The Pathogenesis of Nonalcoholic Steatohepatitis and Other Fatty Liver Diseases: A Four-Step Model including the Role of Lipid Release and Hepatic Venular Obstruction in the Progression to Cirrhosis

Fatty liver disease involves the accumulation of triglycerides in hepatocytes, necrosis of hepatocytes, inflammation, and often fibrosis with progression to cirrhosis. The two-hit model summarizes the important early metabolic events leading to hepatocellular necrosis in nonalcoholic steatohepatitis (NASH). In this article, we provide evidence of lipid release from hepatocytes in posttransplant fat necrosis and in NASH and quantify vascular obliteration in a series of biopsies with NASH. Obliteration of small hepatic veins (<30 μm) in small numbers is compensated by collateral flow. Obliteration of larger hepatic veins (>30 μm) is associated with fibrotic collapse lesions that are not easily resorbed. Based on these observations, we propose a new four-step model that includes the later events that lead to cirrhosis after necrosis has occurred. This model is applicable to nonalcoholic fatty liver disease (NAFLD), alcoholic disease, postjejunoileal bypass disease, and posttransplant fat necrosis. The first step is steatosis facilitated by insulin, and the second is necrosis induced by intracellular lipid toxicity or lipid peroxidation, or both, modified by alcohol, drugs, and ischemia. The third step is release of bulk lipid from hepatocytes into the interstitium leading to direct and inflammatory injury to hepatic veins. The fourth step is venous obstruction with secondary collapse and ultimately fibrous septation and cirrhosis.

KEYWORDS

Nonalcoholic fatty liver disease - NAFLD - nonalcoholic steatohepatitis - NASH - alcohol - lipopeliosis - steatosis - transplantation - steatohepatitis - jejunoileal bypass

REFERENCES

• 1 Wanless I R, Bargman J M, Oreopoulos D G, Vas S I. Subcapsular steatonecrosis in response to peritoneal insulin delivery: a clue to the pathogenesis of steatonecrosis in obesity.  Mod Pathol. 1989;  2 69-74
• 2 Woodside W F, Heimberg M. The metabolism of oleic acid by the perfused rat liver in experimental diabetes induced by antiinsulin serum.  Metabolism. 1978;  27 1763-1777
• 3 Sohn J, Siegelman E, Osiason A. Unusual patterns of hepatic steatosis caused by the local effect of insulin revealed on chemical shift MR imaging.  AJR Am J Roentgenol. 2001;  176 471-474
• 4 Battaglia D M, Wanless I R, Brady A P, Mackenzie R L. Intrahepatic sequestered segment of liver presenting as focal fatty change.  Am J Gastroenterol. 1995;  90 2238-2239
• 5 Redston M, Wanless I R. The effect of insulin on development of fatty liver in choline deficient rats.  Mod Pathol. 1991;  4 95A
• 6 Wanless I R, Lentz J S. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors.  Hepatology. 1990;  12 1106-1110
• 7 King E G, Nakane P K, Ashbaugh D G. The canine oleic acid model of fibrin localization in fat embolism.  Surgery. 1971;  69 782-787
• 8 Mavrelis P G, Ammon H V, Gleysteen J J, Komorowski R A, Charaf U K. Hepatic free fatty acids in alcoholic liver disease and morbid obesity.  Hepatology. 1983;  3 226-231
• 9 Day C P, James O F. Steatohepatitis: a tale of two “hits”?.  Gastroenterology. 1998;  114 842-845
• 10 Caldwell S H, Swerdlow R H, Khan E M et al.. Mitochondrial abnormalities in non-alcoholic steatohepatitis.  J Hepatol. 1999;  31 430-434
• 11 Sanyal A J, Campbell-Sargent C, Mirshahi F et al.. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities.  Gastroenterology. 2001;  120 1183-1192
• 12 Diehl A M. Nonalcoholic steatosis and steatohepatitis IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines.  Am J Physiol Gastrointest Liver Physiol. 2002;  282 G1-G5
• 13 Videla L A, Rodrigo R, Orellana M et al.. Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients.  Clin Sci (Lond). 2003;  103 261-268
• 14 Neuschwander-Tetri B A, Caldwell S H. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference.  Hepatology. 2003;  37 1202-1219
• 15 Wanless I R, Sweeney G, Dhillon A P et al.. Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia.  Blood. 2002;  100 1566-1569
• 16 Cha I, Bass N, Ferrell L D. Lipopeliosis. An immunohistochemical and clinicopathologic study of five cases.  Am J Surg Pathol. 1994;  18 789-795
• 17 Edmondson H A, Peters R L, Reynolds T B, Kuzma O T. Sclerosing hyaline necrosis of the liver in the chronic alcoholic. a recognizable clinical syndrome.  Ann Intern Med. 1963;  59 646-673
• 18 Edmondson H A, Peters R L, Frankel H H, Borowsky S. The early stage of liver injury in the alcoholic.  Medicine (Baltimore). 1967;  46 119-129
• 19 Brunt E M, Tiniakos D G. Pathology of steatohepatitis.  Best Pract Res Clin Gastroenterol. 2002;  16 691-707
• 20 Goodman Z D, Ishak K G. Occlusive venous lesions in alcoholic liver disease. A study of 200 cases.  Gastroenterology. 1982;  83 786-796
• 21 Nakanuma Y, Ohta G, Doishita K. Quantitation and serial section observations of focal veno-occlusive lesions of hepatic veins in liver cirrhosis.  Virchows Arch A Pathol Anat Histopathol. 1985;  405 429-438
• 22 Burt A D, MacSween R N. Hepatic vein lesions in alcoholic liver disease: retrospective biopsy and necropsy study.  J Clin Pathol. 1986;  39 63-67
• 23 Wanless I R, Nakashima E, Sherman M. Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis.  Arch Pathol Lab Med. 2000;  124 1599-1607
• 24 Rimarenko S, Jagirdar J. Veno-occlusive syndrome of the liver in an alcoholic man.  Mt Sinai J Med. 1984;  51 292-294
• 25 Wanless I R. Vascular disorders. In: Macsween RNM, Burt AD, Portmann BC Pathology of the Liver, 4th ed. Edinburgh; Churchill Livingstone 2002: 539-574
• 26 Tanaka M, Wanless I R. Pathology of the liver in Budd-Chiari syndrome: portal vein thrombosis and the histogenesis of veno-centric cirrhosis, veno-portal cirrhosis, and large regenerative nodules.  Hepatology. 1998;  27 488-496
• 27 Wanless I R, Shiota K, Heathcote E J. Role of hepatic vein obliteration in the progression of non-alcoholic steatohepatitis (NASH) to cirrhosis.  Hepatology. 2002;  36 730A
• 28 Shimamatsu K, Wanless I R. Role of ischemia in causing apoptosis, atrophy, and nodular hyperplasia in human liver.  Hepatology. 1997;  26 343-350
• 29 Nanji A A, Jokelainen K, Tipoe G L, Rahemtulla A, Dannenberg A J. Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration.  J Pharmacol Exp Ther. 2001;  299 638-644
• 30 Day C P. Pathogenesis of steatohepatitis.  Best Pract Res Clin Gastroenterol. 2002;  16 663-678