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BACKGROUND AND AIMS: The Cochrane Hepato-Biliary Group (CHBG) is one of the 52 collaborative review groups within The Cochrane Collaboration. The activities of the CHBG focus on collecting hepato-biliary randomized clinical trials (RCT) and controlled clinical trials (CCT), and including them in systematic reviews with meta-analyses of the trials. In this overview, we present the growth of The CHBG Controlled Trials Register, as well as the systematic reviews that have been produced since March 1996. RESULTS: The CHBG register includes almost 11,000 RCT and 700 CCT publications. The earliest RCT in the register were published in 1955, and the earliest CCT in 1945. From 1945 to 1980, there were less than 100 publications each year. From 1981 to 1997, their number increased from over 100 to 600 a year. After 1997, the number of publications seems to have been decreasing. The CHBG has published 199 protocols for systematic reviews and 107 systematic reviews through to August 2009 in which 21% of the RCT and CCT were included. The CHBG reviews have been cited approximately 1200 times. CONCLUSIONS: A large amount of work has been carried out since 1996. However, there is still much to do, as the CHBG register contains a great number of RCT and CCT on topics that have not yet been systematically reviewed.

Background Cochrane systematic reviews are of higher quality than reviews published in scientific journals, yet are used less than other sources for clinical decision-making. Aim To assess whether the characteristics of the Cochrane systematic reviews can account for their scant use by physicians. Materials and methods We analysed the 87 Cochrane hepato-biliary reviews dealing with therapeutic topics posted in the Cochrane Database of Systematic Reviews through December 2008, which we classified according to four characteristics: empty reviews; outdated reviews; content of reviews; implications for practice. Results Six empty reviews found no eligible randomised trials and six found one trial, precluding a systematic review; some empty reviews investigated irrelevant topics. Twenty-one reviews investigated outdated interventions, and thirteen of them were posted ten or more years after the publication of the most recent trial included. Most reviews were too lengthy (median: 40 pages) and their consultation was time-consuming with respect to clinical content. They generally compared two treatments, disregarding other options, and usually did not report any non-randomised (although convincing) evidence of potential use in clinical decision-making. Conclusions If generalized to the entire Cochrane Database of Systematic Reviews, these characteristics may largely explain why physicians undervalue the Cochrane reviews as a source of evidence for clinical decision-making.

A persistent increase in non-virus non-alcohol related aminostransferase levels can have multiple causes, which differ in terms of prevalence and clinical importance. In the general population, the most frequent cause is non-alcoholic hepatic steatosis, which can evolve into steato-hepatitis and cirrhosis. The treatment for steatosis and non-alcoholic steato-hepatitis consists of modifying lifestyles, whereas the effectiveness of drug treatment remains to be determined. Other much less frequent (yet not rare) causes of persistent non-virus non-alcohol related elevations in aminotransferase levels are celiac disease and hemochromatosis, whereas autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and alpha-1-anti-trypsin deficit are rare. Given that some of these conditions are susceptible to treatment, early diagnosis is important. No epidemiological data are available for evaluating the prevalence of elevated aminotransferase levels correlated with the toxicity of drugs or other xenobiotics, including herbal products. The present document, created by a panel of experts based on a systematic review of scientific evidence, is mainly geared towards physicians working in General Medicine and Transfusion Centres, who generally represent the first contact of persons with elevated aminotransferase levels. The document includes suggestions for diagnosing causes of persistent non-virus non-alcohol related increases in aminotransferase levels, considering the frequency and response to treatment. The conditions requiring specialized visits are also indicated.

Two hundred and twenty-four consecutive inpatients with cirrhosis, mostly of nonalcoholic etiology, and ascites were prospectively investigated on admission for spontaneous bacterial peritonitis (SBP) by culture, smear, and polymorphonuclear (PMN) counts of ascitic fluid. Positive cultures were found in 54 patients. A possible intraabdominal source of infection was apparent in five of them, all with clinically overt peritonitis (secondary peritonitis). No intraabdominal source of infection was identified in the remaining 49. These patients were classified into the following groups: (a) SBP, 27 patients (positive cultures plus PMN counts ± 250 per mm3). Nine of them had no clinical features of peritonitis (silent SBP) in contrast to the other 18 (symptomatic SBP). (b) Bacteriascites (BA), 18 patients (positive culture with PMN counts less than 250 per mm3 in the absence of clinical peritonitis). Four patients were unclassified. Among 170 patients with negative culture, six had an overt peritonitis plus a positive smear and PMNs ± 250 per mm3 into ascites and were considered as probable SBP. The remaining 164 patients were classified as sterile ascites. A single strain of Gram-negative bacteria (usually of enteric origin) was recovered frequently in patients with symptomatic or silent SBP (79%) whereas Gram-positive bacteria were more frequently found in patients with BA (61%, p < 0.01). In-hospital mortality showed a statistically significant difference among patients with SBP (48%) and those with BA (22%) or sterile ascites (18%) (p < 0.05 and p < 0.0005, respectively). We conclude that SBP is frequent event in nonalcoholic cirrhosis. Bacterial contamination of ascites may remain in balance or progress to overt peritonitis according to the pathogenicity of the agent. SBP carries a high mortality in comparison to sterile ascites or BA despite early antibiotic treatment.

Liver transplantation significantly improves the survival and quality of life of patients with end-stage cirrhosis. However, a large proportion of cirrhotic patients still die while on the transplant list because of an insufficient number of donors and because of the lack of an accurate prediction of life expectancy. Although many prognostic models have been proposed in the last two decades to predict mortality in cirrhosis, the Child–Pugh score [1] is by far the most largely used both in clinical practice and in clinical research. Recently, the model for end stage liver disease (MELD) has replaced the Child–Pugh score in the United States for prioritizing liver donor allocation [2]. MELD is considered more reproducible than the Child– Pugh score because it does not include subjective variables such as ascites and encephalopathy. However, obtaining the score requires computing and it is, therefore, much less practical than the Child–Pugh score for individual estimates at the bedside. Moreover, the MELD score has not been proven to be superior to the Child–Pugh score in terms of predictive accuracy [3], and both may be unsatisfactory when applied separately to compensated and decompensated patients [4]. It is in fact well known that life expectancies in compensated and decompensated cirrhosis are strikingly different and it is, therefore, conceivable that prognostic indicators may be different or may have a different weight according to the disease stage [4]. In this article we outline the natural history of cirrhosis and report on a systematic review of the literature regarding predictors of mortality in cirrhosis in order to

Source Department of Medicine and Pneumology, V Cervello Hospital, Via Trabucco 180, 90146 Palermo, Italy. lindpas@yahoo.it Abstract BACKGROUND AND METHODS: Host may have a role in the evolution of chronic HCV liver disease. We performed two cross-sectional prospective studies to evaluate the prevalence of cirrhosis in first degree relatives of patients with cirrhosis and the role of two major histocompatibility complex class III alleles BF and C4 versus HCV as risk factors for familial clustering. FINDINGS: Ninety-three (18.6%) of 500 patients with cirrhosis had at least one cirrhotic first degree relative as compared to 13 (2.6%) of 500 controls, (OR 7.38; CI 4.21-12.9). C4BQ0 was significantly more frequent in the 93 cirrhotic patients than in 93 cirrhotic controls without familiarity (Hardy-Weinberg equilibrium: chi2 5.76, P = 0.016) and in 20 families with versus 20 without aggregation of HCV related cirrhosis (29.2% versus 11.3%, P = 0.001); the association C4BQ0-HCV was found almost only in cirrhotic patients with a family history of liver cirrhosis. CONCLUSIONS: Our studies support the value of C4BQ0 as a risk indicator of familial HCV related cirrhosis.

Background : Increased prevalence of cirrhosis in cirrhotics' families in previous studies. Aims : To compare the prevalence of cirrhosis in cirrhotics' families with that in families of patients with non-hepatic diseases. Methods : Case-control study including 500 index cases with cirrhosis and 500 pair-matched controls with chronic non-hepatic diseases, interviewed about cirrhosis in first-degree relatives and spouses using standardized forms. Results : Ninety-three index cases (88% anti-hepatitis C virus (HCV)-positive) and 13 controls had one or more cirrhotics among first-degree relatives and/or spouses (odds ratio (OR) 7.38, 95% confidence interval (CI) 4.21–12.9); cirrhosis was found in 123/4485 first-degree relatives of the index cases and in 16/4086 of controls (OR 7.17 95% CI 4.25–12.09), in 14/467 spouses of the index cases and in 1/416 spouses of controls (OR 12.8, 95% CI 1.67–97.96). The percentage of secondary cases in the families of 440 anti-HCV-positive and 60 anti-HCV-negative index cases was similar (18.8 and 21.6%, respectively). Almost all the secondary cases in families of anti-HCV-positive index cases and none in families of anti-HCV-negative index cases were anti-HCV-positive. Conclusions : Cirrhosis is significantly more frequent among first-degree relatives and spouses of patients with cirrhosis, mostly HCV-related, than among first-degree relatives and spouses of controls.

Summary Background Morphological, haemodynamic and clinical stages of cirrhosis have been proposed, although no definite staging system is yet accepted for clinical practice. Aim To investigate whether clinical complications of cirrhosis may define different prognostic disease stages. Methods Analysis of the database from a prospective inception cohort of 494 patients. Decompensation was defined by ascites, bleeding, jaundice or encephalopathy. Explored potential prognostic stages: 1, compensated cirrhosis without oesophago-gastric varices; 2, compensated cirrhosis with varices; 3, bleeding without other complications; 4, first nonbleeding decompensation; 5, any second decompensating event. Patient flow across stages was assessed by a competing risks analysis. Results Major patient characteristics were: 199 females, 295 males, 404 HCV+, 377 compensated, 117 decompensated cirrhosis. The mean follow-up was 145 ± 109 months without dropouts. Major events: 380 deaths, 326 oesophago-gastric varices, 283 ascites, 158 bleeding, 146 encephalopathy, 113 jaundice, 126 hepatocellular carcinoma and 19 liver transplantation. Patients entering each prognostic stage along the disease course were: 202, stage 1; 216, stage 2; 75 stage 3; 206 stage 4; 213 stage 5. Five-year transition rate towards a different stage, for stages 1–4 was 34.5%, 42%, 65% and 78%, respectively (P

Background. Although band ligation is now recommended for prevention of rebleeding from oesophageal varices in cirrhosis, sclerotherapy is still widely used. Patients submitted to chronic sclerotherapy undergo several endoscopies and experience a large number of serious complications. However, long-term outcome is poorly defined. Aims. To assess the clinical course and prognostic indicators of patients undergoing chronic sclerotherapy for prevention of variceal rebleeding as a basis for future evaluation of long-term band ligation outcome. Methods. Prospective cohort study prognostic analysis by the Cox proportional hazards model. Results. A total of 218 consecutive cirrhotic patients (37 Child class A, 154 B, 27 CJ were enrolled in the study. Varices were obliterated in 139 (64%) patients in a mean of 5 (±2.6) sessions and recurred in 58 139 (41.7%) within one year. A total of 132 (60%) patients experienced 283 rebleeding episodes and 73 (33%) died. Bleeding from oesophageal ulcers was the most serious complication causing 14% of all rebleeding episodes. Significant prognostic indicators of sclerotherapy outcome were: Child-Pugh class for variceal obliteration; gastric varices and platelet count for recurrence of varices; failure to obliterate varices, variceal size and gastric varices for rebleeding; blood urea nitrogen and failure to obliterate varices for death. Presence of gastric varices was the only prognostic indicator for death in the 79 patients not achieving variceal obliteration. A mean of 10 endoscopies and of 6 hospital admissions were needed per each patient with an estimated cost of US$ 7154 per patient during the first two years of therapy. Conclusions. Sclerotherapy is a very demanding and costly treatment, and is associated with frequent and serious side-effects. The probability of treatment failure is significantly higher in Child C patients with gastric varices. Alternative treatments should be considered for these patients.

Non-insulin-dependent diabetes mellitus (NIDDM) may be associated with chronic hepatitis C virus (HCV) infection. This was studied further in two parts. First, 1,151 patients with HCV-related cirrhosis and 181 patients with hepatitis B virus (HBV)-related cirrhosis, well matched for age, sex, and severity of cirrhosis, were reviewed retrospectively. The prevalence of diabetes mellitus was higher in HCV-related cirrhosis (23.6%) than in HBV-related cirrhosis (9.4%; odds ratio [OR], 2.78; 95% confidence interval [CI], 1.6-4.79; P =.0002). The prevalence of diabetes mellitus was associated closely with the Child-Pugh score (OR, 3.83; 95% CI, 2. 38-6.17; P.0001) and increasing age (OR, 1.02; 95% CI, 1.00-1.03; P =.0117). Second, 235 patients with biopsy confirmed chronic HBV or HCV underwent an oral glucose tolerance test. Only 1 of 70 patients with chronic viral hepatitis without cirrhosis was diabetic. However, 31 of 127 patients with HCV-related cirrhosis (24.4%) were diabetic compared with 3 of 38 patients with HBV-related cirrhosis (7.9%, P =.0477). The major variables associated with NIDDM were cirrhosis (OR, 14.39; 95% CI, 1.91-108; P =.0096) and male sex (OR, 4.64; 95% CI, 1. 32-16.18; P =.0161). Fasting insulin levels in 30 patients with HCV-related cirrhosis and diabetes mellitus were elevated significantly, which was consistent with insulin resistance. However, acute insulin responsiveness was reduced in all patients with HCV infection and diabetes suggesting concomitant B-cell dysfunction. This study confirms an association between HCV and NIDDM.

Continuing advances in the knowledge of the pathophysiology of portal hypertension result in the progressive expansion of the spectrum of drugs with a potential role for clinical practice, with objectives that now tend to include the prevention of the enlargement or even the development of esophageal varices. This systematic review summarizes the evidence of efficacy of drug therapy for portal hypertension and draws recommendations for clinical practice. Although there is not yet enough evidence to support the treatment for the prevention of the development or enlargement of varices, nonselective beta-blockers are the first-choice therapy to prevent the first bleeding in patients with medium or large-sized varices and rebleeding in patients surviving a bleeding episode. The clinical role of isosorbide-5-mononitrate either alone or in association with beta-blockers still remains unsettled. Vasoactive drugs are generally effective and safe in controlling acute variceal bleeding, although the evidence is not equivalent for each of them.

No data on mortality in celiac disease are currently available in southern Europe. Our aim was to evaluate mortality and the cause of death in adult celiac disease in a Mediterranean area. In all, 228 adults with celiac disease were histologically diagnosed in our department from 1980 to 1997. Full information on their state of health was obtained in 216 of 228 patients. A tabulation of patient-years at risk was constructed in terms of age at diagnosis and the interval from diagnosis. Standardized mortality ratio was calculated by dividing the number of observed deaths by the number of expected deaths. Twelve deaths were observed, whereas 3.12 deaths were expected (SMR = 3.8; 95% CI 2-7). The increased mortality was mainly observed within four years from diagnosis (8 observed; 1.4 expected) (SMR = 5.8; 95% CI 2.5-11.5). Twelve tumors were observed (six lymphomas). In conclusion, mortality from adult celiac disease in our geographical area is increased compared with the general population, and this increased risk seems due to non-Hodgkin's lymphoma.

Epidemiological studies on pancreatic pseudocysts are retrospective analyses on alcoholic patients. The aims of this study were to investigate the incidence, natural history, and predictors of the appearance and disappearance of pancreatic fluid collections and pseudocysts after nonalcoholic acute pancreatitis. We carried out a prospective cohort study in a series of 926 patients with acute pancreatitis. Pancreatic fluid collections or pseudocysts were treated only after complications. We studied pancreatic fluid collections from 83 patients (8.9%): 48 of whom developed pseudocysts (5.1%). Both were less frequent after biliary pancreatitis (P < 0.0001). In the first 60 days of follow-up, patients with fluid collections or pseudocysts showed more complications than spontaneous disappearance; two of them died. After the 60th day, spontaneous disappearance was more frequent, and at one year the cumulative incidence of complications and spontaneous disappearance was 36% and 56%, respectively. A total of 33 patients with fluid collection needed interventional treatment (surgery or percutaneous or endoscopic drainage). Pseudocysts that were small (

In June 1996, the American Association for the Study of Liver Diseases sponsored a single topic workshop combining a two-day symposium on liver microcirculation in health and diseases1 followed by a two day consensus workshop on portal hypertension and variceal bleeding. The goal of the combined conference was to identify areas of critical importance in the understanding and treatment of portal hypertension and to foster future collaborative research projects. The portal hypertension-variceal bleeding conference consisted of eight panel discussions, each highlighting a specific topic related to evaluation and treatment of portal hypertension. The chair of each panel was charged to summarize the current state of knowledge in the field and to suggest areas for future investigation. In addition, there were three invited lecturers on specific areas of interest. This report will summarize the conclusions of each of the panels. In comparing the summary statements from the different panels, there may be differences in emphasis, definitions of endpoints, or choices for therapy. These differences are a reflection of the state of the field where areas of disagreement exist.

Background/Aims: To evaluate whether sustained response to α-interferon improves clinical outcome in patients with chronic hepatitis C. Methods: A cohort of 410 consecutive patients (65% with chronic hepatitis, 35% with cirrhosis) were treated with α-interferon in two trials (mean follow-up 62.1 months, range 7–109 months). All were serum HCV RNA positive before therapy and received first 10 then 5 million units of α-2b or α-n1 interferon three times weekly for 6 to 12 months. Sustained response was defined as normal aminotransferases 12 months after stopping interferon. Results: Sixty-two patients (15.1%: 54 with chronic hepatitis, eight with cirrhosis) were sustained responders. At the end of follow-up, 56 out of 62 sustained responders (90.3%) were serum HCV RNA negative. No biochemical relapse after 12 months was seen in sustained responders, regardless of initial histology, HCV genotype or persistence of HCV RNA. Although three died of non-hepatic causes, no liver-related events were observed among sustained responders. Complications of liver disease occurred in 34 relapser/non-responders: nine hepatocellular carcinomas, 21 ascites and four portal hypertensive bleedings. Eleven relapsers/nonresponders died: eight of hepatic and three of non-hepatic causes. Event-free survival was significantly longer in sustained responders than in all the remaining patients. In a regression analysis, sustained response to interferon, low age and absence of cirrhosis were independent predictors of event-free survival. Conclusion: Hepatitis C virus is probably eradicated and progression of liver disease is prevented in most patients who remain HCV RNA negative with normal transaminases for more than 1 year after stopping treatment.

Background/Aims: To investigate host- and virus-related factors predictive of early and sustained alanine aminotransferase normalization after interferon therapy for HCV-related chronic liver disease, in an area where genotype 1 is highly prevalent. Methods: We studied 100 patients with HCV-RNA positive chronic liver disease (73 chronic hepatitis and 27 cirrhosis) undergoing alpha-interferon treatment. Thirty-four patients had an early response but relapsed, 15 patients remained into sustained response for at least 12 months after therapy, and 51 patients did not respond. Serum HCV-RNA levels were assessed by bDNA (Chiron), and genotype by LiPA (Innogenetics) and by sequencing of the 5′ non-coding region. Results: Mean pre-treatment HCV-RNA level (×10 3 genome equivalents/ml±SD) was lower in sustained responders (3854±7142) than in relapsers (9587±10163) or in non-responders (5709±6618). HCV subtype 1b was highly prevalent (82%), while types 1a, 2a, 3 and 4 were rare (about 5% each). However, the prevalence of 1b was much lower (31 %) under 40 years of age. The prevalence of subtype 1b among sustained responders (74%) was similar to that observed among relapsers (82%) or non-responders (84%), but some nucleotide substitutions in the putative RNA loop of the 5′ non-coding region were seen only among relapsers or non-responders. Multiple logistic regression model showed that early response to interferon was predicted by absence of cirrhosis and a pre-treatment HCV-RNA level below 350. Sustained response to interferon was predicted by pre-treatment HCV-RNA level below 350 and a low fibrosis score. Conclusions: Among patients with hepatitis C from an area where subtype 1b is highly prevalent, absence of cirrhosis and low pre-treatment serum HCV-RNA level are the most important predictors of response to IFN. Some nucleotide substitutions found in the 5′ non-coding region of subtype 1b are associated with non-response or relapse.

To identify predictors of short-term and sustained ALT normalization after interferon treatment in adult patients with chronic hepatitis C, we performed a metanalysis of individual patients'data, with construction and cross-validation of a prediction rule, in 361 patients from two randomized trials. In one trial, 116 subjects with transfusion-related chronic hepatitis C were treated with lymphoblastoid interferon (5 MU/m 2 three times a week for 2 mo, then 3 MU/m 2 three times a week for 4 or 10 mo)

One hundred and forty-seven patients with Child's A cirrhosis and no evidence of hepatocellular carcinoma were followed up in an 8-year prospective surveillance program with testing by ultrasound and alphafetoprotein every 6 months. Eighteen of 147 patients were HBsAg positive. Anti-hepatitis C virus antibodies were found in 103 out of 133 cases tested. Sixteen patients had a history of heavy drinking. Thirty hepatocellular carcinomas were detected during follow up. At the time of diagnosis, ultrasound detected focal lesions in all the patients whereas alphafetoprotein was below diagnostic levels. The hepatocellular carcinoma was single in 26 patients and multiple in four. The overall 8-year cumulative tumor-free rate was 69% (95% confidence interval = 58-73). The yearly hepatocellular carcinoma incidence from 1985 to 1992 was respectively 2%, 1.5%, 2%, 3%, 5%, 4.8%, 7% and 10%. The initial value of AFP50 ng/ml and400 ng/ml was significantly related to the development of hepatocellular carcinoma. This series shows that the cumulative incidence of hepatocellular carcinoma in cirrhosis in Italy is higher than previously reported, but lower than that observed in Asiatic areas. A 6-month interval for ultrasound is reasonable to detect treatable tumors. Alphafetoprotein has no value for early diagnosis, although its intermediate values (50 and400 ng/ml) may indicate the presence of undetectable cancer which will appear during the follow up, and suggests that ultrasound should be employed more frequently in patients with these values.

This study evaluated the performance of third-generation anti-HCV assays in blood donors who were positive by second-generation anti-HCV, and assessed any possible relationship between antibody patterns, HCV replication and liver damage. Fifty-two second-generation enzyme immunoassay-positive asymptomatic Italian blood donors were retested for anti-HCV by third-generation enzyme immunoassay and recombinant immunoblot assay (Ortho third-generation enzyme immunoassay, third-generation recombinant immunoblot assay), utilising recombinant C33c and NS5 and synthetic peptide C100 and C22 antigens, and for HCV-RNA by "nested" polymerase chain reaction with 5' region primers. Alanine aminotransferases were tested monthly for 6 months. Two out of 52 second-generation enzyme immunoassay-positive donors were third-generation enzyme immunoassay, third-generation recombinant immunoblot assay and HCV-RNA negative. Among 50 third-generation enzyme immunoassay-positive cases, two had a third-generation enzyme immunoassay optical densityor = 1: one was third-generation recombinant immunoblot assay and HCV-RNA negative, and the other was third-generation recombinant immunoblot assay "indeterminate" and HCV-RNA-positive. The remaining 48 cases had third-generation enzyme immunoassay optical density1: six were third-generation recombinant immunoblot assay negative (one HCV-RNA+ve), eight "indeterminate" (two HCV-RNA+ve) and 34 positive (22 HCV-RNA+ve). All "indeterminate" subjects reacted only to C22. HCV-RNA was positive in 22/34 cases with positive third-generation recombinant immunoblot assay (two or more Ags), 3/9 "indeterminate" and 1/11 negative. Alanine amino-transferases were abnormal in 13 cases with positive third-generation recombinant immunoblot assay, one was "indeterminate" and three were negative.(ABSTRACT TRUNCATED AT 250 WORDS)

The randomised clinical trials testing the effectiveness of interferon treatment on Chronic Hepatitis B patients were reviewed by means of meta-analysis. Twenty-two trials, published between 1987 and 1990, have identified where 1290 adult patients had been studied. Overall, interferon increased the rates of serum HBV-DNA clearance and amino-transferases normalization about 3 times at one year. However, when an analysis of internal consistency, clinical relevance and methodology of these studies was made, the trials were not sufficient to confirm the clinical effectiveness of the treatment since they had been planned for short-term assessment based on biochemical and viral end points alone. The link of these end points to other outcomes of more obvious clinical relevance (i.e. evolution to cirrhosis or deterioration of cirrhosis, death) is, in fact, questionable and thus the value of a meta-analysis based on currently available trials is uncertain as a source for practical guidelines. We conclude that the effectiveness of interferon in patients with chronic hepatitis B has yet to be confirmed by long-term prospective studies which assess the outcome by clinically meaningful end points such as cirrhosis, liver failure, or death.

The administration of ursodeoxycholic acid, a hydrophilic bile acid not hepatotoxic to humans, has been suggested for treatment of primary biliary cirrhosis to improve cholestasis and reduce hepatocellular damage. Efficacy of treatment has been studied mainly in patients with asymptomatic or early-stage disease. In January 1988, to establish the efficacy and safety of ursodeoxycholic acid in a population with more severe disease, we started a multicenter, double-blind, placebo-controlled trial in patients with symptomatic disease, that is, with pruritus or serum bilirubin exceeding 2 mg/dl. Forty-four patients were assigned to ursodeoxycholic acid, 500 mg daily (corresponding to about 8.7 mg/kg body weight in these patients), and 44 to a placebo. As planned at the beginning of the study, a preliminary analysis was performed when all patients had been followed for at least 6 months (33 patients up to 12 months). Pruritus, self-evaluated by the patients, and cholestyramine consumption, as recorded in a diary, decreased significantly ( p p p p p p

Meta-analysis was used to evaluate 4 clinical trials comparing distal spleno-renal shunt (DSRS) with endoscopic sclerotherapy (EVS) in the prevention of variceal rebleeding: the interval between bleeding and therapy ranges from 100 days. A questionnaire was sent to each author of the published trials concerning methods, definitions and results of the trials in order to obtain more detailed and up-to-date information. The selected end-points for the meta-analysis were: rebleeding, mortality and chronic encephalopathy. Analysis of the results in the questionnaires was made using the method proposed by Collins. The pooled relative risk (i.e. the combined Odds ratio of each trial as an estimate of overall efficacy) of rebleeding was statistically reduced by DSRS (0.16; 95% confidence interval 0.10-0.27). Despite this, the overall risk of death following DSRS was only marginally decreased (0.78; 95% confidence interval 0.47-1.29); the lack of homogeneity in the results does not permit any significant conclusions on this end-point. However, in non-alcoholic patients, the decrease in risk of death was greater, and this without heterogeneity, following DSRS than EVS (0.59; 95% confidence interval 0.23-1.50). The overall risk of chronic encephalopathy was slightly increased after DSRS (1.86; 95% confidence interval 0.90-3.86). In conclusion, DSRS significantly reduced the risk of rebleeding compared to EVS without increasing the risk of chronic hepatic encephalopathy. However, DSRS did not significantly affect the overall death risk. Only in non-alcoholic disease did it seem to show an advantage over EVS.

Both high and low anti-hepatitis C virus antibody (anti-HCV) prevalence has been reported in autoimmune chronic active hepatitis. Therefore, we studied 15 consecutive HBsAg-negative, ELISA anti-HCV-positive, autoantibody-positive patients with biopsy proven chronic active hepatitis in order to confirm ELISA specificity by immunoblot test (RIBA-HCV), and to evaluate HCV replication by serum HCV-RNA. Nine patients were anti-nuclear, three type 1 anti-liver-kidney microsomal and three anti-smooth muscle antibody positive. None had associated autoimmune disease. All cases showed mild clinical disease and only moderate necroinflammatory activity. Response to prednisone was poor. RIBA-HCV confirmed ELISA results in all patients. HCV-RNA was found in the serum from 10 patients. Institution of α-interferon treatment in three steroid non-responsive patients was followed by prompt normalization of transaminases. Thus, a subgroup of autoantibody-positive chronic active hepatitis can be recognized as HCV-related and should be clinically and etiologically distinguished from autoimmune chronic active hepatitis. Trials of α-interferon treatment are worthwhile in this condition.

We reviewed randomised clinical trials evaluating the effect of lymphoblastoid or recombinant α-interferon in non-A, non-B chronic hepatitis. The outcomes assessed were the rates of serum alanine aminotransferase normalization and relapse during and after stopping interferon. Data were pooled by meta-analysis and a 50% overall rate difference, favouring treated patients, was found. Results showed homogeneity in direction of treatment effect both after short-term (2–6 months, ≥ 2 mega-units thrice weekly) and long-term (9–18 months, variable dose) interferon course. Moreover, results did not change when type of publication (abstracts vs. full reports) and treatment duration or schedule were accounted for. About 50% of patients originally responding to treatment relapsed within 6 months of either dose reduction or stopping interferon, thus suggesting that only in about one out of four patients is benefit from treatment sustained up to 1 year. We conclude that larger trials are needed to identify an optimal schedule of treatment and to evaluate predictors of interferon effectiveness in patients with non-A, non-B chronic hepatitis.

We evaluated the specificity and clinical relevance of anti-hepatitis C virus antibody positivity in 22 HBsAg-negative patients with autoimmune (anti-nuclear, anti-actin or anti-liver-kidney microsomal antibody positive) chronic active hepatitis. An ELISA anti-HCV test and a recombinant immunoblot assay (RIBA-HCV) were used. Thirteen patients (59%) were anti-HCV positive and five (23%) anti-HCV negative by both ELISA and RIBA-HCV tests. Four patients (18%) were borderline positive by ELISA (OD less than 1.0), and three of them (all with severe disease) were negative by RIBA. Histologic necroinflammation, AST/ALT and gamma-globulins levels were higher and response to prednisolone treatment was better in RIBA anti-HCV-negative than in anti-HCV-positive cases. We confirmed with both RIBA and ELISA tests the high prevalence of anti-HCV already reported by ELISA in anti-nuclear and anti-liver-kidney microsomal antibody positive chronic active hepatitis. False positive for anti-HCV (i.e., a positive ELISA test not confirmed by RIBA) occurred only among patients with severe disease. Since RIBA-negative subjects showed the best response to corticosteroid, they might represent the only subset of cases of 'true' autoimmune chronic active hepatitis.

Virus-specific T-cell responses are believed to be involved in the pathogenesis of liver cell injury secondary to hepatitis B virus infection. In this study, liver biopsy specimens from patients with chronic hepatitis B virus infection were analyzed for expression of two major pathways of adhesion used by cytotoxic T cells to interact with target cells. The lymphocyte function-associated antigen 3 was found preferentially expressed on hepatocytes of patients with active hepatitis B virus replication, whereas the expression of the intercellular adhesion molecule 1 on hepatocytes seemed more closely related with inflammatory activity. Adhesion molecules were also highly expressed on T lymphocytes found in areas of piecemeal and spotty necrosis, indicating the presence of antigen-specific "memory" T cells at the site of hepatocellular injury. This study suggests that the expression of the lymphocyte function-associated antigen 3 on hepatocytes may be important for viral elimination. The coordinate expression of the intercellular adhesion molecule 1 may regulate inflammatory response and enhance viral antigen presentation to T cells. Conversely, the absence of hepatocyte adhesion molecules might be a favorable factor for viral persistence.

In a prospective study of the natural history of congestive gastropathy, 212 consecutive cirrhotic patients (75 treated with sclerotherapy) were included. Mean follow-up was 46 months. Mild gastropathy (mosaiclike pattern) was found in 110 patients and severe gastropathy (granular mucosa with cherry spots) was found in 20. Prevalence of Helicobacter pylori, formerly Campylobacter pylori, was 50% in patients without, 43% in those with mild, and 28% in those with severe gastropathy. Congestive gastropathy was significantly more frequent in patients treated with sclerotherapy (83% vs. 50%, P less than 10(-5)). Sixty-month actuarial proportions of patients free of anemia (in the absence of hematemesis or melena), were 17% with severe, 62% with mild, and 93% without gastropathy (P less than 10(-8]. Corresponding figures for overt bleeding were 25%, 73%, and 87% (P less than 10(-7], whereas those for survival were 46%, 72%, and 85% (P = 0.0005), respectively. A multivariate regression analysis supported the following conclusions: (a) sclerotherapy and the presence of large esophageal varices significantly increase the risk of congestive gastropathy, which (b) is a significant risk indicator of both chronic and overt bleeding but does not independently affect survival.

OBJECTIVE: Percutaneous ethanol injection may prolong the survival of patients with small hepatocellular carcinoma associated with cirrhosis. The aim was to identify prognostic factors of survival and of local recurrence, as well as separate new lesions. METHODS: We performed Cox regression analysis in 115 consecutive patients with hepatocellular carcinoma (81 Child-Pugh class A, 34 Child-Pugh class B) treated by percutaneous ethanol injection. The validity of the model was tested by comparing predicted and observed survival in 105 independent patients from an external series. RESULTS: Overall survival rates were 89%, 63%, and 43% at 1, 2, and 3 yr, respectively. The 1-, 2-, and 3-yr survival rates were 96%, 78%, and 63%, respectively, for Child-Pugh class A patients and were 73%, 35%, 12%, respectively, for Child-Pugh class B. The albumin level was the only independent variable significantly associated with survival (p < 0.0001). The 3-yr rate of appearance of separate new lesions and local recurrence were 41% and 23%, respectively. The survival predicted by the model agreed with that observed in the independent patients. CONCLUSIONS: Survival of patients with hepatocellular carcinoma treated by percutaneous ethanol injection is related to baseline albumin level. The high rate of recurrence (both local and distant) points out the palliative role of this therapy.

The purpose of this study was to evaluate the clinical usefulness of surrogate markers of the interferon effect (i.e., alanine aminotransferase levels and serum HCV-RNA status) as predictors of long term response, and to identify the optimal schedule of treatment for patients with chronic hepatitis C by means of meta-analysis.Pertinent randomized clinical trials and prospective studies were selected using MEDLINE (1986-1996), a reference list from published articles or reviews. Twenty-six prospective studies reporting data on surrogate markers of interferon response were selected. Thirty-nine trials comparing interferon alpha to no treatment and 25 trials comparing different schedules of interferon were reviewed. Conventional meta-analysis according to the DerSimonian and Laird method was used for the pooling of results.The pooled probability of late relapse among sustained responders with negative serum HCV-RNA 6 months after treatment was very low (8.7%; 95% confidence interval 5.8-11.6%). The overall risk difference between treated and control groups was 16.63% (95% confidence interval 11.95-21.31%) for sustained aminotransferase normalization. Therapy with higher interferon dose compared with standard dose significantly improves the rate of sustained response (pooled risk difference 10.56%, 95% CI 5.47-15.65%). Cumulative meta-analyses suggest that a clear dose-response relationship exists across a wide range of interferon dosages. The multivariate meta-regression model confirms that the total interferon dose is an independent predictor of sustained response and that it seems more important than the length of treatment.Testing for serum HCV-RNA, 6 months after interferon therapy in sustained biochemical responders, is useful for predicting long term response. The current standard total interferon dose of 234 mega-units is suboptimal. Further trials that directly compare different schedules of treatment are needed.

beta-Blockers and sclerotherapy prevent long-term upper digestive rebleeding in cirrhosis but they seem ineffective for early rebleeding. We compared octreotide with a placebo for the prevention of early rebleeding in cirrhotic patients. After control of acute upper digestive bleeding, 262 consecutive cirrhotic patients were randomized to octreotide 100 microgram subcutaneously three times a day for 15 days (n = 131) or to the placebo (n = 131), in a double blind pragmatic trial in which beta-blockers and/or sclerotherapy were allowed together with the experimental treatment. Separate randomization and analysis were performed according to whether patients were eligible for beta-blockers and/or sclerotherapy (101 placebo, 97 octreotide) or not (30 placebo, 34 octreotide). Rebleeding within 15 days was the primary measure of treatment efficacy; 6-week rebleeding rate was also assessed as a secondary measure. Fifteen-day cumulative proportions of patients rebleeding were 28% in the placebo group and 24% in the octreotide group (P = .40); corresponding figures among the 198 patients eligible to beta-blockers and/or sclerotherapy were 26% and 16% (P = .05) and among the 64 not eligible for these treatments 33% and 49% (P = .29). Among patients eligible to beta-blockers and/or sclerotherapy, a significant reduction of rebleeding episodes (35 vs. 18, P = .03), blood transfusions (75 vs. 50, P = .04), and days of stay in hospital (1,544 vs. 1,190, P = .0001) was also found in the octreotide group: this beneficial effect was confirmed 6 weeks after randomization. Mortality was not affected by octreotide in either group of patients. It is suggested that octreotide may reduce the risk of early rebleeding in cirrhotic patients treated with beta-blockers and/or sclerotherapy after control of acute upper digestive bleeding. Further studies are needed to confirm this result.

Several randomized clinical trials of interferon in chronic hepatitis C have examined the histological changes in paired biopsy specimens. We have attempted a quantitative evaluation by meta-analysis.Randomized Clinical Trials found by MEDLINE search were included if: a) they compared different IFN regimens with non-active treatment or with each other, b) they obtained biopsies before starting and at the time of stopping IFN in a sizable proportion of the treated and control patients, and c) they assessed the biopsy-specimens semi-quantitatively according to Scheuer's numerical scoring system or Knodell's Histological Activity Index, with quantitation of fibrosis and of lobular, portal and periportal necroinflammation.Seventeen trials were identified, in which 1223 adult patients had been studied. All trials homogeneously pointed towards a favorable interferon effect. The pooled data show a statistically significant histological improvement in treated patients as compared with controls for each of the four Histological Activity Index components and for the total Histological Activity Index score (overall improvement was -0.82 in favor of interferon, p0.0001, 95% Confidence Interval -1.25 to -0.40). In the ten trials reporting histological changes separately in biochemical responders (primary and sustained responders) and non-responders, histological improvement was confined to the subset of biochemical responders. No change or very little change occurred in non-responders.Interferon treatment in chronic hepatitis C significantly improves liver histology. The effect of interferon is closely related to biochemical response. Studies assessing histological outcome 1 year or more after interferon treatment in long-term responders and comparatively in non-responders or relapsers would be important to confirm the regression of the necroinflammatory process in the former, as suggested by the normal serum alanine aminotransferase levels.

Aims: To compare the long-term effects of brief and prolonged therapy with alpha-n 1 interferon for transfusion-associated chronic hepatitis C. Methods: One hundred and sixteen subjects (male/female 4868, mean age 46.9 years) were studied. Sixty patients were randomised to brief treatment (group 1: interferon 5 Mu/msq. t.i.w. for 2 months, then 3 Mu/msq. t.i.w. for 4 months), and 56 to prolonged treatment (group 2: interferon 5 Mu/msq. t.i.w. for 2 months, then 3 Mu/msq. t.i.w. for 10 months). All were followed for 12 months after stopping interferon. Results: The early response rate was 47.4% (Group 1 [45%], Group 2 [50%]). No "breakthrough" reactivations were observed. The early response rate was 19% in patients with and 63% in patients without cirrhosis. Twenty-three (19.8%) subjects stopped therapy. Among 54 evaluable early responders, 21 had a sustained response. The rate of sustained response was comparable in group 1 (18.3%) and group 2 (18.2%). All sustained response subjects and some non-responders were HCV-RNA negative at the end of follow-up. Histological improvement was seen only after sustained response. Cirrhosis developed in 20% of non-responders. Overall, interferon induced a long-lasting remission of chronic hepatitis C in about one every five patients. Conclusions: In a population predominantly infected by hepatitis C virus type 1, 12 months of therapy with high doses of interferon does not confer any additional benefit on the early response or sustained response rates as compared to a 6-month course.

To determine if hepatitis C virus infection influences the behavior of type 1 autoimmune hepatitis and to assess the performance parameters of third-generation immunoassays for viral infection in this disease, 64 patients with different patterns of disease behavior were assessed retrospectively for antibodies to hepatitis C virus by third-generation enzyme-linked immunosorbent assay and recombinant immunoblot assay and for HCV RNA by polymerase chain reaction. Hepatitis C virus RNA was detected in seven patients (11%) and antibodies to hepatitis C virus were found in five (8%). All patients who had an acute onset of illness or who sustained remission after therapy lacked HCV RNA in serum. In contrast, four of 31 patients who relapsed (13%) and three of 17 patients who failed treatment (18%) had HCV RNA in serum. Patients with HCV RNA were indistinguishable from those without HCV RNA; in three patients, infection was recognized only by testing for HCV RNA. Four of seven patients with HCV RNA responded fully to corticosteroids, although each relapsed after drug withdrawal. Smooth muscle antibodies (43% versus 91%,P=0.006) and concurrent smooth muscle and antinuclear antibodies (0% versus 60%,P=0.003) occurred less frequently in patients with HCV RNA than in counterparts without HCV RNA. The specificity of the third-generation enzyme immunoassay was 98% and its overall predictability was 94%. Its sensitivity, however, was 57% and false positive results occurred in 20%. Hepatitis C virus infection is an uncommon determinant of disease behavior in type 1 autoimmune hepatitis, but it may be present in relapse or treatment failure. Some patients with HCV RNA may respond fully to corticosteroids, although remission is unsustained.

Background & aims: Emergency sclerotherapy is used as a first-line therapy for variceal bleeding in cirrhosis, although pharmacologic treatment stops bleeding in most patients. We performed a meta-analysis comparing emergency sclerotherapy with pharmacologic treatment. Methods: MEDLINE (1968–2002), EMBASE (1986–2002), and the Cochrane Library (2002;4) were searched to retrieve randomized controlled trials comparing sclerotherapy with vasopressin (± nitroglycerin), terlipressin, somatostatin, or octreotide for variceal bleeding in cirrhosis. Outcome measures were failure to control bleeding, rebleeding, blood transfusions, adverse events, and mortality. Results: Fifteen trials were identified. Sclerotherapy was not superior to terlipressin, somatostatin, or octreotide for any outcome and to vasopressin for rebleeding, blood transfusions, death, and adverse events; it was superior to vasopressin for the control of bleeding in a single trial flawed by a potential detection bias. Sclerotherapy was associated with significantly more adverse events than somatostatin. In a predefined sensitivity analysis, combining all of the trials irrespective of the control treatment, risk differences (sclerotherapy minus control) and confidence intervals (CIs) were as follows: failure to control bleeding, −0.03 (−0.06 to 0.01); mortality, −0.035 (−0.07 to 0.008); adverse events, 0.08 (0.02 to 0.14). Mortality risk difference was −0.01 (−0.07 to 0.04) in good-quality trials and −0.08 (−0.14 to −0.02) in poor-quality trials. Conclusions: Available evidence does not support emergency sclerotherapy as the first-line treatment of variceal bleeding in cirrhosis when compared with vasoactive drugs, which control bleeding in 83% of patients. Therefore, endoscopic therapy might be added only in pharmacologic treatment failures.