Journal of Gastroenterology

, Volume 46, Issue 2, pp 257–268 | Cite as

A simple clinical scoring system using ferritin, fasting insulin, and type IV collagen 7S for predicting steatohepatitis in nonalcoholic fatty liver disease

  • Yoshio SumidaEmail author
  • Masato Yoneda
  • Hideyuki Hyogo
  • Kanji Yamaguchi
  • Masafumi Ono
  • Hideki Fujii
  • Yuichiro Eguchi
  • Yasuaki Suzuki
  • Shunsuke Imai
  • Kazuyuki Kanemasa
  • Koji Fujita
  • Kazuaki Chayama
  • Kohichiroh Yasui
  • Toshiji Saibara
  • Norifumi Kawada
  • Kazuma Fujimoto
  • Yutaka Kohgo
  • Takeshi Okanoue
  • Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD)
Original Article—Liver, Pancreas, and Biliary Tract



Liver histology is the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH). Noninvasive, simple, reproducible, and reliable biomarkers are greatly needed to differentiate NASH from nonalcoholic fatty liver disease (NAFLD).


To construct a scoring system for predicting NASH, 177 Japanese patients with biopsy-proven NAFLD were enrolled. To validate the scoring system, 442 biopsy-proven NAFLD patients from eight hepatology centers in Japan were also enrolled.


In the estimation group, 98 (55%) patients had NASH. Serum ferritin [≥200 ng/ml (female) or ≥300 ng/ml (male)], fasting insulin (≥10 μU/ml), and type IV collagen 7S (≥5.0 ng/ml) were selected as independent variables associated with NASH, by multilogistic regression analysis. These three variables were combined in a weighted sum [serum ferritin ≥200 ng/ml (female) or ≥300 ng/ml (male) = 1 point, fasting insulin ≥10 μU/ml = 1 point, and type IV collagen 7S ≥5.0 ng/ml = 2 points] to form an easily calculated composite score for predicting NASH, called the NAFIC score. The area under the receiver operating characteristic (AUROC) curve for predicting NASH was 0.851 in the estimation group and 0.782 in the validation group. The NAFIC AUROC was the greatest among several previously established scoring systems for detecting NASH, but also for predicting severe fibrosis.


NAFIC score can predict NASH in Japanese NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use.


Iron overload Hepatic fibrosis Nonalcoholic steatohepatitis 



The authors thank the following individuals for assistance in preparation of this manuscript: Atsushi Nakajima, M.D., Ph.D., Division of Gastroenterology, Yokohama City University Graduate School of Medicine; Kyoko Sakai, M.D., Yutaka Inada, M.D., Akitoshi Douhara, M.D., Tasuku Hara, M.D., Center for Digestive and Liver Diseases, Nara City Hospital; Tomokazu Ishitobi, M.D., Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University; Yoshihiro Kamada, M.D., Ph.D., Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine; Takaaki Ohtake, M.D., Ph.D., Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa; Yoshito Itoh, M.D., Ph.D., Toshikazu Yoshikawa, M.D., Ph.D., Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine.

Conflicts of interest

The authors have no conflicts of interest to disclose.


  1. 1.
    Ludwig J, Viggiano TR, McGill DB, Ott BJ. Non-alcoholic steatohepatitis. Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–8.PubMedGoogle Scholar
  2. 2.
    Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver diseases: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 2009;7:234–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Saibara T. Nonalcoholic steatohepatitis in Asia-Oceania. Hepatol Res. 2005;33:64–7.CrossRefPubMedGoogle Scholar
  5. 5.
    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
  6. 6.
    Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology. 2009;49:306–17.CrossRefPubMedGoogle Scholar
  7. 7.
    Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology. 2007;46:582–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–906.CrossRefPubMedGoogle Scholar
  9. 9.
    Merriman RB, Ferrell LD, Patti MG, Weston SR, Pabst MS, Aouizerat BE, et al. Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease. Hepatology. 2006;44:874–80.CrossRefPubMedGoogle Scholar
  10. 10.
    Pagadala M, Zein CO, McCullough AJ. Predictors and advanced fibrosis in non-alcoholic fatty liver disease. Clin Liver Dis. 2009;13:591–606.CrossRefPubMedGoogle Scholar
  11. 11.
    Sumida Y, Nakashima T, Yoh T, Furutani M, Hirohama A, Kakisaka Y, et al. Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic liver disease. J Hepatol. 2003;38:32–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.CrossRefPubMedGoogle Scholar
  13. 13.
    Japanese Society for the Study of Obesity. New criteria of obesity (in Japanese). J Jpn Soc Study Obes. 2000;6:18–28.Google Scholar
  14. 14.
    American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997;20:1183–97.Google Scholar
  15. 15.
    Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology. 2001;121:91–100.CrossRefPubMedGoogle Scholar
  16. 16.
    Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab. 2000;85:2402–10.CrossRefPubMedGoogle Scholar
  17. 17.
    Palekar NA, Naus R, Larson SP, Ward J, Harrison SA. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease. Liver Int. 2006;26:151–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Gholam PM, Flancbaum L, Machan JT, Charney DA, Kotler DP. Nonalcoholic fatty liver disease in severely obese subjects. Am J Gastroenterol. 2007;102:399–408.CrossRefPubMedGoogle Scholar
  19. 19.
    Ratziu V, Giral P, Charlotte F, Bruckert E, Thibault V, Theodorou I, et al. Liver fibrosis in overweight patients. Gastroenterology. 1999;118:1117–23.CrossRefGoogle Scholar
  20. 20.
    Harrison SM, Oliver D, Arnold HLM, Gogia SM, Neuschwander-Tetri BAM. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut. 2008;57:1441–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–54.CrossRefPubMedGoogle Scholar
  22. 22.
    Miyaaki H, Ichikawa T, Nakao K, Yatsuhashi H, Furukawa R, Ohba K, et al. Clinicopathological study of nonalcoholic fatty liver disease in Japan: the risk factors for fibrosis. Liver Int. 2008;28:519–24.CrossRefPubMedGoogle Scholar
  23. 23.
    Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Non-alcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–74.CrossRefPubMedGoogle Scholar
  24. 24.
    Bonkovsky HL, Jawaid Q, Tortorelli K, LeClair P, Cobb J, Lambrecht RW, et al. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis. J Hepatol. 1999;31:421–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Bugianesi E, Manzini P, D’Antico S, Vanni E, Longo F, Leone N, et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology. 2004;39:179–87.CrossRefPubMedGoogle Scholar
  26. 26.
    Yoneda M, Nozaki Y, Endo H, Mawatari H, Iida H, Fujita K, et al. Serum ferritin is a clinical biomarker in Japanese patients with nonalcoholic steatohepatitis (NASH) independent of HFE gene mutation. Dig Dis Sci. 2010;55:808–14.CrossRefPubMedGoogle Scholar
  27. 27.
    Chitturi S, Weltman M, Farrell GC, McDonald D, Kench J, Liddle C, et al. HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH and C282Y but not with fibrotic severity. Hepatology. 2002;36:142–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Sumida Y, Yoshikawa T, Okanoue T. Role of hepatic iron in non-alcoholic steatohepatitis. Hepatol Res. 2009;39:213–22.CrossRefPubMedGoogle Scholar
  29. 29.
    Jehn M, Clark JM, Guallar E. Serum ferritin level and risk of the metabolic syndrome in U.S. adults. Diabetes Care. 2004;27:2422–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Pagano G, Pacini G, Musso G, Gambino R, Mecca F, Depetris N, et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome: further evidence for an etiologic association. Hepatology. 2002;35:367–72.CrossRefPubMedGoogle Scholar
  32. 32.
    Marcheisini 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.CrossRefGoogle Scholar
  33. 33.
    Ono M, Saibara T. Clinical features of nonalcoholic steatohepatitis in Japan: evidence from literature. J Gastroenterol. 2006;41:725–32.CrossRefPubMedGoogle Scholar
  34. 34.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Boza C, Riquelme A, Ibañez L, Duarte I, Norero E, Viviani P, et al. Predictors of non-alcoholic steatohepatitis (NASH) in obese patients undergoing gastric bypass. Obes Surg. 2005;15:1148–53.CrossRefPubMedGoogle Scholar
  36. 36.
    Murawaki Y, Ikuta K, Koda M, Kawasaki H. Serum type III procollagen peptide, type IV collagen 7S domain, central triple-helix of type IV collagen and tissue inhibitor of metalloproteinases in patients with chronic viral liver disease: relationship to liver histology. Hepatology. 1994;20:780–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Sakugawa H, Nakayoshi T, Kobashigawa K, Yamashiro T, Maeshiro T, Miyagi S, et al. Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease. World J Gastroenterol. 2005;11:255–9.PubMedGoogle Scholar
  38. 38.
    Yoneda M, Mawatari H, Fujita K, Yonemitsu K, Kato S, Takahashi H, et al. Type IV collagen 7s domain is an independent clinical marker of the severity of fibrosis in patients with nonalcoholic steatohepatitis before the cirrhotic stage. J Gastroenterol. 2007;42:375–81.CrossRefPubMedGoogle Scholar
  39. 39.
    Shimada M, Kawahara H, Ozaki K, Fukura M, Yano H, Tsuchishima M, et al. Usefulness of a combined evaluation of the serum adiponectin level, HOMA-IR, type IV collagen 7S level to predict the early stage of nonalcoholic steatohepatitis. Am J Gastroenterol. 2007;102:1931–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Kaneda H, Hashimoto E, Yatsuji S, Tokushige K, Shiratori K. Hyaluronic acid levels can predict severe fibrosis and platelet counts can predict cirrhosis in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol. 2006;21:1459–65.PubMedGoogle Scholar
  41. 41.
    Suzuki A, Angulo P, Lymp J, Li D, Satomura S, Lindor K. Hyaluronic acid, an accurate serum marker for severe fibrosis in patients with non-alcoholic fatty liver disease. Liver Int. 2005;25:779–86.CrossRefPubMedGoogle Scholar
  42. 42.
    Wong VW, Wong GL, Chim AM, Tse AM, Tsang SW, Hui AY, et al. Validation of the NAFLD fibrosis score in a Chinese population with low prevalence of advanced fibrosis. Am J Gastroenterol. 2008;103:1682–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Fujii H, Enomoto M, Fukushima W, Tamori A, Sakaguchi H, Kawada N. Applicability of BARD score to Japanese patients with NAFLD. Gut. 2009;58:1566–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Yoshio Sumida
    • 1
    Email author
  • Masato Yoneda
    • 2
  • Hideyuki Hyogo
    • 3
  • Kanji Yamaguchi
    • 4
  • Masafumi Ono
    • 5
  • Hideki Fujii
    • 6
  • Yuichiro Eguchi
    • 7
  • Yasuaki Suzuki
    • 8
  • Shunsuke Imai
    • 9
  • Kazuyuki Kanemasa
    • 1
  • Koji Fujita
    • 2
  • Kazuaki Chayama
    • 3
  • Kohichiroh Yasui
    • 4
  • Toshiji Saibara
    • 5
  • Norifumi Kawada
    • 6
  • Kazuma Fujimoto
    • 7
  • Yutaka Kohgo
    • 8
  • Takeshi Okanoue
    • 10
  • Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD)
  1. 1.Center for Digestive and Liver DiseasesNara City HospitalNaraJapan
  2. 2.Division of GastroenterologyYokohama City University Graduate School of MedicineYokohamaJapan
  3. 3.Department of Medicine and Molecular Science, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan
  4. 4.Department of Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
  5. 5.Department of Gastroenterology and HepatologyKochi Medical SchoolKochiJapan
  6. 6.Department of Hepatology, Graduate School of MedicineOsaka City UniversityOsakaJapan
  7. 7.Department of Internal Medicine, Saga Medical SchoolSaga UniversitySagaJapan
  8. 8.Division of Gastroenterology and Hematology/Oncology, Department of MedicineAsahikawa Medical CollegeAsahikawaJapan
  9. 9.Department of PathologyNara City HospitalNaraJapan
  10. 10.Hepatology CenterSaiseikai Suita HospitalOsakaJapan

Personalised recommendations