Digestive Diseases and Sciences

, Volume 63, Issue 9, pp 2259–2266 | Cite as

Identifying Nonalcoholic Fatty Liver Disease Advanced Fibrosis in the Veterans Health Administration

  • Yuval A. PatelEmail author
  • Elizabeth J. Gifford
  • Lisa M. Glass
  • Marsha J. Turner
  • Byungjoo Han
  • Cynthia A. Moylan
  • Steve Choi
  • Ayako Suzuki
  • Dawn Provenzale
  • Christine M. Hunt
Original Article



Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Severe NAFLD with advanced fibrosis results in substantial morbidity and mortality. Associated with metabolic syndrome, NAFLD is often initially clinically silent, yet intensive lifestyle intervention with 7% or greater weight loss can improve or resolve NAFLD. Using a Veterans Health Administration (VHA) liver biopsy cohort, we evaluated simple noninvasive fibrosis scoring systems to identify NAFLD with advanced fibrosis (or severe disease) to assist providers.


In our retrospective study of a national VHA sample of patients with biopsy-proven NAFLD or normal liver (2005–2015), we segregated patients by fibrosis stage (0–4). Non-NAFLD liver disease was excluded. We evaluated the diagnostic accuracy of the NAFLD fibrosis score (NFS), fibrosis-4 calculator (FIB-4), aspartate aminotransferase-to-alanine aminotransferase ratio (AST/ALT ratio), AST-to-platelet ratio index (APRI), and body mass index, AST/ALT ratio, and diabetes (BARD) score by age groups.


We included 329 patients with well-defined liver histology (296 NAFLD and 33 normal controls without fibrosis), in which 92 (28%) had advanced (stage 3–4) fibrosis. Across all age groups, NFS and FIB-4 best predicted advanced fibrosis (NFS with 0.676 threshold: AUROC 0.71–0.76, LR + 2.30–22.05, OR 6.00–39.58; FIB-4 with 2.67 threshold: AUROC of 0.62–0.80, LR + 4.70–27.45, OR 16.34–59.65).


While NFS and FIB-4 scores exhibit good diagnostic accuracy, FIB-4 is optimal in identifying NAFLD advanced fibrosis in the VHA. Easily implemented as a point-of-care clinical test, FIB-4 can be useful in directing patients that are most likely to have advanced fibrosis to GI/hepatology consultation and follow-up.


Fatty liver Nonalcoholic steatohepatitis Fibrosis Fibrosis prediction score 



Area under the ROC


Alanine aminotransferase


Aspartate aminotransferase


AST-to-platelet ratio index

BARD score

Body mass index, AST/ALT ratio, and diabetes


Alcohol Use Disorders Identification Test Alcohol Consumption Questions


Body mass index


Fibrosis-4 calculator


Hepatocellular carcinoma


Nonalcoholic fatty liver


Nonalcoholic fatty liver disease


NAFLD fibrosis score


Nonalcoholic steatohepatitis


Receiver operating characteristic curve


Veterans Health Administration


Author’s contribution

All authors had access to the data and a role in writing/preparing the manuscript.


This work was supported in part by resources from the Veterans Affairs (VA) Cooperative Studies Program Epidemiology Center, Durham, and the VA Ann Arbor Healthcare Systems.

Compliance with ethical standards

Conflict of interest

The views expressed in this paper are those of the authors and do not necessarily represent the policies or position of, nor imply endorsement from, the Department of Veterans Affairs, or US Government. Christine M. Hunt has received consultancy fees from Otsuka and Indivior.

Supplementary material

10620_2018_5123_MOESM1_ESM.docx (26 kb)
Supplementary material 1 (DOCX 25 kb)


  1. 1.
    Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md). 2018;67:328–357.CrossRefGoogle Scholar
  2. 2.
    Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Nonalcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol. 2016;65:589–600.CrossRefPubMedGoogle Scholar
  3. 3.
    EASL-EASD-EASO. Clinical practice guidelines for the management of nonalcoholic fatty liver disease. J Hepatol. 2016;64:1388–1402.Google Scholar
  4. 4.
    Rinella ME. Nonalcoholic fatty liver disease: a systematic review. Jama. 2015;313:2263–2273.CrossRefPubMedGoogle Scholar
  5. 5.
    Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–854.CrossRefPubMedGoogle Scholar
  6. 6.
    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.e310.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Younossi ZM, Blissett D, Blissett R, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016;64:1577–1586.CrossRefPubMedGoogle Scholar
  8. 8.
    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
  9. 9.
    Goldberg D, Ditah IC, Saeian K, et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology. 2017;152:1090–1099.e1091.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Golabi P, Otgonsuren M, Cable R, et al. Nonalcoholic fatty liver disease (NAFLD) is associated with impairment of health related quality of life (HRQOL). Health Qual Outcomes. 2016;14:18.CrossRefGoogle Scholar
  11. 11.
    Sayiner M, Otgonsuren M, Cable R, et al. Variables associated with inpatient and outpatient resource utilization among Medicare beneficiaries with nonalcoholic fatty liver disease with or without cirrhosis. J Clin Gastroenterol. 2017;51:254.PubMedGoogle Scholar
  12. 12.
    Bril F, Barb D, Portillo-Sanchez P, et al. Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease. Hepatology. 2017;65:1132–1144.CrossRefPubMedGoogle Scholar
  13. 13.
    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.e649.CrossRefPubMedGoogle Scholar
  14. 14.
    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
  15. 15.
    Bedossa P, Burt AD, Gouw A, et al. Utility and appropriateness of the FLIP algorithm and SAF score in the evaluation of biopsies of nonalcoholic fatty liver disease. Hepatology. 2014;60:565–567.CrossRefPubMedGoogle Scholar
  16. 16.
    Vuppalanchi R, Ünalp 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.CrossRefPubMedGoogle Scholar
  17. 17.
    Tapper EB, Lok AS-F. Use of liver imaging and biopsy in clinical practice New England. J Med. 2017;377:756–768.Google Scholar
  18. 18.
    Tapper EB, Sengupta N, Hunink MM, Afdhal NH, Lai M. Cost-effective evaluation of nonalcoholic fatty liver disease with NAFLD fibrosis score and vibration controlled transient elastography. Am J Gastroenterol. 2015;110:1298.CrossRefPubMedGoogle Scholar
  19. 19.
    Cui J, Ang B, Haufe W, et al. Comparative diagnostic accuracy of magnetic resonance elastography vs. eight clinical prediction rules for non-invasive diagnosis of advanced fibrosis in biopsy-proven nonalcoholic fatty liver disease: a prospective study. Aliment Pharmacol Ther. 2015;41:1271–1280.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–1325.CrossRefPubMedGoogle Scholar
  21. 21.
    Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57:1441–1447.CrossRefPubMedGoogle Scholar
  22. 22.
    Kanwal F, Kramer JR, Duan Z, Yu X, White D, El-Serag HB. Trends in the burden of nonalcoholic fatty liver disease in a United States cohort of veterans. Clin Gastroenterol Hepatol. 2016;14:301–308.e302.CrossRefPubMedGoogle Scholar
  23. 23.
    Mittal S, El-Serag HB, Sada YH, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2016;14:124–131.e121.CrossRefPubMedGoogle Scholar
  24. 24.
    Patel YA, Gifford EJ, Glass LM, et al. Risk factors for biopsy-proven advanced nonalcoholic fatty liver disease in the Veterans Health Administration. Aliment Pharmacol Ther. 2017;47:268–278.CrossRefPubMedGoogle Scholar
  25. 25.
    Shah AG, Lydecker A, Murray K, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7:1104–1112.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    McPherson S, Hardy T, Dufour J-F, et al. Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis. Am J Gastroenterol. 2017;112:740.CrossRefPubMedGoogle Scholar
  27. 27.
    Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518–526.CrossRefPubMedGoogle Scholar
  28. 28.
    Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis relationship to cirrhosis. Gastroenterology. 1988;95:734–739.CrossRefPubMedGoogle Scholar
  29. 29.
    Eusebi P. Diagnostic accuracy measures. Cerebrovasc Dis. 2013;36:267–272.CrossRefPubMedGoogle Scholar
  30. 30.
    Seed P. DIAGT: Stata module to report summary statistics for diagnostic tests compared to true disease status. EconPapers: 2010. Available at: Accessed 30 Mar 2018.
  31. 31.
    National Center for Veterans Analysis and Statistics. Profile of Veterans (2016). Data from the American Community Survey; 2018. Available at: Accessed 10 Mar 2018.
  32. 32.
    Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149:367–378.e365.CrossRefPubMedGoogle Scholar
  33. 33.
    Del Re AC, Maciejewski ML, Harris AH. MOVE: weight management program across the veterans health administration: patient-and facility-level predictors of utilization. BMC Health Serv Res. 2013;13:511.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Batch BC, Goldstein K, Yancy WS Jr, et al. Outcome by gender in the veterans health administration motivating overweight/obese veterans everywhere weight management program. J Women’s Health (Larchmt). 2018;27:32–39.CrossRefGoogle Scholar
  35. 35.
    Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403.CrossRefPubMedGoogle Scholar
  36. 36.
    Haw JS, Galaviz KI, Straus AN, et al. Long-term sustainability of diabetes prevention approaches: a systematic review and meta-analysis of randomized clinical trials. JAMA Intern Med. 2017;177:1808–1817.CrossRefPubMedGoogle Scholar
  37. 37.
    Brito JP, Montori VM, Davis AM. Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by international diabetes organizations. Jama. 2017;317:635–636.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149:379–388.CrossRefPubMedGoogle Scholar
  39. 39.
    Saab S, Mallam D, Cox GA, Tong MJ. Impact of coffee on liver diseases: a systematic review. Liver Int. 2014;34:495–504.CrossRefPubMedGoogle Scholar
  40. 40.
    Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, Harrison SA. Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology.. 2012;55:429–436.CrossRefPubMedGoogle Scholar
  41. 41.
    Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with nonalcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387:679–690.CrossRefPubMedGoogle Scholar
  42. 42.
    Neuschwander-Tetri BA, Clark JM, Bass NM, et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology. 2010;52:913–924.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Yuval A. Patel
    • 1
    Email author
  • Elizabeth J. Gifford
    • 2
  • Lisa M. Glass
    • 3
    • 4
  • Marsha J. Turner
    • 5
  • Byungjoo Han
    • 5
  • Cynthia A. Moylan
    • 1
  • Steve Choi
    • 1
  • Ayako Suzuki
    • 1
  • Dawn Provenzale
    • 1
    • 5
  • Christine M. Hunt
    • 1
    • 5
  1. 1.Department of MedicineDuke University Medical Center, Durham Veterans Administration Medical CenterDurhamUSA
  2. 2.Sanford School of Public PolicyDuke UniversityDurhamUSA
  3. 3.Department of MedicineUniversity of MichiganAnn ArborUSA
  4. 4.VA Ann Arbor Healthcare SystemsAnn ArborUSA
  5. 5.Cooperative Studies Program Epidemiology CenterDurham Veterans Administration Medical CenterDurhamUSA

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