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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 4 years. 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: 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.

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

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

Several genotypes of hepatitis C virus (HCV) have been recently identified by phylogenetic analysis, but their clinical relevance in the liver transplant setting is unknown. We evaluated the incidence and course of recurrent hepatitis C after transplantation in 50 patients who underwent transplantation for HCV-related liver disease. Liver biopsy specimens were obtained when clinically indicated and at yearly intervals; hepatitis was histologically graded and staged according to standard criteria. HCV-RNA was detected by nested reverse-transcription polymerase chain reaction (RT-PCR). HCV genotyping was performed by primer specific PCR. Follow-up was 6 to 62 months. HCV genotype distribution after transplantation of our 50 patients was as follows: 31 type 1b, 13 type 2a, 3 type 1a, 1 type 3a, 1 type 1b/2a, and 1 undetermined. Actuarial rates of recurrent hepatitis and of severe fibrosis or cirrhosis 5 years after transplantation were 56% and 20%, respectively, in patients infected by type lb and 33% (P = .18) and 8% (P = .16) in those infected by 2a. In conclusion, this study provides evidence that in patients infected by HCV type lb there is a trend for a more aggressive recurrent liver disease

Although steroid withdrawal has been successfully performed in heart and kidney transplant recipients, no controlled studies of SW have been carried out in liver transplant patients. To evaluate this possibility a prospective controlled study was carried out in 46 liver transplant recipients operated on after may 1991. They all received a sequential quadruple immunosuppression consisting of 3 mg/kg antithymocyte globulins (RATG) for the first 5 postoperative days, cyclosporin A (starting from day 3–5 and maintaining parenteral whole‐blood trough levels at 200–300 ng/ml during the first month and at 150–250 thereafter), azathioprine (1 mg/kg per day for the first month) and steroids. Prednisone was started at a dose of 200 mg per day 1 and then tapered to 20 mg/day over the first posteroperative week; this dose was maintained until day 90 when the patients were randomly allocated either to long‐term steroid therapy (0.1 mg/kg per day) or to steroid withdrawal. Minimum follow‐up after randomization was 6 months (6–27 months). Liver biochemistry was checked at regular intervals throughout the follow‐up period. Liver biopsies were performed whenever clinically indicated and also in the first 19 patients during readmission for annual review. The incidence ot acute and chronic rejection 90 days from liver transplantation was 2.5% in patients maintained on long‐term therapy. No patient in the steroid‐withdrawal group had experienced either an acute or a chronic rejection episode so far. Steroid‐related complications did not differ significantly between the two groups. The most recent interim analysis showed that steroid withdrawal is a safe undertaking in liver transplant recipients arid may be successfully accomplished in almost all patients. Copyright © 1994, Wiley Blackwell. All rights reserved

Neurological complications of cyclosporin (CyA) therapy are frequent, usually occurring within the 1st month after transplantation. Though leukoencephalopathy is one of them, it is rarely documented. Here we report the case of an anti-HCV-positive patient with cirrhosis who underwent liver transplantation and developed cyclosporin-induced leukoencephalopathy. The presenting symptoms were dysarthria, difficulty walking, and dysphagia. They were first noted 6 months after transplantation in association with an episode of recurrent HCV acute hepatitis. White matter abnormalities were evident on computed tomography (CT) scanning and magnetic resonance (MR) imaging. This condition improved to some degree after cyclosporin withdrawal. To our knowledge this is the second reported case of CyA neurotoxicity occurring late after liver transplantation. Moreover, the association with acute hepatitis suggests the possibility of graft dysfunction as a contributing and triggering factor. © 1993 Springer-Verlag

From December 1985 to December 1990, 100 liver orthotopic transplantations (OLTX) were performed in 89 adults with cirrhosis and various other liver diseases; eight patients had two transplants and three of these had three transplants. Organ perfusion was done with Eurocollins in the first 30, then with UW solution. Immunosuppressants were a combination of cyclosporin A and steroids for the first 30 patients, and then a combination of antilymphocyte globulin, azathioprine, methylprednisolone and cyclosporin A. The OLTXs were examined as a whole and also divided into two groups, one for 1985-88 and one for 1989-90. The cumulative survival was 63% after 12 months, 40% after 36 and 42 months. It was poor for the patients who received transplants between 1985 and 1988, but for the second group, survival was improved to 78% after 12 and 18 months. For neoplastic patients, overall survival was 49% after 18 months and 23% after 36 and 42 months. In the second group it was markedly better (83% after 18 months). The recurrence rate for patients surviving more than three months was 17% for hepatocellular carcinoma and 50% for cholangiocarcinoma. Five patients (38%) out of 13 HBsAg-positives before the transplant and surviving more than three months had recurrent hepatitis-B virus. The remaining eight patients are HBsAg negative at present. The improved actuarial survival for the second group is accounted for by the better surgical and intensive care given now and the methodological differences

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