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

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

Number of patients showing different levels of inflammation, fibrosis, cirrhosis, or ascites.

<p>All patients here possessed HCC. The percentage shows the proportion in each level of identical phenotype. Unknown: Information was not available.</p><p>Number of patients showing different levels of inflammation, fibrosis, cirrhosis, or ascites.</p

Correlation in the AIM level and the liver function under liver injury.

<p>Correlation in AIM levels and various biomarkers representing liver function in men (blue) and women (yellow), with or without HCC. ICG score was only available in HCC patients.</p

AIM-index distinguishes HCC and non-HCC patients.

<p>(A) AIM-TB index vs. AIM-ALB index, AIM-PLT index or AIM-AST index in men with or without HCC. TB vs. ALB, PLT or AST are also presented. (B) AIM-ALB index vs. AIM-%PT index in women with or without HCC. ALB vs. %PT is also presented. r: correlation coefficients; p: p value determined by ANCOVA. Blue dots and bars: HCC patients, red dots and bars: non-HCC patients.</p

Circulating AIM levels in healthy indivisuals.

<p>(A) AIM levels in different generations. Error bar: SEM. ***: <i>p</i><0.001 vs. the value of women in 20s. ###: <i>p</i><0.001 vs. the value of men in 20s. (B) Means ± SD (µg/ml) of AIM levels in whole men and women. AIM levels were significantly higher in women than in men. (C) Correlation of AIM and IgM levels in men and women. IgM levels were analyzed by ELISA in 20 individuals exhibiting a variety of AIM levels in each generation in men and women. (D) Correlation in AIM levels and BMI, obesity index, % of fat mass or waist circumference, LDL cholesterol levels, HbA1C, FBS, systolic or diastolic blood pressure in women. (E) Correlation in AIM and AST or ALT levels in males and females. In C-E, r: correlation coefficients in single linear regression analysis, p: p value, n: number of samples. Blue dots: men, yellow dots: women.</p

Clinical features of patients analyzed for AIM.

<p>The mean ± SD as well as the range of diversity are presented for each parametric variable. The ICG score was only available in HCC patients.</p><p>Clinical features of patients analyzed for AIM.</p

Number of patients in each type of liver injury.

<p>The percentage shows the proportion in total number of each gender with or without HCC.</p><p>Number of patients in each type of liver injury.</p