Patrizia Burra

Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis

BACKGROUND/AIMS Little is known about the pathogenesis of liver damage related to hepatitis C virus. The presence of steatosis or increased ferritin levels, and preliminary data on the relevance of iron as a prognostic factor prompted us to ascertain whether hepatitis C virus-related liver damage might be mediated by iron accumulation. METHODS We evaluated the degree of hepatic inflammation and steatosis, serum ferritin, transferrin saturation and iron levels, tissue iron concentrations and iron index, liver glutathione and malondialdehyde in 33 males and 20 females with chronic hepatitis C virus- or hepatitis B virus-related hepatitis (42 + 11). We also considered six patients with both alcohol abuse and hepatitis C virus, four males with chronic alcoholic liver disease and four males with genetic hemochromatosis, giving a total of 67. All diagnoses were histologically confirmed. Patients with cirrhosis were excluded. RESULTS Our data show that: 1. Steatosis is more frequent in hepatitis C virus and hepatitis C virus+alcohol abuse patients; 2. In males, serum ferritin and tissue iron are significantly higher in hepatitis C virus- than in hepatitis B virus-positive patients (p < 0.01 and 0.05); transferrin saturation is higher (p < 0.05) in hepatitis C virus-positive than in hepatitis B virus-positive patients only when males and females are considered together; 3. Serum ferritin and transferrin saturation only correlate with liver iron (r = 0.833 and r = 0.695, respectively, p = 0.00001); tissue iron is significantly higher in hepatitis C virus- than in hepatitis B virus-positive patients (p < 0.05); 4. In patients with chronic hepatitis, serum ferritin is a better marker of liver iron storage than transferrin saturation, both in males and in females; 5. Hepatitis C virus-positive patients have higher malondialdehyde levels and activation of turnover of glutathione, probably in response to free-radical-mediated liver damage. Females have lower liver iron levels but similar trends. CONCLUSIONS These findings suggest that hepatitis C virus-related liver damage is characterized by increased iron storage (possibly induced by the virus) which elicits a free-radical-mediated peroxidation, with consequent steatosis and activation of glutathione turnover.

European collaborative study on factors influencing outcome after liver transplantation for hepatitis C

BACKGROUND & AIMS Liver transplantation for hepatitis C virus (HCV)-related liver disease is characterized by frequent graft infection by HCV. The prognosis and risk factors for morbidity and mortality in this condition were determined. METHODS A retrospective study of 652 consecutive anti-HCV-positive patients undergoing liver transplantation between 1984 and 1995 in 15 European centers was conducted; 102 patients coinfected with hepatitis B virus (HBV) received immunoglobulin prophylaxis for antibody to hepatitis B surface antigen. RESULTS Overall, 5-year survival was 72%. Five-year actuarial rates of hepatitis and cirrhosis were 80% and 10%. Genotypes 1b, 1a, and 2 were detected in 214 (80%), 24 (9%), and 24 (9%) of 268 patients analyzed. The only discriminant factor for patient or graft survival was hepatocellular carcinoma as primary indication. Independent risk factors for recurrent hepatitis included the absence of HBV coinfection before transplantation (relative risk [RR], 1.7; 95% confidence interval [CI], 1.2-2.6; P = 0.005), genotype 1b (RR, 2; 95% CI, 1.3-2.9; P = 0.01), and age > 49 years (RR, 1.4; 95% CI, 1.1-1.8; P = 0.01). CONCLUSIONS The results of transplantation for HCV-related disease are compromised by a significant risk of cirrhosis, although 5-year survival is satisfactory. Genotype 1b, age, and absence of pretransplantation coinfection by HBV are risk factors for recurrent HCV.

Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma.

Objective:To determine the long-term results of liver transplantation for well- or moderately differentiated hepatocellular carcinoma (HCC). Summary Background Data:HCC patient selection for liver transplantation remains controversial, and deciding exclusively on the strength of criteria such as number and size of nodules appears prognostically inaccurate. Methods:Since 1991, preoperative tumor grading has been used at our center to establish whether a patient with HCC is fit for transplantation. Poorly differentiated HCC cases were excluded, while size and number of nodules were not considered as absolute selection criteria. Thirty-three patients with moderately or well-differentiated HCC were prospectively studied after liver transplantation. A group of 15 patients with incidental HCC transplanted during the same period were also evaluated and compared with the 33 patients with preoperatively diagnosed HCC. Results:On histologic examination, 38% of the entire group of 48 patients did not meet the “Milan criteria” and 42% were pTNM stages III and IV. The median follow-up was 44 months. The 5-year actuarial survival rate was 75% and recurrence-free survival was 92%. HCC recurred in only 3 patients (6%). The only histomorphologic variable differing significantly between incidental and nonincidental HCC was nodule size. The timing of diagnosis (incidental vs. nonincidental HCC), the Milan criteria, and the TNM stage revealed no statistically significant impact on overall and recurrence-free survival rates. Conclusions:The routine pre-orthotopic liver transplantation tumor grading may represent a valid tool in the selection of unresectable HCC patients for transplantation.

Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness.

OBJECTIVE:Although transcatheter arterial chemoembolization (TACE) is effective in hepatocellular carcinoma (HCC), it is not considered a curative procedure. Among the factors potentially interfering with its effectiveness is a hypothetical neoangiogenic reaction due to ischemia. In our study, we evaluated the changes in the levels of two angiogenic factors (vascular endothelial growth factor [VEGF] and basic fibroblast growth factor [b-FGF]) and one parameter of invasiveness (urokinase-type plasminogen activator [uPA]) in patients treated with TACE.METHODS:Three blood samples were provided from 71 HCC patients undergoing TACE: before TACE (t0), after 3 days (t1), and after 4 wk, when they had spiral computed tomography (sCT) scanning (t2). The referring radiologists blindly evaluated tumor burden and vascularization at t0 and residual activity at t2. The choice of TACE as treatment was based on the American Association for the Study of Liver Diseases (AASLD) guidelines.RESULTS:Complete response at sCT was recorded in 27% of patients; mean survival was 35 months (confidence interval [CI] 31–40) and the 4-yr survival was 57%. VEGF levels were significantly correlated with the number of nodes and were higher in nonresponders at t2 (P = 0.01); below-median VEGF levels predicted a longer survival (P = 0.008). b-FGF correlated with VEGF, tumor size, vascularization, and residual activity, showing a borderline correlation with survival. uPA correlated with tumor size and VEGF. VEGF was singled out in the Cox multivariate analysis as an independent predictor of survival.CONCLUSIONS:When TACE is not totally effective, it may induce a significant neoangiogenetic reaction, as suggested by an increase in VEGF and b-FGF following treatment; this affects patient survival. VEGF emerges as the most reliable prognostic parameter, so it could be measured for judging TACE efficacy. Finally, antiangiogenic drugs may be indicated in TACE-treated HCC.

Report of the Paris consensus meeting on expanded criteria donors in liver transplantation.

Because of organ shortage and a constant imbalance between available organs and candidates for liver transplantation, expanded criteria donors are needed. Experience shows that there are wide variations in the definitions, selection criteria, and use of expanded criteria donors according to different geographic areas and different centers. Overall, selection criteria for donors have tended to be relaxed in recent years. Consensus recommendations are needed. This article reports the conclusions of a consensus meeting held in Paris in March 2007 with the contribution of experts from Europe, the United States, and Asia. Definitions of expanded criteria donors with respect to donor variables (including age, liver function tests, steatosis, infections, malignancies, and heart‐beating versus non–heart‐beating, among others) are proposed. It is emphasized that donor quality represents a continuum of risk rather than “good or bad.” A distinction is made between donor factors that generate increased risk of graft failure and factors independent of graft function, such as transmissible infectious disease or donor‐derived malignancy, that may preclude a good outcome. Updated data concerning the risks associated with different donor variables in different recipient populations are given. Recommendations on how to safely expand donor selection criteria are proposed. Liver Transpl 14:1694–1707, 2008.

Prospective evaluation of anticoagulation and transjugular intrahepatic portosistemic shunt for the management of portal vein thrombosis in cirrhosis

There is no established management algorithm for portal vein thrombosis (PVT) in cirrhotic patients. The aim of our study was to prospectively evaluate anticoagulation and transjugular intrahepatic portosystemic shunt (TIPS) to treat PVT.

Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry).

Alcohol‐related liver disease (ALD) is one of the most common indications for liver transplantation (LT). Long‐term outcome after LT for ALD versus other etiologies is still under debate. The aim of this study was to compare outcome after LT of patients with ALD, viral (VIR), and cryptogenic cirrhosis. Donor, graft and recipient ELTR variables were analysed in transplants for alcoholic and nonalcoholic cirrhosis (1988–2005) and were correlated with patient survival. Causes of death and/or graft failure were compared between groups. Nine thousand eight hundred eighty ALD, 10 943 VIR, 1478 ALD + VIR and 2410 cryptogenic (CRYP) liver transplants were evaluated. One, 3, 5 and 10 years graft survival rates after LT in ALD patients were 84%, 78%, 73%, 58%, significantly higher than in VIR and CRYP (p = 0.04, p = 0.05). By multivariate analysis, ALD + VIR (RR 1.14) and viral alone (RR 1.06) were significant risk factors for mortality. De novo tumors, cardiovascular and social causes were causes of death/graft failure in higher percentage in ALD groups versus other etiologies. LT for ALD cirrhosis has a favorable outcome, however, hepatitis C virus co‐infection seems to eliminate this advantage. Screening for de novo tumors and prevention of cardiovascular complications are essential to provide better long‐term results.

Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation

BACKGROUND/AIMS The long-term prophylaxis of hepatitis B after liver transplantation requires further optimization. In a randomized trial we investigated a regimen where the initially given hepatitis B immunoglobulin (HBIg) is replaced by long-term lamivudine treatment. METHODS Twenty-four liver transplant recipients (all HBsAg-positive/HBV DNA-negative before transplantation), who had received HBIg for at least 6 months without HBV recurrence, were randomized to receive lamivudine (n = 12) or HBIg (n = 12) for 52 weeks. The efficacy criteria involved seronegativity for HBsAg and undetectable HBsAg/ HBcAg in the liver. RESULTS Twenty-one of 24 patients completed the study without hepatitis B virus (HBV) recurrence (11 on HBIg, ten on lamivudine), while three patients became HBsAg-positive. Amongst those without HBV recurrence HBV DNA was detectable only by polymerase chain reaction, intermittently in serum and lymphocytes, and in liver specimens from six of eight patients receiving HBIg and five of seven receiving lamivudine. YMDD variant was found in four cases with no viral antigen expression. Eight patients continued lamivudine after the study and during an additional 6-22 months remained HBsAg-negative with normal graft function. CONCLUSIONS Substitution of HBIg with lamivudine is effective for prevention of HBV recurrence in low-risk liver transplant recipients and offers a convenient and cost-effective alternative for long-term HBV prophylaxis.

β‐Blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta‐analysis

Introduction: Bacterial infections have been hypothetized to be a trigger of variceal bleeding in cirrhotic patients and β‐blockers may have a protective effect by decreasing bacterial translocation, reducing portal pressure. The aim of our study was to evaluate the possible role of β‐blockers in preventing spontaneous bacterial peritonitis (SBP) in patients with liver cirrhosis and ascites.

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

BackgroundThe potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.Methods/DesignThe study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.DiscussionIf our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.Trial RegisterTrial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36)