Skip to main content

Advertisement

SpringerLink
Log in

Serum aldo–keto reductase family 1 member B10 predicts advanced liver fibrosis and fatal complications of nonalcoholic steatohepatitis

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

Abstract

Background

Nonalcoholic steatohepatitis (NASH) is associated with liver inflammation in patients with nonalcoholic fatty liver disease, and it can progress to liver fibrosis at an advanced stage, as well as hepatocellular carcinoma (HCC) and portal hypertension. Although liver fibrosis is accurately diagnosed via biopsy, noninvasive methods are preferable. Aldo–keto reductase family 1 member B10 (AKR1B10) is associated with HCC and is secreted into the blood by liver cells via a lysosome-mediated nonclassical pathway. Accordingly, we analyzed whether secretion of AKR1B10 protein is associated with advanced NASH.

Methods

We performed histological staging in 85 Matteoni classification type III and IV NASH patients and evaluated the incidence of HCC, formation of gastroesophageal varices, and prognosis according to serum AKR1B10 and Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP)(M2BPGi) and by comparison with conventional markers of fibrosis.

Results

 A positive correlation was found between the Brunt classification and serum AKR1B10 level. In Brunt stage 4 patients, AKR1B10 levels were higher than those of other liver fibrosis markers, with higher specificity. The cutoff values for AKR1B10 and WFA(+)-M2BP for stage 4 fibrosis were 1.03 and 3.11, respectively. The rates of stage 4 fibrosis, HCC incidence, and gastroesophageal varix formation were significantly different between the two groups subdivided according to these cutoff levels. Moreover, the patients in the higher value group had significantly worse prognosis after NASH diagnosis

Conclusion

AKR1B10 is a useful serum biomarker for advanced liver fibrosis in NASH and, combined with serum WFA(+)-M2BP, can predict HCC development, gastroesophageal varix formation, and poor prognosis.

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

Similar content being viewed by others

References

  1. Sayiner M, Koenig A, Henry L, et al. Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the World. Clin Liver Dis. 2016;20:205–14.

    Article  PubMed  Google Scholar 

  2. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84.

    Article  PubMed  Google Scholar 

  3. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–46.

    Article  CAS  PubMed  Google Scholar 

  4. Okanoue T, Ebise H, Kai T, et al. A simple scoring system using type IV collagen 7S and aspartate aminotransferase for diagnosing nonalcoholic steatohepatitis and related fibrosis. J Gastroenterol. 2018;53:129–39.

    Article  CAS  PubMed  Google Scholar 

  5. Abe M, Miyake T, Kuno A, et al. Association between Wisteria floribunda agglutinin-positive Mac-2 binding protein and the fibrosis stage of non-alcoholic fatty liver disease. J Gastroenterol. 2015;50:776–84.

    Article  CAS  PubMed  Google Scholar 

  6. Kawaguchi K, Honda M, Ohta H, et al. Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts hepatocellular carcinoma incidence and recurrence in nucleos(t)ide analogue therapy for chronic hepatitis B. J Gastroenterol. 2018;53:740–51.

    Article  CAS  PubMed  Google Scholar 

  7. Kawanaka M, Tomiyama Y, Hyogo H, et al. Wisteria floribunda agglutinin-positive Mac-2 binding protein predicts the development of hepatocellular carcinoma in patients with non-alcoholic fatty liver disease. Hepatol Res. 2018;48:521–8.

    Article  CAS  PubMed  Google Scholar 

  8. Cao D, Fan ST, Chung SS. Identification and characterization of a novel human aldose reductase-like gene. J Biol Chem. 1998;273:11429–35.

    Article  CAS  PubMed  Google Scholar 

  9. Heringlake S, Hofdmann M, Fiebeler A, et al. Identification and expression analysis of the aldo-ketoreductase 1-B10 gene in primary malignant liver tumours. J Hepatol. 2010;52:220–7.

    Article  CAS  PubMed  Google Scholar 

  10. Starmann J, Falth M, Spindelbock W, et al. Gene expression profiling unravels cancer-related hepatic molecular signatures in steatohepatitis but not in steatosis. PLoS One. 2012;7:e46584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sumida Y, Yoneda M, Hyogo H, et al. Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol. 2012;12:2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  PubMed  Google Scholar 

  13. Ooi A, Wong JC, Petillo D, et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell. 2011;20:511–23.

    Article  CAS  PubMed  Google Scholar 

  14. Fukumoto S, Yamauchi N, Moriguchi H, et al. Overexpression of the aldo-keto reductase family protein AKR1B10 is highly correlated with smokers’ non-small cell lung carcinomas. Clin Cancer Res. 2005;11:1776–85.

    Article  CAS  PubMed  Google Scholar 

  15. Chung YT, Matkowskyj KA, Li H, et al. Overexpression and oncogenic function of aldo-keto reductase family 1B10 (AKR1B10) in pancreatic carcinoma. Mod Pathol. 2012;25:758–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ma J, Luo DX, Huang C, et al. AKR1B10 overexpression in breast cancer: association with tumor size, lymph node metastasis and patient survival and its potential as a novel serum marker. Int J Cancer. 2012;131:E862–71.

    Article  CAS  PubMed  Google Scholar 

  17. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(389–97):e10.

    Google Scholar 

  18. Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet. 2008;40:1461–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Alessi MC, Bastelica D, Mavri A, et al. Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation. Arterioscler Thromb Vasc Biol. 2003;23:1262–8.

    Article  CAS  PubMed  Google Scholar 

  20. Charlton M, Angulo P, Chalasani N, et al. Low circulating levels of dehydroepiandrosterone in histologically advanced nonalcoholic fatty liver disease. Hepatology. 2008;47:484–92.

    Article  CAS  PubMed  Google Scholar 

  21. Angulo P, Hui JM, Marchesini G, 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. Yoneda M, Imajo K, Eguchi Y, et al. Noninvasive scoring systems in patients with nonalcoholic fatty liver disease with normal alanine aminotransferase levels. J Gastroenterol. 2013;48:1051–60.

    Article  CAS  PubMed  Google Scholar 

  23. 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. 2011;46:257–68.

    Article  CAS  PubMed  Google Scholar 

  24. Harrison SA, Oliver D, Arnold HL, et al. 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 

  25. Xu C, Chen Y, Xu L, et al. Serum complement C3 levels are associated with nonalcoholic fatty liver disease independently of metabolic features in Chinese population. Sci Rep. 2016;6:23279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Daniels SJ, Leeming DJ, Eslam M, et al. ADAPT: an algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis. Hepatology. 2018. https://doi.org/10.1002/hep.30163.

    Article  PubMed  Google Scholar 

  27. Itoh Y, Seko Y, Shima T, et al. Accuracy of non-invasive scoring systems for diagnosing non-alcoholic steatohepatitis-related fibrosis: multicenter validation study. Hepatol Res. 2018;48:1099–107.

    Article  CAS  PubMed  Google Scholar 

  28. Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–74.

    Article  CAS  PubMed  Google Scholar 

  29. Nishikawa H, Enomoto H, Iwata Y, et al. Clinical significance of serum Wisteria floribunda agglutinin positive Mac-2-binding protein level in non-alcoholic steatohepatitis. Hepatol Res. 2016;46:1194–202.

    Article  CAS  PubMed  Google Scholar 

  30. Ishiba H, Sumida Y, Tanaka S, et al. The novel cutoff points for the FIB4 index categorized by age increase the diagnostic accuracy in NAFLD: a multi-center study. J Gastroenterol. 2018;53:1216–24.

    Article  PubMed  Google Scholar 

  31. Luo D, Bu Y, Ma J, et al. Heat shock protein 90-alpha mediates aldo-keto reductase 1B10 (AKR1B10) protein secretion through secretory lysosomes. J Biol Chem. 2013;288:36733–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shirabe K, Bekki Y, Gantumur D, et al. Mac-2 binding protein glycan isomer (M2BPGi) is a new serum biomarker for assessing liver fibrosis: more than a biomarker of liver fibrosis. J Gastroenterol. 2018;53:819–26.

    Article  CAS  PubMed  Google Scholar 

  33. Narimatsu H. Development of M2BPGi: a novel fibrosis serum glyco-biomarker for chronic hepatitis/cirrhosis diagnostics. Expert Rev Proteom. 2015;12:683–93.

    Article  CAS  Google Scholar 

  34. Yamasaki K, Tateyama M, Abiru S, et al. Elevated serum levels of Wisteria floribunda agglutinin-positive human Mac-2 binding protein predict the development of hepatocellular carcinoma in hepatitis C patients. Hepatology. 2014;60:1563–70.

    Article  CAS  PubMed  Google Scholar 

  35. Umemura T, Joshita S, Sekiguchi T, et al. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein level predicts liver fibrosis and prognosis in primary biliary cirrhosis. Am J Gastroenterol. 2015;110:857–64.

    Article  CAS  PubMed  Google Scholar 

  36. Nishikawa H, Enomoto H, Iwata Y, et al. Impact of serum Wisteria floribunda agglutinin positive Mac-2-binding protein and serum interferon-gamma-inducible protein-10 in primary biliary cirrhosis. Hepatol Res. 2016;46:575–83.

    Article  CAS  PubMed  Google Scholar 

  37. Xu WP, Wang ZR, Zou X, et al. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein evaluates liver function and predicts prognosis in liver cirrhosis. J Dig Dis. 2018;19:242–53.

    Article  CAS  PubMed  Google Scholar 

  38. Ito K, Murotani K, Nakade Y, et al. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein levels and liver fibrosis: a meta-analysis. J Gastroenterol Hepatol. 2017;32:1922–30.

    Article  CAS  PubMed  Google Scholar 

  39. Petta S, Sebastiani G, Bugianesi E, et al. Non-invasive prediction of esophageal varices by stiffness and platelet in non-alcoholic fatty liver disease cirrhosis. J Hepatol. 2018;69:878–85.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Nami Nishiyama for managing the serum samples.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa, 920-8641, Japan

    Masataka Kanno, Kazunori Kawaguchi, Masao Honda, Rika Horii, Hajime Takatori, Tetsuro Shimakami, Kazuya Kitamura, Kuniaki Arai, Taro Yamashita, Yoshio Sakai, Tatsuya Yamashita, Eishiro Mizukoshi & Shuichi Kaneko

Authors
  1. Masataka Kanno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazunori Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masao Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rika Horii
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hajime Takatori
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tetsuro Shimakami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuya Kitamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kuniaki Arai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Taro Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshio Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tatsuya Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eishiro Mizukoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shuichi Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masao Honda.

Ethics declarations

Conflict of interest

The author(s) declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kanno, M., Kawaguchi, K., Honda, M. et al. Serum aldo–keto reductase family 1 member B10 predicts advanced liver fibrosis and fatal complications of nonalcoholic steatohepatitis. J Gastroenterol 54, 549–557 (2019). https://doi.org/10.1007/s00535-019-01551-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-019-01551-3

Keywords

Search

Navigation