Journal of Gastroenterology

, Volume 47, Issue 6, pp 696–703 | Cite as

Metabolic markers and ALT cutoff level for diagnosing nonalcoholic fatty liver disease: a community-based cross-sectional study

  • Teruki Miyake
  • Teru Kumagi
  • Masashi Hirooka
  • Mitsuhito Koizumi
  • Shinya Furukawa
  • Teruhisa Ueda
  • Yoshio Tokumoto
  • Yoshio Ikeda
  • Masanori Abe
  • Kohichiro Kitai
  • Yoichi Hiasa
  • Bunzo Matsuura
  • Morikazu OnjiEmail author
Original Article—Liver, Pancreas, and Biliary Tract



Untreated nonalcoholic fatty liver disease (NAFLD) may progress to liver cirrhosis or failure and is associated with the development of hepatocellular carcinoma, diabetes, and cardiovascular disease. It is therefore essential to diagnose and treat NAFLD at an early stage. To assist in this effort, this retrospective study explored the risk factors for NAFLD, and derived new surrogates, a revised alanine aminotransferase (ALT) cutoff level and a novel NAFLD index, to identify previously undiagnosed cases of NAFLD.


Using a community-based, cross-sectional design, the records of 6,370 Japanese subjects who had undergone at least 1 annual health check-up were reviewed for the identification of subjects meeting the diagnostic criteria for NAFLD and the variables associated with NAFLD for the estimation of ideal ALT cutoff levels.


The results of multivariate analysis of the 1,346 subjects who met the diagnostic criteria for NAFLD confirmed that metabolic disease markers and a novel NAFLD index, using the variables derived from multivariate analysis, were also markers of NAFLD. The ALT cutoff levels for NAFLD diagnosis were estimated at 25 U/L for males and 17 U/L for females.


ALT level and the novel NAFLD index were confirmed to be surrogate markers for NAFLD in addition to metabolic disease markers. The ALT cutoff level used in NAFLD diagnosis should be revised downward to identify subjects at risk of NAFLD to prevent NAFLD progression and the development of associated diseases.


Alanine aminotransferase Metabolic markers Nonalcoholic fatty liver disease NAFLD index 


Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

535_2012_534_MOESM1_ESM.doc (42 kb)
Supplementary material 1 (DOC 42 kb)


  1. 1.
    Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–23.PubMedCrossRefGoogle Scholar
  2. 2.
    Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50:1844–50.PubMedCrossRefGoogle Scholar
  3. 3.
    Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123:1705–25.PubMedCrossRefGoogle Scholar
  4. 4.
    Yoshioka Y, Hashimoto E, Yatsuji S, Kaneda H, Taniai M, Tokushige K, et al. Nonalcoholic steatohepatitis: cirrhosis, hepatocellular carcinoma, and burnt-out NASH. J Gastroenterol. 2004;39:1215–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Shimada M, Hashimoto E, Taniai M, Hasegawa K, Okuda H, Hayashi N, et al. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol. 2002;37:154–60.PubMedCrossRefGoogle Scholar
  6. 6.
    Jimba S, Nakagami T, Takahashi M, Wakamatsu T, Hirota Y, Iwamoto Y, et al. Prevalence of nonalcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med. 2005;22:1141–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Kojima S, Watanabe N, Numata M, Ogawa T, Matsuzaki S. Increase in the prevalence of fatty liver in Japan over the past 12 years: analysis of clinical background. J Gastroenterol. 2003;38:954–61.PubMedCrossRefGoogle Scholar
  8. 8.
    Hashimoto E, Tokushige K. Prevalence, gender, ethnic variations, and prognosis of NASH. J Gastroenterol. 2011;46:S63–9.CrossRefGoogle Scholar
  9. 9.
    Siest G, Schiele F, Galteau MM, Panek E, Steinmetz J, Fagnani F, et al. Aspartate aminotransferase and alanine aminotransferase activities in plasma: statistical distributions, individual variations, and reference values. Clin Chem. 1975;21:1077–87.PubMedGoogle Scholar
  10. 10.
    Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000;27(342):1266–71.CrossRefGoogle Scholar
  11. 11.
    Prati D, Taioli E, Zanella A, Torre ED, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1–9.PubMedGoogle Scholar
  12. 12.
    Lee JK, Shim JH, Lee HC, Lee SH, Kim KM, Lim YS, et al. Estimation of the healthy upper limits for serum alanine aminotransferase in Asian populations with normal liver histology. Hepatology. 2010;51:1577–83.PubMedCrossRefGoogle Scholar
  13. 13.
    Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328:983.PubMedCrossRefGoogle Scholar
  14. 14.
    Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Lee JH, Kim D, Kim HJ, Lee CH, Yang JI, Kim W, et al. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis. 2010;42:503–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Darby SC, Ewart DW, Giangrande PLF, Spooner RJD, Rizza CR, Dusheiko GM, et al. Mortality from liver cancer and liver disease in haemophiliac men and boys in UK given blood products contaminated with hepatitis C. Lancet. 1997;350:1425–31.PubMedCrossRefGoogle Scholar
  17. 17.
    Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;44:865–73.PubMedCrossRefGoogle Scholar
  18. 18.
    Examination Committee of Criteria for ‘Obesity Disease’ in Japan, Japan Society for the Study of Obesity. New criteria for ‘obesity disease’ in Japan. Circ J. 2002;66:987–92.CrossRefGoogle Scholar
  19. 19.
    Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med. 2005;143:722–8.PubMedGoogle Scholar
  20. 20.
    Yajima Y, Ohta K, Narui T, Abe R, Suzuki H, Ohtsuki M. Ultrasonographical diagnosis of fatty liver: significance of the liver-kidney contrast. Tohoku J Exp Med. 1983;139:43–50.PubMedCrossRefGoogle Scholar
  21. 21.
    Gore RM. Diffuse liver disease. In: Gore RM, Levine MS, Laufer I, editors. Textbook of gastrointestinal radiology. Philadelphia: Saunders; 1994. p. 1968–2017.Google Scholar
  22. 22.
    Moscatiello S, Manini R, Marchesini G. Diabetes and liver disease: an ominous association. Nutr Metab Cardiovasc Dis. 2007;17:63–70.PubMedCrossRefGoogle Scholar
  23. 23.
    Sung KC, Ryan MC, Wilson AM. The severity of nonalcoholic fatty liver disease is associated with increased cardiovascular risk in a large cohort of non-obese Asian subjects. Atherosclerosis. 2009;203:581–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology. 2005;42:44–52.PubMedCrossRefGoogle Scholar
  25. 25.
    Kunde SS, Lazenby AJ, Clements RH, Abrams GA. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology. 2005;42:650–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Chang Y, Ryu S, Sung E, Jang Y. Higher concentrations of alanine aminotransferase within the reference interval predict nonalcoholic fatty liver disease. Clin Chem. 2007;53:686–92.PubMedCrossRefGoogle Scholar
  27. 27.
    Joy D, Thava VR, Scott BB. Diagnosis of fatty liver disease: is biopsy necessary? Eur J Gatroenterol Hepatol. 2003;15:539–43.Google Scholar
  28. 28.
    Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology. 2007;46:582–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Perez NE, Siddiqui FA, Mutchnick MG, Dhar R, Tobi M, Ullah N, et al. Ultrasound diagnosis of fatty liver in patients with chronic liver disease. A retrospective observational study. J Clin Gastroenterol. 2007;41:624–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Tobari M, Hashimoto E, Yatsuji S, Torii N, Shiratori K. Imaging of nonalcoholic steatohepatitis: advantages and pitfalls of ultrasonography and computed tomography. Intern Med. 2009;48:739–46.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  • Teruki Miyake
    • 1
  • Teru Kumagi
    • 1
  • Masashi Hirooka
    • 1
  • Mitsuhito Koizumi
    • 1
    • 2
  • Shinya Furukawa
    • 1
  • Teruhisa Ueda
    • 1
  • Yoshio Tokumoto
    • 1
  • Yoshio Ikeda
    • 1
  • Masanori Abe
    • 1
  • Kohichiro Kitai
    • 2
  • Yoichi Hiasa
    • 1
  • Bunzo Matsuura
    • 1
  • Morikazu Onji
    • 1
    Email author
  1. 1.Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonJapan
  2. 2.Ehime General Health Care AssociationEhimeJapan

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