Digestive Diseases and Sciences

, Volume 61, Issue 5, pp 1348–1355 | Cite as

Histological Assessment of NAFLD

Review

Abstract

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of histological lesions ranging from steatosis to a complex pattern with hepatocyte injury and inflammation in an appropriate clinical context. The disease has been artificially dichotomized into NAFL (steatosis) and NASH (steatosis with hepatocellular injury and inflammation), but it is increasingly clear that intermediate patterns may exist. More than NASH, the stage of fibrosis was shown to govern prognosis, and for such evaluation, a liver biopsy of adequate size and width is needed. Like for any other chronic liver diseases, semi-quantitative histologic scores have been proposed. They are not useful in clinical practice but concur to categorize homogeneous group of patients according to their histology. Pediatric NAFLD is a growing concern. While a subgroup of children may harbor different but characteristic histological patterns, most of them display a mixed pattern or features similar to the adults. Today, liver histology is the mainstay for clinical trials. Biopsy is used both for enrollment and for assessing benefit of clinical trials. End points such as reversion of NASH or regression of fibrosis are acceptable but require a clear histological definition.

Keywords

Liver biopsy NAFLD NASH Fibrosis 

References

  1. 1.
    Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–690.CrossRefPubMedGoogle Scholar
  2. 2.
    Bedossa P, Moucari R, Chelbi E, et al. Evidence for a role of nonalcoholic steatohepatitis in hepatitis C: a prospective study. Hepatology. 2007;46:380–387.CrossRefPubMedGoogle Scholar
  3. 3.
    Brunt EM, Ramrakhiani S, Cordes BG, et al. Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease. Mod Pathol. 2003;16:49–56.CrossRefPubMedGoogle Scholar
  4. 4.
    Kleiner DE, Bedossa P. Liver histology and clinical trials for nonalcoholic steatohepatitis-perspectives from 2 pathologists. Gastroenterology. 2015;149:1305–1308.CrossRefPubMedGoogle Scholar
  5. 5.
    Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration joint workshop. Hepatology. 2015;61:1392–1405.CrossRefPubMedGoogle Scholar
  6. 6.
    Nalbantoglu IL, Brunt EM. Role of liver biopsy in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20:9026–9037.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38:1449–1457.CrossRefPubMedGoogle Scholar
  8. 8.
    Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–1906.CrossRefPubMedGoogle Scholar
  9. 9.
    Vuppalanchi R, Unalp A, Van Natta ML, et al. Effects of liver biopsy sample length and number of readings on sampling variability in nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7:481–486.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Goldstein NS, Hastah F, Galan MV, Gordon SC. Fibrosis heterogeneity in nonalcoholic steatohepatitis and hepatitis C virus needle core biopsy specimens. Am J Clin Pathol. 2005;123:382–387.CrossRefPubMedGoogle Scholar
  11. 11.
    Colloredo G, Guido M, Sonzogni A, Leandro G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J Hepatol. 2003;39:239–244.CrossRefPubMedGoogle Scholar
  12. 12.
    Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53:1874–1882.CrossRefPubMedGoogle Scholar
  13. 13.
    Bedossa P, FLIP Pathology Consortium. 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;60:565–575.CrossRefPubMedGoogle Scholar
  14. 14.
    Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol. 2012;107:811–826.CrossRefPubMedGoogle Scholar
  15. 15.
    Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010;53:372–384.CrossRefPubMedGoogle Scholar
  16. 16.
    Tiniakos DG. Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis: histological diagnostic criteria and scoring systems. Eur J Gastroenterol Hepatol. 2010;22:643–650.PubMedGoogle Scholar
  17. 17.
    Tandra S, Yeh MM, Brunt EM, et al. Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease. J Hepatol. 2011;55:654–659.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42:641–649.CrossRefPubMedGoogle Scholar
  19. 19.
    Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321.CrossRefPubMedGoogle Scholar
  20. 20.
    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;116:1413–1419.CrossRefPubMedGoogle Scholar
  21. 21.
    Listenberger LL, Han X, Lewis SE, et al. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci. 2003;100:3077–3082.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yamaguchi K, Yang L, McCall S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007;45:1366–1374.CrossRefPubMedGoogle Scholar
  23. 23.
    Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin Gastroenterol Hepatol. 2015;13:643–654.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Pais R, Charlotte F, Fedchuk L, et al. A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. J Hepatol. 2013;59:550–556.CrossRefPubMedGoogle Scholar
  25. 25.
    McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62:1148–1155.CrossRefPubMedGoogle Scholar
  26. 26.
    Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–873.CrossRefPubMedGoogle Scholar
  27. 27.
    Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121:91–100.CrossRefPubMedGoogle Scholar
  28. 28.
    Campos GM, Bambha K, Vittinghoff E, et al. A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients. Hepatology. 2008;47:1916–1923.CrossRefPubMedGoogle Scholar
  29. 29.
    Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–438.PubMedGoogle Scholar
  30. 30.
    Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010;7:195–203.CrossRefPubMedGoogle Scholar
  31. 31.
    Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology. 2014;147:754–764.CrossRefPubMedGoogle Scholar
  32. 32.
    Bedossa P, Poitou C, Veyrie N, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology. 2012;56:1751–1759.CrossRefPubMedGoogle Scholar
  33. 33.
    Sakhuja P. Pathology of alcoholic liver disease, can it be differentiated from nonalcoholic steatohepatitis? World J Gastroenterol. 2014;20:16474–16479.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Brunt EM, Kleiner DE, Wilson LA, 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;49:809–820.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51:371–379.CrossRefPubMedGoogle Scholar
  36. 36.
    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;48:821–828.CrossRefPubMedGoogle Scholar
  37. 37.
    Argo CK, Ikura Y, Lackner C, Caldwell SH. The fat droplet in hepatocellular ballooning and implications for scoring nonalcoholic steatohepatitis therapeutic response. Hepatology. 2015. doi:10.1002/hep.28009.Google Scholar
  38. 38.
    Caldwell S, Ikura Y, Dias D, et al. Hepatocellular ballooning in NASH. J Hepatol. 2010;53:719–723.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Caldwell SH, Redick JA, Chang CY, Davis CA, Argo CK, Al Osaimi KA. Enlarged hepatocytes in NAFLD examined with osmium fixation: does microsteatosis underlie cellular ballooning in NASH? Am J Gastroenterol. 2006;101:1677–1678.CrossRefPubMedGoogle Scholar
  40. 40.
    Guy CD, Suzuki A, Burchette JL, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    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;94:2467–2474.CrossRefPubMedGoogle Scholar
  42. 42.
    Gill RM, Belt P, Wilson L, Bass NM, Ferrell LD. Centrizonal arteries and microvessels in nonalcoholic steatohepatitis. Am J Surg Pathol. 2011;35:1400–1404.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Richardson MM, Jonsson JR, Powell EE, et al. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology. 2007;133:80–90.CrossRefPubMedGoogle Scholar
  44. 44.
    Ekstedt M, Hagstrom H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61:1547–1554.CrossRefPubMedGoogle Scholar
  45. 45.
    Patton HM, Yates K, Unalp-Arida A, et al. Association between metabolic syndrome and liver histology among children with nonalcoholic Fatty liver disease. Am J Gastroenterol. 2010;105:2093–2102.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Molleston JP, White F, Teckman J, Fitzgerald JF. Obese children with steatohepatitis can develop cirrhosis in childhood. Am J Gastroenterol. 2002;97:2460–2462.CrossRefPubMedGoogle Scholar
  47. 47.
    Nobili V, Marcellini M, Devito R, et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology. 2006;44:458–465.CrossRefPubMedGoogle Scholar
  48. 48.
    Carter-Kent C, Yerian LM, Brunt EM, et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology. 2009;50:1113–1120.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Fukusato T, Fukushima J, Shiga J, et al. Interobserver variation in the histopathological assessment of nonalcoholic steatohepatitis. Hepatol Res. 2005;33:122–127.CrossRefPubMedGoogle Scholar
  50. 50.
    Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54:344–353.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA, Network NCR. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53:810–820.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kleiner DE, Brunt EM. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin Liver Dis. 2012;32:3–13.CrossRefPubMedGoogle Scholar
  53. 53.
    Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–2307.CrossRefPubMedGoogle Scholar
  54. 54.
    Lavine JE, Schwimmer JB, Van Natta ML, 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;305:1659–1668.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Torres DM, Jones FJ, Shaw JC, Williams CD, Ward JA, Harrison SA. Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open-label trial. Hepatology. 2011;54:1631–1639.CrossRefPubMedGoogle Scholar
  56. 56.
    Loomba R, Lutchman G, Kleiner DE, et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2009;29:172–182.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–1685.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385:956–965.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© European Union 2016

Authors and Affiliations

  1. 1.Hôpital Beaujon, Assistance Publique – Hôpitaux de ParisUniversité Paris-DiderotParisFrance

Personalised recommendations