S. Fagiuoli

Sustained virological response to interferon-α is associated with improved outcome in HCV-related cirrhosis: A retrospective study†‡

The effect of achieving a sustained virological response (SVR) following interferon‐α (IFNα) treatment on the clinical outcomes of patients with HCV‐related cirrhosis is unknown. In an attempt to assess the risk of liver‐related complications, HCC and liver‐related mortality in patients with cirrhosis according to the response to IFNα treatment, a retrospective database was developed including all consecutive patients with HCV‐related, histologically proven cirrhosis treated with IFNα monotherapy between January 1992 and December 1997. SVR was an undetectable serum HCV‐RNA by PCR 24 weeks after IFNα discontinuation. HCC was assessed by ultrasound every 6 months. Independent predictors of all outcomes were assessed by Cox regression analysis. Of 920 patients, 124 (13.5%) were classified as achieving a SVR. During a mean follow‐up of 96.1 months (range: 6‐167) the incidence rates per 100 person‐years of liver‐related complications, HCC and liver‐related death were 0, 0.66, and 0.19 among SVR and 1.88, 2.10, and 1.44 among non‐SVR (P < 0.001 by log‐rank test). Multivariate analyses found that non‐SVR was associated with a higher risk of liver‐related complications (hazard ratio, HR, not applicable), HCC (HR 2.59; 95% CI 1.13‐5.97) and liver‐related mortality (HR 6.97; 95% CI 1.71‐28.42) as compared to SVR. Conclusion: Thus, in patients with HCV‐related, histologically proven cirrhosis, achievement of a SVR after IFNα therapy was associated with a reduction of liver‐related mortality lowering both the risk of complications and HCC development. Irrespective of SVR achievement, all patients should continue surveillance because the risk of occurrence of HCC was not entirely avoided. (HEPATOLOGY 2007;45:579–587.)

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.

Renal failure and bacterial infections in patients with cirrhosis: Epidemiology and clinical features

The aim of the study was to investigate the prevalence and clinical course of renal failure that was induced by the various types of bacterial infections in patients with cirrhosis and ascites. Three hundred and nine patients, who were consecutively admitted to the 3 major hospitals of Padova, Italy, during the first 6 months of 2005, were studied prospectively. Of these, 233 patients (75.4%) had evidence of ascites. In 104 patients with cirrhosis and ascites (44.6%) a bacterial infection was diagnosed. A bacterial infection‐induced renal failure was observed in 35 of 104 patients (33.6%). The prevalence of renal failure was higher in biliary or gastrointestinal tract infections and in spontaneous bacterial peritonitis (SBP) and in than in other types of infections. In addition, the progressive form of renal failure was only precipitated by biliary or gastrointestinal tract infections, SBP, and urinary tract infections (UTI). In a multivariate analysis only MELD score (P = 0.001), the peak count of neutrophil leukocyte in blood (P = 0.04), and the lack of resolution of infection (P = 0.03) had an independent predictive value on the occurrence of renal failure. Conclusion: The results of the study show that the development of bacterial‐induced renal failure in patients with cirrhosis and ascites is related to the MELD score, and to both the severity and the lack of resolution of the infection. A progressive form of renal failure occurs only as a consequence of biliary or gastrointestinal tract infections, SBP, and UTI. (HEPATOLOGY 2007;45:223–229.)

Association between reactive oxygen species and disease activity in chronic hepatitis C

Reactive Oxygen Species (ROS) may be involved in the damage occurring in the course of chronic HCV infection. Individuals with chronic hepatitis C present increased hepatic levels of malondialdehyde (MDA) and reduced levels of glutathione. To determine whether these observations are associated with serological evidence for ROS injury, MDA and protein carbonyl content (PCC) of serum was determined in 20 HCV positive patients (14 chronic active hepatitis -- CAH and 6 cirrhosis) and 20 controls. Compared to controls, HCV positive subjects had increased levels of MDA (13.33 +/- 0.21 SE ng/ml vs. 9.90 +/- 0.65 P < .05) and PCC (4.74 +/- 0.21 mmol/mg vs 3.68 +/- 0.21, p < .02). Patients with CAH had higher levels than did cirrhotics. Both MDA and PCC correlated with serum ALT levels (r = .792 and r = .818 respectively, p < .001). A common origin for MDA and PCC found in patients with chronic hepatitis C was suggested by the correlation between the two measures (r = .741, p < .001). No correlation were found between MDA or PCC and the hepatic iron content. These data demonstrate that: (1) lipid and protein oxidation occur in chronic hepatitis C, (2) oxidative damage can be demonstrated as increased serum levels of MDA and PCC, and (3) both MDA and PCC levels correlate with disease activity.

Percutaneous ablation procedures in cirrhotic patients with hepatocellular carcinoma submitted to liver transplantation: Assessment of efficacy at explant analysis and of safety for tumor recurrence

Aims of this retrospective study were to analyze the efficacy and safety of percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) in cirrhotic patients with hepatocellular carcinoma (HCC) submitted to orthotopic liver transplantation (OLT). We studied 40 patients undergoing OLT in whom 46 HCC nodules had been treated with PEI (13 nodules), RFA (30 nodules), or PEI+RFA (3 nodules). Child‐Turcotte‐Pugh class was A in 18 cases, B in 18, and C in 4. The mean waiting time for OLT was 9.5 months. The effectiveness of ablation techniques was evaluated by histological examination of the explanted livers. Complete necrosis was found in 19 nodules (41.3%), partial or absent necrosis in 27 nodules (58.7%). Among the 30 nodules treated by RFA, 14 were completely necrotic (46.7%) and 16 demonstrated partial necrosis (53.3%). Considering the 13 neoplasms undergoing PEI, 3 nodules showed complete necrosis (23.1%), 6 partial necrosis (46.1%), and 4 absent necrosis (30.8%). The rate of complete necrosis was 53.1% for nodules smaller than 3 cm and 14.3% for larger lesions (P = 0.033) but increased to 61.9% when considering only the lesions smaller than 3 cm treated by RFA. During the follow up, HCC recurred in 3 patients treated by PEI. No cases of HCC recurrence at the abdominal wall level were recorded. Percutaneous ablation procedures are effective treatments in cirrhotic patients with HCC submitted to OLT and are not associated to an increased risk of tumor recurrence. RFA provides complete necrosis in most nodules smaller than 3 cm, and appears to be the best treatment option in these cases. (Liver Transpl 2005;11:1117–1126.)

Liver transplantation for HCV cirrhosis: Improved survival in recent years and increased severity of recurrent disease in female recipients: Results of a long term retrospective study

In recent years, a worsening outcome of hepatitis C virus (HCV)‐positive recipients and a faster progression of recurrent disease to overt cirrhosis has been reported. Our aims were to 1) assess patient survival and development of severe recurrent disease (Ishak fibrosis score > 3) in different transplant years; and 2) model the effects of pre‐ and post‐liver transplantation (LT) variables on the severity of recurrent disease. A multicenter retrospective analysis was conducted on 502 consecutive HCV‐positive transplant recipients between January 1990 and December 2002. Protocol liver biopsies were obtained at 1, 3, 5, 7, and 10 yr post‐LT in almost 90% of the patients. All 502 patients were included in the overall survival analysis, while only the 354 patients with a follow‐up longer than 1 yr were considered for the analysis of predictors of disease progression. The overall Kaplan–Meier survival rates were 78.7%, 66.3%, and 58.6%, at 12, 60, and 120 months, respectively, and a trend for a better patient survival over the years emerged from all 3 centers. The cumulative probability of developing HCV‐related recurrent severe fibrosis (Ishak score 4‐6) in the cohort of 354 patients who survived at least 1 yr remained unchanged over the years. Multivariate analysis indicated that older donors (P = 0.0001) and female gender of recipient (P = 0.02) were the 2 major risk factors for the development of severe recurrent disease, while the adoption of antilymphocytic preparations was associated with a less aggressive course (P = 0.03). Two of these prognostic factors, donor age and recipient gender, are easily available before LT and their combination showed an important synergy, such that a female recipient not only had a much higher probability of severe recurrent disease than a male recipient but her risk increased with the increasing age of the donor, reaching almost 100% when the age of the donor was 60 or older. In conclusion, a trend for a better patient survival was observed in more recent years but the cumulative probability of developing severe recurrent disease remained unchanged. The combination of a female recipient receiving an older graft emerged as a strong risk factor for a severe recurrence. Liver Transpl, 2007.

Liver transplantation for Wilson's disease: The burden of neurological and psychiatric disorders

A retrospective data analysis on liver transplantation for Wilsons disease (WD) was performed among Italian Liver Transplant Centers. Thirty‐seven cases were identified. The main indication for liver transplantation was chronic advanced liver disease in 78% of patients. Mixed hepatic and neuropsychiatric symptoms were recorded in 32.3%. Eight patients presented with fulminant liver failure; 44.8% were on medical treatment. Patient and graft survival at 3 months, 12 months, 3 years, 5 years, and 10 years after transplantation were, respectively, 91.8%, 89.1%, 82.9%, 75.6%, and 58.8%, and 85.3%, 83.0%, 77.1%, 70.3%, and 47.2%. Neurological symptoms significantly improved after orthotopic liver transplantation (OLT), but the survival of patients with mixed hepatic and neuropsychiatric involvement was significantly lower than in patients with liver disease alone (P = 0.04). WD characterized by hepatic involvement alone is a rare but good indication for liver transplantation when specific medical therapy fails. Patients with neuropsychiatric signs have a significantly shorter survival even though liver transplantation has a positive impact on neurological symptoms. In conclusion, a combination of hepatic and neuropsychiatric conditions deserves careful neurological evaluation, which should contraindicate OLT in case of severe neurological impairment. (Liver Transpl 2005;11:1056–1063.)

Histological features after liver transplantation in alcoholic cirrhotics

BACKGROUND/AIMS Though alcoholic cirrhosis is a common indication for liver transplantation, it carries the risk of alcohol recidivism and consequent graft failure. This study aims to evaluate the effect of alcohol recidivism on survival rates and histological parameters in patients transplanted for alcoholic cirrhosis, with and without hepatitis C virus (HCV) infection. METHODS Fifty-one out of 189 consecutive transplanted patients underwent psychosocial evaluation and liver biopsy at 6 and 12 months, then yearly after transplantation. RESULTS The cumulative 84 month survival rate was identical in patients transplanted for alcoholic (51%) and non-alcoholic cirrhosis (52%). No difference emerged between anti-HCV negative vs. positive alcoholic cirrhosis patients. Psycho-social evaluation revealed alcohol recidivism in 11/34 long-term survivors, but this did not affect overall survival rate in patients with or without HCV. In anti-HCV negative cases, fatty changes and pericellular fibrosis were significantly more common in heavy drinkers than in occasional drinkers and abstainers. When HCV status was considered regardless of alcohol intake, fibrosis was significantly more frequent in patients with HCV. CONCLUSION Alcohol recidivism after transplantation in alcoholic cirrhosis patients does not affect survival, irrespective of HCV status. Fatty changes and pericellular fibrosis are the most relevant histological signs of heavy alcohol intake.

Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis

BACKGROUND Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. PATIENTS AND METHODS A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS: Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. CONCLUSION Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.BACKGROUND Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. PATIENTS AND METHODS A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. CONCLUSION Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.

Histology predicts cirrhotic evolution of post transplant hepatitis C

Background: Hepatitis C recurring after orthotopic liver transplantation varies in severity and some patients rapidly develop fully established liver cirrhosis. Neither clinical nor biological markers of such rapid cirrhotic evolution are available. Aim: To assess the value of histology in identifying patients who will develop cirrhosis shortly after liver transplantation. Patients and methods: Only cases of recurrent hepatitis C diagnosed by both hepatitis C virus-RNA positive serum and liver changes consistent with hepatitis, with no other causes of allograft injury, were considered. A total of 128 liver biopsies were scored from 29 consecutive patients with a mean follow up of 48 (13.97) months. The histological activity index was evaluated according to Ishak et al. The time of the first histological diagnosis of recurrent hepatitis C in the absence of rejection was defined as time of histological recurrence (RHC-T). Results: First histological diagnosis of recurrent hepatitis with no features of rejection was obtained at the six month biopsy in 23 of 29 cases. By the end of follow up, nine patients had developed cirrhosis (mean follow up 38 (14.39) months (range 18–60)). The remainder (mean follow up 46 (13.40) months (24–72)) showed a spectrum of fibrosis but no cirrhosis. Severe necroinflammatory lesions at RHC-T significantly correlated with rapid development of cirrhosis. At the RHC-T biopsy, only cases evolving into cirrhosis showed confluent necrosis. The median value of the histological activity index was 11 (mean 11.11 (1.76) (range 9–14)) in patients who developed cirrhosis and four (mean 4 (1.78) (range 1–8)) in the others (p<0.0001). A histological activity index ≥9 was associated with rapid development of cirrhosis in 100% of cases. Conclusions: After liver transplantation, the histological activity of recurrent hepatitis C predicts the risk of development of cirrhosis. By adopting Ishaks scoring system, a histological activity index ≥9 was 100% sensitive/specific in identifying subjects who rapidly developed cirrhosis.