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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.

Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. The mechanistic basis of bilirubin excretion and hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome, an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, coproporphyrinuria, and near-absent hepatic uptake of anionic diagnostics, has remained enigmatic. Here, we analyzed 8 Rotor-syndrome families and found that Rotor syndrome was linked to mutations predicted to cause complete and simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3. These important detoxification-limiting proteins mediate uptake and clearance of countless drugs and drug conjugates across the sinusoidal hepatocyte membrane. OATP1B1 polymorphisms have previously been linked to drug hypersensitivities. Using mice deficient in Oatp1a/1b and in the multispecific sinusoidal export pump Abcc3, we found that Abcc3 secretes bilirubin conjugates into the blood, while Oatp1a/1b transporters mediate their hepatic reuptake. Transgenic expression of human OATP1B1 or OATP1B3 restored the function of this detoxification-enhancing liver-blood shuttle in Oatp1a/1b-deficient mice. Within liver lobules, this shuttle may allow flexible transfer of bilirubin conjugates (and probably also drug conjugates) formed in upstream hepatocytes to downstream hepatocytes, thereby preventing local saturation of further detoxification processes and hepatocyte toxic injury. Thus, disruption of hepatic reuptake of bilirubin glucuronide due to coexisting OATP1B1 and OATP1B3 deficiencies explains Rotor-type hyperbilirubinemia. Moreover, OATP1B1 and OATP1B3 null mutations may confer substantial drug toxicity risks.

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.

The detection and quantification of hepatitis B virus (HBV) genomes in molecular biology-based assays appear to be the most reliable methods for monitoring HBV infection and assessing responses to antiviral treatment. The aim of this study was to evaluate the performance of three HBV-DNA detection and quantification assays currently used for the management of HBV-infected patients: a solution-hybridization assay based on hybrid-capture (Digene Hybrid-Capture™, Murex Diagnostics, Dartford, UK); a signal-amplification assay based on ‘branched-DNA’ (bDNA) technology (Quantiplex™ HBV DNA, Bayer Diagnostics, Emeryville, CA); and a target-amplification assay based on competitive polymerase chain reaction (Amplicor HBV Monitor™, Roche Molecular Systems, Pleasanton, CA). The Monitor assay was significantly more sensitive than both the hybrid-capture and bDNA methods. This better sensitivity appeared to be clinically relevant. The linear ranges of quantification in the hybrid-capture, bDNA and Monitor methods were 6.5–9 log 10 genome copies/ml, 6.5–9.5 log 10 genome equivalents/ml, and 3–5.5 log 10 genome copies/ml, respectively. However, the HBV-DNA units used in the three assays were not comparable. The specificity of the hybrid-capture, bDNA and Monitor assays was 99.2% (95% confidence interval: 97.7–100.0%), 99.2% (97.7–100.0%), and 97.8% (95.3–100%), respectively. Their within-run coefficients of variation and log 10 SDs were 5.5% (±0.025 log 10 copies/ml), 6.7% (±0.029 log 10 Eq/ml) and 21.0% (±0.093 log 10 copies/ml), respectively. Between-run coefficients of variation ranged from 4.4–39.1%, 5–39.5%, and 17.8–96.1%, respectively. The competitive PCR-based Monitor assay appears to be significantly more sensitive but slightly less specific and reproducible than the hybrid-capture and bDNA methods. Given their respective performance, these three assays should be used in complementary fashion in the management of HBV-infected patients.

The objective of the study was to compare the clinical sensitivity and specificity of versions 1.0 and 2.0 of the branched DNA (bDNA)-based hepatitis C virus (HCV) RNA quantification assay, and also to compare the values yielded by the two versions according to the HCV genotype. Serum samples from 268 patients tested routinely by a non-quantitative HCV RNA PCR assay (group A) were tested with version 2.0 of the bDNA assay. Samples from 342 HCV PCR-positive patients with chronic hepatitis C eligible for interferon treatment (group B) were tested with both version 1.0 and version 2.0 of the bDNA assay. Version 2.0 had a clinical sensitivity of 92% (95% confidence interval (CI): 87-97%) in group A and 89% (86-92%) in group B. In group B, the gain in sensitivity with bDNA 2.0 was 16% relative to bDNA 1.0 (P0.001). The log values of the two assays correlated with samples positive by both assays (r = 0.83, P0.0001), but the distribution of values was larger in samples containing HCV genotypes 2 and 3. The mean ratio of assay 2.0/assay 1.0 values was 1.69 +/- 1.44 (range: 0.33-13.43). The mean ratio was close to 1 with samples containing genotype 1 or 4, but ranged from 0.33 to more than 5. The mean ratio was close to 3 with samples containing genotype 2 or 3, and ranged from 0.5 to more than 13. HCV RNA levels were significantly lower in samples containing genotype 4 than in those containing other genotypes. Sera from 200 anti-HCV-negative, HCV RNA PCR-negative blood donors (group C), and from 164 anti-HCV-negative patients with symptoms of chronic liver disease (group D) were used to assess the clinical specificity of bDNA 2.0. In addition, samples with an HCV RNA titer between 0.2 (assay cutoff) and 0.5 MEq/ml from a group of 546 patients tested routinely for HCV RNA load by bDNA 2.0 (group E) were retested by bDNA 2.0 and by qualitative PCR. The specificity of bDNA 2.0 was 100% (98-100%) in group C and 99% (97-100%) in group D. Among the 41 samples from group E, 38 were positive by bDNA 2.0 retesting (36 were PCR-positive) and three were negative by bDNA 2.0 retesting (all were PCR-positive). It is concluded that version 2.0 of the bDNA assay is markedly more sensitive than version 1.0 and has a good specificity. In contrast with version 1.0, version 2.0 is not influenced by the HCV genotype. The relationship between values obtained with assays 1.0 and 2.0 on clinical specimens is not linear, indicating that HCV RNA titers cannot reliably be calculated from the results of version 1.0.

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.

Background/Aims: Chronic hepatitis C virus infections are often associated with extra-hepatic immunological manifestations, including various autoimmune disorders. The aims of this study were: (i) to determine the prevalence of hepatitis C virus markers in patients with autoimmune thrombocytopenic purpura, and (ii) to determine whether a relationship could exist between autoimmune thrombocytopenic purpura and hepatitis C virus infections. Methods: One hundred and thirty-nine patients with autoimmune thrombocytopenic purpura (45 men, 94 women, mean age 42 years, range 16–90) were studied. Anti-HCV antibodies were sought in their first and last available cryopreserved sera. In case of seropositivity, all their available cryopreserved sera were tested for anti-HCV antibodies and for HCV-RNA. Results: Anti-HCV antibodies were detected in 14 of the 139 patients (10%). Four patients had transient anti-HCV seropositivity due to passive transfer of anti-HCV antibodies secondary to the infusion of intravenous immunoglobulin concentrates. Three patients seroconverted during follow up, due to intravenous drug use in one case, transfusion of non-HCV-screened blood units in one case, and infusion of intravenous immunoglobulins in one case. Seven patients had chronic hepatitis C discovered at the same time as autoimmune thrombocytopenic purpura. In two of them, hepatitis C virus transmission was the consequence of autoimmune thrombocytopenic purpura treatment but, in five cases, hepatitis C virus infection predated autoimmune thrombocytopenic purpura, so that the role of hepatitis C virus in autoimmune thrombocytopenic purpura could be suggested. Conclusions: Whereas hepatitis C virus does not appear to be the main etiological agent of autoimmune thrombocytopenic purpura, a role for hepatitis C virus in the occurrence of some cases of autoimmune thrombocytopenic purpura can be envisaged. On the other hand, treatment of autoimmune thrombocytopenic purpura or autoimmune thrombocytopenic purpura-related symptoms by blood product infusion can be complicated by hepatitis C virus transmission.

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.

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.

One hundred and seventy patients were analysed for interstitial pneumonitis and 151 for venocclusive disease of the liver after bone marrow transplantation. We present our results with emphasis on the role of the parameters of single fraction total body irradiation.

This study examines the risk associated with oral contraceptive (OC) use in women with focal nodular hyperplasia (FNH). A total of 216 women (mean age, 36.2 years) with FNH were studied during 1989-98. The studied women were separated into five groups: no OC use (n = 28); high-dose OC use (50 mcg ethinyl estradiol, n = 46); low-dose OC use (30 mcg or less ethinyl estradiol, n = 98); low-dose and high-dose OC use (n = 33); pure progestagen use (n = 11). In each group, the mean diameter and the number of lesions per patient were assessed via magnetic resonance imaging (MRI). Findings revealed no differences between the five groups as to the number and the size of the lesions. The data showed that neither the intake nor the type of OC influenced the size and number of FNHs. A total of 128 women were followed up with serial MRI done after a mean of 23 months: 89 discontinued OCs, 14 remained without OCs, and 25 had taken or remained on low-dose OCs. In those who discontinued OCs, the FNH had decreased in size in two lesions and increased in size in one lesion. Despite continuation of OCs, the largest FNH disappeared 2 years after the first diagnosis, whereas the other FNH remained unchanged. Moreover, during this follow-up study, 12 women became pregnant; no increase in lesion size was seen during pregnancy. These findings indicate that low-dose OCs can be maintained in young women with FNH.