title: Circulating apoptotic and necrotic cell death markers in patients with acute liver injury.
abstract: BACKGROUND
  The host response to cell death underpins the immune activation that follows acute liver injury, and measurement of circulating cell death markers could therefore aid prognostication following paracetamol overdose. Nucleosomes, formed during apoptosis, can complex with high-mobility group box 1 (HMGB1) protein and may play a pathogenic role in liver injury.
  
  
  OBJECTIVE
  To explore the levels and prognostic significance of nucleosomes, HMGB1, and other cell death markers following acute liver injury.
  
  
  METHODS
  Levels of plasma nucleosomes, HMGB1, caspase-cleaved cytokeratin-18 (M30) and total cytokeratin-18 (M65) were measured by immunoassay, in a cohort of 33 patients with paracetamol- and non-paracetamol-induced acute liver injury.
  
  
  RESULTS
  Admission nucleosome levels in paracetamol overdose patients were significantly higher than in chronic liver disease and healthy control subjects, but were similar in paracetamol and non-paracetamol patients (P=0.11). Nucleosome levels were not associated with death or requirement for liver transplantation, fulfillment of poor prognostic criteria or organ failure in paracetamol patients. Nucleosome levels correlated with levels of HMGB1 (r=0.500, P=0.009), alanine aminotransferase (r=0.410, P=0.038) and M65 (r=0.709, P<0.001), but not with M30 (r=0.309, P=0.124). None of the cell death markers analysed improved prognostication in paracetamol patients beyond the King's College criteria.
  
  
  CONCLUSIONS
  Plasma nucleosomes are significantly elevated following acute liver injury. Neither apoptotic nor necrotic cell death markers accurately predict survival following paracetamol-induced hepatotoxicity, suggesting that the extent and type of cell death play a limited role in determining outcome.
authors: Royal Infirmary of Edinburgh, Little France, Edinburgh, UK. darrencraig@doctors.org.uk
authors: Darren G N
authors: DG
authors: Craig
authors: Patricia
authors: P
authors: Lee
authors: Elizabeth A
authors: EA
authors: Pryde
authors: Gail S
authors: GS
authors: Masterton
authors: Peter C
authors: PC
authors: Hayes
authors: Kenneth J
authors: KJ
authors: Simpson
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects; D000328:Adult; D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects; D000704:Analysis of Variance; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis / Q000209:etiology / Q000473:pathology / Q000601:surgery; D016009:Chi-Square Distribution; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D024243:HMGB1 Protein / Q000097:blood; D006801:Humans; D053538:Keratin-18 / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D017114:Liver Failure, Acute / Q000097:blood* / Q000175:diagnosis / Q000209:etiology / Q000473:pathology / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012606:Scotland; D012720:Severity of Illness Index
chemical_list: D018712:Analgesics, Non-Narcotic; D015415:Biomarkers; D024243:HMGB1 Protein; C488421:KRT18 protein, human; D053538:Keratin-18; C561463:M30 cytokeratin-18 peptide, human; D009707:Nucleosomes; D010446:Peptide Fragments; D000082:Acetaminophen