Molecular epidemiology in HCV-related hepatocellular carcinoma: first steps.
J Hepatol. 2012 Jan 23;
Authors: Villanueva A, Forns X, Llovet JM
Abstract
Chronic viral hepatitis is the most important risk factor for progression to hepatocellular carcinoma (HCC). To identify genetic risk factors for progression to HCC in individuals with chronic hepatitis C virus (HCV), we analyzed 467,538 SNPs in 212 Japanese individuals with chronic HCV with HCC and 765 individuals with chronic HCV without HCC. We identified one intronic SNP in the DEPDC5 locus on chromosome 22 associated with HCC risk and confirmed the association using an independent case-control population (710 cases and 1,625 controls). The association was highly significant when we analyzed the stages separately as well as together (rs1012068, P(combined) = 1.27 × 10(-13), odds ratio = 1.75). The significance level of the association further increased after adjustment for gender, age and platelet count (P = 1.35 × 10(-14), odds ratio = 1.96). Our findings suggest that common variants within the DEPDC5 locus affect susceptibility to HCC in Japanese individuals with chronic HCV infection.
PMID: 22282033 [PubMed - as supplied by publisher]
Prevention of Acute Kidney Injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.
J Hepatol. 2012 Jan 17;
Authors: Shah N, Dhar D, Mohammed F, Habtesion A, Davies NA, Jover-Cobos M, Macnaughtan J, Sharma V, Oldedamink S, Mookerjee RP, Jalan R
Abstract
BACKGROUND AND AIMS: Superimposed infection and/or inflammation precipitates renal failure in cirrhosis. This study aimed to test the hypothesis that increased gut bacterial translocation in cirrhosis primes the kidney to the effect of superimposed inflammation by upregulating expression of, toll-like receptor-4 (TLR4), NFkB and cytokines. A well-characterized bile-duct ligated (BDL) model of cirrhosis which develops renal failure following superimposed inflammatory insult with LPS was used and selective gut decontamination was performed using Norfloxacin. METHODS: Sprague-Dawley rats were studied: Sham, Sham+LPS; BDL, BDL+LPS; an additional BDL and BDL+LPS groups were selectively decontaminated with Norfloxacin. Plasma biochemistry, plasma renin activity (PRA) and cytokines and, protein expression of TLR4, NFkB and cytokines were measured in the kidney homogenate. The kidneys were stained for TLR4, TLR2, and caspase-3. Endotoxemia was measured using neutrophil burst and LAL assays. RESULTS: The groups treated with Norfloxacin showed significant attenuation in the increase in plasma creatinine, plasma and renal TNFa and renal tubular injury on histology. The increased renal protein expression of TLR4, NFkB and caspase-3 in the untreated animals was significantly attenuated in the Norfloxacin treated animals. PRA was reduced in the treated animals and severity of endotoxemia was reduced. CONCLUSIONS: The results show for the first time that the kidneys in cirrhosis show an increased expression of TLR4, NFkB and the pro-inflammatory cytokine, TNFa which makes them susceptible to a further inflammatory insult. This increased susceptibility to LPS can be prevented with selective decontamination, providing novel insights into the pathophysiology of renal failure in cirrhosis.
PMID: 22266601 [PubMed - as supplied by publisher]
Efficacy of non-selective β-blockers as adjunct to endoscopic prophylactic treatment for gastric variceal bleeding: A randomized controlled trial.
J Hepatol. 2012 Jan 17;
Authors: Hung HH, Chang CJ, Hou MC, Liao WC, Chan CC, Huang HC, Lin HC, Lee FY, Lee SD
Abstract
BACKGROUND AND AIMS: Gastric variceal obturation (GVO) therapy is the current treatment of choice for gastric variceal bleeding (GVB). However, the efficacy of non-selective ß-blockers (NSBB) in the secondary prevention of GVB is still debatable. This study aimed to evaluate the efficacy of additional NSBB to repeated GVO in the secondary prevention of GVB. METHODS: From April 2007 to March 2011, 95 patients with GVB after primary hemostasis using GVO were enrolled. Repeated GVO were performed until GV eradication. Forty-eight and 47 patients were randomized into the GVO alone group (Group A) and the GVO+NSBB group (Group B), respectively. Primary outcomes in terms of re-bleeding and overall survival were analyzed by multivariate analysis. RESULTS: After a mean follow-up of 18.10 months in group A, 26 patients bled and 20 died. In group B, 22 patients bled and 22 died after a mean follow-up of 20.29 months. The overall re-bleeding and survival rates analyzed by the Kaplan-Meier method were not different between the two groups (p=0.336 and 0.936, respectively). The model of end-stage liver disease (MELD) score and main portal vein thrombosis (MPT) were independent determinants of re-bleeding while MPT and re-bleeding were independent factors of mortality by time-dependent Cox-regression model. Asthenia was the most common adverse event and was higher in group B (p<0.001). CONCLUSION: Adding NSBB therapy to repeated GVO provides no benefit for the secondary prevention of bleeding and mortality in patients with GVB.
PMID: 22266602 [PubMed - as supplied by publisher]
A Randomized Trial of 48 versus 24 Weeks of Combination Pegylated Interferon and Ribavirin Therapy in Genotype 6 Chronic Hepatitis C.
J Hepatol. 2012 Jan 17;
Authors: Thu Thuy PT, Bunchorntavakul C, Tan Dat H, Rajender Reddy K
Abstract
BACKGROUND AND AIMS: Genotype 6 chronic hepatitis C is encountered predominantly in Southeast Asia and data on optimal treatment strategy is limited. This study was aimed to assess the rate and predictors of sustained virological response (SVR) in genotype 6 chronic HCV following 48 and 24 weeks of pegylated interferon and ribavirin therapy. METHODS: This investigator-initiated, open-label randomized trial was conducted in Vietnam between 2008 and 2010. One hundred and five treatment-naïve HCV genotype 6 patients were randomized to either 48-week (N=70) or 24-week (N=35) duration of pegylated interferon (PEG-IFN) alfa-2a 180 mcg/week and ribavirin (RBV) 15 mg/kg/day; 92 patients completed the study (63 in 48-week and 29 in 24-week group). Primary outcome was sustained virological response (SVR) as intention-to-treat analysis. RESULTS: There was no statistical difference in SVR between 48-week and 24-week treated groups (71% vs. 60%, respectively; p=0.24). In the 48-week and 24-week treatment groups, 81% and 80% achieved rapid virological response (RVR) (p=0.86) and 86% and 80% achieved complete early virological response (p=0.45). Among those with RVR, SVR was in 86% (48-weeks) and 75% (24-weeks), whereas following non-RVR, only 8% had an SVR with 48-week treatment duration. CONCLUSION: Overall, RVR was achieved in the majority of genotype 6 patients and, in them, similar and high rates of SVR were noted following 24 weeks and 48 weeks therapy. This observation however needs validation in a larger study to demonstrate non-inferiority of the shorter duration therapy. In non-RVR patients, even 48 weeks therapy achieved low SVR rates.
PMID: 22266603 [PubMed - as supplied by publisher]
Molecular forms of HMGB1 and Keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity.
J Hepatol. 2012 Jan 17;
Authors: Antoine DJ, Jenkins RE, Dear JW, Williams DP, McGill MR, Sharpe MR, Craig DG, Simpson KJ, Jaeschke H, Kevin Park B
Abstract
BACKGROUND & AIMS: Full length keratin-18 (FL-K18) and High Mobility Group Box-1 (HMGB1) represent circulating indicators of necrosis during acetaminophen (APAP) hepatotoxicity in vivo. In addition, the caspase-cleaved fragment of K18 (cK18) and hyper-acetylated HMGB1 represent serum indicators of apoptosis and immune cell activation respectively. The study aim was to assess their mechanistic utility to establish the balance between apoptosis, necrosis and immune cell activation throughout the time course of clinical APAP hepatotoxicity. METHODS: HMGB1 (total, acetylated) and K18 (apoptotic, necrotic) were identified and quantified by novel LC-MS/MS assays in APAP overdose patients (n=78). RESULTS: HMGB1 (total; 15.4±1.9ng/ml, p<0.01, acetylated; 5.4±2.6ng/ml, p<0.001), cK18 (5649.8±721.0U/l, p<0.01) and FL-K18 (54770.2±6717.0U/l, p<0.005) were elevated in the sera of APAP overdose patients with liver injury compared to overdose patients without liver injury and healthy volunteers. HMGB1 and FL-K18 correlated with alanine aminotransferase (ALT) activity (R(2)=0.60 and 0.58 respectively, p<0.0001) and prothrombin time (R(2)=0.62 and 0.71 respectively, p<0.0001). Increased total and acetylated HMGB1 and FL-K18 were associated with worse prognosis (King’s College Criteria) or patients that died/required liver transplant compared to spontaneous survivors (all p<0.05-0.001), a finding not reflected by ALT and supported by ROC analysis. Acetylated HMGB1 was a better predictor of outcome than the other markers of cell death. CONCLUSION: K18 and HMGB1 represent blood-based tools to investigate the cell death balance clinical APAP hepatotoxicity. Activation of the immune response was seen later in the time course as shown by the distinct profile of acetylated HMGB1 and was associated with worse outcome.
PMID: 22266604 [PubMed - as supplied by publisher]
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