Skip to main content

Advertisement

SpringerLink
Log in

Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

The prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome have been increasing worldwide. The associations between metabolic factors and the histologic severity of NAFLD have not yet been clarified. Therefore, we studied the relationships between relevant metabolic factors and the histological severity of NAFLD.

Methods

In a cross-sectional multicenter study conducted in Japan, we examined 1,365 biopsy-proven NAFLD patients. The frequencies of underlying lifestyle-related diseases and their relationships to the NAFLD histology were investigated.

Results

The hepatic fibrosis stages (Stage 0/1/2/3/4) were 22.6/34.1/26.7/14.5/2.1 (%) in the male patients, and 16.2/31.7/23.9/21.6/6.6 (%) in the female patients. Dyslipidemia was present in 65.7 % (hypertriglyceridemia, 45.3 %; increased low-density lipoprotein cholesterol, 37.5 %; decreased high density lipoprotein cholesterol, 19.5 %) of patients. Hypertension was present in 30.2 %, and diabetes mellitus (DM) in 47.3 %. The fibrosis stage increased with age, especially in postmenopausal females. The body mass index was positively correlated with the fibrosis stage. Deterioration of glucose control was positively correlated with the fibrosis stage, this correlation being more prominent in females. Multivariate analysis identified age and DM as significant risk factors for advanced fibrosis. No significant correlation of the fibrosis stage was observed with hypertension. There was a negative correlation between the serum triglyceride levels and the fibrosis stage.

Conclusions

DM appeared to be a significant risk factor for advanced fibrosis in patients with NAFLD, and would therefore need to be properly managed to prevent the progression of NAFLD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

IR:

Insulin resistance

DM:

Diabetes mellitus

NAFL:

Nonalcoholic fatty liver

BMI:

Body mass index

CT:

Computed tomography

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

GGT:

Gamma glutamyl transpeptidase

ChE:

Cholinesterase

HDL:

High density lipoprotein

LDL:

Low-density lipoprotein

FPG:

Fasting plasma glucose

HbA1c:

Hemoglobin A1c

FFA:

Free fatty acid

CRP:

C-reactive protein

IRI:

Immunoreactive insulin

HOMA-IR:

Homeostasis model assessment-insulin resistance

SD:

Standard deviation

IGT:

Impaired glucose tolerance

NGT:

Normal glucose tolerance

References

  1. 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 Int Med. 2005;143:722–8.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. Amarapurkar DN, Hashimoto E, Lesmana LA, Sollano JD, Chen PJ, Goh KL, Asia-Pacific Working Party on NAFLD. How common is non-alcoholic fatty liver disease in the Asia-Pacific region and are there local differences? J Gastroenterol Hepatol. 2007;22:788–93.

    Article  PubMed  Google Scholar 

  4. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. 1995;22:1714–9.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  PubMed  Google Scholar 

  6. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: spectrum of clinical and pathological severity. Gastroenterology. 1999;116:1413–9.

    Article  CAS  PubMed  Google Scholar 

  7. James O, Day C. Non-alcoholic steatohepatitis: another disease of affluence. Lancet. 1999;353:1634–6.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. Hui JM, Farrell GC. Clear messages from sonographic shadows? Links between metabolic disorders and liver disease, and what to do about them. J Gastroenterol Hepatol. 2003;18:1115–7.

    Article  PubMed  Google Scholar 

  11. 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.

    Article  PubMed  Google Scholar 

  12. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–31.

    Article  CAS  PubMed  Google Scholar 

  13. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43:S99–112.

    Article  CAS  PubMed  Google Scholar 

  14. Angulo P. Obesity and nonalcoholic fatty liver disease. Nutr Rev. 2007;65:S57–63.

    Article  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Larter CZ, Chitturi S, Heydet D, Farrell GC. A fresh look at NASH pathogenesis. Part 1: the metabolic movers. J Gastroenterol Hepatol. 2010;25:672–90.

    Article  CAS  PubMed  Google Scholar 

  17. Fracanzani AL, Valenti L, Bugianesi E, Andreoletti M, Colli A, Vanni E, et al. Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: a role for insulin resistance and diabetes. Hepatology. 2008;48:792–8.

    Article  CAS  PubMed  Google Scholar 

  18. 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 

  19. Hossain N, Afendy A, Stepanova M, Nader F, Srishord M, Rafiq N, et al. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7:1224–9.

    Article  CAS  PubMed  Google Scholar 

  20. Yoneda M, Fujii H, Sumida Y, Hyogo H, Itoh Y, Ono M, et al. Platelet count for predicting fibrosis in nonalcoholic fatty liver disease. J Gastroenterol. 2011;46:1300–6.

    Article  PubMed  Google Scholar 

  21. Sumida Y, Yoneda M, Hyogo H, Yamaguchi K, Ono M, Fujii 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. 2011;46:257–68.

    Article  CAS  PubMed  Google Scholar 

  22. The World Medical Association, Inc. Declaration of Helsinki; Ethical principle for medical research involving human subject. Seoul: WMA General Assembly; 2008.

    Google Scholar 

  23. Iwamoto K, Kanno K, Hyogo H, Yamagishi S, Takeuchi M, Tazuma S, et al. Advanced glycation end products enhance the proliferation and activation of hepatic stellate cells. J Gastroenterol. 2008;43:298–304.

    Article  CAS  PubMed  Google Scholar 

  24. Hyogo H, Tazuma S, Arihiro K, Iwamoto K, Nabeshima Y, Inoue M, et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism. 2008;57:1711–8.

    Article  CAS  PubMed  Google Scholar 

  25. Matsuzawa U, Inoue S, Ikeda Y, Sakata T, Saito Y, Sato Y, Japanese Society for the Study of Obesity, et al. New criteria of obesity (in Japanese). J Jpn Soc Study Obes. 2000;6:18–28.

    Google Scholar 

  26. Ricci C, Longo R, Gioulis E, Bosco M, Pollesello P, Masutti F, et al. Noninvasive in vivo quantitative assessment of fat content in human liver. Noninvasive in vivo quantitative assessment of fat content in human liver. J Hepatol. 1997;27:108–13.

    Article  CAS  PubMed  Google Scholar 

  27. World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: report of a WHO/IDF consultation. Geneva: World Health Organization; 2006.

    Google Scholar 

  28. 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 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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 

  31. Paul Angulo. Nonalcoholic fatty liver disease. N Engl J Med. 2002;18:1221–31.

    Google Scholar 

  32. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–8.

    CAS  PubMed  Google Scholar 

  33. Liou I, Kowdley KV. Natural history of nonalcoholic steatohepatitis. J Clin Gastroenterol. 2006;40(Suppl 1):S11–6.

    PubMed  Google Scholar 

  34. Abdelmalek MF, Diehl AM. Nonalcoholic fatty liver disease as a complication of insulin resistance. Med Clin North Am. 2007;91:1125–49.

    Article  CAS  PubMed  Google Scholar 

  35. Kamada Y, Kiso S, Yoshida Y, Chatani N, Kizu T, Hamano M, et al. Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet. Am J Physiol Gastrointest Liver Physiol. 2011;301:1031–43.

    Article  Google Scholar 

  36. Zhu L, Brown WC, Cai Q, Krust A, Chambon P, McGuinness OP, et al. Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance. Diabetes. 2013;62:424–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Eguchi Y, Hyogo H, Ono M, Mizuta T, Ono N, Fujimoto K, et al. Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study. J Gastroenterol. 2012;47:586–95.

    Article  CAS  PubMed  Google Scholar 

  38. 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;57:1441–7.

    Article  CAS  PubMed  Google Scholar 

  39. Donati G, Stagni B, Piscaglia F, Venturoli N, Morselli-Labate AM, Rasciti L, et al. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut. 2004;53:1020–3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodés J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology. 1988;8:1151–7.

    Article  CAS  PubMed  Google Scholar 

  41. Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet. 1991;337:776–8.

    Article  CAS  PubMed  Google Scholar 

  42. Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology. 2001;34:738–44.

    Article  CAS  PubMed  Google Scholar 

  43. Megyesi C, Samols E, Marks V. Glucose tolerance and diabetes in chronic liver disease. Lancet. 1967;18:1051–6.

    Article  Google Scholar 

  44. Petrides AS, DeFronzo RA. Glucose and insulin metabolism in cirrhosis. J Hepatol. 1989;8:107–14.

    Article  CAS  PubMed  Google Scholar 

  45. Arase Y, Kobayashi M, Suzuki F, Suzuki Y, Kawamura Y, Akuta N, et al. Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C. Hepatology. 2013;57:964–73.

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

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

    Takashi Nakahara, Hideyuki Hyogo, Hiroshi Aikata & Kazuaki Chayama

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

    Masato Yoneda, Kento Imajo & Atushi Nakajima

  3. Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan

    Yoshio Sumida & Yoshito Itoh

  4. Liver Center, Saga Medical School, Saga, Japan

    Yuichiro Eguchi

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

    Hideki Fujii

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

    Masafumi Ono & Toshiji Saibara

  7. Division of Gastroenterology, Department of Medicine and Digestive Disease Information and Research, Kurume University School of Medicine, Kurume, Japan

    Takumi Kawaguchi & Michio Sata

  8. Center for Digestive and Liver Disease, Nara City Hospital, Nara, Japan

    Saiyu Tanaka & Kazuyuki Kanemasa

  9. Internal Medicine, Saga Medical School, Saga, Japan

    Kazuma Fujimoto & Keizo Anzai

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

    Takeshi Okanoue

  11. Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, USA

    Masato Yoneda

Authors
  1. Takashi Nakahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideyuki Hyogo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masato Yoneda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshio Sumida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuichiro Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hideki Fujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masafumi Ono
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takumi Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kento Imajo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroshi Aikata
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Saiyu Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kazuyuki Kanemasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kazuma Fujimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Keizo Anzai
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Toshiji Saibara
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Michio Sata
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Atushi Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Yoshito Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Kazuaki Chayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Takeshi Okanoue
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD)

Corresponding author

Correspondence to Masato Yoneda.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 25 kb)

535_2013_911_MOESM2_ESM.tif

Supplementary Figure 1. Distribution of the fibrosis stage by age and sex. The horizontal axis shows the age distribution stratified by 10-year age categories in male and female NAFLD patients, and the longitudinal axis shows the percentage of patients with each fibrosis stage (TIFF 184 kb)

535_2013_911_MOESM3_ESM.tif

Supplementary Figure 2. Prevalence of obesity in patients with each stage of fibrosis. The horizontal axis shows the fibrosis stage and the longitudinal axis shows the percentage of patients with obesity (BMI ≥ 25) (TIFF 137 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakahara, T., Hyogo, H., Yoneda, M. et al. Type 2 diabetes mellitus is associated with the fibrosis severity in patients with nonalcoholic fatty liver disease in a large retrospective cohort of Japanese patients. J Gastroenterol 49, 1477–1484 (2014). https://doi.org/10.1007/s00535-013-0911-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-013-0911-1

Keywords

Search

Navigation