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Introduction: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are associated with high morbidity and mortality in the developing world. The global mortality caused by viral hepatitis is higher than that caused by HIV infection. Screening of two different populations - blood donors and patients with suspected hepatic cirrhosis - can help to estimate the seroprevalence in the population and what the burden of the infection is on liver disease., Methods: This was a cross-sectional, descriptive study performed in Vanga, a rural region of the Democratic Republic of Congo. Data were used from 2016 to 2018 for blood donors, and patients with ascites and abnormal liver ultrasound., Results: A total of 3,497 blood donors were recruited, among whom 92.5% were male; 3% were positive for HCV antibodies; 3.4% were positive for HBsAg; and 0.4% for HBsAg and HCV, respectively. There were 190 patients with suspected cirrhosis on ultrasound: 71 (37.4%) were female and 119 (62.4%) male; 32.6% and 10.6% were positive for HBV and HCV, respectively; 2.6% were co-infected with HBV and HCV., Conclusion: Blood donors and patients with ascites and liver abnormalities were frequently infected by HBV, HCV, and/or HIV in a rural region of the DRC. Detection is essential for limiting the risk of transmission and treating those infected., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Studies exploring the relationship between muscle fat content and non-alcoholic fatty liver disease (NAFLD) are scarce. Herein, we aimed to evaluate the association of muscle mass and fatty infiltration with biopsy-assessed NAFLD in patients with obesity., Methods: At inclusion (n = 184) and 12 months after a dietary intervention (n = 15) or bariatric surgery (n = 24), we evaluated NAFLD by liver biopsy, and skeletal muscle mass index (SMI) by CT (CT-SMI) or bioelectrical impedance analysis (BIA-SMI). We developed an index to evaluate absolute fat content in muscle (skeletal muscle fat index [SMFI]) from CT-based psoas muscle density (SMFI Psoas )., Results: Muscle mass was higher in patients with NAFLD than in those without (CT-SMI 56.8 ± 9.9 vs. 47.4 ± 6.5 cm 2 /m 2 , p <0.0001). There was no association between sarcopenia and non-alcoholic steatohepatitis (NASH). SMFI Psoas was higher in NASH ≥F2 and early NASH F0-1 than in NAFL (78.5 ± 23.6 and 73.1 ± 15.6 vs. 61.2 ± 12.6, p <0.001). A 1-point change in the score for any of the individual cardinal NASH features (i.e. steatosis, inflammation or ballooning) was associated with an increase in SMFI Psoas (all p <0.05). The association between SMFI Psoas and NASH was highly significant even after adjustment for multiple confounders (all p <0.025). After intervention (n = 39), NASH improvement, defined by NAFLD activity score <3 or a 2-point score reduction, was achieved in more than 75% of patients (n = 25 or n = 27, respectively) that had pre-established NASH at inclusion (n = 32) and was associated with a significant decrease in SMFI Psoas (p <0.001). Strikingly, all patients who had ≥11% reduction in SMFI Psoas achieved NASH improvement (14/14, p <0.05)., Conclusions: Muscle fat content, but not muscle mass, is strongly and independently associated with NASH. All individuals who achieved a ≥11% decrease in SMFI Psoas after intervention improved their NASH. These data indicate that muscle fatty infiltration could be a potential marker for (and perhaps a pathophysiological contributor to) NASH., Lay Summary: The fat content in skeletal muscles is highly reflective of the severity of non-alcoholic fatty liver disease (NAFLD) in patients with morbid obesity. In particular, muscle fat content is strongly associated with non-alcoholic steatohepatitis (NASH) and decreases upon NASH improvement. These data indicate that muscle fatty infiltration could be a marker and possible pathophysiological contributor to NASH., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest in relation to this work to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Immunosuppressive-drugs are needed after solid organ transplantation to prevent allograft rejection but induce severe side effects. Understanding the alloimmune response is critical to modulate it and to achieve graft operational tolerance. The role of regulatory T cells and tolerogenic dendritic cells (Tol-DCs) is undoubtedly essential in tolerance induction. Tacrolimus is considered as the cornerstone of immunosuppression in solid organ transplantation. mTOR inhibitor such as rapamycin are thought to induce tolerance and are used as anticancer drugs in several cancers. The aim of this study was to better understand the effect of these immunosuppressive drugs on the differentiation, maturation and function of human monocyte derived dendritic cells (DCs)., Material and Methods: DCs were differentiated from monocytes of healthy donors with either rapamycin (Rapa-DCs) or tacrolimus (Tac-DCs). The phenotype was evaluated by flow cytometry analysis. The production of pro- and anti-inflammatory cytokines was assessed by ELISA. The mRNA expression level of IDO and PD-L1 was assessed by RTqPCR. Mixed leukocytes reactions were performed to analyse suppressive activity of DCs., Results: Rapa-DC were characterised by a lower expression of the co-stimulatory molecules and CD83 than control-DCs (CTR-DC) (p < 0.05). In contrast, tacrolimus had no effect on the expression of surface markers compared to CTR-DCs. Rapamycin reduced both IL-12 and IL-10 secretions (p < 0.05). Rapa-DCs had a suppressive effect on CD4 + allogenic T cells compared to CTR-DCs (p < 0.05). However, neither Rapa-DCs nor Tac-DCs favoured the emergence of a CD4 + CD25 high Foxp3 + population compared to CTR-DCs. Surprisingly, Rapa-DCs had a reduced expression of IDO and PD-L1 compared to Tac-DCs and CTR-DCs., Conclusion: Rapa-DCs exhibit an incomplete phenotypic tolerogenic profile. To our knowledge this is the first paper showing a reduction of expression of pro-tolerogenic enzyme IDO in DCs. Tacrolimus does not change the phenotypical or functional characteristics of moDCs., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Background & Aim: Chronic liver diseases are characterized by expansion of the small immature cholangiocytes - a mechanism named ductular reaction (DR) - which have the capacity to differentiate into hepatocytes. We investigated the kinetics of this differentiation, as well as analyzing several important features of the newly formed hepatocytes, such as functional maturity, clonal expansion and resistance to stress in mice with long-term liver damage., Methods: We tracked cholangiocytes using osteopontin-iCreER T2 and hepatocytes with AAV8-TBG-Cre. Mice received carbon tetrachloride (CCl 4 ) for >24 weeks to induce chronic liver injury. Livers were collected for the analysis of reporter proteins, cell proliferation and death, DNA damage, and nuclear ploidy; hepatocytes were also isolated for RNA sequencing., Results: During liver injury we observed a transient DR and the differentiation of DR cells into hepatocytes as clones that expanded to occupy 12% of the liver parenchyma by week 8. By lineage tracing, we confirmed that these new hepatocytes derived from cholangiocytes but not from native hepatocytes. They had all the features of mature functional hepatocytes. In contrast to the exhausted native hepatocytes, these newly formed hepatocytes had higher proliferative capability, less apoptosis, a lower proportion of highly polyploid nuclei and were better at eliminating DNA damage., Conclusions: In chronic liver injury, DR cells differentiate into stress-resistant hepatocytes that repopulate the liver. The process might account for the observed parenchymal reconstitution in livers of patients with advanced-stage hepatitis and could be a target for regenerative purposes., Lay Summary: During chronic liver disease, while native hepatocytes are exhausted and genetically unstable, a subset of cholangiocytes clonally expand to differentiate into young, functional and robust hepatocytes. This cholangiocyte cell population is a promising target for regenerative therapies in patients with chronic liver insufficiency., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Patients with chronic hepatitis C virus (HCV) infection and cirrhosis have a higher risk for liver-related complications and have historically been more difficult to cure than patients without cirrhosis. We evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir, without ribavirin, for 12weeks in patients with HCV genotype 1b infection and compensated cirrhosis., Methods: Treatment-naïve and peginterferon/ribavirin treatment-experienced patients received 12weeks of ombitasvir/paritaprevir/ritonavir (25/150/100mg once daily) and dasabuvir (250mgtwicedaily). Key inclusion criteria were hemoglobin ⩾10g/dl, albumin ⩾2.8g/dl, platelet count ⩾25×10(9)/L, creatinine clearance ⩾30ml/min, and Child-Pugh score ⩽6. Efficacy was assessed by the percentage of patients achieving SVR (HCV RNA <25IU/ml) 12weeks post-treatment (SVR12). Efficacy and safety were assessed in all patients receiving study drug., Results: Sixty patients with HCV genotype 1b infection and cirrhosis received treatment. The study population comprised 62% male, 55% treatment-experienced, 83% with IL28B non-CC genotype, 22% with platelet count <90×10(9)/L, and 17% with albumin <3.5g/dl. All 60 patients completed treatment, and SVR12 was achieved in 100% (95% CI, 94.0-100%) of patients. The most common adverse events were fatigue (22%), diarrhea (20%), and headache (18%). Only one patient (1.7%) experienced a serious adverse event. Laboratory abnormalities were infrequently observed and not clinically significant., Conclusions: The HCV regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir without ribavirin for 12weeks achieved 100% SVR12 and was well tolerated in HCV genotype 1b-infected patients with cirrhosis, suggesting that this 12-week ribavirin-free regimen is sufficient in this population., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection., Methods: In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 μg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 μg, 80 μg, 100 μg, 120 μg, or 150 μg once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin. Total treatment duration was 24 weeks or 48 weeks (simeprevir group) based on criteria for response-guided therapy (ie, HCV RNA <25 IU/mL undetectable or detectable at week 4 and undetectable week 12) or 48 weeks (placebo). Patients, study personnel, and the sponsor were masked to treatment assignment. The primary efficacy endpoint was sustained virological response at 12 weeks after the planned end of treatment (SVR12). Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01290679. Results from the primary (SVR12, week 60) analysis are presented., Findings: 209 (81%) of 257 patients in the simeprevir group and 67 (50%) of 134 in the placebo group had SVR12 (adjusted difference 32·2%, 95% CI 23·3-41·2; p<0·0001). The incidences of adverse events were similar in the simeprevir and placebo groups at 12 weeks (246 [96%] vs 130 [97%]) and for the entire treatment (249 [97%] vs 132 [99%]), irrespective of the peginterferon alfa used. The most common adverse events were headache, fatigue, pyrexia, and influenza-like illness at 12 weeks (95 [37%) vs 45 [34%], 89 [35%] vs 52 [39%], 78 [30%] vs 48 [36%], and 66 [26%] vs 34 [25%], respectively) and for the entire treatment (100 [39%] vs 49 [37%], 94 [37%] vs 56 [42%], 79 [31%] vs 53 [40%], and 66 [26%] vs 35 [26%], respectively). Rash and photosensitivity frequencies were higher in the simeprevir group than in the placebo group (61 [24%] vs 15 [11%] and ten [4%] vs one [<1%], respectively). There was no difference in the prevalence of anaemia between the simeprevir and placebo groups (35 [14%] vs 21 [16%], respectively, at 12 weeks, and 53 [21%] vs 37 [28%], respectively, during the entire treatment)., Interpretation: Addition of simeprevir to either peginterferon alfa 2a or peginterferon alfa 2b plus ribavirin improved SVR in treatment-naive patients with HCV genotype 1 infection, without worsening the known adverse events associated with peginterferon alfa plus ribavirin., Funding: Janssen Infectious Diseases-Diagnostics., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background & Aims: Cirrhotic patients with recurrent ascites frequently require paracentesis despite diuretic therapy. Vasopressin receptor antagonists, by increasing free water clearance, may reduce the recurrence of ascites. To investigate the effects of the addition of a vasopressin V(2) receptor antagonist, satavaptan, to 100mg spironolactone on ascites recurrence after a large volume paracentesis in patients with liver cirrhosis irrespective of the presence of hyponatraemia., Methods: One hundred and fifty one cirrhotic patients with recurrent ascites with or without hyponatraemia, and normal to mildly abnormal renal function were randomised in a double-blind study to receive either 5mg (n=39), 12.5mg (n=36), 25mg (n=40) of satavaptan or placebo (n=36) for 12 weeks. Their Child-Pugh scores were 9.2+/-1.3, 8.7+/-1.7, 8.8+/-1.3, and 9.0+/-1.5, respectively., Results: Median time to first paracentesis was 23, 26, and 17 days with satavaptan 5, 12.5, and 25mg, respectively, versus 14 days with placebo (ns for all doses). The frequency of paracenteses was decreased significantly (p<0.05) in all satavaptan groups versus placebo. Mean increase in ascites was 2.82+/-0.48 L/week for placebo versus 2.12+/-0.40, 2.14+/-0.33, and 2.06+/-0.40 L/week for the 5, 12.5, and 25mg of satavaptan, respectively (ns for all doses). Similar numbers of patients experienced major adverse events in all groups. Increases in serum creatinine, orthostatic changes in systolic pressure and thirst were more common with satavaptan., Conclusions: Satavaptan has the potential to reduce recurrence of ascites after a large volume paracentesis at doses from 5 to 25mg in cirrhotic patients with ascites., (Copyright 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is increasing worldwide and is the third cause of cancer-related death. HCC develops in a pre-neoplastic organ, the cirrhotic liver. Therefore, chemoprevention could play a role in the management of HCC. We have previously shown that lanreotide, a somatostatin analogue, inhibits the development of "foci of altered hepatocytes", which represent very early neoplastic changes in rat liver. Here we induced bona fide HCC by means of a different chemically induced model that is known to lead to significant fibrosis before HCC appearance. Lanreotide was given from the beginning of the experiment in one group and from the time when significant fibrosis was present in the second group. Lanreotide decreased the frequency of occurrence of HCC in both groups. In both groups, significant decreases in hepatocyte proliferation and inhibition of fibrosis were demonstrated. When given at the start of the experiment, lanreotide dramatically decreased levels of angiogenic factors and enhanced apoptosis. Further work on the anti-tumoral effect of lanreotide is called for to assess the mechanistic relationships of its anti-proliferative and anti-angiogenic actions on liver neoplastic cells.

Background/aims: While combination of peginterferon-alpha (PEG-IFN) and ribavirin (RBV) therapy is the current standard of care for chronic hepatitis C (CHC), only 44-51% of genotype-1 patients achieve a sustained virological response (SVR), and both agents produce treatment-limiting toxicities. In the hepatitis C virus (HCV) replicon system, merimepodib (MMPD), a novel, selective inhibitor of inosine monophosphate dehydrogenase, has shown potent antiviral effects., Methods: This randomized, placebo-controlled, double-blind study evaluated the safety and antiviral activity of PEG-IFN-alpha2b and RBV combined with either placebo, 25mg MMPD every 12h (q12h), or 50mg MMPD q12h in interferon-alpha (IFN) and RBV nonresponders. After 24 weeks of treatment, subjects with undetectable HCV RNA were proposed to continue assigned treatment for up to 24 additional weeks., Results: The PEG-IFN-alpha, RBV, and MMPD combination was well tolerated at both doses. After 24 weeks, the proportion of HCV RNA undetectable subjects was 8/11 (73%) in the 50-mg MMPD group, 2/10 (20%) in the 25-mg MMPD group, and 3/10 (30%) in the placebo group (P=0.02, Jonckheere-Terpstra test for increasing dose response). Ten subjects entered and completed an extension study, at Week 48, 2 of 2 (100%) of the 25-mg and 3 of 5 (60%) of the 50-mg subjects remained HCV RNA undetectable, compared with 3 of 3 (100%) of the placebo subjects. At Follow-up Week 24, 2 (100%) of the 25-mg , and 1 (25%) of the 50-mg subjects remained undetectable, compared with 1 (33%) of the placebo subjects. Pharmacokinetic and pharmacodynamic analyses showed a correlation between MMPD exposure and early virological response at week 12, but not with hemoglobin decreases often associated with RBV., Conclusions: In conclusion, PEG-IFN-alpha2b and RBV combined with 50 mg MMPD q12h was well tolerated and induced virological response with undetectable HCV RNA in IFN-alpha and RBV nonresponders.

Precision-cut liver slices in culture (PCLS) appears as a useful and widely used model for metabolic studies; the interest to develop an adequate cryopreservation procedure, which would allow maintaining cell integrity upon incubation, is needed to extend its use for human tissues. We have previously shown that cryopreservation of rat PCLS leads to caspase-3 activation and early alterations of their K+ content upon incubation. In this study, we tested the hypothesis that counteracting intracellular K+ loss and/or interfering with cell death signaling pathways could improve the viability of cryopreserved PCLS. PCLS were prepared from male Wistar rat liver and cryopreserved by rapid freezing before incubation. The addition of a caspase inhibitor-Z-DEVD-FMK (2.5 microM)-in the culture medium did not improve viability of cryopreserved PCLS. Incubation of cryopreserved PCLS in a K+ rich medium (135 mM) increased K+ content and avoided caspase-3 activation, but did not improve cell viability. Caspase-3 inhibition, a decrease in cell lysis, and improvement of glycogen content were observed in cryopreserved PCLS after addition of LiCl (100 mM) in the incubation medium. These results indicate that, even if caspase-3 activation is linked to the K+ loss in cryopreserved PCLS, its inhibition does not allow restoring the metabolic capacities. LiCl, acting on a target upstream of caspase-3 inhibition, improves cell viability and allows glycogen accumulation when added in culture medium of cryopreserved PCLS; and could thus be considered as an interesting adjuvant in the culture of cryopreserved PCLS.

Study Objectives: To trace the entire oxyhemoglobin dissociation curve (ODC) in a cohort of cirrhotic patients in stable condition who were candidates for orthotopic liver transplantation (OLT)., Design: Prospective cohort study., Setting: A large academic hospital., Patients and Methods: We traced the entire ODC in whole blood in standard conditions (pH 7.4; PCO2, 40 mm Hg; temperature, 37 degrees C) for 50 cirrhotic candidates for OLT (27 men and 23 women) and 50 age- and height-matched healthy subjects (27 men and 23 women). All subjects were nonsmokers or ex-smokers for at least 5 years. We also measured 2,3 diphosphoglycerate (2,3 DPG) in RBCs, plasma ions, and arterial blood gases in all subjects according to standard methods. Mixed venous blood was also obtained from the 50 cirrhotic patients., Results: Mean ODC was the same in the two groups. However, for the cirrhotic patients, the dispersion of the PO2 values of oxygen saturation percentage (SO2%) from 20 to 80% was significantly larger (p < 0.01 to p < 0.0001). In the cirrhotic patients, the mean PO2 for half-saturation of hemoglobin (P50) was 7.11 + 0.14 mEq/L chloride (p < 0.001) plus 0.36 mEq/L inorganic phosphate (p < 0.05) plus 0.25 micromol/gram of hemoglobin (gHb) 2,3 DPG (p < 0.00002) in absolute numerical values. Sodium, potassium, and calcium, three plasma ions disturbed in cirrhotic patients, did not contribute to determine the mean P50., Discussion: In patients with cirrhosis, increased dispersion of PO2 values for a given level of SO2% may be related to four factors: (1) an observed alteration of the enzymes controlling the phosphoglycerate shunt; (2) hypothyroidism, which may affect 7 to 20% of patients with primary biliary cirrhosis; (3) the type of ongoing treatment, eg, diuretics and/or propranolol; and (4) plasma ion disturbances., Conclusions: We describe the ODC by three indexes: shape, position, and an index of dispersion of the PO2 values for a given level of SO2%. In addition, when the latter is increased, we suggest that other factors than pH, temperature, carbon dioxide, and inorganic phosphates are acting on the position of the ODC.

Background/aims: Previous studies using standard interferon and ribavirin combination therapy suggested that patients infected with HCV-1 and a low pretreatment HCV-RNA level can be treated for 24 weeks without compromising sustained virologic response rates. The aim of the present study was to investigate this schedule in the era of pegylated interferon-alpha plus ribavirin., Methods: Patients chronically infected with HCV-1 (n=235) and a screening viremia < or =600,000 IU/mL (real-time PCR) were treated with peginterferon alfa-2b 1.5 microg/kg subcutaneously once weekly plus ribavirin 800-1400 mg/day based on body weight for 24 weeks., Results: End-of-treatment and sustained virologic response rates were 80 and 50%, respectively. The 48-week historical control (Manns et al., Lancet 2001;358:958-65) had similar end-of-treatment (74%) but higher sustained virologic response rates (71%). This difference was due to a high virologic relapse rate after 24 weeks of therapy (37%) compared with the historical control (4%). A subset of patients who had undetectable serum HCV-RNA at treatment week 4, however, achieved similar sustained virologic response rate (89%) as in the control group (85%)., Conclusions: HCV-1 infected patients with a low baseline HCV-RNA concentration who become HCV-RNA negative at week 4 may be treated for 24 weeks without compromising sustained virologic response rates.

Background/aims: In vitro and animal data suggest that alcohol and hepatitis C virus (HCV) proteins might interfere with Stat3 signaling, a potential regulator of liver cell apoptosis and proliferation., Methods: We assessed Stat3 expression, activity and the apoptotic-proliferation balance in end-stage HCV and alcoholic liver disease (ALD) in man. Explanted livers of HCV and ALD patients were compared to normal and primary biliary cirrhosis (PBC) livers., Results: Although Stat3 expression and phosphorylation was not altered in HCV and ALD cirrhosis, Stat3 DNA-binding was not detected in all ALD and most HCV samples. Deficient Stat3 DNA-binding was associated with high Pias3 expression, but not with increased Socs3 levels. Bcl-2 was up-regulated in HCV and ALD together with decreased Caspase3 activity. Compared to base-line cell proliferation in normal donor livers, HCV cirrhosis showed a marked reduction in cyclin D1 and PCNA, whereas both markers were only slightly reduced in ALD., Conclusions: End-stage HCV and ALD cirrhosis is characterized by impaired Stat3 DNA-binding possibly through up-regulation of Pias3. Therefore, impaired activation of Stat3 target genes might contribute to disturbed liver regeneration and repair. The attempt in cirrhotic livers to favor anti-apoptotic over pro-apoptotic pathways is not sufficient to compensate for the low cellular proliferation rates.

The induction of cytochrome P4502E1 (CYP2E1) is believed to play a role in the development of fibrosis in hepatitis C patients. However, information about CYP2E1 activity in chronic hepatitis C patients is fragmentary and the relationship between CYP2E1 activity and mRNA expression is unknown in this disease. The purpose of this study was (a) to characterise CYP2E1 activity in those patients and (b) to analyse its relationship with CYP2E1 mRNA expression in the liver and in peripheral blood lymphocytes (PBLs), previously proposed as a surrogate to assess changes in CYP2E1 activity. Fourteen chronic hepatitis C patients were submitted to a routine transcutaneous liver biopsy. CYP2E1 activity was assessed by using chlorzoxazone (CZX) pharmacokinetic parameters and hepatic and PBLs CYP2E1 mRNA expression was measured by real-time RT-PCR. The mean oral clearance of CZX (CLT: 21.5+/-10.1L/h) was within the normal range and the chlorzoxazone metabolic ratio (CMR) at t = 2 h was closely related to other CZX pharmacokinetic parameters. None of the pharmacokinetic parameters did significantly correlate with CYP2E1 mRNA, neither in the liver nor in PBLs. Furthermore, there was no significant relationship between CYP2E1 mRNA levels in paired liver and PBL samples. Our data indicate that early stages of chronic hepatitis C are not associated with CYP2E1 induction. In this disease, the determination of the CMR at t = 2 h represents a reliable index to assess CYP2E1 activity. The measurement of CYP2E1 expression, at the mRNA level, in PBLs or in liver is not useful for that purpose.

Background/aims: While oxidative stress is a feature of non-alcoholic steatohepatitis, the causal link between oxidative stress and inflammatory recruitment has yet to be demonstrated. We analysed the role of NF-kappaB redox-sensitive signalling pathway of inflammatory recruitment in experimental steatohepatitis., Methods: Mice were fed the methionine and choline deficient (MCD) or the control diet, with or without curcumin, an NF-kappaB inhibitor, for up to 4 weeks. Histopathology, lipoperoxides, NF-kappaB/DNA binding and expression of NF-kappaB-regulated genes were assessed., Results: MCD-fed mice developed steatohepatitis accompanied by dramatic accumulation of hepatic lipoperoxides, activation of NF-kappaB and induction of pro-inflammatory ICAM-1, COX-2, MCP-1 and CINC mRNA. Curcumin significantly reduced MCD-induced inflammation but had no effect on steatosis or on the level of hepatic lipid peroxides. Curcumin prevented the MCD-induced activation of NF-kappaB and decreased downstream induction of ICAM-1, COX-2 and MCP-1. However, it failed to reduce activation of AP-1, MAPK pathways or CINC expression., Conclusions: Curcumin alleviates the severity of hepatic inflammation in experimental steatohepatitis induced by the MCD diet, an effect likely to be mediated via inhibition of NF-kB activation and dependent pro-inflammatory genes. The NF-kappaB pathway is one among several possible signalling pathways by which inflammation is recruited in experimental steatohepatitis.

Background/aims: Pathogenesis of non-alcoholic steatohepatitis (NASH) remains poorly understood. Cytochrome P450 2E1 (CYP 2E1), cytokines, oxidative stress and activation of hepatic stellate cells seem to play a role in this process. The aim was to determine the potential implication of these factors in the progression from uncomplicated steatosis to steatohepatitis with progressive fibrosis., Methods: Animals were fed a standard diet, a 5% orotic acid-diet (OA) developing hepatic steatosis, or the methionine-choline deficient (MCD) diet inducing steatohepatitis for 2 and 6 weeks. Lipid peroxidation, CYP 2E1 expression and activity, expression of UCP-2, interleukin (IL)-6, transforming growth factor (TGF)beta1, KLF6 mRNAs, and activation of hepatic stellate cells were examined by gas chromatography, high-performance liquid chromatography, Western blotting, quantitative polymerase chain reaction and immunohistochemistry., Results: Lipid peroxidation increased in the MCD model whereas only minor changes occurred in the OA model. KLF6 and TGFbeta1 mRNAs were selectively up-regulated in MCD animals. Stellate cell activation, inflammation and collagen deposition only occurred in the MCD group. CYP 2E1 expression and activity increased in the OA group while both decreased in MCD animals. UCP-2 and IL-6 mRNA increased in both groups., Conclusions: In the context of steatosis, lipid peroxidation is associated with inflammation and stellate cell activation with concomitant increase in TGFbeta1 production, possibly through up-regulation of KLF6.

Background: Retrorsine, a naturally occurring pyrrolizidine alkaloid, impairs liver regeneration after partial hepatectomy by mechanisms that are still unclear., Aim: The aim of the study was to clarify the influence of retrorsine on cell cycle progression in the regenerating liver lobes of rats after portal branch ligation (PBL)., Methods: Liver weight, protein and DNA contents, DNA synthesis (5'-bromodeoxyuridine (BrdU) incorporation) and cellular levels of Cyclin E, CDK-2, CDK-4 and proliferating cell nuclear antigen (PCNA) were assessed before and 24, 48, 72 and 168 h after PBL., Results: Before surgery, higher levels of cyclin E, CDK-2, CDK-4 and PCNA as well as BrdU incorporation were found in the liver of retrorsine-treated rats than in untreated rats. Liver weight gain, protein and DNA synthesis as well as induction of cell cycle related proteins were all strongly impaired by retrorsine in the regenerating lobes after PBL., Conclusions: In conclusion, retrorsine impairs liver regeneration in the PBL model not only by an S or G2/M phase block, but also by a block located before the G1/S transition of the cell cycle.

In rats, activation of the cytokine-inducible transcription factor signal transducer and activator of transcription 3 (Stat3) is impaired in the liver after ethanol administration. The aim was to examine Stat3 expression, localization, and activity in alcoholic liver disease (ALD) in humans. Explanted livers of ALD patients were compared to normal and primary biliary cirrhosis livers. Protein expression, DNA-binding, and subcellular localization of Stat3 was examined by Western blotting, electrophoretic mobility shift assays, and immunohistochemistry; and interleukin-6, Stat3, and suppressor of cytokine signaling (SOCS)-3 mRNA expression by quantitative polymerase chain reaction. Stat3 proteins increased markedly in ALD, mainly in hepatocyte and proliferating biliary epithelial cell nuclei. In contrast to normal and primary biliary cirrhosis livers where Stat3 DNA-binding occurred normally, no Stat3 DNA-binding complexes were observed in ALD, although the tyrosine and serine phosphorylation of Stat3 was not altered. Elevated interleukin-6 mRNA was found in ALD whereas Stat3 and suppressor of cytokine signaling-3 mRNA levels were decreased. Although end-stage ALD is characterized by up-regulation of Stat3 proteins, this transcription factor appears to be functionally inactive. Furthermore, decreased transcription of the Stat3 gene in ALD might also affect cytoplasmic reserves of inactivated Stat3 in the long term. Impaired activation and restoration of Stat3 might thus contribute to the development of cell damage leading to liver cirrhosis in ALD.

Background/aims: Fatty liver is known to be associated with increased mortality and morbidity after liver resection. The ability of fatty liver to regenerate after two-thirds partial hepatectomy was studied in three different models of steatosis in rats: obese Zucker rats, orotic acid-fed Wistar rats and Wistar rats fed a methionine-low, choline-deficient diet., Methods: Liver regeneration was assessed 24 h after partial hepatectomy by bromodeoxyuridine incorporation (immunohistochemistry), proliferating cell nuclear antigen, cyclin E and cyclin-dependent kinase 2 protein expression (Western blot analysis) and cyclin-dependent kinase 2 activity (kinase assays using histone H1 as a substrate)., Results: No significant difference of proliferative response was found between orotic acid or methionine-low, choline-deficient diet-fed and control Wistar rats 24 h after partial hepatectomy. In contrast, hepatocyte proliferation in obese Zucker rats after partial hepatectomy was significantly reduced when compared with their lean controls., Conclusions: Steatosis per se does not impair liver regeneration. The reduced liver regeneration observed in obese Zucker rats may not be due to fatty infiltration itself but to other factors such as leptin receptor dysfunction.

Background/aims: Patients with genotypic Cys282Tyr homozygous hemochromatosis differ largely in phenotypic presentation. The HFE mutation on itself does not explain the different manifestations of hemochromatosis. We hypothesized that the genetic haptoglobin (Hp) polymorphism, because of its effect on iron metabolism, could be a modifying factor that influences the clinical presentation of hereditary hemochromatosis., Methods: In 167 Cys282Tyr homozygous hemochromatotic patients, the frequencies of Hp types (1-1, 2-1 and 2-2) and alleles (Hp1, Hp2) were compared with those in 918 healthy subjects. Clinical and laboratory indices of iron overload were incorporated in the analysis., Results: The Hp 2-2 type was overrepresented in the patient group (P<0.01). Male patients carrying Hp 2-2 had higher serum iron (P=0.003) and ferritin levels (P=0.03) than those with a Hp 1-1 or 2-1 type. The amount of iron removed with phlebotomy was also higher in Hp 2-2 patients (P=0.03)., Conclusions: The Hp 2-2 type is overrepresented among Cys282Tyr homozygous hemochromatotic patients. At diagnosis, iron overload was more pronounced in male patients carrying Hp 2-2. Our data suggest that Hp polymorphism affects iron metabolism in hereditary hemochromatosis.

Background/aims: Patients with end-stage liver disease due to chronic hepatitis B infection in whom a YMDD escape hepatitis B virus (HBV) mutant has emerged under lamivudine treatment are generally denied liver transplantation (OLT)., Methods: We report the case of a male patient who was started on prophylactic treatment with lamivudine in the context of recurrent episodes of HBV reactivation during high dose immunosuppressive therapy for relapsing severe pulmonary sarcoidosis., Results: Following the emergence of a YMDD escape mutant virus under lamivudine treatment, he developed subacute liver failure requiring liver transplantation. The patient was treated with a combination of intravenous hepatitis B immune globulin (HBIG) which was started perioperatively and also continued lamivudine after OLT. Twelve months after OLT, there was no evidence of HBV reinfection of the liver graft with the use of HBIG and lamivudine., Conclusions: This observation suggests that emergence of the YMDD mutation is not a contra-indication to OLT, providing adequate immunoprophylaxis using HBIG and lamivudine combination therapy.

Several cryopreservation methods for precision-cut rat liver slices (PCLS) have been proposed, allowing a short-term (a few hours) maintainance of viability and functionality upon thawing. The aim of the present study was to test the metabolic capacity of PCLS cryopreserved by an ultrarapid method. The biotransformation of paracetamol to its glucuronide and sulfate conjugates and of midazolam to its hydroxylated metabolites was studied in thawed PCLS incubated for 24 hours at 37 degrees C in Williams' medium E. In addition, protein levels of the key enzymes involved in these metabolic reactions, i.e. UGT1A1, ST1A1, CYP2E1 and CYP3A2 were determinated. In addition, biological markers of cell function (ATP and glycogen levels) and toxicity (LDH leakage in the medium) were also measured. Compared to controls (non cryopreserved PCLS), CYP3A2 activity and content and CYP2E1 content were maintained at the same level all along the incubation, whereas paracetamol glucuronidation and sulfation dropped to 24 and 21% of the control value, respectively, immediately after thawing. Freezing-thawing conditions also modified cell functionality, leading to a lower intracellular ATP and glycogen content, and an increase in cell lysis, as shown by LDH released in the medium. The results of this study suggest that cryopreserved PCLS are able to maintain some phase I activities for 24 hours after thawing whereas some phase II metabolic capacities are not maintained.

Background/aims: In rats, partial ligation of portal branches produces atrophy of the deprived lobes and hypertrophy of the intact lobes. The hepatocyte proliferation observed in the nondeprived lobes is viewed as a compensatory hyperplasia, implying that the atrophy somewhat precedes the initiation of the proliferative response. As this has not been demonstrated, the time course and magnitude of those two sequences of events were investigated and compared with the well-defined response to a partial hepatectomy., Methods: The portal branch feeding the anterior liver lobes was ligated in male Wistar rats. One-third and two-thirds partial hepatectomies were also performed. Liver weight, the aminopyrine demethylation rate, an index of the liver mass, the DNA content and various indices of cell proliferation were measured., Results: Resection of the anterior lobes (PH) or ligation of their portal blood supply (PBL) induced a marked DNA synthesis in the posterior lobes (3H-thymidine incorporation) reaching its maximum 24 h after both interventions. This response can even be accelerated by performing a sham operation 6 h before the PBL. The process leading to DNA synthesis thus seems to start as early after PBL as after a PH, although the weight of the liver or the aminopyrine demethylation rate was nearly unchanged 2 h following PBL. The initiation of the proliferative response clearly precedes and is thus independent of the reduction of the liver mass. On the other hand, the progressive reduction of the liver mass seems to determine the magnitude of the proliferative response, which is, for instance, greatly increased following the excision of the deprived lobes, as late as 10 h after ligation of their portal branches. In comparison with the results obtained after a 113 PH, the peak of DNA synthesis at the 24th hour is greater than predicted by the liver weight loss, but this parameter could underestimate the reduction of the functional liver mass., Conclusion: The proliferative response following a PBL can be divided into an early phase occurring independently of the reduction of the liver mass and a late phase controlled by this reduction. The paradox of the proliferative response which seems to start before the atrophy to be compensated is resolved by this hypothesis.

Azathioprine (AZA) is characterized by high interindividual differences in bioavailability and metabolization. The aim of the present study was to analyze, in patients treated with AZA for various immune system disorders, whether the variation in red blood cell mean corpuscular volume (deltaMCV) could be used as an indirect estimation of the level of the active immune modifier metabolite 6-thioguanine nucleotides (6-TGN). In 43 consecutive patients treated with a stable dose of AZA for at least 6 months who were not initially anemic, the erythrocyte 6-TGN levels with routine hematologic parameters were determined two to four times at 1-month intervals. In most patients MCV significantly increased after 3 months of therapy and stabilized after 6 months. The correlation between the daily dose of AZA and the 6-TGN level was mild (r = 0.51; P<.001). A weak correlation was also found between the dose of AZA and the deltaMCV after at least 6 months of therapy (r = 0.36; P<.05). The correlation between deltaMCV and 6-TGN level, however, was much better (r = 0.74; P<.001). The lack of a significant increase in MCV after 3 to 4 months of AZA therapy reflects low 6-TGN levels, sometimes a result of undertreatment. A determination of the 6-TGN level during the first months after AZA therapy is begun will allow more accurate adaptation of the effective dose. We observed that deltaMCV could be used as an indicator of 6-TGN levels after 6 months of AZA treatment. An increase in MCV of at least 6 fL is expected to reflect a 6-TGN level of about 175 pmol/8x10(8) red blood cells (probably being within a therapeutic value).

Cytochrome P-450 3A (CYP 3A) enzymes, the prominent subfamily in the cytochrome system, are expressed in various extrahepatic tissues. Until now, their expression has been demonstrated in human polymorphic neutrophils (PMNs) but not in lymphocytes using immunohistochemistry and immunoblot analysis. Moreover, their potential modulation has not been determined yet. To study such an expression in different peripheral blood cell populations, rifampicin (600 mg/day during 6 days) was given to 8 healthy subjects. PMNs and lymphocytes were isolated by centrifugation of whole white blood cell fractions using Ficoll gradients before drug administration, immediately after, and 3 days after drug withdrawal. PMN and lymphocyte smears and homogenates were subjected to immunostaining and immunoblotting, respectively, with a mouse monoclonal antibody recognizing all CYP 3A proteins. These proteins were quantified by densitometric analysis. Before and after rifampicin administration, a positive cytoplasmic staining was observed in all PMNs and in about 50% of lymphocytes. CYP 3A expression in lymphocytes was further confirmed by positive immunoblots for lymphocyte homogenates. Neither in PMNs nor in lymphocytes, induction of CYP 3A protein expression was observed after rifampicin treatment despite overall induction of CYP 3A activity assessed by the urinary excretion of 6beta-hydroxycortisol. These results demonstrate that CYP 3A proteins are constitutively expressed not only in PMNs but also in lymphocytes. However, in both cell lineages CYP 3A protein expression was not induced by rifampicin.

We have developed a HPLC method which allows the determination of chlorzoxazone and its hydroxy metabolite in rat liver microsomes and in human plasma. We found that dehalogenated chlorzoxazone or 2-benzoxazolinone was a convenient and stable internal standard. Proteins were precipitated with diluted perchloric acid and the supernatant was extracted with ethyl acetate. Complete resolution of the peaks was achieved within 20 min with a Spherisorb ODS-1 column. The inter-day R.S.D.s were 6.5% at 0.5 microgram/ml of hydroxychlorzoxazone and 5.8% at 1 microgram/ml of chlorzoxazone in human plasma. The reproducibility of the method has been demonstrated for a large number of samples over a long period.

A sensitive high-performance liquid chromatographic method is described for the quantification of midazolam and 1'-hydroxymidazolam in human plasma. Sample (1 ml plasma) preparation involved a simple solvent extraction step with a recovery of approximately 90% for both compounds. An aliquot of the dissolved residue was injected onto a 3 microm capillary C18 column (150 mm x 0.8 mm I.D.). A gradient elution was used. The initial mobile phase composition (phosphate buffer-acetonitrile, 65:35) was maintained during 16 min and was then changed linearly during a 1-min period to phosphate buffer-acetonitrile, 40:60. The flow-rate of the mobile phase was 16 microl/min and the eluate was monitored by UV detection. The limits of quantification for midazolam and 1'-hydroxymidazolam were 1 ng/ml and 0.5 ng/ml, respectively. The applicability of the method was demonstrated by studying the pharmacokinetics of midazolam, and its major metabolite 1'-hydroxymidazolam, in human volunteers following i.v. bolus administration of a subtherapeutic midazolam dose (40 microg/kg).

Background/aim: Fatty liver has been associated with an increased risk of primary graft non-function and drug toxicity. However, these effects have been observed mainly in fatty liver with inflammation, a situation characterized by an overall reduction in cytochrome P-450 (CYP)-dependent activities as well as a contrasting increase in CYP2E1 activity. Our aim was to examine the impact of liver-fat accumulation on CYP in two animal models of fatty liver without necroinflammation., Methods: Ducks were force-fed with a high-glucidic diet and male Wistar rats, after 48 h fasting, were refed a high-glucidic, fat-free diet for 48 h. Total CYP, aminopyrine- (AND), erythromycin-N-demethylase (END) and chlorzoxazone hydroxylase (CZOHase) activities as well as CYP2E1 and CYP3A proteins were quantified on microsomal proteins., Results: Livers from force-fed ducks exhibited significant decreases in total CYP, AND, END and CZOHase activities, inversely correlated with fat-liver content. Refeeding male Wistar rats a high-glucidic, fat-free diet after 48 h fasting, resulting in a 235% increased liver fat content, was associated with a decrease in total CYP (55%), AND (78%), END (55%) and CZOHase (62%) activities as well as in CYP3A (70%) and CYP2E1 (80%) protein content. A significant inverse correlation was observed between CYP and total lipid content., Conclusions: In these models of steatosis induced by nutritional manipulations, fat liver accumulation was associated with a significant decrease in CYP activities and in CYP protein expression. Furthermore, the decreases in both CYP content and related activities were correlated with the degree of liver fat content.

The activities of lipoprotein lipase (LPL) and hepatic lipase (HL) were investigated after 23 days of ciprofibrate (100 mg or 200 mg) therapy or fenofibrate (200 mg) therapy. In a double-blind, double-placebo, cross-over study, three groups of six healthy volunteers received either 100 mg ciprofibrate/day followed by 200 mg fenofibrate 'high bioavailability' (HB)/day, or vice versa (group A), 200 mg ciprofibrate HB/day followed by 200 mg fenofibrate HB/day, or vice versa (group B), or 100 mg ciprofibrate/day followed by 200 mg ciprofibrate/day, or vice versa (group C). Fasting plasma lipid levels and safety parameters were evaluated before and after treatment. One hundred milligrams ciprofibrate/day therapy was found to be approximately as effective as 200 mg fenofibrate HB/day therapy in altering the lipid profile. The highest activation of LPL was obtained after treatment with 200 mg ciprofibrate/day. A modest, but statistically significant, increase in HL activity was found after 100 or 200 mg ciprofibrate treatment. Investigation of the pharmacokinetics of ciprofibrate and fenofibric acid revealed a shorter time to reach peak plasma levels, but a longer elimination half life for the ciprofibrate preparations in comparison with fenofibrate. A dose of 200 mg ciprofibrate/day is more effective than 100 mg ciprofibrate/day at increasing LPL and HL activity; however, 200 mg ciprofibrate/day is also associated with a potential detrimental change in safety parameters. Two hundred milligrams fenofibrate HB/day therapy may represent an alternative therapy to 100 mg ciprofibrate/day for hyperlipidaemic patients.

A method to determine the activity of the cytochrome P-450 1A1 enzyme, by measuring 7-ethoxyresorufin-O-deethylase (EROD) activity using high-performance liquid chromatography (HPLC) with fluorescence or with visible absorbance detection of resorufin, is described. The lowest quantifiable activity (0.2 pmol/mg min) is obtained by incubation of 0.3 mg of human duodenal microsomal proteins using HPLC fluorescence detection. Using HPLC with visible absorbance detection, sensivity was ten times lower. However, the equipment for this last method is available in most laboratories. The use of both HPLC assays allows determination of the low EROD activity level in samples of small size, such as two or three human duodenal biopsies obtained by routine endoscopy. These methods will be a useful tool to study the role of drug intestinal metabolism by cytochrome P-450 1A1.

The case of a pregnant woman in whom hepatitis developed after administration of high-dose fenoterol during the third trimester of a second pregnancy is described.

We report eight cases of liver injury related to amoxycillin-clavulanate. Liver biopsy performed in seven patients revealed varying degrees of injury to interlobular bile ducts in all cases. Lesions included irregularity of the nuclei, vacuolization of the cytoplasm, lymphocytic infiltration, destruction and endothelialization of the bile duct epithelium. Ductopenia was not observed. In two patients liver injury was accompanied by prominent extrahepatic manifestations (acute interstitial nephritis in one and acute lacrimal gland inflammation and sialadenitis with prolonged xerostomia in the other). We conclude that interlobular bile-duct lesions of varying severity are a common feature in liver injury related to amoxycillin-clavulanate. Side effects of the drug include acute interstitial nephritis and sialadenitis.

Drug hepatotoxicity is partially determined by genetic factors involved in drug metabolism, which may involve the debrisoquine oxidation polymorphism mediated by cytochrome (CYP) 2D6. The purpose of this study was to assess the relationship between drug hepatotoxicity and another genetic polymorphism of drug oxidation, namely that of S-mephenytoin metabolism mediated by CYP2CMP. Mephenytoin hydroxylation capacity was assessed by a hydroxylation index in 24 patients with drug-induced hepatitis and in 23 healthy controls. Hydroxylation index was calculated as the ratio of S-mephenytoin dose to the (0-10 h) urinary excretion of 4-hydroxymephenytoin after oral administration of 100 mg racemic mephenytoin. The test was performed following the patient's recovery. In three patients, hepatitis was related to Atrium, a drug containing phenobarbital, febarbamate and difebarbamate. The mean hydroxylation index (+/- SD) value in patients with Atrium hepatitis (12.4 +/- 8.3) was markedly higher than that found in healthy controls (1.8 +/- 0.4) or in patients with other drug-induced hepatitis (2.5 +/- 3.3). Mean hydroxylation index values were similar in the two latter groups. Considered individually, oxidation capacity was low (hydroxylation index > 9) in two of the three patients with Atrium hepatitis and intermediate (hydroxylation index between 4 and 9) in the third patient. In contrast, all 23 healthy subjects exhibited a high oxidation capacity (hydroxylation index < 4). In the 21 patients with other drug-induced hepatitis, oxidation capacity was high in 19 subjects, intermediate in one subject with chlorpromazine hepatitis, and low in one subject with dapsone hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

In an attempt to design a liver function test which takes into account both portal-systemic shunting and hepatocellular dysfunction, we investigated a group of patients with cirrhosis with or without surgical porta-caval shunt for d-propoxyphene and its major metabolite, norpropoxyphene kinetics. A small dose of d-propoxyphene (0.7 mg/kg body weight) was given orally to seven normal subjects, 15 patients with cirrhosis and seven patients with cirrhosis and surgical portacaval shunt. D-propoxyphene and norpropoxyphene areas under the plasma concentration-time from 0 to 4-h (AUC) were determined by the trapezoidal method. As d-propoxyphene is a high extraction drug and since the production of norpropoxyphene should reflect the amount of d-propoxyphene available to the hepatocytes, we tested the hypothesis that norpropoxyphene/d-propoxyphene AUC ratios should reflect both the degree of portal-systemic shunting and the severity of hepatocyte dysfunction. Norpropoxyphene/d-propoxyphene AUC ratios were significantly lower in patients with cirrhosis (mean +/- S.D.: 0.92 +/- 0.59) than in controls (2.51 +/- 0.45) and also significantly lower in patients with cirrhosis and a surgical shunt (0.53 +/- 0.23) than in patients with cirrhosis but without surgical shunt (1.10 +/- 0.63). Moreover, there was an overall statistically significant correlation between norpropoxyphene/d-propoxyphene AUC ratios and branched to aromatic amino acids ratios (rs = 0.91) and fasting venous NH4 (rs = -0.63). On the other hand, there was only a weak correlation between norpropoxyphene/d-propoxyphene AUC ratios and the 14C-aminopyrine breath test (rs = 0.43). These data suggest that the norpropoxyphene/d-propoxyphene AUC ratio reflects both shunting and reduced hepatocellular function.(ABSTRACT TRUNCATED AT 250 WORDS)

The evolution from a characteristic picture of autoimmune chronic hepatitis type I to primary biliary cirrhosis is reported in a middle-aged woman. The initial diagnosis of autoimmune chronic liver disease was based on clinical, bio-serological and histological grounds. It was further confirmed by complete remission following immunosuppressive treatment and prompt relapses at the time of therapy withdrawal. After 7 years, the characteristics of liver disease were altered with increased biochemical cholestasis and serum IgM concentrations, positivation of previously negative anti-M2 antimitochondrial antibodies and the appearance of a typical histological picture of stage I primary biliary cirrhosis. We believe that this is the first reported case in which autoimmune chronic hepatitis highly responsive to immunosuppressive therapy has been followed by the development of a characteristic picture of primary biliary cirrhosis.

The influence of two inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, simvastatin and pravastatin, on the level of urinary 6 beta-hydroxycortisol/17-hydroxycorticosteroids (6 beta-OHC/17-OHCS) ratio was determined in two groups of normolipidemic Caucasian subjects (n = 18 and n = 14, respectively). The 6 beta-OHC/17-OHCS ratio increased significantly after simvastatin administration (20 mg day-1 for 17 days) (P = 0.0125) whereas no modification was observed after pravastatin administration (20 mg day-1 during 17 days). As the level of 6 beta-OHC/17-OHCS ratio is a function of cytochrome P-450 3A activity, these results suggest that in Caucasian subjects, simvastatin but not pravastatin could be a weak inducer of cytochrome P-450 3A. This contrasting effect could be related to the major pharmacological differences existing between these two drugs.