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Background. Ascites is one of the most frequent severe complications in patients with liver cirrhosis. The treatment of this chronic disease usually requires the prolonged use of albumin, frequently continued even after patients' discharge from the hospital. Aims. Aim of the study was to define a consensus among Italian physicians with regard to the use of albumin in patients with decompensated cirrhosis and ascites. Methods. The study adopted the Delphi technique to conduct the consensus activities. All controversial issues related to the use of albumin were identified by the experts' board and proposed to the 68 participating hepatology centres through two subsequent questionnaires. The questionnaires, returned by the specialists involved, were collected and the answers classified to verify the elements on which a consensus was reached. Results. The home use of albumin can help to improve the patient's general conditions and well-being. About 77% of the experts involved considered likely that albumin administration could shorten hospital stays or could reduce the number of hospital admissions. The results of the study, along with a socioeconomic analysis, were presented to the Italian Drug Commission, which subsequently removed the specific hypoalbuminemia level as a prerequisite for having the drug reimbursed by the National Health Service. Conclusions. For an outpatient prescription, the hypoalbuminemia limit of 2.5 g/dl or less is not sufficient, while the decision whether to administer the drug requires the evaluation of patient's overall clinical conditions as an essential criterion for the prescription of a home treatment with albumin.

Between December 1985 and February 1995, 260 orthotopic liver transplantations (OLTX) were performed on 238 patients at Niguarda Hospital. Sixty-three patients had hepatocellular carcinoma (HCC); in 13 of the patients HCC was incidental. All patients had negative lymph nodes. According to the Child classification, 13 patients were Child A, 30 Child B, and 18 Child C. According to the TNM classification, 11 patients were stage I, 22 stage II, 15 stage III, and 15 stage IVa. Pre-OLTX chemoembolization was performed on 25 patients. The perioperative mortality rate was 27% (17 patients). Overall survival and disease-free actuarial survival rates at 1, 3, and 5 years were 94%, 76%, 76%, and 83%, 75%, 75%, respectively. Survival curves were compared for 16 different variables. No difference was observed for all parameters analyzed except tumor site, TNM stage, pre-OLTX AFP levels and vascular infiltration. These results seem to demonstrate that the OLTX for unresectable HCC can be considered in specifically selected cases as the treatment of choice. An adequate tumor staging is also necessary for a better patient selection in order to increase survival.

Phosphate may promote the onset and progression of chronic nephropathies. Here we evaluated the relationships between baseline serum phosphate levels, disease progression, and response to ACE inhibition in 331 patients with proteinuric nephropathies in the prospective Ramipril Efficacy In Nephropathy (REIN) trial. Independent of treatment, patients with phosphate levels in the highest two quartiles progressed significantly faster either to ESRD or to a composite endpoint of doubling of serum creatinine or ESRD compared with patients with phosphate levels below the median (P < 0.001). Results were similar when we analyzed phosphate as a continuous variable (P ≤ 0.004). The renoprotective effect of ramipril decreased as serum phosphate increased (P ≤ 0.008 for interaction); this modification of the treatment effect by phosphate persisted despite adjusting for potential confounders such as GFR and urinary protein. In summary, these data suggest that phosphate is an independent risk factor for progression of renal disease among patients with proteinuric CKD, and high levels of phosphate may even attenuate the renoprotective effect of ACE inhibitors. Future trials should test whether reducing serum phosphate improves renal outcomes and optimizes the renoprotective effect of ACE inhibition.

The level of success that we confidently expect in liver transplantation today directly results from several factors including surgical technique, the scientific use of immunosuppressive drugs and most importantly patient selection. The goal of an accurate selection is to recognize those patients that will benefit the most from the surgical procedure. This approach is crucial if we consider the limited availability of suitable donors. In general terms a patient with chronic liver disease and a Child Pugh score between 9 and 10 is considered suitable for grafting. Recent studies have shown that liver transplantation can be cost effective and lead to complete social and working rehabilitation provided that the 'timing' for the procedure is not inappropriately delayed. Medium term survival rates after liver transplantation (at 5 years) range between 60 and 80%. Disease recurrence greatly affects the morbidity and mortality after grafting. In patients transplanted for hepatitis B, active vital replication at the time of operation represents the strongest predictor of recurrence although the recent availability of antiviral nucleosids has provided effective prophylactic and therapeutic options. Recurrence of HCV infection is almost universal after transplantation but only 50% of the patients develop histologic hepatitis. The combination therapy with interferon and ribavirin has proved beneficial in modifying the natural history of recurrent disease. If untreated, recurrent hepatitis C can progress to cirrhosis in up to 15% of the patients. Lastly, the strict selection of patients undergoing liver transplantation on account of hepatocellular carcinoma has been associated with favourable results not different from those obtained with other indications

Experience in liver transplantation (OLT) in Italy over a ten-year period is reported. Data were obtained using a multiple-items form collected from Italian liver transplant centres (reference centres) and other Italian institutions actively involved both in the processes of evaluation of the candidates and the follow-up of liver transplant recipients (afference centres). During this period, a total of 1046 liver transplants were performed on 954 patients, with a cumulative proportional survival of 71%. The most common indication for liver transplantation was post-hepatitic cirrhosis due to either hepatitis B virus (+/-hepatitis Delta virus) or hepatitis C virus infection. Good survival rates were observed, particularly in controversial indications, such as alcoholic cirrhosis, post-hepatitic hepatitis B virus-related cirrhosis and hepatocellular carcinoma, most likely due to proper and careful selection of the patients. Cirrhosis, secondary to an autoimmunity-based liver disease, showed the highest rate of rejection episodes. Infections, in our study population, were the most common cause of death after transplantation

Previous studies have shown similar effects of rabeprazole and omeprazole, when used at the same dose in the treatment of reflux oesophagitis. However, such studies have been conducted as superiority studies but interpreted as equivalence ones.To properly assess the comparative efficacy of rabeprazole and omeprazole in inducing complete endoscopic healing and symptom relief in patients with reflux oesophagitis.Patients (n=560) with Savary-Miller grade I-III reflux oesophagitis were randomised in a double-blind, double-dummy fashion to rabeprazole or omeprazole 20 mg once daily for 4-8 weeks. Then, patients endoscopically healed and symptomatically relieved were openly maintained with rabeprazole 10 mg or 2x10 mg once daily (in the event of clinical and/or endoscopic relapse) for a maximum of 48 weeks.After 4-8 weeks of treatment, healing (primary end-point) was observed in 228/233 (97.9%) patients in the rabeprazole group and in 231/237 (97.5%) in the omeprazole one (equivalence effect demonstrated by p0.0001 at Blackwelder test and an upper confidence limit at 97.5% of 0.023). However, rabeprazole was faster in inducing heartburn relief than omeprazole (2.8+/-0.2 versus 4.7+/-0.5 days of therapy to reach the first day with satisfactory heartburn relief, p=0.0045 at log-rank test). In the maintenance phase, 15.2% of patients had an endoscopic and/or clinical relapse.Rabeprazole is equivalent to omeprazole in healing reflux oesophagitis, but shows a faster activity on reflux symptoms in the early treatment phase.

From December 1985 to December 1990 100 orthotopic liver transplantations were performed in 89 adult patients in the Department of Transplantation, Niguarda Hospital, Milan. Techniques of donor's and recipient's operation were, with some modifications, those described by Starzl and associates. Patients were divided into two series (the first 32 OLTX and the last 68) on the basis of substantial variation occurred in operative indications, graft preservation and immunosuppression. Cumulative survival was 63% after 12 months, 46% after 36 and 42 months; in the second group it was 78% after 12 and 24 months. In neoplastic patients survival was 49% at 18 months and 23% at 36 and 42 months; in the second group, however, which included 5 occasional findings in cirrhotic patients, survival at 24 months was markedly better (83%). Out of 13 patients who were HBsAg positive before OLTX with a follow-up of more than 3 months, 10 were anti-HDV positive. Five (38%) had HBV recurrence (4 co-infection HBV-HDV), 1 with histological picture of active liver cirrhosis after 8 months. The other 8 patients did not evidence recurrence. Six patients underwent OLTX for acute fulminant hepatitis and all were negative for HGsAg and anti-HCV: 3 survived and are in good condition. Survival was markedly influenced by the preoperative status of the patients and by intraoperative blood loss. The improved survival in the second group is accounted for, in conclusion, by a better surgical/intensive care experience and methodological differences: 1. emergency operations in terminal patients are now limited; 2. selection criteria are much more restrictive; 3. actual preservation solutions allow improved graft function; 4. multidrug immunosuppression permit a better control of rejection

This study aimed to obtain a more precise estimation of the efficacy and tolerability of interferon-ribavirin combination therapy for chronic hepatitis C.A meta-analysis was carried out of individual patient data comprising about 90% of the published experience with combination therapy. The study was set in four European university-affiliated liver referral centers. A total of 186 individuals with chronic hepatitis C who had participated in three randomized controlled trials and one open study were selected for the study. Fifty-one had received ribavirin monotherapy (1000-1200 mg/day), 37 interferon monotherapy (3 MU 3x/week) and 78 interferon-ribavirin combination therapy (dosage as for monotherapy) for 6 months. Twenty patients served as controls. Follow-up after therapy was 6 months. Data analysis was by the multivariate logistical regression method.The primary outcome measure for efficacy was the percentage with a sustained response (ALT normalization and HCV RNA negativity 6 months after therapy). The sustained response rate was significantly higher for interferon-ribavirin combination therapy than for interferon or ribavirin monotherapy (odds ratio IFN-Riba vs IFN = 9.8, 95% CI 1.9-50). The estimated probability of sustained response following interferon-ribavirin combination therapy was 51% for patients without previous IFN therapy, 52% for patients with previous IFN therapy and response-relapse, and 16% for previous IFN non-responders. No serious adverse events were observed and less than 10% withdrew.The efficacy of interferon-ribavirin therapy appears to be enhanced two- to threefold over interferon monotherapy in all major subgroups of chronic hepatitis C patients tested. In view of its acceptable toxicity profile, interferon-ribavirin combination therapy is a candidate for the new standard therapy for chronic hepatitis C.

Aims: The aim of this study was to assess the incidence of fatal, life-threatening side effects and the de novo appearance of non-hepatic morbidity during interferon alfa therapy for chronic viral hepatitis. The relationship of these adverse events to actual total dose and duration of interferon was also evaluated. Methods: We conducted a retrospective study at 73 Italian centers of 11 241 consecutive patients with chronic vital hepatitis who underwent interferon alfa treatment. Results: Five patients died during interferon therapy due to liver failure ( n =4) or complications arising from sepsis. Life-threatening side effects were observed in eight patients: two cases where depression developed and led to a suicide attempt and six patients with bone marrow suppression (granulocytes 3 or platelets 3 ). These symptoms and signs completely disappeared after interferon withdrawal. During interferon treatment, 131 patients developed the following de novo non-hepatic disorders: symptomatic thyroid disease ( n =71), impotence ( n =5), systemic autoimmune disease ( n =5), immune-mediated dermatologic disease ( n =14), diabetes mellitus ( n =10), cardiovascular disease ( n =7), psychosis n =10), seizures ( n =4), peripheral neuropathy ( n =3) and hemolytic anemia ( n =2). Most of these complications are reversible or can be ameliorated. Fatal or life-threatening side effects were not related to actual total dose or duration of interferon alfa, while the majority of patients with de novo non-hepatic morbidity received medium/high doses ( > 200 million units) of interferon alfa or were treated for periods longer than 16 weeks (68% and 80%, respectively). Conclusions: Treatment with interferon alfa may have fatal or life-threatening side effects, their incidence in this study being low (0.04% and 0.07%, respectively) and perhaps no different than in untreated patients with chronic viral hepatitis. Moreover de novo non-hepatic morbidity occurred in 1.2% of patients, and the dose and duration of interferon therapy seem important in determining the frequency of this complication. The development of clinically-overt thyroid disease was most common.

IgM anti-HBc levels were measured by the IMx Core-M Abbott assay in 939 serum samples in order to define a specific and sensitive cut-off value for diagnosis of chronic hepatitis B. The sera used were obtained from 52 chronic HBV patients and 10 HBV carriers with HCV or HDV co-infections and 155 asymptomatic subjects without evidence of liver disease. A Youden index value of 95.4% with 98% sensitivity and 97.4% specificity was obtained for an IMx Index value of 0.204 as cut-off. A one-year follow-up study with monthly tests has shown that quantitative analysis of IgM anti-HBc can serve as a noninvasive tool for monitoring HBV infection, and provides an accurate diagnosis of hepatitis B exacerbations. Significant elevations of IgM anti-HBc levels were associated with hepatitis B exacerbations in 96.2% of the cases but with none of the ALT flare-ups observed in HCV or HDV infected individuals. These results suggest that quantitative analysis of IgM anti-HBc provides the highest degree of confidence in definition of spontaneous and therapy-induced exacerbations or remissions of hepatitis B.

Tauroursodeoxycholic acid is a promising drug for the treatment of chronic cholestatic liver diseases since it has more favourable physicochemical and metabolic properties than ursodeoxycholic acid. Tauroursodeoxycholic acid may be of benefit also for necroinflammatory liver disease, especially for HCV-related chronic hepatitis in which bile duct damage and some degree of cholestasis are frequently seen at histology.One hundred and fifty patients with chronic hepatitis were randomly assigned to receive tauroursodeoxycholic acid at daily doses of 500 mg or 750 mg, or a placebo for 6 months.A consistent decrease in aminotransferase serum levels was observed in patients treated with tauroursodeoxycholic acid compared with placebo (p0.001) and a progressive improvement with time was also found (p0.05; linear time effect).Tauroursodeoxycholic acid improves the biochemical expression of chronic hepatitis. Long-term studies with clinically relevant end-points are warranted.

There have been few trials comparing the efficacy of determinations of cholesterol, fibronectin and triglycerides for diagnosis of malignant ascites. In this study we measured these in 200 ascitic fluids from 93 cirrhotic patients (Group A), 47 hepatocellular-carcinoma patients (Group B), 60 extra-hepatic tumour patients (Group C), 44 of them with malignant cells (Group Cpos) and 16 without (Group Cneg). Anova one-way and the Bonferroni test for multiple comparisons showed that fibronectin and cholesterol were significantly higher in the ascitic fluids of patients of group C than of groups A and B (mean +/- ESM) (Cholesterol in A: 27.2 +/- 2.8; in B 23.5 +/- 1.5; in C: 68.6 +/- 5.3 mg/dl. Fibronectin in A: 32.7 +/- 2.8; in B 31.3 +/- 2.6; in C 127.7 +/- 11.1 mg/l). Both were significantly higher in Group Cpos than in Group Cneg (Cholesterol in Cneg: 41.2 +/- 6.7; in Cpos: 78.6 +/- 6.2 mg/dl. Fibronectin in Cneg: 55.0 +/- 11.2; in Cpos 154 +/- 12.3 mg/dl). We found no differences between cirrhotic ascites and malignant ascites due to primary liver hepatocellular-carcinoma. No difference at all in triglycerides were detected. With the Receiver-Operating Characteristic (ROC) curve, cholesterol had the best Youden Index (57%) at a cut-off of 32 mg/dl (sensitivity 78.3%, specificity 79.3% at this level); the best Youden Index (64%) for fibronectin had a cut-off of 60 mg/dl (sensitivity 65%, specificity 89.3%). Triglycerides appeared to be a great deal less effective as a diagnostic marker, with their best Youden Index (23%) at a cut-off 32 mg/dl (sensitivity 66.7%, specificity 56.4%).(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this investigation was to study the oxidative phenomena which take place in the early recovery phase after alcohol withdrawal. Furthermore, the effects of a novel natural antioxidant, Bionormalizer (BN), in such a clinical setting was studied.Forty-six alcoholics with moderate drinking habits (daily ethanol intake:80g to120g) were enrolled in the study, divided into two groups and given either a placebo or 9g of BN by mouth every night for one week. The patients agreed to stop drinking alcohol, and daily blood sampling was obtained for routine tests and to check plasma and erythrocyte levels of MDA, SOD, GPX and the hydroperoxide level. The groups were comparable in terms of initial biochemical parameters.BN prevented the early increase of plasma TBARS observed in the placebo group, enabling a near-to-normal level of plasma and erythrocyte MDA by the fourth day. BN also prevented the significant drop of erythrocyte GPX and the transient decrease of plasma SOD observed in the placebo group. Despite alcohol withdrawal, plasma lipid hydroperoxide remained significantly elevated in the placebo group, but this phenomenon was rapidly improved by BN.To a significant extent, BN is able to prevent the free radical-mediated lipoperoxidative changes that occur soon after alcohol withdrawal, while fastening the recovery mechanisms.

Experience in liver transplantation (OLT) in Italy over a ten-year period is reported. Data were obtained using a multiple-items form collected from Italian liver transplant centres (reference centres) and other Italian institutions actively involved both in the processes of evaluation of the candidates and the follow-up of liver transplant recipients (afference centres). During this period, a total of 1046 liver transplants were performed on 954 patients, with a cumulative proportional survival of 71%. The most common indication for liver transplantation was post-hepatitic cirrhosis due to either hepatitis B virus (+/-hepatitis Delta virus) or hepatitis C virus infection. Good survival rates were observed, particularly in controversial indications, such as alcoholic cirrhosis, post-hepatitic hepatitis B virus-related cirrhosis and hepatocellular carcinoma, most likely due to proper and careful selection of the patients. Cirrhosis, secondary to an autoimmunity-based liver disease, showed the highest rate of rejection episodes. Infections, in our study population, were the most common cause of death after transplantation.

Background Autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis represent the three major autoimmune liver diseases (AILDs). Their management is highly specialized, requires a multidisciplinary approach and often relies on expensive, orphan drugs. Unfortunately, their treatment is often unsatisfactory, and the care pathway heterogeneous across different centers. Disease-specific clinical outcome indicators (COIs) able to evaluate the whole cycle of care are needed to assist both clinicians and administrators in improving quality and value of care. Aim of our study was to generate a set of COIs for the three AILDs. We then prospectively validated these indicators based on a series of consecutive patients recruited at three tertiary clinical centers in Lombardy, Italy. Methods In phase I using a Delphi method and a RAND 9-point appropriateness scale a set of COIs was generated. In phase II the indicators were applied in a real-life dataset. Results Two-hundred fourteen patients were enrolled and followed-up for a median time of 54 months and the above COIs were recorded using a web-based electronic medical record program. The COIs were easy to collect in the clinical practice environment and their values compared well with the available natural history studies. Conclusions We have generated a comprehensive set of COIs which sequentially capture different clinical outcome of the three AILDs explored. These indicators represent a critical tool to implement a value-based approach to patients with these conditions, to monitor, compare and improve quality through benchmarking of clinical performance and to assess the significance of novel drugs and technologies. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Background & Aims: Chronic liver diseases (CLDs) are major health problems that require complex and costly treatments. Liver-specific clinical outcome indicators (COIs) able to assist both clinicians and administrators in improving the value of care are presently lacking. The Value-Based Medicine in Hepatology (VBMH) study aims to fill this gap, devising and testing a set of COIs for CLD, that could be easily collected during clinical practice. Here we report the COIs generated and recorded for patients with HBV or HCV infection at different stages of the disease. Methods/Results: In the first phase of VBMH study, COIs were identified, based on current international guidelines and literature, using a modified Delphi method and a RAND 9-point appropriateness scale. In the second phase, COIs were tested in an observational, longitudinal, prospective, multicentre study based in Lombardy, Italy. Eighteen COIs were identified for HBV and HCV patients. Patients with CLD secondary to HBV (547) or HCV (1391) were enrolled over an 18-month period and followed for a median of 4years. The estimation of the proposed COIs was feasible in the real-word clinical practice and COI values compared well with literature data. Further, the COIs were able to capture the impact of new effective treatments like direct-acting antivirals (DAAs) in the clinical practice. Conclusions: The COIs efficiently measured clinical outcomes at different stages of CLDs. While specific clinical practice settings and related healthcare systems may modify their implementation, these indicators will represent an important component of the tools for a value-based approach in hepatology and will positively affect care delivery.

Background/Aims: Liver transplantation for end-stage liver cirrhosis provides a useful model to investigate the pathogenetic role of hepatotropic viral agents. Recently, a new member of the Flaviviridae family, provisionally named HGV/GBV-C virus, has been associated with acute and chronic non A–E hepatitis. We studied 136 patients with cirrhosis consecutively transplanted at out institution for evidence of hepatitis G virus infection and correlation with the patients' clinical course. MEthods: All patients survived for at least 6 months after transplantation (median follow-up 44 months) and underwent routine liver biopsies. Hepatitis G virus infection was studied using both direct viral RNA identification by RT-PCR and indirect detection of antibodies to the E2 glycoprotein. Results: There was high frequency of the hepatitis G virus among patients undergoing liver transplantation, with HGV RNA and anti-E2 prevalence rates of 18.4% and 26.5%, respectively. HGV RNA prevalences significantly increased after transplantation (47.8%), with 47.3% rate of new infections in susceptible subjects. Anti-E2 antibodies were significantly more prevalent among patients transplanted for HCV-related cirrhosis and represented a strong protective factor against hepatitis G virus reinfection or recurrent infection. No correlation was found between HGV RNA or anti-E2 prevalences and survival after transplantation or rates of recurrent liver damage. Conclusions: All available evidence suggests that, although liver transplant patients are heavily exposed to hepatitis G virus both before and after transplantation, hepatitis G virus does not induce liver disease in this setting. Most infections appear to be self-limited and induce a protective immunity which is marked by the presence of anti-E2 antibodies.

Hepatitis C virus (HCV) infection is a dynamic process during which molecular variants are continuously selected as the result of virus adaptation to the host. Understanding the nature of HCV genetic variation is central to current theories of pathogenesis and immune response. We prospectively studied hypervariable region 1 (HVR1) variation in the E2 gene of 36 hepatitis C patients, including 10 asymptomatic carriers, followed up for 1 to 2 years. Sequence changes in single and consecutive serum samples were assessed and correlated with clinical and virological parameters of liver disease. A region of the E1 gene was sequenced for comparison in 3 subjects. HVR1 heterogeneity at single time points widely varied in individual patients, did not increase cumulatively over the follow-up period, and did not correlate with HVR1 evolutionary rates. Conversely, the process of HVR1 sequence diversification, although differed considerably among patients, was stable over time and directly correlated with infections by HCV type 2, lower alanine aminotransferase (ALT) levels, and absence of cirrhosis. HCV carriers showed the highest HVR1 variation rates. Our findings indicate that HVR1 variation has an adaptive significance and is associated with favorable features of liver disease and suggest that prospective, rather than static, observations are required to model the process of HCV variation.

OBJECTIVES: To assess the relationship between the type of chronic liver diseases (CLDs), clinical severity and patients’ HRQoL. METHODS: A naturalistic, multicentre study has been conducting to identify and test quality of care indicators. Adult CLDs patients (age>18 years) have been enrolling at gastroenterology unit of 3 Italian hospitals. We are collecting socio-demographic, clinical and HRQoL data with the EQ-5D-3L. Patients are sub-grouped according to CLD type and to clinical severity using the modified Child-Turcotte-Pugh score: with this instrument, patients are classified as non-cirrhotic, early cirrhotic (class A), advanced cirrhotic (classes B and C). We conducted Kruskall-Wallis tests to assess relationship between EQ-5D-VAS score and disease type or severity score. RESULTS: Results are based on data from 2,221 patients (67% male, median age=62 years), classified into the following subgroups: HCV or HBV chronic hepatitis (36.0%), compensated cirrhosis (CC, 23.5%), hepatocellular carcinoma (HCC, 19.8%), decompensated cirrhosis (DC, 13.5%), patients in evaluation or listed for liver transplant (LT, 7.2%). Non-cirrhotic patients (HCV or HBV chronic hepatitis) had significantly (p