title: Variability in definitions of transaminase upper limit of the normal impacts the APRI performance as a biomarker of fibrosis in patients with chronic hepatitis C: "APRI c'est fini ?".
abstract: BACKGROUND
  The aspartate aminotransferase platelet ratio index (APRI) is a validated, non-patented blood test for diagnosing fibrosis or cirrhosis in patients with chronic hepatitis C. We assess the impact of two limitations, the variability of the upper limit of normal for aspartate aminotransferase (AST-ULN) and the risk of overestimating fibrosis stage due to necroinflammatory activity.
  
  
  METHODS
  The variability of AST-ULN was assessed by an overview of the literature and an assessment of AST-ULN in 2 control populations 7521 healthy volunteers and 393 blood donors. We assessed the impact of AST-ULN variability on APRI performance for estimating fibrosis prevalence and on the Obuchowski measure using individual data of 1651 patients with APRI, FibroTest and biopsy.
  
  
  RESULTS
  The overview, and the analysis of the control populations found that ULN-AST ranged from 26 to 49 IU/L according to gender, body mass index and serum cholesterol. When this AST-ULN variability was applied to the chronic hepatitis group, the prevalence of advanced fibrosis and cirrhosis as presumed by APRI varied (P<0.001) from 34.7% to 68.5%, and from 11.4% to 32.3%, respectively. This spectrum effect induced variability in APRI performance, which could be similar 0.862 (if AST-ULN=26 IU/L) or lower 0.820 (AST-ULN≥30IU/L) than the stable FibroTest performance (0.867; P=0.35 and P<0.0001 respectively). When applied to 18 acute hepatitis C patients, the rate of false positives of APRI varied from 0% to 61% due to AST-ULN.
  
  
  CONCLUSIONS
  The AST-ULN variability is high highly associated with the variability of metabolic risk factors between the different control groups. This variability induces a spectrum effect, which could cause misleading interpretations of APRI performance for the staging of fibrosis, comparisons of APRI with other non-invasive tests, and estimates of false positive rate.
authors.affiliation: Hepatology Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France.
authors.forename: Hugo
authors.initials: H
authors.lastname: Perazzo
authors.affiliation: Hepatology Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France; UMR_S 938, INSERM, Université Pierre et Marie Curie, Université Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), Centre de Recherche Saint-Antoine & Paris, France.
authors.forename: Raluca
authors.initials: R
authors.lastname: Pais
authors.affiliation: BioPredictive, Paris, France.
authors.forename: Mona
authors.initials: M
authors.lastname: Munteanu
authors.affiliation: BioPredictive, Paris, France.
authors.forename: Yen
authors.initials: Y
authors.lastname: Ngo
authors.affiliation: Biochemistry Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Monneret
authors.affiliation: Biochemistry Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Imbert-Bismut
authors.affiliation: Hepatology Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Moussalli
authors.affiliation: Hepatology Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Lebray
authors.affiliation: Hepatology Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Benhamou
authors.affiliation: Hepatology Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Thabut
authors.affiliation: Hepatology Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France.
authors.forename: Vlad
authors.initials: V
authors.lastname: Ratziu
authors.affiliation: Hepatology, Hôpital Haut Leveque, Bordeaux, France.
authors.forename: Victor
authors.initials: V
authors.lastname: de Ledhingen
authors.affiliation: Hepatology Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 47-83, boulevard de l'Hôpital, 75651 Paris cedex 13, France; UMR_S 938, INSERM, Université Pierre et Marie Curie, Université Paris 06, Institute of Cardiometabolism and Nutrition (ICAN), Centre de Recherche Saint-Antoine & Paris, France. Electronic address: tpoynard@teaser.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Poynard
mesh_terms: D000328:Adult; D001219:Aspartate Aminotransferases / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D005260:Female; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000150:complications; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood* / Q000209:etiology; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D012016:Reference Values; D012189:Retrospective Studies
chemical_list: D015415:Biomarkers; D001219:Aspartate Aminotransferases