TUMOR-NECROSIS-FACTOR GENOMIC POLYMORPHISM AND OUTCOME OF ACETAMINOPHEN (PARACETAMOL)-INDUCED ACUTE LIVER-FAILURE

Background/Aims: High levels of tumor necrosis factor-alpha are associ ated with an increased risk of severe encephalopathy in acute liver fa ilure, and experimental studies suggest that tumor necrosis factor-alp ha plays a role in the development of acetaminophen (paracetamol)-indu ced liver injury and associated multiple organ failure. Inter-individu al variations in the production of tumor necrosis factor-alpha have be en linked to genomic polymorphisms within the tumor necrosis factor-al pha locus. This study examined whether specific tumor necrosis factor polymorphisms are associated with variations in the severity of clinic al features in acetaminophen-induced acute liver failure. Methods: Gen otypes at the -308 tumor necrosis factor A and tumor necrosis factor B Nco1 polymorphic sites were determined in 97 patients with severe ace taminophen-induced hepatotoxicity and 109 controls, using polymerase c hain reaction and restriction fragment length polymorphism. The relati onship between liver injury, multiple organ failure and encephalopathy , determined retrospectively from clinical notes and genotype, was exa mined. Results: No significant association was found between either tu mor necrosis factor A or B genotype and parameters for multiple organ failure or liver injury. The tumor necrosis factor B1B1 genotype was s ignificantly under-represented in those patients developing severe enc ephalopathy (p=0.03) and a multivariate logistic regression analysis c onfirmed the influence of tumor necrosis factor B genotype (p<0.01), T he association was independent of the HLA class II allele DRB103, whi ch is closely linked to the TNFB locus. Conclusions: The development o f acute liver failure is unlikely to be primarily sepsis driven. Howev er, the apparent protective effect of the tumor necrosis factor B1B1 g enotype on the development of severe encephalopathy may be related to the effects of this genotype on tumor necrosis factor-alpha production in sepsis.