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

Banini, Bubu A. MD, PhD*; Cazanave, Sophie C. PhD*,†; Yates, Katherine P. ScM; Asgharpour, Amon MD*,§; Vincent, Robert MD, PhD*,∥; Mirshahi, Faridoddin MSc*; Le, Peter BSc*; Contos, Melissa J. MD; Tonascia, James PhD; Chalasani, Naga P. MBBS#; Kowdley, Kris V. MD**; McCullough, Arthur J. MD††; Behling, Cynthia A. MD, PhD‡‡; Schwimmer, Jeffrey B. MD§§,∥∥; Lavine, Joel E. MD, PhD¶¶; Sanyal, Arun J. MD* for the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)

doi: 10.1097/MCG.0000000000001142

Background: Haptoglobin (Hp) genotype has been linked to oxidative stress and cardiovascular outcomes in response to vitamin E (VitE) among patients with diabetes mellitus. Its effect on histologic 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 2 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 nonalcoholic fatty 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% vs. 20%; OR=4.2; P=0.006), resolution of steatohepatitis (44% vs. 12%; OR=6.2; P=0.009), decrease in nonalcoholic fatty liver disease Activity Score (NAS) (−2.2 vs. −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 enzyme.

Conclusions: Hp 2 allele is associated with greater histologic and biological improvement in NASH with VitE treatment compared with the Hp 1 allele.

*Division of Gastroenterology, Department of Internal Medicine

Division of Surgical Pathology, Department of Pathology, VCU School of Medicine, Richmond, VA

Glympse Bio, Cambridge, MA

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

§Department of Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sanai

¶¶Department of Pediatrics, Columbia University, New York, NY

Indiana Gastroenterology and Hepatology

#Division of Gastroenterology and Hepatology, Indiana Fatty Liver Disease Research Group, Indiana University School of Medicine, Indianapolis, IN

**Liver Care Network, Swedish Medical Center, Seattle, WA

††Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, OH

‡‡Department of Pathology, Sharp Health System

∥∥Department of Gastroenterology, Rady Children's Hospital San Diego, San Diego

§§Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, CA

The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, U01DK061713). Additional support is received from the National Center for Advancing Translational Sciences (NCATS) (grants UL1TR000439, UL1TR000077, UL1TR000436, UL1TR000150, UL1TR000424, UL1TR000006, UL1TR000448, UL1TR000040, UL1TR000100, UL1TR000004, UL1TR000423, UL1TR000058, UL1TR000454, UL1TR000040). Vitamin E and similar-appearing placebo used in PIVENS and TONIC were provided by Pharmavite under a Clinical Trial Agreement with the NIH but without any financial support or involvement in the writing of the trial protocol, the conduct of the trial or analysis of the results. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, and by T32 DK 7150-40 and RO1 DK 105961 from NIDDK to A.J.S.A.J.S. is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect, and Galmed. He has served as a consultant to Astra Zeneca, Nitto Denko, Enyo, Ardelyx, Conatus, Nimbus, Amarin, Salix, Tobira, Takeda, Jannsen, Gilead, Terns, Birdrock, Merck, Valeant, Boehringer-Ingelheim, Lilly, Hemoshear, Zafgen, Novartis, Novo Nordisk, Pfizer,Exhalenz, and Genfit. He has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Fractyl, Syntlogic, Affimune, Chemomab, Zydus, Nordic Bioscience, Albireo, Prosciento, Surrozen, and Bristol Myers Squibb. His institution has received grant support from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, Astra Zeneca, Malinckrodt, Cumberland, and Novartis. He receives royalties from Elsevier and UptoDate. The remaining authors declares no conflict of interest.

Address correspondence to: Arun J. Sanyal, MD and Bubu A. Banini, MD, PhD, MCV Box 980341, Richmond, VA 23298-0341 (e-mails:;;

Received May 11, 2018

Accepted September 13, 2018

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