Skip to main content

Advertisement

SpringerLink
Log in

Natural History of Nonalcoholic Fatty Liver Disease

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

Abstract

Nonalcoholic fatty liver disease (NAFLD) remains among the most common liver diseases worldwide, with increasing prevalence in concert with the obesity and metabolic syndrome epidemic. The evidence on the natural history, albeit with some ambiguity, suggests the potential for some subsets of NAFLD to progress to cirrhosis, liver-related complications and mortality with fibrosis being the most important predictor of hard long-term endpoints such as mortality and liver complications. In this setting, NAFLD proves to be a formidable disease entity, with considerable clinical burden, for both the present and the future. Our understanding of the natural history of NAFLD is constantly evolving, with nascent data challenging current dogma. Further clarification of the natural history is required with well-designed, well-defined studies using prospectively collected data. Identifying the predictors of long-term outcomes should be used to direct development of clinical trial endpoints in NAFLD.

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.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. 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 

  2. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–2023.

    Article  PubMed  Google Scholar 

  3. Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis. 2001;21:17–26.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol. 2011;9:524–530.

    Article  PubMed  Google Scholar 

  6. Younossi ZM, Henry L. Economic and quality-of-life implications of nonalcoholic fatty liver disease. PharmacoEconomics. 2015. doi:10.1007/s40273-015-0316-5.

    PubMed  Google Scholar 

  7. Charlton MR, Burns JM, Pedersen RA, et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141:1249–1253.

    Article  PubMed  Google Scholar 

  8. Satapathy SK, Sanyal AJ. Epidemiology and natural history of nonalcoholic fatty liver disease. Semin Liver Dis. 2015;35:221–235.

    Article  PubMed  Google Scholar 

  9. Zhu JZ, Dai YN, Wang YM, et al. Prevalence of nonalcoholic fatty liver disease and economy. Dig Dis Sci. 2015;60:3194–3202. doi:10.1007/s10620-015-3728-3.

    Article  CAS  PubMed  Google Scholar 

  10. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–121.

    Article  PubMed  Google Scholar 

  11. Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in nonalcoholic fatty liver disease. J Hepatol. 2008;49:608–612.

    Article  PubMed  Google Scholar 

  12. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am J Gastroenterol. 2008;103:2263–2271.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lazo M, Hernaez R, Bonekamp S, et al. Nonalcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ. 2011;343:d6891.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–1419.

    Article  CAS  PubMed  Google Scholar 

  15. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. 1995;22:1714–1719.

    Article  CAS  PubMed  Google Scholar 

  16. Dam-Larsen S, Franzmann M, Andersen IB, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53:750–755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7:234–238.

    Article  PubMed  Google Scholar 

  18. 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 

  19. Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;51:595–602.

    Article  PubMed  Google Scholar 

  20. Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of nonalcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43:617–649.

    Article  PubMed  Google Scholar 

  21. 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 

  22. Brunt EM, Kleiner DE, Wilson LA, et al. 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 

  23. 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 

  24. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389–397.

    Article  PubMed  Google Scholar 

  25. Adams LA, Ratziu V. Nonalcoholic fatty liver—perhaps not so benign. J Hepatol. 2015;62:1002–1004.

    Article  PubMed  Google Scholar 

  26. Wong VW, Wong GL, Choi PC, et al. Disease progression of nonalcoholic fatty liver disease: a prospective study with paired liver biopsies at 3 years. Gut. 2010;59:969–974.

    Article  PubMed  Google Scholar 

  27. Pais R, Charlotte F, Fedchuk L, et al. A systematic review of follow-up biopsies reveals disease progression in patients with nonalcoholic fatty liver. J Hepatol. 2013;59:550–556.

    Article  CAS  PubMed  Google Scholar 

  28. McPherson S, Hardy T, Henderson E, et al. 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 

  29. Singh S, Allen AM, Wang Z, et al. 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 

  30. Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology. 1990;11:74–80.

    Article  PubMed  Google Scholar 

  31. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42:132–138.

    Article  PubMed  Google Scholar 

  32. Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Am J Gastroenterol. 2003;98:2042–2047.

    Article  PubMed  Google Scholar 

  33. Evans CD, Oien KA, MacSween RN, Mills PR. Nonalcoholic steatohepatitis: a common cause of progressive chronic liver injury? J Clin Pathol. 2002;55:689–692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40:820–826.

    PubMed  Google Scholar 

  35. Hui AY, Wong VW, Chan HL, et al. Histological progression of nonalcoholic fatty liver disease in Chinese patients. Aliment Pharmacol Ther. 2005;21:407–413.

    Article  CAS  PubMed  Google Scholar 

  36. Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in nonalcoholic steatohepatitis. J Hepatol. 2009;51:371–379.

    Article  CAS  PubMed  Google Scholar 

  37. McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8:521–533.

    Article  PubMed  Google Scholar 

  38. Onnerhag K, Nilsson PM, Lindgren S. Increased risk of cirrhosis and hepatocellular cancer during long-term follow-up of patients with biopsy-proven NAFLD. Scand J Gastroenterol. 2014;49:1111–1118.

    Article  PubMed  Google Scholar 

  39. Hui JM, Kench JG, Chitturi S, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology. 2003;38:420–427.

    Article  PubMed  Google Scholar 

  40. Sanyal AJ, Banas C, Sargeant C, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology. 2006;43:682–689.

    Article  PubMed  Google Scholar 

  41. Bhala N, Angulo P, van der Poorten D, et al. The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology. 2011;54:1208–1216.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Yatsuji S, Hashimoto E, Tobari M, et al. Clinical features and outcomes of cirrhosis due to nonalcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol. 2009;24:248–254.

    Article  CAS  PubMed  Google Scholar 

  43. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140.

    Article  PubMed  Google Scholar 

  44. Caldwell SH, Crespo DM. The spectrum expanded: cryptogenic cirrhosis and the natural history of nonalcoholic fatty liver disease. J Hepatol. 2004;40:578–584.

    Article  PubMed  Google Scholar 

  45. Ong J, Younossi ZM, Reddy V, et al. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl. 2001;7:797–801.

    Article  CAS  PubMed  Google Scholar 

  46. McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis. 2015;19:223–238.

    Article  PubMed  Google Scholar 

  47. Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in nonalcoholic fatty liver disease: an emerging menace. J Hepatol. 2012;56:1384–1391.

    Article  PubMed  Google Scholar 

  48. Younossi ZM, Otgonsuren M, Henry L, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62:1723–1730.

    Article  CAS  PubMed  Google Scholar 

  49. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10:1342–1359.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kawada N, Imanaka K, Kawaguchi T, et al. Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis. J Gastroenterol. 2009;44:1190–1194.

    Article  PubMed  Google Scholar 

  51. Haflidadottir S, Jonasson JG, Norland H, et al. Long-term follow-up and liver-related death rate in patients with nonalcoholic and alcoholic related fatty liver disease. BMC Gastroenterol. 2014;14:166.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Hamaguchi E, Takamura T, Sakurai M, et al. Histological course of nonalcoholic fatty liver disease in Japanese patients: tight glycemic control, rather than weight reduction, ameliorates liver fibrosis. Diabetes Care. 2010;33:284–286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chan WK, Ida NH, Cheah PL, Goh KL. Progression of liver disease in nonalcoholic fatty liver disease: a prospective clinicopathological follow-up study. J Dig Dis. 2014;15:545–552.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

A. J. M. was supported in part by NIH DDK U505.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore

    George Boon-Bee Goh

  2. Duke-NUS Graduate Medical School, Singapore, Singapore

    George Boon-Bee Goh

  3. Department of Gastroenterology, Cleveland Clinic Foundation, 9500 Euclid Avenue/A30, Cleveland, OH, 44195, USA

    Arthur J. McCullough

  4. Department of Pathobiology, Cleveland Clinic Foundation, Cleveland, OH, USA

    Arthur J. McCullough

Authors
  1. George Boon-Bee Goh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arthur J. McCullough
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arthur J. McCullough.

Ethics declarations

Conflicts of interest

All authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Goh, G.BB., McCullough, A.J. Natural History of Nonalcoholic Fatty Liver Disease. Dig Dis Sci 61, 1226–1233 (2016). https://doi.org/10.1007/s10620-016-4095-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-016-4095-4

Keywords

Search

Navigation