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; Arthur J. McCullough; Srinivasan Dasarathy; Mangesh Pagadala; Ruth Sargent; Lisa Yerian; Claudia Zein; Raphael Merriman; Anthony 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; Joel E. Lavine; 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; Kris V. Kowdley; Jane Park; Tracey Pierce; Jody Mooney; James Nelson; Cheryl Shaw; Alice Stead; Chia Wang; Elizabeth M. Brunt; 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

doi:10.1002/hep.25856

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, Arthur J. McCullough, Srinivasan Dasarathy, Mangesh Pagadala, Ruth Sargent, Lisa YerianClaudia Zein, Raphael Merriman, Anthony 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, Joel E. Lavine, 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, Kris V. Kowdley, Jane Park, Tracey Pierce, Jody Mooney, James Nelson, Cheryl Shaw, Alice Stead, Chia Wang, Elizabeth M. Brunt, 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 journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	1730-1740
Number of pages	11
Journal	Hepatology
Volume	56
Issue number	5
DOIs	https://doi.org/10.1002/hep.25856
State	Published - Nov 1 2012

ASJC Scopus subject areas

Hepatology

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10.1002/hep.25856

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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., McCullough, A. J., Dasarathy, S., Pagadala, M., Sargent, R., ... 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

Nelson, JE, Brunt, EM, Kowdley, KV, Abrams, SH, Fairly, LA, McCullough, AJ, Brandt, P, Bringman, D, Dasarathy, S, Dasarathy, J, Hawkins, C, Liu, YC, Rogers, N, Stager, M, Whitwell, J, McCullough, AJ, Dasarathy, S, Pagadala, M, Sargent, R, Yerian, L, Zein, C, Merriman, R, Nguyen, A, Mohan, P, Nair, K, DeVore, S, Kohli, R, Lake, K, Xanthakos, S, Cosme, Y, Lavine, JE, Mencin, A, Ovchinsky, N, Abdelmalek, MF, Buie, S, Diehl, AM, Gottfried, M, Guy, C, Hanna, M, Kigongo, C, Killenberg, P, Kwan, S, Pan, YP, Piercy, D, Smith, M, Srivastava, S, Byam, E, Chalasani, N, Cummings, OW, Ghabril, M, Klipsch, A, Molleston, JP, Ragozzino, L, Subbarao, G, Tandra, S, Vuppalanchi, R, Devadason, C, Pfeifer, K, Scheimann, A, Torbenson, M, Kerkar, N, Narayanappa, S, Suchy, F, Dunne, K, Fishbein, MH, Jacques, K, Quinn, A, Riazi, C, Whitington, PF, Barlow, S, Derdoy, J, King, D, Morris, A, Siegner, J, Stewart, S, Neuschwander-Tetri, BA, Thompson, J, Behling, C, Collins, J, Durelle, J, Hassanein, T, Lavine, JE, Loomba, R, Morgan, A, Rose, S, Patton, H, Schwimmer, JB, Sirlin, C, Stein, T, Aouizerat, B, Bambha, K, Bass, M, Bass, NM, Ferrell, LD, Filipowski, D, Fleck, S, Hameed, B, Langlois, C, Pabst, M, Rosenthal, M, Rosenthal, P, Steel, T, Coffey, M, Galdzicka, S, Murray, K, Yeh, M, Boyett, S, Contos, MJ, Fuchs, M, Jones, A, Luketic, VAC, Puri, P, Sandhu, B, Sanyal, AJ, Sargeant, C, Noble, K, White, M, Ackermann, S, Kowdley, KV, Park, J, Pierce, T, Mooney, J, Nelson, J, Shaw, C, Stead, A, Wang, C, Brunt, EM, Kleiner, DE, Grave, GD, Doo, EC, Hoofnagle, JH, Robuck, PR, Sherker, A, Belt, P, Brancati, FL, Clark, JM, Colvin, R, Donithan, M, Green, M, Hollick, R, Isaacson, M, Jin, WK, Lydecker, A, Mann, P, May, KP, Miriel, L, Sternberg, A, Tonascia, J, Ünalp-Arida, A, Van Natta, M, Vaughn, I, Wilson, L & Yates, K 2012, 'Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations', Hepatology, vol. 56, no. 5, pp. 1730-1740. https://doi.org/10.1002/hep.25856

@article{a917c7b9de4c45b987a440ae98ec56a0,

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

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.",

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

year = "2012",

month = nov,

day = "1",

doi = "10.1002/hep.25856",

language = "English (US)",

volume = "56",

pages = "1730--1740",

journal = "Hepatology",

issn = "0270-9139",

publisher = "John Wiley and Sons Ltd",

number = "5",

}

TY - JOUR

T1 - Lower serum hepcidin and greater parenchymal iron in nonalcoholic fatty liver disease patients with C282Y HFE mutations

AU - Nelson, James E.

AU - Brunt, Elizabeth M.

AU - Kowdley, Kris V.

AU - Abrams, Stephanie H.

AU - Fairly, Leanel Angeli

AU - McCullough, Arthur J.

AU - Brandt, Patricia

AU - Bringman, Diane

AU - Dasarathy, Srinivasan

AU - Dasarathy, Jaividhya

AU - Hawkins, Carol

AU - Liu, Yao Chang

AU - Rogers, Nicholette

AU - Stager, Margaret

AU - Whitwell, Judy

AU - McCullough, Arthur J.

AU - Dasarathy, Srinivasan

AU - Pagadala, Mangesh

AU - Sargent, Ruth

AU - Yerian, Lisa

AU - Zein, Claudia

AU - Merriman, Raphael

AU - Nguyen, Anthony

AU - Mohan, Parvathi

AU - Nair, Kavita

AU - DeVore, Stephanie

AU - Kohli, Rohit

AU - Lake, Kathleen

AU - Xanthakos, Stavra

AU - Cosme, Yohaime

AU - Lavine, Joel E.

AU - Mencin, Ali

AU - Ovchinsky, Nadia

AU - Abdelmalek, Manal F.

AU - Buie, Stephanie

AU - Diehl, Anna Mae

AU - Gottfried, Marcia

AU - Guy, Cynthia

AU - Hanna, Meryt

AU - Kigongo, Christopher

AU - Killenberg, Paul

AU - Kwan, Samantha

AU - Pan, Yi Ping

AU - Piercy, Dawn

AU - Smith, Melissa

AU - Srivastava, Savita

AU - Byam, Elizabeth

AU - Chalasani, Naga

AU - Cummings, Oscar W.

AU - Ghabril, Marwan

AU - Klipsch, Ann

AU - Molleston, Jean P.

AU - Ragozzino, Linda

AU - Subbarao, Girish

AU - Tandra, Sweta

AU - Vuppalanchi, Raj

AU - Devadason, Caroline

AU - Pfeifer, Kimberly

AU - Scheimann, Ann

AU - Torbenson, Michael

AU - Kerkar, Nanda

AU - Narayanappa, Sreevidya

AU - Suchy, Frederick

AU - Dunne, Katherine

AU - Fishbein, Mark H.

AU - Jacques, Katie

AU - Quinn, Ann

AU - Riazi, Cindy

AU - Whitington, Peter F.

AU - Barlow, Sarah

AU - Derdoy, Jose

AU - King, Debra

AU - Morris, Andrea

AU - Siegner, Joan

AU - Stewart, Susan

AU - Neuschwander-Tetri, Brent A.

AU - Thompson, Judy

AU - Behling, Cynthia

AU - Collins, Jennifer

AU - Durelle, Janis

AU - Hassanein, Tarek

AU - Lavine, Joel E.

AU - Loomba, Rohit

AU - Morgan, Anya

AU - Rose, Steven

AU - Patton, Heather

AU - Schwimmer, Jeffrey B.

AU - Sirlin, Claude

AU - Stein, Tanya

AU - Aouizerat, Bradley

AU - Bambha, Kiran

AU - Bass, Marissa

AU - Bass, Nathan M.

AU - Ferrell, Linda D.

AU - Filipowski, Danuta

AU - Fleck, Shannon

AU - Hameed, Bilal

AU - Langlois, Camille

AU - Pabst, Mark

AU - Rosenthal, Monique

AU - Rosenthal, Philip

AU - Steel, Tessa

AU - Coffey, Melissa

AU - Galdzicka, Sarah

AU - Murray, Karen

AU - Yeh, Matthew

AU - Boyett, Sherry

AU - Contos, Melissa J.

AU - Fuchs, Michael

AU - Jones, Amy

AU - Luketic, Velimir A.C.

AU - Puri, Puneet

AU - Sandhu, Bimalijit

AU - Sanyal, Arun J.

AU - Sargeant, Carol

AU - Noble, Kimberly

AU - White, Melanie

AU - Ackermann, Sarah

AU - Kowdley, Kris V.

AU - Park, Jane

AU - Pierce, Tracey

AU - Mooney, Jody

AU - Nelson, James

AU - Shaw, Cheryl

AU - Stead, Alice

AU - Wang, Chia

AU - Brunt, Elizabeth M.

AU - Kleiner, David E.

AU - Grave, Gilman D.

AU - Doo, Edward C.

AU - Hoofnagle, Jay H.

AU - Robuck, Patricia R.

AU - Sherker, Averell

AU - Belt, Patricia

AU - Brancati, Frederick L.

AU - Clark, Jeanne M.

AU - Colvin, Ryan

AU - Donithan, Michele

AU - Green, Mika

AU - Hollick, Rosemary

AU - Isaacson, Milana

AU - Jin, Wana K.

AU - Lydecker, Alison

AU - Mann, Pamela

AU - May, Kevin P.

AU - Miriel, Laura

AU - Sternberg, Alice

AU - Tonascia, James

AU - Ünalp-Arida, Aynur

AU - Van Natta, Mark

AU - Vaughn, Ivana

AU - Wilson, Laura

AU - Yates, Katherine

PY - 2012/11/1

Y1 - 2012/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84868213438&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868213438&partnerID=8YFLogxK

U2 - 10.1002/hep.25856

DO - 10.1002/hep.25856

M3 - Article

C2 - 22611049

AN - SCOPUS:84868213438

SN - 0270-9139

VL - 56

SP - 1730

EP - 1740

JO - Hepatology

JF - Hepatology

IS - 5

ER -

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

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