Advertisement

Digestive Diseases and Sciences

, Volume 58, Issue 10, pp 3017–3023 | Cite as

Predictors of All-Cause Mortality and Liver-Related Mortality in Patients with Non-Alcoholic Fatty Liver Disease (NAFLD)

  • Maria Stepanova
  • Nila Rafiq
  • Hala Makhlouf
  • Ritambhara Agrawal
  • Ishmeet Kaur
  • Zahra Younoszai
  • Arthur McCullough
  • Zachary Goodman
  • Zobair M. YounossiEmail author
Original Article

Abstract

Aim

Non-alcoholic steatohepatitis (NASH) patients are at increased risk for progression to cirrhosis. The aim of this study was to assess all-cause and liver-specific mortality in a cohort of non-alcoholic fatty liver disease (NAFLD) patients.

Methods

Biopsy-proven NAFLD patients with and without NASH from two historic databases were included. Clinico-demographic information from the time of biopsy was available. Mortality data were obtained from National Death Index-Plus and used for estimating overall and cause-specific mortality. The non-parametric Kaplan–Meier method with log-rank test and multivariate analyses with Cox proportional hazard model were used to compare cohorts.

Results

Two hundred eighty-nine NAFLD patients were included (50.3 ± 14.5 years old, 39.4 % male, 78.6 % Caucasian, 46.0 % obese, 26.0 % diabetic, 5.9 % with family history of liver diseases). Of these, 59.2 % had NASH whereas 40.8 % had non-NASH NAFLD. NASH patients were predominantly female, had higher aspartate aminotranserase, alanine aminotransferase and fasting serum glucose. During follow-up (median 150 months, maximum 342 months), patients with NASH had higher probability of mortality from liver-related causes than non-NASH NAFLD patients (p value = 0.0026). In the entire NAFLD cohort, older age [aHR = 1.07 (95 % CI = 1.05–1.10)] and presence of type II diabetes [aHR = 2.09 (1.39–3.14)] were independent predictors of overall mortality. However, in addition to age [aHR = 1.06 (1.02–1.10)] having histologic NASH [aHR = 9.16 (2.10–9.88)] was found to be an independent predictor of liver-related mortality. Additionally, presence of type II diabetes was associated with liver-related mortality [aHR = 2.19 (1.00–4.81)].

Conclusions

This long-term follow-up of NAFLD patients confirms that NASH patients have higher risk of liver-related mortality than non-NASH. Additionally, patients with NAFLD and type II diabetes are at highest risk for overall and liver-related mortality.

Keywords

Non-alcoholic fatty liver disease (NAFLD) Follow-up study Non-alcoholic steatohepatitis (NASH) Mortality 

Abbreviations

NAFLD

Non-alcoholic fatty liver disease

NASH

Non-alcoholic steatohepatitis

BMI

Body mass index

CDC

Center for disease control

NDI

National death index

ALT

Alanine aminotransferase

AST

Aspartate aminotranserase

LRM

Liver-related mortality

aHR

Adjusted hazard ratio

95 % CI

95 % Confidence interval

Notes

Acknowledgments

This study has been supported in part by the Liver Disease Outcomes Fund of the Center for Liver Diseases at Inova Fairfax Hospital, Inova Health System, Falls Church, VA.

Conflict of interest

None.

References

  1. 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.PubMedGoogle Scholar
  2. 2.
    Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008;48:792–798.PubMedCrossRefGoogle Scholar
  3. 3.
    Ong JP, Younossi ZM. Epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Clin Liver Dis. 2007;11:1–16.PubMedCrossRefGoogle Scholar
  4. 4.
    Rafiq N, Younossi ZM. Effects of weight loss on non-alcoholic fatty liver disease. Semin Liver Dis. 2008;28:427–433.PubMedCrossRefGoogle Scholar
  5. 5.
    Younossi Z, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988–2008. Clin Gastroenterol Hepatol. 2011;9:524–530.PubMedCrossRefGoogle Scholar
  6. 6.
    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. Hepatology. 2012;55:2005–2023.PubMedCrossRefGoogle Scholar
  7. 7.
    Ong JP, Elariny H, Collantes R, et al. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg. 2005;15:310–315.PubMedCrossRefGoogle Scholar
  8. 8.
    Gholam PM, Flanebaum L, Machan JT. Nonalcoholic fatty liver disease in severely obese subjects. Am J Gastroenterol. 2007;102:399–408.PubMedCrossRefGoogle Scholar
  9. 9.
    Beymer C, Kowdley KV, Larson AA. Prevalence and predictors of asymptomatic liver disease in patients undergoing gastric bypass surgery. Arch Surg. 2003;138:1240–1244.PubMedCrossRefGoogle Scholar
  10. 10.
    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.PubMedCrossRefGoogle Scholar
  11. 11.
    Younossi ZM, Stepanova M, Rafiq N, et al. Pathologic criteria for non-alcoholic steatohepatitis (NASH): inter-protocol agreement and ability to predict liver-related mortality. Hepatology. 2011;53(6):1874–1882.PubMedCrossRefGoogle Scholar
  12. 12.
    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.PubMedCrossRefGoogle Scholar
  13. 13.
    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.PubMedCrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7(2):234–238.PubMedCrossRefGoogle Scholar
  16. 16.
    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.PubMedCrossRefGoogle Scholar
  17. 17.
    Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med. 2011;43:617–49. doi: 10.3109/07853890.2010.518623.
  18. 18.
    Rafiq N, Younossi ZM. Nonalcoholic fatty liver disease: a practical approach to evaluation and management. Clin Liver Dis. 2009;13:249–266.PubMedCrossRefGoogle Scholar
  19. 19.
    Ong J, Pitts A, Younossi ZM. Increased mortality and liver-related mortality in patients with nonalcoholic fatty liver disease. J Hepatol. 2008;49:608–612.PubMedCrossRefGoogle Scholar
  20. 20.
    Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut. 2010;59:1410–1415.PubMedCrossRefGoogle Scholar
  21. 21.
    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.PubMedCrossRefGoogle Scholar
  22. 22.
    World Health Organization. ICD 10: International Statistical Classification of Diseases and Related Health Problems. Arlington, VA: American Psychiatric Publishing, Inc.; 1992.Google Scholar
  23. 23.
    Larter CZ, Chitturi S, Heydet D, Farrell GC. A fresh look at NASH pathogenesis. Part 1: the metabolic movers. J Gastroenterol Hepatol. 2010;25:672–690.PubMedCrossRefGoogle Scholar
  24. 24.
    Cusi K. Role of insulin resistance and lipotoxicity in non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13:545–563.PubMedCrossRefGoogle Scholar
  25. 25.
    Gentile CL, Pagliassotti MJ. The role of fatty acids in the development and progression of nonalcoholic fatty liver disease. J Nutr Biochem. 2008;19:567–576.PubMedCrossRefGoogle Scholar
  26. 26.
    Fracanzani AL, Valenti L, Bugianesi E, et al. Risk of non alcoholic steatohepatitis and fibrosis in patients with non alcoholic fatty liver disease and low visceral adiposity. J Hepatol. 2011;54:1244–1249. doi: 10.1016/j.jhep.2010.09.037.Google Scholar
  27. 27.
    Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and prognosis of NASH. J Gastroenterol. 2011;46:63–69.PubMedCrossRefGoogle Scholar
  28. 28.
    Younossi ZM, Otgonsuren M, Venkatesan C, Mishra A. In patients with non-alcoholic fatty liver disease (NAFLD), metabolically abnormal individuals are at a higher risk for mortality while metabolically normal individuals are not. Metabolism. 2013;62:352–360. doi: 10.1016/j.metabol.2012.08.005.
  29. 29.
    Younossi ZM, Gramlich T, Matteoni C, Boparai N, McCullough A. Non-alcoholic fatty liver disease in patients with type II diabetes. Clin Gastroenterol Hepatol. 2004;2:262–265.PubMedCrossRefGoogle Scholar
  30. 30.
    Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis. 2007;191:235–240.PubMedCrossRefGoogle Scholar
  31. 31.
    Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon? Diabetologia. 2008;51:1947–1953.PubMedCrossRefGoogle Scholar
  32. 32.
    Targher G, Day CP. Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease. Hepatology. 2011;53:375. doi: 10.1002/hep.23901.Google Scholar
  33. 33.
    Stepanova M, Younossi ZM. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol. 2012;10:646–650.Google Scholar
  34. 34.
    Xu J, Kochanek KD, Murphy SL, Tejada-Vera B. Deaths: final data for 2007. Natl Vital Stat Rep. 2010;58:1–136.Google Scholar
  35. 35.
    Lam B, Younossi ZM. Treatment options for nonalcoholic fatty liver disease. Therap Adv Gastroenterol. 2010;3:121–137.PubMedCrossRefGoogle Scholar
  36. 36.
    Younossi ZM, Venkatesan C. A 2012 clinical update for internists in adult nonalcoholic fatty liver disease. Panminerva Med. 2012;54:29–37. Review.Google Scholar
  37. 37.
    Venkatesan C, Younossi ZM. Potential mechanisms underlying the associations between liver enzymes and risk for type 2 diabetes. Hepatology. 2012;55:968–970.PubMedCrossRefGoogle Scholar
  38. 38.
    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.e1; quiz e60.Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Maria Stepanova
    • 1
    • 4
  • Nila Rafiq
    • 1
  • Hala Makhlouf
    • 2
  • Ritambhara Agrawal
    • 1
  • Ishmeet Kaur
    • 1
  • Zahra Younoszai
    • 1
  • Arthur McCullough
    • 3
  • Zachary Goodman
    • 1
    • 4
  • Zobair M. Younossi
    • 1
    • 4
    Email author
  1. 1.Center for Liver Diseases at Inova Fairfax HospitalFalls ChurchUSA
  2. 2.Armed Forces Institutes of PathologyWashingtonUSA
  3. 3.Department of GastroenterologyCleveland Clinic FoundationClevelandUSA
  4. 4.Betty and Guy Beatty Center for Integrated ResearchInova Health SystemFalls ChurchUSA

Personalised recommendations