Chronic hepatitis C associated with anti-liver/kidney microsome-1 antibody is not a subgroup of autoimmune hepatitis

Abstract

To determine whether “autoimmune hepatitis type IIb” should be categorized as a subgroup of autoimmune hepatitis, we conducted a clinicopathological study of 25 adult Japanese patients who were positive for anti-liver/kidney microsome-1 (anti-LKM-1) antibody and infected with the hepatitis C virus (HCV). Anti-LKM-1 was determined by indirect immunofluo-rescence and by the double immunodiffusion assays we have developed. Twenty-two patients did not present any unusual symptoms or any associated diseases during the course of their chronic HCV infection. The spectrum of HCV genotypes of these patients did not significantly differ from that of anti-LKM-1-negative Japanese patients with chronic hepatitis C. Histological examination of liver biopsy specimens showed the usual characteristics of chronic hepatitis C and lack of characteristics of autoimmune hepatitis type I. No disease-specific HLA haplotypes were noted, and HLA-DR4, which is detectable in 88.7% of Japanese patients with autoimmune hepatitis type I, was detected in only 50.0% of our group, the same rate as the background frequency. Prednisolone was effective in none of the six patients treated, but interferon was effective in six of ten treated patients (60%). From these results, we conclude that “autoimmune hepatitis type IIb” should not be categorized as autoimmune hepatitis, and that this subgroup is essentially chronic hepatitis C in which an autoantibody has been produced during the course of chronic HCV infection.

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References

  1. 1.

    Smith MGM, Williams R, Walker G, et al. Hepatic disorders associated with liver/kidney microsomal antibodies. BMJ 1974;2:80–84.

    PubMed  CAS  Google Scholar 

  2. 2.

    Homberg JC, Abuaf N, Bernard O, et al. Chronic active hepatitis associated with anti-liver/kidney microsome antibody type 1: A second type of “autoimmune hepatitis”. Hepatology 1987;7:1333–1339.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Manns MP. Autoantibodies and antigens in liver diseases—up dated. J Hepatol 1989;9:272–280.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Michel G, Ritter A, Gerken G, et al. Anti-GOR and hepatitis C virus in autoimmune liver diseases. Lancet 1992;339:267–269.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Miyakawa H, Kako M, Nagai K, et al. HCV-RNA in type 2 autoimmune hepatitis. Am J Gastroenterol 1991;86:1688–1689.

    PubMed  CAS  Google Scholar 

  6. 6.

    Lenzi M, Ballardini G, Fusconi M, et al. Type 2 autoimmune hepatitis and hepatitis C virus infection. Lancet 1990;335:258–259.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Vento S, DiPerri G, Luzzati R, et al. Type 2 autoimmune hepatitis and hepatitis C virus infection. Lancet 1990;335:921–922.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Garson JA, Lenzi M, Ring C, et al. Hepatitis C viraemia in adults with type 2 autoimmune hepatitis. J Med Virol 1991;34:223–226.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Zeniya M, Watanabe F, Aizawa Y, et al. Genetic background of autoimmune hepatitis in Japan. In: Nishioka M, Toda G, Zeniya M, editors Autoimmune hepatitis. Amsterdam: Elsevier, 1994;267–279.

    Google Scholar 

  10. 10.

    Johnson PJ, McFarlane IG. Meeting report: International autoimmune hepatitis group. Hepatology 1993;18:998–1005.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Rizzetto M, Bianchi FB, Doniach D. Characterization of the microsomal antigen related to a subclass of active chronic hepatitis. Immunology 1973;26:589–601.

    Google Scholar 

  12. 12.

    Manns MP, Nakamura RM. Autoimmune liver diseases. Clin Lab Med 1988;8:281–301.

    PubMed  CAS  Google Scholar 

  13. 13.

    Martini E, Abuaf N, Cavalli F, et al. Antibody to liver cytosol (anti-LC1) in patients with autoimmune chronic active hepatitis type 2. Hepatology 1988;8:1662–1666.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970;227:680–685.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of protein from polyacrylamide gels to nitrocellulose sheets. Proc Natl Acad Sci USA 1979;76:4350–4354.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Alvarez H, Bernard O, Homberg J-C, et al. Anti-liver kidney microsome antibody recognizes a 50000 molecular weight protein of the endoplasmic reticulum. J Exp Med 1985;161:1231–1236.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Miyakawa H, Abe K, Kako M. Heterogeneity of autoantigen to anti-liver kidney microsome 1 (LKM1)—by Western blot analysis. Int Hepatol Commun 1995;4:1–5.

    Article  Google Scholar 

  18. 18.

    Okamoto H, Osada S, Sugiyama Y, et al. Detection of hepatitis C virus RNA by a two-stage polymerase chain reaction with two pairs of primers deduced from the 5'-noncoding region. Jpn J Exp Med 1990;60:1105–1113.

    Google Scholar 

  19. 19.

    Okamoto H, Kurai K, Okada S, et al. Fill-length sequence of a hepatitis C virus genome having poor homology to reported isolates: Comparative study of four distinct genotypes. Virology 1992;188:331–341.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Terasaki PI, Bernoco D, Park MS, et al. Microdroplet testing for HLA-A,-B,-C, and-D antigens. Am J Clin Pathol 1978;69:103–120.

    PubMed  CAS  Google Scholar 

  21. 21.

    Desmet V, Gerber M, Hoofnagle JH, et al. Classification of chronic hepatitis, diagnosis, grading and staging. Hepatology 1994;19:1513–1520.

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Johnson PJ, McFarlane IG, Eddleston ALWF. The natural course and heterogeneity of autoimmune-type chronic active hepatitis. Semin Liver Dis 1991;11:187–196.

    PubMed  CAS  Google Scholar 

  23. 23.

    Bach N, Thung SN, Schaffner F. The histological features of chronic hepatitis C and autoimmune chronic hepatitis: A comparative analysis. Hepatology 1992;15:572–577.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Seki K, Kiyosawa K, Inoko H, et al. Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients. Hepatology 1990;12:1300–1304.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Homberg JC, Andre C, Abuaf N. A new anti-liver-kidney microsome antibody (anti-LKM-2) in tientilic acid-induced hepatitis. Clin Exp Immunol 1984;55:561–570.

    PubMed  CAS  Google Scholar 

  26. 26.

    Coo QL, Kuo G, Weiner AJ, et al. Isolation of cDNA clone derived from a blood-borne non-A, non-B, viral hepatitis genome. Science 1989;224:359–362.

    Google Scholar 

  27. 27.

    Manns MP, Johnson EF, Griffin KJ, et al. Major antigen of liver kidney microsome autoantibodies in ideopathic autoimmune hepatitis is cytochrome P450 db1. J Clin Invest 1989;83:1066–1072.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Gueguen M, Boniface O, Bernard O, et al. Identification of the main epitope on human cytochrome P450IID6 recognized by anti-liver kidney microsome antibody. J Autoimmun 1991;4:607–615.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Yamamoto AM, Cresteil D, Boniface O, et al. Identification and analysis of cytochrome P450IID6 antigenic sites recognized by anti-liver-kidney microsome type-1 antibodies (LKM1). Eur J Immunol 1993;23:1105–1111.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Manns MP, Griffin KJ, Sullivan KF, et al. LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome p-450 monooxygenase. J Clin Invest 1991;88:1370–1378.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Miyakawa H, Kako M, Usuda S, et al. Reactivity of sera from Japanese patients with type 2 autoimmune hepatitis to peptides derived from host genes, cytochrome HLD8-2 and GOR. In: Nishioka K, Suzuki H, Mishiro S, Oda T, editors. Viral hepatitis and liver disease. Tokyo Berlin Heidelberg New York: Springer-Verlag, 1994;229–231.

    Google Scholar 

  32. 32.

    Mishiro S, Hoshi Y, Takeda K, et al. Non-A, non-B hepatitis-specific antibodies directed at host-derived epitope: Implication for an autoimmune process. Lancet 1990;336:1400–1403.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Lenzi M, Cassini F, Ballardini G, et al. Anti-HCV, anti-GOR, and autoimmunity. Lancet 1992;339:871–872.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Mishiro S, Takeda K, Hoshi Y, et al. An autoantibody cross-reactive to hepatitis C virus core and a host nuclear antigen. Autoimmunity 1991;10:269–273.

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Michitaka K, Durazzo M, Tillmann HL, et al. Analysis of hepatitis C virus genome in patients with autoimmune hepatitis type 2. Gastroenterology 1994;106:1603–1610.

    PubMed  CAS  Google Scholar 

  36. 36.

    Clifford BD, Donahue D, Smith L, et al. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology 1995;21:613–619.

    PubMed  CAS  Google Scholar 

  37. 37.

    Manns MP, Krüger M. Immunogenetics of chronic liver diseases. Gastroenterology 1994;106:1676–1697.

    PubMed  CAS  Google Scholar 

  38. 38.

    Lenzi M, Mantovani W, Cataleta M, et al. HLA typing in autoimmune hepatitis (AI-CAH) type 2 (abstract). J Hepatol 1991; 16(Suppl 1):59.

    Google Scholar 

  39. 39.

    Manns MP, Jentsch M, Mergener K, et al. HLA class I–III in autoimmune hepatitis type 2 and its association with hepatitis virus infection (abstract). J Hepatol 1991;16(Suppl 1):16.

    Google Scholar 

  40. 40.

    Czaja AJ. Treatment of autoimmune hepatitis. In: Nishioka M, Toda G, Zeniya M, editors. Autoimmune hepatitis. Amsterdam: Elsevier, 1994;283–304.

    Google Scholar 

  41. 41.

    Vergani D, Mielk-Vergani G. Type II autoimmune hepatitis. What is the role of the hepatitis C virus? Gastroenterology 1993;104:1970–1973.

    Google Scholar 

  42. 42.

    Mackie FD, Peakman M, Yun M, et al. Primary and secondary liver/kidney microsomal autoantibody response following infection with hepatitis C virus. Gastroenterology 1994;106:1672–1675.

    PubMed  CAS  Google Scholar 

  43. 43.

    Meyer zum Büshenfelde KH, Lohse AW, Gerken G, et al. The role of autoimmunity in hepatitis C infection. J Hepatol 1995;22(Suppl 1):93–96.

    Google Scholar 

  44. 44.

    Abe K, Miyakawa H, Miyachi K, et al. Anti-LKM1-positive chronic hepatitis C with type I cryoglobulinemia responding to interferon. Intern Med 1995;34:1114–1119.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Todros L, Touscoz G, D'Urso N. Hepatitis C virus-related chronic liver disease with autoantibodies to liver-kidney microsomes (LKM). Clinical characterization from idiopathic LKM-positive disorders. J Hepatol 1991;13:128–131.

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Lunel F, Abuaf N, Frangeul L, et al. Liver/kidney microsome antibody type I and hepetitis C virus infection. Hepatology 1992;16:630–636.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Strassberg CP, Manns MP. Autoimmune hepatitis versus viral hepatitis C. Liver 1995;15:225–232.

    Google Scholar 

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Correspondence to Hiroshi Miyakawa.

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Miyakawa, H., Kitazawa, E., Abe, K. et al. Chronic hepatitis C associated with anti-liver/kidney microsome-1 antibody is not a subgroup of autoimmune hepatitis. J Gastroenterol 32, 769 (1997). https://doi.org/10.1007/BF02936953

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Key words

  • autoimmune hepatitis type IIb
  • HCV-RNA
  • HCV genotype
  • interferon
  • HLA