Presence of precore and core promoter mutants limits the probability of response to peginterferon in HBeAg-positive chronic hepatitis B.
Hepatology. 2012 Feb 6;
Authors: Sonneveld MJ, Rijckborst V, Zeuzem S, Heathcote EJ, Simon K, Senturk H, Pas SD, Hansen BE, Janssen HL
Abstract
Peginterferon (PEG-IFN) treatment of HBeAg-positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of HBV DNA and HBsAg from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG-IFN treatment affects serological and virological response. A total of 214 HBeAg-positive CHB patients treated with PEG-IFN±lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non-WT (detectable mutants at PC/BCP) by line-probe assay. Response was assessed at 6 months post-treatment and through long-term follow-up(LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg and HBsAg levels than patients with non-WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA<10,000 copies/mL (response, 34 versus 11%,p<0.001) and HBsAg clearance (18 versus 2%,p<0.001) at week 78 than non-WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non-WT patients,p<0.001 for both). Presence of WT virus at baseline was an independent predictor of response (OR 2.90, 95%CI:1.15-7.31,p=0.023) and HBsAg clearance (OR 5.58, 95%CI:1.26-24.63,p=0.013) and patients with non-A genotypes with detectable mutants had a low probability of response. CONCLUSION: Presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG-IFN for HBeAg-positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG-IFN therapy. (HEPATOLOGY 2012.).
PMID: 22307831 [PubMed - as supplied by publisher]
Inter-strain differences in liver injury and one-carbon metabolism in alcohol-fed mice.
Hepatology. 2012 Feb 6;
Authors: Tsuchiya M, Ji C, Kosyk O, Shymonyak S, Melnyk S, Kono H, Tryndyak V, Muskhelishvili L, Pogribny IP, Kaplowitz N, Rusyn I
Abstract
Alcoholic liver injury is a major public health issue worldwide. Even though the major mechanisms of this disease have been established over the past decades, little is known about genetic susceptibility factors that may predispose individuals who abuse alcoholic beverages to liver damage and subsequent pathological conditions. We hypothesized that a panel of genetically diverse mouse strains may be used to examine the role of ER stress and one-carbon metabolism in the mechanism of inter-individual variability in alcoholic liver injury. We administered alcohol (up to 27 mg/kg/d) in high fat diet using intragastric intubation model for 28 days to male mice from 14 inbred strains (129S1/SvImJ, AKR/J, BALB/cJ, BALB/cByJ, BTBR T+tf/J, C3H/HeJ, C57BL/10J, DBA/2J, FVB/NJ, KK/HIJ, MOLF/EiJ, NZW/LacJ, PWD/PhJ, and WSB/EiJ). Profound inter-strain differences (more than 3-fold) in alcohol-induced steatohepatitis were observed among the strains in spite of consistently high levels of urine alcohol that was monitored throughout the study. We found that endoplasmic reticulum stress genes were induced only in strains with the highest liver injury. Liver glutathione and methyl donor levels were affected in all strains, albeit to a different degree. Most pronounced effects that were closely associated with the degree of liver injury were hyperhomocysteinemia and strain-dependent differences in expression patterns of one-carbon metabolism-related genes. CONCLUSION: Our data demonstrate that strain differences in alcohol-induced liver injury and steatosis are striking and independent of alcohol exposure and the most severely affected strains exhibit major differences in the expression of ER stress markers and genes of one-carbon metabolism. (HEPATOLOGY 2012.).
PMID: 22307928 [PubMed - as supplied by publisher]
Predictors of pre-transplant dropout and post-transplant recurrence in patients with perihilar cholangiocarcinoma.
Hepatology. 2012 Jan 30;
Authors: Murad SD, Ray Kim W, Therneau T, Gores GJ, Rosen CB, Martenson JA, Alberts SR, Heimbach JK
Abstract
We have previously reported excellent outcomes with liver transplantation for selected patients with early-stage perihilar cholangiocarcinoma (CCA) following neoadjuvant chemoradiotherapy. Our aim was to identify predictors of dropout before transplantation and predictors of cancer recurrence after transplantation. We reviewed all patients with unresectable perihilar CCA treated with neoadjuvant chemoradiation in anticipation for transplantation between 1993 and 2010. Predictors were identified by uni- and multivariable Cox regression analysis of clinical variables. In total 199 patients were enrolled, of whom 62 dropped out and 131 underwent transplantation at our institution, with 6 undergoing transplantation elsewhere. Predictors of dropout were CA 19-9 ≥ 500 U/ml (HR 2.3; P=.04), mass ≥ 3 cm (HR 2.1; P=.05), malignant brushing or biopsy (HR 3.6; P=.001) and MELD score ≥ 20 (HR 3.5; P=.02). Post-transplant, recurrence-free 5-year survival was 68%. Predictors of recurrence were elevated CA 19-9 (HR 1.8; P=.01), portal vein encasement (HR 3.3; P=.007) and residual tumor on explant (HR 9.8; P<.001). PSC, age, history of cholecystectomy and waiting time were not independent predictors. Conclusion: Outcome following neoadjuvant chemoradiation and liver transplantation for perihilar CCA is excellent. Risk of dropout is related to patient and tumor characteristics and this can be used to guide patient counseling prior to enrolment. Recurrence risk is mostly associated with presence of residual cancer on explant. PSC patients do not have an independent survival advantage over de-novo patients, but present with more favorable tumor characteristics. (HEPATOLOGY 2012.).
PMID: 22290335 [PubMed - as supplied by publisher]
Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease. , can develop into cirrhosis, hepatic failure, and hepatocellular carcinoma. While several metabolic pathways are disrupted, the mechanism of NASH development remains unclear. While several metabolic pathways are disrupted and endogenous metabolites may change in NASH, alterations in serum metabolites during NASH development remain unclear. To gain insight into disease mechanism, Serum metabolite changes were assessed using metabolomics with ultra-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry and a conventional mouse NASH model induced by a methionine- and choline-deficient (MCD) diet. Significant decreases in serum palmitoyl-, stearoyl-, and oleoyl-lysophosphatidylcholine (LPC) and marked increases in tauro-β-muricholate, taurocholate, and 12-hydroxyeicosatetraenoic acid (12-HETE) were detected in mice with NASH. In agreement with these metabolite changes, hepatic mRNAs encoding enzymes and proteins involved in LPC degradation [lysophosphatidylcholine acyltransferase (Lpcat) 1-4], basolateral bile acid excretion [ATP-binding cassette sub-family C member (Abcc) 1/4/5 and organic solute transporter β], and 12-HETE synthesis (arachidonate 12-lipoxygenase) were significantly up-regulated. In contrast, the expression of sodium/taurocholate transport protein (Slc10a1) and solute carrier organic anion transporter family member (Slco) 1a1 and 1b2, responsible for transporting bile acids into hepatocytes, were markedly suppressed. Supplementation of methionine to the MCD diet revealed that the changes in serum metabolites and the related gene expression were derived from steatohepatitis, but not dietary choline deficiency or steatosis. Furthermore, Tumor necrosis factor-α and transforming growth factor-β1 induced the expression of Lpcat2/4 and Abcc1/4 and down-regulated Slc10a1 and Slco1a1 in primary hepatocytes, suggesting an association between the changes in serum LPC and bile acids and pro-inflammatory cytokines. Finally, induction of hepatitis to ob/ob mice by D-galactosamine injection led to similar changes in serum metabolites and the related gene expression. Conclusion: Phospholipid and bile acid metabolism is disrupted in NASH, likely due to enhanced hepatic inflammatory signaling. Serum LPC and bile acids may be biomarkers of NASH. (HEPATOLOGY 2012.).
PMID: 22290395 [PubMed - as supplied by publisher]
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