Nathalie Ganne-Carrié

Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome : corticoresistance and effective treatment by cyclosporine A

SummaryWe report a case of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome treated with cyclosporine A. Features of primary biliary cirrhosis were pruritus, high titer of antimitochondrial antibodies, inflammatory infiltrates surrounding interlobular bile ducts, and periportal granuloma. Features suggestive of autoimmune hepatitis were high titer of antinuclear antibodies, very high total immunoglobulins, and piecemeal necrosis. Because corticosteroids and ursodeoxycholic acid were inefficient, cyclosporine A was started at a dose of 3 mg/kg/day. A dramatic improvement in clinical condition, liver tests, and histology was noted. Discontinuation of cyclosporine A was followed by a clinical and histological relapse. Cyclosporine A reintroduction was again associated with a significant improvement. This case report suggests that in corticoresistant cases cyclosporine A could be an effective therapy for primary biliary cirrhosis-autoimmune hepatitis overlap syndrome.

Impact of cytokine gene variants on the prediction and prognosis of hepatocellular carcinoma in patients with cirrhosis

BACKGROUND & AIMS Genetic polymorphisms modulate the expression of proinflammatory cytokines. We prospectively assessed the influence of 6 single nucleotide polymorphisms (SNPs) in TNFα, IL6, and IL1β genes on the risk of hepatocellular carcinoma (HCC) in patients with cirrhosis. METHODS TNFα (G-238A, C-863A, G-308A), IL6 (C-174G), and IL1β (C-31T, C-511T) SNPs were assessed in 232 alcoholics and 253 HCV-infected patients with biopsy-proven cirrhosis, prospectively followed-up and screened for HCC. Their influence on HCC development was assessed using the Kaplan-Meier method. RESULTS These variants did not influence the risk of HCC in alcoholic patients. Conversely, two variants influenced the risk of HCC occurrence in patients with HCV-related cirrhosis, namely the TNFα-308 (A) allele (HR = 2.4 [1.6-3.7], Log-rank <0.0001) and the IL1β-31 (T) allele (HR = 1.5 [1.1-2.1], Log-rank = 0.004). When stratifying HCV-infected patients into four genotypic associations expected to progressively increase TNFα and IL1β production, we observed increasing risk of HCC occurrence (Log-rank <0.0001) from group 1 to 4. The TNFα-308 (A) allele was the only genetic trait independently associated with risk of HCC in these patients, along with older age, male gender, BMI, and platelet count. These variables led to construction of a predictive score able to separate patients with HCV-related cirrhosis into three subgroups with progressively increasing 5-year cumulative incidences of 4.7%, 14.1%, and 36.3%, respectively (Log-rank <0.0001). CONCLUSIONS Genetic heterogeneity in the TNFα and IL1β gene promoters influences the risk of HCC in patients with HCV-induced cirrhosis. These genetic data, when incorporated into clinical scores, are able to refine selection of risk classes of HCC.

Effects of ethanol on hepatitis B virus Pre-S/S gene expression in the human hepatocellular carcinoma derived HEP G2 hepatitis B DNA positive cell line.

BACKGROUND/AIMS Among the reported interactions between ethanol and hepatitis B virus (HBV), studies of transgenic mice have suggested an effect of ethanol on the secretion of viral envelope proteins. METHODS We further investigated these interactions in vitro by determining HBs antigen levels and performing northern blots of viral mRNA in human cell culture (HepG2 HBV positive cells) exposed for 3 to 12 days to various concentrations of ethanol. RESULTS In cultures exposed to 200 mM ethanol, HBs antigen concentrations increased in the medium (p < 0.05) after 3 days as Pre-S1 and Pre-S2 protein concentrations. This increase was not specific, as albumin and ferritin increased in the same proportions. Ethanol also increased the HBs antigen concentration in the cells (p < 0.05), whereas levels of viral mRNA encoding surface proteins were unaffected. CONCLUSIONS These findings show that short-term ethanol exposure in vitro can induce HBs antigen overexpression via a post-transcriptional mechanism.

The epidemiology of Budd–Chiari syndrome in France

INTRODUCTION Epidemiological data is lacking on primary Budd-Chiari syndrome (BCS) in France. METHODS Two approaches were used: (1) A nationwide survey in specialized liver units for French adults. (2) A query of the French database of discharge diagnoses screening to identify incident cases in adults. BCS associated with cancer, alcoholic/viral cirrhosis, or occurring after liver transplantation were classified as secondary. RESULTS Approach (1) 178 primary BCS were identified (prevalence 4.04 per million inhabitants (pmi)), of which 30 were incident (incidence 0.68 pmi). Mean age was 40 ± 14 yrs. Risk factors included myeloproliferative neoplasms (MPN) (48%), oral contraceptives (35%) and factor V Leiden (16%). None were identified in 21% of patients, ≥2 risk factors in 25%. BMI was higher in the group without any risk factor (25.7 kg/m2 vs 23.7 kg/m2, p < 0.001). Approach (2) 110 incident primary BCS were admitted to French hospitals (incidence 2.17 pmi). MPN was less common (30%) and inflammatory local factors predominated (39%). CONCLUSION The entity of primary BCS as recorded in French liver units is 3 times less common than the entity recorded as nonmalignant hepatic vein obstruction in the hospital discharge database. The former entity is mostly related to MPN whereas the latter with abdominal inflammatory diseases.

Virologic control and severity of liver disease determine survival after radiofrequency ablation of hepatocellular carcinoma on cirrhosis

BACKGROUND We aimed to identify the main determinants of long-term overall survival (OS), including virologic control, and recurrence after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) on cirrhosis. METHODS Cirrhotic patients treated by RFA for HCC within Milan criteria were included. Associations between patient features and events were estimated by the Kaplan-Meier method with the log rank test and using uni/multivariate Cox models. RESULTS 389 cirrhotic patients (Child-Pugh A 86.6%, 473 tumors) were included. OS was 79.8%, 42.4% and 16%, and overall tumor recurrence 45%, 78% and 88% at 2, 5 and 10 years, respectively. In multivariate analysis, age, Child-Pugh, GGT, HCC near major vessels, esophageal varices, alkaline phosphatase and HBV predicted OS. Gender, ALT, AFP and alcohol intake were associated with tumor recurrence. Multinodular HCC (19.5%) was associated with risk of tumor recurrence outside Milan criteria. HBV patients had longer OS than other patients (P = 0.0059); negative HBV PCR at RFA was associated with decreased tumor recurrence (P = 0.0157). Using time-dependent analysis in HCV patients, a sustained virologic response was associated with increased OS (124.5 months) compared to other patients (49.2 months, P < 0.001). CONCLUSION Virologic response and severity of underlying liver disease were the main determinants of long-term OS after RFA for HCC developing on cirrhosis.

Traitements percutanés du carcinome hépatocellulaire : quelle modalité pour quel patient ?

L’ablation percutanee est le seul traitement non chirurgical a visee curative du carcinome hepatocellulaire. La radiofrequence (RF) monopolaire est la technique qui a ete a ce jour la plus largement utilisee et la mieux evaluee. La RF monopolaire est indiquee pour les « petits » CHC definis comme une tumeur unifocale de moins de 3 cm de diametre ou une tumeur au maximum trifocale dont le plus gros nodule ne depasse pas 3 cm de diametre (stade Barcelona Clinic Liver Cancer 0/A). Son principal avantage est de pouvoir etre utilisee chez les patients avec hypertension portale (sans ascite) ou insuffisance hepatique moderee (Child-Pugh B6/7) et etre repetee en cas de recidive tumorale intrahepatique. Plusieurs etudes suggerent que la RF monopolaire est une alternative efficace a la resection hepatique en cas de CHC unique de moins de 3 cm de diametre. En outre, chez les patients appartenant a la classe A de Child-Pugh sans hypertension portale, le traitement percutane peut etre utilise en premiere ligne avant une eventuelle transplantation hepatique en cas de recidive (transplantation « de sauvetage »). De nouvelles methodes, parmi lesquelles la RF multipolaire, les micro-ondes de seconde generation et l’electroporation irreversible sont en cours d’evaluation et pourraient permettre l’extension des indications de l’ablation percutanee. La RF multipolaire augmente de facon controlee le volume tumoral pouvant etre detruit, les micro-ondes de seconde generation augmentent le nombre de petits nodules pouvant etre detruits en une seule seance, et l’electroporation irreversible (methode non thermique) permet de traiter des tumeurs de localisations dangereuses considerees jusqu’ici comme des contre-indications absolues aux methodes thermiques.