Skip to main content

Advertisement

SpringerLink
Log in

Histological Assessment of NAFLD

  • Review
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–690.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  4. Kleiner DE, Bedossa P. Liver histology and clinical trials for nonalcoholic steatohepatitis-perspectives from 2 pathologists. Gastroenterology. 2015;149:1305–1308.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  6. Nalbantoglu IL, Brunt EM. Role of liver biopsy in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20:9026–9037.

    PubMed  PubMed Central  Google Scholar 

  7. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38:1449–1457.

    Article  PubMed  Google Scholar 

  8. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–1906.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  16. Tiniakos DG. Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis: histological diagnostic criteria and scoring systems. Eur J Gastroenterol Hepatol. 2010;22:643–650.

    PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatology. 2005;42:641–649.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  30. Brunt EM. Pathology of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2010;7:195–203.

    Article  PubMed  Google Scholar 

  31. Yeh MM, Brunt EM. Pathological features of fatty liver disease. Gastroenterology. 2014;147:754–764.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  33. Sakhuja P. Pathology of alcoholic liver disease, can it be differentiated from nonalcoholic steatohepatitis? World J Gastroenterol. 2014;20:16474–16479.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. Caldwell S, Ikura Y, Dias D, et al. Hepatocellular ballooning in NASH. J Hepatol. 2010;53:719–723.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  48. Carter-Kent C, Yerian LM, Brunt EM, et al. Nonalcoholic steatohepatitis in children: a multicenter clinicopathological study. Hepatology. 2009;50:1113–1120.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Fukusato T, Fukushima J, Shiga J, et al. Interobserver variation in the histopathological assessment of nonalcoholic steatohepatitis. Hepatol Res. 2005;33:122–127.

    Article  PubMed  Google Scholar 

  50. Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology. 2011;54:344–353.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kleiner DE, Brunt EM. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin Liver Dis. 2012;32:3–13.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hôpital Beaujon, Assistance Publique – Hôpitaux de Paris, Université Paris-Diderot, Paris, France

    Pierre Bedossa

Authors
  1. Pierre Bedossa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pierre Bedossa.

Ethics declarations

Conflict of interest

No conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bedossa, P. Histological Assessment of NAFLD. Dig Dis Sci 61, 1348–1355 (2016). https://doi.org/10.1007/s10620-016-4062-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-016-4062-0

Keywords

Search

Navigation