M. Pleguezuelo

Impact of donor graft steatosis on overall outcome and viral recurrence after liver transplantation for hepatitis C virus cirrhosis

The aim of this study was to determine the influence of donor graft steatosis on overall outcome, viral recurrence, and fibrosis progression in orthotopic liver transplantation (OLT) for hepatitis C virus (HCV) cirrhosis. One hundred twenty patients who underwent OLT for HCV cirrhosis between 1995 and 2005 were included in the study. Donor steatosis was categorized as absent (0%‐10%; n = 40), mild (10%‐30%; n = 32), moderate (30%‐60%; n = 29), or severe (>60%; n = 19). A Cox multivariate analysis for marginal donor variables and a Model for End‐Stage Liver Disease index were performed. Fibrosis evolution was analyzed in liver biopsies (fibrosis < 2 or ≥2) 3, 6, and 12 months post‐OLT and in the late post‐OLT period. Fifty‐six grafts were lost (46%). The survival of the grafts was inversely proportional to donor liver steatosis: 82%, 72%, and 72% at 1, 2, and 3 years post‐OLT in the absence of steatosis; 73%, 63%, and 58% with mild steatosis; 74%, 62%, and 43% with moderate steatosis; and 62%, 49%, and 42% with severe steatosis (P = 0.012). HCV recurrence was earlier and more frequent in recipients with steatosis > 30% (46% versus 32% at 3 months, P = 0.017; 58% versus 43% at 6 months, P = 0.020; 70% versus 56% at 12 months, P = 0.058; and 95% versus 69% at 3 years post‐OLT, P = 0.0001). Graft survival was lower in alcoholic liver disease recipients versus HCV recipients when steatosis was >30% at 3, 6, and 12 months post‐OLT (P = 0.042) but not when steatosis was <30% (P = 0.53). A higher fibrosis score was obtained 3 months post‐OLT (P = 0.033), 6 months post‐OLT (P = 0.306), 12 months post‐OLT (P = 0.035), and in the late post‐OLT period (P = 0.009). In conclusion, donor graft steatosis influences the outcome of OLT for HCV cirrhosis. HCV recurrence is more frequent and earlier in recipients of moderately and severely steatotic livers. Fibrosis evolution is higher when graft steatosis is >30%. OLT with >30% steatotic donor livers should be precluded in HCV recipients. Liver Transpl 15:37–48, 2009.

Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C

BACKGROUNDnThe widely-accepted treatment outcome for chronic hepatitis C is the sustained viral response (that is, no measurable viral RNA in blood six months after treatment). However, this surrogate outcome (as well as the previously employed biochemical and histologic ones) has never been validated. This situation exists because there are very few randomized clinical trials that have used clinical events (mortality or manifestations of decompensated cirrhosis) as outcomes, because those clinical events only occur after many years of infection. Patients in whom initial therapy fails to produce sustained viral responses do become potential candidates for retreatment; some of these individuals are not candidates for ribavirin or protease inhibitors and consideration could be given to retreatment with interferon alone.nnnOBJECTIVESnTo assess the benefits and harms of interferon monotherapy retreatment in chronic hepatitis C patients and to validate the currently employed surrogate outcomes in this group of patients.nnnSEARCH METHODSnWe searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until 16 August 2012.nnnSELECTION CRITERIAnRandomized trials comparing interferon versus placebo or no treatment in chronic hepatitis C nonresponders and relapsers to previous interferon.nnnDATA COLLECTION AND ANALYSISnThe primary outcomes were mortality (all-cause and hepatic), quality of life, and adverse events. Secondary outcomes were liver-related morbidity, sustained viral responses, biochemical responses, histologic improvements, and costs. We used both fixed-effect and random-effects model meta-analyses, reporting only the former if no difference existed.nnnMAIN RESULTSnSeven trials were identified. Two of them were at low risk of bias (the HALT-C and EPIC3 trials) and included 1676 patients. Both of these trials addressed the role of long-term low-dose pegylated interferon therapy in patients with severe fibrosis (demonstrated on liver biopsy) and were designed to assess the clinical outcomes. The remaining five trials included 300 patients and were at high risk of bias. Based on all trials reporting the outcomes, no significant difference was observed in either all-cause mortality (78/843 (9.3%) versus 62/867 (7.2%); risk ratio (RR) 1.30, 95% confidence interval (CI) 0.95 to 1.79; 3 trials) or hepatic mortality (41/532 (7.7%) versus 40/552 (7.2%); RR 1.07, 95% CI 0.70 to 1.63; 2 trials); however, when only the two trials at low risk of bias were combined, all-cause mortality was significantly higher in the recipients of the pegylated interferon (78/828 (9.4%) versus 57/848 (6.7%); RR 1.41, 95% CI 1.02 to 1.96) although trial sequential analysis could not exclude the possibility of random error. There was less variceal bleeding in the recipients of the interferon (4/843 (0.5%) versus 18/867 (2.1%); RR 0.24, 95% CI 0.09 to 0.67; 3 trials), although again trial sequential analysis could not exclude the presence of a type I error and the effect could not be confirmed in a random-effects model meta-analysis. No significant differences were seen with regard to the development of ascites, encephalopathy, hepatocellular carcinoma, or the need for liver transplantation. One trial reported quality of life data; the pain score was significantly worse in the recipients of the pegylated interferon. Adverse effects tended to be more common in the interferon recipients; the ones that were significantly more common included hematologic complications, infections, flu-like symptoms, and rash. The recipients of interferon had significantly more sustained viral responses (20/557 (3.6%) versus 1/579 (0.2%); RR 15.38, 95% CI 2.93 to 80.71; 4 trials) and a type I error was excluded by trial sequential analysis. The METAVIR activity score also improved (36/55 (65%) versus 20/46 (43.5%); RR 1.49, 95% CI 1.02 to 2.18; 2 trials). No significant differences were seen with regard to histologic fibrosis assessments.nnnAUTHORS CONCLUSIONSnThe clinical data were limited to patients with histologic evidence of severe fibrosis who were retreated with pegylated interferon. In this scenario, retreatment with interferon did not appear to provide significant clinical benefit and, when only the trials at low risk of bias were considered, retreatment for several years may even have increased all-cause mortality. Such treatment also produced adverse events. On the other hand, the treatment did result in improvement in some surrogate outcomes, namely sustained viral responses and histologic evidence of inflammation. Interferon monotherapy retreatment cannot be recommended for these patients. No clinical data are available for patients with less severe fibrosis. The sustained viral response cannot be used as a surrogate marker for hepatitis C treatment in this clinical setting with low sustained viral response rates and needs to be validated in others in which higher sustained viral response rates are reported.

Optimizing the management of patients with BCLC stage-B hepatocellular carcinoma: Modern surgical resection as a feasible alternative to transarterial chemoemolization

OBJECTIVEnTo analyse the impact of liver resection (LR) in patients with Hepatocellular Carcinoma (HCC) within the Barcelona-Clinic-Liver-Cancer (BCLC)-B stage.nnnMETHODSnAnalysis of patients with BCLC-B HCC treated with LR or transarterial chemoembolization (TACE) between 2007 and 2012 in our hospital. Survival/recurrence analyses were performed by log-rank tests and Cox multivariate models. Further analyses were specifically obtained for the HCC subclassification (B1-2-3-4) proposed recently.nnnRESULTSnEighty patients were treated (44-TACE/36-LR). Number of nodules was [1.8(1.1)], being multinodular in 50% of cases. Although resected patients had a higher hospital stay than those who underwent TACE (14 ± 13 vs 7 ± 6; P = 0.004), the rate and severity of complications was lower measured by Dindo-Clavien scale (P < 0.05). Overall survival was 40% with a median follow-up of 29.5 months (0.07-96.9). Five-years survival rates were 62.9%, 28.1% and 15.4%, respectively (P = 0.004) for B1, B2 and B3-4 stages. Cox model showed that only total bilirubin [OR = 2.055(1.23-3.44)] and BCLC subclassification B3-4 [OR = 2.439(1.04-5.7)] and B2 [OR = 2.79(1.35-5.77)] vs B1 were independent predictors of 5-years-survival. In B1 patients, surgical approach led a significant decrease in 5-years recurrence-rate (25% vs 60%; P = 0.018). In the surgical subgroup analysis, better results were observed if well/moderate differentiation combined with no microvascular-invasion (VI) in 5-years-survival (84.6%; P = 0.001) and -recurrence (23.1%; P = 0.041), respectively. These survival and recurrence trends were remarkable in B1 stages.nnnCONCLUSIONSnManagement of Intermediate BCLC-B HCC stage should be more complex and include updated criteria regarding B-stage subclassifications, VI and tumour differentiation. Modern surgical resection would offer improved survival benefit with acceptable safety in selected BCLC-B stage patients.

Proteomic analysis for developing new biomarkers of hepatocellular carcinoma

AIMnTo identify new markers of hepatocellular carcinoma (HCC) using a proteomic analysis.nnnMETHODSnPatients with liver cirrhosis of the three most frequent etiologies: hepatitis C virus, hepatitis B virus and alcoholic liver disease, were included in the study. The samples were analysed by 2D-electrophoresis in order to determine the differential protein expression. The proteins were separated according to the charge in immobilized pH 3-10 gradient strips and then by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins of interest were excised, digested with trypsin and the resulting peptides were separated and identified.nnnRESULTSnThree differentially expressed apolipoproteins (Apo) were identified based on the protein profile using proteomic techniques: Apo-A1, Apo-A4 and Apo-E. Apo-A4 levels were significantly lower in HCC than in non-HCC patients regardless of etiology (P < 0.01). Multivariate logistic regression showed that Apo-A4 and Apo-A1 were the only independent factors related to HCC diagnosis (P < 0.05). The receiver operating characteristic (ROC) curve including both Apo-A4 and Apo-A1 showed an area under the ROC of 0.944 (P < 0.001), a sensitivity of 0.89 and a specificity of 0.81 for diagnosis of HCC.nnnCONCLUSIONnApo-A4 and Apo-A1 may be used clinically as biomarkers of HCC with a high sensibility and specificity. These findings may provide additional insights into the mechanism of HCC development and progression.

Establishment of a Pediatric Liver Transplantation Program: Experience With 100 Transplantation Procedures

OBJECTIVEnTo analyze the primary factors that influence the development and consolidation of a pediatric liver transplantation program.nnnPATIENTS AND METHODSnThis was a retrospective study of 100 liver transplantation procedures performed in 84 pediatric patients between May 1990 and November 2007. The male-female ratio was 40:60. Mean (SD) age was 5 years (40 patients were younger than 2 years); cold ischemia time was 7.10 (3.1) hours; surgery time was 5.2 (2.2) hours; and time on the waiting list for transplantation was 75 (range, 1-1012) days. Indications for transplantation included cholestatic disease (43%), acute hepatic failure (AHF; 34%), metabolic disorders (14%), and cirrhosis (9%). Transplanted organs included 3 split grafts, 29 partial grafts, and 8 living-donor grafts.nnnRESULTSnMean graft survival was 70.4%, 59.2%, and 58.1% at 1, 3, and 5 years, respectively. Factors that influenced graft outcome were age younger than 2 years; surgery time more than 6 hours; and AHF vs cholestatic disease, metabolic disorders, and cirrhosis. There were no significant differences in long-term (51% vs 59%) and short-term (71% vs 70%) graft survival between procedures performed in 1990-1998 compared with those performed in 1999-2007; however, there was a higher percentage (P = .005) of recipients at high risk (age younger than 2 years or with AHF) in the later period. All data were consistent with those of the European Liver Transplant Registry 2007.nnnCONCLUSIONSnA pediatric liver transplantation program can be established by a group experienced in liver transplantation.