DOI QR코드

DOI QR Code

Hepcidin Levels and Pathological Characteristics in Children with Fatty Liver Disease

  • Tsutsumi, Norito (Department of Pediatrics and Adolescent Medicine, Tokyo Medical University) ;
  • Nishimata, Shigeo (Department of Pediatrics and Adolescent Medicine, Tokyo Medical University) ;
  • Shimura, Masaru (Department of Pediatrics and Adolescent Medicine, Tokyo Medical University) ;
  • Kashiwagi, Yasuyo (Department of Pediatrics and Adolescent Medicine, Tokyo Medical University) ;
  • Kawashima, Hisashi (Department of Pediatrics and Adolescent Medicine, Tokyo Medical University)
  • Received : 2020.09.01
  • Accepted : 2021.02.02
  • Published : 2021.05.15

Abstract

Purpose: Hepcidin levels have previously been reported to be correlated with liver damage. However, the association between hepcidin levels and liver fibrosis in children with fatty liver disease remains unclear. This study therefore aimed to investigate the pathophysiology of fibrosis in children with fatty liver disease and its association with hepcidin levels. Methods: This retrospective case series included 12 boys aged 6-17 years who were diagnosed with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) at the Tokyo Medical University Hospital. Sixteen liver biopsy samples from 12 subjects were analyzed. Serum hepcidin levels were assayed using enzyme-linked immunosorbent assay. Immunostaining for hepcidin was performed, and the samples were stratified by staining intensity. Results: Serum hepcidin levels were higher in pediatric NAFLD/NASH patients than in controls. Conversely, a significant inverse correlation was observed between hepcidin immunostaining and Brunt grade scores and between hepcidin scores and gamma-glutamyltranspeptidase, hyaluronic acid, and leukocyte levels. We observed inverse correlations with a high correlation coefficient of >0.4 between hepcidin immunostaining and aspartate aminotransferase, alanine aminotransferase, total bile acid, and platelet count. Conclusion: There was a significant inverse correlation between hepcidin immunoreactivity and fibrosis in pediatric NAFLD patients; however, serum hepcidin levels were significantly higher, suggesting that these patients experienced a reduction in the hepcidin-producing ability of the liver in response to iron levels, leading to subsequent fibrosis. Therefore, hepcidin levels can be used as markers to identify the progression of fibrosis in patients with NAFLD.

Keywords

References

  1. American Gastroenterological Association. American Gastroenterological Association medical position statement: nonalcoholic fatty liver disease. Gastroenterology 2002;123:1702-4. https://doi.org/10.1053/gast.2002.36569
  2. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD single topic conference. Hepatology 2003;37:1202-19. https://doi.org/10.1053/jhep.2003.50193
  3. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113-21. https://doi.org/10.1053/j.gastro.2005.04.014
  4. Eguchi Y, Hyogo H, Ono M, Mizuta T, Ono N, Fujimoto K, et al.JSG-NAFLD. Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study. J Gastroenterol 2012;47:586-95. https://doi.org/10.1007/s00535-012-0533-z
  5. Moran JR, Ghishan FK, Halter SA, Greene HL. Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am J Gastroenterol 1983;78:374-7. PUBMED
  6. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67:328-57. https://doi.org/10.1002/hep.29367
  7. Anderson EL, Howe LD, Jones HE, Higgins JP, Lawlor DA, Fraser A. The prevalence of non-alcoholic fatty liver disease in children and adolescents: a systematic review and meta-analysis. PLoS One 2015;10:e0140908. https://doi.org/10.1371/journal.pone.0140908
  8. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006;118:1388-93. https://doi.org/10.1542/peds.2006-1212
  9. Tominaga K, Kurata JH, Chen YK, Fujimoto E, Miyagawa S, Abe I, et al. Prevalence of fatty liver in Japanese children and relationship to obesity. An epidemiological ultrasonographic survey. Dig Dis Sci 1995;40:2002-9. https://doi.org/10.1007/BF02208670
  10. Park HS, Han JH, Choi KM, Kim SM. Relation between elevated serum alanine aminotransferase and metabolic syndrome in Korean adolescents. Am J Clin Nutr 2005;82:1046-51. https://doi.org/10.1093/ajcn/82.5.1046
  11. Milic S, Mikolasevic I, Orlic L, Devcic E, Starcevic-Cizmarevic N, Stimac D, et al. The role of iron and iron overload in chronic liver disease. Med Sci Monit 2016;22:2144-51. https://doi.org/10.12659/MSM.896494
  12. Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest 2013;123:2337-43. https://doi.org/10.1172/JCI67225
  13. Ramos E, Ruchala P, Goodnough JB, Kautz L, Preza GC, Nemeth E, et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood 2012;120:3829-36.
  14. Ahmed U, Latham PS, Oates PS. Interactions between hepatic iron and lipid metabolism with possible relevance to steatohepatitis. World J Gastroenterol 2012;18:4651-8. https://doi.org/10.3748/wjg.v18.i34.4651
  15. Messner DJ, Rhieu BH, Kowdley KV. Iron overload causes oxidative stress and impaired insulin signaling in AML-12 hepatocytes. Dig Dis Sci 2013;58:1899-908. https://doi.org/10.1007/s10620-013-2648-3
  16. Nelson JE, Wilson L, Brunt EM, Yeh MM, Kleiner DE, Unalp-Arida A, et al. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology 2011;53:448-57. https://doi.org/10.1002/hep.24038
  17. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol 2012;107:811-26. https://doi.org/10.1038/ajg.2012.128
  18. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413-9. https://doi.org/10.1016/S0016-5085(99)70506-8
  19. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-21. https://doi.org/10.1002/hep.20701
  20. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999;94:2467-74. https://doi.org/10.1016/S0002-9270(99)00433-5
  21. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276:7806-10. https://doi.org/10.1074/jbc.M008922200
  22. Leong WI, Lonnerdal B. Hepcidin, the recently identified peptide that appears to regulate iron absorption. J Nutr 2004;134:1-4. https://doi.org/10.1093/jn/134.1.1
  23. Vuppalanchi R, Troutt JS, Konrad RJ, Ghabril M, Saxena R, Bell LN, et al. Serum hepcidin levels are associated with obesity but not liver disease. Obesity (Silver Spring) 2014;22:836-41. https://doi.org/10.1002/oby.20403
  24. Cakir M, Erduran E, Turkmen ES, Aliyazicioglu Y, Reis GP, Cobanoglu U, et al. Hepcidin levels in children with chronic liver disease. Saudi J Gastroenterol 2015;21:300-5. https://doi.org/10.4103/1319-3767.166205
  25. Takahashi Y, Inui A, Fujisawa T, Takikawa H, Fukusato T. Histopathological characteristics of nonalcoholic fatty liver disease in children: comparison with adult cases. Hepatol Res 2011;41:1066-74. https://doi.org/10.1111/j.1872-034X.2011.00855.x
  26. Schwimmer JB, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork NJ, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology 2005;42:641-9. https://doi.org/10.1002/hep.20842
  27. Lee P, Peng H, Gelbart T, Wang L, Beutler E. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci U S A 2005;102:1906-10. https://doi.org/10.1073/pnas.0409808102
  28. Tomosugi N. [The discovering of hepcidin and following develop]. Nihon Naika Gakkai Zasshi 2010;99:1180-7. Japanese. https://doi.org/10.2169/naika.99.1180
  29. Gardenghi S, Renaud TM, Meloni A, Casu C, Crielaard BJ, Bystrom LM, et al. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood 2014;123:1137-45. https://doi.org/10.1182/blood-2013-08-521625
  30. Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 2007;109:353-8. https://doi.org/10.1182/blood-2006-07-033969
  31. Datz C, Felder TK, Niederseer D, Aigner E. Iron homeostasis in the metabolic syndrome. Eur J Clin Invest 2013;43:215-24. https://doi.org/10.1111/eci.12032
  32. Chung B, Matak P, McKie AT, Sharp P. Leptin increases the expression of the iron regulatory hormone hepcidin in HuH7 human hepatoma cells. J Nutr 2007;137:2366-70. https://doi.org/10.1093/jn/137.11.2366
  33. Aigner E, Theurl I, Theurl M, Lederer D, Haufe H, Dietze O, et al. Pathways underlying iron accumulation in human nonalcoholic fatty liver disease. Am J Clin Nutr 2008;87:1374-83. https://doi.org/10.1093/ajcn/87.5.1374
  34. Barisani D, Pelucchi S, Mariani R, Galimberti S, Trombini P, Fumagalli D, et al. Hepcidin and iron-related gene expression in subjects with Dysmetabolic Hepatic Iron Overload. J Hepatol 2008;49:123-33. https://doi.org/10.1016/j.jhep.2008.03.011
  35. Aigner E, Weiss G, Datz C. Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver. World J Hepatol 2015;7:177-88. https://doi.org/10.4254/wjh.v7.i2.177
  36. Rockey DC, Chung JJ. Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing. J Clin Invest 1996;98:1381-8. https://doi.org/10.1172/JCI118925
  37. Han CY, Koo JH, Kim SH, Gardenghi S, Rivella S, Strnad P, et al. Hepcidin inhibits Smad3 phosphorylation in hepatic stellate cells by impeding ferroportin-mediated regulation of Akt. Nat Commun 2016;7:13817. https://doi.org/10.1038/ncomms13817
  38. Mitsuyoshi H, Yasui K, Harano Y, Endo M, Tsuji K, Minami M, et al. Analysis of hepatic genes involved in the metabolism of fatty acids and iron in nonalcoholic fatty liver disease. Hepatol Res 2009;39:366-73. https://doi.org/10.1111/j.1872-034X.2008.00464.x
  39. Bekri S, Gual P, Anty R, Luciani N, Dahman M, Ramesh B, et al. Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology 2006;131:788-96. https://doi.org/10.1053/j.gastro.2006.07.007