Pathology of Alcoholic and Nonalcoholic Fatty Liver Disease

  • Pierre Bedossa
  • David E. KleinerEmail author


Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are two of the most common pathologies to affect the liver. They share many of the same features, including steatosis (the accumulation of fat droplets in hepatocytes), inflammation, ballooning injury, Mallory–Denk bodies, and fibrosis that can progress to cirrhosis. Although there are similarities, they are etiologically and pathogenetically distinct entities, and these issues have been addressed in other chapters. There are also differences in the character of the pathology between NAFLD and ALD. Both of these diseases may manifest in different patterns of injury, and recognition of these specific patterns still requires invasive testing through liver biopsy. In the sections that follow, the pathological manifestations of NAFLD and ALD are discussed, along with the grading and staging systems that are used in clinical management.


Liver histology NAFLD Activity Score NAS Nonalcoholic steatohepatitis: ballooning Mallory–Denk bodies Steatosis Perisinusoidal fibrosis 


  1. 1.
    Kleiner DE, Brunt EM. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin Liver Dis. 2012;32:3–13.PubMedCrossRefGoogle Scholar
  2. 2.
    Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine JE, Ratziu V, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54:344–53.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–8.PubMedGoogle Scholar
  5. 5.
    Zimmerman HJ, Mac MF, Rappaport H, Alpert LK. Studies on the liver in diabetes mellitus. II. The significance of fatty metamorphosis and its correlation with insulin sensitivity. J Lab Clin Med. 1950;36:922–8.PubMedGoogle Scholar
  6. 6.
    Zimmerman HJ, Mac MF, Rapparport H, Alpert LK. Studies of the liver in diabetes mellitus. I. Structural and functional abnormalities. J Lab Clin Med. 1950;36:912–21.PubMedGoogle Scholar
  7. 7.
    Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis. 2001;21:3–16.PubMedCrossRefGoogle Scholar
  8. 8.
    Ramesh S, Sanyal AJ. Hepatitis C and nonalcoholic fatty liver disease. Semin Liver Dis. 2004;24:399–413.PubMedCrossRefGoogle Scholar
  9. 9.
    Chalasani N, Wilson L, Kleiner DE, Cummings OW, Brunt EM, Unalp A, Network NCR. Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease. J Hepatol. 2008;48:829–34.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Caldwell SH, Lee VD, Kleiner DE, Al-Osaimi AM, Argo CK, Northup PG, Berg CL. NASH and cryptogenic cirrhosis: a histological analysis. Ann Hepatol. 2009;8:346–52.PubMedGoogle Scholar
  11. 11.
    Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29:664–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Contos MJ, Cales W, Sterling RK, Luketic VA, Shiffman ML, Mills AS, Fisher RA, et al. Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis. Liver Transpl. 2001;7:363–73.PubMedCrossRefGoogle Scholar
  13. 13.
    Tandra S, Yeh MM, Brunt EM, Vuppalanchi R, Cummings OW, Unalp-Arida A, Wilson LA, et al. Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease. J Hepatol. 2011;55:654–9.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Rensen SS, Slaats Y, Nijhuis J, Jans A, Bieghs V, Driessen A, Malle E, et al. Increased hepatic myeloperoxidase activity in obese subjects with nonalcoholic steatohepatitis. Am J Pathol. 2009;175:1473–82.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, Gores GJ. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology. 2003;125:437–43.PubMedCrossRefGoogle Scholar
  16. 16.
    Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology. 2006;44:27–33.PubMedCrossRefGoogle Scholar
  17. 17.
    Brunt EM, Kleiner DE, Wilson LA, Unalp A, Behling CE, Lavine JE, Neuschwander-Tetri BA, et al. Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-Clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network. Hepatology. 2009;49:809–20.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Lefkowitch JH, Haythe JH, Regent N. Kupffer cell aggregation and perivenular distribution in steatohepatitis. Mod Pathol. 2002;15:699–704.PubMedCrossRefGoogle Scholar
  19. 19.
    Gadd VL, Skoien R, Powell EE, Fagan KJ, Winterford C, Horsfall L, Irvine K, et al. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology. 2014;59:1393–405.PubMedCrossRefGoogle Scholar
  20. 20.
    Omary MB, Ku NO, Strnad P, Hanada S. Toward unraveling the complexity of simple epithelial keratins in human disease. J Clin Invest. 2009;119:1794–805.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Lackner C, Gogg-Kamerer M, Zatloukal K, Stumptner C, Brunt EM, Denk H. Ballooned hepatocytes in steatohepatitis: the value of keratin immunohistochemistry for diagnosis. J Hepatol. 2008;48:821–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Guy CD, Suzuki A, Burchette JL, Brunt EM, Abdelmalek MF, Cardona D, McCall SJ, et al. Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease. Hum Pathol. 2012;43:790–800.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, Grimaldi A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–906.PubMedCrossRefGoogle Scholar
  24. 24.
    Neuschwander-Tetri BA, Clark JM, Bass NM, Van Natta ML, Unalp-Arida A, Tonascia J, Zein CO, et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology. 2010;52:913–24.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Torbenson M, Chen YY, Brunt E, Cummings OW, Gottfried M, Jakate S, Liu YC, et al. Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus. Am J Surg Pathol. 2006;30:508–13.PubMedCrossRefGoogle Scholar
  26. 26.
    Kleiner DE, Behling C, Guy CD, Torbenson M, Yeh MM, Belt PH, Neuschwander-Tetri BA, et al. Glycogenosis is associated with measures of insulin resistance in adults with non-alcoholic fatty liver disease (NAFLD). Mod Pathol. 2012;25:416A.CrossRefGoogle Scholar
  27. 27.
    Caldwell SH, Swerdlow RH, Khan EM, Iezzoni JC, Hespenheide EE, Parks JK, Parker Jr WD. Mitochondrial abnormalities in non-alcoholic steatohepatitis. J Hepatol. 1999;31:430–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Wanless IR, Geddie WR. Mineral oil lipogranulomata in liver and spleen. A study of 465 autopsies. Arch Pathol Lab Med. 1985;109:283–6.PubMedGoogle Scholar
  29. 29.
    Nelson JE, Wilson L, Brunt EM, Yeh MM, Kleiner DE, Unalp-Arida A, Kowdley KV, et al. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology. 2011;53:448–57.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Schwimmer JB, Behling C, Newbury R, Deutsch R, Nievergelt C, Schork NJ, Lavine JE. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42:641–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Patton HM, Lavine JE, Van Natta ML, Schwimmer JB, Kleiner D, Molleston J, Nonalcoholic Steatohepatitis Clinical Research Network. Clinical correlates of histopathology in pediatric nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1961–71.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Kleiner DE, Berk PD, Hsu JY, Courcoulas AP, Flum D, Khandelwal S, Pender J, et al. Hepatic pathology among patients without known liver disease undergoing bariatric surgery: observations and a perspective from the longitudinal assessment of bariatric surgery (LABS) study. Semin Liver Dis. 2014;34:98–107.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Garg A. Acquired and inherited lipodystrophies. N Engl J Med. 2004;350:1220–34.PubMedCrossRefGoogle Scholar
  34. 34.
    Vallet-Pichard A, Mallet V, Pol S. Nonalcoholic fatty liver disease and HIV infection. Semin Liver Dis. 2012;32:158–66.PubMedCrossRefGoogle Scholar
  35. 35.
    Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM, Premkumar A, Kleiner DE, et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology. 2005;41:753–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Safar Zadeh E, Lungu AO, Cochran EK, Brown RJ, Ghany MG, Heller T, Kleiner DE, et al. The liver diseases of lipodystrophy: the long-term effect of leptin treatment. J Hepatol. 2013;59:131–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Monto A, Alonzo J, Watson JJ, Grunfeld C, Wright TL. Steatosis in chronic hepatitis C: relative contributions of obesity, diabetes mellitus, and alcohol. Hepatology. 2002;36:729–36.PubMedCrossRefGoogle Scholar
  39. 39.
    Amacher DE, Chalasani N. Drug-induced hepatic steatosis. Semin Liver Dis. 2014;34:205–14.PubMedCrossRefGoogle Scholar
  40. 40.
    Holtmann M, Kopf D, Mayer M, Bechtinger E, Schmidt MH. Risperidone-associated steatohepatitis and excessive weight-gain. Pharmacopsychiatry. 2003;36:206–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Parsons B, Allison DB, Loebel A, Williams K, Giller E, Romano S, Siu C. Weight effects associated with antipsychotics: a comprehensive database analysis. Schizophr Res. 2009;110:103–10.PubMedCrossRefGoogle Scholar
  42. 42.
    Bodasing N, Fox R. HIV-associated lipodystrophy syndrome: description and pathogenesis. J Infect. 2003;46:149–54.PubMedCrossRefGoogle Scholar
  43. 43.
    Hofman P, Nelson AM. The pathology induced by highly active antiretroviral therapy against human immunodeficiency virus: an update. Curr Med Chem. 2006;13:3121–32.PubMedCrossRefGoogle Scholar
  44. 44.
    Brunt EM, Ramrakhiani S, Cordes BG, Neuschwander-Tetri BA, Janney CG, Bacon BR, Di Bisceglie AM. Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease. Mod Pathol. 2003;16:49–56.PubMedCrossRefGoogle Scholar
  45. 45.
    Hourigan LF, Macdonald GA, Purdie D, Whitehall VH, Shorthouse C, Clouston A, Powell EE. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology. 1999;29:1215–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Hwang SJ, Luo JC, Chu CW, Lai CR, Lu CL, Tsay SH, Wu JC, et al. Hepatic steatosis in chronic hepatitis C virus infection: prevalence and clinical correlation. J Gastroenterol Hepatol. 2001;16:190–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Sanyal AJ, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Stravitz RT, Mills AS. Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Am J Gastroenterol. 2003;98:2064–71.PubMedCrossRefGoogle Scholar
  48. 48.
    Dongiovanni P, Donati B, Fares R, Lombardi R, Mancina RM, Romeo S, Valenti L. PNPLA3 I148M polymorphism and progressive liver disease. World J Gastroenterol. 2013;19:6969–78.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Perumalswami P, Kleiner DE, Lutchman G, Heller T, Borg B, Park Y, Liang TJ, et al. Steatosis and progression of fibrosis in untreated patients with chronic hepatitis C infection. Hepatology. 2006;43:780–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Hindi M, Levy C, Couto CA, Bejarano P, Mendes F. Primary biliary cirrhosis is more severe in overweight patients. J Clin Gastroenterol. 2013;47:e28–32.PubMedCrossRefGoogle Scholar
  51. 51.
    Thomopoulos KC, Arvaniti V, Tsamantas AC, Dimitropoulou D, Gogos CA, Siagris D, Theocharis GJ, et al. Prevalence of liver steatosis in patients with chronic hepatitis B: a study of associated factors and of relationship with fibrosis. Eur J Gastroenterol Hepatol. 2006;18:233–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Tsochatzis E, Papatheodoridis GV, Manesis EK, Chrysanthos N, Kafiri G, Archimandritis AJ. Hepatic steatosis in chronic hepatitis B develops due to host metabolic factors: a comparative approach with genotype 1 chronic hepatitis C. Dig Liver Dis. 2007;39:936–42.PubMedCrossRefGoogle Scholar
  53. 53.
    Vuppalanchi R, Unalp A, Van Natta ML, Cummings OW, Sandrasegaran KE, Hameed T, Tonascia J, et al. Effects of liver biopsy sample length and number of readings on sampling variability in nonalcoholic Fatty liver disease. Clin Gastroenterol Hepatol. 2009;7:481–6.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Arun J, Jhala N, Lazenby AJ, Clements R, Abrams GA. Influence of liver biopsy heterogeneity and diagnosis of nonalcoholic steatohepatitis in subjects undergoing gastric bypass. Obes Surg. 2007;17:155–61.PubMedCrossRefGoogle Scholar
  55. 55.
    Larson SP, Bowers SP, Palekar NA, Ward JA, Pulcini JP, Harrison SA. Histopathologic variability between the right and left lobes of the liver in morbidly obese patients undergoing Roux-en-Y bypass. Clin Gastroenterol Hepatol. 2007;5:1329–32.PubMedCrossRefGoogle Scholar
  56. 56.
    Tonkin MJ, Larson SP. Kriging water levels with a regional-linear and point-logarithmic drift. Ground Water. 2002;40:185–93.PubMedCrossRefGoogle Scholar
  57. 57.
    Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38:1449–57.PubMedCrossRefGoogle Scholar
  58. 58.
    Brunetti E, Silini E, Pistorio A, Cavallero A, Marangio A, Bruno R, Filice C. Coarse vs. fine needle aspiration biopsy for the assessment of diffuse liver disease from hepatitis C virus-related chronic hepatitis. J Hepatol. 2004;40:501–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Bedossa P, Consortium FP. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology. 2014;60:565–75.PubMedCrossRefGoogle Scholar
  60. 60.
    Sorrentino P, Terracciano L, D’Angelo S, Ferbo U, Bracigliano A, Vecchione R. Predicting fibrosis worsening in obese patients with NASH through parenchymal fibronectin, HOMA-IR, and hypertension. Am J Gastroenterol. 2010;105:336–44.PubMedCrossRefGoogle Scholar
  61. 61.
    Pais R, Charlotte F, Fedchuk L, Bedossa P, Lebray P, Poynard T, Ratziu V, et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol. 2013;59:550–6.PubMedCrossRefGoogle Scholar
  62. 62.
    Kleiner DE, Belt PH, Wilson LA, Brunt EM, Guy CD, Yeh MM, Kowdley KV, et al. Natural history of non-alcoholic fatty liver disease in adults: a paired biopsy study from the NASH CRN. Hepatology. 2013;58:483A.Google Scholar
  63. 63.
    Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, Austin AS, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135:1176–84.PubMedCrossRefGoogle Scholar
  65. 65.
    Lindor KD, Kowdley KV, Heathcote EJ, Harrison ME, Jorgensen R, Angulo P, Lymp JF, et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 2004;39:770–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, Podevin P, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial. Gastroenterology. 2008;135:100–10.PubMedCrossRefGoogle Scholar
  67. 67.
    Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–74.PubMedCrossRefGoogle Scholar
  68. 68.
    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.PubMedCrossRefGoogle Scholar
  69. 69.
    Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–307.PubMedCrossRefGoogle Scholar
  70. 70.
    Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA. 2011;305:1659–68.PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Brunt EM, Kleiner DE, Wilson LA, Unalp A, Tonascia J, Neuschwander-Tetri BA. Histologic predictors of improvement in fibrosis in NASH: results from the Clinical Research Network PIVENS Trial. Hepatology. 2012;56:887A.Google Scholar
  72. 72.
    Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V, Tordjman J, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology. 2012;56:1751–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Mendler MH, Kanel G, Govindarajan S. Proposal for a histological scoring and grading system for non-alcoholic fatty liver disease. Liver Int. 2005;25:294–304.PubMedCrossRefGoogle Scholar
  74. 74.
    Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, Doo E, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–96.PubMedCrossRefGoogle Scholar
  75. 75.
    Schwartz JM, Reinus JF. Prevalence and natural history of alcoholic liver disease. Clin Liver Dis. 2012;16:659–66.PubMedCrossRefGoogle Scholar
  76. 76.
    Tilg H, Day CP. Management strategies in alcoholic liver disease. Nat Clin Pract Gastroenterol Hepatol. 2007;4:24–34.PubMedCrossRefGoogle Scholar
  77. 77.
    Singal AK, Chaha KS, Rasheed K, Anand BS. Liver transplantation in alcoholic liver disease current status and controversies. World J Gastroenterol. 2013;19:5953–63.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    O’Shea RS, Dasarathy S, McCullough AJ, Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology. 2010;51:307–28.PubMedCrossRefGoogle Scholar
  79. 79.
    European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol. 2012;57:399–420.CrossRefGoogle Scholar
  80. 80.
    Bouchier IA, Hislop WS, Prescott RJ. A prospective study of alcoholic liver disease and mortality. J Hepatol. 1992;16:290–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Brunt EM, Tiniakos DG. Pathology of steatohepatitis. Best Pract Res Clin Gastroenterol. 2002;16:691–707.PubMedCrossRefGoogle Scholar
  82. 82.
    Christoffersen P, Braendstrup O, Juhl E, Poulsen H. Lipogranulomas in human liver biopsies with fatty change. A morphological, biochemical and clinical investigation. Acta Pathol Microbiol Scand A. 1971;79:150–8.PubMedGoogle Scholar
  83. 83.
    Delladetsima JK, Horn T, Poulsen H. Portal tract lipogranulomas in liver biopsies. Liver. 1987;7:9–17.PubMedCrossRefGoogle Scholar
  84. 84.
    Stewart RV, Dincsoy HP. The significance of giant mitochondria in liver biopsies as observed by light microscopy. Am J Clin Pathol. 1982;78:293–8.PubMedGoogle Scholar
  85. 85.
    Yokoo H, Singh SK, Hawasli AH. Giant mitochondria in alcoholic liver disease. Arch Pathol Lab Med. 1978;102:213–4.PubMedGoogle Scholar
  86. 86.
    Teli MR, Day CP, Burt AD, Bennett MK, James OF. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver. Lancet. 1995;346:987–90.PubMedCrossRefGoogle Scholar
  87. 87.
    Dam-Larsen S, Franzmann MB, Christoffersen P, Larsen K, Becker U, Bendtsen F. Histological characteristics and prognosis in patients with fatty liver. Scand J Gastroenterol. 2005;40:460–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Uchida T, Kao H, Quispe-Sjogren M, Peters RL. Alcoholic foamy degeneration—a pattern of acute alcoholic injury of the liver. Gastroenterology. 1983;84:683–92.PubMedGoogle Scholar
  89. 89.
    Morgan MY, Sherlock S, Scheuer PJ. Acute cholestasis, hepatic failure, and fatty liver in the alcoholic. Scand J Gastroenterol. 1978;13:299–303.PubMedCrossRefGoogle Scholar
  90. 90.
    Randall B. Fatty liver and sudden death. A review. Hum Pathol. 1980;11:147–53.PubMedCrossRefGoogle Scholar
  91. 91.
    Yuzuriha T, Okudaira M, Tominaga I, Hori S, Suzuki H, Matsuo Y, Shoji M, et al. Alcohol-related sudden death with hepatic fatty metamorphosis: a comprehensive clinicopathological inquiry into its pathogenesis. Alcohol Alcohol. 1997;32:745–52.PubMedCrossRefGoogle Scholar
  92. 92.
    Mathurin P, O’Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, Ramond MJ, et al. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60:255–60.PubMedCrossRefGoogle Scholar
  93. 93.
    Lebrec D, Goldfarb G, Degott C, Rueff B, Benhamou JP. Transvenous liver biopsy: an experience based on 1000 hepatic tissue samplings with this procedure. Gastroenterology. 1982;83:338–40.PubMedGoogle Scholar
  94. 94.
    Kalambokis G, Manousou P, Vibhakorn S, Marelli L, Cholongitas E, Senzolo M, Patch D, et al. Transjugular liver biopsy—indications, adequacy, quality of specimens, and complications—a systematic review. J Hepatol. 2007;47:284–94.PubMedCrossRefGoogle Scholar
  95. 95.
    Alcoholic liver disease: morphological manifestations. Review by an international group. Lancet. 1981;1:707–11.Google Scholar
  96. 96.
    Elphick DA, Dube AK, McFarlane E, Jones J, Gleeson D. Spectrum of liver histology in presumed decompensated alcoholic liver disease. Am J Gastroenterol. 2007;102:780–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Bhathal PS, Wilkinson P, Clifton S, Rankin JG, Santamaria JN. The spectrum of liver diseases in alcoholism. Aust N Z J Med. 1975;5:49–57.PubMedCrossRefGoogle Scholar
  98. 98.
    Nissenbaum M, Chedid A, Mendenhall C, Gartside P. Prognostic significance of cholestatic alcoholic hepatitis. VA Cooperative Study Group #119. Dig Dis Sci. 1990;35:891–6.PubMedCrossRefGoogle Scholar
  99. 99.
    Bedossa P, Poynard T, Naveau S, Martin ED, Agostini H, Chaput JC. Observer variation in assessment of liver biopsies of alcoholic patients. Alcohol Clin Exp Res. 1988;12:173–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Forrest EH, Evans CD, Stewart S, Phillips M, Oo YH, McAvoy NC, Fisher NC, et al. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score. Gut. 2005;54:1174–9.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Mathurin P, Beuzin F, Louvet A, Carrie-Ganne N, Balian A, Trinchet JC, Dalsoglio D, et al. Fibrosis progression occurs in a subgroup of heavy drinkers with typical histological features. Aliment Pharmacol Ther. 2007;25:1047–54.PubMedCrossRefGoogle Scholar
  102. 102.
    Sorensen TI, Orholm M, Bentsen KD, Hoybye G, Eghoje K, Christoffersen P. Prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis. Lancet. 1984;2:241–4.PubMedCrossRefGoogle Scholar
  103. 103.
    Dominguez M, Rincon D, Abraldes JG, Miquel R, Colmenero J, Bellot P, Garcia-Pagan JC, et al. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol. 2008;103:2747–56.PubMedCrossRefGoogle Scholar
  104. 104.
    Mathurin P, Duchatelle V, Ramond MJ, Degott C, Bedossa P, Erlinger S, Benhamou JP, et al. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroenterology. 1996;110:1847–53.PubMedCrossRefGoogle Scholar
  105. 105.
    Katoonizadeh A, Laleman W, Verslype C, Wilmer A, Maleux G, Roskams T, Nevens F. Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study. Gut. 2010;59:1561–9.PubMedCrossRefGoogle Scholar
  106. 106.
    Mookerjee RP, Lackner C, Stauber R, Stadlbauer V, Deheragoda M, Aigelsreiter A, Jalan R. The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis. J Hepatol. 2011;55:1103–11.PubMedCrossRefGoogle Scholar
  107. 107.
    Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, Durand F, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144:1426–37, 1437 e1421–9.PubMedCrossRefGoogle Scholar
  108. 108.
    Duvoux C, Radier C, Roudot-Thoraval F, Maille F, Anglade MC, Van Nhieu JT, Rosa I, et al. Low-grade steatosis and major changes in portal flow as new prognostic factors in steroid-treated alcoholic hepatitis. Hepatology. 2004;40:1370–8.PubMedCrossRefGoogle Scholar
  109. 109.
    Dominguez M, Miquel R, Colmenero J, Moreno M, Garcia-Pagan JC, Bosch J, Arroyo V, et al. Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis. Gastroenterology. 2009;136:1639–50.PubMedCrossRefGoogle Scholar
  110. 110.
    Nasrallah SM, Nassar VH, Galambos JT. Importance of terminal hepatic venule thickening. Arch Pathol Lab Med. 1980;104:84–6.PubMedGoogle Scholar
  111. 111.
    Scheuer PJ, Maggi G. Hepatic fibrosis and collapse: histological distinction by orcein staining. Histopathology. 1980;4:487–90.PubMedCrossRefGoogle Scholar
  112. 112.
    Spahr L, Rubbia-Brandt L, Genevay M, Hadengue A, Giostra E. Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients with alcoholic steatohepatitis. BMC Gastroenterol. 2011;11:115.PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Altamirano J, Miquel R, Katoonizadeh A, Abraldes JG, Duarte-Rojo A, Louvet A, Augustin S, et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology. 2014;146:1231–9 e1231–6.PubMedCentralPubMedCrossRefGoogle Scholar
  114. 114.
    Edmondson HA, Peters RL, Reynolds TB, Kuzma OT. Sclerosing hyaline necrosis of the liver in the chronic alcoholic. A recognizable clinical syndrome. Ann Intern Med. 1963;59:646–73.PubMedCrossRefGoogle Scholar
  115. 115.
    Goodman ZD, Ishak KG. Occlusive venous lesions in alcoholic liver disease. A study of 200 cases. Gastroenterology. 1982;83:786–96.PubMedGoogle Scholar
  116. 116.
    Burt AD, MacSween RN. Hepatic vein lesions in alcoholic liver disease: retrospective biopsy and necropsy study. J Clin Pathol. 1986;39:63–7.PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    Worner TM, Lieber CS. Perivenular fibrosis as precursor lesion of cirrhosis. JAMA. 1985;254:627–30.PubMedCrossRefGoogle Scholar
  118. 118.
    Nakano M, Worner TM, Lieber CS. Perivenular fibrosis in alcoholic liver injury: ultrastructure and histologic progression. Gastroenterology. 1982;83:777–85.PubMedGoogle Scholar
  119. 119.
    Michalak S, Rousselet MC, Bedossa P, Pilette C, Chappard D, Oberti F, Gallois Y, et al. Respective roles of porto-septal fibrosis and centrilobular fibrosis in alcoholic liver disease. J Pathol. 2003;201:55–62.PubMedCrossRefGoogle Scholar
  120. 120.
    Colombat M, Charlotte F, Ratziu V, Poynard T. Portal lymphocytic infiltrate in alcoholic liver disease. Hum Pathol. 2002;33:1170–4.PubMedCrossRefGoogle Scholar
  121. 121.
    Rygiel KA, Robertson H, Marshall HL, Pekalski M, Zhao L, Booth TA, Jones DE, et al. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab Invest. 2008;88:112–23.PubMedCrossRefGoogle Scholar
  122. 122.
    Williams MJ, Clouston AD, Forbes SJ. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology. 2014;146:349–56.PubMedCrossRefGoogle Scholar
  123. 123.
    Lee FI. Cirrhosis and hepatoma in alcoholics. Gut. 1966;7:77–85.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Yerian L. Histopathological evaluation of fatty and alcoholic liver diseases. J Dig Dis. 2011;12:17–24.PubMedCrossRefGoogle Scholar
  125. 125.
    Fauerholdt L, Schlichting P, Christensen E, Poulsen H, Tygstrup N, Juhl E. Conversion of micronodular cirrhosis into macronodular cirrhosis. Hepatology. 1983;3:928–31.PubMedCrossRefGoogle Scholar
  126. 126.
    Wanless IR, Nakashima E, Sherman M. Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med. 2000;124:1599–607.PubMedGoogle Scholar
  127. 127.
    Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology. 2004;127:S87–96.PubMedCrossRefGoogle Scholar
  128. 128.
    Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–50.PubMedCrossRefGoogle Scholar
  129. 129.
    Bralet MP, Regimbeau JM, Pineau P, Dubois S, Loas G, Degos F, Valla D, et al. Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases. Hepatology. 2000;32:200–4.PubMedCrossRefGoogle Scholar
  130. 130.
    Libbrecht L, Desmet V, Roskams T. Preneoplastic lesions in human hepatocarcinogenesis. Liver Int. 2005;25:16–27.PubMedCrossRefGoogle Scholar
  131. 131.
    Terasaki S, Kaneko S, Kobayashi K, Nonomura A, Nakanuma Y. Histological features predicting malignant transformation of nonmalignant hepatocellular nodules: a prospective study. Gastroenterology. 1998;115:1216–22.PubMedCrossRefGoogle Scholar
  132. 132.
    Cardinale V, Semeraro R, Torrice A, Gatto M, Napoli C, Bragazzi MC, Gentile R, et al. Intra-hepatic and extra-hepatic cholangiocarcinoma: new insight into epidemiology and risk factors. World J Gastrointest Oncol. 2010;2:407–16.PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Wu TT, Levy M, Correa AM, Rosen CB, Abraham SC. Biliary intraepithelial neoplasia in patients without chronic biliary disease: analysis of liver explants with alcoholic cirrhosis, hepatitis C infection, and noncirrhotic liver diseases. Cancer. 2009;115:4564–75.PubMedCrossRefGoogle Scholar
  134. 134.
    Pariente EA, Degott C, Martin JP, Feldmann G, Potet F, Benhamou JP. Hepatocytic PAS-positive diastase-resistance inclusions in the absence of alpha-1-antitrypsin deficiency—high prevalence in alcoholic cirrhosis. Am J Clin Pathol. 1981;76:299–302.PubMedGoogle Scholar
  135. 135.
    Yip WW, Burt AD. Alcoholic liver disease. Semin Diagn Pathol. 2006;23:149–60.PubMedCrossRefGoogle Scholar
  136. 136.
    Gerber MA, Thung SN. Hepatic oncocytes. Incidence, staining characteristics, and ultrastructural features. Am J Clin Pathol. 1981;75:498–503.PubMedGoogle Scholar
  137. 137.
    Jakobovits AW, Morgan MY, Sherlock S. Hepatic siderosis in alcoholics. Dig Dis Sci. 1979;24:305–10.PubMedCrossRefGoogle Scholar
  138. 138.
    Batts KP. Iron overload syndromes and the liver. Mod Pathol. 2007;20 Suppl 1:S31–9.PubMedCrossRefGoogle Scholar
  139. 139.
    Bridle K, Cheung TK, Murphy T, Walters M, Anderson G, Crawford DG, Fletcher LM. Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease. Alcohol Clin Exp Res. 2006;30:106–12.PubMedCrossRefGoogle Scholar
  140. 140.
    Kohgo Y, Ohtake T, Ikuta K, Suzuki Y, Hosoki Y, Saito H, Kato J. Iron accumulation in alcoholic liver diseases. Alcohol Clin Exp Res. 2005;29:189S–93.PubMedCrossRefGoogle Scholar
  141. 141.
    Sebastiani G, Walker AP. HFE gene in primary and secondary hepatic iron overload. World J Gastroenterol. 2007;13:4673–89.PubMedCentralPubMedCrossRefGoogle Scholar
  142. 142.
    Deugnier Y, Turlin B, le Quilleuc D, Moirand R, Loreal O, Messner M, Meunier B, et al. A reappraisal of hepatic siderosis in patients with end-stage cirrhosis: practical implications for the diagnosis of hemochromatosis. Am J Surg Pathol. 1997;21:669–75.PubMedCrossRefGoogle Scholar
  143. 143.
    Ludwig J, Hashimoto E, Porayko MK, Moyer TP, Baldus WP. Hemosiderosis in cirrhosis: a study of 447 native livers. Gastroenterology. 1997;112:882–8.PubMedCrossRefGoogle Scholar
  144. 144.
    Cassiman D, Vannoote J, Roelandts R, Libbrecht L, Roskams T, Van den Oord J, Fevery J, et al. Porphyria cutanea tarda and liver disease. A retrospective analysis of 17 cases from a single centre and review of the literature. Acta Gastroenterol Belg. 2008;71:237–42.PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Hôpitaux Universitaires Paris Nord Val de Seine, Département d’Anatomie Pathologique, Hôpital Beaujon – INSERM U1149Université Paris Diderot, UFR de médecineParisFrance
  2. 2.Laboratory of PathologyNCIBethesdaUSA

Personalised recommendations