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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

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).

Methods

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.

Results

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.

Conclusions

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

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References

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  4. Saibara T. Nonalcoholic steatohepatitis in Asia-Oceania. Hepatol Res. 2005;33:64–7.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  7. Wieckowska A, McCullough AJ, Feldstein AE. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis: present and future. Hepatology. 2007;46:582–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  10. Pagadala M, Zein CO, McCullough AJ. Predictors and advanced fibrosis in non-alcoholic fatty liver disease. Clin Liver Dis. 2009;13:591–606.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  28. Sumida Y, Yoshikawa T, Okanoue T. Role of hepatic iron in non-alcoholic steatohepatitis. Hepatol Res. 2009;39:213–22.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  33. Ono M, Saibara T. Clinical features of nonalcoholic steatohepatitis in Japan: evidence from literature. J Gastroenterol. 2006;41:725–32.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

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.

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Authors and Affiliations

  1. Center for Digestive and Liver Diseases, Nara City Hospital, Higashi Kidera-cho 1-50-1, Nara, 630-8305, Japan

    Yoshio Sumida & Kazuyuki Kanemasa

  2. Division of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Masato Yoneda & Koji Fujita

  3. Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

    Hideyuki Hyogo & Kazuaki Chayama

  4. Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Kanji Yamaguchi & Kohichiroh Yasui

  5. Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan

    Masafumi Ono & Toshiji Saibara

  6. Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan

    Hideki Fujii & Norifumi Kawada

  7. Department of Internal Medicine, Saga Medical School, Saga University, Saga, Japan

    Yuichiro Eguchi & Kazuma Fujimoto

  8. Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical College, Asahikawa, Japan

    Yasuaki Suzuki & Yutaka Kohgo

  9. Department of Pathology, Nara City Hospital, Nara, Japan

    Shunsuke Imai

  10. Hepatology Center, Saiseikai Suita Hospital, Osaka, Japan

    Takeshi Okanoue

Authors
  1. Yoshio Sumida
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  2. Masato Yoneda
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Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD)

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Correspondence to Yoshio Sumida.

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All authors are members of the Japan Study Group of NAFLD (JSG-NAFLD).

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Sumida, Y., Yoneda, M., Hyogo, H. et al. A simple clinical scoring system using ferritin, fasting insulin, and type IV collagen 7S for predicting steatohepatitis in nonalcoholic fatty liver disease. J Gastroenterol 46, 257–268 (2011). https://doi.org/10.1007/s00535-010-0305-6

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  • DOI: https://doi.org/10.1007/s00535-010-0305-6

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