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Background: We hypothesized that in patients with hepatitis C virus (HCV) genotype 2 or 3 in whom HCV RNA is not detectable after 4 weeks of therapy, 12 weeks of treatment is as effective as 24 weeks.Methods: A total of 283 patients were randomly assigned to a standard 24-week regimen of peginterferon alfa-2b at a dose of 1.0 mug per kilogram weekly plus ribavirin at a dose of 1000 mg or 1200 mg daily, on the basis of body weight. Of these, 70 patients were assigned to the 24-week regimen (standard-duration group) and 213 patients to a variable regimen (variable-duration group) of 12 or 24 weeks, depending on whether tests for HCV RNA were negative or positive at week 4. The primary end point was HCV that was not detectable by polymerase-chain-reaction (PCR) assay 24 weeks after the completion of therapy.Results: In the standard-duration group, 45 (64 percent) patients had HCV that was not detectable by PCR assay at week 4, as compared with 133 (62 percent) in the variable-duration group (difference [the rate in the standard-duration group minus that in the variable-duration group], 2 percent; 95 percent confidence interval, -11 to 15 percent). Fifty-three patients (76 percent) in the standard-duration group and 164 patients (77 percent) in the variable-duration group had a sustained virologic response (difference, -1 percent; 95 percent confidence interval, -13 to 10 percent). Fewer patients in the variable-duration group receiving the 12-week regimen had adverse events and withdrew than in the group receiving the 24-week regimen (P=0.045). The rate of relapse (defined as HCV not detectable at the end of treatment but detectable at the end of follow-up) was 3.6 percent in the standard-duration group and 8.9 percent in the variable-duration group (P=0.16). Overall, the rate of sustained virologic response was 80 percent among patients with HCV genotype 2 and 66 percent among those with genotype 3 (P<0.001).Conclusions: A shorter course of therapy over 12 weeks with peginterferon alfa-2b and ribavirin is as effective as a 24-week course for patients with HCV genotype 2 or 3 who have a response to treatment at 4 weeks. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether and to which extent respiratory function abnormalities may complicate the earliest stages of chronic liver disease (CLD). Aim of this study was to compare pulmonary capillary volumes and gas exchange efficiency of CLD patients with and without cirrhosis., Methods: Sixty-seven participants (mean age 56.5 years; women 22.4%) were divided into three groups (matched by age, sex, smoking) according to the baseline CLD stage as follows: (a) healthy controls (Group A, n=20); (b) non-cirrhotic CLD patients (Group B; n=23); (c) cirrhotic CLD patients (Group C; n=24). All participants underwent clinical assessment, respiratory function tests, gas exchange estimation by the alveolar diffusion of carbon monoxide (TLCO) measurement and 6-min walking test. Groups were compared by chi-square and one-way anova tests., Results: Chronic liver disease patients had significantly lower levels of TLCO (Group B=17.7 ml/min mmHg, and Group C=14.2 ml/min mmHg) compared with healthy controls (Group A=24.4 ml/min mmHg). Consistent results were obtained when analyses were performed using TLCO expressed as percentage of the predicted value. TLCO adjusted for the alveolar volume was lower in cirrhotic patients compared with both controls and non-cirrhotic CLD patients (P<0.001 and P=0.035 respectively). Group C participants presented blood gas parameters tending to a compensated chronic respiratory alkalosis status compared with the other groups., Conclusions: Pulmonary microvascular and gas exchange modifications are present at early stages of CLD. Future studies should be focused at evaluating the pathophysiological mechanisms underlying this relationship., (© 2011 John Wiley & Sons A/S.)

Background & Aims: The benefit of individualizing treatment for patients with genotype 3 HCV infection on the basis of viral clearance at week 4 (wk4-R) has not been firmly established., Methods: Four hundred and fourteen patients received Peg-interferon alpha-2b plus 1000-1200 mg of ribavirin daily according with body weight > or <75 kg. Patients were randomized to standard 24 weeks (Std24) or to a 12 or 36 weeks variable treatment duration (Var12/36). In the variable treatment arm, patients with or without wk4-R were allocated to either 12 or 36 weeks duration., Results: At treatment week 4, HCV RNA was undetectable in 262 patients (63.3%), 136 in the Std24, and 126 in the Var12/36 group (p=0.41). In patients with wk4-R, end-of-treatment (EOT) responses were 80.4% (CI 85.4-95.3) and 97.6% (CI 94.9-99.9) in the two arms, respectively (p=0.019). In patients without wk4-R, corresponding rates were 61.9% (50.6-73.2) and 75.3% (CI 65.9-84.6) (p=0.08). SVR was attained in 302 patients, 71.4% (CI 65.3-77.6) in the St24 group and 74.3% (CI 58.4-80.3) in the variable 12/36 arm. Among patients with wk4-R, SVR was 81.6% (CI 75.1-88.1) and 82.5% (75.9-89.1), respectively. In patients without wk4-R, SVR amounted to 52.1% (CI 40.4-63.7) and 61.7 (CI 51.1-72.3) in the two arms (p=0.25)., Conclusions: HCV genotype 3 patients with week4-R may be treated safely with 12 weeks of therapy, provided that sufficiently high doses of ribavirin are administered. For patients still viremic at treatment week 4, SVR rates were numerically higher after 36 weeks of treatment than after the currently recommended 24 weeks., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

We report a case series of three HBeAg positive and five HBeAg negative patients (7 males, mean age 50.6 +/- 14.6 years) with chronic HBV infection experiencing seroconversion after treatment with entecavir (0.5 mg/day or 1 mg/day), initiated in 2007. Overall, the mean time to HBsAg clearance was 9.4 +/- 4.5 months. Seroconversion occurred in all patients, after a mean time of 8.0 +/- 3.7 months. In HBeAg negative patients, mean time to HBsAg clearance and to seroconversion were 9.2 +/- 5.9 and 6.8 +/- 4.0 months, respectively. In HBeAg positive patients, mean time to HBsAg clearance and to seroconversion were 9.7 +/- 0.6 months and 10.0 +/- 2.6 months, respectively. In this case series, seroconversion was maintained and was observed both in HBeAg positive patients and in HBeAg negative patients. Therefore, it may be preliminarily suggested that treatment with entecavir could be associated to HBsAg seroconversion in a short period of time, in both HBeAg positive and HBeAg negative HBV patients.

Portopulmonary hypertension (PoPH) is a serious condition without an established treatment. Drugs used to treat pulmonary hypertension may have detrimental effects on portal hypertension. This study was designed to assess in patients with PoPH the acute effects of inhaled iloprost (iILO) on pulmonary and hepatic hemodynamics and to evaluate the clinical outcome after 12 months of treatment. We conducted 2 separate studies. In the first one, 21 patients with PoPH were acutely tested with 2.8 microg of iILO. Pulmonary and hepatic hemodynamics were assessed at the baseline and through 60 minutes after iILO. In the second one, we retrospectively evaluated 12 patients treated with iILO (30 microg/day) for more than 1 year. The 6-minute walk distance (6MWD), functional class (FC), and echocardiogram were analyzed at the baseline and after 12 months of treatment. In the acute study, iILO rapidly reduced pulmonary artery pressure (PAP; -16% + or - 8%, P < 0.001) and pulmonary vascular resistance (-18% + or - 14%, P < 0.001). The cardiac output did not change initially but decreased after 30 minutes. The hepatic venous pressure gradient (HVPG) and hepatic blood flow did not vary through the study. Pulmonary vasodilation induced by iILO was inversely related to HVPG. In the long-term evaluation, iILO improved FC by 1 or more in 7 patients (P = 0.04) and increased 6MWD by 67 + or - 59 m at 12 months (P < 0.001). No change in systolic PAP was observed. Two patients died because of hepatic complications, and 4 additional patients presented clinically significant events that were related to hepatic disease in 2 and worsening of pulmonary hypertension in 2. We conclude that in patients with PoPH, iILO produces rapid and selective pulmonary vasodilation without altering the hepatic hemodynamics. Its long-term use may provide sustained improvements in symptoms and exercise tolerance in some patients with PoPH. A randomized, controlled trial is warranted to establish its clinical role in this serious condition.

Unlabelled: In hepatitis C virus (HCV) genotypes 2 and 3 patients, the high rate of relapse after 12 to 16 weeks of antiviral therapy is the main concern for shortening treatment duration. This study was undertaken to delineate predictors of relapse after short treatment in patients with undetectable HCV RNA at treatment week 4 (RVR), and to report in RVR patients with relapse the sustained virological response (SVR) after a second 24-week course of therapy. RVR patients received pegylated interferon (Peg-IFN) alfa-2b (1.5 microg/kg) and ribavirin (1000-1200 mg/day) for 12 weeks; those who relapsed were re-treated with the same drug doses but for the extended standard duration of 24 weeks. Logistic regression analysis was applied to delineate predictors of relapse by using age, sex, route of transmission, body mass index (BMI), serum alanine aminotransferase (ALT), HCV genotypes, serum HCV RNA levels, and platelet counts as covariates. Of 718 patients with genotypes 2 and 3 who were started on therapy, 496 (69.1%) had undetectable HCV RNA at week 4. Of them, 409 patients (82.5%, CI 79.1-85.8) attained SVR, and 67 (14.1%, CI 10.4-16.5) relapsed. At regression analysis, only platelet count less than 140,000 mm(3) [odds ratio, 2.51; confidence interval (CI), 1.49-4.20] and BMI 30 or higher (odds ratio, 1.7; CI, 1.03-2.70) were independently associated with relapse. Forty-three of 67 patients with relapse agreed to be re-treated, and an SVR was achieved in 30 (70.0%) of them., Conclusion: We recommend 12 weeks course of therapy for patients with undetectable HCV RNA at treatment week 4, providing they present with no advanced fibrosis and low BMI.

Unlabelled: It was hypothesized that in hepatitis C virus (HCV) genotype 1 patients, variable treatment duration individualized by first undetectable HCV RNA is as effective as standard 48-week treatment. Patients (n = 696) received peginterferon alfa-2a, 180 mg/week, or peginterferon alfa-2b, 1.5 mg/kg/week, plus ribavirin, 1000-1200 mg/day, for 48 weeks (standard, n = 237) or for 24, 48, or 72 weeks if HCV-RNA-negative at weeks 4, 8, or 12, respectively (variable, n = 459). Sustained virologic response (SVR) was achieved in 45.1% [95% confidence interval (CI) 38.8-51.4] of the patients in the standard group and in 48.8% (CI 44.2-53.3) of the patients in the variable group (P = 0.37). The percentages of patients who first achieved undetectable HCV RNA at weeks 4, 8, or 12 were 26.7%, 27.8%, and 11.3%, respectively. In the standard treatment group, 87.1%, 70.3%, and 38.1% of patients who first achieved undetectable HCV RNA at 4, 8, or 12 weeks attained SVRs, respectively. In the variable group, corresponding SVR rates were 77.2%, 71.9%, and 63.5%. Low viremia levels and young age were independent predictors of response at week 4 [rapid virologic response (RVR)]. RVR patients with baseline viremia >or=400,000 IU/mL achieved higher SVR rates when treated for 48 weeks rather than 24 weeks (86.8% versus 73.1%, P = 0.14). The only predictive factor of SVR in RVR patients was advanced fibrosis., Conclusion: Variable treatment duration ensures SVR rates similar to those of standard treatment duration, sparing unnecessary side effects and costs.

The role of acute pulmonary vasodilator testing in portopulmonary hypertension (PoPH), a current contraindication for orthotopic liver transplantation (OLT), has not been thoroughly elucidated. The purpose of this work was to analyze the results of acute vasodilator testing with inhaled nitric oxide (NO), to compare them with intravenous epoprostenol (PGI(2)), and to investigate the acute effects of the oral vasodilator isosorbide-5-mononitrate (Is-5-MN), in patients with PoPH. A total of 19 patients with PoPH (male/female = 9/10) were studied. Pulmonary hemodynamic measurements were performed at baseline and during NO inhalation (40 ppm); additionally, 15 patients were tested with PGI(2) (2-12 mug/kg/minute) and 8 were tested with Is-5-MN (20-40 mg). Inhaled NO reduced pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) by 5.7% and 11.0%, respectively. PGI(2) elicited greater reductions in PAP (11.8%) and PVR (-24.0%), and produced a 28% drop in systemic vascular resistance (SVR) and a 17% increase in the cardiac index (CI). Is-5-MN reduced PAP by 25.6% and PVR by 21.5%, without systemic changes. There was good agreement between the response to PGI(2) and Is-5-MN: 6 patients of the whole series (32%) decreased PAP >20% from baseline, reaching a final value < or = 35 mmHg, the current limit for OLT. In conclusion, acute vasodilator testing has a relevant role in PoPH, as it identifies one-third of patients able to reach a more favorable hemodynamic situation, which can be determinant for their management. For vasodilator testing, PGI(2) is more suitable than NO in PoPH. Is-5-MN exerts a selective effect on pulmonary circulation in patients who had already responded to PGI(2)., ((c) 2007 AASLD.)

Cytological analysis of microsporogenesis in 72 popcorn plants, comprising nine from the original population (CMS-43, S(0)) and 63 from seven cycles of self-fertilization (S(1) to S(7)), one plant of S(0) generation (plant 2) was identified with B chromosomes. The number of B chromosomes varied from two to three in the same anther. The pattern of chromosome pairing and meiotic behavior of Bs were similar to those found in other plant species. The presence of B chromosomes did not affect chiasma frequency and chiasma distribution in A chromosomes. This is the first report of B chromosomes in popcorn.

We determined whether triple therapy comprising amantadine (AMA), ribavirin (RBV) and either peginterferon (PEG-IFN) alpha-2a or conventional IFN alpha-2a would improve sustained virological response (SVR) rates over dual therapy with IFN alpha-2a and RBV in patients with chronic HCV infection. A total of 362 treatment-naïve patients were randomized to 48 weeks of treatment with: PEG-IFN alpha-2a 180 microg/week (group A) or IFN alpha-2a 3 MU tiw (groups B and C). All patients received RBV 1000 or 1200 mg/day and those in groups A and B received AMA 200 mg/day. SVR was defined as an undetectable HCV RNA after 24 weeks of untreated follow-up. At the end of therapy, 74.4% (95% CI 0.66-0.82) of patients in group A were HCV RNA-negative compared with 42.5% (95% CI 0.33-0.50) of those in group B (P = 0.0001) and 48.8% (95% CI 0.40-0.56) of those in group C. SVR was achieved in a significantly greater proportion of patients in group A compared with groups B and C: 65.3% (95% CI 0.53-0.56), 33.3% (95% CI 0.25-0.41) and 44.6% (95% CI 0.36-0.53; P = 0.0001) respectively. In patients with genotype 1, SVR rates were 55.2, 22.8 and 28.8% with the three regimens respectively. Factors independently associated with SVR were HCV genotype 2 or 3, therapy with PEG-IFN, female gender and age. In treatment-naive patients with chronic hepatitis C, triple therapy with PEG-IFN alpha-2a, RBV and AMA produces higher SVR than dual or triple therapy with conventional IFN alpha-2a.

Management of HCV infection and related liver disease with treatment currently available lead to a sustained virological response in 20% of patients using interferon (IFN)-alpha mono-therapy and approximately 40-45% in those on combination therapy with ribavirin.The aim of the present investigation was to compare the effect of consensus interferon alphacon-1 (C-IFN), and IFN-alpha 2b plus ribavirin, in patients relapsing after treatment with interferon alone. A total of 112 randomised patients with relapsing HCV infection (M/F=53/59), were treated for 24 weeks with: (A) IFN-alpha 2b starting with 5/6MU/day till negativity of HCV-RNA followed by 3MU every other day, plus ribavirin 15mg/kg/day (n=34); (B) C-IFN 9microg/day (n=40); (C) ursodeoxycholic acid (UDCA; sodium salt) 450mg/day (n=37). At the end of treatment, patients were observed at follow-up for 24 weeks.Clearance of HCV-RNA was achieved by the end of treatment in 23 patients (68%) in Group A and 21 also showed a biochemical response with normal ALT; in Group B, 33 patients (82%) had both a virological and a biochemical response; in Group C, one patient cleared HCV-RNA. At the end of follow-up (sustained-response), 29% of patients in Group A (n=10/34) had negative PCR (seven patients relapsed at the 4th week, six at the 12th); in Group B, a sustained response was achieved in 58% (p<0.03; two patients relapsed at the 4th week, three at the 12th and five at the 24th).MAJOR SIDE EFFECTS COMPRISED: neutropenia (n=17) and decrease in Hb>1.5g/dl (n=33) in Group A, recurrence of psoriasis in two patients in Group B and abdominal discomfort and diarrhoea in 11 patients in Group C.Rapid clearance of circulating HCV-RNA was induced by C-IFN (66% at three weeks, 71% at six weeks): this was a good prognostic index both for end of treatment and sustained response. Treatment with C-IFN lead to a higher response rate compared to that of recombinant IFN-alpha 2b in association with ribavirin. The action of C-IFN is superior in the time taken to reach the maximal response rate during treatment and in the lower prevalence of relapse of the infection.

The amount of copies of HCV-RNA and count of CD8(+) lymphocytes was retrospectively evaluated in 326 patients: sampling was performed in basal condition, during treatment with alpha-IFN (n=232) and post-treatment follow-up, and at the same time points in untreated patients (n=94). In the treated group the difference between CD8(+) lymphocytes in the patients successfully treated (n=65) and those with an unfavourable outcome (n=176) is statistically significant (898+/-172 vs., 440+/-176 CD8(+) lymphocytes per mm(3) P<0.005 ANOVA). Also, in the untreated patients the average count of CD8(+) cells is statistically higher in patients with a favourable outcome (P<0.01 ANOVA). The present data show that the count of CD8(+) lymphocyte is of clinical value in order to predict the outcome of HCV infection and may be used together with the viral load and genotype, already established predictors.

Background: Treatment of hepatitis C virus (HCV) infection with interferon (IFN) in older patients may not be feasible on account of side effects: we, therefore, attempted combined treatment with amantadine hydrochloride (AH) in order to improve not only the flu-like symptoms associated with IFN but also the anti-viral effect. Methods: Patients over 65 years of age, (n=165), who had failed to eradicate HCV infection after previous treatment with IFN were randomized into three groups and treated for 12 months, group A received AH 100 mg twice per day; group B received IFNalpha-n(3) 6 M units every other day for 3 months followed by 3 MU and group C the same dose of IFNalpha-n(3), as in B, and AH 200 mg per day. Results: Group A, 42 patients agreed to undergo treatment (genotype 1b n=39); at the end of treatment 21 patients (50%) had normal ALT and seven (17%) negative polymerase chain reaction (PCR). HCV-RNA was not detectable in seven patients at the sixth month follow-up and in six (14%) after 23plus minus2 months. Group B, 39 patients accepted the treatment (genotype 1b n=31); at the end of treatment, 17 patients (44%) had normal ALT and 13 negative PCR (13%). HCV-RNA was not detectable in nine patients (23%) at the sixth month of follow-up and in eight (21%) after 22plus minus4 months. Group C, 38 patients accepted the treatment (genotype 1b n=32); at the end of treatment, 20 (53%) patients had normal ALT and 15 negative PCR (39%). HCV-RNA was not detectable in 15 patients at the sixth month follow-up and in 11 after 21plus minus4 months (29%). Forty-six patients did not accept the scheme of treatment and 26 of them had a follow-up of 20plus minus3 months. HCV-RNA copies and prevalence of genotype 1b were comparable to the treated groups: HCV-RNA was fluctuating or unchanged during the entire follow-up. Conclusions: AH associated with IFN was able to improve the negativization of HCV-RNA and sustained response to IFN and decreased the malaise associated with IFN; an increase in viral copies was observed under AH in about 40%.

Objective: Infection with hepatotropic viruses is associated with a variable degree of liver disease, and there is evidence that more severe lesions are related to the association with another viral infection. The aim of this investigation is to establish the relationship between different viral infections occurring in the same individual and the presence and progression of liver disease., Design: The study population comprises 754 intravenous (IV) drug abusers exposed to hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) or cytomegalovirus (CMV). All individuals were followed for an average of 2 years. Liver disease was assessed by liver function tests, 99m-technetium (99mTc) liver scintigraphy, and also by liver biopsy in a subset (n = 136) of patients. The different viral patterns and presence of disease were analysed by logistic regression, and the risk factors were calculated. Contingency tables of patients with single or associated infections were drawn up to evaluate progression of liver disease., Results: Association of HIV with at least one other viral infection was constant. Surface antigens of HBV (HBsAg) were always associated with HIV (n = 19); in this group, 18 patients had signs of liver disease. A past infection with HBV, as revealed by the presence of at least antibodies against the surface antigen (HBsAb) and antibodies against the core antigen of HBV (HBcAb), was detected in 463 patients (61.4%). The overall prevalence of HCV antibodies was 63.91% (n = 482). In 96.8% of the 406 patients tested, HCV-RNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The majority of patients with high alanine transaminase (ALT) had anti-HBV antibodies in the presence of HCV (56.1%). At the end of follow-up, all of these patients showed signs of active liver disease, and scoring was significantly worse than in patients with either HBV or HCV alone. An infection/reactivation of CMV was found in patients previously exposed to HBV and with increased ALT values., Conclusions: Data emerging from this study reveal the association of HCV or CMV, or both, with a previous HBV infection, as demonstrated by HBsAb and HBcAb, and rapid progression of the disease in this group of patients. A previous HBV infection therefore appears to be an important risk factor for subsequent viral-related liver disease.

Background/Aims. The aim of this study was to estabilish the 'true' therapeutical gain of a combined therapy interferon - ribavirin versus interferon monotherapy in hepatitis C virus infection.Methods. A systematic review of published trials comparing combined treatment (interferon+ribavirin) vs interferon monotherapy, was performed on articles printed from 1991 to 1999.Results. The meta-analysis of retrieved trials showed that ribavirin significantly enhances the sustained response rate to interferon therapy in all types of patients. The results of almost all studies were homogeneous: combined therapy approximately doubles response rates compared to interferon monotherapy. At the end of the treatment, ribavirin increased the rate of viral clearance approximately 22% and the biochemical response of about 31%. The net gain was about 24% for both viral and biochemical response rate after 24 weeks of follow-up.Conclusion. Combined therapy showed a significantly higher efficacy in terms of sustained negativity of viral genome in all classes of patients (naives, relapsers, non-responders) becoming the therapy of choice. Nevertheless, more than about 50% of patients infected by hepatitis C virus show no sustained response to treatment. The whole weight of final data is beared by the major trials all with similar results.

Many different aetiological agents stimulate alanine aminotransferase (ALT) production. Viral markers and other aetiologies were investigated in 2166 individuals, randomly selected from 10,000 consecutive blood donors. Elevation of ALT was found in 10.8% of subjects. Grouping donors according to ALT level and correlating with, respectively, hepatitis B core antibody (HBcAb), cytomegalovirus antibody alone, or associated with HBcAb, showed similar findings (high ALT 11.1%, normal 11.6%; high 85.4%, normal 81.4%; high 10.2%, normal 11.0%, respectively). Hepatitis C virus (HCV) antibody was found to be significantly associated with elevated ALT levels (high 1.7%, normal 0.26%). Other causes of ALT elevation were alcohol abuse (17%), obesity (25%) and dyslipidaemia (38%), but in 11% there was no obvious aetiology. Although HCV is a rare cause of elevated ALT in blood donors, it seems to be the only virus, among those tested, to account for liver damage. This may be due to the non-protective role of HCV antibody, the low specificity of ALT, or the pathogenic role of uninvestigated viruses.

The aim of the study was to investigate whether the immunoblot pattern for HCV is a predictor of the response to interferon treatment. In a group of 60 patients with persistent rise of aminotransferase, all were treated with 3-6MU of Alfa-IFN from normal leucocytes every other day for 6 months, followed by one weekly dose of 1-3 MU for 3 months. HCV serum markers were detected before treatment and every three months thereafter. In 22 out of 60 (36.6%) patients aminotransferase normalized and remained so for 3 months after therapy; 12 patients (54.5%) relapsed during a follow-up of 9-12 months. The most frequent pattern in responders and non responders was the positivity to four antibodies (55%). The pattern did not change during or after IFN therapy, nor was it related to the variation of aminotransferases. Three patients lost antibodies linked to viral replication (c100-3, 5-1-1) and 3 others became positive to the same antigens. No changes were observed during the follow-up of patients who had an initial normalization of ALT/AST levels and who then relapsed (either during the maintenance dose or during the whole follow-up:n = 19 pts). Therefore neither the antibody clearance of viral replication (c100-3 and 5-1-1) nor the antibody pattern is a valid predictor as to the efficacy of interferon therapy.

The pattern of individual bilirubin pigments during a 24 hour caloric restriction (400 Kcal) was investigated in three groups of patients: one group with constitutional hyperbilirubinaemia (n = 29), another with microcytaemia and signs of haemolysis (n = 15) and the third consisting of patients without signs of hepatic disease (n = 11). The different bilirubin fractions (unconjugated, mono- and di-conjugated) were separated as methylated tetrapyrroles by t.l.c. following alkaline methanolysis. In all patients fasting induced an enhancement of the unconjugated bilirubin while the concentration of mono- and di-methyl esters of conjugated bilirubins remained within the normal range. When a pre-fasting concentration of total bilirubin equal to 1.2 mg/dl was used as a discriminating point, two different patterns in the fasting-induced increase in unconjugated bilirubin were identified. An increase of more than 1 mg/dl was found in 30 patients and 28 of these had constitutional hyperbilirubinaemia as diagnosed by exclusion of other disorders. The group with an increase of less than 1 mg/dl was composed of 25 patients, only one of whom had constitutional hyperbilirubinaemia: 14 were affected by microcytaemia and 10 were outpatients without signs of disease. The "fasting-induced increase in unconjugated bilirubin" has a specificity of 78%, a sensitivity of 84% and a positive and negative predictive value of 85 and 76%, respectively, for the diagnosis of constitutional hyperbilirubinaemia.

A retrospective study was carried out in 56 patients to establish the association of cytomegalovirus (CMV) with active or inactive hepatitis B virus (HBV) infection as a possible risk factor in the development of severe liver disease. Patients with positive CMV serology and active or inactive HBV infection had elevated alanine aminotransferase activity and had a relatively high incidence of more severe lesions (chronic hepatitis and active cirrhosis). In the absence of CMV, only one case of cirrhosis was identified compared with seven cases of hepatic fibrosis. By analogy with hepatitis C virus, CMV may bring about activation of the host inflammatory response against hepatocytes following HBV infection, resulting in the development of severe hepatitic disease.

The clinical and laboratory findings of 37 patients with primary sclerosing cholangitis (PSC) were reviewed. Mean age was 43.8 years, sex ratio between males and females was 3:1; IBD was present in 91% of patients with 51% having ulcerative colitis, 23% unclassified colitis and 17% Crohn's disease. Twenty-seven patients (73%) were symptomatic presenting most commonly with fatigue, pruritus and hepato-splenomegaly. Cholangiography revealed abnormalities affecting both extrahepatic and intrahepatic biliary ductal systems in 51.8% of cases, and only the intrahepatic or extrahepatic biliary tree, respectively in 11.1% and in 37% of cases. The last prevalence was very high compared with that previously known. Clinical and biochemical data, when compared between asymptomatics and symptomatics, demonstrated a significant difference only for alkaline phosphatase which increased in the symptomatic group and for prothrombin activity which decreased among symptomatic patients. Nevertheless, predictive value of sALP for the presence of PSC was high when pts were pooled together with a randomly selected group of 36 non-affected persons that underwent ERCP for suspected primary sclerosing cholangitis: sensitivity was 94% and specificity 78%.

Intravenous infusion of glucagon (100 micrograms/hr/100 g body weight) in rats produces a 20 to 35% increase in bile flow and enhances the activity of hepatic bilirubin uridine diphosphate-glucuronyltransferase to 132% after a 90 min infusion. When a bilirubin load is given to produce a constant and apparently maximal biliary bilirubin excretion rate (or transport maximum) the administration of glucagon increased the bilirubin transport maximum. The excretion rate of bilirubin monoglucuronides was more enhanced than that of diglucuronide. The enhanced rate of glucuronidation, assayed in vitro, correlated with the augmented biliary output and inversely with the plasma unconjugated bilirubin levels. It is concluded that glucagon, at the dosage used, leads to a higher formation rate of bilirubin monoconjugates and that the choleresis, also induced by the hormone, enhances the biliary secretion of the monoconjugates formed. The enhanced conjugation results in a decreased plasma concentration of unconjugated bile pigment and the associated choleresis leads to a decreased di- to monoconjugate ratio, opposite to what has been observed during bilirubinostasis and cholestasis. The secretory efficacy, as assessed from the bile-to-plasma concentration ratio, is enhanced for all bilirubin pigments after glucagon administration.

The aim of the present investigation was to define the role of the synthetic terpenoid epomediol on biliary secretion in rats recovered from anaesthesia, in stabilized conditions and receiving an intravenous infusion of Na+ taurocholate (120 or 240 nmol.min-1 per 100 g body wt.) or physiologic saline (NaCl 0.16 M). Epomediol was administered at the rate of 20 and 50 mg.kg-1 per h, through a second syringe connected to the same vein catheter. Bile flow was increased up to 67% according to the model. The effect of epomediol is dose-dependent, associated with enhanced Na+ transport into bile and with an increased anionic gap. The extent of epomediol action also changes according to the different rates of bile acid secretion. At low secretory rates a greater choleretic action was observed with epomediol. The effect was negligible for a secretion of bile acids above 350 nmol.min-1 per 100 g body wt. Excretion into bile of the epomediol glucuronide was not hampered by high Na+ taurocholate output. This suggests that there is no competition of the two anions for a common excretory pathway at the studied rates. The effect of epomediol seems due to a mechanism of action both independent and additive to the mechanism for bile acids. The presence of additivity of the two choleretic mechanisms at low flow and bile acid secretion and the loss of action at high secretory rates, suggests that the maximal capacity of passage for water into bile was reached.

Fifty-one patients with signs of past HBV infection were investigated for the HCV virus antibody. All patients were at least HBsAb, HBcAb positive. Two groups were selected: patients with increased serum AST activity (32/51) and patients with normal serum AST activity (19/51). Prevalence of HCV infection was higher (81.2%) in the group with high serum aminotransferases as compared to that found in the second group (31.6%) (p less than 0.002). Furthermore, histological findings showed higher prevalence of HCV infection in patients with cirrhosis as compared to patients with hepatic fibrosis. Results show that lack of clinical remission in patients with past HBV infection could be due to the presence of HCV, thus representing an unrecognized cause of "cryptogenetic" liver diseases.

We tested the hypothesis that serum factors present in Crohn's disease interfere with the process of lymphocyte activation. The mitogen-induced proliferation and the expression of early activation antigens by normal lymphocytes cultured in the presence of either Crohn's disease sera or sera from different controls were evaluated. The mitogen-induced proliferation was significantly impaired in the presence of Crohn's disease sera. These sera markedly inhibited the mitogen-induced interleukin-2 receptor (IL-2R) expression (48% inhibition), while the effect of sera on the expression of the transferrin receptor and the 4F2 antigen was much less pronounced. Diafiltration experiments showed that the inhibitory effect was confined to a 30-50-kD serum fraction. Such a serum property was not related to the patients' disease activity and disappeared after surgical removal of the affected bowel. The capability of inhibiting the mitogen-induced IL-2R expression was not restricted to Crohn's disease and was observed with sera from other inflammatory and neoplastic gastrointestinal disorders. This study indicates that a marked inhibition of the IL-2R is a mechanism underlying the immunosuppressive property of the serum in Crohn's disease and in other gastrointestinal conditions.

Treatment of both male and female rats with 5 IU/day mepartricin for 7-10 days administered by gastric tubing resulted in an increased faecal excretion of some steroids. Mean rate of elimination of total oestrogens was enhanced by 45% in male rats and by 14% in female rats, and the average excretion of conjugated oestrogen was also increased in the female animals. Faecal elimination of cholesterol was 37% and 42% higher in male and female rats, respectively, after mepartricin treatment, and in male rats plasma concentrations of cholesterol were reduced following treatment. It is suggested mepartricin acts either by changing the intestinal flora or by acting directly on the steroid moieties, and it is speculated that a similar mechanism may occur in man.

Sulfate glycolithocholic acid (SGLC) has been shown to be highly cholestatic in the rat. This study was performed in order to gain understanding of the mechanisms of SGLC-induced cholestasis and the aim of the investigation was to explore the hypothesis that SGLC could cause a precipitation of calcium in bile. We studied the effects of intravenously administrated SGLC on bile flow, biliary lipids secretion and calcium excretion in the female bile fistula hamster. We also performed in-vitro studies with a Ca2(+)-selective electrode in order to measure the calcium binding capacity of SGLC. The results showed that after 1 h of infusion of 8 mumol/100 g body weight [14C]SGLC bile flow dropped to zero. During the infusion period a fine white sludge was visible in the test tube used for bile collection. TLC and HPLC analysis of both the supernatant and the precipitate showed that unchanged SGLC was excreted into bile. Up to 20% of biliary SGLC and more than 50% of the total Ca2+ present in bile was precipitated. The SGLC/Ca2+ molar ratio in the precipitate was 1.12 +/- 0.3 (mean +/- S.D. of four experiments). Light and electron microscopy of the liver did not show any specific abnormalities. The Ca2+ binding activity of SGLC in vitro, was highest among the bile acids tested at a concentration of 0.1 mM, when almost 100% of bile acids are in the monomeric (non-micellar) form. This suggests that among the bile acids, SGLC exerts the strongest binding activity on free calcium ions.(ABSTRACT TRUNCATED AT 250 WORDS)

Subcellular fractionation of liver homogenates from treated rats was carried out in order to study the mechanism of action of the gastrointestinal polypeptides on glucoronidation. Rats were treated for 90 min with an intravenous infusion of secretin (0.4 cU/h/100 g body weight), glucagon (100 micrograms/h/100 g body weight) and vasoactive intestinal polypeptide (VIP) (300 ng/h/100 g body weight); controls were sham-treated rats. For comparison, another group of animals was treated with a daily injection of phenobarbitone (10 mg/kg), a well-established enzyme inducer. Treatment with the different polypeptides produced minor changes in the subcellular localization of the enzyme. The bulk of activity was always recovered in the microsomal fraction, as identified by both differential centrifugation and the enrichment in specific activity of glucose-6-phosphatase, esterase and NADPH-cytochrome c reductase. Secretin produced a specific increase of bilirubin glucuronidation, more evident in all nuclear fractions. Glucagon increased both bilirubin and p-nitrophenol glucuronidation in all subcellular fractions. VIP had a selective action on p-nitrophenol conjugation of similar extent in nuclear and microsomal fractions. The type of changes observed is suggestive of physicochemical modifications occurring into the cell, perhaps at the membrane environment of different organelles, able to modify the overall conjugation of different substrates by the cell.

Somatostatin was administered intravenously to male Wistar rats, recovered for 3 h from an anesthesia during which the common bile duct and jugular vein were cannulated. Different bile acid-secretory rates were obtained by infusion of saline, or of Na+-taurocholate (150 nmol/min/100 g body wt), or by 8-h bile depletion. At the dose of 2 micrograms/h/100 g body wt, somatostatin causes a prompt decrease of bile flow (about 30%) and of bile acid secretion (32%-47%). The bile acid-independent fraction of canalicular bile is more decreased than the one associated with bile acid secretion. The changes are dose dependent and show a saturation pattern, with half-maximal saturation already at 2.2 ng/min/100 g body wt. Despite this cholestasis, endogenous bilirubin secretion remained unchanged, pointing to different secretory mechanisms for bilirubin and bile acids. In the isolated and perfused liver, somatostatin displays an anticholeretic effect, proportional to the amount of Na+-taurocholate present in the system. Hepatic blood flow and O2 consumption remained constant during perfusion, and were not affected by somatostatin. The hepatic transport of bile acid, and the water and electrolyte secretion are directly affected by somatostatin, and the experimentally-induced cholestasis seems a new and suitable model for studying mechanisms of bile secretion.

A study of 108 patients with acute or acute relapsing gallstone pancreatitis was carried out in order to evaluate the incidence of biliary lithiasis and microlithiasis. The severity of pancreatic damage associated with both clinical states and the physicochemical characteristics of the minute stones were also evaluated. The results suggest that the risk of acute pancreatitis is increased in patients with microlithiasis and that in patients with acute pancreatitis due to microlithiasis the lesions are more severe. These results warrant the conclusion that cholecystectomy should be performed upon all patients with echographically detected microlithiasis, even in the absence of symptoms. Early surgical treatment must be performed whenever pancreatitis develops.

Mepartricin was given to cirrhotic patients in order to evaluate its effect on the imbalance of sex steroids which is typical of this disorder. Patients were divided into two group: one group received placebo (n = 19) and the other received 150,000 IU/day mepartricin for 30 days (n = 19). The patients were evaluated by separate medical staff who were unaware of the treatment. Mepartricin significantly decreased the plasma concentration of testosterone, oestradiol and prolactin as compared with the values at the start of the trial, while no significant changes were seen in the occurrence of gynaecomastia. No relevant changes were seen in patients receiving the control, except for a slight increase in the peripheral concentration of androstenedione, aldosterone and follicle stimulating hormone.

The apparent maximal transport capacity (Tm) of the liver for bilirubin was studied in rats after oral treatment for two weeks with the two flavonoids (+)-cyanidanol-3 and palmitoyl-catechin in order to investigate a possible mechanism of action on jaundice described in humans. (+)-Cyanidanol-3 produces no changes in bilirubin-Tm, and the analysis of bilirubin and its conjugates in the different compartments reveals a decreased amount of the whole bilirubin taken up by the liver. Palmitoyl-catechin, a more lipophilic derivative of catechin, produces a slight increase in bilirubin-Tm. This appears related to the increased conjugation rate demonstrated in vitro for bilirubin. A multicompartimental analysis shows a different distribution of bilirubins as compared to controls. It is likely that physicochemical changes of the membrane environment, where the enzyme is buried, have modified the capacity of the hepatocyte to dispose bilirubin.

The activity of bilirubin UDP-glucuronyltransferase in liver tissue was increased 1.5-fold after 90 min of secretion administration (4 i.u./h per kg body wt.) in anaesthetized Wistar rats biopsied half-hourly over a period of 2 h. In unanaesthetized R/A Wistar rats, activities of liver enzymes were assayed after administration secretin for 1 h. Bilirubin UDP-glycosyltransferase activities and cytochrome P-450 concentration were increased, but p-nitrophenol UDP-glucuronyltransferase and UDP-glucose dehydrogenase activities remained unchanged.

This controlled study in cirrhotic patients investigated whether two antialdosteronic steroids, spironolactone (100-200 mg/day; n = 12 patient pairs) and potassium canrenoate (50-100 mg/day, n = 32 patient pairs) which are reported to bind to intracellular membranes and modify cytochrome P-450, could also produce nuclear changes. The model used was the response of peripheral lymphocytes to blastogenic agents by studying lymphocyte sub-populations. No changes occurred in the B- and T-lymphocyte sub-populations or in the helper and suppressor sub-types. The response to the blastogenic agents, phytohaemagglutinin and purified protein derived from mycobacteria, did not change significantly from before entry into the study to the follow-up (18.1 +/- 2.9 months). All control patients (n = 44 patient pairs) had slightly greater mitogenic activity compared with patients treated with spironolactone; no difference was found when control patients were compared with patients given potassium canrenoate. The difference between spironolactone and potassium canrenoate might be due to toxicity caused by the thio group of spironolactone. Overall, however, both drugs may be regarded as safe, in terms of effects on lymphatic tissue, occurring during the course of cirrhosis.