title: Mechanism of cell death in acute-on-chronic liver failure: a clinico-pathologic-biomarker study.
abstract: OBJECTIVE
  Mortality of patients who develop acute-on-chronic liver failure (ACLF) is unacceptably high but the predominant mode of cell death is unknown. The aim of this study was to evaluate whether plasma levels of caspase-cleaved cytokeratin M30 (marker of apoptosis) and uncleaved cytokeratin M65 (marker of total cell death) are altered in ACLF patients and relate this to liver histology.
  
  
  METHODS
  Twenty-seven patients with acute decompensation of liver disease were divided into two groups: no-ACLF (n = 11) or ACLF (n-16). Healthy controls (n = 8) and acute liver failure (ALF) patients (n = 10) were also enrolled. Cell death was assessed in plasma using an ELISA kit (M30 and M65). Simultaneous biopsy samples were analysed for M30 and caspase-3 staining.
  
  
  RESULTS
  Plasma M30 value was significantly elevated in ACLF patients compared with healthy volunteers (P = 0.0001), it was also significantly higher in ACLF patients compared with no-ACLF patients (P = 0.002). M65 levels were higher in ALF compared with ACLF patients (P = 0.002) but the apoptotic index defined by M30/M65 ratio was significantly higher in ACLF patients. Patients with extra-hepatic failure had higher M30 levels compared with patients without organ failure (P = 0.03). M30 staining in liver was more marked in the patients with ACLF and was observed in all the patients that died.
  
  
  CONCLUSIONS
  The results of this study suggest that hepatocyte apoptosis is the predominant mode of cell death in ACLF, which can be identified in the peripheral blood. Further studies are required to validate our findings and to determine whether M30 can be used as a biomarker of apoptosis or as a target for therapy.
authors: Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK.
authors: Danielle
authors: D
authors: Adebayo
authors: Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK.
authors: Vincenzo
authors: V
authors: Morabito
authors: Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK.
authors: Fausto
authors: F
authors: Andreola
authors: Sheila Sherlock, Liver Center and UCL, Institute of Liver and Digestive Health, Royal Free Hospital, London, UK.
authors: Giulia
authors: G
authors: Pieri
authors: Department of Cellular Pathology, Royal Free Hospital NHS Foundation Trust, London, UK.
authors: Tu-Vin
authors: TV
authors: Luong
authors: Department of Cellular Pathology, Royal Free Hospital NHS Foundation Trust, London, UK.
authors: Amar
authors: A
authors: Dhillon
authors: Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK.
authors: Rajeshwar
authors: R
authors: Mookerjee
authors: Liver Failure Group, Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK.
authors: Rajiv
authors: R
authors: Jalan
mesh_terms: D065290:Acute-On-Chronic Liver Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000328:Adult; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D005260:Female; D006801:Humans; D053538:Keratin-18 / Q000097:blood*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood*; D013223:Statistics as Topic
chemical_list: D015415:Biomarkers; D053538:Keratin-18; C561463:M30 cytokeratin-18 peptide, human; D010446:Peptide Fragments; D053148:Caspase 3
keywords: apoptosis; cell death; liver failure; necrosis