title: Circulating AIM as an indicator of liver damage and hepatocellular carcinoma in humans.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mori
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Arai
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tateishi
authors.affiliation: Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Abe
authors.affiliation: Shunkaikai, Inoue Hospital, Nagasaki, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Ban
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Nishijima
authors.affiliation: Shunkaikai, Inoue Hospital, Nagasaki, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Department of Gastroenterology, Jichi Medical University, Saitama Medical Center, Omiya, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Asano
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kai
authors.affiliation: Shunkaikai, Inoue Hospital, Nagasaki, Japan.
authors.forename: Kiyohiro
authors.initials: K
authors.lastname: Izumino
authors.affiliation: Shunkaikai, Inoue Hospital, Nagasaki, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Takahashi
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Aoyama
authors.affiliation: Department of Preventive Medicine and Public Health, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Harada
authors.affiliation: Department of Preventive Medicine and Public Health, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Takebayashi
authors.affiliation: Center for Preventive Medicine, NTT Medical Center Tokyo, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Gunji
authors.affiliation: National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Ohnishi
authors.affiliation: Shunkaikai, Inoue Hospital, Nagasaki, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Seto
authors.affiliation: Department of Gastroenterology, Jichi Medical University, Saitama Medical Center, Omiya, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hiasa
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.affiliation: Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamamura
authors.affiliation: Shunkaikai, Inoue Hospital, Nagasaki, Japan.
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo, Japan; CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Miyazaki
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000473:pathology; D005260:Female; D006801:Humans; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000097:blood* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D051116:Receptors, Scavenger / Q000097:blood*; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C492821:CD5L protein, human; D051116:Receptors, Scavenger