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Published in: Journal of Gastroenterology 6/2019

01-06-2019 | Hepatocellular Carcinoma | Original Article—Liver, Pancreas, and Biliary Tract

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

Authors: 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

Published in: Journal of Gastroenterology | Issue 6/2019

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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.
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Literature
1.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
2.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
3.
go back to reference Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–46.CrossRefPubMed Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–46.CrossRefPubMed
4.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
5.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
6.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
7.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
8.
go back to reference Cao D, Fan ST, Chung SS. Identification and characterization of a novel human aldose reductase-like gene. J Biol Chem. 1998;273:11429–35.CrossRefPubMed Cao D, Fan ST, Chung SS. Identification and characterization of a novel human aldose reductase-like gene. J Biol Chem. 1998;273:11429–35.CrossRefPubMed
9.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
10.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
11.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
12.
go back to reference Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.CrossRefPubMed Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.CrossRefPubMed
13.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
14.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
15.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
16.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
17.
go back to reference 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. 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.
18.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
19.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
20.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
21.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
22.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
23.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
24.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
25.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
27.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
28.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
29.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
30.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
31.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
32.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
33.
go back to reference Narimatsu H. Development of M2BPGi: a novel fibrosis serum glyco-biomarker for chronic hepatitis/cirrhosis diagnostics. Expert Rev Proteom. 2015;12:683–93.CrossRef Narimatsu H. Development of M2BPGi: a novel fibrosis serum glyco-biomarker for chronic hepatitis/cirrhosis diagnostics. Expert Rev Proteom. 2015;12:683–93.CrossRef
34.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
35.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
36.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
37.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
38.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
39.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
Metadata
Title
Serum aldo–keto reductase family 1 member B10 predicts advanced liver fibrosis and fatal complications of nonalcoholic steatohepatitis
Authors
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
Publication date
01-06-2019
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 6/2019
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-019-01551-3

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