Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort).

UNLABELLED: Various critical events, liver related or not, occur in patients with compensated cirrhosis, but their respective burden remains to be prospectively assessed. The aim of this prospective cohort study involving 35 French centers was to capture the whole spectrum of complications occurring in compensated viral cirrhosis (VC) using competing risks analyses. Inclusion criteria were: histologically proven cirrhosis resulting from hepatitis C virus (HCV) or hepatitis B virus (HBV); Child-Pugh A; and no previous hepatic complications. The cohort was considered as a multistate disease model, cumulative incidences (CumIs) of events were estimated in a competing risks framework. A total of 1,654 patients were enrolled from 2006 to 2012 (HCV, 1,308; HBV, 315; HCV-HBV, 31). During a median follow-up of 34 months, at least one liver nodule was detected in 271 patients, confirmed as hepatocellular carcinoma (HCC) in 128 (4-year cumI: 10.5%) and cholangiocarcinoma in 3. HCC incidence was higher in HCV (4-year cumI: 11.4% vs. 7.4%; P = 0.05). HCC fulfilled Milan criteria in 79.3%, leading to curative treatment in 70.4%. Liver decompensation occurred more frequently in HCV patients (4-year cumI: 10.8% vs. 3.6%; P = 0.0004). Virological eradication/control was achieved in 34.1% of HCV and 88.6% of HBV patients and was associated with a marked decrease in HCC, decompensation, and bacterial infection incidences. Survival was shorter in HCV patients (4-year cumI: 91.6% vs. 97.2%; P = 0.0002). Death (n = 102; missing data: 6) was attributed to liver disease in 48 (47%; liver cancer: n = 18; miscellaneous, n = 30) and extrahepatic causes in 48 (47%; bacterial infection: n = 13; extrahepatic cancers: n = 10; cardiovascular events: n = 5; miscellaneous, n = 20). CONCLUSION: After 3 years of follow-up, extrahepatic events still explained half of deaths in patients with compensated VC. A strong decrease in complications was linked to virological eradication/control.

Subjective parameters markedly limit the referral of transplantation candidates to liver transplant centres.

BACKGROUND & AIMS: Equality of access to organ transplantation is a mandatory public health requirement. Referral from a local to a university hospital and then registration on the national waiting list are the two key steps enabling access to liver transplantation (LT). Although the latter procedure is well defined using the Model for End-stage Liver Disease score that improves equality of access, the former is mostly reliant on the practices of referring physicians. The aim of this study was to clarify the factors determining this initial step. METHODS: This observational study included consecutive inpatients with cirrhosis of whatever origin in a cohort constituted between 2003 and 2008, using medical records and structured questionnaires concerning patient characteristics and the opinions of hospital clinicians. Candidates for LT were defined in line with these opinions. RESULTS: Four hundred and thirty-three patients, mostly affected by alcoholic cirrhosis, were included, 21.0% of whom were considered to be candidates for LT. Factors independently associated with their candidature were: physician empathy [odds ratio (OR) = 10.8; 95% CI: 4.0-29.5], adherence to treatment (OR = 16.6; 95% CI: 3.7-75.2), geographical area (OR = 6.8; 95% CI: 2.2-21.3) and the patient's physiological age (OR = 2.3; 95% CI: 1.1-4.7). CONCLUSIONS: Several subjective markers restrict the referral of patients from local hospitals to liver transplant centres. Their advancement to this second step is thus markedly weakened by initial subjectivity. The development of objective guidelines for local hospital physicians to assist them with their initial decision-making on LT is now necessary.

Efficacy and safety of extracorporeal shock wave lithotripsy for chronic pancreatitis.

INTRODUCTION: There is still uncertainty regarding the efficacy and optimal modalities of extracorporeal shock wave lithotripsy (ESWL) in the treatment of chronic pancreatitis. The aims of the present study were to assess the safety and the efficacy of ESWL, either alone or followed by therapeutic endoscopic retrograde cholangiopancreatography (adjuvant ERCP) and to determine predictive factors of efficacy, in a real-life setting. PATIENTS AND METHODS: This study included all consecutive patients who underwent an ESWL in a single University Hospital between 2001 and 2012. The indication for ESWL was obstructive stone(s) of the main pancreatic duct resulting in either painful chronic pancreatitis or recurrent acute pancreatitis. Success was defined by resolution of pain, no analgesic treatment, no acute pancreatitis and no surgical treatment for chronic pancreatitis 6 months after the ESWL. RESULTS: One hundred and forty-six patients were studied; 6/146 (4%) had a complication of ESWL. Among the 132 patients in whom follow-up was completed, 91 (69%) had an adjuvant ERCP. After 6 months of follow-up, 100/132 (76%) patients achieved success. In multivariate analysis, the single significant predictive factor of the success of the ESWL treatment was chronic pain (p = 0.03). Patients who had chronic pain and needed opioid treatment had less chance of success than patients without chronic pain (OR 95%CI 0.31 [0.07-1.14]). We found no difference in the success rates between patients who underwent adjuvant ERCP and those who had ESWL only (p = 0.93). CONCLUSION: This study shows that the ESWL is a safe and effective treatment for patients with chronic pancreatitis and obstructive stones within the main pancreatic duct. Systematic association with therapeutic ERCP appears to provide no additional benefit and is therefore not recommended.

[Not Available]. / Le microbiote et les stéatopathies métaboliques.

Non alcoholic fatty liver diseases (NAFLD) is a clinicopathological entity that encompasses simple steatosis, necroinflammation known as non alcoholic steatohepatitis (NASH) with or without fibrosis. It is strongly associated with the metabolic syndrome. NAFLD is by far the most common cause of liver disease. Key issues in the diagnosis of patients with NAFLD are the differentiation of NASH from simple steatosis and the degree of liver fibrosis. Patients with NASH are at greatest risk of developing complications of chronic liver disease, such as hepatocellular carcinoma even in the absence of cirrhosis. Liver biopsy, which is the gold standard diagnostic method, cannot be proposedfor all patients, given the risk of this procedure and the prevalence of NAFLD. There are some noninvasive scoring systems to find out whether patients have advanced hepatic fibrosis. Knowledge about the interaction between the intestinal microbiota in obesity has rapidly increased in the past few years. Several lines of evidence suggest a role for the gut microbiota in the pathogenesis of NAFLD. Dysbiosis, i.e. imbalance of the intestinal microbiome, may have a role in the progression of NAFLD. At the present time, there are limited treatment options wich include lifestyle modification to lose weight, treatment of the disorders included in the metabolic syndrome and different therapeutic agents. However results are disappointing concerning liver inflammation and fibrosis. Manipulating the gut microbiota may represent a new strategy for patients with NAFLD.

GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation.

BACKGROUND & AIMS: Mosaic G-protein alpha-subunit (GNAS)-activating mutations are responsible for the McCune-Albright (MCA) syndrome. This oncogene that activates the adenylate cyclase is also mutated in various tumor types leading to the accumulation of cyclic-AMP. Identification of a hepatocellular adenoma (HCA) in two MCA patients led us to search for GNAS activation in benign and malignant hepatocellular carcinogenesis. METHODS: GNAS mutations were screened by sequencing 164 HCA, 245 hepatocellular carcinoma (HCC), and 17 fibrolamellar carcinomas. Tumors were characterized by quantitative RT-PCR, gene mutation screening and pathological reviewing. The consequences of wild type and mutant GNAS expression were analyzed in hepatocellular cell lines. RESULTS: A somatic GNAS-activating mutation was identified in 5 benign tumors and in 2 HCC. In benign tumors, GNAS mutations were exclusive from HNF1A, CTNNB1, and IL6ST mutations whereas one HCC demonstrated both CTNNB1 and GNAS mutations. Quantitative RT-PCR showed an activation of the IL-6 and interferon pathways in GNAS-mutated tumor tissues. Accordingly, pathological reviewing identified in GNAS-mutated tumors an inflammatory phenotype characterized by fibrosis and STAT3 activation. We further demonstrated in HCC cell lines that GNAS mutant expression induced inflammatory response and STAT3 activation. CONCLUSIONS: We identified for the first time the association between two rare diseases, MCA syndrome and HCA occurrence, but also that somatic GNAS-activating mutations in sporadic benign and malignant liver tumors are characterized by an inflammatory phenotype. These results showed a cross-talk between cyclic-AMP and JAK/STAT pathways in liver tumors and they reinforce the role of STAT3 activation in liver tumorigenesis.

Prediction of drainage effectiveness during endoscopic stenting of malignant hilar strictures: the role of liver volume assessment.

BACKGROUND: The optimal endoscopic approach to the drainage of malignant hilar strictures remains controversial, especially with regard to the extent of desirable drainage and unilateral or bilateral stenting. OBJECTIVE: To identify useful criteria for predicting successful endoscopic drainage. DESIGN AND SETTING: Retrospective 2-center study in the greater Paris area in France. PATIENTS: A total of 107 patients who had undergone endoscopic stenting for hilar tumors Bismuth type II, III, or IV and a set of contemporaneous cross-sectional imaging data available. INTERVENTIONS: The relative volumetry of the 3 main hepatic sectors (left, right anterior, and right posterior) was assessed on CT scans. The liver volume drained was estimated and classified into 1 of 3 classes: less than 30%, 30% to 50%, and more than 50% of the total liver volume. MAIN OUTCOME MEASUREMENTS: The primary outcome was effective drainage, defined as a decrease in the bilirubin level of more than 50% at 30 days after drainage. Secondary outcomes were early cholangitis rate and survival. RESULTS: The main factor associated with drainage effectiveness was a liver volume drained of more than 50% (odds ratio 4.5, P = .001), especially in Bismuth III strictures. Intubating an atrophic sector (<30%) was useless and increased the risk of cholangitis (odds ratio 3.04, P = .01). A drainage > 50% was associated with a longer median survival (119 vs 59 days, P = .005). LIMITATIONS: Heterogeneous population and volume assessment methodology to improve in further prospective studies. CONCLUSION: Draining more than 50% of the liver volume, which frequently requires bilateral stent placement, seems to be an important predictor of drainage effectiveness in malignant, especially Bismuth III, hilar strictures. A pre-ERCP assessment of hepatic volume distribution on cross-sectional imaging may optimize endoscopic procedures.

Association of CYP1B1 germ line mutations with hepatocyte nuclear factor 1alpha-mutated hepatocellular adenoma.

Biallelic somatic mutations of TCF1 coding for hepatocyte nuclear factor 1alpha (HNF1alpha) are found in 50% of the hepatocellular adenoma (HCA) cases usually associated with oral contraception. In rare cases, HNF1alpha germ line mutations could also predispose to familial adenomatosis. In order to identify new genetic factors predisposing to HNF1alpha-mutated HCA, we searched for mutations in genes involved in the metabolism of estrogen. For 10 genes (CYP1A1, CYP1A2, CYP3A4, CYP3A5, COMT, UGT2B7, NQO1, GSTM1, GSTP1, and GSTT1), we did not find mutations nor differences in the allele distribution among 32 women presenting HNF1alpha-mutated adenomas compared with 58 controls. In contrast, we identified a CYP1B1 germ line heterozygous mutation in 4 of 32 women presenting HNF1alpha-mutated adenomas compared with none in 58 controls. We confirmed these results with the identification of four additional CYP1B1 mutations in a second series of 26 cases. No mutations were found in the control group, which was extended to 98 individuals, and only a known rare genetic variant was observed in two controls (P = 0.0003). We did an ethoxyresorufin O-deethylase assay to evaluate the functional consequence of the CYP1B1 mutations. We found reduced enzymatic activity in each CYP1B1 variant. In addition, an E229K CYP1B1 mutation was found in a woman with a germ line HNF1alpha mutation in a familial adenomatosis context. In this large family, all three patients with adenomatosis bore both HNF1 and CYP1B1 germ line mutations. In conclusion, our data suggested that CYP1B1 germ line-inactivating mutations might increase the incidence of HCA in women with HNF1alpha mutations.

Independent and opposite associations of trunk fat and leg fat with liver enzyme levels.

BACKGROUND: In contrast to trunk fat mass (TFM), which is associated with cardiovascular risk markers, leg fat mass (LFM) displays independent protective effects against atherosclerosis. Little is known about the respective influence of central and peripheral adiposity on liver enzyme levels. AIMS: To assess the respective influence of TFM and LFM on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) levels, and to test whether LFM might protect against an increase of liver enzyme levels. METHODS: Cross-sectional study on 1442 patients (women: 1155; men: 287) referred for overweight/obesity over 3 years. Body composition was analysed by dual-energy X-ray absorptiometry. The relationships among liver enzymes, age, weight, height, body mass index (BMI), biological indices and body composition were studied. RESULTS: The mean BMI was 39.7 +/- 7.9 kg/m(2) in women and 38.2 +/- 6.6 kg/m(2) in men. In women, after adjustement for confounding factors, ALT, AST and GGT were negatively and independently correlated with LFM and positively with TFM. Similar independent associations were observed for ALT and AST in men. The strongest associations were found for ALT in both women and men. CONCLUSIONS: As observed for cardiovascular risk factors, LFM and TFM are inversely and independently correlated with liver enzyme levels in obese patients. LFM may confer independent protective effects against obesity-associated liver damage.

Effects of biliary obstruction on the penetration of ciprofloxacin and cefotaxime.

OBJECTIVE: To evaluate the biliary penetration of ciprofloxacin and cefotaxime in patients with obstructed bile ducts and to determine simple predictive markers of effective biliary concentrations of these drugs. METHODS: Sixty-two patients treated with endoscopic biliary drainage were prospectively included in a nonrandomized way and received intravenous ciprofloxacin (200 mg twice daily) or cefotaxime (1 g three times a day) for more than 24 h before exploration. Blood and bile samples were collected at the time of drainage. Ciprofloxacin and cefotaxime concentrations were measured using high-performance liquid chromatography. Biliary penetration was assessed by the bile-to-plasma ratio of the concentrations of both antibiotics. RESULTS: Biliary penetration ranged from 0.06 to 42.7 for ciprofloxacin and from 0.01 to 1.14 for cefotaxime. The ratio was more than one in only 10 patients (35%) and three patients (9%) in ciprofloxacin and cefotaxime groups, respectively. Biliary concentration of the drug was more than 10 times the minimal inhibitory concentration in only 10 patients (35%) and in 12 patients (35%) in ciprofloxacin and cefotaxime groups, respectively. Serum bilirubin, alkaline phosphatase or gamma-glutamyl-transpeptidase were not good predictive markers of the biliary diffusion of the antibiotics. CONCLUSION: In patients with obstructed bile ducts, the biliary penetration of ciprofloxacin is poor and reaches effective biliary concentrations in a minority of patients. Cefotaxime biliary penetration is even poorer. No liver test can predict accurately the biliary penetration of the drugs.

[Chronic hepatitis B: current therapy]. / Hépatite chronique B: modalités actuelles du traitement.

HBV cannot be fully eradicated from the body because of the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. True cure is infrequent, but persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma. Treatment options for chronic hepatitis B include pegylated interferon and 4 licensed oral nucleosides/nucleotides (lamivudine, adefovir entecavir and tenofovir). Interferon is the only drug with a defined duration of treatment. It is effective in 30% to 40% of patients but is poorly tolerated. In contrast to interferon, nucleotide/nucleoside analogs have only minor adverse effects. However, a resurgence of the infection may occur when these drugs are withdrawn, implying that treatment may have to continue indefinitely. The onset of viral resistance to these agents also limits their long-term use but can be minimized by ensuring potent suppression of viral replication.

Effect of prolonged interferon therapy on the outcome of hepatitis C virus-related cirrhosis: a randomized trial.

BACKGROUND & AIMS: The impact of interferon (IFN) treatment on the occurrence of complications related to hepatitis C virus (HCV)-related cirrhosis is debated because the majority of studies are retrospective. We designed a randomized controlled trial comparing the efficacy of prolonged IFN alfa-2a treatment vs nontreatment on complication-free survival in patients with compensated HCV cirrhosis. METHODS: A total of 102 patients (mean age, 60.5 +/- 9.5 y; male/female ratio, .82) with biopsy examination-proven HCV cirrhosis, Child-Pugh score A, who were hepatocellular carcinoma (HCC) free, and had at least 1 risk factor of complications were randomized to receive IFN or no therapy for 24 months. RESULTS: During the follow-up evaluation, the complication rate was 24.5%: HCC occurred in 12 and decompensation unrelated to HCC occurred in 13 patients. The number of HCC patients was similar in both groups. The probability of complication-free survival was not significantly different between treated and untreated patients (98% and 72.3% vs 90% and 70.7% at 12 and 24 mo, respectively, P = .59). The median time until complication occurrence was 17.1 months in the treated group vs 13.6 months in the untreated group (P = .2). CONCLUSIONS: This randomized controlled trial showed that a 2-year course of IFN has little or no impact on complication-free survival in patients with high-risk compensated HCV cirrhosis.

[Fatal liver failure after hepatitis B reactivation following chemotherapy for lymphoma in a patient with only anti-HBc antibody and review of the literature]. / Evolution fatale après réactivation d'une hépatite chronique virale B occulte dans les suites d'une chimiothérapie pour lymphome chez un malade porteur de l'anticorps anti-HBc isolé

Hepatitis B reactivation after chemotherapy is well known when Ag HBs is positive. Recommendation is to give preventive antiviral treatment before starting chemotherapy. The reactivation when there is only an anti-HBc antibody is rare. We report the case of a woman who developed an hepatitis B reactivation two weeks after the end of a chemotherapy for a high grade non Hodgkin lymphoma. Before chemotherapy, hepatitis B virus serology was positive only for anti-HBc antibody and viral load was negative. She had a fulminant hepatitis with fatal issue although a treatment by lamivudine and adefovir was rapidly started. In the literature, only 13 cases of patients with positive anti body anti-HBc alone who developed an hepatitis B reactivation after chemotherapy have been reported.

[Duodenal duplication revealed by acute pancreatitis: endoscopic treatment]. / Duplication duodénale révélée par une pancréatite aiguë: traitement endoscopique.

We report the case of a 17 year old man who presented with several episodes of acute pancreatitis due to a duodenal duplication. This was successfully treated by an incision by sphincterotome during interventional duodenoscopy. The patient is symptom free without recurrence 20 months after endoscopic treatment.

Interferon-alpha-induced hyperthyroidism: a three-stage evolution from silent thyroiditis towards Graves' disease.

Autoimmune thyroid disease is a common side-effect of interferon-alpha (IFN-alpha) treatment of viral hepatitis C. We have described three patients with hepatitis C for whom IFN-alpha and ribavirin were prescribed and who developed two successive phases of silent thyroiditis followed by hyperthryroidism relapse due to Graves' disease. These three men had no known history of familial or personal thyroid disease. Destructive thyrotoxicosis appeared 4-6 months after starting IFN-alpha, followed by Graves' hyperthyroidism within 8 to 11 months. The thyrotropin (TSH) level was normal before IFN-alpha was started. The diagnosis of destructive thyroiditis was confirmed by anti-TSH receptor antibody (TSHRAb) negativity and the absence of radionuclide ((123)I or (99)Tc) uptake on thyroid scintiscans. Eight to eleven months after starting treatment, TSHRAb positivity and intense scintigraphic uptake confirmed the appearance of Graves' disease. IFN-alpha was continued in only one patient. Hence, hyperthyroidism induced by IFN-alpha could correspond to the first phase of silent thyroiditis, to Graves' disease or to the succession of both. Rigorous diagnostic procedures with repeated scintiscans and TSHRAb titering are necessary to avoid a false diagnosis and inappropriate therapy.

Imatinib mesylate-induced acute hepatitis with autoimmune features.

Autoimmune hepatitis is a disorder of unknown aetiology. Imatinib belongs to a new class of anticancer agents with high selectivity toward a specific molecular target. Its main indications are chronic myeloid leukaemia and gastrointestinal tumours. We report here, for the first time to our knowledge, imatinib mesylate-induced hepatitis with autoimmune features.

Assessment of prescription practices for serological tests for viral hepatitis B and C in the Greater Parisian area in 2002.

OBJECTIVES: The aim of this study was to ascertain the reasons for the prescription of serological tests for viral hepatitis B (HBV) and C (HCV) in the Greater Parisian area, and to assess standards of prescription with respect to current guidelines. PATIENTS AND METHODS: The population studied comprised patients affiliated to the three main health insurance schemes in the Greater Parisian area, for whom at least one serological test for HBV or HCV was reimbursed on May 14th or 15th, 2002. Data was collected from prescribing and laboratory heads. RESULTS: The sample consisted of 1 046 prescription orders for HBV and/or HCV tests. The mean age of patients was 39 years, and 68% were females. The main medical indications declared by the prescribing physicians were: screening for HBV or HCV (40%), tests for pregnant women (19%), suspected hepatitis B or C (13%), pre- and post-vaccination tests for HBV (7%), medically assisted procreation (6%), follow-up of diagnosed chronic hepatitis (4%). Assessment of the standards of prescription orders showed a lack of compliance with guidelines for 71% of HBV tests, and 56% of HCV tests. CONCLUSIONS: The implementation of guidelines for the prescription of serological tests for HBV and HCV needs to be improved in clinical practice.

Solid adenoma with exclusive hepatocellular differentiation: a new variant among pancreatic benign neoplasms?

We report a unique, previously unreported pancreatic tumor with hepatoid differentiation associated with serous microcystic adenoma in a 70-year-old man. These two lesions localized, respectively, at the body and the tail of the pancreas, were found incidentally on abdominal ultrasonography. Serum alpha-fetoprotein was not increased and no hepatic lesion was displayed on computed tomography. A subtotal pancreatectomy with splenectomy was performed. The patient is alive and well 12 months after resection. Pathological examination showed a very unusual encapsulated solid tumor with hepatocytic differentiation, bile production and immunoreactivity for hepatocyte paraffin-1 antibody. The tumor cells were negative for endocrine (neuron-specific enolase, chromogranin A, synaptophysin) and acinar (amylase, trypsin) markers. Ultrastructurally, zymogen and neurosecretory granules were absent. The features of the tumor were almost indistinguishable from those of hepatocellular adenoma; therefore, we believe that this solid hepatoid tumor may represent a variant of pancreatic adenoma. Recognition of this entity is important because the only reported pancreatic hepatoid tumors to date have been malignant. The main differential diagnoses include hepatoid ductal adenocarcinoma, hepatoid acinar cell carcinoma, primitive hepatoid endocrine tumor, and metastatic hepatocellular carcinoma.

Refractory chylothorax in hepatic cirrhosis: successful treatment by transjugular intrahepatic portosystemic shunt.

Patients with cirrhosis and portal hypertension have increased thoracic duct lymph flow. Correction of portal hypertension is associated with decreases in thoracic duct flow. The authors present a case of rapid resolution of refractory chylothorax caused by thoracic duct injury proven by lymphangiography and helical CT scan in a patient with cirrhosis of the liver by using a transjugular intrahepatic portosystemic shunt to decrease portal pressure and thereby reduce thoracic duct lymph flow.

[Groove pancreatitis: a rare segmental form of chronic pancreatitis]. / La pancréatite de la rainure.

Groove pancreatitis is a rare form of segmental chronic pancreatitis which is localized within the head of the pancreas, the duodenum and the common bile duct. Symptoms are due to common bile duct stenosis or duodenal stenosis. Radiologically, there is a pancreatic mass, which hinders differential diagnosis with pancreatic carcinoma. We report here a case of groove pancreatitis observed in a 41-year-old man treated by pancreatoduodenectomy. Histological features of the groove scar were noted. Our case and cases reported in the literature lead to hypotheses concerning the pathogenesis and clinical, biological, and radiological features suggestive of the diagnosis.