B. Le Bail

Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study

Background: Transient elastography (FibroScan) is a new, non-invasive, rapid, and reproducible method allowing evaluation of liver fibrosis by measurement of liver stiffness. In cirrhotic patients, liver stiffness measurements range from 12.5 to 75.5 kPa. However, the clinical relevance of these values is unknown. The aim of this prospective study was to evaluate the accuracy of liver stiffness measurement for the detection of cirrhosis in patients with chronic liver disease. Methods: A total of 711 patients with chronic liver disease were studied. Aetiologies of chronic liver diseases were hepatitis C virus or hepatitis B virus infection, alcohol, non-alcoholic steatohepatitis, other, or a combination of the above aetiologies. Liver fibrosis was evaluated according to the METAVIR score. Results: Stiffness was significantly correlated with fibrosis stage (r = 0.73, p<0.0001). Areas under the receiver operating characteristic curve (95% confidence interval) were 0.80 (0.75–0.84) for patients with significant fibrosis (F>2), 0.90 (0.86–0.93) for patients with severe fibrosis (F3), and 0.96 (0.94–0.98) for patients with cirrhosis. Using a cut off value of 17.6 kPa, patients with cirrhosis were detected with a positive predictive value and a negative predictive value (NPV) of 90%. Liver stiffness was significantly correlated with clinical, biological, and morphological parameters of liver disease. With an NPV >90%, the cut off values for the presence of oesophageal varices stage 2/3, cirrhosis Child-Pugh B or C, past history of ascites, hepatocellular carcinoma, and oesophageal bleeding were 27.5, 37.5, 49.1, 53.7, and 62.7 kPa, respectively. Conclusion: Transient elastography is a promising non-invasive method for detection of cirrhosis in patients with chronic liver disease. Its use for the follow up and management of these patients could be of great interest and should be evaluated further.

Association of Helicobacter species with hepatitis C cirrhosis with or without hepatocellular carcinoma

Background and aims: Recent studies have suggested that bacterial coinfection with Helicobacter species in patients already infected with hepatitis C virus (HCV) could be involved in the development of cirrhosis and hepatocellular carcinoma (HCC). A retrospective cross sectional study was performed in order to explore the association between Helicobacter species and HCV associated liver diseases. Methods: The presence of Helicobacter species was tested by polymerase chain reaction on liver samples from four groups of patients. Results:Helicobacter 16S rDNA was found in only 4.2% of liver samples from control patients (n = 24) and in 3.5% of liver samples from patients with non-cirrhotic chronic hepatitis C (n = 29) while it was found in 68.0% of liver samples from patients with HCV positive cirrhosis without HCC (n = 25) as well as in 61.3% of cirrhotic liver samples from patients with HCV positive cirrhosis and HCC (n = 31). In addition, when the HCC tumour tissue was tested (n = 21), 90.5% of samples were positive. DNA from Helicobacter pylori- and Helicobacter pullorum-like organisms was found. Conclusions: There is an association between the presence of Helicobacter species DNA in the liver and hepatitis C cirrhosis, with or without HCC. Indeed, the presence of these bacteria could be the result of structural changes in the liver. Alternatively, Helicobacter species could be a co-risk factor in HCV chronic liver diseases. This result warrants prospective studies to determine the possible causal role of these bacteria in the progression of chronic hepatitis C.

Variability of the area under the receiver operating characteristic curves in the diagnostic evaluation of liver fibrosis markers: impact of biopsy length and fragmentation

The area under the receiver operating characteristic (ROC) curve is widely used as an estimate of the diagnostic value for fibrosis markers. Biopsy length and fragmentation are known as risk factors of false positive or false negative of biopsy but their quantitative impact on area under the receiver operating characteristic curve variability has not been assessed.

Transient elastography and biomarkers for liver fibrosis assessment and follow‐up of inactive hepatitis B carriers

Background  Non invasive methods for fibrosis evaluation remain to be validated longitudinally in hepatitis B.

Expression and cellular localization of the urokinase‐type plasminogen activator and its receptor in human hepatocellular carcinoma

The urokinase‐type plasminogen activator (uPA) and its receptor (uPAR) play an important role in tumour invasion. Previous studies have shown by RT‐PCR that uPA and uPAR mRNAs are expressed in human hepatocellular carcinoma (HCC). Here, in situ hybridization, immunohistochemistry, and double immunofluorescence were used to identify the cells expressing uPA and uPAR in 26 HCCs. The results indicate that uPA and uPAR were expressed in every case, almost exclusively in stromal cells, mostly myofibroblasts and macrophages, except for rare tumoural hepatocytes expressing cytokeratin 7. These results show the important role of stromal cells of HCC in the pericellular proteolysis which facilitates cancer cell invasion. Copyright

Hepatic steatosis in HIV-HCV coinfected patients in France: comparison with HCV monoinfected patients matched for body mass index and HCV genotype

Background  Significance of steatosis in HIV‐HCV coinfection remains controversial.

327 XL PROBE OF FIBROSCAN® IN PATIENTS WITH CHRONIC LIVER DISEASE. A PROSPECTIVE EVALUATION IN COMPARISON WITH LIVER BIOPSY, M PROBE, FIBROTEST AND APRI

most sensitive (p < 0.001 between % changes) of 5 blood tests for detecting fibrosis progression (0.25±0.29 at baseline vs 0.31±0.32 at 2 years, p = 0.003). CM was also reproducible (ric = 0.815). The % change in CM was significantly (p = 0.039) higher (median:32.3%) than that of area of fibrosis (median: 19.9%), which was the histological characteristic having the most significant change but poorly reproducible (ric = 0.439). Conclusion: For the diagnosis of cirrhosis, a specific test is more appropriate than a standard fibrosis test. A specific test offers the advantages of a high correct classification rate and excellent dynamic sensitivity and reproducibility. Its detailed classification (6 classes) also offers precise diagnostic probability. Thus, the CM test, with its specific classification, offers a more exact diagnostic method adapted to clinical practice.

392 LONGITUDINAL ASSESSMENT OF LIVER FIBROSIS USING TRANSIENT ELASTOGRAPHY AND FOUR BIOMARKERS IN HCV PATIENTS WITH F3–F4 FIBROSIS: RELATIONSHIP WITH ANTIVIRAL TREATMENT RESPONSE AND CLINICAL OUTCOME

accelerated in HCV patients with significant steatosis and/or insulin resistance (IR). There is little data regarding the impact of these factors on the accuracy of TE. Aim: To evaluate the influence of metabolic variables on the performance of TE for predicting fibrosis in HBV/HCV subjects. Methods: This study enrolled treatment-naive subjects with positive HBsAg or detectable HCVRNA ≥6 months, submitted to liver biopsy (LB) and TE on the same day. METAVIR score was used for histological analysis. Steatosis ≥30% was considered significant. TE cut-offs: 7.2 (F ≥ 2) and 8.1 (F ≥ 3) kPa for HBV; 7.1 (F ≥ 2) and 9.5 (F ≥ 3) kPa for HCV. IR was defined by HOMA-IR ≥3 and obesity by a BMI ≥30kg/m. Results: After excluding 48 cases (7.8%) with unreliable/unsuccessful TE measurement, 565 patients were analyzed (HBV = 202; HCV = 363). Mean age was 46.1±11.2 years, 67% male. Obesity and diabetes were identified in 6% and 5%, respectively. Significant steatosis was observed in 118 cases (21%) and 141 (25%) had IR. METAVIR F ≥2 was seen in 42% and 54% in HBV and HCV groups, respectively (P = 0.005). Higher TE values were observed in diabetics (P < 0.001), subjects with significant steatosis (P < 0.001), and in those with IR (P < 0.001). Obesity had no influence on TE values (P = 0.607). There was no correlation between TE and BMI (r = 0.108; P = 0.11) and positive but weak correlations were found between TE and HOMA-IR (r = 0.213; P = 0.001) and glucose (r = 0.217; P < 0.001). Discordant results between LB and TE were observed in 117/565 cases (21%). Discordant cases were comparable to concordant ones regarding age, etiology, gender, ALT, AST, GGT, A2/3 METAVIR grade, and all metabolic factors. TE overestimation of fibrosis was identified in 33/565 cases (6%). Among these, none had diabetes or obesity and no association was found between overestimation and metabolic factors. Conclusions: Higher TE values are observed in chronic viral hepatitis patients with metabolic disorders (IR, diabetes, significant steatosis). However, this seems not to exert a significant negative impact on the diagnostic performance of TE for predicting liver fibrosis.

P.364 Noninvasive prediction of cirrhosis in patients with chronic hepatitis C: prospective comparison of Lok index, Fibroscan, Fibrotest and APRI with liver biopsy

Background and Objectives: A novel noninvasive index based on standard laboratory tests (platelet count, AST/ALT ratio, and INR) has been proposed recently for prediction of cirrhosis in patients with chronic hepatitis C (CHC) (Lok et al., Hepatology 2005). The aim of this prospective study was to validate independently the accuracy of this index for the detection of cirrhosis in CHC patients, as compared with transient elastography (FibroScan) and other serum markers (FibroTest and APRI). Methods: 412 consecutive CHC patients (231 males, mean age 52±12 yrs) who underwent a liver biopsy at our institution between January 2003 and November 2005 were studied. Of these patients, 264 also had on the day of liver biopsy a FibroScan, a FibroTest, and laboratory tests allowing to calculate the APRI (AST/platelet) and Lok indexes. These patients did not differ from the total group for most characteristics including age, gender, and fibrosis stage distribution. Fibrosis was scored according to METAVIR by two independent pathologists. Diagnostic performances were assessed using areas under the receiving operating characteristic curve (AUROC). Results: Histological fibrosis score distribution was: F0-F1 24%; F2 36%; F3 20%; F4 20%. Mean liver biopsy length was 19±8mm. AUROC (95% Cl) for the diagnosis of cirrhosis (F4) of Lok index was 0.81 (0.75-0.87). A Lok index 0.5 to confirm cirrhosis would misclassify 6% of patients (sensitivity 50%, specificity 93%, positive predictive value 64%); 195 patients (47%) who were between these two values could not be correctly classified. Liver stiffness measurement could not be obtained in 12 patients (4.5%). In the 252 patients evaluated, AUROC (95% Cl) for the diagnosis of cirrhosis of Lok index was 0.81 (0.74-0.88), compared with 0.95 (0.92-0.98) for FibroScan, 0.86 (0.81-0.91) for FibroTest, and 0.80 (0.73-0.86) for APRI. Conclusion: Diagnostic performances of Lok index in our patients were similar to those of APRI but lower than those of FibroScan and FibroTest. FibroScan appears as the best method for non-invasive prediction of cirrhosis in CHC patients.

Biopsie hépatique pour cytolyse inexpliquée : résultats préliminaires de l’étude CYTOL 2002

On estime que 0,5 % de la population presente une cytolyse chronique. Lorsque qu’aucune etiologie habituelle (consommation excessive d’alcool, infection virale C ou B, hemochromatose, toxique) n’est retrouvee par le bilan clinico-biologique initial de debrouillage, un bilan plus large est entrepris et une biopsie hepatique est proposee, representant environ 10 % des indications de PBH. L’etude multicentrique CYTOL 2002 a inclus a ce jour 178 patients presentant une cytolyse inexpliquee avec bilan initial negatif. Un recueil exhaustif de donnees clinico-biologiques a ete realise et les donnees histologiques des biopsies ont ete analysees selon une grille de lecture simple comportant 21 items descriptifs et 7 items conclusifs (diagnostic final). Une relecture a ete realisee sur les 96 biopsies realisees hors centre promoteur. Nous rapportons ici 1) les lesions histologiques trouvees chez ces 178 patients et 2) la reproductibilite inter-observateurs des parametres histologiques etudies. En premiere lecture, les biopsies mesuraient en moyenne 16 mm (SEM : 8,09). Les lesions elementaires les plus frequemment observees etaient : steatose a predominance macrovacuolaire : 67,4 %, fibrose portale : 44,4 %, inflammation lobulaire : 44,4 % et portale : 41,6 %, surcharge en fer : 34 %, ballonnisation hepatocytaire : 33,7 %. La fibrose, evaluee selon METAVIR, etait nulle ou minime (F0 et F1) dans 45,5 %, et les fibroses graves (F3 et F4) representaient 6,8 % des cas. Les conclusions les plus frequemment portees etaient : steatohepatite : 32,6 %, steatose pure : 23 %, et foie normal dans 22,5 % des cas. Les hemosideroses isolees, les fibroses hepatiques congenitales, et les hepatites granulomateuses ne representaient que 1,8 %, 0,6 % et 0,6 des diagnostics, respectivement. La reproductibilite de lecture etait excellente pour la presence de steatose a predominance macro-vacuolaire et pour definir le degre de steatose (K > 0,81) ; elle etait bonne (K : 0,61-0,8) pour le diagnostic de foie normal et de steatohepatite, et mediocre (K : 0,4-0,8) pour l’item steatose a predominance microvacuolaire, et pour le diagnostic de steatose pure. Au total, les biopsies realisees pour cytolyse inexpliquee montrent essentiellement des lesions de steatohepatite ou de steatose pure (57 % des cas), une surcharge en fer (34 %), et une fibrose grave dans environ 7 % des cas, les foies juges normaux ne representant que 22,5 %. Il existe un consensus entre pathologistes pour definir la steatose macrovacuolaire et la grader ; par contre, la steatose microvacuolaire reste diversement appreciee.