F. Roudot-Thoraval

The burden of liver disease in Europe. A review of available epidemiological data.

To survey the burden of liver disease in Europe and its causes 260 epidemiological studies published in the last five years were reviewed. The incidence and prevalence of cirrhosis and primary liver cancer are key to understand the burden of liver disease. They represent the end-stage of liver pathology and thus are indicative of the associated mortality. About 0.1% of Hungarian males will die of cirrhosis every year compared with 0.001% of Greek females. WHO estimate that liver cancer is responsible for around 47,000 deaths per year in the EU. Harmful alcohol consumption, viral hepatitis B and C and metabolic syndromes related to overweight and obesity are the leading causes of cirrhosis and primary liver cancer in Europe. Chronic hepatitis B affects 0.5-0.7% of the European population. In the last decade the prevalence of chronic hepatitis C was 0.13-3.26%. It is of great concern that about 90% of people in Europe infected by viral hepatitis are unaware of their status. Available data suggest the prevalence rate of NAFLD is 2-44% in the general European population (including obese children) and 42.6-69.5% in people with type 2 diabetes. Each of these four major causes of liver disease is amenable to prevention and treatment, reducing the burden of liver disease in Europe and saving lives. Further surveys are urgently needed to implement cost-effective prevention programmes and novel treatments to tackle this problem.

Microbial dysbiosis in colorectal cancer (CRC) patients.

The composition of the human intestinal microbiota is linked to health status. The aim was to analyze the microbiota of normal and colon cancer patients in order to establish cancer-related dysbiosis. Patients and Methods Stool bacterial DNA was extracted prior to colonoscopy from 179 patients: 60 with colorectal cancer, and 119 with normal colonoscopy. Bacterial genes obtained by pyrosequencing of 12 stool samples (6 Normal and 6 Cancer) were subjected to a validated Principal Component Analysis (PCA) test. The dominant and subdominant bacterial population (C. leptum, C. coccoides, Bacteroides/Prevotella, Lactobacillus/Leuconostoc/Pediococcus groups, Bifidobacterium genus, and E. coli, and Faecalibacterium prausnitzii species) were quantified in all individuals using qPCR and specific IL17 producer cells in the intestinal mucosa were characterized using immunohistochemistry. Findings Pyrosequencing (Minimal sequence 200 nucleotide reads) revealed 80% of all sequences could be assigned to a total of 819 taxa based on default parameter of Classifier software. The phylogenetic core in Cancer individuals was different from that in Normal individuals according to the PCA analysis, with trends towards differences in the dominant and subdominant families of bacteria. Consequently, All-bacteria [log10 (bacteria/g of stool)] in Normal, and Cancer individuals were similar [11.88±0.35, and 11.80±0.56, respectively, (P = 0.16)], according to qPCR values whereas among all dominant and subdominant species only those of Bacteroides/Prevotella were higher (All bacteria-specific bacterium; P = 0.009) in Cancer (-1.04±0.55) than in Normal (-1.40±0.83) individuals. IL17 immunoreactive cells were significantly expressed more in the normal mucosa of cancer patients than in those with normal colonoscopy. Conclusion This is the first large series to demonstrate a composition change in the microbiota of colon cancer patients with possible impact on mucosal immune response. These data open new filed for mass screening and pathophysiology investigations.

Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C : Comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores

BACKGROUND/AIMS To assess prospectively the accuracy of transient elastography (TE, FibroScan) for the detection of cirrhosis and oesophageal varices (OV) in chronic hepatitis C (CHC), as compared with currently available non-invasive methods (AST/ALT ratio (AAR), APRI, prothrombin index (PI), platelet count (PC), FibroTest (FT) and Lok index). METHODS All tests were performed the day of liver biopsy (LB), taken as reference, in 298 consecutive CHC patients (cirrhosis: 70; Child-Pugh A: 70; OV: 25). RESULTS TE had the best diagnostic accuracy for detection of cirrhosis (AUROCs: TE 0.96 vs. FT 0.82, Lok and APRI 0.80, PC 0.79, PI 0.73, AAR 0.61, respectively; p < 0.0001). Overall, the percentage of saved LB was: TE (cut-off: 12.5 kPa) 90%, PC 82%, FT 79%, PI 77%, AAR 76%, APRI 70%, and Lok 45%, respectively. At a cut-off of 21.5 kPa, TE predicted the presence of OV with 76% sensitivity and 78% specificity and correctly classified 73% of patients vs. AAR 81%, Lok 77%, FT, PI 70%, PC 69%, and APRI 66%, respectively. CONCLUSIONS TE is currently the most accurate non-invasive method for early detection of cirrhosis in CHC (cut-off: 12.5 kPa), as compared with other available methods, but cannot replace endoscopy for OV screening.

Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria.

BACKGROUND & AIMS The aim of this study was to generate an improved prognostic model for predicting recurrence in liver transplant candidates with hepatocellular carcinoma (HCC). METHODS Predictors of recurrence were tested by a Cox model analysis in a training cohort of 537 patients transplanted for HCC. A prognostic score was developed and validated in a national cohort of 435 patients followed up prospectively. RESULTS α-Fetoprotein (AFP) independently predicted tumor recurrence and correlated with vascular invasion and differentiation. At a Cox score threshold of 0.7 (area under the receiver operating characteristic curve, 0.701; 95% confidence interval, 0.63-0.76; accuracy, 75.8%), a model combining log(10) AFP, tumor size, and number was highly predictive of tumor recurrence and death. By using a simplified version of the model, with untransformed AFP values, a cut-off value of 2 was identified. In the validation cohort, a score greater than 2 predicted a marked increase in 5-year risk of recurrence (50.6% ± 10.2% vs 8.8% ± 1.7%; P < .001) and decreased survival (47.5% ± 8.1% vs 67.8% ± 3.4%; P = .002) as compared with others. Among patients exceeding Milan criteria, a score of 2 or lower identified a subgroup of patients with AFP levels less than 100 ng/mL with a low 5-year risk of recurrence (14.4% ± 5.3% vs 47.6% ± 11.1%; P = .006). Among patients within Milan criteria, a score greater than 2 identified a subgroup of patients with AFP levels greater than 1000 ng/mL at high risk of recurrence (37.1% ± 8.9% vs 13.3% ± 2.0%; P < .001). Net reclassification improvement showed that predictability of the AFP model was superior to Milan criteria. CONCLUSIONS Prediction of tumor recurrence is improved significantly by a model that incorporates AFP. We propose the adoption of new selection criteria for HCC transplant candidates, taking into account AFP.

Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C

Cannabinoids present in Cannabis sativa (marijuana) exert biological effects via cannabinoid receptors CB1 and CB2. We recently demonstrated that CB1 and CB2 receptors regulate progression of experimental liver fibrosis. We therefore investigated the impact of cannabis smoking on fibrosis progression rate in patients with chronic hepatitis C (CHC). Two hundred seventy consecutive untreated patients with CHC of known duration undergoing liver biopsy were studied. Demographic, epidemiological, metabolic, and virological data were recorded, and detailed histories of cannabis, alcohol, and tobacco use over the span of hepatitis C virus infection were obtained. Fibrosis stage, steatosis, and activity grades were scored according to Metavir system. Patients were categorized as noncannabis users (52.2%), occasional users (14.8%), or daily users (33.0%), and the relationship between cannabis use and fibrosis progression rate (FPR) or fibrosis stage was assessed. On multivariate analysis, six factors were independently related to a FPR greater than 0.074 (median value of the cohort): daily cannabis use (OR = 3.4 [1.5‐7.4]), Metavir activity grade A2 or higher (OR = 5.4 [2.9‐10.3]), age at contamination of more than 40 years (OR = 10.5 [3.0‐37.1]), genotype 3 (OR = 3.4 [1.5‐7.7]), excessive alcohol intake (OR = 2.2 [1.1‐4.5]), and steatosis (OR = 2.0 [1.0‐4.1]). Daily cannabis use was also an independent predictor of a rapid FPR (>0.15) (OR = 3.6 [1.5‐7.5]). Finally, severe fibrosis (≥F3) was also predicted by daily cannabis use (OR = 2.5 [1.1‐5.6]; P = .034), independently of Metavir activity grade, excessive alcohol intake, age at liver biopsy, steatosis, and tobacco smoking. In conclusion, daily cannabis smoking is significantly associated with fibrosis progression during CHC. Patients with ongoing CHC should be advised to refrain from regular cannabis use. (HEPATOLOGY 2005;.)

Changing of hepatitis C virus genotype patterns in France at the beginning of the third millenium: The GEMHEP GenoCII Study.

Summary.  This cross‐sectional study aimed to investigate, during a short period between 2000 and 2001, in a large population of patients with chronic hepatitis C, the epidemiological characteristics of hepatitis C virus (HCV) genotypes in France. Data from 26 referral centres, corresponding to 1769 patients with chronic hepatitis C were collected consecutively during a 6‐month period. HCV genotyping in the 5′‐non‐coding region (NCR) was performed in each center using the line probe assay (LiPA, in 63% of cases), sequencing (25%) or primer‐specific polymerase chain reaction (PCR) (12%). HCV genotypes 1a, 1b, 2, 3, 4, 5, non‐subtyped 1 and mixed infection were found in 18, 27, 9, 21, 9, 3, 11 and 1% of our population, respectively. HCV genotype distribution was associated with gender, age, source and duration of infection, alanine aminotransferase (ALT) levels, cirrhosis, alcohol consumption, hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection. In multivariate analysis, only the source of infection was the independent factor significantly associated with genotype (P = 0.0001). In conclusion, this study shows a changing pattern of HCV genotypes in France, with i.v. drug abuse as the major risk factor, an increase of genotype 4, and to a lesser extent 1a and 5, and a decrease of genotypes 1b and 2. The modification of the HCV genotype pattern in France in the next 10 years may require new therapeutic strategies, and further survey studies.

Genetic Complexity of the Hypervariable Region 1 (HVR1) of Hepatitis C Virus (HCV): Influence on the Characteristics of the Infection and Responses to Interferon Alfa Therapy in Patients With Chronic Hepatitis C

HCV exists within its host as pools of related genetic variants referred to as quasispecies. The hypervariable region 1 (HVR1) of the E2 envelope gene is subjected to strong selective pressure from neutralizing antibodies. The genetic complexity of this region is defined as the total number of genetic variants within the quasispecies population. The genetic complexity of the HVR1 region was examined in patients with chronic hepatitis C and its relationship with the epidemiology of HCV infection, and its influence on liver disease and the response to interferon treatment were determined in 114 patients with chronic hepatitis C. The genetic complexity of the HVR1 major variants was measured before treatment by using a polymerase chain reaction (PCR)‐single‐strand conformation polymorphism (SSCP) technique, and was compared with epidemiological, clinical, virological and histological features. The patients were treated with 3 megaunits of interferon (IFN) alfa for 3 to 6 months and the response to treatment was assessed at 3, 6 and 12 months. The HVR1 could be studied in 101 of the 114 patients (89%). Genetic complexity was significantly higher in patients infected through blood transfusion than intravenous drug use (mean complexity index: 5.7 ± 2.3 vs. 4.7 ± 1.5, respectively; P = 0.04). This relationship was independent of age and the estimated time since infection. No significant relationship was found with other parameters of infection or liver disease. In univariate analysis, the genetic complexity of HVR1 major variants did not affect the rates of ALT normalization at months 3 and 6 of IFN treatment. HVR1 genetic complexity was lower in patients with a sustained virological response than in non‐responders (4.0 ± 1.7 vs. 5.4 ± 2.0, respectively; P = 0.07). In multivariate analysis of pretreatment parameters associated with a sustained virological response to treatment, three parameters appeared to be independent predictors of such a response: a low viral load (P < 0.04), a low anti‐HCV core IgM titer (P = 0.03) and a low genetic complexity of HVR1 major variants (P < 0.04). In conclusion, the HVR1 of HCV has a quasispecies distribution in infected individuals. Its genetic complexity is significantly higher in transfusion recipients than in intravenous drug users, suggesting that the size of the initial inoculum affects the later emergence and development of viral quasispecies. The genetic complexity of HVR1, together with viral load and the anti‐HCV IgM titer, are independent predictors of a sustained virological response to IFN alfa in patients with chronic hepatitis C. J. Med. Virol. 54:256–264, 1998.

Different mechanisms of steatosis in hepatitis C virus genotypes 1 and 3 infections

Summary.  This study reports evidence that hepatocellular steatosis, a frequent histological feature of chronic hepatitis C, is principally metabolic in hepatitis C virus (HCV) genotype 1‐infected patients, whereas it is principally virus‐induced in HCV genotype 3‐infected patients. Multivariate analysis of data on 176 patients with chronic hepatitis C revealed that the severity of steatosis was independently related to HCV RNA load alone in patients infected by HCV genotype 3, whereas it was independently related to the body mass index, daily alcohol intake and histological activity grade (but not viral load) in patients infected by HCV genotype 1. These findings suggest that steatosis is a cytopathic lesion induced by HCV genotype 3, whereas HCV genotype 1 is not steatogenic per se or at the usual in vivo expression levels.

Impact of moderate alcohol consumption on histological activity and fibrosis in patients with chronic hepatitis C, and specific influence of steatosis: a prospective study

Aim : To evaluate the effects of minimal to moderate alcohol consumption on the severity of histological lesions in patients with chronic hepatitis C.

Epidemiological characteristics and response to peginterferon plus ribavirin treatment of hepatitis C virus genotype 4 infection

Summary.  Hepatitis C virus genotype 4 (HCV‐4) infection is progressing in Europe, where epidemiology and sustained virological response (SVR) seem to be different than in the Middle East. We analysed epidemiological features and SVR rates in a retrospective study of 1532 HCV‐4‐infected patients, including 1056 patients infected in France, 227 immigrants infected in Egypt and 249 in sub‐Saharan Africa. SVR rates were assessed in 242 naive patients of the 1532, who received peginterferon plus ribavirin for 48 weeks. HCV subtype 4a or 4d was the most common among patients infected in France, where the predominant route of transmission was intravenous drug abuse. The 4a subtype was largely predominant (93%) among patients infected in Egypt, where transmission was mostly because of parenteral treatment for schistosomiasis. More than seven different subtypes and no predominant route of infection were found in patients infected in sub‐Saharan Africa. Liver fibrosis was significantly less severe in patients infected in France and Africa than in patients infected in Egypt. SVR rates were higher in patients infected in Egypt, compared with those infected in France or Africa (54.9%, 40.3% and 32.4%, respectively, P < 0.05). An overall better response was observed in patients infected with the 4a subtype. In multivariate analysis, two factors were associated independently with SVR: the Egyptian origin of transmission and the absence of severe fibrosis. In conclusion, the distribution of HCV‐4 subtypes varies with the geographical origin of transmission and affects the SVR following antiviral treatment.