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Clinical Reviews in Allergy & Immunology

, Volume 45, Issue 1, pp 143–148 | Cite as

Autoimmune Features in Metabolic Liver Disease: A Single-Center Experience and Review of the Literature

  • Koichi Tsuneyama
  • Hayato Baba
  • Kentaro Kikuchi
  • Takeshi Nishida
  • Kazuhiro Nomoto
  • Shinichi Hayashi
  • Shigeharu Miwa
  • Takahiko Nakajima
  • Yuko Nakanishi
  • Shinji Masuda
  • Mitsuhiro Terada
  • Johji Imura
  • Carlo Selmi
Article

Abstract

Non-alcoholic steatohepatitis (NASH) is the progressive phenotype of non-alcoholic fatty liver disease associated with the metabolic syndrome. The existence of autoimmune features in NASH has been reported, but its significance remains unclear. We herein report the autoantibody profile of 54 patients with histologically proven NASH and further determined the development of autoimmunity in three different murine NASH models (monosodium glutamate, CDAA (choline-deficient l-amino acid-defined), and TSOD (Tsumura Suzuki, Obese Diabetes)) at 48 weeks of age. Forty-eight percent (26/54) of NASH cases were positive for antinuclear (ANA) or antimitochondrial antibody and manifested histological signs of overlap with autoimmune hepatitis and primary biliary cirrhosis, respectively. These patients were significantly older (60 ± 10 versus 50 ± 16 years), more frequently women (81 % versus 43 %), and with more severe portal inflammatory infiltrate compared with patients without autoimmunity. In one third of mice, regardless of the model, we observed a marked lymphoid infiltrate with non-suppurative cholangitis, and several cases were ANA-positive, but none AMA-positive. Our data suggest that autoimmunity may share some pathogenetic traits with the chronic inflammation of NASH, possibly related to advanced age.

Keywords

Metabolic syndrome Female sex Non-alcoholic fatty liver disease 

Abbreviations

AIH

Autoimmune hepatitis

AMA

Anti-mitochondrial antibodies

ANA

Anti-nuclear antibodies

CDAA

Choline-deficient l-amino acid-defined

CNSDC

Chronic non-suppurative destructive cholangitis

IL-6

Interleukin-6

MSG

Monosodium glutamate

NAFLD

Non-alcoholic fatty liver disease

NASH

Non-alcoholic steatohepatitis

PBC

Primary biliary cirrhosis

TNF-α

Tumor necrosis factor-α

TSOD

Tsumura Suzuki, Obese Diabetes

Notes

Acknowledgments

The authors are thankful to Mr. Tokimasa Kumada and Mr. Hideki Hatta for their help and technical assistance with experiments and to Ms. Yukari Inoue for the excellent support in the manuscript preparation. This work was supported by JSPS KAKENHI Grant Numbers 0293341 and 10293341 and a Research grant of 2010 Takeda Science Foundation.

References

  1. 1.
    Selmi C, Mackay IR, Gershwin ME (2007) The immunological milieu of the liver. Semin Liver Dis 27:129–139PubMedCrossRefGoogle Scholar
  2. 2.
    Williams CD, Stengel J, Asike MI et al (2011) Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140:124–131PubMedCrossRefGoogle Scholar
  3. 3.
    Liberal R, Grant CR, Mieli-Vergani G, Vergani D (2013) Autoimmune hepatitis: a comprehensive review. J Autoimmun 41:126–139PubMedCrossRefGoogle Scholar
  4. 4.
    Selmi C, Bowlus CL, Gershwin ME, Coppel RL (2011) Primary biliary cirrhosis. Lancet 377:1600–1609PubMedCrossRefGoogle Scholar
  5. 5.
    Selmi C, Invernizzi P, Keeffe EB et al (2004) Epidemiology and pathogenesis of primary biliary cirrhosis. J Clin Gastroenterol 38:264–271PubMedCrossRefGoogle Scholar
  6. 6.
    Boberg KM, Chapman RW, Hirschfield GM, Lohse AW, Manns MP, Schrumpf E (2011) Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 54:374–385PubMedCrossRefGoogle Scholar
  7. 7.
    Miyakawa H, Kikuchi K, Jong-Hon K et al (2001) High sensitivity of a novel ELISA for anti-M2 in primary biliary cirrhosis. J Gastroenterol 36:33–38PubMedCrossRefGoogle Scholar
  8. 8.
    Miyakawa H, Kitazawa E, Fujikawa H et al (2000) Analysis of two major anti-M2 antibodies (anti-PDC-E2/anti-BCOADC-E2) in primary biliary cirrhosis: relationship to titers of immunofluorescent anti-mitochondrial antibody. Hepatol Res Off J Jpn Soc Hepatol 18:1–9CrossRefGoogle Scholar
  9. 9.
    Invernizzi P, Selmi C, Ranftler C, Podda M, Wesierska-Gadek J (2005) Antinuclear antibodies in primary biliary cirrhosis. Semin Liver Dis 25:298–310PubMedCrossRefGoogle Scholar
  10. 10.
    Mahady SE, George J (2012) Management of nonalcoholic steatohepatitis: an evidence-based approach. Clin Liver Dis 16:631–645PubMedCrossRefGoogle Scholar
  11. 11.
    Kleiner DE, Brunt EM, Van Natta M et al (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41:1313–1321PubMedCrossRefGoogle Scholar
  12. 12.
    Nakanishi Y, Tsuneyama K, Fujimoto M et al (2008) Monosodium glutamate (MSG): a villain and promoter of liver inflammation and dysplasia. J Autoimmun 30:42–50PubMedCrossRefGoogle Scholar
  13. 13.
    Sasaki Y, Shimada T, Iizuka S et al (2011) Effects of bezafibrate in nonalcoholic steatohepatitis model mice with monosodium glutamate-induced metabolic syndrome. Eur J Pharmacol 662:1–8PubMedCrossRefGoogle Scholar
  14. 14.
    Sasaki Y, Suzuki W, Shimada T et al (2009) Dose dependent development of diabetes mellitus and non-alcoholic steatohepatitis in monosodium glutamate-induced obese mice. Life Sci 85:490–498PubMedCrossRefGoogle Scholar
  15. 15.
    Kawaratani H, Tsujimoto T, Kitazawa T et al (2008) Innate immune reactivity of the liver in rats fed a choline-deficient l-amino-acid-defined diet. World J Gastroenterol WJG 14:6655–6661CrossRefGoogle Scholar
  16. 16.
    Sakaida I, Okita K (2005) The role of oxidative stress in NASH and fatty liver model. Hepatol Res Off J Jpn Soc Hepatol 33:128–131CrossRefGoogle Scholar
  17. 17.
    Nishida T, Tsuneyama K, Fujimoto M et al (2013) Spontaneous onset of nonalcoholic steatohepatitis and hepatocellular carcinoma in a mouse model of metabolic syndrome. Laboratory investigation. J Tech Methods Pathol 93:230–241Google Scholar
  18. 18.
    Lidar M, Lipschitz N, Agmon-Levin N et al (2012) Infectious serologies and autoantibodies in hepatitis C and autoimmune disease-associated mixed cryoglobulinemia. Clin Rev Allergy Immunol 42:238–246PubMedCrossRefGoogle Scholar
  19. 19.
    Agmon-Levin N, Ram M, Barzilai O et al (2009) Prevalence of hepatitis C serum antibody in autoimmune diseases. J Autoimmun 32:261–266PubMedCrossRefGoogle Scholar
  20. 20.
    Keppeke GD, Nunes E, Ferraz ML et al (2012) Longitudinal study of a human drug-induced model of autoantibody to cytoplasmic rods/rings following HCV therapy with ribavirin and interferon-alpha. PLoS One 7:e45392PubMedCrossRefGoogle Scholar
  21. 21.
    Fischer S, Agmon-Levin N, Shapira Y et al (2013) Toxoplasma gondii: bystander or cofactor in rheumatoid arthritis. Immunol Res 56:287–292PubMedCrossRefGoogle Scholar
  22. 22.
    Shapira Y, Poratkatz BS, Gilburd B et al (2012) Geographical differences in autoantibodies and anti-infectious agents antibodies among healthy adults. Clin Rev Allergy Immunol 42:154–163PubMedCrossRefGoogle Scholar
  23. 23.
    Wakabayashi K, Lian ZX, Leung PS et al (2008) Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology 48:531–540PubMedCrossRefGoogle Scholar
  24. 24.
    Wakabayashi K, Lian ZX, Moritoki Y et al (2006) IL-2 receptor alpha(−/−) mice and the development of primary biliary cirrhosis. Hepatology 44:1240–1249PubMedCrossRefGoogle Scholar
  25. 25.
    Wakabayashi K, Yoshida K, Leung PS et al (2009) Induction of autoimmune cholangitis in non-obese diabetic (NOD).1101 mice following a chemical xenobiotic immunization. Clin Exp Immunol 155:577–586PubMedCrossRefGoogle Scholar
  26. 26.
    Tsuneyama K, Moritoki Y, Kikuchi K, Nakanuma Y (2012) Pathological features of new animal models for primary biliary cirrhosis. Int J Hepatol 2012:403954PubMedGoogle Scholar
  27. 27.
    Yang GX, Lian ZX, Chuang YH et al (2008) Adoptive transfer of CD8(+) T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice. Hepatology 47:1974–1982PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang W, Sharma R, Ju ST et al (2009) Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis. Hepatology 49:545–552PubMedCrossRefGoogle Scholar
  29. 29.
    Shoenfeld Y, Tincani A, Gershwin ME (2012) Sex gender and autoimmunity. J Autoimmun 38:J71–J73PubMedCrossRefGoogle Scholar
  30. 30.
    Sawalha AH, Wang L, Nadig A et al (2012) Sex-specific differences in the relationship between genetic susceptibility, T cell DNA demethylation and lupus flare severity. J Autoimmun 38:J216–J222PubMedCrossRefGoogle Scholar
  31. 31.
    Pennell LM, Galligan CL, Fish EN (2012) Sex affects immunity. J Autoimmun 38:J282–J291PubMedCrossRefGoogle Scholar
  32. 32.
    Amur S, Parekh A, Mummaneni P (2012) Sex differences and genomics in autoimmune diseases. J Autoimmun 38:J254–J265PubMedCrossRefGoogle Scholar
  33. 33.
    Selmi C, Tsuneyama K (2010) Nutrition, geoepidemiology, and autoimmunity. Autoimmun Rev 9:A267–A270PubMedCrossRefGoogle Scholar
  34. 34.
    Markle JG, Frank DN, Mortin-Toth S et al (2013) Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339:1084–1088PubMedCrossRefGoogle Scholar
  35. 35.
    Atarashi K, Honda K (2011) Microbiota in autoimmunity and tolerance. Curr Opin Immunol 23:761–768PubMedCrossRefGoogle Scholar
  36. 36.
    Lathrop SK, Bloom SM, Rao SM et al (2011) Peripheral education of the immune system by colonic commensal microbiota. Nature 478:250–254PubMedCrossRefGoogle Scholar
  37. 37.
    Fasano A (2012) Leaky gut and autoimmune diseases. Clin Rev Allergy Immunol 42:71–78PubMedCrossRefGoogle Scholar
  38. 38.
    Lee TP, Chiang BL (2012) Sex differences in spontaneous versus induced animal models of autoimmunity. Autoimmun Rev 11:A422–A429PubMedCrossRefGoogle Scholar
  39. 39.
    Miyashita T, Toyoda Y, Tsuneyama K, Fukami T, Nakajima M, Yokoi T (2012) Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models. J Toxicol Sci 37:931–942PubMedCrossRefGoogle Scholar
  40. 40.
    Toyoda Y, Miyashita T, Endo S et al (2011) Estradiol and progesterone modulate halothane-induced liver injury in mice. Toxicol Lett 204:17–24PubMedCrossRefGoogle Scholar
  41. 41.
    Yoshikawa Y, Miyashita T, Higuchi S et al (2012) Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries. Toxicol Appl Pharmacol 264:42–50PubMedCrossRefGoogle Scholar
  42. 42.
    Selmi C, Brunetta E, Raimondo MG, Meroni PL (2012) The X chromosome and the sex ratio of autoimmunity. Autoimmun Rev 11:A531–A537PubMedCrossRefGoogle Scholar
  43. 43.
    Pollard KM (2012) Gender differences in autoimmunity associated with exposure to environmental factors. J Autoimmun 38:J177–J186PubMedCrossRefGoogle Scholar
  44. 44.
    Carp HJ, Selmi C, Shoenfeld Y (2012) The autoimmune bases of infertility and pregnancy loss. J Autoimmun 38:J266–J274PubMedCrossRefGoogle Scholar
  45. 45.
    Fujisaka S, Usui I, Ikutani M et al (2013) Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1alpha-dependent and HIF-1alpha-independent manner in obese mice. Diabetologia 56:1403–1412PubMedCrossRefGoogle Scholar
  46. 46.
    Smorlesi A, Frontini A, Giordano A, Cinti S (2012) The adipose organ: white-brown adipocyte plasticity and metabolic inflammation. Obes Rev Off J Int Assoc Stud Obes 13(Suppl 2):83–96CrossRefGoogle Scholar
  47. 47.
    Potenza MV, Mechanick JI (2009) The metabolic syndrome: definition, global impact, and pathophysiology. Nutr Clin Pract Off Publ Am Soc Parenter Enteral Nutr 24:560–577CrossRefGoogle Scholar
  48. 48.
    Fujii H, Ikura Y, Arimoto J et al (2009) Expression of perilipin and adipophilin in nonalcoholic fatty liver disease; relevance to oxidative injury and hepatocyte ballooning. J Atheroscler Thromb 16:893–901PubMedCrossRefGoogle Scholar
  49. 49.
    Mitsuyoshi H, Yasui K, Harano Y et al (2009) Analysis of hepatic genes involved in the metabolism of fatty acids and iron in nonalcoholic fatty liver disease. Hepatol Res Off J Jpn Soc Hepatol 39:366–373CrossRefGoogle Scholar
  50. 50.
    Salunga TL, Cui ZG, Shimoda S et al (2007) Oxidative stress-induced apoptosis of bile duct cells in primary biliary cirrhosis. J Autoimmun 29:78–86PubMedCrossRefGoogle Scholar
  51. 51.
    Tsuneyama K, Harada K, Kono N et al (2002) Damaged interlobular bile ducts in primary biliary cirrhosis show reduced expression of glutathione-S-transferase-pi and aberrant expression of 4-hydroxynonenal. J Hepatol 37:176–183PubMedCrossRefGoogle Scholar
  52. 52.
    Folci M, Meda F, Gershwin ME, Selmi C (2012) Cutting-edge issues in primary biliary cirrhosis. Clin Rev Allergy Immunol 42:342–354PubMedCrossRefGoogle Scholar
  53. 53.
    De Santis M, Selmi C (2012) The therapeutic potential of epigenetics in autoimmune diseases. Clin Rev Allergy Immunol 42:92–101PubMedCrossRefGoogle Scholar
  54. 54.
    Miller FW, Alfredsson L, Costenbader KH et al (2012) Epidemiology of environmental exposures and human autoimmune diseases: findings from a National Institute of Environmental Health Sciences Expert Panel Workshop. J Autoimmun 39:259–271PubMedCrossRefGoogle Scholar
  55. 55.
    Miller FW, Pollard KM, Parks CG et al (2012) Criteria for environmentally associated autoimmune diseases. J Autoimmun 39:253–258PubMedCrossRefGoogle Scholar
  56. 56.
    Selmi C, Gershwin ME (2009) The role of environmental factors in primary biliary cirrhosis. Trends in immunology 30:415–420PubMedCrossRefGoogle Scholar
  57. 57.
    Henao-Mejia J, Elinav E, Thaiss CA, Flavell RA (2013) The intestinal microbiota in chronic liver disease. Adv Immunol 117:73–97PubMedCrossRefGoogle Scholar
  58. 58.
    Albano E (2012) Role of adaptive immunity in alcoholic liver disease. Int J Hepatol 2012:893026PubMedGoogle Scholar
  59. 59.
    Selmi C, Lu Q, Humble MC (2012) Heritability versus the role of the environment in autoimmunity. J Autoimmun 39:249–252PubMedCrossRefGoogle Scholar
  60. 60.
    Tian L, De Hertogh G, Fedeli M et al (2012) Loss of T cell microRNA provides systemic protection against autoimmune pathology in mice. J Autoimmun 38:39–48PubMedCrossRefGoogle Scholar
  61. 61.
    Quintero OL, Amador-Patarroyo MJ, Montoya-Ortiz G, Rojas-Villarraga A, Anaya JM (2012) Autoimmune disease and gender: plausible mechanisms for the female predominance of autoimmunity. J Autoimmun 38:J109–J119PubMedCrossRefGoogle Scholar
  62. 62.
    Menon R, Di Dario M, Cordiglieri C et al (2012) Gender-based blood transcriptomes and interactomes in multiple sclerosis: involvement of SP1 dependent gene transcription. J Autoimmun 38:J144–J155PubMedCrossRefGoogle Scholar
  63. 63.
    Bogdanos DP, Smyk DS, Rigopoulou EI et al (2012) Twin studies in autoimmune disease: genetics, gender and environment. J Autoimmun 38:J156–J169PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Koichi Tsuneyama
    • 1
  • Hayato Baba
    • 1
  • Kentaro Kikuchi
    • 2
  • Takeshi Nishida
    • 1
  • Kazuhiro Nomoto
    • 1
  • Shinichi Hayashi
    • 1
  • Shigeharu Miwa
    • 1
  • Takahiko Nakajima
    • 1
  • Yuko Nakanishi
    • 1
  • Shinji Masuda
    • 3
  • Mitsuhiro Terada
    • 4
  • Johji Imura
    • 1
  • Carlo Selmi
    • 5
    • 6
  1. 1.Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical SciencesUniversity of ToyamaToyamaJapan
  2. 2.Fourth Department of Internal MedicineTeikyo University Mizonokuchi HospitalKanagawaJapan
  3. 3.Department of PathologyKouseiren Takaoka HospitalTakaokaJapan
  4. 4.Department of Internal MedicineKouseiren Takaoka HospitalTakaokaJapan
  5. 5.Division of Rheumatology and Clinical ImmunologyHumanitas Clinical and Research CenterMilanItaly
  6. 6.Division of Rheumatology, Allergy, and Clinical ImmunologyUniversity of CaliforniaDavisUSA

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