title: Patients with the worst outcomes after paracetamol (acetaminophen)-induced liver failure have an early monocytopenia.
abstract: Acute liver failure (ALF) is associated with significant morbidity and mortality. Studies have implicated the immune response, especially monocyte/macrophages as being important in dictating outcome.
  
  
  
  To investigate changes in the circulating monocytes and other immune cells serially in patients with ALF, relate these with cytokine concentrations, monocyte gene expression and patient outcome.
  
  
  
  In a prospective case-control study in the Scottish Liver Transplant Unit, Royal Infirmary Edinburgh, 35 consecutive patients admitted with paracetamol-induced liver failure (POD-ALF), 10 patients with non-paracetamol causes of ALF and 16 controls were recruited. The peripheral blood monocyte phenotype was analysed by flow cytometry, circulating cytokines quantified by protein array and monocyte gene expression array performed and related to outcome.
  
  
  
  On admission, patients with worst outcomes after POD-ALF had a significant monocytopenia, characterised by reduced classical and expanded intermediate monocyte population. This was associated with reduced circulating lymphocytes and natural killer cells, peripheral cytokine patterns suggestive of a 'cytokine storm' and increased concentrations of cytokines associated with monocyte egress from the bone marrow. Gene expression array did not differentiate patient outcome. At day 4, there was no significant difference in monocyte, lymphocyte or natural killer cells between survivors and the patients with adverse outcomes.
  
  
  
  Severe paracetamol liver failure is associated with profound changes in the peripheral blood compartment, particularly in monocytes, related with worse outcomes. This is not seen in patients with non-paracetamol-induced liver failure. Significant monocytopenia on admission may allow earlier clarification of prognosis, and it highlights a potential target for therapeutic intervention.
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: J K
authors.initials: JK
authors.lastname: Moore
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: MacKinnon
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: T Y
authors.initials: TY
authors.lastname: Man
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Manning
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Forbes
authors.affiliation: Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Simpson
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000150:complications / Q000175:diagnosis* / Q000401:mortality; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced* / Q000150:complications / Q000175:diagnosis* / Q000401:mortality; D017114:Liver Failure, Acute / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis / Q000401:mortality; D016031:Liver Transplantation / Q000009:adverse effects / Q000401:mortality; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000473:pathology*; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D018712:Analgesics, Non-Narcotic; D016207:Cytokines; D000082:Acetaminophen