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

J Gastroenterol. 2018 Jun;53(6):770-779. doi: 10.1007/s00535-017-1398-y. Epub 2017 Oct 30.


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.

Keywords: Apoptosis inhibitor of macrophage; Hepatocellular carcinoma; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor / blood*
  • Biopsy
  • Carcinoma, Hepatocellular / diagnosis*
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / pathology
  • Female
  • Humans
  • Immunoglobulin M / blood
  • Liver / pathology
  • Liver Neoplasms / diagnosis*
  • Liver Neoplasms / etiology
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Non-alcoholic Fatty Liver Disease / complications*
  • Non-alcoholic Fatty Liver Disease / pathology
  • ROC Curve
  • Receptors, Scavenger / blood*
  • Severity of Illness Index


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