Circulating markers of endothelial activation in acetaminophen induced acute liver failure

Background

Once defined clinical criteria are fulfilled, survival following acetaminophen overdose is very poor without emergency liver transplantation. The early identification of patients developing multiple organ failure (MOF) is important for prompt listing for transplantation. MOF is associated with early elevations of the circulating markers of endothelial activation E-Selectin, VCAM-1 and ICAM-1 and Von Willebrand Factor (VWF). We determined their levels and those of Interleukin-6 (IL-6) on admission in acetaminophen overdose patients, to evaluate their use in the identification of those who would require transplantation.

Patients

Nine healthy controls and 20 patients were studied. Eleven patients became encephalopathic and seven patients either died or required emergency liver transplantation.

Methods

E-selectin, VCAM, ICAM, IL-6 and VWF were determined on admission using commercial ELISA. Statistical testing used Mann-Whitney U tests and Spearmans Rank correlation. Results were corrected for multiple testing.

Results

All molecules assayed were significantly higher in patients than controls (P_c < 10^-4). IL-6 alone was higher in non survivors than survivors [158 pg/ml (range 22–440) vs 32 pg/ml (3.5–177), P_c < 0.05]. Adhesion molecule levels were consistent with multiple organ failure of a non-septic aetiology. VWF was elevated in those patients who became encephalopathic : 371 U/dl (149–658) vs 178 U/dl (65–340), P < 0.04 and correlated strongly with mean arterial pressure (r = 0.664, P < 0.005).

Conclusions

ICAM, VCAM and E-selectin are poorly predictive of outcome in ALF, but suggest a non-septic aetiology of MOF. The pathogenesis of encephalopathy may involve endothelial activation and cardiovascular dysfunction. IL-6 appears the most useful early marker of a poor outcome in ALF.