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Activation of apoptosis inhibitor of macrophage is a sensitive diagnostic marker for NASH-associated hepatocellular carcinoma

  • Original Article—Liver, Pancreas, and Biliary Tract
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Abstract

Background

A diagnostic marker is needed enabling early and specific diagnosis of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH). Our recent findings have indicated that circulating apoptosis inhibitor of macrophage (AIM), which usually associates with IgM pentamer in the blood, is activated by its dissociation from IgM. We investigated the serum levels of IgM-free AIM for AIM activation and its possible relationship with development of HCC in NASH.

Methods

Serum levels of IgM-associated and IgM-free AIM were evaluated in patients with non-alcoholic fatty liver, NASH, and NASH-HCC using enzyme-linked immunosorbent assays and immunoblots. Liver biopsy specimens were graded and staged using Brunt’s classification.

Results

Forty-two patients with fatty liver, 141 with NASH, and 26 with NASH-HCC were evaluated. Patients with stage 4 or grade 3 NASH (with or without HCC) exhibited significantly higher levels of both IgM-free and total AIM than those with fatty liver, whereas the ratio of IgM-free-to-total AIM was equivalent in these groups. Among patients with the same fibrosis stage of NASH, those with HCC had significantly higher IgM-free but not total AIM levels, resulting in a proportional increase in the IgM-free/total AIM ratio. Analysis of the areas under the receiver operating characteristic curves indicated the high sensitivity of the IgM-free AIM for NASH-HCC.

Conclusions

Our observations suggest the activation of AIM in blood in the presence of NASH-HCC, with a significant increase in IgM-free AIM levels. IgM-free AIM serum levels appear to be a sensitive diagnostic marker for NASH-HCC.

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Acknowledgements

This study was conducted based on the research collaboration contract between Saiseikai Suita Hospital and Eidia Co Ltd. and on the research collaboration contract between Toru Miyazaki in Tokyo University and Eidia Co Ltd. The authors thank the Department of Clinical Laboratory of Saiseikai Suita Hospital for suggestions for this study and carrying out clinical laboratory tests. This work was partly supported by CREST (AMED; to T.M.) and by the Research Program on Hepatitis from AMED (to T.O.).

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Author notes

  1. Noriyuki Koyama

    Present address: Eisai Co Ltd, Tokyo, Japan

  2. Noriyuki Koyama and Tomoko Yamazaki are contributed equally.

Authors and Affiliations

  1. Research and Development Division, Eidia Co Ltd, Tokyo, Japan

    Noriyuki Koyama

  2. Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Tomoko Yamazaki, Satoko Arai & Toru Miyazaki

  3. Research and Development Division, Sekisui Medical Co Ltd, Tokyo, Japan

    Yuka Kanetsuki, Jiro Hirota & Tomohide Asai

  4. Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita City, Osaka, Japan

    Yasuhide Mitsumoto, Masayuki Mizuno, Toshihide Shima & Takeshi Okanoue

  5. Department of Digestive Surgery, Saiseikai Suita Hospital, Suita City, Osaka, Japan

    Yoshihiro Kanbara

  6. CREST, Japan Agency for Medical Research and Development, Tokyo, Japan

    Toru Miyazaki

  7. Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo, Japan

    Toru Miyazaki

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  1. Noriyuki Koyama
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  2. Tomoko Yamazaki
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Correspondence to Takeshi Okanoue.

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Employment: Noriyuki Koyama/Eisai Co Ltd. Yuka Kanetsuki/Sekisui Medical Co Ltd. Jiro Hirota/Sekisui Medical Co Ltd. Tomohide Asai/Sekisui Medical Co Ltd.

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Koyama, N., Yamazaki, T., Kanetsuki, Y. et al. Activation of apoptosis inhibitor of macrophage is a sensitive diagnostic marker for NASH-associated hepatocellular carcinoma. J Gastroenterol 53, 770–779 (2018). https://doi.org/10.1007/s00535-017-1398-y

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  • DOI: https://doi.org/10.1007/s00535-017-1398-y

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