Plasma angiopoietin 2 as a novel prognostic biomarker in alcohol- related cirrhosis and hepatitis

Background and aim:Severe alcoholic hepatitis(SAH),the most florid form of alcohol-related liver dis-ease(ALD),has a mortality rate of 16%at 28 days.The angiopoietin-Tie 2 system regulates angiogenesis and inflammation,both of which are implicated in the pathogenesis of ALD.This study examined plasma and hepatic gene expression of angiopoietin 1(ANG1)and angiopoietin 2(ANG2)in patients with SAH and ALD and investigated their roles as prognostic biomarkers.Methods:A case-control study was performed measuring plasma levels of ANG1 and ANG2 by enzyme-linked immunosorbent assay(ELISA)from 30 patients with SAH(Maddrey's discriminant function32),32 patients with ALD cirrhosis and 15 healthy controls(HC).RNA sequencing for ANG1,ANG2,TIE1(codes for Tie1 receptor)and TEK(codes for Tie2 receptor)gene expression from a separate cohort study of 79 patients was also performed.Results:Plasma levels of ANG1 were lower(P=0.010)and ANG2 were higher(P<0.0001)in patients with ALD/SAH compared to HC.The ANG2:ANG1 ratio was higher in those with ALD/SAH compared to HC(P<0.0001).ANG2 levels were the highest in patients who developed sepsis(P=0.030)and those dying within 90 days(P=0.020).ANG2 levels correlated positively with model for end-stage liver disease(MELD)score(r=0.30,P=0.020),Child-Pugh score(r=0.38,P=0.003),international normalized ratio(r=0.41,P=0.001)and white blood cell count(r=0.28,P=0.040)and inversely correlated with albumin(r=0.26,P=0.040).ANG1 gene expression from liver biopsies was higher in SAH than that in HC(P<0.0001),and greater in severe disease(P<0.0001).ANG2 gene expression trended towards being lower in SAH than that in HC(P=0.070)though was upregulated in severe disease(P=0.0003).Conclusions:Plasma ANG2 is raised in SAH and ALD and could be useful as a prognostic biomarker in this patient population.