Cryptogenic Cirrhosis: What Are We Missing?
- 575 Downloads
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.
KeywordsCryptogenic 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
- 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. , which strengthened the epidemiologic associations. Powell et al. also noted one of the earliest associations of this condition with hepatocellular cancer.CrossRefPubMedGoogle Scholar
- 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
- 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
- 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.  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
- 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.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.Yatsuji S, Hashimoto E, Noto H, et al.: Clinicopathological features in nonalcoholic steatohepatitis autopsy cases. Gastroenterology 2008, 134(Suppl 1):A783.Google Scholar
- 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
- 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.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