Journal of Gastroenterology

, Volume 48, Issue 4, pp 515–525 | Cite as

Clinicopathological features of liver injury in patients with type 2 diabetes mellitus and comparative study of histologically proven nonalcoholic fatty liver diseases with or without type 2 diabetes mellitus

  • Toshihide Shima
  • Hirofumi Uto
  • Kohjiro Ueki
  • Toshinari Takamura
  • Yutaka Kohgo
  • Sumio Kawata
  • Kohichiroh Yasui
  • Hyohun Park
  • Naoto Nakamura
  • Tatsuaki Nakatou
  • Nobuyoshi Tanaka
  • Atsushi Umemura
  • Masayuki Mizuno
  • Junko Tanaka
  • Takeshi OkanoueEmail author
Original Article—Liver, Pancreas, and Biliary Tract



The Japan Society of Diabetes Mellitus reported that the leading cause of death in patients with diabetes mellitus (DM) was chronic liver disease; however, there are limited studies investigating the cause of liver injury in these patients. Our study aimed to clarify the clinicopathological features of liver injury and the characteristics of nonalcoholic fatty liver disease (NAFLD) in DM patients.


In total, 5,642 DM patients and 365 histologically proven NAFLD patients were enrolled. Clinical and laboratory parameters and liver biopsy results were, respectively, recorded and analyzed for the two sets of patients.


Positivity rates for Hepatitis B surface antigens (HBsAg) and anti-hepatitis C virus antibodies (anti-HCV Ab) were 1.7 and 5.1 %, respectively. The proportion of drinkers consuming 20–59 g and ≥60 g alcohol daily was 14.9 and 4.3 %, respectively. The percentage of DM patients with elevated serum alanine aminotransferase (ALT) levels (≥31 IU/L) was 28.6 %. Alcohol consumption had no significant effect on serum ALT levels. Seventy-two percent of HBsAg-positive patients were serum hepatitis B virus (HBV)-DNA negative, whereas 10 % exhibited high levels of the same (>4.0 log copies/ml). Thirty-eight percent of anti-HCV Ab-positive patients were serum HCV-RNA negative. Among the NAFLD patients, the frequencies of NASH and advanced stage NASH were significantly higher in male DM patients than in male patients without DM.


Although HBsAg- and anti-HCV Ab-positivity rates were high in our Japanese DM patients, a majority of liver injuries could be associated with NAFLD/nonalcoholic steatohepatitis.


Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis Diabetes mellitus Hepatitis virus carrier Alcoholic liver disease Nationwide study 



Hepatocellular carcinoma


Nonalcoholic fatty liver disease


Diabetes mellitus


Nonalcoholic steatohepatitis


Hepatitis B virus


Hepatitis C virus


Aspartate aminotransferase


Alanine aminotransferase


Gamma glutamyl transpeptidase


Fasting plasma glucose


The homeostasis model assessment of insulin resistance index


Hepatitis B surface antigen

anti-HBc Ab

Anti-hepatitis B core antibody

anti-HCV Ab

Anti-hepatitis C virus antibody


Hepatitis B virus-deoxyribonucleic acid


Hepatitis C virus-ribonucleic acid


Odds ratio


Confidence interval



This work was supported by a Grant-in-Aid from the Ministry of Health, Labour and Welfare, Japan (T. O., H20-Hepatitis-general-008).

Conflict of interest

The authors declare that they have no conflicts of interest to disclose.


  1. 1.
    International Diabetes Federation. IDF Diabetes Atlas (article online). 5th ed. International Diabetes Federation: Brussels; 2011. Accessed 6 May 2012.
  2. 2.
    El-Serag HB, Rudolph L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.PubMedCrossRefGoogle Scholar
  3. 3.
    Ikai I, Kudo M, Arii S, Omata M, Kojiro M, Sakamoto M, et al. Report of the 18th follow-up survey of primary liver cancer in Japan. Hepatol Res. 2010;40:1043–59.CrossRefGoogle Scholar
  4. 4.
    Hotta N, Nakamura J, Iwamoto Y, Ohno Y, Kasuga M, Kikkawa R, et al. Causes of death in Japanese diabetics based on the results of a survey of 18,385 diabetics during 1991–2000—report of committee on cause of death in diabetes mellitus. J Jpn Diab Soc. 2007;50:47–61.Google Scholar
  5. 5.
    The Ministry of Health, Labour and Welfare, Japan. Annual change in causes of death among Japanese patients who died of malignancy. Accessed 8 July 2012.
  6. 6.
    The Ministry of Health, Labour and Welfare, Japan.Causes of death in Japan. Available from 8July 2012.
  7. 7.
    Okanoue T, Umemura A, Yasui K, Itoh Y. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in Japan. J Gastroenterol Hepatol. 2011;26:153–62.PubMedCrossRefGoogle Scholar
  8. 8.
    Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–74.PubMedCrossRefGoogle Scholar
  10. 10.
    Tanaka J, Koyama T, Mizui M, Uchida S, Katayama K, Matsuo J, et al. Total numbers of undiagnosed carriers of hepatitis C and B viruses in Japan estimated by age- and area- specific prevalence on the national scale. Intervirology. 2011;54:185–95.PubMedCrossRefGoogle Scholar
  11. 11.
    Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Minami M, Okanoue T. Management of HBV infection in Japan. Hepatol Res. 2007;37:S79–82.PubMedCrossRefGoogle Scholar
  13. 13.
    Sinha S, Kumar M. Pregnancy and chronic hepatitis B virus infection. Hepatol Res. 2010;40:31–48.PubMedCrossRefGoogle Scholar
  14. 14.
    Seeff LB, Hoofnagle JH. Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity. Oncogene. 2006;25:3771–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Michitaka K, Nishiguchi S, Aoyagi Y, Hiasa Y, Tokumoto Y, Onji M, et al. Etiology of liver cirrhosis in Japan: a nationwide survey. J Gastroenterol. 2010;45:86–94.PubMedCrossRefGoogle Scholar
  16. 16.
    Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Neuschwander-Tetri BA, Clark JM, Bass NM, Van Natta ML, Unalp-Arida A, Tonascia J, et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology. 2010;52:913–24.PubMedCrossRefGoogle Scholar
  18. 18.
    Mayaaki 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.CrossRefGoogle Scholar
  19. 19.
    Lo L, McLennan SV, Williams PF, Bonner J, Chowdhury S, McCaughan GW, et al. Diabetes is a progression factor for hepatic fibrosis in a high fat fed mouse obesity model of non-alcoholic steatohepatitis. J Hepatol. 2011;55:435–44.PubMedCrossRefGoogle Scholar
  20. 20.
    Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer. Consensus report. Diabetes Care. 2010;33:1674–85.PubMedCrossRefGoogle Scholar
  21. 21.
    Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology. 2011;54:463–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Tokushige K, Hashimoto E, Horie Y, Taniai M, Higuchi S. Hepatocellular carcinoma in Japanese patients with nonalcoholic fatty liver disease, alcoholic liver disease, and chronic liver disease of unknown etiology: report of the nationwide survey. J Gastroenterol. 2011;46:1230–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Kawada N, Imanaka K, Kawaguchi T, Tamai C, Ishihara R, Matsunaga T, et al. Hepatocellular carcinoma arising from non-cirrhotic nonalcoholic steatohepatitis. J Gastroenterol. 2009;44:1190–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9:428–33.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  • Toshihide Shima
    • 1
  • Hirofumi Uto
    • 2
  • Kohjiro Ueki
    • 3
  • Toshinari Takamura
    • 4
  • Yutaka Kohgo
    • 5
  • Sumio Kawata
    • 6
  • Kohichiroh Yasui
    • 7
  • Hyohun Park
    • 8
  • Naoto Nakamura
    • 9
  • Tatsuaki Nakatou
    • 10
  • Nobuyoshi Tanaka
    • 11
  • Atsushi Umemura
    • 1
  • Masayuki Mizuno
    • 1
  • Junko Tanaka
    • 12
  • Takeshi Okanoue
    • 1
    Email author
  1. 1.Department of Gastroenterology and HepatologySaiseikai Suita HospitalSuitaJapan
  2. 2.Digestive and Life-style Related DiseaseKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
  3. 3.Diabetes and Metabolic Diseases, Graduate School of MedicineThe University of TokyoTokyoJapan
  4. 4.Disease Control and HomeostasisKanazawa University Graduate School of Medical ScienceKanazawaJapan
  5. 5.Gastroenterology and Hematology/Oncology, Department of MedicineAsahikawa Medical CollegeAsahikawaJapan
  6. 6.GastroenterologyYamagata University Faculty of MedicineYamagataJapan
  7. 7.Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
  8. 8.Diabetes and Metabolic DiseasesSaiseikai Suita HospitalSuitaJapan
  9. 9.Endocrinology and MetabolismKyoto Prefectural University of MedicineKyotoJapan
  10. 10.Diabetes CenterOkayama Saiseikai General HospitalOkayamaJapan
  11. 11.GastroenterologyFukui-ken Saiseikai HospitalFukuiJapan
  12. 12.Department of Epidemiology, Infectious Disease Control and PreventionHiroshima University Graduate School of Biomedical SciencesHiroshimaJapan

Personalised recommendations