Skip to main content
SpringerLink
Log in

Impact of circulating miR-122 for histological features and hepatocellular carcinoma of nonalcoholic fatty liver disease in Japan

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background and aim

Relationships between circulating microRNA-122 (miR-122) and histological features of nonalcoholic fatty liver disease (NAFLD) are unclear.

Methods

The impact of serum miR-122 levels for histological features and hepatocellular carcinoma (HCC) was investigated in 305 Japanese patients with histological proven NAFLD. Twenty-three patients were with HCC at the time of diagnosis of NAFLD, and four patients developed HCC during the follow-up. The cross-sectional or longitudinal evaluations were performed to investigate the impact for HCC.

Results

Serum miR-122 levels (calibrated relative to the median levels of patients) partly affected severity of steatosis, ballooning, lobular inflammation, and stage. Multivariate analysis identified HCC and/or histological components of NASH as morphological factors that independently influenced serum miR-122 levels at the diagnosis of NAFLD. There was a strong correlation between serum miR-122 levels and AST, ALT levels. In cross-sectional evaluation, serum miR-122 levels of patients without HCC were significantly higher than those with HCC in patients of stage 3 but not stage 4. In longitudinal evaluation of one patient with follow-up time of 25 years, from the diagnosis of NAFLD until HCC, serum miR-122 levels had already tended to decrease before the progression of fibrosis stage.

Conclusions

HCC and/or histological components of NASH affected serum miR-122 levels, independently. In longitudinal evaluation of HCC patients, serum miR-122 levels had already tended to decrease before the progression of fibrosis stage. Further prospective studies are needed to investigate the impact of serum miR-122 for histological features and hepatocarcinogenesis 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

References

  1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221–1231

  2. Williams R. Global changes in liver disease. Hepatology 2006;44:521–526

  3. Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 2008;134:1682–1698

  4. Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: selected practical issues in their evaluation and management. Hepatology 2009;49:306–317

  5. Kawamura Y, Arase Y, Ikeda K, Seko Y, Imai N, Hosaka T, et al. Large-scale long-term follow-up study of Japanese patients with non-alcoholic fatty liver disease for the onset of hepatocellular carcinoma. Am J Gastroenterol 2012;107:253–261

  6. Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2014;20:475–85

  7. Kleiner DE, Brunt EM. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research. Semin Liver Dis 2012;32:3–13

  8. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675–1685

  9. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385:956–965

  10. Sookoian S, Pirola CJ. The genetic epidemiology of nonalcoholic fatty liver disease: toward a personalized medicine. Clin Liver Dis 2012;16:467–485

  11. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461–1465

  12. Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, et al. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2014;46:352–356

  13. Akuta N, Kawamura Y, Arase Y, Suzuki F, Sezaki H, Hosaka T, et al. Relationships between genetic variations of PNPLA3, TM6SF2 and histological features of nonalcoholic fatty liver disease in Japan. Gut Liver 2015 Nov 27 (epub ahead of print)

  14. Li YY. Genetic and epigenetic variants influencing the development of nonalcoholic fatty liver disease. World J Gastroenterol 2012;18:6546–6551

  15. Cermelli S, Ruggieri A, Marrero JA, Ioannou GN, Beretta L. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One 2011;6:e23937

  16. Yamada H, Suzuki K, Ichino N, Ando Y, Sawada A, Osakabe K, et al. Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. Clin Chim Acta 2013;424:99–103

  17. Pirola CJ, Fernández Gianotti T, Castaño GO, Mallardi P, San Martino J, Mora Gonzalez Lopez Ledesma M, et al. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 2015;64:800–812

  18. Takaki Y, Saito Y, Takasugi A, Toshimitsu K, Yamada S, Muramatsu T, et al. Silencing of microRNA-122 is an early event during hepatocarcinogenesis from non-alcoholic steatohepatitis. Cancer Sci 2014;105:1254–1260

  19. 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;41:1313–1321

  20. 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;94:2467–2474

  21. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413–1419

  22. Kroh EM, Parkin RK, Mitchell PS, Tewari M. Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). Methods 2010;50:298–301

  23. Yu S, Liu Y, Wang J, Guo Z, Zhang Q, Yu F, et al. Circulating microRNA profiles as potential biomarkers for diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab 2012;97:2084–2092

  24. Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, Fortmann SP, et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 2002;106:388–391

  25. Yamada H, Ohashi K, Suzuki K, Munetsuna E, Ando Y, Yamazaki M, et al. Longitudinal study of circulating miR-122 in a rat model of non-alcoholic fatty liver disease. Clin Chim Acta 2015;446:267–271

Download references

Acknowledgements

The authors thank the following individuals for assistance in pathological diagnosis: Masafumi Inoue, M.D., Department of Pathology, Toranomon Hospital; Keiichi Kinowaki, M.D., Department of Pathology, Toranomon Hospital; Fukuo Kondo, M.D., Department of Pathology, Teikyo University School of Medicine; Toshio Fukusato, M.D., Department of Pathology, Teikyo University School of Medicine; and Takeshi Fujii, M.D., Department of Pathology, Toranomon Hospital.

Author information

Authors and Affiliations

  1. Department of Hepatology, Toranomon Hospital, and Okinaka Memorial Institute for Medical Research, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan

    Norio Akuta, Yusuke Kawamura, Fumitaka Suzuki, Satoshi Saitoh, Yasuji Arase, Hideo Kunimoto, Yushi Sorin, Shunichiro Fujiyama, Hitomi Sezaki, Tetsuya Hosaka, Masahiro Kobayashi, Yoshiyuki Suzuki, Kenji Ikeda & Hiromitsu Kumada

  2. Liver Research Laboratory, Toranomon Hospital, Tokyo, Japan

    Mariko Kobayashi

Authors
  1. Norio Akuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yusuke Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fumitaka Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Satoshi Saitoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yasuji Arase
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hideo Kunimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yushi Sorin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shunichiro Fujiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hitomi Sezaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tetsuya Hosaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masahiro Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoshiyuki Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mariko Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kenji Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Hiromitsu Kumada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Norio Akuta.

Ethics declarations

Funding

The authors had not received grant support in this study.

Conflict of interest

Hiromitsu Kumada has received honorarium from MSD K.K., Bristol-Myers Squibb, Janssen Pharmaceutical K.K., GlaxoSmithKline K.K., and holds rights for royalty from SRL. Inc.. Fumitaka Suzuki has received honorarium from Bristol-Myers Squibb. Yoshiyuki Suzuki has received honorarium from Bristol-Myers Squibb. Yasuji Arase has received honorarium from MSD K.K. Kenji Ikeda has received honorarium from Dainippon Sumitomo Pharma, Eisai Co., Ltd. All other authors declare no conflict of interest.

Ethical approval

The study protocol was in compliance with the Good Clinical Practice Guidelines and the 1975 Declaration of Helsinki, and was approved by the institutional review board at Toranomon Hospital. All patients provided written informed consent at the time of liver histological diagnosis.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akuta, N., Kawamura, Y., Suzuki, F. et al. Impact of circulating miR-122 for histological features and hepatocellular carcinoma of nonalcoholic fatty liver disease in Japan. Hepatol Int 10, 647–656 (2016). https://doi.org/10.1007/s12072-016-9729-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-016-9729-2

Keywords

Search

Navigation