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

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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.

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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

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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  4. Rafiq N, Younossi ZM. Effects of weight loss on non-alcoholic fatty liver disease. Semin Liver Dis. 2008;28:427–433.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  8. Gholam PM, Flanebaum L, Machan JT. Nonalcoholic fatty liver disease in severely obese subjects. Am J Gastroenterol. 2007;102:399–408.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. Rafiq N, Younossi ZM. Nonalcoholic fatty liver disease: a practical approach to evaluation and management. Clin Liver Dis. 2009;13:249–266.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  22. World Health Organization. ICD 10: International Statistical Classification of Diseases and Related Health Problems. Arlington, VA: American Psychiatric Publishing, Inc.; 1992.

  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.

    Article  PubMed  CAS  Google Scholar 

  24. Cusi K. Role of insulin resistance and lipotoxicity in non-alcoholic steatohepatitis. Clin Liver Dis. 2009;13:545–563.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and prognosis of NASH. J Gastroenterol. 2011;46:63–69.

    Article  PubMed  Google Scholar 

  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. 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.

    Article  PubMed  Google Scholar 

  30. Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis. 2007;191:235–240.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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. 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. Lam B, Younossi ZM. Treatment options for nonalcoholic fatty liver disease. Therap Adv Gastroenterol. 2010;3:121–137.

    Article  PubMed  CAS  Google Scholar 

  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. Venkatesan C, Younossi ZM. Potential mechanisms underlying the associations between liver enzymes and risk for type 2 diabetes. Hepatology. 2012;55:968–970.

    Article  PubMed  CAS  Google Scholar 

  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 

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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.

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Authors and Affiliations

  1. Center for Liver Diseases at Inova Fairfax Hospital, Falls Church, VA, USA

    Maria Stepanova, Nila Rafiq, Ritambhara Agrawal, Ishmeet Kaur, Zahra Younoszai, Zachary Goodman & Zobair M. Younossi

  2. Armed Forces Institutes of Pathology, Washington, DC, USA

    Hala Makhlouf

  3. Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, OH, USA

    Arthur McCullough

  4. Betty and Guy Beatty Center for Integrated Research, Inova Health System, 3300 Gallows Road, Falls Church, VA, 22042, USA

    Maria Stepanova, Zachary Goodman & Zobair M. Younossi

Authors
  1. Maria Stepanova
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  2. Nila Rafiq
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  3. Hala Makhlouf
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  4. Ritambhara Agrawal
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  6. Zahra Younoszai
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  7. Arthur McCullough
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  9. Zobair M. Younossi
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Corresponding author

Correspondence to Zobair M. Younossi.

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Stepanova, M., Rafiq, N., Makhlouf, H. et al. Predictors of All-Cause Mortality and Liver-Related Mortality in Patients with Non-Alcoholic Fatty Liver Disease (NAFLD). Dig Dis Sci 58, 3017–3023 (2013). https://doi.org/10.1007/s10620-013-2743-5

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  • DOI: https://doi.org/10.1007/s10620-013-2743-5

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