Advertisement

Digestive Diseases and Sciences

, Volume 56, Issue 12, pp 3421–3438 | Cite as

Cryptogenic Chronic Hepatitis and Its Changing Guise in Adults

  • Albert J. CzajaEmail author
Review

Abstract

Cryptogenic chronic hepatitis is a disease that is unexplained by conventional clinical, laboratory and histological findings, and it can progress to cirrhosis, develop hepatocellular carcinoma, and require liver transplantation. The goals of this review are to describe the changing phenotype of cryptogenic chronic hepatitis in adults, develop a diagnostic algorithm appropriate to current practice, and suggest treatment options. The frequency of cryptogenic hepatitis is estimated at 5.4%. Cryptogenic cirrhosis is diagnosed in 5–30% of patients with cirrhosis, and it is present in 3–14% of adults awaiting liver transplantation. Nonalcoholic fatty liver disease has been implicated in 21–63% of patients, and autoimmune hepatitis is a likely diagnosis in 10–54% of individuals. Viral infections, hereditary liver diseases, celiac disease, and unsuspected alcohol or drug-induced liver injury are recognized infrequently in the current cryptogenic population. Manifestations of the metabolic syndrome heighten the suspicion of nonalcoholic fatty liver disease, and the absence of hepatic steatosis does not discount this possibility. The diagnostic scoring system of the International Autoimmune Hepatitis Group can support the diagnosis of autoimmune hepatitis in some patients. Certain genetic mutations may have disease-specificity, and they suggest that some patients may have an independent and uncharacterized disease. Corticosteroid therapy is effective in patients with autoimmune features, and life-style changes and specific therapies for manifestations of the metabolic syndrome are appropriate for all obese patients. The 1- and 5-year survivals after liver transplantation have ranged from 72–85% to 58–73%, respectively.

Keywords

Cryptogenic hepatitis Autoantibody-negative Chronic hepatitis 

Notes

Conflict of interest

This work did not receive financial support from a funding agency or institution, and Albert J. Czaja, MD has no conflict of interests to declare.

References

  1. 1.
    Czaja AJ, Hay JE, Rakela J. Clinical features and prognostic implications of severe corticosteroid-treated cryptogenic chronic active hepatitis. Mayo Clin Proc. 1990;65:23–30.PubMedGoogle Scholar
  2. 2.
    Czaja AJ, Carpenter HA, Santrach PJ, Moore SB, Homburger HA. The nature and prognosis of severe cryptogenic chronic active hepatitis. Gastroenterology. 1993;104:1755–1761.PubMedGoogle Scholar
  3. 3.
    Baeres M, Herkel J, Czaja AJ, et al. Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics. Gut. 2002;51:259–264.PubMedCrossRefGoogle Scholar
  4. 4.
    Czaja AJ, Donaldson PT, Lohse AW. Antibodies to soluble liver antigen/liver pancreas and HLA risk factors for type 1 autoimmune hepatitis. Am J Gastroenterol. 2002;97:413–419.PubMedCrossRefGoogle Scholar
  5. 5.
    Ma Y, Okamoto M, Thomas MG, et al. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology. 2002;35:658–664.PubMedCrossRefGoogle Scholar
  6. 6.
    Abuaf N, Johanet C, Chretien P, et al. Characterization of the liver cytosol antigen type 1 reacting with autoantibodies in chronic active hepatitis. Hepatology. 1992;16:892–898.PubMedCrossRefGoogle Scholar
  7. 7.
    Czaja AJ, Pfeifer KD, Decker RH, Vallari AS. Frequency and significance of antibodies to asialoglycoprotein receptor in type 1 autoimmune hepatitis. Dig Dis Sci. 1996;41:1733–1740.PubMedCrossRefGoogle Scholar
  8. 8.
    Hausdorf G, Roggenbuck D, Feist E, et al. Autoantibodies to asialoglycoprotein receptor (ASGPR) measured by a novel ELISA–revival of a disease-activity marker in autoimmune hepatitis. Clin Chim Acta. 2009;408:19–24.PubMedCrossRefGoogle Scholar
  9. 9.
    Manns MP, Obermayer-Straub P. Cytochromes P450 and uridine triphosphate-glucuronosyltransferases: model autoantigens to study drug-induced, virus-induced, and autoimmune liver disease. Hepatology. 1997;26:1054–1066.PubMedCrossRefGoogle Scholar
  10. 10.
    Caldwell SH, Oelsner DH, Iezzoni JC, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29:664–669.PubMedCrossRefGoogle Scholar
  11. 11.
    Maheshwari A, Thuluvath PJ. Cryptogenic cirrhosis and NAFLD: are they related? Am J Gastroenterol. 2006;101:664–668.PubMedCrossRefGoogle Scholar
  12. 12.
    Caldwell SH, Lee VD, Kleiner DE, et al. NASH and cryptogenic cirrhosis: a histological analysis. Ann Hepatol. 2009;8:346–352.PubMedGoogle Scholar
  13. 13.
    Caldwell S. Cryptogenic cirrhosis: what are we missing? Curr Gastroenterol Rep. 2010;12:40–48.PubMedCrossRefGoogle Scholar
  14. 14.
    Hodges JR, Millward-Sadler GH, Barbatis C, Wright R. Heterozygous MZ alpha 1-antitrypsin deficiency in adults with chronic active hepatitis and cryptogenic cirrhosis. N Engl J Med. 1981;304:557–560.PubMedCrossRefGoogle Scholar
  15. 15.
    Battle WM, Matarazzo SA, Selhat GF, Catalano E. Alpha-1-antitrypsin deficiency—a cause of cryptogenic liver disease in the elderly. J Clin Gastroenterol. 1982;4:269–273.PubMedCrossRefGoogle Scholar
  16. 16.
    Vecchio FM, Fabiano A, Orsini G, Ragusa D, Massi G. Alpha-1-antitrypsin MZ phenotype and cryptogenic chronic liver disease in adults. Digestion. 1983;27:100–104.PubMedCrossRefGoogle Scholar
  17. 17.
    Thatcher BS, Winkelman EI, Tuthill RJ. Alpha 1-antitrypsin deficiency presenting as cryptogenic cirrhosis in adults over 50. J Clin Gastroenterol. 1985;7:405–408.PubMedCrossRefGoogle Scholar
  18. 18.
    Bell H, Schrumpf E, Fagerhol MK. Heterozygous MZ alpha-1-antitrypsin deficiency in adults with chronic liver disease. Scand J Gastroenterol. 1990;25:788–792.PubMedCrossRefGoogle Scholar
  19. 19.
    Gill HH, Shankaran K, Desai HG. Wilson’s disease: varied hepatic presentations. Indian J Gastroenterol. 1994;13:95–98.PubMedGoogle Scholar
  20. 20.
    Czaja AJ. Frequency and significance of phenotypes for alpha1-antitrypsin deficiency in type 1 autoimmune hepatitis. Dig Dis Sci. 1998;43:1725–1731.PubMedCrossRefGoogle Scholar
  21. 21.
    Graziadei IW, Joseph JJ, Wiesner RH, et al. Increased risk of chronic liver failure in adults with heterozygous alpha1-antitrypsin deficiency. Hepatology. 1998;28:1058–1063.PubMedCrossRefGoogle Scholar
  22. 22.
    Perlmutter DH. Alpha-1-antitrypsin deficiency: diagnosis and treatment. Clin Liver Dis. 2004;8:839–859, viii–ix.Google Scholar
  23. 23.
    Regev A, Guaqueta C, Molina EG, et al. Does the heterozygous state of alpha-1 antitrypsin deficiency have a role in chronic liver diseases? Interim results of a large case-control study. J Pediatr Gastroenterol Nutr. 2006;43:S30–S35.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhou H, Fischer HP. Hereditary hemochromatosis, alpha-1-antitrypsin deficiency and Wilson’s disease. Pathogenesis, clinical findings and pathways to diagnosis. Pathologe. 2008;29:73–83.PubMedCrossRefGoogle Scholar
  25. 25.
    Pietrangelo A. Inherited metabolic disease of the liver. Curr Opin Gastroenterol. 2009;25:209–214.PubMedCrossRefGoogle Scholar
  26. 26.
    Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology. 2010;139:393–408, e391–e392.Google Scholar
  27. 27.
    Kodali VP, Gordon SC, Silverman AL, McCray DG. Cryptogenic liver disease in the United States: further evidence for non-A, non-B, and non-C hepatitis. Am J Gastroenterol. 1994;89:1836–1839.PubMedGoogle Scholar
  28. 28.
    Charlton M, Adjei P, Poterucha J, et al. TT-virus infection in North American blood donors, patients with fulminant hepatic failure, and cryptogenic cirrhosis. Hepatology. 1998;28:839–842.PubMedCrossRefGoogle Scholar
  29. 29.
    Dalton HR, Stableforth W, Thurairajah P, et al. Autochthonous hepatitis E in Southwest England: natural history, complications and seasonal variation, and hepatitis E virus IgG seroprevalence in blood donors, the elderly and patients with chronic liver disease. Eur J Gastroenterol Hepatol. 2008;20:784–790.PubMedCrossRefGoogle Scholar
  30. 30.
    Czaja AJ, Abdulkarim AS, Carpenter HA, et al. GB virus-C infection in type 1 autoimmune hepatitis. Mayo Clin Proc. 1998;73:412–418.PubMedCrossRefGoogle Scholar
  31. 31.
    Berasain C, Betes M, Panizo A, et al. Pathological and virological findings in patients with persistent hypertransaminasaemia of unknown aetiology. Gut. 2000;47:429–435.PubMedCrossRefGoogle Scholar
  32. 32.
    Di SR, Ferraro D, Bonura C, et al. Are hepatitis G virus and TT virus involved in cryptogenic chronic liver disease? Dig Liver Dis. 2002;34:53–58.PubMedCrossRefGoogle Scholar
  33. 33.
    Umemura T, Tanaka E, Ostapowicz G, et al. Investigation of SEN virus infection in patients with cryptogenic acute liver failure, hepatitis-associated aplastic anemia, or acute and chronic non-A-E hepatitis. J Infect Dis. 2003;188:1545–1552.PubMedCrossRefGoogle Scholar
  34. 34.
    Dinh MH, Stosor V, Rao SM, Miller FH, Green RM. Cryptogenic liver disease in HIV-seropositive men. HIV Med. 2009;10:447–453.PubMedCrossRefGoogle Scholar
  35. 35.
    Gotti D, Foca E, Albini L, et al. Cryptogenic liver diseases: sailing by sight from HIV co-infection with hepatitis viruses to HIV mono-infection through the Pillars of Hercules. Curr HIV Res. 2011;9:61–69.PubMedCrossRefGoogle Scholar
  36. 36.
    Volta U, De Franceschi L, Lari F, et al. Coeliac disease hidden by cryptogenic hypertransaminasaemia. Lancet. 1998;352:26–29.PubMedCrossRefGoogle Scholar
  37. 37.
    Volta U, Granito A, De Franceschi L, Petrolini N, Bianchi FB. Anti tissue transglutaminase antibodies as predictors of silent coeliac disease in patients with hypertransaminasaemia of unknown origin. Dig Liver Dis. 2001;33:420–425.PubMedCrossRefGoogle Scholar
  38. 38.
    Kaukinen K, Halme L, Collin P, et al. Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure. Gastroenterology. 2002;122:881–888.PubMedCrossRefGoogle Scholar
  39. 39.
    Abdo A, Meddings J, Swain M. Liver abnormalities in celiac disease. Clin Gastroenterol Hepatol. 2004;2:107–112.PubMedCrossRefGoogle Scholar
  40. 40.
    Volta U. Liver dysfunction in celiac disease. Minerva Med. 2008;99:619–629.PubMedGoogle Scholar
  41. 41.
    Volta U. Pathogenesis and clinical significance of liver injury in celiac disease. Clin Rev Allergy Immunol. 2009;36:62–70.PubMedCrossRefGoogle Scholar
  42. 42.
    Czaja AJ, Taswell HF, Rakela J, Schimek CM. Frequency and significance of antibody to hepatitis C virus in severe corticosteroid-treated cryptogenic chronic active hepatitis. Mayo Clin Proc. 1990;65:1303–1313.PubMedGoogle Scholar
  43. 43.
    Diodati G, Tagger A, Bonetti P, et al. Antibody to hepatitis C virus in cryptogenic chronic liver disease. J Medical Virol. 1991;35:151–154.CrossRefGoogle Scholar
  44. 44.
    Barnes RE, Meyer RA, Gordon SC. Prevalence of anti-HCV in cryptogenic cirrhosis in a suburban Detroit community. Am J Gastroenterol. 1992;87:1001–1004.PubMedGoogle Scholar
  45. 45.
    Jeffers LJ, Hasan F, De Medina M, et al. Prevalence of antibodies to hepatitis C virus among patients with cryptogenic chronic hepatitis and cirrhosis. Hepatology. 1992;15:187–190.PubMedCrossRefGoogle Scholar
  46. 46.
    Czaja AJ, Taswell HF, Rakela J, Schimek C. Frequency of antibody to hepatitis C virus in asymptomatic HBsAg-negative chronic active hepatitis. J Hepatol. 1992;14:88–93.PubMedCrossRefGoogle Scholar
  47. 47.
    Brown J, Dourakis S, Karayiannis P, et al. Seroprevalence of hepatitis C virus nucleocapsid antibodies in patients with cryptogenic chronic liver disease. Hepatology. 1992;15:175–179.PubMedCrossRefGoogle Scholar
  48. 48.
    Schmidt WN, Wu P, Cederna J, et al. Surreptitious hepatitis C virus (HCV) infection detected in the majority of patients with cryptogenic chronic hepatitis and negative HCV antibody tests. J Infect Dis. 1997;176:27–33.PubMedCrossRefGoogle Scholar
  49. 49.
    Januszkiewicz-Lewandowska D, Wysocki J, Jozwiak H, et al. Significance of molecular identification of hepatitis C virus RNA in diagnosis of cryptogenic hepatitis in children. Acta Virol. 2001;45:257–260.PubMedGoogle Scholar
  50. 50.
    Poonawala A, Nair SP, Thuluvath PJ. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology. 2000;32:689–692.PubMedCrossRefGoogle Scholar
  51. 51.
    Sakugawa H, Nakasone H, Nakayoshi T, et al. Clinical characteristics of patients with cryptogenic liver cirrhosis in Okinawa, Japan. Hepatogastroenterology. 2003;50:2005–2008.PubMedGoogle Scholar
  52. 52.
    Sutedja DS, Gow PJ, Hubscher SG, Elias E. Revealing the cause of cryptogenic cirrhosis by posttransplant liver biopsy. Transpl Proc. 2004;36:2334–2337.CrossRefGoogle Scholar
  53. 53.
    Yalamanchili K, Saadeh S, Klintmalm GB, Jennings LW, Davis GL. Nonalcoholic fatty liver disease after liver transplantation for cryptogenic cirrhosis or nonalcoholic fatty liver disease. Liver Transpl. 2010;16:431–439.PubMedGoogle Scholar
  54. 54.
    Marmur J, Bergquist A, Stal P. Liver transplantation of patients with cryptogenic cirrhosis: clinical characteristics and outcome. Scand J Gastroenterol. 2010;45:60–69.PubMedCrossRefGoogle Scholar
  55. 55.
    Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11:74–80.PubMedCrossRefGoogle Scholar
  56. 56.
    Mulhall BP, Ong JP, Younossi ZM. Non-alcoholic fatty liver disease: an overview. J Gastroenterol Hepatol. 2002;17:1136–1143.PubMedCrossRefGoogle Scholar
  57. 57.
    Preiss D, Sattar N. Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci (Lond). 2008;115:141–150.CrossRefGoogle Scholar
  58. 58.
    Oh MK, Winn J, Poordad F. Review article: diagnosis and treatment of non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;28:503–522.PubMedCrossRefGoogle Scholar
  59. 59.
    Nayak NC, Vasdev N, Saigal S, Soin AS. End-stage nonalcoholic fatty liver disease: evaluation of pathomorphologic features and relationship to cryptogenic cirrhosis from study of explant livers in a living donor liver transplant program. Human Pathol. 2010;41:425–430.CrossRefGoogle Scholar
  60. 60.
    Duclos-Vallee JC, Yilmaz F, Johanet C, et al. Could post-liver transplantation course be helpful for the diagnosis of so called cryptogenic cirrhosis? Clin Transpl. 2005;19:591–599.CrossRefGoogle Scholar
  61. 61.
    Gassert DJ, Garcia H, Tanaka K, Reinus JF. Corticosteroid-responsive cryptogenic chronic hepatitis: evidence for seronegative autoimmune hepatitis. Dig Dis Sci. 2007;52:2433–2437.PubMedCrossRefGoogle Scholar
  62. 62.
    Potthoff A, Deterding K, Trautwein C, et al. Steroid treatment for severe acute cryptogenic hepatitis. Z Gastroenterol. 2007;45:15–19.PubMedCrossRefGoogle Scholar
  63. 63.
    Heringlake S, Schutte A, Flemming P, et al. Presumed cryptogenic liver disease in Germany: high prevalence of autoantibody-negative autoimmune hepatitis, low prevalence of NASH, no evidence for occult viral etiology. Z Gastroenterol. 2009;47:417–423.PubMedCrossRefGoogle Scholar
  64. 64.
    Chitturi S, Farrell GC. Drug-induced liver disease. Curr Treat Options Gastroenterol. 2000;3:457–462.PubMedCrossRefGoogle Scholar
  65. 65.
    Czaja AJ. Behavior and significance of autoantibodies in type 1 autoimmune hepatitis. J Hepatol. 1999;30:394–401.PubMedCrossRefGoogle Scholar
  66. 66.
    Montano-Loza AJ, Carpenter HA, Czaja AJ. Frequency, behavior, and prognostic implications of antimitochondrial antibodies in type 1 autoimmune hepatitis. J Clin Gastroenterol. 2008;42:1047–1053.PubMedCrossRefGoogle Scholar
  67. 67.
    Montano-Loza AJ, Shums Z, Norman GL, Czaja AJ. Prognostic implications of antibodies to Ro/SSA and soluble liver antigen in type 1 autoimmune hepatitis. Liver Int. 2011/08/03.Google Scholar
  68. 68.
    Czaja AJ, Taswell HF, Rakela J, Rabe D. Duration and specificity of antibodies to hepatitis C virus in chronic active hepatitis. Gastroenterology. 1992;102:1675–1679.PubMedGoogle Scholar
  69. 69.
    Greeve M, Ferrell L, Kim M, et al. Cirrhosis of undefined pathogenesis: absence of evidence for unknown viruses or autoimmune processes. Hepatology. 1993;17:593–598.PubMedCrossRefGoogle Scholar
  70. 70.
    Charlton MR, Kondo M, Roberts SK, et al. Liver transplantation for cryptogenic cirrhosis. Liver Transpl Surg. 1997;3:359–364.PubMedCrossRefGoogle Scholar
  71. 71.
    MacSween RN, Scott AR. Hepatic cirrhosis: a clinico-pathological review of 520 cases. J Clin Pathol. 1973;26:936–942.PubMedCrossRefGoogle Scholar
  72. 72.
    Rajeshwari K, Gogia S. The clinical spectrum of chronic liver disease in children presenting to a tertiary level teaching hospital in New Delhi. Trop Doct. 2008;38:101–102.PubMedCrossRefGoogle Scholar
  73. 73.
    Tanaka N, Tanaka E, Sheena Y, et al. Useful parameters for distinguishing nonalcoholic steatohepatitis with mild steatosis from cryptogenic chronic hepatitis in the Japanese population. Liver Inter. 2006;26:956–963.CrossRefGoogle Scholar
  74. 74.
    de Ledinghen V, Combes M, Trouette H, et al. Should a liver biopsy be done in patients with subclinical chronically elevated transaminases? Eur J Gastroenterol Hepatol. 2004;16:879–883.PubMedCrossRefGoogle Scholar
  75. 75.
    Ku NO, Gish R, Wright TL, Omary MB. Keratin 8 mutations in patients with cryptogenic liver disease. N Engl J Med. 2001;344:1580–1587.PubMedCrossRefGoogle Scholar
  76. 76.
    Bahar RJ, Yanni GS, Martin MG, et al. Orthotopic liver transplantation for autoimmune hepatitis and cryptogenic chronic hepatitis in children. Transplantation. 2001;72:829–833.PubMedCrossRefGoogle Scholar
  77. 77.
    Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003;98:960–967.PubMedCrossRefGoogle Scholar
  78. 78.
    Hay JE, Czaja AJ, Rakela J, Ludwig J. The nature of unexplained chronic aminotransferase elevations of a mild to moderate degree in asymptomatic patients. Hepatology. 1989;9:193–197.PubMedCrossRefGoogle Scholar
  79. 79.
    Mathiesen UL, Franzen LE, Fryden A, Foberg U, Bodemar G. The clinical significance of slightly to moderately increased liver transaminase values in asymptomatic patients. Scand J Gastroenterol. 1999;34:85–91.PubMedCrossRefGoogle Scholar
  80. 80.
    Lo Iacono O, Petta S, Venezia G, et al. Anti-tissue transglutaminase antibodies in patients with abnormal liver tests: is it always coeliac disease? Am J Gastroenterol. 2005;100:2472–2477.PubMedCrossRefGoogle Scholar
  81. 81.
    Thakur V, Guptan RC, Hashmi AZ, et al. Absence of hemochromatosis associated Cys282Tyr HFE gene mutation and low frequency of hemochromatosis phenotype in nonalcoholic chronic liver disease patients in India. J Gastroenterol Hepatol. 2004;19:86–90.PubMedCrossRefGoogle Scholar
  82. 82.
    Czaja AJ. Autoimmune hepatitis. Part B: diagnosis. Expert Rev Gastroenterol Hepatol. 2007;1:129–143.PubMedCrossRefGoogle Scholar
  83. 83.
    Czaja AJ, Manns MP. Advances in the diagnosis, pathogenesis and management of autoimmune hepatitis. Gastroenterology. 2010;139:58–72.PubMedCrossRefGoogle Scholar
  84. 84.
    Manns MP, Czaja AJ, Gorham JD, et al. Practice guidelines of the American association for the study of liver diseases. Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51:2193–2213.PubMedCrossRefGoogle Scholar
  85. 85.
    Czaja AJ. Autoimmune hepatitis. Part A: pathogenesis. Expert Rev Gastroenterol Hepatol. 2007;1:113–128.PubMedCrossRefGoogle Scholar
  86. 86.
    Czaja AJ. Performance parameters of the conventional serological markers for autoimmune hepatitis. Dig Dis Sci. 2011;56:545–554.PubMedCrossRefGoogle Scholar
  87. 87.
    Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48:169–176.PubMedCrossRefGoogle Scholar
  88. 88.
    Czaja AJ. The role of autoantibodies as diagnostic markers of autoimmune hepatitis. Expert Rev Clin Immunol. 2006;2:33–48.PubMedCrossRefGoogle Scholar
  89. 89.
    Alvarez F, Berg PA, Bianchi FB, et al. International autoimmune hepatitis group report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929–938.PubMedCrossRefGoogle Scholar
  90. 90.
    Czaja AJ, Carpenter HA. Validation of scoring system for diagnosis of autoimmune hepatitis. Dig Dis Sci. 1996;41:305–314.PubMedCrossRefGoogle Scholar
  91. 91.
    Czaja AJ. Performance parameters of the diagnostic scoring systems for autoimmune hepatitis. Hepatology. 2008;48:1540–1548.PubMedCrossRefGoogle Scholar
  92. 92.
    Pratt DS, Fawaz KA, Rabson A, Dellelis R, Kaplan MM. A novel histological lesion in glucocorticoid-responsive chronic hepatitis. Gastroenterology. 1997;113:664–668.PubMedCrossRefGoogle Scholar
  93. 93.
    Okano N, Yamamoto K, Sakaguchi K, et al. Clinicopathological features of acute-onset autoimmune hepatitis. Hepatol Res. 2003;25:263–270.PubMedCrossRefGoogle Scholar
  94. 94.
    Misdraji J, Thiim M, Graeme-Cook FM. Autoimmune hepatitis with centrilobular necrosis. Am J Surg Pathol. 2004;28:471–478.PubMedCrossRefGoogle Scholar
  95. 95.
    Kessler WR, Cummings OW, Eckert G, et al. Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis. Clin Gastroenterol Hepatol. 2004;2:625–631.PubMedCrossRefGoogle Scholar
  96. 96.
    Ludwig J, Czaja AJ, Dickson ER, LaRusso NF, Wiesner RH. Manifestations of nonsuppurative cholangitis in chronic hepatobiliary diseases: morphologic spectrum, clinical correlations and terminology. Liver. 1984;4:105–116.PubMedGoogle Scholar
  97. 97.
    Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Autoimmune cholangitis within the spectrum of autoimmune liver disease. Hepatology. 2000;31:1231–1238.PubMedCrossRefGoogle Scholar
  98. 98.
    Czaja AJ, Muratori P, Muratori L, Carpenter HA, Bianchi FB. Diagnostic and therapeutic implications of bile duct injury in autoimmune hepatitis. Liver Int. 2004;24:322–329.PubMedCrossRefGoogle Scholar
  99. 99.
    Kaymakoglu S, Cakaloglu Y, Demir K, et al. Is severe cryptogenic chronic hepatitis similar to autoimmune hepatitis? J Hepatol. 1998;28:78–83.PubMedCrossRefGoogle Scholar
  100. 100.
    Czaja AJ. Autoantibodies as prognostic markers in autoimmune liver disease. Dig Dis Sci. 2010;55:2144–2161.PubMedCrossRefGoogle Scholar
  101. 101.
    Czaja AJ, Shums Z, Norman GL. Frequency and significance of antibodies to soluble liver antigen/liver pancreas in variant autoimmune hepatitis. Autoimmunity. 2002;35:475–483.PubMedCrossRefGoogle Scholar
  102. 102.
    Targan SR, Landers C, Vidrich A, Czaja AJ. High-titer antineutrophil cytoplasmic antibodies in type-1 autoimmune hepatitis. Gastroenterology. 1995;108:1159–1166.PubMedCrossRefGoogle Scholar
  103. 103.
    Bansi D, Chapman R, Fleming K. Antineutrophil cytoplasmic antibodies in chronic liver diseases: prevalence, titre, specificity and IgG subclass. J Hepatol. 1996;24:581–586.PubMedCrossRefGoogle Scholar
  104. 104.
    Terjung B, Bogsch F, Klein R, et al. Diagnostic accuracy of atypical p-ANCA in autoimmune hepatitis using ROC- and multivariate regression analysis. Eur J Med Res. 2004;9:439–448.PubMedGoogle Scholar
  105. 105.
    Johnson PJ, McFarlane IG, McFarlane BM, Williams R. Auto-immune features in patients with idiopathic chronic active hepatitis who are seronegative for conventional auto-antibodies. J Gastroenterol Hepatol. 1990;5:244–251.PubMedCrossRefGoogle Scholar
  106. 106.
    Czaja AJ, Shums Z, Norman GL. Nonstandard antibodies as prognostic markers in autoimmune hepatitis. Autoimmunity. 2004;37:195–201.PubMedCrossRefGoogle Scholar
  107. 107.
    Czaja AJ, Manns MP, Homburger HA. Frequency and significance of antibodies to liver/kidney microsome type 1 in adults with chronic active hepatitis. Gastroenterology. 1992;103:1290–1295.PubMedGoogle Scholar
  108. 108.
    Geller SA, Nichols WS, Rojter SE, et al. Hepatitis C virus is not recoverable from liver tissue in cryptogenic cirrhosis: failure to identify hepatitis C virus-RNA using reverse transcription-mediated polymerase chain reaction. Hum Pathol. 1996;27:1161–1165.PubMedCrossRefGoogle Scholar
  109. 109.
    Iorio R, Pensati P, Botta S, et al. Chronic cryptogenic hepatitis in childhood is unrelated to hepatitis G virus. Pediatr Infect Dis J. 1999;18:347–351.PubMedCrossRefGoogle Scholar
  110. 110.
    Syn WK, Nightingale P, Gunson B, Hubscher SG, Neuberger JM. Natural history of unexplained chronic hepatitis after liver transplantation. Liver Transpl. 2007;13:984–989.PubMedCrossRefGoogle Scholar
  111. 111.
    Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–438.PubMedGoogle Scholar
  112. 112.
    Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–1231.PubMedCrossRefGoogle Scholar
  113. 113.
    Skelly MM, James PD, Ryder SD. Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol. 2001;35:195–199.PubMedCrossRefGoogle Scholar
  114. 114.
    Licata A, Nebbia ME, Cabibbo G, et al. Hyperferritinemia is a risk factor for steatosis in chronic liver disease. World J Gastroenterol. 2009;15:2132–2138.PubMedCrossRefGoogle Scholar
  115. 115.
    Czaja AJ. Recurrence of nonalcoholic steatohepatitis after liver transplantation. Liver Transpl Surg. 1997;3:185–186.PubMedCrossRefGoogle Scholar
  116. 116.
    Contos MJ, Cales W, Sterling RK, et al. Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis. Liver Transpl. 2001;7:363–373.PubMedCrossRefGoogle Scholar
  117. 117.
    Chagas AL, Kikuchi LO, Oliveira CP, et al. Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients? Braz J Med Biol Res. 2009;42:958–962.PubMedCrossRefGoogle Scholar
  118. 118.
    Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140.PubMedCrossRefGoogle Scholar
  119. 119.
    Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Host- and disease-specific factors affecting steatosis in chronic hepatitis C. J Hepatol. 1998;29:198–206.PubMedCrossRefGoogle Scholar
  120. 120.
    Powell EE, Jonsson JR, Clouston AD. Metabolic factors and non-alcoholic fatty liver disease as co-factors in other liver diseases. Dig Dis. 2010;28:186–191.PubMedCrossRefGoogle Scholar
  121. 121.
    Kaviani MJ, Behbahani B, Mosallaii MJ, Sari-Aslani F, Taghavi SA. Occult hepatitis B virus infection and cryptogenic chronic hepatitis in an area with intermediate prevalence of HBV infection. World J Gastroenterol. 2006;12:5048–5050.PubMedGoogle Scholar
  122. 122.
    De Filippi F, Fraquelli M, Conte D, et al. High prevalence but low pathogenicity of hepatitis G virus infection in Italian patients with genetic haemochromatosis. Ital J Gastroenterol Hepatol. 1998;30:529–533.PubMedGoogle Scholar
  123. 123.
    Tagger A, Ribero ML, Larghi A, et al. Prevalence of GB virus-C/hepatitis G virus infection in patients with cryptogenic chronic liver disease and in patients with primary biliary cirrhosis or Wilson’s disease. Am J Gastroenterol. 1999;94:484–488.PubMedCrossRefGoogle Scholar
  124. 124.
    Dalton HR, Bendall R, Ijaz S, Banks M. Hepatitis E: an emerging infection in developed countries. Lancet Infect Dis. 2008;8:698–709.PubMedCrossRefGoogle Scholar
  125. 125.
    Madejon A, Vispo E, Bottecchia M, et al. Lack of hepatitis E virus infection in HIV patients with advanced immunodeficiency or idiopathic liver enzyme elevations. J Viral Hepat. 2009;16:895–896.PubMedCrossRefGoogle Scholar
  126. 126.
    Kwo PY, Schlauder GG, Carpenter HA, et al. Acute hepatitis E by a new isolate acquired in the United States. Mayo Clin Proc. 1997;72:1133–1136.PubMedCrossRefGoogle Scholar
  127. 127.
    Piaggio F, Dodi F, Bottino G, et al. Torque teno virus—cause of viral liver disease following liver transplantation: a case report. Transpl Proc. 2009;41:1378–1379.CrossRefGoogle Scholar
  128. 128.
    Irshad M, Mandal K, Singh S, Agarwal SK. Torque teno virus infection in hemodialysis patients in North India. Int Urol Nephrol. 2010;42:1077–1083.PubMedCrossRefGoogle Scholar
  129. 129.
    Tsuge M, Noguchi C, Akiyama R, et al. G to A hypermutation of TT virus. Virus Res. 2010;149:211–216.PubMedCrossRefGoogle Scholar
  130. 130.
    Asim M, Singla R, Gupta RK, Kar P. Clinical and molecular characterization of human TT virus in different liver diseases. Indian J Med Res. 2010;131:545–554.PubMedGoogle Scholar
  131. 131.
    Akiba J, Umemura T, Alter HJ, Kojiro M, Tabor E. SEN virus: epidemiology and characteristics of a transfusion-transmitted virus. Transfusion. 2005;45:1084–1088.PubMedCrossRefGoogle Scholar
  132. 132.
    Omar M, El-Din SS, Fam N, et al. SEN virus infection in Egyptian patients with chronic hepatitis C and patients undergoing hemodialysis. Medscape J Med. 2008;10:290.Google Scholar
  133. 133.
    Loutfy SA, Hafez MM, Massoud WA, et al. SEN virus infection in Egyptian patients undergoing maintenance hemodialysis: prevalence and clinical importance. J Microbiol Immunol Infect. 2009;42:464–470.PubMedGoogle Scholar
  134. 134.
    Karimi-Rastehkenari A, Bouzari M. High frequency of SEN virus infection in thalassemic patients and healthy blood donors in Iran. Virol J. 2010;7:1.PubMedCrossRefGoogle Scholar
  135. 135.
    Brandhagen DJ, Fairbanks VF, Batts KP, Thibodeau SN. Update on hereditary hemochromatosis and the HFE gene. Mayo Clin Proc. 1999;74:917–921.PubMedCrossRefGoogle Scholar
  136. 136.
    Adams PC. Population screening for hemochromatosis. Hepatology. 1999;29:1324–1327.PubMedCrossRefGoogle Scholar
  137. 137.
    Adams PC. Nonexpressing homozygotes for C282Y hemochromatosis: minority or majority of cases? Mol Genet Metab. 2000;71:81–86.PubMedCrossRefGoogle Scholar
  138. 138.
    Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G–>A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002;359:211–218.PubMedCrossRefGoogle Scholar
  139. 139.
    Adams PC, Passmore L, Chakrabarti S, et al. Liver diseases in the hemochromatosis and iron overload screening study. Clin Gastroenterol Hepatol. 2006;4:918–923.PubMedCrossRefGoogle Scholar
  140. 140.
    Dever JB, Mallory MA, Mallory JE, Wallace D, Kowdley KV. Phenotypic characteristics and diagnoses of patients referred to an iron overload clinic. Dig Dis Sci. 2010;55:803–807.PubMedCrossRefGoogle Scholar
  141. 141.
    Fracanzani AL, Piperno A, Valenti L, et al. Hemochromatosis in Italy in the last 30 years: role of genetic and acquired factors. Hepatology. 2010;51:501–510.PubMedCrossRefGoogle Scholar
  142. 142.
    Mayr R, Janecke AR, Schranz M, et al. Ferroportin disease: a systematic meta-analysis of clinical and molecular findings. J Hepatol. 2010;53:941–949.PubMedCrossRefGoogle Scholar
  143. 143.
    Le Lan C, Mosser A, Ropert M, et al. Sex and acquired cofactors determine phenotypes of ferroportin disease. Gastroenterology. 2011;140:1199–1207, e1192.Google Scholar
  144. 144.
    Gattoni A, Parlato A, Vangieri B, et al. Role of hemochromatosis genes in chronic hepatitis C. Clin Ter. 2006;157:61–68.PubMedGoogle Scholar
  145. 145.
    Sebastiani G, Vario A, Ferrari A, et al. Hepatic iron, liver steatosis and viral genotypes in patients with chronic hepatitis C. J Viral Hepat. 2006;13:199–205.PubMedCrossRefGoogle Scholar
  146. 146.
    Bonkovsky HL, Naishadham D, Lambrecht RW, et al. Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology. 2006;131:1440–1451.PubMedCrossRefGoogle Scholar
  147. 147.
    Ferrara F, Ventura P, Vegetti A, et al. Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C. Am J Gastroenterol. 2009;104:605–616.PubMedCrossRefGoogle Scholar
  148. 148.
    Isom HC, McDevitt EI, Moon MS. Elevated hepatic iron: a confounding factor in chronic hepatitis C. Biochim Biophys Acta. 2009;1790:650–662.PubMedCrossRefGoogle Scholar
  149. 149.
    Carneiro MV, Souza FF, Teixeira AC, et al. The H63D genetic variant of the HFE gene is independently associated with the virological response to interferon and ribavirin therapy in chronic hepatitis C. Eur J Gastroenterol Hepatol. 2010;22:1204–1210.PubMedCrossRefGoogle Scholar
  150. 150.
    Lambrecht RW, Sterling RK, Naishadham D, et al. Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C. Gastroenterology. 2011;140:1490–1500.Google Scholar
  151. 151.
    Conte D, Corsetti M, Colli A, et al. Iron-related indexes in chronic alcoholics. Effect of alcohol withdrawal. Ital J Gastroenterol Hepatol. 1998;30:534–538.PubMedGoogle Scholar
  152. 152.
    Kohgo Y, Ohtake T, Ikuta K, et al. Iron accumulation in alcoholic liver diseases. Alcohol Clin Exp Res. 2005;29:189S–193S.PubMedCrossRefGoogle Scholar
  153. 153.
    Hernaez R, Yeung E, Clark JM, et al. Hemochromatosis gene and nonalcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol. 2011/02/24.Google Scholar
  154. 154.
    Lam M, Torbenson M, Yeh MM, Vivekanandan P, Ferrell L. HFE mutations in alpha-1-antitrypsin deficiency: an examination of cirrhotic explants. Mod Pathol. 2010;23:637–643.PubMedCrossRefGoogle Scholar
  155. 155.
    Sikorska K, Stalke P, Izycka-Swieszewska E, Romanowski T, Bielawski KP. The role of iron overload and HFE gene mutations in the era of pegylated interferon and ribavirin treatment of chronic hepatitis C. Med Sci Monit. 2010;16:CR137–CR143.Google Scholar
  156. 156.
    Lal P, Fernandes H, Koneru B, Albanese E, Hameed M. C282Y mutation and hepatic iron status in hepatitis C and cryptogenic cirrhosis. Arch Pathol Lab Med. 2000;124:1632–1635.PubMedGoogle Scholar
  157. 157.
    Panigrahi I, Ahmad F, Kapoor R, et al. Evidence for non-HFE linked hemochromatosis in Asian Indians. Indian J Med Sci. 2006;60:491–495.PubMedCrossRefGoogle Scholar
  158. 158.
    Elzouki AN, Eriksson S. Risk of hepatobiliary disease in adults with severe alpha 1-antitrypsin deficiency (PiZZ): is chronic viral hepatitis B or C an additional risk factor for cirrhosis and hepatocellular carcinoma? Eur J Gastroenterol Hepatol. 1996;8:989–994.PubMedCrossRefGoogle Scholar
  159. 159.
    Morin T, Martin JP, Feldmann G, et al. Heterozygous alpha 1-antitrypsin deficiency and cirrhosis in adults, a fortuitous association. Lancet. 1975;1:250–251.PubMedCrossRefGoogle Scholar
  160. 160.
    Feld RD. Heterozygosity of alpha 1-antitrypsin: a health risk? Crit Rev Clin Lab Sci. 1989;27:461–481.PubMedCrossRefGoogle Scholar
  161. 161.
    Eriksson S. Liver disease and intermediate alpha 1-antitrypsin deficiency. Acta Med Scand. 1981;210:241–244.PubMedCrossRefGoogle Scholar
  162. 162.
    Bals R. Alpha-1-antitrypsin deficiency. Best Pract Res Clin Gastroenterol. 2010;24:629–633.PubMedCrossRefGoogle Scholar
  163. 163.
    Davies LP, Macintyre G, Cox DW. New mutations in the Wilson disease gene, ATP7B: implications for molecular testing. Genet Test. 2008;12:139–145.PubMedCrossRefGoogle Scholar
  164. 164.
    Ferenci P, Czlonkowska A, Merle U, et al. Late-onset Wilson’s disease. Gastroenterology. 2007;132:1294–1298.PubMedCrossRefGoogle Scholar
  165. 165.
    Xuan A, Bookman I, Cox DW, Heathcote J. Three atypical cases of Wilson disease: assessment of the Leipzig scoring system in making a diagnosis. J Hepatol. 2007;47:428–433.PubMedCrossRefGoogle Scholar
  166. 166.
    Ferenci P, Caca K, Loudianos G, et al. Diagnosis and phenotypic classification of Wilson disease. Liver Int. 2003;23:139–142.PubMedCrossRefGoogle Scholar
  167. 167.
    Mak CM, Lam CW. Diagnosis of Wilson’s disease: a comprehensive review. Crit Rev Clin Lab Sci. 2008;45:263–290.PubMedCrossRefGoogle Scholar
  168. 168.
    Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47:2089–2111.PubMedCrossRefGoogle Scholar
  169. 169.
    Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology. 2008;48:1167–1174.PubMedCrossRefGoogle Scholar
  170. 170.
    Schilsky ML. Wilson disease: current status and the future. Biochimie. 2009;91:1278–1281.PubMedCrossRefGoogle Scholar
  171. 171.
    Tanzi RE, Petrukhin K, Chernov I, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993;5:344–350.PubMedCrossRefGoogle Scholar
  172. 172.
    Caca K, Ferenci P, Kuhn HJ, et al. High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis. J Hepatol. 2001;35:575–581.PubMedCrossRefGoogle Scholar
  173. 173.
    Firneisz G, Lakatos PL, Szalay F, et al. Common mutations of ATP7B in Wilson disease patients from Hungary. Am J Med Genet. 2002;108:23–28.PubMedCrossRefGoogle Scholar
  174. 174.
    Mugica F, Castiella A, Otazua P, et al. Prevalence of coeliac disease in unexplained chronic hypertransaminasemia. Rev Esp Enferm Dig. 2001;93:707–714.PubMedGoogle Scholar
  175. 175.
    Bardella MT, Fraquelli M, Quatrini M, et al. Prevalence of hypertransaminasemia in adult celiac patients and effect of gluten-free diet. Hepatology. 1995;22:833–836.PubMedGoogle Scholar
  176. 176.
    Sedlack RE, Smyrk TC, Czaja AJ, Talwalkar JA. Celiac disease-associated autoimmune cholangitis. Am J Gastroenterol. 2002;97:3196–3198.PubMedCrossRefGoogle Scholar
  177. 177.
    Volta U, De Franceschi L, Molinaro N, et al. Frequency and significance of anti-gliadin and anti-endomysial antibodies in autoimmune hepatitis. Dig Dis Sci. 1998;43:2190–2195.PubMedCrossRefGoogle Scholar
  178. 178.
    Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults—the evidence report. National Institutes of Health. Obes Res. 1998;6:51S–209S.Google Scholar
  179. 179.
    Janssen I, Katzmarzyk PT, Ross R. Body mass index, waist circumference, and health risk: evidence in support of current National Institutes of Health guidelines. Arch Intern Med. 2002;162:2074–2079.PubMedCrossRefGoogle Scholar
  180. 180.
    Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology. 1994;107:1103–1109.PubMedGoogle Scholar
  181. 181.
    Goldstein NS, Kodali VP, Gordon SC. Histologic spectrum of cryptogenic chronic liver disease and comparison with chronic autoimmune and chronic type C hepatitis. Am J Clin Pathol. 1995;104:567–573.PubMedGoogle Scholar
  182. 182.
    Czaja AJ, Carpenter HA. Sensitivity, specificity, and predictability of biopsy interpretations in chronic hepatitis. Gastroenterology. 1993;105:1824–1832.PubMedGoogle Scholar
  183. 183.
    Czaja AJ, Carpenter HA. Histological findings in chronic hepatitis C with autoimmune features. Hepatology. 1997;26:459–466.PubMedCrossRefGoogle Scholar
  184. 184.
    Hall P, Herrmann R, Brennan J, Mackinnon M. Detection of alpha-1-antitrypsin in hepatocytes in acute and chronic hepatitis. Pathology. 1987;19:415–418.PubMedCrossRefGoogle Scholar
  185. 185.
    Morisco F, Pagliaro L, Caporaso N, et al. Consensus recommendations for managing asymptomatic persistent non-virus non-alcohol related elevation of aminotransferase levels: suggestions for diagnostic procedures and monitoring. Dig Liver Dis. 2008;40:585–598.PubMedCrossRefGoogle Scholar
  186. 186.
    Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci. 2011;56:958–976.PubMedCrossRefGoogle Scholar
  187. 187.
    Perdigoto R, Carpenter HA, Czaja AJ. Frequency and significance of chronic ulcerative colitis in severe corticosteroid-treated autoimmune hepatitis. J Hepatol. 1992;14:325–331.PubMedCrossRefGoogle Scholar
  188. 188.
    Abdalian R, Dhar P, Jhaveri K, et al. Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: evaluating the role of routine magnetic resonance imaging. Hepatology. 2008;47:949–957.PubMedCrossRefGoogle Scholar
  189. 189.
    Lewin M, Vilgrain V, Ozenne V, et al. Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: a prospective magnetic resonance imaging and histological study. Hepatology. 2009;50:528–537.PubMedCrossRefGoogle Scholar
  190. 190.
    Fink S, Schilsky ML. Inherited metabolic disease of the liver. Curr Opin Gastroenterol. 2007;23:237–243.PubMedCrossRefGoogle Scholar
  191. 191.
    Czaja AJ, Norman GL. Autoantibodies in the diagnosis and management of liver disease. J Clin Gastroenterol. 2003;37:315–329.PubMedCrossRefGoogle Scholar
  192. 192.
    Czaja AJ. Autoantibodies in autoimmune liver disease. Adv Clin Chem. 2005;40:127–164.PubMedCrossRefGoogle Scholar
  193. 193.
    Czaja AJ, Carpenter HA. Optimizing diagnosis from the medical liver biopsy. Clin Gastroenterol Hepatol. 2007;5:898–907.PubMedCrossRefGoogle Scholar
  194. 194.
    Bittencourt PL, Farias AQ, Porta G, et al. Frequency of concurrent autoimmune disorders in patients with autoimmune hepatitis: effect of age, gender, and genetic background. J Clin Gastroenterol. 2008;42:300–305.PubMedGoogle Scholar
  195. 195.
    Czaja AJ, Carpenter HA. Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly. Hepatology. 2006;43:532–538.PubMedCrossRefGoogle Scholar
  196. 196.
    Ku NO, Wright TL, Terrault NA, Gish R, Omary MB. Mutation of human keratin 18 in association with cryptogenic cirrhosis. J Clin Invest. 1997;99:19–23.PubMedCrossRefGoogle Scholar
  197. 197.
    Tweezer-Zaks N, Doron-Libner A, Weiss P, et al. Familial Mediterranean fever and cryptogenic cirrhosis. Medicine (Baltimore). 2007;86:355–362.CrossRefGoogle Scholar
  198. 198.
    Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord. 2002;26:1407–1433.PubMedCrossRefGoogle Scholar
  199. 199.
    Brennan AM, Mantzoros CS. Drug Insight: the role of leptin in human physiology and pathophysiology—emerging clinical applications. Nat Clin Pract Endocrinol Metab. 2006;2:318–327.PubMedCrossRefGoogle Scholar
  200. 200.
    Liangpunsakul S, Chalasani N. Relationship between unexplained elevations in alanine aminotransferase and serum leptin in U.S. adults: results from the third national health and nutrition examination survey (NHANES III). J Clin Gastroenterol. 2004;38:891–897.PubMedCrossRefGoogle Scholar
  201. 201.
    Angulo P, Alba LM, Petrovic LM, et al. Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease. J Hepatol. 2004;41:943–949.PubMedCrossRefGoogle Scholar
  202. 202.
    Charlton M, Angulo P, Chalasani N, et al. Low circulating levels of dehydroepiandrosterone in histologically advanced nonalcoholic fatty liver disease. Hepatology. 2008;47:484–492.PubMedCrossRefGoogle Scholar
  203. 203.
    Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–1465.Google Scholar
  204. 204.
    Czaja AJ, dos Santos RM, Porto A, Santrach PJ, Moore SB. Immune phenotype of chronic liver disease. Dig Dis Sci. 1998;43:2149–2155.PubMedCrossRefGoogle Scholar
  205. 205.
    Czaja AJ, Donaldson PT. Gender effects and synergisms with histocompatibility leukocyte antigens in type 1 autoimmune hepatitis. Am J Gastroenterol. 2002;97:2051–2057.PubMedCrossRefGoogle Scholar
  206. 206.
    Miozzo M, Selmi C, Gentilin B, et al. Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis. Hepatology. 2007;46:456–462.PubMedCrossRefGoogle Scholar
  207. 207.
    Donaldson PT, Doherty DG, Hayllar KM, et al. Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors. Hepatology. 1991;13:701–706.PubMedCrossRefGoogle Scholar
  208. 208.
    Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Significance of HLA DR4 in type 1 autoimmune hepatitis. Gastroenterology. 1993;105:1502–1507.PubMedCrossRefGoogle Scholar
  209. 209.
    Czaja AJ, Strettell MD, Thomson LJ, et al. Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis. Hepatology. 1997;25:317–323.PubMedCrossRefGoogle Scholar
  210. 210.
    Czaja AJ. Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis. Clin Gastroenterol Hepatol. 2008;6:379–388.PubMedCrossRefGoogle Scholar
  211. 211.
    Giannini EG, Marabotto E, Savarino V, et al. Hepatocellular carcinoma in patients with cryptogenic cirrhosis. Clin Gastroenterol Hepatol. 2009;7:580–585.PubMedCrossRefGoogle Scholar
  212. 212.
    Heneghan MA, Zolfino T, Muiesan P, et al. An evaluation of long-term outcomes after liver transplantation for cryptogenic cirrhosis. Liver Transpl. 2003;9:921–928.PubMedCrossRefGoogle Scholar
  213. 213.
    Dehghani SM, Bahador A, Gholami S, et al. Pediatric liver transplantation in Iran: evaluation of the first 50 cases. Pediatr Transpl. 2007;11:256–260.CrossRefGoogle Scholar
  214. 214.
    Sanjeevi A, Lyden E, Sunderman B, et al. Outcomes of liver transplantation for cryptogenic cirrhosis: a single-center study of 71 patients. Transpl Proc. 2003;35:2977–2980.CrossRefGoogle Scholar
  215. 215.
    Mukherjee S, Rogge J, Weaver LK, Schafer DF. De novo cryptogenic hepatitis after sustained eradication of hepatitis C following liver transplantation. Transpl Proc. 2004;36:1494–1497.CrossRefGoogle Scholar
  216. 216.
    Czaja AJ. Comparability of probable and definite autoimmune hepatitis by international diagnostic scoring criteria. Gastroenterology. 2011;140:1472–1480.Google Scholar
  217. 217.
    Czaja AJ. Treatment strategies in autoimmune hepatitis. Clin Liver Dis. 2002;6:799–824.PubMedCrossRefGoogle Scholar
  218. 218.
    Czaja AJ. Current and future treatments of autoimmune hepatitis. Expert Rev Gastroenterol Hepatol. 2009;3:269–291.PubMedCrossRefGoogle Scholar
  219. 219.
    Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–129.PubMedCrossRefGoogle Scholar
  220. 220.
    Kistler KD, Brunt EM, Clark JM, et al. Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am J Gastroenterol. 2011;106:460–468.PubMedCrossRefGoogle Scholar
  221. 221.
    Azzalini L, Ferrer E, Ramalho LN, et al. Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats. Hepatology. 2010;51:1567–1576.PubMedCrossRefGoogle Scholar
  222. 222.
    Nedeltcheva AV, Kilkus JM, Imperial J, Schoeller DA, Penev PD. Insufficient sleep undermines dietary efforts to reduce adiposity. Ann Intern Med. 2010;153:435–441.PubMedGoogle Scholar
  223. 223.
    Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–1022.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of Gastroenterology and HepatologyMayo Clinic College of MedicineRochesterUSA

Personalised recommendations