Current Gastroenterology Reports

, Volume 12, Issue 1, pp 40–48 | Cite as

Cryptogenic Cirrhosis: What Are We Missing?

  • Stephen CaldwellEmail author


Cryptogenic cirrhosis remains a common clinical condition although recent advances have allowed for a better understanding of underlying conditions and associations. The evolving terminology applied to this condition has resulted in some confusion and persistent variation among pathologists and clinicians. Typical patients are middle aged with only minor liver enzyme abnormalities. Presentations range from incidentally discovered cirrhosis to complications of advanced portal hypertension and hepatocellular cancer. Clinicopathologic analysis of these patients indicates that the leading causes include previously unrecognized nonalcoholic steatohepatitis, silent autoimmune hepatitis, non-B, non-C viral hepatitis, and occult past ethanol exposure. In this article, we review these associations as well as a proposed classification system for cryptogenic cirrhosis and other lesser known genetic and syndromic associations that warrant consideration when evaluating these individuals.


Cryptogenic cirrhosis NASH (non-alcoholic steatohepatitis) NAFLD (non-alcoholic fatty liver disease) Autoimmune hepatitis Alcohol-related liver disease Viral hepatitis 



No potential conflict of interest relevant to this article was reported.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Clark JM, Diehl AM: Nonalcoholic fatty liver disease: an under-recognized cause of cryptogenic cirrhosis. JAMA 2003, 289:3000–3004.CrossRefPubMedGoogle Scholar
  2. 2.
    Caldwell SH, Crespo DM: The spectrum expanded: cryptogenic cirrhosis and the natural history of nonalcoholic fatty liver disease. J Hepatol 2004, 40:578–584.CrossRefPubMedGoogle Scholar
  3. 3.
    • 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. This landmark paper from Powell et al. established that NASH can progress to a state of cirrhosis that lacks sufficient histologic change to define it as steatohepatitis (i.e., cryptogenic cirrhosis). Once established, this link led to our subsequent epidemiologic study (next reference) and that of Poonawala et al. [5], which strengthened the epidemiologic associations. Powell et al. also noted one of the earliest associations of this condition with hepatocellular cancer.CrossRefPubMedGoogle Scholar
  4. 4.
    Caldwell SH, Oelsner DH, Iezzoni JC, et al.: Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999, 29:664–669.CrossRefPubMedGoogle Scholar
  5. 5.
    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.CrossRefPubMedGoogle Scholar
  6. 6.
    Bugianesi E, Leone N, Vanni E, et al.: Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular cancer. Gastroenterology 2002, 123:134–140.CrossRefPubMedGoogle Scholar
  7. 7.
    • Maheshwari A, Thuluvath PJ: Cryptogenic cirrhosis and NAFLD: are they related? Am J Gastroenterol 2006, 101:664–668. This compilation clearly demonstrated consistency between different studies confirming the relationship among obesity, diabetes, and cryptogenic cirrhosis now thought to often represent late-stage NASH.CrossRefPubMedGoogle Scholar
  8. 8.
    Duseja A, Nanda M, Das A, et al.: Prevalence of obesity, diabetes mellitus and hyperlipidemia in patients with cryptogenic liver cirrhosis. Trop Gastroenterol 2004, 25:15–17.PubMedGoogle Scholar
  9. 9.
    Kojima H, Sakuri S, Matsumura M, et al.: Cryptogenic cirrhosis in the region where obesity is not prevalent. World J Gastroenterol 2006, 12:2080–2085.PubMedGoogle Scholar
  10. 10.
    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
  11. 11.
    Caldwell SH, Harris DM, Hespenheide EE: Is NASH under diagnosed among African Americans? Am J Gastroenterol 2002, 97:1496–1500.CrossRefPubMedGoogle Scholar
  12. 12.
    Browning JD, Kumar KS, Saboorian MH, Thiele DL: Ethnic differences in the prevalence of cryptogenic cirrhosis. Am J Gastroenterol 2004, 99:292–298.CrossRefPubMedGoogle Scholar
  13. 13.
    Heringlake S, Schütte 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.CrossRefPubMedGoogle Scholar
  14. 14.
    Rubio-Tapia A, Murray JA: The liver in celiac disease. Hepatology 2007, 46:1650–1658.CrossRefPubMedGoogle Scholar
  15. 15.
    Adams LA, Sanderson S, Lindor KD, Angulo P: The histological course of nonalcoholic fatty liver disease: A longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005, 42:132–138.CrossRefPubMedGoogle Scholar
  16. 16.
    Abdelmalek M, Ludwig J, Lindor KD: Two cases from the spectrum of nonalcoholic steatohepatitis. J Clin Gastroenterol 1995, 20:127–130.CrossRefPubMedGoogle Scholar
  17. 17.
    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.CrossRefPubMedGoogle Scholar
  18. 18.
    Caldwell SH, Al-Osaimi AMS, Argo CK: Nonalcoholic fatty liver disease. In Schiff’s Diseases of the Liver, edn 10. Edited by Schiff ER, Sorrell MF, Maddrey WC. Philadelphia: Lippincott Williams and Wilkins; 2007:1122.Google Scholar
  19. 19.
    Lee RG: Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol 1989, 20:594–598.CrossRefPubMedGoogle Scholar
  20. 20.
    Struben VMD, Hespenheide EE, Caldwell SH: Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. Am J Med 2000, 108:9–13.CrossRefPubMedGoogle Scholar
  21. 21.
    Willner IR, Waters B, Patil SR, et al.: Ninety patients with nonalcoholic steatohepatitis: Insulin resistance, familial tendency, and severity of disease. Am J Gastroenterol 2001, 96:2957–2961.CrossRefPubMedGoogle Scholar
  22. 22.
    Abdelmalek MF, Liu C, Shuster J, et al.: Familial aggregation of insulin resistance in first-degree relatives of patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2006, 4:1162–1169.CrossRefPubMedGoogle Scholar
  23. 23.
    Chitturi S, Farrell GC: Etiopathogenesis of nonalcoholic steatohepatitis. Semin Liv Dis 2001, 21:27–41.CrossRefGoogle Scholar
  24. 24.
    Crawford DH, Shepherd RW, Halliday JW, et al.: Body composition in nonalcoholic cirrhosis: the effect of disease etiology and severity on nutritional compartments. Gastroenterology 1994, 106:1611–1617.PubMedGoogle Scholar
  25. 25.
    Cotler SJ, Kanji K, Keshavarzian A, et al.: Prevalence and significance of autoantibodies in patients with non-alcoholic steatohepatitis. J Clin Gastroenterol 2004, 38:801–804.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    Koskinas J, Kenna JG, Bird GL, et al.: Immunoglobulin A antibody to a 200-kilodalton cytosolic acetaldehyde adduct in alcoholic hepatitis. Gastroenterology 1992, 103:1860–1867.PubMedGoogle Scholar
  28. 28.
    Nagore N, Scheuer PJ: Does a linear pattern of sinusoidal IgA deposition distinguish between alcoholic and diabetic liver disease? Liver 1988, 8:281–286.PubMedGoogle Scholar
  29. 29.
    • Ayata G, Gordon FD, Lewis WD, et al.: Cryptogenic cirrhosis: clinicopathologic findings at and after liver transplantation. Human Pathol 2002, 33:1098–1104. Along with Berg et al. [30] and the work of Duclos-Vallee et al., these authors proposed a working classification of cryptogenic cirrhosis based on clinicopathologic correlates and including cases attributable to NASH, silent autoimmune, unrecognized biliary disease, occult viral hepatitis, and occult ethanol exposure. This classification is continuing to evolve; a modified and extended form is included as Table 3 in the present paper.CrossRefGoogle Scholar
  30. 30.
    Berg T, Neuhaus R, Klein R, et al.: Distinct enzyme profiles in patients with cryptogenic cirrhosis reflect heterogeneous causes with different outcomes after liver transplantation (OLT): a long-term documentation before and after OLT. Transplantation 2002, 74:792–798.CrossRefPubMedGoogle Scholar
  31. 31.
    • Caldwell S, Lee V, Kleiner D, et al.: NASH and cryptogenic cirrhosis: a histological analysis. Ann Hepatol 2009, 8:346–352. This article, we believe, is the first of several focused studies to be published reporting on histologic footprints of NASH among series of patients with late-stage cryptogenic cirrhosis and prior histologically proven NASH. These studies have been consistent in showing histologic markers for prior steatohepatitis, including such findings as residual ballooning, glycogenated nuclei, and megamitochondria.PubMedGoogle Scholar
  32. 32.
    Clark ME, Ghotb A, Merriman RB: Longitudinal histologic evidence of loss of steatosis with progression of NAFLD to cirrhosis and liver transplantation. Gastroenterology (abstract) 2009, 136(suppl):T1017.Google Scholar
  33. 33.
    Yatsuji S, Hashimoto E, Noto H, et al.: Clinicopathological features in nonalcoholic steatohepatitis autopsy cases. Gastroenterology 2008, 134(Suppl 1):A783.Google Scholar
  34. 34.
    Caldwell SH, Hespenheide EE: Subacute liver failure in obese females. Am J Gastroenterol 2002, 97:2058–2062.CrossRefPubMedGoogle Scholar
  35. 35.
    Cotrim HP, Parana R, Braga E, Lyra L: Nonalcoholic steatohepatitis and hepatocellular cancer: natural history? Am J Gastroenterol 2000, 95:3018–3019.CrossRefPubMedGoogle Scholar
  36. 36.
    Ratzui V, Bonyhay L, Di Martino V, et al.: Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 2002, 35:1485–1493.CrossRefGoogle Scholar
  37. 37.
    Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM: Obesity and hepatocellular carcinoma. Gastroenterology 2004, 127 (Suppl 1):S97–S103.CrossRefPubMedGoogle Scholar
  38. 38.
    Sanyal AJ, Banas C, Sargeant C, et al.: Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 2006, 43:682–689.CrossRefPubMedGoogle Scholar
  39. 39.
    Gastaldelli A, Kozakova M, Højlund K, et al., and RISC Investigators: Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology 2009, 49:1537–1544.CrossRefPubMedGoogle Scholar
  40. 40.
    Nair S, Verma S, Thuluvath PJ: Obesity and the effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002, 35:105–109.CrossRefPubMedGoogle Scholar
  41. 41.
    Ong J, Younossi ZM, Reddy V, et al.: Cryptogenic cirrhosis and post-transplantation non-alcoholic fatty liver disease. Liver Transplant 2001, 7:797–801.CrossRefGoogle Scholar
  42. 42.
    Sutedja DS, Gow PJ, Hubscher SG, Elias E: Revealing the cause of cryptogenic cirrhosis by posttransplant liver biopsy. Transplant Proc 2004, 36:2334–2337.CrossRefPubMedGoogle Scholar
  43. 43.
    Charlton MR, Kondo M, Roberts SK, et al.: Liver transplantation for cryptogenic cirrhosis. Liver Transpl Surg 1997, 3:359–364.CrossRefPubMedGoogle Scholar
  44. 44.
    Duclos-Vallee JC, Yilmaz F, Johanet C, et al.: Could post-liver transplantation course be helpful for the diagnosis of so called cryptogenic cirrhosis? Clinical Transplant 2005, 19:591–599.Google Scholar
  45. 45.
    Heneghan MA, Zolfino T, Muiesan P, et al.: An evaluation of long-term outcomes after transplantation for cryptogenic cirrhosis. Liver Transpl 2003, 9:921–928.CrossRefPubMedGoogle Scholar
  46. 46.
    Roberts SK, Therneau TM, Czaja AJ: Prognosis of histological cirrhosis in type 1 autoimmune hepatitis. Gastroenterology 1996, 110:848–857.CrossRefPubMedGoogle Scholar
  47. 47.
    Greeve M, Ferrell L, Kim M, et al.: Cirrhosis of undefined pathogenesis: absence of evidence for unknown or autoimmune processes. Hepatology 1993, 17:593–598.CrossRefPubMedGoogle Scholar
  48. 48.
    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
  49. 49.
    Pessoa MG, Terrault LD, Ferrell LD, et al.: Hepatitis G virus in patients with cryptogenic liver disease undergoing liver transplantation. Hepatology 1997, 25:1266–1270.CrossRefPubMedGoogle Scholar
  50. 50.
    Castillo I, Pardo M, Bartolome J, et al.: Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver-function tests is unknown. J Infect Dis 2004, 189:7–14.CrossRefPubMedGoogle Scholar
  51. 51.
    Brechot C, Thiers V, Kremsdorf D, et al.: Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely “occult”? Hepatology. 2001, 34:194–203.CrossRefPubMedGoogle Scholar
  52. 52.
    Chung HT, Lai CL, Lok AS: Pathogenic role of hepatitis B virus in hepatitis B surface antigen-negative decompensated cirrhosis. Hepatology 1995, 22:25.PubMedGoogle Scholar
  53. 53.
    Hayashi PH, Harrison SA, Torgerson S, et al.: Cognitive lifetime drinking history in nonalcoholic fatty liver disease: some cases may be alcohol related. Am J Gastroenterol 2004, 99:76–81.CrossRefPubMedGoogle Scholar
  54. 54.
    Naveau S, Giraud V, Borotto E, et al.: Excess weight risk factor for alcoholic liver disease. Hepatology 1997, 25:108–111.CrossRefPubMedGoogle Scholar
  55. 55.
    Diehl AM: Obesity and alcoholic liver disease. Alcohol 2004, 34:81–87.CrossRefPubMedGoogle Scholar
  56. 56.
    Davies MJ, Baer DJ, Judd JT, et al.: Effects of moderate alcohol intake on fasting insulin and glucose concentrations and insulin sensitivity in postmenopausal women. JAMA 2003, 287:2559–2562.CrossRefGoogle Scholar
  57. 57.
    Dunn W, Xu R, Schwimmer JB: Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease. Hepatology 2008, 47:1947–1954.CrossRefPubMedGoogle Scholar
  58. 58.
    Cotrim HP, Freitas LA, Alves E, et al.: Effects of light-to-moderate alcohol consumption on steatosis and steatohepatitis in severely obese patients. Eur J Gastroenterol Hepatol 2009, 21:969–972.CrossRefPubMedGoogle Scholar
  59. 59.
    Pinto HC, Baptista A, Camilo ME, et al.: Nonalcoholic steatohepatitis. Clinicopathological comparison with alcoholic hepatitis in ambulatory and hospitalized patients. Dig Dis Sci 1996, 41:172–179.CrossRefPubMedGoogle Scholar
  60. 60.
    Sanderson SO, Smyrk TC: The use of protein tyrosine phosphatase 1B and insulin receptor immunostains to differentiate nonalcoholic from alcoholic steatohepatitis in liver biopsy specimens. Am J Clin Pathol 2005, 123:503–509.CrossRefPubMedGoogle Scholar
  61. 61.
    Ratziu V, Bugianesi E, Dixons J, et al.: Histological progression of non-alcoholic fatty liver disease: a critical reassessment based on liver sampling variability. Aliment Pharmacol Ther 2007, 26:821–830.PubMedCrossRefGoogle Scholar
  62. 62.
    Nosadini R, Avogaro A, Mollo F, et al.: Carbohydrate and lipid metabolism in cirrhosis. Evidence that hepatic uptake of gluconeogenic precursors and of free fatty acids depends on effective hepatic flow. J Clin Endocr Metab 1984, 58:1125–1132.Google Scholar
  63. 63.
    Matsui O, Kadoya M, Takahashi S, et al.: Focal sparing of segment IV in fatty livers shown by sonography and CT: correlation with aberrant gastric venous drainage. Am J Roentgenol 1995, 164:1137–1140.Google Scholar
  64. 64.
    Seifalian AM, Piasecki C, Agarwal A, Davidson BR: The effect of graded steatosis on flow in the hepatic parenchymal microcirculation. Transplantation 1999, 68:780–784.CrossRefPubMedGoogle Scholar
  65. 65.
    Roskams T, Yang SQ, Koteish A, et al.: Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol 2003, 163:1301–1311.PubMedGoogle Scholar
  66. 66.
    Richardson MM, Jonsson JR, Powell EE, et al.: Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology 2007, 133:80–90.CrossRefPubMedGoogle Scholar
  67. 67.
    Lackner C, Gogg-Kamerer M, Zatloukal K, et al.: Ballooned hepatocytes in steatohepatitis: The value of keratin immunohistochemistry for diagnosis. J Hepatol 2008, 48:821–828.CrossRefPubMedGoogle Scholar
  68. 68.
    Carrozzo R, Hirano M, Fromenty B, et al.: Multiple mtDNA deletions features in autosomal dominant and recessive diseases suggest distinct pathogeneses. Neurology 1998, 50:99–106.PubMedGoogle Scholar
  69. 69.
    Johns DR: Mitochondrial DNA and disease. N Engl J Med 1995, 333:638–644.CrossRefPubMedGoogle Scholar
  70. 70.
    Tweezer-Zaks N, Doron-Libner A, Weiss P, et al.: Familial Mediterranean fever and cryptogenic cirrhosis. Medicine 2007, 86:355–362.CrossRefPubMedGoogle Scholar
  71. 71.
    Chowdhary VR, Crowson CS, Poterucha JJ, Moder KG: Liver involvement in systemic lupus erythematosus: case review of 40 patients. J Rheumatol 2008, 35:2159–2164.CrossRefPubMedGoogle Scholar
  72. 72.
    Janello S, Bosco P, Camuto M, et al.: A mild form of Alstrom disease associated with metabolic syndrome and very high fasting free fatty acids: Two cases diagnosed in adult age. Am J Med Sci 2004, 327:284–288.CrossRefGoogle Scholar
  73. 73.
    Badano JL, Mistuma N, Beales PL, Katsanis N: The ciliopathies: An emerging class of human genetic diseases. Annu Rev Genomics Hum Genet 2006, 7:125–148.CrossRefPubMedGoogle Scholar
  74. 74.
    Bonnefont-Rousselot D, Condat B, Sassolas A, et al.: Cryptogenic cirrhosis in a patient with familial hypocholesterolemia due to a new truncated form of apolipoprotein B. Eur J Gastroenterol Hepatol 2009, 21:104–108.CrossRefPubMedGoogle Scholar
  75. 75.
    Alder JK, Chen JJL, Lancaster L, et al.: Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A 2008, 105:13051–13056.CrossRefPubMedGoogle Scholar
  76. 76.
    Ghobadloo SM, Yaghmaei B, Bakayev V, et al.: GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis. J Gastrointest Surg 2004, 8:423–427.CrossRefPubMedGoogle Scholar
  77. 77.
    Ku N-M, Gish R, Wright TL, Omary B: Keratin 8 mutations in patients with cryptogenic liver disease. N Engl J Med 2001, 344:1580–1587.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Digestive Health Center, GI/Hepatology DivisionUniversity of Virginia Health Science CenterCharlottesvilleUSA

Personalised recommendations