Tumor necrosis factor genomic polymorphism and outcome of acetaminophen (paracetamol)-induced acute liver failure

Background/Aims: High levels of tumor necrosis factor-alpha are associated with an increased risk of severe encephalopathy in acute liver failure, and experimental studies suggest that tumor necrosis factor-alpha plays a role in the development of acetaminophen (paracetamol)-induced liver injury and associated multiple organ failure. Inter-individual variations in the production of tumor necrosis factor-alpha have been linked to genomic polymorphisms within the tumor necrosis factor-alpha locus. This study examined whether specific tumor necrosis factor polymorphisms are associated with variations in the severity of clinical features in acetaminophen-induced acute liver failure. Methods: Genotypes at the -308 tumor necrosis factor A and tumor necrosis factor B Nco1 polymorphic sites were determined in 97 patients with severe acetaminophen-induced hepatotoxicity and 109 controls, using polymerase chain reaction and restriction fragment length polymorphism. The relationship between liver injury, multiple organ failure and encephalopathy, determined retrospectively from clinical notes and genotype, was examined. Results: No significant association was found between either tumor necrosis factor A or B genotype and parameters for multiple organ failure or liver injury. The tumor necrosis factor B1B1 genotype was significantly under-represented in those patients developing severe encephalopathy (p=0.03) and a multivariate logistic regression analysis confirmed the influence of tumor necrosis factor B genotype (p<0.01), The association was independent of the HLA class II allele DRB1*03, which is closely linked to the TNFB locus. Conclusions: The development of acute liver failure is unlikely to be primarily sepsis driven. However, the apparent protective effect of the tumor necrosis factor B1B1 genotype on the development of severe encephalopathy may be related to the effects of this genotype on tumor necrosis factor-alpha production in sepsis.