title: Neutrophil gelatinase-associated lipocalin is a biomarker of acute-on-chronic liver failure and prognosis in cirrhosis.
abstract: Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in cirrhosis characterized by organ failure(s) and high mortality rate. There are no biomarkers of ACLF. The LCN2 gene and its product, neutrophil gelatinase-associated lipocalin (NGAL), are upregulated in experimental models of liver injury and cultured hepatocytes as a result of injury by toxins or proinflammatory cytokines, particularly Interleukin-6. The aim of this study was to investigate whether NGAL could be a biomarker of ACLF and whether LCN2 gene may be upregulated in the liver in ACLF.
  
  
  
  We analyzed urine and plasma NGAL levels in 716 patients hospitalized for complications of cirrhosis, 148 with ACLF. LCN2 expression was assessed in liver biopsies from 29 additional patients with decompensated cirrhosis with and without ACLF.
  
  
  
  Urine NGAL was markedly increased in ACLF vs. no ACLF patients (108(35-400) vs. 29(12-73)μg/g creatinine; p<0.001) and was an independent predictive factor of ACLF; the independent association persisted after adjustment for kidney function or exclusion of variables present in ACLF definition. Urine NGAL was also an independent predictive factor of 28day transplant-free mortality together with MELD score and leukocyte count (AUROC 0.88(0.83-0.92)). Urine NGAL improved significantly the accuracy of MELD in predicting prognosis. The LCN2 gene was markedly upregulated in the liver of patients with ACLF. Gene expression correlated directly with serum bilirubin and INR (r=0.79; p<0.001 and r=0.67; p<0.001), MELD (r=0.68; p<0.001) and Interleukin-6 (r=0.65; p<0.001).
  
  
  
  NGAL is a biomarker of ACLF and prognosis and correlates with liver failure and systemic inflammation. There is remarkable overexpression of LCN2 gene in the liver in ACLF syndrome.
  
  
  
  Urine NGAL is a biomarker of acute-on-chronic liver failure (ACLF). NGAL is a protein that may be expressed in several tissues in response to injury. The protein is filtered by the kidneys due to its small size and can be measured in the urine. Ariza, Graupera and colleagues found in a series of 716 patients with cirrhosis that urine NGAL was markedly increased in patients with ACLF and correlated with prognosis. Moreover, gene coding NGAL was markedly overexpressed in the liver tissue in ACLF.
authors.affiliation: Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: X
authors.initials: X
authors.lastname: Ariza
authors.affiliation: Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Graupera
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Coll
authors.affiliation: Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Solà
authors.affiliation: Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Barreto
authors.affiliation: Data Management Centre, EASL-CLIF Consortium, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: García
authors.affiliation: Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Moreira
authors.affiliation: Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Elia
authors.affiliation: University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain; Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Morales-Ruiz
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Llopis
authors.affiliation: Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Huelin
authors.affiliation: Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Solé
authors.affiliation: University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Fabrellas
authors.affiliation: Inserm, U1149, Centre de Recherche sur l'Inflammation (CRI), Clichy and Paris, France; UMRS1149, Université Paris Diderot, Paris, France; Département Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, Assistance Publique des Hôpitaux de Paris, Clichy, France; Laboratoire d'Excellence Inflamex, ComUE Sorbonne Paris Cité, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Weiss
authors.affiliation: Division of Liver and Biliopancreatic Disorders, University Hospitals of Leuven, KU Leuven, University of Leuven, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Nevens
authors.affiliation: Liver Center Munich, Department of Internal Medicine II, University Hospital LMU Munich, Grosshadern, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Gerbes
authors.affiliation: Department of Internal Medicine I, University of Bonn, Bonn, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Trebicka
authors.affiliation: Hôpital Paul Brousse, Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Saliba
authors.affiliation: University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain; Hepatobiliary Surgery & Liver Transplant, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Fondevila
authors.affiliation: Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain; Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Hernández-Gea
authors.affiliation: Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Fernández
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bernardi
authors.affiliation: EASL-CLIF Consortium, Barcelona, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Arroyo
authors.affiliation: University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain; Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: W
authors.initials: W
authors.lastname: Jiménez
authors.affiliation: Data Management Centre, EASL-CLIF Consortium, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Deulofeu
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain; Data Management Centre, EASL-CLIF Consortium, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pavesi
authors.affiliation: Unit of Hepatic Emergencies and Liver Transplantation, Department of Surgery, University of Padova, Padova, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Angeli
authors.affiliation: Liver Failure Group, University College London Institute for Liver and Digestive Health, University College London Medical School, Royal Free Hospital, London, United Kingdom.
authors.forename: R
authors.initials: R
authors.lastname: Jalan
authors.affiliation: Inserm, U1149, Centre de Recherche sur l'Inflammation (CRI), Clichy and Paris, France; UMRS1149, Université Paris Diderot, Paris, France; Département Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, Assistance Publique des Hôpitaux de Paris, Clichy, France; Laboratoire d'Excellence Inflamex, ComUE Sorbonne Paris Cité, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Moreau
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Sancho-Bru
authors.affiliation: Liver Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain; University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, Spain. Electronic address: pgines@clinic.cat.
authors.forename: P
authors.initials: P
authors.lastname: Ginès
mesh_terms: D058186:Acute Kidney Injury; D065290:Acute-On-Chronic Liver Failure; D015415:Biomarkers; D006801:Humans; D000071068:Lipocalin-2; D008103:Liver Cirrhosis; D011379:Prognosis
chemical_list: D015415:Biomarkers; D000071068:Lipocalin-2
keywords: Acute-on-chronic liver failure; Biomarker; Lipocalin-2; NGAL