Haptoglobin 2 Allele is Associated With Histologic Response to Vitamin E in Subjects With Nonalcoholic Steatohepatitis

Background: Haptoglobin (Hp) genotype has been linked to oxidative stress and response to vitamin E (VitE) in patients with dyslipidemia. Its effect on histological response to VitE in nonalcoholic steatohepatitis (NASH) is unknown. Goals: Our objective was to determine if Hp genotype associates with response to VitE in patients with NASH. Study: A post hoc analysis of 228 patients receiving VitE or placebo in two clinical trials was performed. Regression analysis was used to assess the effect of VitE versus placebo, by Hp genotype (1–1, 2–1, or 2–2), on histologic features and laboratory markers of liver disease, comparing baseline to end of treatment values. An interaction term was included in the regression models to assess differential treatment effect across Hp genotype. Results: Hp 2–2 patients treated with VitE versus placebo showed significant histologic improvement (51% versus 20%, OR=4·2, p=0·006), resolution of steatohepatitis (44% versus 12%, OR=6.2, p=0·009), decrease in NAFLD Activity Score (NAS) (−2·2 versus −0·6, p=0·001), and decrease in liver enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and γ-glutamyl transpeptidase. Hp 2–1 patients on VitE versus placebo showed improved resolution of steatohepatitis, NAS and liver enzymes. Hp 1–1 patients showed no significant improvement in histology or liver enzymes. VitE had no effect on fibrosis stage in any group. Regression analysis showed incremental benefit of having Hp 2–2 or 2–1 versus 1–1 for all liver enzymes. Conclusion: Hp 2 allele is associated with greater histological and biological improvement in NASH with VitE treatment compared to the Hp 1 allele

The use of cell free DNA in the diagnosis of HCC

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is associated with high mortality. The currently used methods for diagnosing HCC, including imaging modalities and liver biopsy, detect tumors at a relatively advanced stage or are invasive. Non-invasive biomarkers are urgently needed to facilitate screening and early diagnosis of HCC, as well as treatment monitoring and detection of tumor recurrence. Liquid biopsy, the analysis of blood or other body fluids to obtain genetic and epigenetic information, has historically been applied to other types of cancer including breast and prostate cancer. Over the past few decades, liquid biopsy analysis has shed significant insights on genetic and epigenetic aberrations in HCC detectable in peripheral blood. Aberrations in nucleic acids found circulating freely in body fluids or contained within extracellular vesicles such as exosomes or microvesicles show potential clinical utility as non-invasive biomarkers. In this review, we present available literature on cell-free nucleic acids in the diagnosis of HCC

Exercise Does Not Independently Improve Histological Outcomes in Biopsy-Proven Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis

Introduction: The independent effect of exercise on liver histology in non-alcoholic fatty liver disease (NAFLD) remains unclear. As such, we conducted a systematic review and meta-analysis of the effect of exercise alone on histological endpoints in biopsy-proven NAFLD. Materials and Methods: A systematic literature search was conducted to include controlled clinical trials investigating the effect of exercise alone on liver histology in biopsy-proven NAFLD. Meta-analysis was conducted for histological outcomes with available data from a minimum of three studies. Pooled estimates of the effect of exercise on histological endpoints were calculated using random-effects models. Results: We identified three controlled clinical trials that assessed the independent effect of exercise on histological outcomes in patients with biopsy-proven NAFLD. The studies consisted of 72 total participants, including 40 subjects in the exercise intervention and 32 individuals in the comparison group. Meta-analysis showed that exercise did not significantly improve Brunt grade, NAFLD activity score, and fibrosis in NAFLD. Discussion: Exercise alone may not lead to significant histopathological improvement in NAFLD. Future well-powered randomized controlled trials are needed to better characterize the impact of exercise on histological outcomes and clinical endpoints

Brivanib attenuates hepatic fibrosis in vivo and stellate cell activation in vitro by inhibition of FGF, VEGF and PDGF signaling.

Brivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) tyrosine kinases, which are both involved in mechanisms of liver fibrosis. We hypothesized that inhibition of VEGFR and FGFR by brivanib would inhibit liver fibrosis. We therefore examined the effect of brivanib on liver fibrosis in three mouse models of fibrosis.In vivo, we induced liver fibrosis by bile duct ligation (BDL), chronic carbon tetrachloride (CCl4), and chronic thioacetamide (TAA) administration. Liver fibrosis was examined by immunohistochemistry and Western immunoblotting. In vitro, we used LX-2 human hepatic stellate cells (HSCs) to assess the effect of brivanib on stellate cell proliferation and activation.After in vivo induction with BDL, CCl4, and TAA, mice treated with brivanib showed reduced liver fibrosis and decreased expression of collagen Iα1 and α-smooth muscle actin in the liver. In vitro, brivanib decreased proliferation of HSCs induced by platelet-derived growth factor (PDGF), VEGF, and FGF. Brivanib also decreased stellate cell viability and inhibited PDGFBB-induced phosphorylation of its cognate receptor.Brivanib reduces liver fibrosis in three different animal models and decreases human hepatic stellate cell activation. Brivanib may represent a novel therapeutic approach to treatment of liver fibrosis and prevention of liver cancer