =0.03), lymphiod aggregates ( p =0.002) and fibrosis ( p =0.008)_were also improved, according to the Knodell score. Low scores for fibrosis, steatosis and cholangiolar proliferation on the pretreatment liver biopsy could be considered predictive factors for alanine aminotransferase normalization at 6 months. There was no relationship between biochemical response and modification of fibrosis. Conclusion : Our results suggest that: (a) a decrease in fibrosis might be detected only after a 12-month interferon treatment, and (b) initial fibrosis, cholangiolar proliferation and steatosis are predictive of a lack of biochemical response. The absence of a relation between biochemical response and evolution of fibrosis implies that the evaluation of treatments in chronic hepatitis C should always include a detailed histopathological study.

Resume Tous les carcinomes hepatocellulaires jusqu’ici rapportes chez des malades atteints de steato-hepatite non alcoolique se sont developpes sur une cirrhose pre-existante. Nous rapportons ici l’observation d’un homme de 68 ans atteint d’une steato-hepatite non alcoolique et chez qui un carcinome hepatocellulaire est survenu en l’absence de cirrhose. Cette observation conduit a envisager une filiation entre la steato-hepatite non alcoolique et/ou l’obesite, et le carcinome hepatocellulaire independamment de la cirrhose et invite a la conduite d’etudes epidemiologiques pour preciser la reelle incidence de cette association.

Background & Aims: During liver fibrogenesis, myofibroblastic liver cells proliferate and synthesize components of fibrosis. Fibroblast growth factor 2 (FGF-2) is expressed in vivo in myofibroblastic liver cells (MFLCs) during fibrogenesis, and exogenous FGF-2 is mitogenic for MFLCs. The aim of this study was to study the expression and role of endogenous FGF-2 in cultured human MFLCs. Methods: FGF-2 and FGF-2 receptors were studied using immunoblotting. All RNA studies used ribonuclease protection. Growth of MFLCs was studied using [ 3 H]thymidine incorporation and direct cell counting. Results: MFLCs expressed FGF-2 and its receptors FGF receptor 1 and FGF receptor 2. An antibody to FGF-2 blocked the mitogenic effect of transforming growth factor β1 (TGF-β1) for MFLCs but not TGF-β1-induced increase in cellular fibronectin messenger RNA (mRNA). TGF-β1 increased levels of FGF-2 and FGF receptor mRNAs in MFLCs. We have previously shown that TGF-β1 also increased platelet-derived growth factor (PDGF) A chain mRNA in these cells and that anti-PDGF antibody blunted the mitogenic effect of TGF-β1. The present results show that anti-FGF-2 and anti-PDGF-AA are not additive and that FGF-2 and PDGF-AA are not sequentially induced by TGF-β1. Conclusions: FGF-2 mediates the mitogenic but not the profibrogenic effect of TGF-β1 for human MFLCs, and autocrine FGF-2 and PDGF-A interact in the mediation of the mitogenic effect of TGF-β1.

This study examined the relationships between hepatitis C virus (HCV) genotypes and the routes of HCV transmission in 101 patients with chronic hepatitis C. Patients who received blood transfusions (43%) and those with chronic hepatitis C of unknown cause (37%) had similar mean ages, age distribution, and HCV genotype distribution (1a, 19% vs. 14% ; 16, 52% vs. 54% ; 3a, 10% vs. 9% ; other, 19% vs. 23%). Intravenous drug users (IVDUs) were significantly younger and had a different genotype distribution (1a, 33% ; 16, 0 ; 3a, 63% ; other, 5% ; P < .001). Transmission of HCV 3a has been observed only over the past 20 years ; other genotypes were transmitted up to 40 years ago. These results suggest that for 20 years there have been two independent ongoing hepatitis C epidemics. One affects persons who received blood transfusions or whose source of infection is unknown. These persons are older and are mainly infected by HCV 1b. The second type of infection occurs in IVDUs and infects younger persons, mainly with HCV 3a.

Background/Aims: Because the effects of interferon in the presence and absence of cirrhosis are still debated in chronic active hepatitis type non-A, non-B, C (NANB/ C), the aim of this study was to determine to what extent the presence of cirrhosis influences the response to interferon. Methods: We compared the response to interferon alfa in 108 patients with chronic active hepatitis NANB/C with or without cirrhosis. The patients were randomly assigned to one of the two regimens: one group received 6 months of interferon 3 MU 3 times weekly, while the second group received a 12-month course, 3 MU three times weekly during the first 6 months, 2 MU for the following 3 months, and 1 MU for the last 3 months. Results: In both regimens, the proportion of patients with normal alanine aminotransferase at the end of treatment was significantly lower in the cirrhotic than in the noncirrhotic patients. In males, abnormal serum alkaline phosphatase levels and gamma glutamyl transpeptidase were also related to a lesser response independent of cirrhosis. The response at the end of treatment was not significantly different between the two regimens in either the cirrhotic or the noncirrhotic patients. However, the 12-month regimen gave a significantly higher rate of sustained response 6 months after the end of treatment in patients without cirrhosis. Conclusions: It is suggested that the presence of cirrhosis markedly reduces the rate of response to interferon and that in noncirrhotic patients, a 1-year treatment regimen could improve the beneficial effect of interferon.

Objective The combination of pegylated interferon (PEG-IFN), ribavirin (RBV) and a protease inhibitor (PI) has been approved in summer 2011 for the treatment of genotype 1 (G1) hepatitis C virus (HCV)-infected patients, with a substantially improved efficacy. The aim of this study was to estimate the number of G1 patients to be treated in France in 2012 and associated costs. Methods A published model of HCV and data on PEG-IFN sales were used to estimate patients needing treatment using three scenarios. (1) HCV screening rate unchanged versus 2010; proportion of treated F0–F1 patients unchanged, proportion of treated F2–F4 patients increased to the current proportion of treated F2–F4 G2/3 patients. (2) Scenario 1 but the proportion of treated F0–F1 patients increased to the current proportion of treated F0–F1 G2/3 patients. (3) Scenario 2 but a 5% increase in the HCV screening rate. To estimate cost, treatment duration was multiplied by drug unit cost. Probabilities corresponding to treatment duration were estimated based on liver fibrosis stage, treatment-naive or experienced status of the patient and virological response kinetics on treatment. Results Compared with the 5100 G1 patients treated in 2010, the number of G1 patients receiving treatment in 2012 would be 15 000 in scenario 1, 18 300 in scenario 2 and 19 400 in scenario 3, among whom 2.5–3.7% may receive PEG-IFN/RBV and 96.3–97.5% PEG-IFN/RBV+PI. Costs associated with this regimen use ranged from 497 to 638 million Euros. Conclusion These model-based estimates indicate that new anti-HCV treatments may result in a three- to fourfold increase in the number of G1 patients to be treated in France in 2012.

A new case of anti-factor V inhibitor is described in a 46-year-old man, who received a liver transplantation for hepatocellular carcinoma, without exposure to bovine thrombin or fibrin glue during the operative course. The inhibition occurred on the 14th postoperative day, while the patient was being treated with oxacillin, azathioprine, and a new immunosuppressive drug, FK506. The inhibition was of short duration (3 days), and no bleeding complication occurred despite a very low plasmatic level of factor V activity and antigen (

The clinical and pathological findings of five adult cases of idiopathic nonsyndromatic paucity of interlobular bile ducts are reported. Patients were 18–32 years old at the onset of the disease; four presented with pruritus and/or jaundice and one with bleeding of the esophageal varices. Two patients were siblings. Serum alkaline phosphatase counts ranged from 1 to 16 times the upper normal value, and total bilirubin counts ranged from 0.6 to 8.8 mg/dL (10 to 150 μmol/L). Initial liver biopsy showed portal and periportal fibrosis with cholangiolar proliferation and reduction in the number of interlobular bile ducts. Antimitochondrial antibodies were absent, and bile ducts were normal after opacification. The patients were observed for 3–11 years. Repeated liver biopsies in the five patients showed progression of the lesions, with development of biliary type cirrhosis in four. Two of the four patients with cirrhosis died of hepatic failure 3 and 11 years after onset of the disease. In the two other cases, liver transplantation was performed successfully. These cases suggest that chronic cholestasis with marked ductopenia resembling the nonsyndromatic paucity described in infancy and childhood may reveal itself at an adult age. This disorder, possibly familial, may rapidly progress to severe and even fatal liver disease and could be a new indication for liver transplantation.

Background/Aims Some patients receiving adefovir at the approved dose of 10mg daily for chronic hepatitis B have a "suboptimal" virological response characterized by a slow and moderate decrease in viral replication. Methods We assessed the efficacy and safety of adefovir 20mg daily in patients with hepatitis B e antigen-positive chronic hepatitis B resistant to lamivudine and a suboptimal virological response to adefovir 10mg daily add-on. Results No amino acid substitutions known to confer adefovir resistance were found in these patients. In the five treated patients, the switch from 10mg to 20mg of adefovir daily significantly improved antiviral efficacy (−1.78±0.28 log international units/mL versus −3.73±0.51 log international units/mL, respectively, p =0.0039), and alanine aminotransferase levels normalized in all but one of the patients. No signs of renal dysfunction occurred. Conclusions These results suggest: (i) that suboptimal responses to adefovir 10mg daily are due to underdosing; and (ii) that increasing the adefovir dose to 20mg daily is beneficial and safe in patients with lamivudine-resistant HBV and a suboptimal response to adefovir 10mg daily, especially when alanine aminotransferase levels are elevated and/or the liver disease is severe or rapidly progressive. Careful monitoring of renal function is necessary.

A proper diagnosis of cirrhosis is essential for the management of patients with chronic liver diseases. We assessed the accuracy of liver stiffness measurement by Fibroscan for the diagnosis of cirrhosis in 1,257 patients with chronic liver diseases of various causes enrolled in a prospective multicenter study as well as clarified causes of discrepancies between liver histology and Fibroscan. One hundred thirty-two patients had unsuitable biopsy specimens, and 118 had unreliable liver stiffness measurements. Because 232 patients overlapped with a previous study, analysis was performed in the 775 new patients then derived in the whole population (1,007; 165 cirrhosis). Diagnostic accuracy was assessed by receiver operator curve (ROC) analysis. Liver samples were re-analyzed in case of discrepancies. The area under the ROC (AUROC) was 0.95 (95% CI, 0.93-0.96) for the diagnosis of cirrhosis in either 775 or 1,007 patients. The cutoff value with optimal diagnosis accuracy was 14.6 kPa in 1,007 patients (positive and negative predictive values, 74% and 96%) with discrepancies among the etiological groups. Eighty patients were misclassified: (1) among 45 patients without cirrhosis with liver stiffness 14.6 kPa or greater, 27 (60%) had extensive fibrosis and 10 (22%) significant perisinusoidal fibrosis; and (2) among 35 patients with cirrhosis and liver stiffness less than 14.6 kPa, 10 (29%) had a macronodular pattern and 25 (71%) either none or mild activity. In conclusion, Fibroscan is a reliable method for the diagnosis of cirrhosis in patients with chronic liver diseases, better at excluding than at predicting cirrhosis using a threshold of 14.6 kPa. False-negatives are mainly attributable to inactive or macronodular cirrhosis.

Background: Chronic hepatitis C in HIV-infected patients is an increasing cause of death dependent on the development of liver fibrosis, which is currently assessed by liver biopsy despite its limitations. Liver stiffness measurement, a new noninvasive method, allows the evaluation of liver fibrosis. The aim of this prospective study was to assess the accuracy of liver stiffness measurement for the detection of fibrosis and cirrhosis in HIV/hepatitis C virus (HCV)-coinfected patients and to compare its accuracy with other noninvasive methods. Methods: We studied 72 consecutive HIV patients with chronic hepatitis C who had a simultaneous liver biopsy and liver stiffness measurement by transient elastography (FibroScan; Echosens, Paris, France) for the assessment of liver fibrosis. Results: Liver stiffness values ranged from 3.0 to 46.4 kilopascal. Liver stiffness was significantly correlated to fibrosis stage (Kendall T-b = 0.48; P < 0.0001). The area under the receiver operating characteristic (AUROC) curve of liver stiffness measurement was 0.72 for F ≥ 2 and 0.97 for F = 4. For the diagnosis of cirrhosis, AUROC curves of liver stiffness measurement were significantly higher than those for platelet count (P = 0.02), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (P = 0.0001), Aspartate aminotransferase-to-Platelet Ratio Index (APRI) (P = 0.01), and FIB-4 (P = 0.004). Conclusion: Liver stiffness measurement is a promising noninvasive method for the assessment of fibrosis in HIV-infected patients with chronic HCV infection. Its use for the follow-up of these patients should be further evaluated.

The antifungal drug terbinafine has infrequently been incriminated in the occurrence of acute liver injury. We report a case of prolonged cholestasis that occurred in a 75-year-old woman, following terbinafine administration. Jaundice followed by pruritus appeared after four weeks of therapy and was associated with mixed hepatocellular and cholestatic liver tests abnormalities. Following drug withdrawal, serum bilirubin returned to normal values within three months, but anicteric cholestasis persisted for over six months. A liver biopsy performed after six months showed centrilobular cholestasis, discrete portal fibrosis, and a reduction in the number of interlobular biliary ducts. Terbinafine should be added to the list of drugs that can cause reduction in interlobular bile ducts.

Two distinct forms of hepatocellular steatosis can be seen in patients with chronic hepatitis C virus (HCV) infection. Classical metabolic risk factors for hepatocellular steatosis account for the vast majority of cases of steatosis in patients infected by non-genotype 3 HCV strains. In contrast, in patients infected by HCV genotype 3, steatosis is generally induced by the virus itself through a direct cytopathic effect, the mechanisms of which remain debated. Mixed forms of steatosis can also be seen in HCV genotype 3-infected patients with metabolic risk factors. Hepatocellular steatosis appears to be associated with more rapid progression of hepatic fibrosis. However, it is unclear whether this association is due to steatosis itself, or rather to metabolic and host factors that promote steatosis and fibrosis concomitantly. This review discusses current knowledge of HCV-induced steatosis and its relation to chronic HCV-associated liver disease.

Background/Aims: Prediction of sustained virological response (SVR) during treatment would allow clinicians to identify patients most likely to benefit from therapy. Methods: Retrospective analysis of data from 1121 adults with chronic hepatitis C treated for 48 weeks with peginterferon alfa-2a (40 KD) 180 mu g/week plus placebo or ribavirin (1000/1200 mg/day), or interferon alfa-2b 3 MIU three times/week plus ribavirin in a randomized, multinational, study. Results: 67% of patients treated with peginterferon alfa-2a (40 KD)/ribavirin with early virological responses (HCV RNA negative or >= 2 log(10) decrease) at week 12 had SVRs at week 72 (HCV RNA < 50 IU/mL). The negative predictive value (NPV) was 97%. The probability of an SVR increased with the rapidity of HCV RNA suppression. The highest SVR rates were achieved in patients with rapid virological responses at week 4, but the corresponding NPV (74%) is too low for a decision criterion. In patients with early virological responses by week 12, the SVR rate was approximate to 20 % lower in those who received < 80 % compared with patients who received > 80 % of the planned ribavirin dose. Conclusions: Early, sustained suppression of HCV replication portends an SVR. Cessation of treatment may be contemplated in patients without a >= 2 log(10) reduction in HCV RNA after 12 weeks. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

We thank Ratziu et al for their interest in our work.1 To grade steatosis, we used the Metavir scoring system, shown by their group to be accurate …

Interferon-alpha (IFN) monotherapy results in sustained virological clearance in a minority of patients with chronic hepatitis C. The aim of this study was to assess the effect of a reinforced regimen combining ribavirin and high-dose IFN for 48 weeks compared with a nonreinforced regimen combining a standard IFN regimen and ribavirin for 24 weeks in nonresponders with chronic hepatitis C. A total of 231 patients with chronic hepatitis C and previous nonresponse to IFN monotherapy were randomized. The reinforced group (n = 114) received IFN-2b 6 million units (MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the nonreinforced group (n = 117) received IFN-2b 3 MU TIW and ribavirin for 24 weeks. The main outcome measure was a sustained virological response, defined as negative serum hepatitis C virus (HCV)-RNA 24 weeks following the end of treatment. This endpoint was determined in 98 patients of the reinforced group and 105 patients of the nonreinforced group. At the end of follow-up, a sustained virological response was observed in 29 of the 98 patients (29.6%) in the reinforced group vs 16 of the 105 patients (15.2%) in the nonreinforced group (P = 0.014). In multivariate analysis, factors associated with a sustained virological response were treated with a reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype 2 or 3 (OR 8.8; P < 0.0002). A total of 160 patients had paired biopsies before and after treatment. Histological activity improvement was observed in 32 of 80 patients (40%) and fibrosis worsening in 26 of 80 patients (33%) in the reinforced group vs 13 of 80 (16%) and 19 of 80 (24%) in the nonreinforced group (P = 0.30 and 0.20, respectively). Hence in nonresponders, a high-dose 48-week regimen of IFN and ribavirin combination was more effective than a regimen with interferon at lower dose and ribavirin for 24 weeks only.

Background and aims: Steatosis, a frequent histological finding in patients with chronic hepatitis C (CHC), has been suggested to influence liver fibrosis progression. The aim of the present study was to evaluate in patients with CHC and paired liver biopsies the relationship between the evolution of steatosis and that of fibrosis between the two biopsies. Methods: Ninety six patients were selected according to the following criteria: absence of treatment; absence of cirrhosis at initial biopsy; and serum hepatitis B surface antigen and human immunodeficiency virus antibody negativity. Degrees of necroinflammatory activity, fibrosis, and steatosis grades were assessed in the two biopsies. In addition to histological lesions, parameters studied included the source of infection, duration of infection, body mass index, alcohol intake, alanine aminotransferase levels, hepatitis C virus genotype, and viral load. Results: The mean interval between the two biopsies was 48 (32) months. Steatosis was found in 54% of patients at first biopsy, and was severe in 9%. Worsening of steatosis was observed in 34% of patients, stability in 50%, and improvement in 16%. Worsening of steatosis was significantly associated with hepatic fibrosis progression in patients with (p=0.03) or without (p

Aims and methods: To examine the association between smoking and histological liver lesions in chronic hepatitis C, we studied 244 consecutive patients (152 men, 92 women; mean age 45.9 (12.6) years) with histologically proven chronic hepatitis C. Daily tobacco consumption during the six months preceding liver biopsy was recorded as the number of cigarettes smoked daily. Total lifetime tobacco consumption was recorded as the number of cigarette packs smoked per year (packs-years). Liver biopsy specimens were graded for histological activity and fibrosis according to the METAVIR scoring system. Results: The proportion of patients with moderate (A2) or marked (A3) activity increased gradually from 62.0% in non-smokers to 81.7% in patients who smoked more than 15 cigarettes per day (p

Background Posttransplant lymphoproliferative disorder (PTLD) is a well-known complication of organ transplantation that leads to death in more than 50% of cases. The aim of this work was to identify specific risk factors for lymphoproliferative disorders after liver transplantation in adults. Methods A total of 480 consecutive patients who underwent transplantation between 1986 and 1997 were studied (323 men, 157 women; mean age: 49.8+/-10.4 years). Demographics, the indication for transplantation, the immunosuppressive regimens, the incidence of rejection episodes, and Epstein-Barr virus infection were analyzed. Univariate and multivariate analysis were used to identify factors predictive of PTLD. Results Sixteen cases of PTLD (3.3%) occurred at a median of 5.5 (range, 1-39) months after liver transplantation. All 16 cases occurred in patients with evidence of exposure to Epstein-Barr virus before transplantation. In multivariate analysis, the use of antilymphocyte antibodies (P=0.007, relative risk [RR]=4.2, 95% confidence interval [CI]=1.5-11.7), age older than 50 years (P=0.037, RR=3.5, 95% CI=0.95-13.0), liver transplantation for hepatitis C virus cirrhosis (P=0.015, RR=8.7, 95% CI=1-78.3), and liver transplantation for alcoholic cirrhosis (P=0.015, RR=9.6, 95% CI=1.2-77.2) were independently associated with the onset of PTLD. Conclusion Liver transplantation for hepatitis C virus-related and alcoholic cirrhosis and age older than 50 years are three additional risk factors for lymphoproliferative disorder independent of the use of antilymphocyte antibodies. The use of antilymphocyte antibodies after liver transplantation should be avoided in these categories of patients, especially those older than 50 years.

Background: Focal nodular hyperplasia (FNH) of the liver is a benign hepatic lesion relatively common in women. No studies specifically designed to describe the presentation and imaging findings in males have been published. Aims: The aims of this study were: (a) to describe the clinical and imaging findings in 18 men with FNH, and (b) to compare these data with those observed in 216 women with FNH observed during the same nine year period. Patients and methods: According to a final diagnosis of FNH assessed either by pathological examination or by magnetic resonance (MR), the medical charts of 18 men with FNH observed at our institution were reviewed. In order to compare clinical and MR presentations, the files of 216 women with a total of 291 FNH lesions, investigated during the same nine year period, were reviewed. Results: Eighteen FNH lesions, with a mean diameter of 37.5 mm, were demonstrated in the 18 male patients. A total of 291 lesions with a mean diameter of 63.4 mm were comparatively demonstrated in 216 female patients. Mean age at diagnosis was significantly higher in men (p

Background Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C. Methods A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 μg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks. Results A significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) than of patients who received interferon alfa-2b plus ribavirin (56 percent vs. 44 percent, P

Background & Aims: Because most patients with focal nodular hyperplasia (FNH) are young women, an important decision is whether to discontinue oral contraceptive (OC) use. The aims of this study were to evaluate (1) the number and size of FNH lesions in women with various patterns of OC use and in women without OC use and (2) the modifications in the number and size of FNH lesions during follow-up, according to OC use. Methods: In a 9-year study in 216 women with FNH, the diameter and number of lesions documented by magnetic resonance (MR) imaging were evaluated (1) at diagnosis according to OC use as follows: group A, no OC use (n = 28); group B, high-dose OC use (n = 46); group C, low-dose OC use (n = 98); group D, successive use of high-dose and low-dose OCs (n = 33); and group E, use of progestogens only (n = 11); and (2) during follow-up in 136 women, 14 of whom were OC nonusers who stayed off OCs, 89 discontinued OC use, 26 took low-dose OCs, and 7 stayed on a progestogen only. Twelve women became pregnant. In 168 women, the diagnosis of FNH was made based on a combination of rigorously defined MR criteria. In the remaining 48 patients, diagnosis was by surgical biopsy (n = 36) or resection (n = 12). Mean diameter and number of lesion(s) per patient were assessed by MR imaging using the same protocol in all study patients. Results: No significant differences in the number or size of lesions were found in the 5 patient groups. During follow-up, a change in lesion diameter occurred in only 4 women; this event was not influenced by OC use. In the 12 patients who became pregnant, lesion size was unchanged after delivery, pregnancy was uneventful, and delivery occurred spontaneously. Conclusions: These data suggest that (1) neither the size nor the number of FNH lesions are influenced by OC use; (2) size changes during follow-up are rare and do not seem to depend on OC use; and (3) pregnancy is not associated with FNH changes or complications. GASTROENTEROLOGY 2000;118:560-564

Background. The aim of this study was to describe the features of posttransplantation tumors observed in a series of liver transplant recipients with special reference to patients receiving a transplant for alcoholic cirrhosis. Methods. Among 171 consecutive liver transplant recipients, 90 patients who had received a first liver allograft for cirrhosis were studied. After liver transplantation, detection of de novo malignancies was prospectively undertaken and the characteristics of the patients in whom tumors occurred were compared with those in whom tumors did not develop. Results. With a follow-up of 45.2±21.2 months, 11 tumors were observed in 90 patients (overall incidence of 12.2%). The incidence of tumors was higher in patients receiving a transplant for alcoholic cirrhosis than in patients receiving a transplant for nonalcoholic cirrhosis (26.7% vs. 5.0%, P

BACKGROUND & AIMS: Dual infection by hepatitis GB virus type C (GBV-C) and hepatitis C virus (HCV) is common. To assess the histopathologic impact of GBV-C infection on liver lesions, liver biopsy specimens of 105 patients chronically infected with HCV, 17 of whom (15%) were also infected with GBV-C, were reviewed. METHODS: Semiquantitative histopathologic assessment of liver lesions was performed using the Knodell's score and the METAVIR grading system. RESULTS: Hepatitis activity was mild, moderate, or severe in 3 (18%), 11 (64%), and 3 (18%) patients, respectively, infected with GBV-C and HCV vs. 26 (29%), 56 (64%), and 6 (7%) patients, respectively, infected with HCV alone (no significant difference). Cirrhosis was present in 4 (24%) coinfected patients vs. 19 (22%) HCV-positive patients (no significant difference). No significant difference in fibrosis, presence of portal lymphoid aggregates, steatosis, and hemosiderosis was observed between the two groups. There was no significant difference in the evaluation of each item of the Knodell's score. CONCLUSIONS: This detailed histopathologic evaluation of GBV-C infection in chronic hepatitis C shows that GBV-C infection does not affect histopathologic severity and characteristics of chronic hepatitis C, thus suggesting a minor role of GBV-C infection in liver disease. (Gastroenterology 1997 Jan;112(1):188-92)

In a study designed to assess the prevalence of antibodies to hepatitis C virus (HCV) in pregnant women, anti-HCV positivity in French pregnant women was twice as high as that found in French blood donors. Positive ELISA 2 results were confirmed by positive RIBA 2 in most subjects, and seven of nine RIBA 2 positive patients also tested positive for HCV-RNA by PCR. High rates of anti-HCV positivity were seen among immigrant pregnant women, partly because of false positive results with ELISA 2. RIBA 2 results suggested that the prevalence of HCV infection was not any higher in immigrant compared with French pregnant women.

A case of primary sclerosing cholangitis associated with cystic dilatations of intrahepatic bile ducts simulating Caroli's disease is described. The diagnosis of primary sclerosing cholangitis was based upon cholangiogram features, liver histologic examination and the association with chronic ulcerative colitis. It may be suggested that the cystic dilatation of intrahepatic bile duct represents an extreme form of the usual mild dilatations (cholangiectases) described in primary sclerosing cholangitis. We suggest that cystic dilatation of intrahepatic bile ducts could be included among the radiologic features of this disease.

The effects of ursodeoxycholic acid (UDCA, 750-1250 mg/day) were evaluated prospectively in 15 patients with primary sclerosing cholangitis (PSC). Five patients had associated inflammatory bowel disease. After 6 months of treatment, the proportion of patients suffering from fatigue or pruritus decreased from 60% to 20% and from 33% to 20%, respectively. No exacerbation of associated disorders was observed. Serum alkaline phosphatase levels (normal less than 100 IU/l) decreased from 401 +/- 53 to 222 +/- 42 (mean +/- S.E.; p less than 0.001), those of gamma-glutamyl transpeptidase, (normal less than 40 IU/l) from 520 +/- 89 to 185 +/- 32 (p less than 0.001) and those of alanine aminotransferases, (normal less than 30 IU/l) from 79 +/- 12 to 42 +/- 6 (p less than 0.02). In three patients, the discontinuation of UDCA was associated with an aggravation of the liver test results. In conclusion, this study shows that 6 months of treatment with UDCA leads to clinical and biochemical improvements in patients with PSC. These results suggest that UDCA could be an effective treatment for PSC, and may justify a controlled therapeutic trial.