P.H. Bernard

Changes of non-invasive markers and FibroScan values during HCV treatment

Summary.  The recent advent of non‐invasive methods for assessment of fibrosis allows serial assessments in all patients with hepatitis C. The aim of this prospective study was to evaluate changes in liver fibrosis, as measured with non‐invasive methods, in a large cohort of HCV‐infected patients with and without treatment. From May 2003 through March 2006, all previously untreated HCV‐infected patients were enrolled in this study. Liver fibrosis was staged with FibroScan and Fibrotest at inclusion, then every year in untreated patients, and at the end of treatment and 6 months later in treated patients. The study population consisted of 416 patients, of whom 112 started treatment after enrolment. In the treatment group, FibroScan and Fibrotest values were significantly higher before and after treatment than in untreated patients at baseline and after 1 year. However, there was no significant difference between treated and untreated patients at the end of follow‐up. FibroScan and Fibrotest values fell in all treated patients, whatever their virological response. In multivariate analysis, treatment was the only factor independently associated with a fall in the FibroScan value. In conclusion, whatever the virological response, treatment for HCV infection is associated with an improvement of FibroScan and Fibrotest values. Further studies are needed to compare these non‐invasive methods with liver biopsy. These non‐invasive methods, and especially FibroScan, should be useful for assessing treatment efficacy in clinical trials of new drugs.

Liver fibrosis on account of chronic hepatitis C is more severe in HIV-positive than HIV-negative patients despite antiretroviral therapy

Summary.  The recent availability of non‐invasive tools to measure liver fibrosis has allowed examination of its extent and determination of predictors in all patients with chronic hepatitis C virus (HCV) infection. On the other hand, most information on hepatic fibrosis in HCV/human immunodeficiency virus (HIV)‐coinfected patients has been derived from liver biopsies taken before highly active antiretroviral therapy (HAART) was widely available. All consecutive HCV patients with elevated aminotransferases seen during the last 3 years were evaluated and liver fibrosis measured using transient elastography (FibroScan®) and biochemical indexes. Patients were split according to their HIV serostatus. A total of 656 (69.6%) HCV‐monoinfected and 287 (30.4%) HIV/HCV‐coinfected patients were assessed. Mean CD4 count of coinfected patients was 493 cells/μL and 88% were under HAART (mean time, 4.2 ± 2.4 years). Advanced liver fibrosis or cirrhosis was recognized in 39% of the coinfected and 18% of the monoinfected patients (P < 0.005). A good correlation was found between FibroScan® and biochemical indexes [AST to platelet ratio index (r = 0.405, P < 0.0001), FIB‐4 (r = 0.393, P < 0.0001) and Forns (r = 0.407, P < 0.0001)], regardless of the HIV status. In the multivariate analysis, age >45 years, body mass index (BMI) >25 kg/m2, and HIV infection were independently associated with advanced liver fibrosis or cirrhosis. HIV/HCV‐coinfected patients have more advanced liver fibrosis than HCV‐monoinfected patients despite the immunologic benefit of HAART.

Non-invasive tests for fibrosis and liver stiffness predict 5-year survival of patients chronically infected with hepatitis B virus.

Liver stiffness and non‐invasive tests predict overall survival in chronic hepatitis C. However, in patients chronically infected with hepatitis B virus (HBV), only the association between liver stiffness and the risk of hepatocellular carcinoma has been published.

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.

Impact on adherence and sustained virological response of psychiatric side effects during peginterferon and ribavirin therapy for chronic hepatitis C

The psychiatric side effects of interferon, often responsible for dose reduction or treatment discontinuation, represent a major limitation in the treatment of chronic hepatitis C (CHC).

Progression from idiopathic portal hypertension to incomplete septal cirrhosis with liver failure requiring liver transplantation

We report the case of a 30-year-old male patient suffering from what was initially thought to be end-stage cryptogenic cirrhosis with portal hypertension and liver failure, who underwent liver transplantation. Histological examination of the surgical specimen showed incomplete septal cirrhosis. At the age of 17 this patient had presented pancytopenia and splenomegaly, which were treated by splenectomy. The surgeon discovered portal hypertension. Re-examination of the wedge liver biopsy taken at this time revealed features of idiopathic portal hypertension. This case clearly shows that incomplete septal cirrhosis may be a late manifestation of idiopathic portal hypertension. The presence of sinusoidal dilatation and peliosis as well as early evidence of fibrosis which are already visible on the initial biopsy and are still present on the late specimen, are indirect evidence of a continuous process which ultimately led to incomplete cirrhosis with liver failure.

Adenomatous hyperplasia in cirrhotic livers: Histological evaluation, cellular density, and proliferative activity of 35 macronodular lesions in the cirrhotic explants of 10 adult french patients

We examined 41 consecutive cirrhotic liver explants from French patients for the presence of nodules of adenomatous hyperplasia (AH) and then analyzed these lesions, together with underlying cirrhosis (C) and associated hepatocellular carcinoma (HCC), for various histological parameters, cellular density, and proliferative activity. Thirty-five AHs were identified in 10 livers (prevalence, 24%); seven of 10 were HCV positive. Hepatocellular carcinoma was more frequent in patients with AH than in patients without. The AHs consisted of 17 ordinary (OAH) and 18 atypical (AAH) adenomatous hyperplasia lesions. There was a malignant focus in five of the 18 AAHs. Wide areas of large liver cell dysplasia were frequent in OAH but never found in AAH. Obvious steatosis was frequent in HCC but exceptional in AAH and absent in OAH. There was a significant increase in cellular density in AAH and HCC as compared with C and OAH. Proliferative cell nuclear antigen immunostaining similarly showed an increase in proliferation from OAH or C to AAH and HCC. These data suggest that, in Europe as in Japan, one pathway of hepatocarcinogenesis is a multistep process in which AAH should be considered as a premalignant lesion very close to grade I HCC, while OAH seems to correspond to a regenerative nodule with limited proliferative ability.

Multiple black hepatocellular adenomas in a male patient.

A 65-year-old man presented with multiple liver tumours. Imaging techniques could not differentiate between adenomas and hepatocellular carcinomas. He had no relevant past medical history. Liver function tests were normal except for a 1.5-fold rise in GGT. AFP was normal. Viral markers were negative. During laparoscopy, numerous black tumours of different sizes were seen. These tumours were adenomas without malignant transformation. Tumoral hepatocytes contained a brown pigment in the canalicular area without evidence of cholestasis. This pigment was Fontana positive and looked like Dubin-Johnson pigment by electron microscopy. The expression of the canalicular multispecific organic anion transporter (cMOAT) was decreased in the tumours but normal in the non-tumoral liver ruling out the diagnosis of Dubin-Johnson syndrome. There was mild iron deposition possibly related to an homozygous H63D mutation in the HFE gene. Three years after their discovery, the size of the tumours remained stable. It is concluded that this male patient with multiple adenomas and mild iron overload is at risk of developing an hepatocellular carcinoma and that the black colour of adenomas is probably due to a partial defect in excretion of organic anions.

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.