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Comment in Does cirrhosis associated with well controlled viral hepatitis confer a risk for extrahepatic cancer? Yang JD, Gores GJ. Hepatology. 2018 Oct;68(4):1217-1219. doi: 10.1002/hep.30063. Epub 2018 Jul 10.; International audience; Data on extrahepatic cancers (EHCs) in compensated viral cirrhosis are limited. The objective of the prospective multicenter Agence Nationale de Recherche sur le SIDA et les Hépatites virales CO12 CirVir cohort was to assess the occurrence of all clinical events in patients with compensated viral cirrhosis, including all types of cancer. Patients with the following inclusion criteria were enrolled in 35 French centers: (1) biopsy-proven hepatitis B virus (HBV) or hepatitis C virus (HCV) cirrhosis, (2) Child-Pugh A, or (3) absence of previous liver complications including primary liver cancer (PLC). Patients were followed up prospectively every 6 months. The standardized mortality ratio (SMR) was calculated according to age and gender using 5-year periods. The impact of sustained viral response (SVR) in HCV patients and maintained viral suppression in HBV patients were assessed using time-dependent analysis. A total of 1,671 patients were enrolled between 2006 and 2012 (median age, 54.9 years; men, 67.3%; HCV, 1,323; HBV, 317; HCV-HBV, 31). Metabolic features and excessive alcohol and tobacco consumption were recorded in 15.2%, 36.4%, and 56.4% of cases, respectively. After a median follow-up of 59.7 months, 227 PLCs were diagnosed (5-year cumulative incidence [CumI] 13.4%) and 93 patients developed EHC (14 patients with lymphoid or related tissue cancer and 79 with solid tissue cancer; 5-year EHC CumI, 5.9%). Compared to the general French population, patients were younger at cancer diagnosis, with significantly higher risk of EHC in HCV patients (SMR, 1.31; 95 confidence interval [CI], 1.04-1.64; P = 0.017) and after SVR (SMR = 1.57; 95% CI, 1.08-2.22; P = 0.013). EHC was the fourth leading cause of death in the whole cohort and the first in patients with viral control/eradication.CONCLUSION: Compared to the general French population, HCV cirrhosis is associated with a higher risk of EHC and the first cause of death in patients with viral cirrhosis who achieve virological control/eradication. (Hepatology 2018).

Nonalcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH), are rapidly becoming among the top causes of cirrhosis, hepatocellular carcinoma, and indications for liver transplantation. Other than lifestyle modification through diet and exercise, there are currently no other approved treatments for NASH/NAFLD. Although weight loss can be effective, it is difficult to achieve and sustain. In contrast, bariatric surgery can improve metabolic conditions associated with NAFLD, and has been shown to improve liver histology. To have approved regimens for the treatment of NASH/NAFLD, several issues must be addressed. First, all stakeholders must agree on the most appropriate clinical trial endpoints for NASH. Currently, resolution of NASH (without worsening fibrosis) or reduction of fibrosis stage (without worsening NASH) are the accepted endpoints by the regulatory authorities. It is important to recognize the prognostic implication of histologic features of NASH. In this context, although histologic NASH has been associated with advanced fibrosis, it is not an independent predictor of long-term mortality. In contrast, there are significant data to suggest that fibrosis stage is the only robust and independent predictor of liver-related mortality. In addition to the primary endpoints, several important secondary endpoints, including noninvasive biomarkers, long-term outcomes, and patient-reported outcomes must be considered. In 2018, a few phase 3 clinical trials for the treatment of NASH have been initiated. Additionally, a number of phase 2a and 2b clinical trials targeting different pathogenic pathways in NASH are in the pipeline of emerging therapies. CONCLUSION: Over the next 5 years, some of these regimens are expected to provide potential new treatment options for patients with NASH/NAFLD. (Hepatology 2018;68:361-371).

Nonalcoholic fatty liver disease (NAFLD) is a spectrum comprised of isolated steatosis, nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. The majority of NAFLD subjects do not have NASH and do not carry a significant risk for liver-related adverse outcomes (cirrhosis and mortality). Globally, the prevalence of NAFLD is approximately 25%. In Asia, a gradient of high to low prevalence rates is noted from urban to rural areas. Given the prevalence of NAFLD, the clinical and economic burden of NAFLD and NASH can be substantial. With increasing recognition of NASH as an important liver disease, the diagnosis of NASH still requires a liver biopsy that is suboptimal. Although liver biopsy is the most accurate modality to diagnose and stage the severity of NASH, this method suffers from being invasive, costly, associated with potential complications, and plagued with interobserver variability of individual pathological features. A number of noninvasive modalities to diagnose NASH and stage liver fibrosis are being developed. These modalities include predictive models (NAFLD fibrosis score) and serum biomarkers such as enhanced liver fibrosis (ELF). Other tests are based on radiological techniques, such as transient elastography (TE) or magnetic resonance elastography (MRE), which are used to estimate liver stiffness as a potential surrogate of hepatic fibrosis. Although a dynamic field of research, most of these diagnostic modalities have area under the curve ranging between 0.76 and 0.90%, with MRE having the best predictive performance. In summary, developing safe and easily accessible noninvasive modalities to accurately diagnose and monitor NASH and associated fibrosis is of utmost importance in clinical practice and clinical research. These tests are not only important to risk stratify subjects at the greatest risk for progressive liver disease, but also to serve as appropriate surrogate endpoints for therapeutic clinical trials of NASH. (Hepatology 2018;68:349-360).

Patients with obstructive sleep apnea (OSA) are at risk for the development of fatty liver as a result of being overweight. Several data suggest that OSA per se could be a risk factor of liver injury; ischemic hepatitis during OSA has been reported, and OSA is an independent risk factor for insulin resistance. Therefore, we investigated liver damage and potential mechanisms in 163 consecutive nondrinking patients with nocturnal polysomnographic recording for clinical suspicion of OSA. Serum levels of liver enzymes were measured in all patients. Liver biopsy was offered to patients with elevated liver enzymes. Intrahepatic hypoxia was assessed by the expression of vascular endothelial growth factor (VEGF) on liver biopsy specimens. Severe OSA (apnea-hypopnea index [AHI] > 50/hr) was seen in 27% of patients; 52% had moderate OSA (AHI 10-50/hr), and 21% had no OSA. Overall, 20% had elevated liver enzymes. Independent parameters associated with elevated liver enzymes were body mass index (BMI) (OR: 1.13; CI: 1.03-1.2) and severe OSA (OR: 5.9; CI: 1.2-29). Liver biopsy was performed in 18 of 32 patients with elevated liver enzymes and showed steatohepatitis in 12 cases, associated with fibrosis in 7 cases. Patients with severe OSA were more insulin-resistant according to homeostasis model assessment, had higher percentage of steatosis as well as scores of necrosis and fibrosis, despite similar BMI. Hepatic immunostaining used as an indirect marker of hypoxia was not different between patients with or without severe OSA. In conclusion, severe OSA is a risk factor for elevated liver enzymes and steatohepatitis independent of body weight. Promotion of insulin resistance is probably involved. Further studies are needed to determine whether hypoxia contributes directly to liver injury. (HEPATOLOGY 2005;41:1290–1296.)

Early identification of patients with severe (discriminant function ≥32) biopsy-proven alcoholic hepatitis (AH) who are not responding to corticosteroids would be clinically relevant. Our goal was to develop simple criteria that will help physicians to promptly identify nonresponders to corticosteroids. A total of 238 patients were included. We used 6 months survival as an end point because of the rule requiring 6 months for listing alcoholic patients for transplantation. Overall survival at 1 and 6 months was 85% ± 2.3% and 64.3% ± 3.3%, respectively. An early change in bilirubin levels (ECBL) at 7 days (defined as bilirubin level at 7 days lower than bilirubin level on the first day of treatment) was observed in 73% of patients. At 7 days, in patients with ECBL, bilirubin decreased (84 ± 75 μmol/L [4.94 ± 4.40 mg/dL]), whereas it increased in patients without ECBL (76.5 ± 77 μmol/L [4.50 ± 4.54 mg/dL], P < .0001). Ninety-five percent of patients with ECBL continued to have improved liver function during treatment. At 6 months, survival of patients with ECBL was significantly higher than that of patients without ECBL, 82.8% ± 3.3% versus 23% ± 5.8%, P < .0001. On multivariate analysis, ECBL, discriminant function and creatinine were independent prognostic variables, and ECBL had the most important prognostic value. In conclusion, ECBL is a very simple predictive factor for identifying nonresponders. A recommendation to discontinue corticosteroids after 7 days in patients without ECBL, suggested by our results, awaits additional confirmation. (Hepatology 2003;38:1363-1369.)

The aim of our multicenter study was to assess the efficacy of ursodeoxycholic acid (UDCA) on the survival of patients with alcohol-induced cirrhosis and jaundice. We included patients with histologically proven alcohol-induced cirrhosis and serum bilirubin >50 micromol/L. After randomization, patients received either UDCA (13-15 mg/kg/d) or a placebo for 6 months. Two hundred twenty-six patients (113 in each group) were included in 24 centers. There were 139 men and 87 women, mean age of 50.3 years. Seventy-four percent had associated alcohol-induced hepatitis, and 24% received a corticosteroid therapy. At inclusion, the 2 groups were comparable for the main clinical and biologic parameters, but serum bilirubin was higher in the UDCA group than in the placebo group (163 micromol/L vs. 145 micromol/L, P

Sustained viral suppression using monotherapy with interferon alfa (IFN-alpha) or lamivudine can only be achieved in a small percentage of patients with chronic hepatitis B. The concomitant administration of lamivudine and IFN-alpha does not enhance efficacy. We postulated that the optimal timing of therapy might be sequential treatment with lamivudine and IFN-alpha. The aim of this study was therefore to assess the efficacy of sequential treatment in patients resistant to IFN-alpha alone. Fourteen male patients, with a median age of 40 years, nonresponders to IFN-alpha with hepatitis B virus (HBV) DNA100 pg/mL (branched DNA [bDNA] Chiron) and positive hepatitis B e antigen (HBeAg) in 11 of 14 patients, were treated with lamivudine 100 mg/d alone for 20 weeks, then with both IFN-alpha2b 5 MU 3 times per week and lamivudine for 4 weeks, and lastly with IFN-alpha alone for 24 weeks. At the end of lamivudine therapy, all patients had undetectable serum HBV DNA, and none exhibited an emergence of HBV polymerase mutant or breakthrough. Sustained serum HBV-DNA clearance 6 months after the end of sequential treatment was achieved in 8 of 14 patients, HBeAg-to-anti-HBe seroconversion in 5 of 11 patients, and HBeAg and hepatitis B surface antigen (HBsAg) seroconversions in 3 of 14 patients (anti-HBs100 IU/mL). All sustained responders had normalized their alanine transaminase (ALT) values and exhibited histologic improvements. In conclusion, the results of this pilot study suggest that sequential treatment with lamivudine and IFN-alpha can induce a sustained virologic response, including HBs seroconversion, in patients with chronic hepatitis B not responding to IFN-alpha alone, without the selection of drug-resistant mutants. This therapeutic schedule warrants further evaluation in clinical trials.

The association of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) is thought to be rare, and its optimal treatment is unknown. Of 130 consecutive patients with a diagnosis of PBC, we identified 12 cases (9.2%) of overlap syndrome (10 females, 2 males; median age, 50 years) strictly defined by the presence of at least two of the three recognized biochemical, serological, and histological criteria of each disease. One patient had initially pure PBC and developed AIH characterized by a flare of alanine transaminase (ALT) (1,330 IU/L; N < 35), elevated immunoglobulin G (IgG) (42 g/L; N < 14.0), and presence of anti-smooth muscle antibodies (ASMA) after 20 months of ursodeoxycholic acid (UDCA) therapy. A complete clinical and biochemical remission was achieved under combination of corticosteroids and UDCA. Eleven patients had features of both diseases at presentation: high serum levels of alkaline phosphatase (AP) (median: 280 IU/L; N < 100), ALT (140 IU/L), and IgG (30.8 g/L), presence of mitochondrial antibodies (n = 9) or ASMA (n = 9), florid bile duct lesions (n = 8), and moderate or severe periportal or periseptal lymphocytic piecemeal necrosis (n = 11). UDCA (13-15 mg/kg/d) given alone in 5 patients induced a significant decrease in biochemical cholestasis but not in ALT levels, and liver fibrosis progressed in 3 patients. Corticosteroids given alone in 6 patients induced a significant decrease in ALT, IgG, and AP levels, but none had a biochemical normalization. The patients with persistently abnormal liver tests under either UDCA or corticosteroids received both UDCA and corticosteroids. A further marked biochemical improvement was observed, and all patients became asymptomatic. We conclude that, in patients with PBC: 1) overlap syndrome with AIH is not rare; 2) flares of AIH may occur either spontaneously or under UDCA; and 3) combination of UDCA and corticosteroids is required in most patients to obtain a complete biochemical response. Overlap syndrome may represent an important and unrecognized cause of resistance to UDCA in patients with PBC.

The aim of this study was to assess the incidence of decompensation (ascites, jaundice, variceal bleeding, and encephalopathy), hepatocellular carcinoma (HCC) and death or liver transplantation in patients with compensated hepatitis C virus (HCV)-related cirrhosis, taking into account the viral genotype and interferon (IFN) therapy. Between 1989 and 1994, 668 patients with no clinical evidence of decompensation were referred to our department for liver biopsy because of positivity for anti-HCV antibodies and elevated aminotransferase activity; 103 of these patients had cirrhosis. The median follow-up was 40 months. Fifty-nine patients were treated with IFN for a mean duration of 11 ± 6 months; 3 (5%) had a prolonged biochemical and virological response. Baseline characteristics of IFN-treated and untreated patients were not significantly different. HCV genotypes (InnoLiPa) were predominantly 1b (48%) and 3a (20%). During follow-up, complications of cirrhosis occurred in 26 patients, HCC in 11 patients, and decompensation not related to HCC in 19 patients. Sixteen patients died, 94% of liver disease. Three patients were transplanted for liver failure. The 4-year risk of HCC was 11.5% (annual incidence 3.3%) and that of decompensation was 20%. Survival probability was 96% and 84% at 2 and 4 years, respectively. In multivariate analysis, the absence of IFN therapy was the only independent factor predictive both for HCC and decompensation. A low albumin level at entry and the absence of IFN therapy were the two independent factors predictive of death or liver transplantation. Probability of survival at 2 and 4 years was significantly different between IFN-treated and untreated patients (respectively 97% and 92% vs 95% and 63%,P< .0001). In conclusion, in patients with compensated HCV-related cirrhosis: 1) complications of cirrhosis are frequent, whatever the viral genotype; and 2) the severity of cirrhosis and the absence of IFN therapy are independently predictive of bad outcome

In a cohort of 483 blood donors positive for antibody to hepatitis C virus on second-generation enzyme-linked immunosorbent, the confirmatory second-generation recombinant immunoblot assay (Ortho Diagnostic Systems) was positive in 172 cases (36%), indeterminate in 113 (23%), and negative in 198 (41%). We further studied 94 of the donors (recombinant immunoblot assay positive in 85, indeterminate in 6, and negative in 3). Alanine transaminase (ALT) activity, assayed on three occasions, was elevated in at least one assay in 85% of the 85 recombinant immunoblot assay-positive donors. Liver disease was present in 95% of these patients (chronic persistent hepatitis, 35%; chronic active hepatitis, 53%; cirrhosis, 7%). Ten of the 13 recombinant immunoblot assay-positive donors with normal ALT activity had liver disease; polymerase chain reaction testing for viral RNA was predictive of liver disease in most cases. Donors with cirrhosis differed significantly from cirrhosis-free donors in terms of age, sex ratio, ALT activity, and excessive alcohol consumption. Three of the 6 recombinant immunoblot assay-indeterminate donors (isolated C 22) who underwent histological examination had elevated ALT activity and liver disease. The 3 recombinant immunoblot assay-negative donors evaluated were free of liver disease. This study shows that anti-HCV second-generation enzyme-linked immunosorbent positivity is confirmed in fewer than 40% of blood donors by the second-generation recombinant immunoblot assay, and that liver disease is present in 95% of recombinant immunoblot assay-positive donors. Recombinant immunoblot assay positivity combined with viremia is frequently associated with the existence of liver disease, regardless of transaminase activity. Excessive alcohol consumption may be an important factor in the onset of cirrhosis in anti-HCV-positive blood donors.

Studies of blood donors positive for antibody to hepatitis C virus on enzyme-linked immunosorbent assay are probably biased by the large number of false-positive results. We evaluated the epidemiological and biological characteristics of 177 such donors with regard to the confirmatory secondgeneration RIBA test (Ortho Diagnostic Systems) and have compared the results to those from an age- and sex-matched control group of 177 donors negative for antibody to hepatitis C virus on enzyme-linked immunosorbent assay. Second-generation recombinant immunoblot assay was positive in 38% of cases, indeterminate in 6% and negative in 56%. The case-control study showed a significantly higher frequency of intravenous drug abuse (27% vs. 0%), blood transfusion (22% vs. 9%), history of jaundice (21% vs. 7%), elevated ALT level (49% vs. 4%) and HBc antibody positivity (32% vs. 7%) in second-generation recombinant immunoblot assay–positive donors. No such differences were found between the second-generation recombinant immunoblot assay–negative donors and their controls. The 35 second-generation recombinant immunoblot assay–positive donors without histories of transfusion or intravenous drug abuse had a significantly higher frequency of surgery with major blood loss or prolonged stays in areas of hepatitis B virus endemicity than did their controls (20% vs. 0% and 49% vs. 26%, respectively). In conclusion, at least one risk factor for HCV infection was identified in 82% of the secondgeneration recombinant immunoblot assay–positive donors, 91% of whom could have been identified on the basis of these risk factors, ALT level and presence of HBc antibody. (HEPATOLOGY 1993;17:183–187.)