Semin Liver Dis 2001; 21(1): 003-016
DOI: 10.1055/s-2001-12925
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Nonalcoholic Steatohepatitis: Definition and Pathology

Elizabeth M. Brunt
  • Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri
Further Information

Publication History

Publication Date:
31 December 2001 (online)

ABSTRACT

Nonalcoholic steatohepatitis (NASH) is a significant form of chronic liver disease in adults and children. The natural history of NASH ranges from indolent to end-stage liver disease. Current studies are focusing on identification of histologic and/or clinical markers of progression. NASH may be an underlying cause of cryptogenic cirrhosis, and the lesions of NASH may recur in allograft livers. An expanding array of clinical conditions and pathogenetic mechanisms have been identified, but many cases remain ``idiopathic''; lack of significant alcohol use is, by definition, common to all cases. Neither clinical evaluation nor laboratory values can ensure either the diagnosis or the exclusion of NASH, and liver biopsy interpretation continues to be considered the ``gold standard'' for diagnosis. The lesions in NASH are similar but not identical to those of alcoholic steatohepatitis; exact, specific histologic criteria for the diagnosis are currently under discussion. The lesions most commonly accepted for NASH include steatosis, hepatocyte ballooning degeneration, mild diffuse lobular mixed acute and chronic inflammation, and perivenular, perisinusoidal collagen deposition. Zone 3 accentuation may be detected. Mallory's hyaline, vacuolated nuclei in periportal hepatocytes, lobular lipogranulomas, and PAS-diastase-resistant Kupffer cells are common. In biopsy specimens from children, portal inflammation may be more prominent than in adults. Progression of fibrosis may result in bridging septa and cirrhosis. The lesions of steatohepatitis may be noted concurrently with other forms of chronic liver disease. A histological ``grading and staging'' system has been developed to reflect the unique features of steatohepatitis, gradations of severity and fibrosis, and to promote uniform reporting of the histopathology.

REFERENCES

  • 1 Teli M R, James O FW, Burt A D. The natural history of nonalcoholic fatty liver: a follow-up study.  Hepatology . 1995;  22 1714-1719
  • 2 Day C P, James O FW. Hepatic steatosis: innocent bystander or guilty party?.  Hepatology . 1998;  27 1463-1466
  • 3 Burt A D, Mutton A, Day C. Diagnosis and interpretation of steatosis and steatohepatitis.  Semin Diagn Pathol . 1998;  15 246-258
  • 4 Gerber M A, Krawczynski K, Alter M J. Histopathology of community acquired chronic hepatitis C.  Mod Pathol . 1992;  5 483-486
  • 5 Scheuer P J, Ashrafzadeh P, Sherlock S. The pathology of hepatitis C.  Hepatology . 1992;  15 567-571
  • 6 Lefkowitch J H, Schiff E R, Davis, G L. Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B.  Gastroenterology . 1993;  104 595-603
  • 7 Matteoni C A, Younossi Z M, Gramlich T. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.  Gastroenterology . 1999;  116 1413-1419
  • 8 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
  • 9 Day C P, James O FW. Steatohepatitis: a tale of two ``hits''?.  Gastroenterology . 1998;  114 842-845
  • 10 Chavin K, Yang S Q, Lin H Z. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion.  J Biol Chem . 1999;  274 5692-5700
  • 11 Deschamps D, De Beco V, Fisch C. Inhibition by perhexiline of oxidative phosphorylation and the β-oxidation of fatty acids: possible role in pseudoalcoholic liver lesions.  Hepatology . 1994;  19 948-961
  • 12 Berson A, De Beco V, Letteron P. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes.  Gastroenterology . 1998;  114 764-774
  • 13 Caldwell S H, Swerdlow R H, Khan E M. Mitochondrial abnormalities in non-alcoholic steatohepatitis.  J Hepatol . 1999;  31 430-434
  • 14 James O FW, Day C P. Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance.  J Hepatol . 1998;  29 495-501
  • 15 Diehl A M. Nonalcoholic steatohepatitis.  Semin Liver Dis . 1999;  19 221-229
  • 16 Rashid M, Roberts E A. Nonalcoholic steatohepatitis in children.  J Pediatr Gastroenterol Nutr . 2000;  30 48-53
  • 17 Powell E E, Cooksley W GE, Hanson R. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years.  Hepatology . 1990;  11 74-80
  • 18 Abdelmalek M, Ludwig J, Lindor K D. Two cases from the spectrum of nonalcoholic steatohepatitis.  J Clin Gastroenterol . 1995;  20 127-130
  • 19 Neuschwander-Tetri B A, Bacon B R. Nonalcoholic steatohepatitis.  Med Clin North Am . 1996;  80 1147-1166
  • 20 Sheth S G, Gordon F D, Chopra S. Nonalcoholic steatohepatitis.  Ann Intern Med . 1997;  126 137-145
  • 21 Lonardo A. Fatty liver and nonalcoholic steatohepatitis. Where do we stand and where are we going?.  Dig Dis . 1999;  17 80-89
  • 22 Ludwig J, McGill D B, Lindor K D. Metabolic liver disease.  Review: nonalcoholic steatohepatitis. J Gastroenterol Hepatol . 1997;  12 398-403
  • 23 Angulo P, Keach J C, Batts K P. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis.  Hepatology . 1999;  30 1356-1362
  • 24 Hay J E, Czaja A J, Rakela J. The nature of unexplained chronic aminotransferase elevations of a mild to moderate degree in asymptomatic patients.  Hepatology . 1989;  9 193-197
  • 25 Byron D, Miruk G Y. Profile of an urban hospital-based practice.  Hepatology . 1996;  24 813-815
  • 26 James O, Day C. Non-alcoholic steatohepatitis: another disease of affluence. Commentary.  Lancet . 1999;  353 1634-1636
  • 27 Daniel S, Ben-Menachem T, Vasudevan G. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients.  Am J Gastroenterol . 1999;  94 3010-3014
  • 28 Baldridge A D, Perez-Atayde A R, Graeme-Cook F. Idiopathic steatohepatitis in childhood: a multicenter retrospective study.  J Pediatr . 1995;  127 700-704
  • 29 Adler M, Schaffner F. Fatty liver hepatitis and cirrhosis in obese patients.  Am J Med . 1979;  67 811-816
  • 30 Itoh S, Yougel T, Kawagoe K. Comparison between nonalcoholic steatohepatitis and alcoholic hepatitis.  Am J Gastroenterol . 1987;  82 650-654
  • 31 Diehl A M, Goodman Z, Ishak K G. Alcohollike liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury.  Gastroenterology . 1988;  95 1056-1062
  • 32 Lee R G. Nonalcoholic steatohepatitis: a study of 49 patients.  Hum Pathol . 1989;  20 594-598
  • 33 Bacon B R, Farahvash M J, Janney C G. Nonalcoholic steatohepatitis: an expanded clinical entity.  Gastroenterology . 1994;  107 1103-1109
  • 34 Ratziu V, Giral P, Charlotte F. Liver fibrosis in overweight patients.  Gastroenterology . 2000;  118 1117-1123
  • 35 French METAVIR Cooperative Study Group. Intraobserver and interobserver variations in liver biopsies in patients with chronic hepatitis C.  Hepatology . 1994;  20 15-20
  • 36 Caldwell S H, Oelsner D H, Iezzonie J C. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.  Hepatology . 1999;  29 664-669
  • 37 Kim W R, Peterucha J J, Porayko M K. Recurrence of non-alcoholic steatohepatitis following liver transplantation.  Transplantation . 1996;  62 1802-1805
  • 38 Carson K, Washington M K, Treem W R. Recurrence of nonalcoholic steatohepatitis in a liver transplant recipient.  Liver Transplant Surg . 1997;  3 174-176
  • 39 Molloy R M, Komorowski R, Varma R R. Recurrent nonalcoholic steatohepatitis and cirrhosis after liver transplantation.  Liver Transplant Surg . 1997;  3 177-178
  • 40 Cotrim H P, Adrade Z A, Parana R. Nonalcoholic steatohepatitis. A toxic liver disease in industrial workers.  Liver . 1999;  19 299-304
  • 41 Blendis L, Oren R, Halpern Z. NASH: can we iron out the pathogenesis?.  <~>Selected summary. Gastroenterology . 2000;  118 981-983
  • 42 Bonkovsky H L, Jawaid Q, Tortorelli K. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis.  J Hepatol . 1999;  31 421-429
  • 43 George D K, Goldwurm S, Macdonald G A. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.  Gastroenterology . 1998;  114 311-318
  • 44 Younossi A M, Gramlich T, Bacon B R. Hepatic iron and nonalcoholic fatty liver disease.  Hepatology . 1999;  30 847-850
  • 45 Mendler M-H, Turlin B, Moriand R. Insulin resistance- associated hepatic iron overload.  Gastroenterology . 1999;  117 1155-1163
  • 46 Macdonald G A, Powell L W. More clues to the relationship between hepatic iron and steatosis: an association with insulin resistance?.  <~>Editorial. Gastroenterology . 1999;  117 1241-1244
  • 47 McCoullough A J, Falck-Ytter Y. Body composition and hepatic steatosis as precursors for fibrosis in liver disease.  Hepatology . 1999;  29 1328-1329
  • 48 Ludwig J, Viggiano T R, McGill D B. Nonalcoholic steatohepatitis. Mayo Clinic experiences with a hitherto unnamed disease.  Mayo Clin Proc . 1980;  55 434-438
  • 49 Brunt E M, Neuschwander-Tetri B A, Di Bisceglie M A. Can steatohepatitis coexist with other forms of chronic liver disease?.  Mod Pathol . 2000;  13 1061A
  • 50 Peters R L, Gay T, Reynolds T B. Post-jejunoileal bypass hepatic disease. Its similarity to alcoholic liver disease.  Am J Clin Pathol . 1975;  63 318-331
  • 51 Marubbio A T, Buchwald H, Schwartz M Z. Hepatic lesions of central pericellular fibrosis in morbid obesity and after jejunoileal bypass.  Am J Clin Pathol . 1976;  66 684-691
  • 52 Hamilton D L, Vest F K, Brown B S. Liver injury with alcoholic like hyaline after gastroplasty for morbid obesity.  Gastroenterology . 1983;  85 722-726
  • 53 Vyberg M, Ravn V, Andersen B. Pattern of progression in liver injury following jejunoileal bypass for morbid obesity.  Liver . 1987;  7 271-276
  • 54 Nagore N, Scheuer P J. The pathology of diabetic hepatitis.  J Pathol . 1988;  156 155-160
  • 55 Wanless I R, Bargman J M, Oreopoulos D G. Subcapsular steatonecrosis in response to peritoneal insulin delivery: a clue to the pathogenesis of steatonecrosis in obesity.  Mod Pathol . 1989;  2 69-74
  • 56 Younossi Z M, Gramlich T, Chang Y. Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations.  Mod Pathol . 1998;  11 560-565
  • 57 Lee R G. Nonalcoholic steatohepatitis: tightening the morphologic screws on a hepatic ramber.  Hepatology . 1995;  21 1742-1743
  • 58 Brunt E M, Janney C G, Di Bisceglie M A. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.  Am J Gastroenterol . 1999;  94 2467-2474
  • 59 Teli M R, Day C P, Burt A D. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver.  Lancet . 1995;  346 987-990
  • 60 Pinto H C, Baptista A, Camilo M E. Nonalcoholic steatohepatitis: clinicopathologic comparison with alcoholic hepatitis in ambulatory and hospitalized patients.  Dig Dis Sci . 1996;  41 172-179
  • 61 Andersen T, Gluud C, Franzmann M-B. Hepatic effects of dietary weight loss in morbidly obese subjects.  J Hepatol . 1991;  12 224-229
  • 62 Lee R G. Diagnostic Liver Pathology.  St. Louis: Mosby, 1994: 167-194
  • 63 Thung S N, Gerber M A. Differential Diagnosis in Pathology: Liver Disorders.  New York: Igaku-Shoin, 1995: 24
  • 64 Hall de la P. Alcoholic liver disease. In: MacSween RNM, Anthony PP, Scheuer PJ, et al. eds. Pathology of the Liver. London: Churchill Livingstone 1994: 317-349
  • 65 Scheuer P J. Classification of chronic viral hepatitis: a need for reassessment.  J Hepatol . 1991;  13 372-374
  • 66 MacSween R NM, Burt A D. Histologic spectrum of alcoholic liver disease.  Semin Liver Dis . 1986;  6 221-232
  • 67 Goodman Z D, Ishak K G. Occlusive venous lesions in alcoholic liver disease. A study of 200 cases.  Gastroenterology . 1982;  83 786-796
  • 68 Washington K, Wright K, Hunter E. Hepatic stellate cell activation in non-alcoholic steatohepatitis.  Mod Pathol . 1999;  12 169A
  • 69 Brunt E M, Fazel A, Brown K E. Lack of zonal association between α-smooth muscle actin (SMA), CD 34 and fibrosis in a variety of liver diseases.  Hepatology . 1999;  30 554A
  • 70 Friedman S L. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies.  N Engl J Med . 1993;  328 1828-1835
  • 71 Ramm G A, Crawford D HG, Powell L W. Hepatic stellate cell activation in genetic hemochromatosis.  J Hepatol . 1997;  26 584-592
  • 72 Cordes B G, Brown K E, Brunt E M. Zonal localization of alpha-smooth muscle actin and CD34 immunoreactivity in chronic cholestatic liver disease.  Mod Pathol . 2000;  13 182A
  • 73 Brunt E M. Grading and staging the histopathological lesions of chronic hepatitis: the Knodell Histology Activity Index and beyond.  Hepatology . 2000;  31 241-246
  • 74 Knodell R G, Ishak K G, Black W C. Formulation and application of numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis.  Hepatology . 1981;  1 431-435
  • 75 Ludwig J. The nomenclature of chronic active hepatitis: an obituary.  Gastroenterology . 1993;  105 274-278
  • 76 Desmet V J, Gerber M, Hoofnagle J H. Classification of chronic hepatitis: diagnosis, grading and staging.  Hepatology . 1994;  19 1513-1520
  • 77 Ishak K G, Baptista A, Bianchi L. Histological grading and staging of chronic hepatitis.  J Hepatol . 1995;  22 696-699
  • 78 Goldin R D, Goldin J G, Burt A D. Intra-observer and inter-observer variation in the histopathological assessment of chronic viral hepatitis.  J Hepatol . 1996;  25 649-654
  • 79 Westin J, Lagging L M, Wejstal R. Interobserver study of liver histopathology using the Ishak score in patients with chronic hepatitis C virus infection.  Liver . 1999;  19 183-187
  • 80 Scheuer P. Primary biliary cirrhosis.  Proc R Soc Med . 1967;  60 1257-1260
  • 81 Ludwig J, Dickson E R, McDonald G S. Staging of chronic non-suppurative destructive cholangitis (syndrome of primary biliary cirrhosis).  Virchows Arch Pathol Anat . 1978;  379 103-112
  • 82 Ludwig J, LaRusso N F, Weisner R H. Primary Sclerosing Cholangitis. In: Peters RC, Craig JR (eds. Contemporary Issues in Surgical Pathology, Vol 8. Liver Pathology. New York: Churchill Livingstone 1986: 193-213
  • 83 Searle J, Kerr J RF, Halliday J W. Iron storage disease. In: MacSween RNM, Anthony PP, Scheuer PJ, et al. Pathology of the Liver London: Churchill Livingstone 1994: 224
  • 84 Ishak K G. Chronic hepatitis: morphology and nomenclature.  Mod Pathol . 1994;  7 690-713
  • 85 McFarlane I G. Hepatitis C and alcoholic liver disease.  Am J Gastroenterol . 1993;  88 982-988
  • 86 Nalpas B, Bhrechot C, Berthelot P. Hepatitis B virus and alcoholism. A puzzling association.  Hepatology . 1988;  18 11-14
  • 87 George D K, Powell L W, Losowsky M S. The haemochromatosis gene: a co-factor for chronic liver disease?.  J Gastroenterol Hepatol . 1999;  14 745-749
  • 88 Fong T-S, Di Bisceglie M A, Waggoner J G. The significance of antibody to hepatitis C virus in patients with chronic hepatitis B.  Hepatology . 1991;  14 64-67
  • 89 DeCastro M, Sanchez J, Herrera J F. Hepatitis C virus antibodies and liver disease in patients with porphyria cutanea tarda.  Hepatology . 1993;  17 551-557
  • 90 Propst T, Propst A, Dietze O. High prevalence of viral infection in adults with homozygous and heterozygous alpha-1-antitrypsin deficiency and chronic liver disease.  Ann Intern Med . 1992;  17 641-645
  • 91 Brunt E M, Tavill A S, Bacon B R. A 49-year-old man with alpha-1-antitrypsin deficiency and abnormal iron studies.  Semin Liver Dis . 1996;  16 97-101
  • 92 Mason A L, Lau J YN, Hoang N. Association of diabetes mellitus and chronic hepatitis C virus infection.  Hepatology . 1999;  29 328-333
  • 93 Caronia S, Taylor K, Pagliaro L. Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection.  Hepatology . 1999;  30 1059-1063
  • 94 Hourigan L F, Macdonald G A, Purdie D. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis.  Hepatology . 1999;  29 1215-1219
  • 95 Moryia K, Yotsuyanagi H, Shintani Y. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice.  J Gen Virol . 1997;  78 1527-1531
  • 96 Rogers D W, Lee C H, Pound D C. Hepatitis C virus does not cause steatohepatitis.  Dig Dis Sci . 1992;  37 1644-1649
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