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A novel controlled attenuation parameter (CAP) has been developed for Fibroscan(®) to assess liver steatosis, simultaneously with liver stiffness measurement (LSM). We assessed CAP diagnostic accuracy in a large cohort of patients with chronic hepatitis C (CHC) virus. A total of 615 patients with CHC, who underwent both Fibroscan(®) and liver biopsy, were analysed. Fibrosis was graded using METAVIR score. Steatosis was categorized by visual assessment as S(0) : steatosis in10% of hepatocytes, S(1) : 11-33%, S(2) : 34-66% and S(3) : 67-100%. Performances of CAP and liver stiffness were determined using receiver operating characteristic (ROC) curve analysis and cross-validated using the bootstrap method. The Obuchowski measure was used to assess overall accuracy of CAP and to differentiate between steatosis grades. In multivariate analysis, CAP was related to steatosis (P10(-15) ) independently of fibrosis stage (which was related to LSM). The areas under ROC curves using CAP to detect steatosis were 0.80 (95% CI, 0.75-0.84) for S ≥ S(1) , 0.86 (0.81-0.92) for S ≥ S(2) and 0.88 (0.73-1) S = S(3) . CAP exhibited a good ability to differentiate steatosis grades (Obuchowski measure = 0.92). Performance of LSM for fibrosis assessment confirmed results from previous studies. CAP is a novel tool to assess the degree of steatosis and both fibrosis and steatosis can be evaluated noninvasively during the same procedure using Fibroscan(®) , in patients with CHC.

Liver steatosis is a main histopathological feature of Hepatitis C (HCV) infection because of genotype 3. Steatosis and/or mechanisms underlying steatogenesis can contribute to hepatocarcinogenesis. The aim of this retrospective study was to assess the impact of infection with HCV genotype 3 on hepatocellular carcinoma (HCC) occurrence in patients with ongoing HCV cirrhosis. Three hundred and fifty-three consecutive patients (193 men, mean age 58 ± 13 years), with histologically proven HCV cirrhosis and persistent viral replication prospectively followed and screened for HCC between 1994 and 2007. Log-rank test and Cox model were used to compare the actuarial incidence of HCC between genotype subgroups. The patients infected with a genotype 3 (n = 25) as compared with those infected with other genotypes (n = 328) had a lower prothrombin activity [78 (interquartile range 60-85) vs 84 (71-195) %, P = 0.03] and higher rate of alcohol abuse (48%vs 29%, P = 0.046). During a median follow-up of 5.54 years [2.9-8.6], 11/25 patients (44%) and 87/328 patients (26%) with a genotype 3 and non-3 genotype, respectively, develop a HCC. HCC incidences were significantly different among the genotype subgroups (P = 0.001). The 5-year occurrence rate of HCC was 34% (95% CI, 1.3-6.3) and 17% (95% CI, 5.7-9.2) in genotype 3 and non-3 genotype groups, respectively (P = 0.002). In multivariate analysis, infection with a genotype 3 was independently associated with an increased risk of HCC occurrence [hazard ratio 3.54 (95% CI, 1.84-6.81), P = 0.0002], even after adjustment for prothrombin activity and alcohol abuse [3.58 (1.80-7.13); P = 0.003]. For patients with HCV cirrhosis and ongoing infection, infection with genotype 3 is independently associated with an increased risk of HCC development.

The objective of this study was to assess the results and tolerance of radiofrequency ablation in patients with cirrhosis and hepatocellular carcinoma (HCC) older than 75 years.Over a period of 9 years from January 2001, 235 patients with cirrhosis and 3 or less HCC≤5 cm of diameter were treated by radiofrequency ablation. Among them, 52 patients older than 75 years were selected for this study.The mean age was 79.4±3. 5 years. There were 36 males, cirrhosis was classified Child-Pugh class A (n=52) related to alcohol (n=13), HCV infection (n=33), or other causes (n=6). The mean tumour diameter was 32.5±10.6 mm, and 14 patients had a multifocal HCC. A complete ablation was obtained in 50/52 patients (96%). No severe complication occurred. The estimated overall survival rates were 62%, 52% and 36% at 3 years, 4 years and 5 years, respectively; it was similar to those observed in patients younger than 75 years.In patients with cirrhosis older than 75 years, radiofrequency ablation of 3 or less HCC≤5cm is well tolerated and survivals rates are similar to those of younger patients.

International audience; BACKGROUND: Hepascore combining serum bilirubin, gamma glutamyl transpeptidase, hyaluronic acid (HA) and alpha2-macroglobulin with age and sex, was reported as relevant in predicting liver fibrosis in patients with chronic HCV infection and was proposed as an alternative to liver biopsy. METHODS: Since an automated HA assay (Latex method, Wako, Japan) became available, we investigated to automate Hepascore by simultaneous measurements of components using an OLYMPUS AU640 analyzer (Tokyo, Japan). For its clinical evaluation, we considered a cohort of chronic HCV patients included in a multicenter prospective study (ANRS HC EP 23 Fibrostar). RESULTS: Automated Hepascore was not significantly different than assayed as previously described. An improvement in HA variability was evidenced. In 512 chronic HCV patients, automated Hepascore, using ROC curves analysis, showed good predictive performances for significant fibrosis (AUROC=0.81), severe fibrosis (AUROC=0.82), and cirrhosis (AUROC=0.88). For significant fibrosis, Hepascore (cut-off=0.5) had a sensitivity of 0.77, a specificity of 0.70, a positive predictive value of 0.71 and a negative predictive value (NPV) of 0.77. Hepascore

Following the failure of a small number of subsea dissimilar joints, there is significant interest in understanding the fracture mechanism(s) and in qualifying future items for avoidance of further failures. Subsea dissimilar joints typically comprise a butter weld deposit onto the joint face of an alloy steel forged hub/tee/elbow, postweld heat treated, and completed with a closure weld to a pipeline steel. The case examined in this paper, consists of a build up of alloy 625 onto an 8630M forging. Hydrogen embrittlement test methods are described and the results from the tests interpreted with respect to their implications for fabrication and service. The microstructure and chemistry across the dissimilar interface is found to be of fundamental importance, and this is illustrated by the relative performance of gas-tungsten arc (GTA), hot-wire GTA and friction welds. Guidance for fabrication, installation and service is given for avoidance of further hydrogen embrittlement failures.Copyright © 2009 by TWI Ltd.

To determine whether specific circulating antibodies from patients with drug-induced immunoallergic hepatitis could be involved in antibody-dependent cell-mediated cytotoxicity, an in vitro model system was set up. Normal human hepatocytes from male kidney transplantation donors were cultured and incubated with clometacin, a drug known to induce immunoallergic hepatitis in humans. After drug exposure and in the presence of lymphoid cells autologous to hepatocytes, addition of sera from patients with clometacin-induced hepatitis consistently resulted in hepatocyte injury characterized by morphological alterations and a decrease in intracellular lactate dehydrogenase and aspartate aminotransferase activities. Sera from patients with hepatitis induced by other drugs, such as cimetidine, halothane or methyldopa, were ineffective and no cytotoxicity occurred in the absence of lymphoid cells or without pre-incubation with clometacin. These results are consistent with the view that clometacin-induced hepatitis has an immunological basis and suggest that human hepatocytes co-cultured with autologous lymphoid cells represent a suitable model to study antibody-dependent cell-mediated cytotoxicity.

Based on uncontrolled observations, we have proposed Ursodeoxycholic acid (UDCA) as a novel therapeutic approach in primary biliary cirrhosis (PBC). To confirm and extend our original findings, we have designed a double-blind multicentre randomized clinical trial. An interim analysis was planned at 6 months, involving all subjects included in the trial, with a final analysis at 2 years. The UDCA-PBC trial began in June 1987 and will be completed in March 1990. Seventy patients were randomized to receive UDCA and 68 a placebo. The two groups were well matched with respect to age, sex, duration and prevalence of symptoms and histologic severity (50% of the UDCA group had stage III–IV disease vs. 37% of the placebo group). During the first 6 months of follow-up, six patients withdrew from the trial. At 6 months, the proportion of patients with jaundice was significantly lower ( p p p p

This radioimmunoassay for type I collagen mainly detects degradation products of the molecule in human serum samples. Type I collagen antigenicity in serum can be separated into two peaks by gel-filtration chromatography. The larger form represents collagen molecules (as shown by immunoblotting experiments), and (or) type I collagen with aminoterminal propeptide or intact procollagen molecules. The smaller form, the exact nature of which is not known, is quantitatively the principal antigenic form and is derived from degradation of type I collagen. The concentration of type I collagen in serum is increased mainly in cirrhotic patients, with or without active liver disease, but also somewhat in alcoholic patients without cirrhosis.This radioimmunoassay for type I collagen mainly detects degradation products of the molecule in human serum samples. Type I collagen antigenicity in serum can be separated into two peaks by gel-filtration chromatography. The larger form represents collagen molecules (as shown by immunoblotting experiments), and (or) type I collagen with aminoterminal propeptide or intact procollagen molecules. The smaller form, the exact nature of which is not known, is quantitatively the principal antigenic form and is derived from degradation of type I collagen. The concentration of type I collagen in serum is increased mainly in cirrhotic patients, with or without active liver disease, but also somewhat in alcoholic patients without cirrhosis.

To evaluate the risk of radiofrequency ablation treatment failure for hepatocellular carcinomas (HCC) next to large vessels.Between May 2000 and October 2002, from a total of 83 patients treated by radiofrequency ablation for HCC in a single center, 13 patients with tumoror=3.5 cm contacting a vesselor=3 mm in diameter (Group A) were matched with 13 patients with similar size tumors located away from large vessels (Group B). Immediate response and recurrence rate were evaluated on CT.After mean follow-up interval of 39+/-16.5 months for Group A and 39+/-14 months for Group B, local recurrence rates were 7/12 versus 1/12 respectively (p=0.03). For Group A, 6/7 local recurrences clearly contacted a large vessel.The cooling effect from flowing blood in large vessels markedly increases the rate of local failure of radiofrequency ablation for small HCC located near large vessels.

Sarcoidosis is a granulomatous disorder with a well-known T helper (Th) type 1 cell commitment and a key pathogenic role of interferon (IFN)-gamma. However, little is known about the influence of type 1 IFNs, such as IFN-alpha and IFN-beta, on the course of previous sarcoidosis. The aim of this study was to determine whether type 1 IFNs can safely be used in patients with sarcoidosis for severe associated disease. The present study examined a series of four patients with sarcoidosis, treated by IFN-alpha or IFN-beta for viral hepatitis (three cases) or multiple sclerosis (one case). IFN was initiated soon after apparent recovery (three cases) or during a worsening phase of sarcoidosis (one case). Hydroxychloroquine was added in the case with active disease. Patients received interferon for 6-24 months and had close monitoring during and after IFN therapy. Interestingly, no recurrence or exacerbation of sarcoidosis had occurred at 4 yrs of follow up. Two patients were cured from viral hepatitis, whilst treatment for another failed. No neurological progression was observed in the remaining patient. This series suggests that, despite the T helper type 1 phenotype of sarcoid granulomatous reaction, type 1 interferons do not exacerbate sarcoidosis in remission and this makes their use possible if indicated. However, their effect in persistent forms of the disease needs further evaluation.

In Western countries, most of the patients with hepatocellular carcinoma (HCC) are not eligible for curative treatments. Intra-arterial treatments have a palliative effect that could lead to extensive tumour necrosis and therefore have been widely used. Arterial embolization, Lipiodol-targeted chemoembolization and intra-arterial injection of radioactive iodine mixed with Lipiodol provided promising results in terms of tumoral growth, but were also responsible for severe side-effects, particularly in patients with cirrhosis. Their influence on survival has been assessed by randomized trials with contradictory results. In patients with advanced cases, embolization alone has limited or no influence on survival, and chemoembolization provided a beneficial effect mostly in patients with viral liver diseases, without liver failure, and with an adequate portal flux. The effects of radioactive iodine either in the treatment of advanced cases or the prevention of recurrences after a curative treatment must be investigated further.

HIGH INCIDENCE: Because of the high incidence of hepatocellular carcinoma (HCC) in patients with cirrhosis (3 to 5% per year) and the fact that curative treatment is currently available only for small sized tumors careful screening is warranted in this high risk population. Earlier screening attempts produced disappointing results in terms of cure and survival, particularly in Europe. Progress in ultrasonography, a better understanding of the risk of developing HCC, and most importantly the advent of local percutaneous treatments have greatly affected the data which should be reexamined. SCREENING METHODS: Patients with cirrhosis, particularly alcoholic or viral cirrhosis, should undergo regular ultrasound examinations, every six months for most screening protocols although the best timing remains unknown. Assay of serum alpha-fetoprotein is of limited use due to its low sensitivity and specificity. Diagnosis of HCC is basically based on helicoidal computed tomography and/or magnetic resonance imaging findings, with or without pathological proof (ultrasound-guided biopsy) that may be difficult to obtain. A probabilistic diagnosis is therefore retained if necessary, based on the presence of risk factors and arterial hypervascularization of a liver nodule. EARLY TREATMENT: With ultrasound screening, the diagnosis of HCC can generally be established early, when curative transplantation, resection or local percutaneous destruction are still feasible. The percutaneous methods use chemical or physical agents to destroy the tumor. There are few contraindications so curative treatment can be proposed for large number of patients. Large-scale prospective studies will be completed in the upcoming years and are expected to provide evidence validating the principle of screening and early treatment.

Rationnel La steatose hepatique non alcoolique affecte souvent les patients obeses ou diabetiques de type 2 et peut evoluer vers la fibrose. Certaines donnees suggerent que la steatose hepatique est un marqueur de risque cardiovasculaire et possiblement un facteur contribuant a l'atherosclerose. L'augmentation de la rigidite arterielle constitue un temoin precoce d'atherosclerose peripherique. Le but etait de rechercher une relation entre la presence et la severite de la fibrose hepatique et la rigidite arterielle chez des patients en surpoids ou obeses, ou diabetiques de type 2. Patients et Methodes : La fibrose hepatique a ete depistee par Fibroscan®. L'examen etait interpretable chez 83/117 patients explores. La rigidite arterielle a ete mesuree, a l'aide du Sphygmocor ® , par la vitesse d'onde de pouls carotido- femorale (VOP) et par les indices d'augmentation aortique et radiale, indices soumis a des variations a plus court terme. Parmi ces 83 patients, 61 % etaient obeses, 71 % diabetiques connus et 49 % hypertendus. Tous etaient indemnes d'antecedent hepatique, de consommation abusive d'alcool et de maladie arterielle connue. Resultats En moyenne, l'index de fibrose hepatique etait de 9,4 ± 9,0 kPa, tres voisin chez diabetiques et non diabetiques, et 31 % des patients avaient une fibrose definie par une mesure moyenne > 7,5 kPa. La VOP etait en moyenne de 10,1 ± 4,0 m/sec, avec une rigidite arterielle chez 25 % d'entre eux (VOP > 11 m/sec). Une correlation positive significative a ete observee entre ces deux parametres : r=0,322, p=0,004. Cette correlation etait retrouvee chez les diabetiques (r = 0,317, p=0,020) et chez les patients obeses ou en surpoids non diabetiques (r = 0,466, p=0,038) consideres separement. Par contre il n'existait pas de correlation significative entre l'index de fibrose hepatique et les indices d'augmentation. Conclusion Chez les diabetiques et chez les patients en surpoids ou obeses, la frequence de la fibrose hepatique est elevee et la severite de la fibrose hepatique est correlee a un temoin precoce d'atherosclerose peripherique et pourrait contribuer a la constitution de l'atherosclerose.

Introduction Les mecanismes impliquant le surpoids dans le mauvais pronostic de la cirrhose post-virale C ne sont pas bien compris. L'objectif de l'etude etait d'evaluer le role eventuel de l'insulino-resistance et des adipocytokines : la leptine augmentee avec ses effets pro-angiogeniques, pro-fibrogeniques, pro-inflammatoires et pro-mitotiques ; l'adiponectine diminuee avec ses effets anti-angiogeniques, anti-mitotiques and anti-inflammatoires. Patients et Methodes Nous avons determine les valeurs predictives de ces facteurs sur la survenue de carcinome hepatocellulaire (CHC), de deces lies a la pathologie hepatique et de transplantation dans une cohorte de 248 patients (âge moyen 58 ± 12 ans, IMC 25,4 ± 4,4 kg/m 2 ) presentant une cirrhose post-hepatite virale C compensee avec infection persistante, et prospectivement suivis et depistes pour le CHC. Resultats L'index de modele homeostasique d'insulinoresistance (HOMA-R) etait de 3,8 ± 3,0 (mediane 2,9). Les taux seriques d'adiponectine et de leptine etaient de 16,8 ± 15 mg/L et 16,8 ± 19 ng/mL respectivement. Apres un suivi moyen de 72 mois, 61 patients avaient developpe un CHC, 58 etaient decedes et 17 avaient ete transplantes. L'incidence (Kaplan Meyer) de CHC selon les terciles bas, moyen et haut de HOMA-R etait de 7, 18 et 27 % a 5 ans (p = 0,017) et de deces ou transplantations de 15, 15 et 29% (p = 0,002) respectivement. En analyse multivariee, l'index HOMA-R etait associe a la survenue d'un CHC (Hazard Ratio 1,10 [intervalle de confiance a 95% 1,01–1,21], p=0,026), ainsi que l'âge, le sexe masculin, l'IMC et le taux de plaquettes ; et etait un facteur predictif de deces ou de transplantation (HR 1,13 [1,07–1,21], p=0,0001) avec le sexe masculin, le TP et le taux de plaquettes. Le diabete, l'adiponectinemie et la leptinemie n'etaient pas associes a la survenue d'evenements. Discussion Ces resultats suggerent des effets deleteres reciproques de l'infection hepatique virale C sur l'insulinoresistance, et de l'augmentation de l'insuline sur le tissu hepatique, sans intervention directe des adipocytokines. Conclusion Chez les patients presentant une cirrhose compensee post-hepatite C avec infection persistante, l'insulinoresistance, mais non les niveaux seriques d'adipocytokines, est predictive de la survenue d'un CHC et de deces.

Viral infection has often been suggested as a possible cause of Sjögren's syndrome or chronic lymphocytic sialadenitis, and Epstein-Barr virus has been found in the salivary glands of patients with this condition. After we had noted Sjögren's syndrome in several patients infected with hepatitis C virus (HCV), a virus also excreted in saliva, we set up a prospective study to investigate the association of chronic lymphocytic sialadenitis, with or without symptoms, to chronic HCV liver disease. The histological appearances of labial salivary glands in patients with proven HCV hepatitis or cirrhosis were compared with those in dead controls. Histological changes characteristic of Sjögren's syndrome were significantly more common in HCV-infected patients (16 of 28, 57%) compared with controls (1 of 20, 5%). Focal lymphocytic sialadenitis characteristic of Sjögren's syndrome (though only 10 patients had xerostomia and none complained of xerophthalmia) appears to be common in patients with chronic HCV liver disease; if this association is confirmed, identification of the underlying mechanism may improve our understanding of both disorders.

In the West, hepatocellular carcinoma rarely occurs in patients without cirrhosis. In these patients, epidemiological factors and the histopathology of the non-neoplastic liver are not well known. The aim of this study was to clarify these points.We studied 30 patients (26 men, 28-87 years) with hepatocellular carcinoma and histologically-proven non-cirrhotic livers. Serological markers of HBV and HCV infection, as well as alcohol and tobacco consumption were evaluated. Pathological changes in the non-tumorous liver (fibrosis, inflammation, steatosis, alcoholic hepatitis lesions, iron overload, and large cell dysplasia) were systematically assessed using semi-quantitative scores.Twenty patients had alcohol intakeor =30 g/d and 16 were smokers. Serological HBV or HCV markers were positive in 10 patients. Only four patients had no exposure to alcohol or tobacco and no serological markers of HBV or HCV Histological examination showed that all livers had pathological changes. Seventeen patients (57%) had clearly-identified chronic liver disease: chronic hepatitis (n = 10) or alcoholic liver disease (n = 7). Non-specific and moderate pathological changes were observed in the 13 other patients (43%), with different degrees of fibrosis, activity, steatosis, and iron overload. Large cell dysplasia was present in 12 patients (40%).In our study, all patients with hepatocellular carcinoma and non-cirrhotic livers had non-tumorous pathological liver changes, especially iron overload and large cell dysplasia. These results suggest that hepatocellular carcinoma originates from an abnormal histological background, even in non-cirrhotic liver.

In patients with hepatocellular carcinoma, prediction of survival is difficult. The aim of this prospective study was to provide a simple classification for predicting survival of patients with hepatocellular carcinoma, based on a multivariable Cox model.Seven hundred and sixty-one patients who presented with hepatocellular carcinoma from 24 Western medical centers were enrolled over a 30-month period. Patients were randomly assigned to either a training sample (n=506, with 418 deaths) from which a classification system was established, or a test sample (n=255, with 200 deaths) for validating its prognostic significance.Five prognostic factors were selected at the 0.0001 level: Karnofsky index80% (relative risk of death=2.2, 95% confidence interval: 1.7-2.7), serum bilirubin50 micromol/l (relative risk=2.1, 95% confidence interval: 1.7-2.6), serum alkaline phosphatase at least twice the upper limit of normal range (relative risk=1.6, 95% confidence interval: 1.3-2.0), serum alpha-fetoprotein35 microg/l (relative risk=1.7, 95% confidence interval: 1.4-2.1), and ultrasonographic portal obstruction (relative risk=1.3, 95% confidence interval: 1.1-1.7). Three risk groups with different 1-year survival rates (72%, 34%, 7%) were derived, and independently validated in the test sample (79%, 31%, 4%).This classification could be useful in the assessment of prognosis from homogeneous groups of patients with respect to their expected outcome.

To explore the role of hepatitis B virus (HBV) X protein in liver carcinogenesis, independently from its role in viral replication, we have analyzed X gene structure and expression in tumorous and non-tumorous tissues obtained from 9 hepatitis B surface antigen (HBsAg)-negative, HBV DNA-positive patients. HBV replication was undetectable in tumorous tissues. HBV X gene was truncated at its 3' end in 5 of 9 tumorous tissues and 1 of 8 non-tumorous livers. Sequence analysis performed on uninterrupted X genes from 3 tumors and 3 surrounding non-tumorous tissues showed a high rate of mutations, selectively in the tumorous livers. In 1 of the 3 tumors, a frameshift mutation induced a new stop at codon 129. HBV RNAs were tested by reverse transcriptase-polymerase chain reaction (RT-PCR) with surface (S), core (C) and X specific primers. X, but not S and C, RNA expression was found in 6 of 8 tumors and in 6 of 7 non-tumorous tissues. This finding was consistent with immunohistochemical detection of X, but not S and C, antigens in all tumors also expressing X RNA. Our results provide evidence for selective expression of HBV X, but not S and C, RNA and protein in the tumorous and non-tumorous tissue of HBsAg-negative, HBV DNA-positive patients. It also shows that the structure of the X gene is modified (interrupted or highly mutated) in the majority of tumorous livers. Taken together, our findings are consistent with a potential role of mutated X proteins in HBV-related liver oncogenesis.

Giant-cell hepatitis is rare in adults and its significance has not been clarified. We report the clinical and histological characteristics and outcome in a group of adult patients with giant-cell hepatitis.Seventeen patients with giant-cell hepatitis, hospitalized in our unit between 1976 and 1992, were studied retrospectively. Giant-cell hepatitis was defined as at least two hepatocytes with four or more nuclei per cell on liver biopsy. Clinical and biochemical parameters, liver histology, and the serological profile of HAV, HBV, HCV, HIV, HSV, EBV, CMV, and paramyxovirus were evaluated. Paramyxovirus immunochemistry was performed in 6 liver biopsies.There were 11 females and 6 males, an average of 48 years old (range: 29-80). Four patients had a well-defined etiology: acute hepatitis B infection with a favorable outcome in 2 cases, clometacine induced-hepatitis resulting in death from liver failure in one case, and chronic hepatitis B and C in one patient with AIDS. Among the 13 patients in which the etiology could not be determined, histologically defined acute hepatitis was observed in 8 and chronic hepatitis in 5. Nine patients were treated with immunosuppressive drugs. One patient was lost to follow-up. Eight patients responded to treatment, but 5 patients progressed to cirrhosis between 5 months and 7 years. Two of the 4 patients with unexplained liver disease who did not receive any treatment died of liver failure.In patient with acute or chronic hepatitis without an identified cause (with or without autoimmune abnormalities), the presence of giant-cell hepatitis seems to have a similar evolution as active autoimmune hepatitis. The poor prognosis of these patients suggests that early immunosuppressive treatment is justified.

Long term treatment by fibrates could induce chronic hepatitis associated with auto-antibodies. The aim of this study was to assess the features of this hepatitis.Baseline clinical and biological features, and liver biopsy in 5 patients with fibrate-induced chronic hepatitis were studied, as well as their outcome.At enrollment, patients (4 men, mean age 65 years) had highly (n = 3) or mildly (n = 2) increased serum aminotransferase activity, hypergammaglobulinemia and high titers of anti-nuclear antibodies (with homogenous fluorescence in 3 cases). Liver biopsies demonstrated a lympho-plasmocytic infiltrate in all cases. Hepatocellular necrosis was multilobular in 2 cases, and mild to moderate, located in lobular and periportal areas in 3 cases. Cirrhosis was found at presentation in 3 cases and developed within a few months in the 2 other patients. After discontinuation of fibrates, aminotransferase activity normalized within 6 weeks either spontaneously (n = 3) or under immunosuppressive treatment (n = 2). Immunosuppression was rapidly withdrawn in 2 patients (18 months) without relapse, while one patient was treated for 4 years because of relapse after early withdrawal. A second liver biopsy performed 6 months after discontinuation of fibrates in an untreated-patient showed no inflammation or necrosis.These observations suggest that fibrates could trigger chronic liver disease resembling type I auto-immune chronic hepatitis, which resolves after drug withdrawal.

Hepatocellular carcinoma occurs almost exclusively in patients with cirrhosis, at least in the West. In most of these patients, potential curative treatments, such as resection or percutaneous alcohol injection, are usually contra-indicated. Transarterial chemoembolization may induce tumor necrosis. In order to avoid massive necrosis of the non tumoral liver, two major contra-indications have been identified: inadequate portal flow and liver failure. The influence of chemoembolization on survival was thought to be high on the basis of non randomized trials. However, no beneficial effects on survival were observed in three randomized trials. In these trials, the beneficial effect on tumor necrosis was counterbalanced by frequent deleterious effects on liver function. Moreover, progressive liver atrophy may follow repeated procedures. As there is no alternative treatment for most of these patients and chemoembolization can still be beneficial in selected cases, efforts have been made to improve patient selection and method to improve the results. Good liver function, a normal portal flow, and a well limited hypervascularized tumor are necessary conditions for treatment, which may even be curative when used in association with percutaneous alcohol injection. Moreover, arterial embolization can be performed without chemotherapy, and the procedure should not be repeated in the short term.

The diagnosis of cirrhosis relies on the histological analysis of a liver sample provided by biopsy made by transparietal or transjugular route according to the haemostasis of the patient. The histological study allows also to characterize the causative process and the severity of the disease. In the absence of histological proof a high probability of cirrhosis could be assumed when a firm liver with a narrow inferior edge is associated or not with signs of hepatic failure or portal hypertension. The most common causes of cirrhosis in France are alcohol abuse, C and B viruses, genetic haemochromatosis, chronic active autoimmune hepatitis, primary biliary cirrhosis. The prevalence of viral causes is increasing.

Although many studies concerning the prognostic factors of resected hepatocellular carcinoma have been performed, the prognostic information provided by needle biopsy of these tumors has not yet been extensively studied.One hundred twenty-four white patients with histologically-confirmed hepatocellular carcinoma were entered into a prospective study from 1990 to 1992 with followed-up through October 1994. Most of the patients had cirrhosis (79%). Patients were classified according to Okuda's staging: Stage I (50%), Stage II (47%), and Stage III (3%). The one-year survival rate was estimated at 58% in Okuda's Stage I, and 15% in Stages II and III. Edmondson's grading, mitotic index, and proliferating cell nuclear antigen labeling index were studied on each biopsy. Univariate and multivariate analyses were performed to determine the prognostic significance of the different parameters.According to Edmondson's critera, 13 of the hepatocellular carcinomas were Grade I, 63 Grade II, 42 Grade III, and 6 Grade IV. There was a significant correlation between Edmondson's grade, mitotic index, and proliferating cell nuclear antigen labeling index (P0.01). Univariate analysis showed both the histologic grade (P0.001) and mitotic index (P0.05) correlated with survival. Cox's model indicated that Edmondson's grading yields additional prognostic information for Okuda's staging (P0.001). The one-year survival rate for Okuda's Stage I was 76% for Edmondson's Grades I + II versus 23% for Grades III + IV.Edmondson's grading appears to be an important prognostic parameter for patients with hepatocellular carcinoma, and could help stratify patients for clinical trials.

We report a case of polyarteritis nodosa occurring in a patient with hepatitis C, ten days after the beginning of alpha-IFN therapy. There was no cryoglobulinemia. Serum HCV-RNA was detectable before INF therapy and disappeared during the vasculites. The patient received boli of methylprednisolone and the neurological and skin lesions regressed after 5 months. This observation could suggest a precocious response to alpha-INF and a relationship between INF and the occurrence of vasculites.

Extrahepatic manifestations have been reported in hepatitis C virus infection. To assess the relationship between diabetes mellitus and hepatitis C virus, we studied 152 patients with chronic hepatitis C and 152 controls hospitalized during the same period with hepatitis B virus (n = 51) or alcohol-induced (n = 101) liver diseases matched for age, sex, and the presence of cirrhosis (prevalence: 58%). Patients with jaundice, ascites, encephalopathy, prothrombin activity65%, or serum albumin35 g/L were excluded.Diabetes, defined by fasting serum glycemia1.4 g/L on at least two separate occasions or previously treated overt diabetes, was present in 38 patients with chronic hepatitis C (24%) and in 13 patients in the control group (9%, P0.002). In the 51 diabetic patients, irrespective of serum anti-hepatitis C virus status, 41 (81%) had non insulin dependent diabetes and 45 (88%) had cirrhosis. Family history of diabetes or obesity was observed in 2 (5%) of the diabetic patients with chronic hepatitis C and in 6 (46%) of the diabetic controls (P = 0.002). Plasma C-peptide (855 +/- 448 pmol/L versus 1,152 +/- 491 pmol/L, NS) and insulin levels (83 +/- 40 pmol/L versus 184 +/- 86 pmol/L, NS), assayed in 17 diabetic patients with chronic hepatitis C and in 9 diabetic controls, were lower in the former. The prevalence of HLA B8, DR3 or DR4 antigens, which was searched for in 77 patients with chronic hepatitis C, was not different in diabetic and non diabetic patients, and, was similar to the reference population. Serum islet-cell antibodies were found in 5 patients with chronic hepatitis C (3 with diabetes) and in 2 controls.Diabetes mellitus is more prevalent in patients with chronic hepatitis C than in patients with other liver diseases, and usually occurs in the absence of predisposing factors. These results suggest a role of hepatitis C virus infection in the pathogenesis of diabetes.

We report an Hepatitis B Virus reactivation, in a patient with an end-stage Human Immunodeficiency Virus infection who developed a rapidly progressive liver failure in four months. The main histological features include ballooning of hepatocytes and ground glass transformation, without significant inflammation. Immunohistochemical staining showed a high expression of viral antigens. This case can be related to "Fibrosing Cholestatic Hepatitis", first described after liver transplantation for cirrhosis B. The mechanism of hepatocellular damage is likely to be a direct cytotoxicity of hepatitis B virus.

T lymphocytes are predominantly involved in the development of Sjögren's syndrome. Their repertoire has recently been claimed to be restricted. Analysis of T cell receptor V beta gene products within the labial salivary glands led us to identify V beta 2 and V beta 8. This study, using a new panel of anti-V beta product monoclonal antibodies and a tissue triple-staining technique, examined the distribution of V beta gene family products in activated as well as non-activated CD4+ or CD8+ T cells subsets in the salivary gland tissue of SS patients. Our results suggest that the V beta genes used by the T CD4+ or T CD8+ cells in situ are similar, irrespective of the activation status of these cells. T lymphocytes homing into exocrine tissues might thus be selected on the basis of their V beta repertoire rather than their activation state.

Due to extensive tumoural invasion, less than 10% of the patients with hepatocellular carcinoma can benefit from surgery. A variety of proposed palliative procedures, including general chemotherapy and radiotherapy, have given quite less than satisfactory results. Percutaneous alcoolization and hormone therapy are currently being evaluated. Increased use of intra-arterial embolization has developed over the last 10 years, initially in Asia and now in Europe. The aim of intra-arterial chemotherapy is to increase the concentration of anticancer agents within the tumour. Adding lipiodol with certain agents would increase the duration of cancer cell exposure. Arterial embolization aims at creating tumour necrosis by ischaemia and relies on the fact that the main blood supply from hepatocellular carcinomas comes from arteries while non-tumoural hepatic tissue is supplied by the portal vein. Numerous reports on intra-arterial treatment protocols combining chemotherapy and embolization have demonstrated that this technique can produce partial or total tumour necrosis. However, due to the variable nature of the natural history of hepatocellular carcinoma the clinically beneficial effect in terms of survival rate has not been established and would not appear to be highly significant, probably due to chemoresistance which cannot be overcome by intra-arterial administration. Indeed, the necrotic effect appears to result from hepatic embolization itself. In two randomized studies necrosis was significantly greater in patients who underwent repeated embolizations than in those receiving general or intra-arterial chemotherapy. It is generally accepted that intra-arterial chemoembolization is contraindicated in cases of portal thrombosis or major liver failure. In addition, each procedure requires at least one week hospitalization with the inherent effect on patient comfort and quality of life. Nevertheless, should intra-arterial, chemoembolization be abandoned? Probably not because there is no alternative method, at least for inoperable patients. Efforts should be made to improve the technique which should be reserved for carefully selected patients. New, more liposoluble drugs and possible combinations with glycoprotein inhibitors could be studied. Until an effective treatment for hepatocellular carcinoma has been developed, the role of palliative care must be evaluated in terms of survival rate, cost and quality of life.

The aim of study was to assess the role of hepatitis C virus (HCV) infection in 164 alcoholic cirrhotic patients. We studied the prevalence of anti-HCV antibodies using ELISA and RIBA first and second generation tests. Twenty-two % of the patients had anti-HCV antibodies detected by ELISA 2, RIBA 2 test was positive in 10% of the patients and indeterminate in 3%. We compared epidemiological, biological and histological characteristics according to the results of the tests. By comparing ELISA 2-RIBA 2 positive patients to ELISA 2 negative patients, we observed, in the former, a) a higher serum aminotransferase activity, b) a lower serum gammaglutamyl transpeptidase activity, and c) a lower histological score of alcoholic hepatitis. In addition, in a group of ELISA 2 positive RIBA 2 negative patients, the values were intermediate between those of the two former groups. However, most of these patients had a negative third generation ELISA test. The whole results suggest that HCV is likely to play a role in the pathogenesis of liver damage in a high number of alcoholic cirrhotic patients.

Two cases of sclerosing cholangitis after oily arterial chemoembolization are reported. In one patient angiocholitis with liver abscesses, in the other patient gradual cholestasis were the main clinical features. In both cases, endoscopic retrograde cholangiogram showed a stricture of the common hepatic bile duct and, in one case, irregularities of intrahepatic biliary tree. Histologic examination of the liver in the two patients pointed out the involvement of small bile ducts and arteriolar endarteritis obliterans. Ischaemia is likely to be the main mechanism of these two cases of sclerosing cholangitis as well as in those described after FUDR intra-arterial chemotherapy. The prevalence of sclerosing cholangitis after arterial oily chemoembolization is probably underestimated because of a non specific clinical presentation and need to be precise by further study.

The aim of this study was to evaluate the relationship between the serum N-terminal peptide of type III procollagen (PIIINP), Knodell's score and the response to treatment in 79 patients with viral C chronic hepatitis. Liver biopsy and serum PIIINP was assessed in all patients. Serum PIIINP was correlated with Knodell'score (r = 0.60; P = 10(-4)). Correlation between serum alanine amino-transferase and Knodell'score was smaller than for PIIINP (r = 0.38; P = 0.02). Forty-nine patients were treated with interferon alpha. A second biopsy and serum PIIINP determination were performed one year after treatment discontinuation. Means of serum PIIINP and Knodell'score significantly decreased after treatment (P0.01; P0.03). Among non-responder patients, serum PIIINP was initially more elevated: 37.5 +/- 12.6 ng/mL versus 22.6 +/- 3.8 (P10(-3)). Knodell's score decreased only among responder patients (P0.01 vs P0.7). Positive and negative predictive value for the response to treatment, evaluated by aminotransferases normalization, of serum PIIINP levelor = 24 ng/mL were 0.6 and 0.9 respectively. These findings suggest that serum PIIINP is a relevant marker of activity in patients with viral C chronic hepatitis and that it might have a predictive value of response to treatment.

The aim of this study was to compare 6 potential serum markers for hepatic fibrosis in patients with alcoholic liver disease. Ninety-three patients (50 +/- 11 years old, 62 males) with biopsy-proven alcoholic liver disease were included in the study. A liver biopsy and serum assays of type I, type III and type IV collagens, N-terminal peptide of type III procollagen, laminin (by radioimmunoassays) and apolipoprotein A1 (by nephelometry) were performed in all patients. A histological score of hepatic fibrosis was established. Alcoholic hepatitis lesions and perisinusoidal fibrosis were assessed separately. A significant correlation was found between the score of hepatic fibrosis and serum levels of type I collagen (r = 0.44, P10(-3)), type III collagen (r = 0.36, P10(-2)), N-terminal peptide of type III procollagen (r = 0.50, P10(-3)), type IV collagen (r = 0.44, P10(-3)), laminin (r = 0.50, P10(-3)), and apolipoprotein A1 (r = 0.21, P0.05). After adjustment for the presence of lesions of alcoholic hepatitis and perisinusoidal fibrosis (partial correlation), serum levels of type I collagen, type III collagen, N-terminal peptide of type III procollagen, type IV collagen, and laminin remained significantly correlated with the score of hepatic fibrosis; in contrast, correlation with serum apolipoprotein A1 was no longer significant. Serum levels of N-terminal peptide of type III procollagen, type IV collagen and laminin were significantly higher in patients with perisinusoidal fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Introduction Le risque de carcinome hepatocellulaire (CHC) sur cirrhose virale semble augmente en cas de diabete, l’insulino-resistance jouant probablement un role. Le but de cette etude retrospective etait d’evaluer l’influence du traitement par metformine sur la survenue de CHC au sein d’une cohorte de diabetiques ayant une cirrhose virale C non guerie et suivis prospectivement. Patients et Methodes Entre 1988 et 2007, 100 diabetiques de type 2 consecutifs (53 hommes, 61 ± 11 ans, index de masse corporelle 26,7 ± 4,7 kg/m 2 ) ayant une cirrhose virale C non guerie ont ete inclus dans un programme prospectif de depistage du CHC par dosage serique d’alfa fœto-proteine (AFP) et echographie hepatique tous les 3 a 6 mois. Resultats 22 patients etaient traites par metformine, 28 par insuline, 20 par insulino-secretagogues et 30 par mesures dietetiques. Il n’y avait pas de difference clinique ou biologique significative au moment de l’inclusion entre les patients traites ou non par metformine. Apres un suivi moyen de 5,9 ± 4,4 ans, 38 patients (38 %) ont developpe un CHC. L’incidence du CHC a 5 ans etait respectivement de 10,9 % et 29,8 % chez les patients traites et non traites par metformine (courbe de Kaplan Meier p = 0,006). En analyse multivariee, le traitement par metformine etait associe a une incidence diminuee de CHC (Odds ratio 0,23 [intervalle de confiance a 95 % 0,06–0,96], p = 0,044) tandis que l’âge (OR 2,33 [1,14–4,77], p = 0,02) et le taux d’AFP (OR 1,02 [1,02–1,03], p = 0,005) etaient associes a une incidence plus forte. Discussion La metformine pourrait agir par son effet activateur de l’AMP-activated protein kinase, une des cibles du gene codant pour la proteine suppressive de tumeur LKB1. Conclusion Dans cette etude prospective portant sur des diabetiques avec cirrhose virale C non guerie, le traitement par metformine est associe a une incidence reduite de CHC.