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Browsing by Author "McCullough, Arthur J."
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Item Haptoglobin 2 Allele is Associated With Histologic Response to Vitamin E in Subjects With Nonalcoholic Steatohepatitis(Wolters Kluwer, 2020-11) Banini, Bubu A.; Cazanave, Sophie C.; Yates, Katherine P.; Asgharpour, Amon; Vincent, Robert; Mirshahi, Faridoddin; Le, Peter; Contos, Melissa J.; Tonascia, James; Chalasani, Naga P.; Kowdley, Kris V.; McCullough, Arthur J.; Behling, Cynthia A.; Schwimmer, Jeffrey B.; Lavine, Joel E.; Sanyal, Arun J.; Medicine, School of MedicineBackground: 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.Item Relationship Between Three Commonly Used Non-invasive Fibrosis Biomarkers and Improvement in Fibrosis Stage in Patients With NASH(Wiley, 2019-02-21) Chalasani, Naga; Abdelmalek, Manal F.; Loomba, Rohit; Kowdley, Kris V.; McCullough, Arthur J.; Dasarathy, Srinivasan; Neuschwander-Tetri, Brent A.; Terrault, Norah; Ferguson, Beatrice; Shringarpure, Reshma; Shapiro, David; Sanyal, Arun J.; Medicine, School of MedicineNon-invasive biomarkers are needed for monitoring changes in liver histology in patients with non-alcoholic steatohepatitis (NASH). Obeticholic acid (OCA) was shown to improve fibrosis in patients with NASH in the FLINT trial; a post hoc analysis of these data was performed to determine the relationship between 3 non-invasive fibrosis markers and liver fibrosis improvement. Methods In the Phase 2b FLINT trial, patients were randomised (1:1) to receive 25 mg OCA or placebo once daily for 72 weeks. Aspartate aminotransferase:platelet ratio index (APRI), fibrosis-4 (FIB-4) index, and non-alcoholic fatty liver disease fibrosis score (NFS) were evaluated in serum at baseline and weeks 24, 48, 72, and 96. Liver biopsies were obtained at baseline and 72 weeks. Results In patients with fibrosis improvement at week 24, scores were reduced by a median of 34% for APRI, 10% for FIB-4, and 4% for NFS. Reductions in APRI (p=0.015) and FIB-4 (p=0.036), but not NFS (p=0.201) at week 24, significantly correlated with ≥1-stage improvement in histologic fibrosis at week 72. Reductions in APRI at week 72 were significantly correlated with fibrosis improvement at week 72 (p=0.012). Patients receiving OCA had significant reductions in all markers compared with patients receiving placebo at week 72 [APRI and FIB-4 (p<0.0001); NFS (p<0.05)]. Conclusions Readily available non-invasive markers may predict improvement in liver fibrosis in patients with NASH. Upon external confirmation and further refinement in larger populations, these markers may serve as surrogate end points in NASH clinical trials.