title: Liver progenitor cell markers correlate with liver damage and predict short-term mortality in patients with alcoholic hepatitis.
abstract: Alcoholic hepatitis (AH) is a severe condition developed in patients with underlying alcoholic liver disease. Ductular reaction has been associated with chronic alcohol consumption but there is no information regarding the extent of liver progenitor cell (LPC) proliferation in AH. The aim of this study was to investigate LPC markers in AH and its correlation with disease severity. Fifty-nine patients with clinical and histological diagnosis of AH were included in the study. LPC markers were assessed by real-time polymerase chain reaction (PCR) and immunohistochemistry. Standard logistic regression analysis and classification and regression trees (CART) analysis were used for statistical analysis. A microarray analysis showed an up-regulation of LPC markers in patients with AH. Real-time PCR demonstrated that epithelial cell adhesion molecule (EpCAM), Prominin-1, and Keratin7 were significantly increased in patients with AH compared with normal livers (P ≤ 0.01), chronic hepatitis C (P ≤ 0.01), and HCV-induced cirrhosis (P ≤ 0.01). Immunohistochemistry scores generated for Keratin7 and EpCAM demonstrated a good correlation with gene expression. Keratin7 gene expression correlated with liver failure as assessed by model for endstage liver disease score (r = 0.41, P = 0.006) and Maddrey's discriminant function (r = 0.43, P = 0.004). Moreover, Keratin7 (OR1.14, P = 0.004) and Prominin-1 (OR1.14, P = 0.002), but not EpCAM (OR1.16, P = 0.06), were identified as independent predictors of 90-day mortality. CART analysis generated an algorithm based on the combination of Keratin7 and EpCAM gene expression that stratified three groups of patients with high, intermediate, and low short-term mortality (89%, 33%, and 6%, respectively; area under the receiver operating curve 0.73, 95% confidence interval 0.60-0.87). Keratin7 expression provided additional discrimination potential to the age, bilirubin, international normalization ratio, creatinine (ABIC) score.
  
  
  CONCLUSIONS
  LPC markers correlate positively with severity of liver disease and short-term mortality in AH patients. This study suggests that LPC proliferation may be an important feature of AH pathophysiology.
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain. psancho@clinic.ub.es
authors.forename: Pau
authors.initials: P
authors.lastname: Sancho-Bru
authors.forename: José
authors.initials: J
authors.lastname: Altamirano
authors.forename: Daniel
authors.initials: D
authors.lastname: Rodrigo-Torres
authors.forename: Mar
authors.initials: M
authors.lastname: Coll
authors.forename: Cristina
authors.initials: C
authors.lastname: Millán
authors.forename: Juan
authors.initials: J
authors.lastname: José Lozano
authors.forename: Rosa
authors.initials: R
authors.lastname: Miquel
authors.forename: Vicente
authors.initials: V
authors.lastname: Arroyo
authors.forename: Juan
authors.initials: J
authors.lastname: Caballería
authors.forename: Pere
authors.initials: P
authors.lastname: Ginès
authors.forename: Ramon
authors.initials: R
authors.lastname: Bataller
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD / Q000032:analysis; D000951:Antigens, Neoplasm / Q000032:analysis; D015415:Biomarkers; D015815:Cell Adhesion Molecules / Q000032:analysis; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D006023:Glycoproteins / Q000032:analysis; D006519:Hepatitis, Alcoholic / Q000401:mortality*; D006801:Humans; D007150:Immunohistochemistry; D053552:Keratin-7 / Q000032:analysis; D008099:Liver / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000032:analysis; D012720:Severity of Illness Index; D013234:Stem Cells / Q000737:chemistry*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D015415:Biomarkers; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins; C507497:KRT7 protein, human; D053552:Keratin-7; C000606023:PROM1 protein, human; D010455:Peptides