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Liver failure
PTU-003 Circulating levels of Interleukin-18 correlate with severity following human acute liver injury
  1. D G Craig1,
  2. A Conway-Morris2,
  3. P Lee3,
  4. A Pryde3,
  5. J Simpson2,
  6. P C Hayes3,
  7. K J Simpson3
  1. 1Scottish Liver Transplantation Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
  2. 2MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
  3. 3Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, UK

Abstract

Introduction Excessive innate immune activation may precipitate multiorgan failure following paracetamol overdose (POD). Identification of amplification loops in this process could reveal novel therapeutic targets. Interleukin (IL)-18 is a potent proinflammatory cytokine which stimulates downstream T helper-1 cell responses and may trigger loss of regulatory natural killer (NK) cells.

Methods Consecutive patients (n=46, (19 (41.3%) male) admitted to the Royal Infirmary of Edinburgh with paracetamol-induced acute liver injury (ALT>1000 IU/l and coagulopathy) were enrolled. IL-18 levels were measured by ELISA. Immunophenotypic analysis of circulating lymphocytes was determined in whole blood by fluorescence-activated cell sorter (FACS) analysis.

Results A total of 29/46 (63.0%) PODs developed hepatic encephalopathy (HE), and therefore acute liver failure. IL-18 levels were significantly higher in PODs (median 457 (IQR 340–671) pg/mL, n=46) compared with chronic liver disease (292 (192–591) pg/ml, n=15, p<0.05) and healthy (163 (90–191) pg/ml, n=13, p<0.001) controls. Admission IL-18 levels in PODs correlated with both pro- and anti-inflammatory cytokines such as IL-6 (Spearman's r=0.491, p=0.001) and IL-10 (r=0.360, p=0.019), with markers of T-cell (IL2-sRα, r=0.567, p<0.0001) and macrophage (neopterin, r=0.422, p=0.015) activation, and with organ failure scores (SOFA, r=0.485, p=0.0007; APACHE II, r=0.466, p=0.001). Admission IL-18 levels were significantly higher in PODs who developed HE (p=0.0006) or the systemic inflammatory response syndrome (p=0.038), and in PODs who died/required emergency liver transplantation (OLT, p=0.020; AUC 71.4% (95% CI 55.4% to 87.4%). Flow cytometry analysis of peripheral blood lymphocytes revealed a significant decrease in the proportion of CD3-/CD56+ NK cells, with rapid recovery following OLT.

Conclusion IL-18 is associated with innate immune activation and adverse outcomes following POD. Future animal studies should explore IL-18 and NK cell modulation following POD.

Competing interests None declared.

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