title: AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease.
abstract: BACKGROUND
  The incidence and mortality of hepatocellular cancer (HCC) complicating alcoholic and non-alcoholic fatty liver diseases (ALD and NAFLD) is rising in western societies. Despite knowing the at risk populations for HCC development, the lack of sensitive and specific means of surveillance hampers disease detection at curable stages. The most widely used serum HCC marker is alpha-fetoprotein (AFP), while PIVKA-II, glypican-3 (GP3) and Squamous Cell Carcinoma Antigen -1 (SCCA-1) have been proposed as new biomarkers. Assessment of these HCC biomarkers has largely been performed in patients with viral hepatitis. We conducted a cross sectional study assessing the value of these serum proteins, as well a novel candidate biomarker -follistatin - in patients with HCC arising on a background of ALD or NAFLD.
  
  
  METHODS
  Pre-treatment serum samples from 50 patients with HCC arising on a background of ALD (n = 31) or NAFLD (n = 19) were assessed by specific ELISA assay for PIVKAII, Glypican-3, SCCA-1 and Follistatin. Results were compared and contrasted with a control patient group with biopsy proven steatohepatitis-related cirrhosis (n = 41). The diagnostic accuracy of each of the candidate biomarkers was evaluated using receiver operating characteristic (ROC) curve analysis, reporting the area under the curve (AUC) and its 95% confidence interval (CI). Performance was compared to that of the established biomarker, AFP.
  
  
  RESULTS
  Serum levels of all proteins were assessed by specific ELISA assays. GP3, SCCA-1 and follistatin had no HCC surveillance benefit in these patients. AFP and PIVKAII were superior to the other markers, particularly in combination.
  
  
  CONCLUSIONS
  We conclude that while novel means of surveillance are urgently required, the combination of AFP and PIVKAII for HCC is an improvement on AFP alone in ALD/NAFLD patients. Furthermore, our data in this homogenous subset of patients- particularly that confirming no role for SCCA-1 - suggests that the choice of optimal biomarkers for HCC surveillance may be determined by the aetiology of underlying chronic liver disease.
authors.affiliation: Paul 'O Gorman Building, Northern Institute for Cancer Research, The Medical School, Framlington Place, Newcastle University, Newcastle-upon-Tyne, UK. gary.beale@ncl.ac.uk
authors.forename: Gary
authors.initials: G
authors.lastname: Beale
authors.forename: Dipankar
authors.initials: D
authors.lastname: Chattopadhyay
authors.forename: Joe
authors.initials: J
authors.lastname: Gray
authors.forename: Stephen
authors.initials: S
authors.lastname: Stewart
authors.forename: Mark
authors.initials: M
authors.lastname: Hudson
authors.forename: Christopher
authors.initials: C
authors.lastname: Day
authors.forename: Paolo
authors.initials: P
authors.lastname: Trerotoli
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Giannelli
authors.forename: Derek
authors.initials: D
authors.lastname: Manas
authors.forename: Helen
authors.initials: H
authors.lastname: Reeves
mesh_terms: D000368:Aged; D000951:Antigens, Neoplasm / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D003937:Diagnosis, Differential; D005234:Fatty Liver / Q000150:complications* / Q000175:diagnosis; D005235:Fatty Liver, Alcoholic / Q000150:complications* / Q000175:diagnosis; D005260:Female; D038681:Follistatin / Q000097:blood; D053673:Glypicans / Q000097:blood; D006801:Humans; D015994:Incidence; D008113:Liver Neoplasms / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D008875:Middle Aged; D011247:Pregnancy; D011498:Protein Precursors / Q000097:blood*; D011516:Prothrombin; D015843:Serpins / Q000097:blood; D016019:Survival Analysis; D000509:alpha-Fetoproteins / Q000096:biosynthesis*
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D014408:Biomarkers, Tumor; D038681:Follistatin; D053673:Glypicans; D011498:Protein Precursors; D015843:Serpins; D000509:alpha-Fetoproteins; C051072:squamous cell carcinoma-related antigen; C008208:acarboxyprothrombin; D011516:Prothrombin