Serum levels of immunoglobulin M‐free inhibitors of macrophage/CD5L as a predictive and early diagnostic marker for nonalcoholic steatohepatitis‐associated hepatocellular carcinoma

Background The apoptosis inhibitor of macrophage (AIM) is usually associated with the immunoglobulin M (IgM) pentamer in the blood and is dissociated from IgM in various diseases, including hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH). We aimed to elucidate whether IgM‐free AIM (fAIM) is useful for detecting latent HCC in NASH. Methods This research consisted of two cohort studies. The levels of serum fAIM, alpha‐fetoprotein (AFP), and des‐gamma carboxy prothrombin (DCP) of 18 NASH patients who developed HCC were measured during the follow‐up period before HCC diagnosis (median, 4.7 years). In total, 199 patients with nonalcoholic fatty liver disease (NAFLD) were included in the HCC survey. The serum fAIM levels were analyzed using enzyme‐linked immunosorbent assays. Results In the cohort of 18 patients with HCC, 12 had high fAIM at the time of the initial blood sample, three had normal fAIM levels throughout the follow‐up period, and three had fAIM elevated from normal to positive. The positive ratio of fAIM prior to HCC diagnosis remained significantly higher than that of AFP and DCP, and the fAIM ratio gradually increased. In a survey of 199 non‐HCC NAFLD patients, a Cox regression analysis using independent variables, such as AFP, fAIM, age, albumin, bilirubin, and fibrosis stage, revealed that fAIM and AFP were significantly associated with the incidence of HCC. Conclusions During the development of NASH‐HCC, AIM activation in blood appears to start even before HCC is diagnostically detectable. Thus, the serum IgM‐free AIM levels could be a new, sensitive biomarker for latent NASH‐HCC.