Virchows Archiv

, Volume 444, Issue 1, pp 3–12 | Cite as

Non-alcoholic fatty liver disease: an emerging pathological spectrum

  • Elie Serge ZafraniEmail author
Review Article


The spectrum of pathological lesions observed in non-alcoholic fatty liver disease (NAFLD) is wide and strongly resembles that of alcohol-induced liver disease. It ranges from fatty liver to steatohepatitis, progressive fibrosis and cirrhosis. Hepatocellular carcinoma is a possible complication of NAFLD, but whether it is related to frequently associated metabolic disorders (e.g., overweight, diabetes) or to underlying cirrhosis is unclear. This disease is the result of a multi-factorial process in which insulin resistance seems to play a major role in the initial accumulation of fat in the liver, whereas multiple causes of mitochondrial dysfunction and oxidative stress can induce the secondary occurrence of necroinflammatory lesions and fibrosis. Genetic factors might explain why only some patients with simple steatosis will develop steatohepatitis and fibrosis. Due to the increasing prevalence of obesity in Western countries, NAFLD will possibly be a public health problem and the liver disease of the future.


Non-alcoholic fatty liver disease Steatohepatitis Liver fibrosis Insulin resistance Mitochondrial dysfunction 


  1. 1.
    Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G (2001) Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 33:1358–1364CrossRefPubMedGoogle Scholar
  2. 2.
    Adler M, Schaffner F (1979) Fatty liver hepatitis and cirrhosis in obese patients. Am J Med 67:811–816PubMedGoogle Scholar
  3. 3.
    Andersen T, Gluud C, Franzmann MB, Christoffersen P (1991) Hepatic effects of dietary weight loss in morbidly obese subjects. J Hepatol 12:224–229PubMedGoogle Scholar
  4. 4.
    Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346:1221–1231CrossRefPubMedGoogle Scholar
  5. 5.
    Angulo P, Keach JC, Batts KP, Lindor KD (1999) Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 30:1356–1362PubMedGoogle Scholar
  6. 6.
    Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA (1994) Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 107:1103–1119PubMedGoogle Scholar
  7. 7.
    Bedossa P, Poynard T (1996) An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 24:289–293PubMedGoogle Scholar
  8. 8.
    Bencheqroun R, Duvoux C, Luciani A, Zafrani ES, Dhumeaux D (2003) Carcinome hépatocellulaire en l’absence de cirrhose au cours d’une stéato-hépatite non alcoolique. Gastroenterol Clin Biol (in press)Google Scholar
  9. 9.
    Berson A, De Beco V, Letteron P, Robin MA, Moreau C, El Kahwaji J, Verthier N, Feldmann G, Fromenty B, Pessayre D (1998) Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology 114:764–774PubMedGoogle Scholar
  10. 10.
    Bressler BL, Guindi M, Tomlinson G, Heathcote J (2003) High body mass index is an independent risk factor for nonresponse to antiviral treatment in chronic hepatitis C. Hepatology 38:639–644CrossRefPubMedGoogle Scholar
  11. 11.
    Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR (1999) Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 94:2467–2474CrossRefPubMedGoogle Scholar
  12. 12.
    Brunt EM, Ramrakhiani S, Cordes BG, Neuschwander-Tetri BA, Janney CG, Bacon BR, Di Bisceglie AM (2003) Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease. Mod Pathol 16:49–56PubMedGoogle Scholar
  13. 13.
    Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, De Paolis P, Capussotti L, Salizzoni M, Rizzetto M (2002) Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123:134–140CrossRefPubMedGoogle Scholar
  14. 14.
    Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ (1999) Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 29:664–669PubMedGoogle Scholar
  15. 15.
    Caldwell SH, Swerdlow RH, Khan EM, Iezzoni JC, Hespenheide EE, Parks JK, Parker WD Jr (1999) Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol 31:430–434CrossRefPubMedGoogle Scholar
  16. 16.
    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638CrossRefPubMedGoogle Scholar
  17. 17.
    Cassarino DS, Swerdlow RH, Parks JK, Parker WD Jr, Bennett JP Jr (1998) Cyclosporin A increases resting mitochondrial membrane potential in SY5Y cells and reverses the depressed mitochondrial membrane potential of Alzheimer’s disease cybrids. Biochem Biophys Res Commun 248:168–173CrossRefPubMedGoogle Scholar
  18. 18.
    Charlton M, Sreekumar R, Rasmussen D, Lindor K, Nair KS (2002) Apolipoprotein synthesis in nonalcoholic steatohepatitis. Hepatology 35:898–904CrossRefPubMedGoogle Scholar
  19. 19.
    Chitturi S, Weltman M, Farrell GC, McDonald D, Liddle C, Samarasinghe D, Lin R, Abeygunasekera S, George J (2002) HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity. Hepatology 36:142–149CrossRefPubMedGoogle Scholar
  20. 20.
    Clark JM, Brancati FL, Diehl AM (2002) Nonalcoholic fatty liver disease. Gastroenterology 122:1649–1657PubMedGoogle Scholar
  21. 21.
    Contos MJ, Cales W, Sterling RK, Luketic VA, Shiffman ML, Mills AS, Fisher RA, Ham J, Sanyal AJ (2001) Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis. Liver Transpl 7:363–373PubMedGoogle Scholar
  22. 22.
    Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A, Diehl AM (1999) Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study. JAMA 282:1659–1664CrossRefPubMedGoogle Scholar
  23. 23.
    Cotrim HP, Andrade ZA, Parana R, Portugal M, Lyra LG, Freitas LA (1999) Nonalcoholic steatohepatitis: a toxic liver disease in industrial workers. Liver 19:299–304PubMedGoogle Scholar
  24. 24.
    Craig R, Neymann T, Jeejeebhoy K, Yokoo H (1980) Severe hepatocellular reaction resembling alcoholic hepatitis with cirrhosis after massive small bowel resection and prolonged total parenteral nutrition. Gastroenterology 79:131–137PubMedGoogle Scholar
  25. 25.
    Day CP, James OF (1998) Steatohepatitis: a tale of two “hits?” Gastroenterology 114:842–845Google Scholar
  26. 26.
    Diehl AM, Goodman Z, Ishak KG (1988) Alcohollike liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury. Gastroenterology 95:1056–1062PubMedGoogle Scholar
  27. 27.
    Dixon JB, Bhathal PS, O’Brien PE (2001) Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 121:91–100PubMedGoogle Scholar
  28. 28.
    Falchuk KR, Fiske SC, Haggitt RC, Federman M, Trey C (1980) Pericentral hepatic fibrosis and intracellular hyalin in diabetes mellitus. Gastroenterology 78:535–541PubMedGoogle Scholar
  29. 29.
    Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ (2003) Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 125:437–443CrossRefPubMedGoogle Scholar
  30. 30.
    George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, Jazwinska EC, Powell LW (1998) Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 114:311–318Google Scholar
  31. 31.
    Hamilton D, Vest T, Brown B, Shah A, Menguy R, Chey W (1983) Liver injury with alcoholic-like hyalin after gastroplasty for morbid obesity. Gastroenterology 85:722–726PubMedGoogle Scholar
  32. 32.
    Hasegawa T, Yoneda M, Nakamura K, Makino I, Terano A (2001) Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol Ther 15:1667–1672CrossRefPubMedGoogle Scholar
  33. 33.
    Honda H, Ikejima K, Hirose M, Yoshikawa M, Lang T, Enomoto N, Kitamura T, Takei Y, Sato N (2002) Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology 36:12–21CrossRefPubMedGoogle Scholar
  34. 34.
    Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, Hall P, Khan M, George J (2003) Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology 38:420–427CrossRefPubMedGoogle Scholar
  35. 35.
    Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ, Lang T, Fukuda T, Yamashina S, Kitamura T, Sato N (2002) Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 122:1399–1410PubMedGoogle Scholar
  36. 36.
    Kaserer K, Fiedler R, Steindl P, Müller C, Wrba F, Ferenci P (1998) Liver biopsy is a useful predictor of response to interferon therapy in chronic hepatitis C. Histopathology 32:454–461CrossRefPubMedGoogle Scholar
  37. 37.
    Kim WR, Poterucha JJ, Porayko MK, Dickson ER, Steers JL, Wiesner RH (1996) Recurrence of nonalcoholic steatohepatitis following liver transplantation. Transplantation 62:1802–1805CrossRefPubMedGoogle Scholar
  38. 38.
    Kimura H, Kako M, Yo K, Oda T (1980) Alcoholic hyalins (Mallory bodies) in a case of Weber-Christian disease: electron microscopic observations of liver involvement. Gastroenterology 78:807–812PubMedGoogle Scholar
  39. 39.
    Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ (2003) Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 38:413–419CrossRefPubMedGoogle Scholar
  40. 40.
    Lee RG (1989) Nonalcoholic steatohepatitis: a study of 49 patients. Hum Pathol 20:594–598PubMedGoogle Scholar
  41. 41.
    Lefkowitch JH, Haythe JH, Regent N (2002) Kupffer cell aggregation and perivenular distribution in steatohepatitis. Mod Pathol 15:699–704PubMedGoogle Scholar
  42. 42.
    Lerat H, Honda M, Beard MR, Loesch K, Sun J, Yang Y, Okuda M, Gosert R, Xiao SY, Weinman SA, Lemon SM (2002) Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology 122:352–365PubMedGoogle Scholar
  43. 43.
    Letteron P, Fromenty B, Terris B, Degott C, Pessayre D (1996) Acute and chronic hepatic steatosis lead to in vivo lipid peroxidation in mice. J Hepatol 24:200–208CrossRefPubMedGoogle Scholar
  44. 44.
    Letteron P, Sutton A, Mansouri A, Fromenty B, Pessayre D (2003) Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice. Hepatology 38:133–140CrossRefPubMedGoogle Scholar
  45. 45.
    Ludwig J, Viggiano TR, McGill DB, Oh BJ (1980) Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55:434–438PubMedGoogle Scholar
  46. 46.
    Marchesini G, Forlani G (2002) NASH: from liver diseases to metabolic disorders and back to clinical hepatology. Hepatology 35:497–499PubMedGoogle Scholar
  47. 47.
    Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M (2003) Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37:917–923CrossRefPubMedGoogle Scholar
  48. 48.
    Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS (2002) NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 36:1349–1354CrossRefPubMedGoogle Scholar
  49. 49.
    Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ (1999) Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116:1413–1419PubMedGoogle Scholar
  50. 50.
    Melinek J, Livingston E, Cortina G, Fishbein MC (2002) Autopsy findings following gastric bypass surgery for morbid obesity. Arch Pathol Lab Med 126:1091–1095PubMedGoogle Scholar
  51. 51.
    Mofrad P, Contos MJ, Haque M, Sargeant C, Fisher RA, Luketic VA, Sterling RK, Shiffman ML, Stravitz RT, Sanyal AJ (2003) Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 37:1286–1292CrossRefPubMedGoogle Scholar
  52. 52.
    Nair S, Mason A, Eason J, Loss G, Perrillo RP (2002) Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology 36:150–155CrossRefPubMedGoogle Scholar
  53. 53.
    Neuschwander-Tetri BA, Caldwell SH (2003) Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology 37:1202–1219CrossRefPubMedGoogle Scholar
  54. 54.
    Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, Weinman SA (2002) Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122:366–375PubMedGoogle Scholar
  55. 55.
    Palmer M, Schaffner F, Thung SN (1991) Excessive weight gain after liver transplantation. Transplantation 51:797–800PubMedGoogle Scholar
  56. 56.
    Pessayre D, Berson A, Fromenty B, Mansouri A (2001) Mitochondria in steatohepatitis. Semin Liver Dis 21:57–69CrossRefPubMedGoogle Scholar
  57. 57.
    Peters RL, Gay T, Reynolds TB (1975) Post-jejunoileal-bypass hepatic disease. Its similarity to alcoholic hepatic disease. Am J Clin Pathol 63:318–331PubMedGoogle Scholar
  58. 58.
    Poonawala A, Nair SP, Thuluvath PJ (2000) Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology 32:689–692CrossRefPubMedGoogle Scholar
  59. 59.
    Powell EE, Searle J, Mortimer R (1989) Steatohepatitis associated with limb lipodystrophy. Gastroenterology 97:1022–1024PubMedGoogle Scholar
  60. 60.
    Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW (1990) The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 11:74–80PubMedGoogle Scholar
  61. 61.
    Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, Khalil L, Turpin G, Opolon P, Poynard T (2000) Liver fibrosis in overweight patients. Gastroenterology 118:1117–1123PubMedGoogle Scholar
  62. 62.
    Ratziu V, Bonyhay L, Di Martino V, Charlotte F, Cavallaro L, Sayegh-Tainturier MH, Giral P, Grimaldi A, Opolon P, Poynard T (2002) Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology 35:1485–1493PubMedGoogle Scholar
  63. 63.
    Reid AE (2001) Nonalcoholic steatohepatitis. Gastroenterology 121:710–723PubMedGoogle Scholar
  64. 64.
    Rubbia-Brandt L, Leandro G, Spahr L, Giostra E, Quadri R, Male PJ, Negro F (2001) Liver steatosis in chronic hepatitis C: a morphological sign suggesting infection with HCV genotype 3. Histopathology 39:119–124CrossRefPubMedGoogle Scholar
  65. 65.
    Sanyal AJ (2002) AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 123:1705–1725PubMedGoogle Scholar
  66. 66.
    Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN (2001) Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120:1183–1192PubMedGoogle Scholar
  67. 67.
    Saxena NK, Ikeda K, Rockey DC, Friedman SL, Anania FA (2002) Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology 35:762–771CrossRefPubMedGoogle Scholar
  68. 68.
    Scheuer PJ, Ashrafzadeh P, Sherlock S, Brown D, Dusheiko GM (1992) The pathology of hepatitis C. Hepatology 15:567–571PubMedGoogle Scholar
  69. 69.
    Shepherd PR, Kahn BB (1999) Glucose transporters and insulin action—implications for insulin resistance and diabetes mellitus. N Engl J Med 341:248–257PubMedGoogle Scholar
  70. 70.
    Sreekumar R, Rosado B, Rasmussen D, Charlton M (2003) Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis. Hepatology 38:244–251CrossRefPubMedGoogle Scholar
  71. 71.
    Teli MR, James OF, Burt AD, Bennett MK, Day CP (1995) The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 22:1714–1719PubMedGoogle Scholar
  72. 72.
    The French METAVIR Cooperative Study Group (1994) Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 20:15–20PubMedGoogle Scholar
  73. 73.
    Tilg H, Diehl AM (2000) Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med 343:1467–1476CrossRefPubMedGoogle Scholar
  74. 74.
    Valenti L, Fracanzani AL, Dongiovanni P, Santorelli G, Branchi A, Taioli E, Fiorelli G, Fargion S (2002) Tumor necrosis factor [alpha] promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology 122:274–280PubMedGoogle Scholar
  75. 75.
    Wanless IR, Lentz JS (1990) Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 12:1106–1110PubMedGoogle Scholar
  76. 76.
    Younossi ZM, Gramlich T, Bacon BR, Matteoni CA, Boparai N, O’Neill R, McCullough AJ (1999) Hepatic iron and nonalcoholic fatty liver disease. Hepatology 30:847–850PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Département de PathologieHôpital Henri MondorCréteil cedexFrance

Personalised recommendations