Association of antioxidant enzyme gene polymorphisms and glutathione status with severe acute pancreatitis

Background & Aims: Genetic variations in antioxidant metabolism may explain varying biological responses to acute pancreatitis (AP). We studied the contribution of oxidative stress to the pathogenesis of severe pancreatitis by examining the prevalence of functional gene polymorphisms of antioxidant enzymes and evidence of heightened oxidative stress. Methods: DNA from 320 patients with AP (90 severe) and 263 controls was genotyped for glutathione S-transferase (Mu-1 [M-1], theta-1 [T-1], and pi-1 [P-1: Ile-105Val]), manganese superoxide dismutase (Ala-9Val), and catalase (C-260T) polymorphisms. Erythrocyte reduced glutathione (GSH) concentration was determined 24 and 72 hours after the onset of pain in 46 patients (11 severe). Disease severity was assessed using Atlanta clinical criteria, Acute Physiology Scores (APS), and peak serum C-reactive protein levels. Results: The functional GSTT-1*A genotype was more prevalent in severe (96%) compared with mild attacks of AP (78%; odds ratio [OR], 5.9; 95% confidence interval [CI], 2-17; P < 0.0001) and controls (76%; OR, 6.6; 95% Cl, 2.3-18.7; P < 0.0001). Compared with null genotype, GSTT-1*A was associated with higher peak C-reactive protein levels (184 vs. 94 g/dL; P = 0.0005) and APS (24 hours, P = 0.04; 48 hours, P = 0.015). Reduced glutathione (GSH) at 24 hours was lower in mild (median, 382 nmol/g) and severe attacks (median, 407 nmol/g) compared with controls (median, 3685 nmol/g; P < 0.001). Levels increased at 72 hours in mild (P = 0.012) but not severe attacks and inversely correlated with APS (r = -0.49; P = 0.04). Conclusions: The functional GSTr-1*A genotype was associated with severe attacks of pancreatitis. Heightened oxidative stress characterized by glutathione depletion may be of importance in mediating the progression from mild to severe pancreatitis.