title: Copeptin as an Indicator of Hemodynamic Derangement and Prognosis in Liver Cirrhosis.
abstract: BACKGROUND
  Advanced liver cirrhosis is associated with systemic hemodynamic derangement leading to the development of severe complications associated with increased mortality. Copeptin is a stable cleavage product of the precursor of arginine vasopressin, a key-regulator in hemodynamic homeostasis. Copeptin is currently considered a reliable prognostic marker in a wide variety of diseases other than cirrhosis. The present study aimed to assess copeptin, both experimentally and clinically, as a potential biomarker of hemodynamic derangement and to evaluate its prognostic significance in cirrhosis.
  
  
  METHODS
  Two studies were executed: 1) in 18 thioacetamide-induced cirrhotic rats and 5 control rats, plasma copeptin and hemodynamic measurements were performed, 2) in 61 cirrhotic patients, serum copeptin concentration was measured in samples collected at time of registration at the waiting list for liver transplantation. In 46 patients, also a second copeptin measurement was performed during follow-up while registered at the waiting list for liver transplantation. To determine the association of serum copeptin and clinical data with outcome, Cox proportional hazard regression analysis and Kaplan Meier analysis were performed.
  
  
  RESULTS
  Plasma copeptin concentration was significantly higher in cirrhotic rats than in controls (1.6 ± 0.5 vs. 0.9 ± 0.1 pmol/L, p< 0.01) and was negatively correlated to the mean arterial blood pressure (r = -0.574, p = 0.013). In cirrhotic patients, serum copeptin concentration was high [11.0 (5.2-24.0) pmol/L] and increased significantly during the time of registration at the waiting list for liver transplantation. MELD and MELD-sodium score were significantly correlated to serum copeptin [MELD: (r = 0.33, p = 0.01), MELD-sodium: (r = 0.29, p = 0.02)], also at time of the second copeptin measurement [MELD and MELD-sodium: r = 0.39, p< 0.01]. In cirrhotic humans, serum copeptin concentration was significantly associated with outcome, independently of the MELD and MELD-sodium score. Patients with a low serum copeptin concentration at time of registration at the liver transplant waiting list had significantly better transplant-free survival rates at 3, 6 and 12 months of follow-up as compared to those with a high serum copeptin concentration (Log-rank: p< 0.01, p< 0.01 and p = 0.02 respectively).
  
  
  CONCLUSIONS
  Circulating copeptin levels are elevated in rats and humans with cirrhosis. Copeptin is independently associated with outcome in cirrhotic patients awaiting liver transplantation.
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Annarein J C
authors.initials: AJ
authors.lastname: Kerbert
authors.affiliation: Department of Liver and Biliopancreatic Diseases, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Len
authors.initials: L
authors.lastname: Verbeke
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Fang W T
authors.initials: FW
authors.lastname: Chiang
authors.affiliation: Department of Liver and Biliopancreatic Diseases, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Laleman
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Johan J
authors.initials: JJ
authors.lastname: van der Reijden
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: van Duijn
authors.affiliation: Department of Liver and Biliopancreatic Diseases, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.affiliation: Department of Medical Statistics and Bio-Informatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Wolterbeek
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van Hoek
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Hein W
authors.initials: HW
authors.lastname: Verspaget
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Minneke J
authors.initials: MJ
authors.lastname: Coenraad
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D005260:Female; D006020:Glycopeptides / Q000097:blood*; D006439:Hemodynamics / Q000502:physiology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood* / Q000473:pathology*; D016031:Liver Transplantation / Q000379:methods; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D015996:Survival Rate; D014850:Waiting Lists
chemical_list: D015415:Biomarkers; D006020:Glycopeptides; C048197:copeptins