Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations

James E. Nelson, Elizabeth M. Brunt, Kris V. Kowdley, Stephanie H. Abrams, Leanel Angeli Fairly, Arthur J. McCullough, Patricia Brandt, Diane Bringman, Srinivasan Dasarathy, Jaividhya Dasarathy, Carol Hawkins, Yao Chang Liu, Nicholette Rogers, Margaret Stager, Judy Whitwell, Mangesh Pagadala, Ruth Sargent, Lisa Yerian, Claudia Zein, Raphael MerrimanAnthony Nguyen, Parvathi Mohan, Kavita Nair, Stephanie DeVore, Rohit Kohli, Kathleen Lake, Stavra Xanthakos, Yohaime Cosme, Joel E. Lavine, Ali Mencin, Nadia Ovchinsky, Manal F. Abdelmalek, Stephanie Buie, Anna Mae Diehl, Marcia Gottfried, Cynthia Guy, Meryt Hanna, Christopher Kigongo, Paul Killenberg, Samantha Kwan, Yi Ping Pan, Dawn Piercy, Melissa Smith, Savita Srivastava, Elizabeth Byam, Naga Chalasani, Oscar W. Cummings, Marwan Ghabril, Ann Klipsch, Jean P. Molleston, Linda Ragozzino, Girish Subbarao, Sweta Tandra, Raj Vuppalanchi, Caroline Devadason, Kimberly Pfeifer, Ann Scheimann, Michael Torbenson, Nanda Kerkar, Sreevidya Narayanappa, Frederick Suchy, Katherine Dunne, Mark H. Fishbein, Katie Jacques, Ann Quinn, Cindy Riazi, Peter F. Whitington, Sarah Barlow, Jose Derdoy, Debra King, Andrea Morris, Joan Siegner, Susan Stewart, Brent A. Neuschwander-Tetri, Judy Thompson, Cynthia Behling, Jennifer Collins, Janis Durelle, Tarek Hassanein, Rohit Loomba, Anya Morgan, Steven Rose, Heather Patton, Jeffrey B. Schwimmer, Claude Sirlin, Tanya Stein, Bradley Aouizerat, Kiran Bambha, Marissa Bass, Nathan M. Bass, Linda D. Ferrell, Danuta Filipowski, Shannon Fleck, Bilal Hameed, Camille Langlois, Mark Pabst, Monique Rosenthal, Philip Rosenthal, Tessa Steel, Melissa Coffey, Sarah Galdzicka, Karen Murray, Matthew Yeh, Sherry Boyett, Melissa J. Contos, Michael Fuchs, Amy Jones, Velimir A.C. Luketic, Puneet Puri, Bimalijit Sandhu, Arun J. Sanyal, Carol Sargeant, Kimberly Noble, Melanie White, Sarah Ackermann, Jane Park, Tracey Pierce, Jody Mooney, Cheryl Shaw, Alice Stead, Chia Wang, David E. Kleiner, Gilman D. Grave, Edward C. Doo, Jay H. Hoofnagle, Patricia R. Robuck, Averell Sherker, Patricia Belt, Frederick L. Brancati, Jeanne M. Clark, Ryan Colvin, Michele Donithan, Mika Green, Rosemary Hollick, Milana Isaacson, Wana K. Jin, Alison Lydecker, Pamela Mann, Kevin P. May, Laura Miriel, Alice Sternberg, James Tonascia, Aynur Ünalp-Arida, Mark Van Natta, Ivana Vaughn, Laura Wilson, Katherine Yates

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Hepcidin regulation is linked to both iron and inflammatory signals and may influence iron loading in nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the relationships among HFE genotype, serum hepcidin level, hepatic iron deposition, and histology in nonalcoholic fatty liver disease (NAFLD). Single-nucleotide polymorphism genotyping for C282Y (rs1800562) and H63D (rs1799945) HFE mutations was performed in 786 adult subjects in the NASH Clinical Research Network (CRN). Clinical, histologic, and laboratory data were compared using nonparametric statistics and multivariate logistic regression. NAFLD patients with C282Y, but not H63D mutations, had lower median serum hepcidin levels (57 versus 65 ng/mL; P = 0.01) and higher mean hepatocellular (HC) iron grades (0.59 versus 0.28; P < 0.001), compared to wild-type (WT) subjects. Subjects with hepatic iron deposition had higher serum hepcidin levels than subjects without iron for all HFE genotypes (P < 0.0001). Hepcidin levels were highest among patients with mixed HC/reticuloendothelial system cell (RES) iron deposition. H63D mutations were associated with higher steatosis grades and NAFLD activity scores (odds ratio [OR], ≥1.4; 95% confidence interval [CI]: >1.0, ≤2.5; P ≤ 0.041), compared to WT, but not with either HC or RES iron. NAFLD patients with C282Y mutations had less ballooning or NASH (OR, ≤0.62; 95% CI: >0.39, <0.94; P ≤ 0.024), compared to WT subjects. Conclusions: The presence of C282Y mutations in patients with NAFLD is associated with greater HC iron deposition and decreased serum hepcidin levels, and there is a positive relationship between hepatic iron stores and serum hepcidin level across all HFE genotypes. These data suggest that body iron stores are the major determinant of hepcidin regulation in NAFLD, regardless of HFE genotype. A potential role for H63D mutations in NAFLD pathogenesis is possible through iron-independent mechanisms.

Original languageEnglish (US)
Pages (from-to)1730-1740
Number of pages11
JournalHepatology
Volume56
Issue number5
DOIs
StatePublished - Nov 1 2012

ASJC Scopus subject areas

  • Hepatology

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    Nelson, J. E., Brunt, E. M., Kowdley, K. V., Abrams, S. H., Fairly, L. A., McCullough, A. J., Brandt, P., Bringman, D., Dasarathy, S., Dasarathy, J., Hawkins, C., Liu, Y. C., Rogers, N., Stager, M., Whitwell, J., Pagadala, M., Sargent, R., Yerian, L., Zein, C., ... Yates, K. (2012). Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations. Hepatology, 56(5), 1730-1740. https://doi.org/10.1002/hep.25856