title: The Circulating IGF System in Hepatocellular Carcinoma: The Impact of Liver Status and Treatment.
abstract: BACKGROUND
  Previous studies have demonstrated an elevated IGF-II mRNA expression and protein levels in tumors and blood from patients with hepatocellular carcinoma (HCC), hereby suggesting a role of IGF-II as a pathogenic marker of HCC. We hypothesized that in HCC, an increased IGF-II secretion would translate into an elevated circulating IGF bioactivity, which would normalize following treatment.
  
  
  METHODS
  Patients with HCC (n=39) were studied before and after radio-frequency ablation and/or transarterial chemo-embolization. Baseline data were compared to healthy subjects (n=150) and patients with liver cirrhosis (n=41). Serum levels of IGF ligands and IGF binding proteins (IGFBPs) were determined using gold standard methods as well as novel assays and compared to liver function tests and HCC treatment status.
  
  
  RESULTS
  At baseline, HCC patients differed from cirrhosis patients and healthy controls regarding IGF-I (29 [23-37] vs. 12 [7-19] vs. 109 [103-116] μg/l), IGF-II (254 [224-288] vs. 118 [102-137] vs. 545 [525-566] μg/l) and IGF bioactivity (0.53 [0.41-0.68] vs. 0.29 [0.24-0.34] vs. 1.43 [1.33-1.53] μg/l) (mean [95% confidence interval], all age-adjusted P<0.001). All variables but IGFBP-2 were strongly associated with liver status (MELD score), and accordingly, differences were either attenuated or disappeared when adjusted for MELD score. There was no effect of treatment on any IGF variables.
  
  
  CONCLUSIONS
  The marked differences in IGF and IGFBP levels between patients with HCC, liver cirrhosis and healthy subjects are mainly explained by variations in liver status. Therefore, this study questions the clinical utility of circulating IGF variables as markers of HCC.
authors.affiliation: Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Ulrick
authors.initials: U
authors.lastname: Espelund
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbæk
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Gerda Elisabeth
authors.initials: GE
authors.lastname: Villadsen
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Kira
authors.initials: K
authors.lastname: Simonsen
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Poul Frølund
authors.initials: PF
authors.lastname: Vestergaard
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jens Otto Lunde
authors.initials: JO
authors.lastname: Jørgensen
authors.affiliation: Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Flyvbjerg
authors.affiliation: Department of Hepatology & Gastroenterology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
authors.affiliation: Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark. Electronic address: frystyk@clin.au.dk.
authors.forename: Jan
authors.initials: J
authors.lastname: Frystyk
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011498:Protein Precursors / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C583557:IGF1 protein, human; C035170:IGF2 protein, human; C577903:IGFBP2 protein, human; C515497:IGFBP3 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D011498:Protein Precursors; C066038:proinsulin-like growth factor II; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II
keywords: Biological assay; Hepatocellular carcinoma; Insulin-like growth factor I; Insulin-like growth factor II; Insulin-like growth factor binding proteins; Kinase receptor activation assay; Liver cirrhosis