Circulating AIM as an indicator of liver damage and hepatocellular carcinoma in humans

PLoS One. 2014 Oct 10;9(10):e109123. doi: 10.1371/journal.pone.0109123. eCollection 2014.


Background: Hepatocellular carcinoma (HCC), the fifth most common cancer type and the third highest cause of cancer death worldwide, develops in different types of liver injuries, and is mostly associated with cirrhosis. However, non-alcoholic fatty liver disease often causes HCC with less fibrosis, and the number of patients with this disease is rapidly increasing. The high mortality rate and the pathological complexity of liver diseases and HCC require blood biomarkers that accurately reflect the state of liver damage and presence of HCC.

Methods and findings: Here we demonstrate that a circulating protein, apoptosis inhibitor of macrophage (AIM) may meet this requirement. A large-scale analysis of healthy individuals across a wide age range revealed a mean blood AIM of 4.99 ± 1.8 µg/ml in men and 6.06 ± 2.1 µg/ml in women. AIM levels were significantly augmented in the younger generation (20s-40s), particularly in women. Interestingly, AIM levels were markedly higher in patients with advanced liver damage, regardless of disease type, and correlated significantly with multiple parameters representing liver function. In mice, AIM levels increased in response to carbon tetrachloride, confirming that the high AIM observed in humans is the result of liver damage. In addition, carbon tetrachloride caused comparable states of liver damage in AIM-deficient and wild-type mice, indicating no influence of AIM levels on liver injury progression. Intriguingly, certain combinations of AIM indexes normalized to liver marker score significantly distinguished HCC patients from non-HCC patients and thus could be applicable for HCC diagnosis.

Conclusion: AIM potently reveals both liver damage and HCC. Thus, our results may provide the basis for novel diagnostic strategies for this widespread and fatal disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor / blood
  • Carcinoma, Hepatocellular / blood*
  • Carcinoma, Hepatocellular / pathology
  • Female
  • Humans
  • Liver / pathology*
  • Liver Neoplasms / blood*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Middle Aged
  • Receptors, Scavenger / blood*
  • Young Adult


  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor
  • CD5L protein, human
  • Receptors, Scavenger

Grants and funding

This work was supported by Grants-in-Aid for Scientific Research (A) (Japan Society for the Promotion of Science), CREST (JST), research grants by ONSENDO Co., Ltd. (to TM), Grants-in-Aid for Scientific Research (B) (Japan Society for the Promotion of Science) (to SA), research grants by The Tokyo Biochemical Research Foundation, Takeda Science Foundation and Ono Medical Research Foundation (to MM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.