Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine University, Düsseldorf, Germany.
Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis and is seen as the clinical manifestation of a low grade cerebral edema associated with oxidative-nitrosative stress. However, comprehensive data on HE-associated molecular derangements in human brain are lacking. In the present study we used a whole human genome micro-array approach for gene expression profiling in post mortem brain samples from cirrhotic patients with or without HE and non-cirrhotic controls. Altered expression levels were found for a total of 1012 genes in liver cirrhotic patients without and with HE and HE-characteristic gene expression changes were identified. Genes with altered expression pattern in HE were related to oxidative stress, microglia activation, receptor signalling, inflammatory pathways, cell proliferation and apoptosis. Despite an up-regulation of genes associated with microglia activation, pro-inflammatory cytokine mRNA profiles remained unchanged in the brain of patients with liver cirrhosis and HE as compared to controls. Interestingly, many genes counteracting pro-inflammatory signalling and inflammatory cytokine expression were up-regulated in the cerebral cortex of patients with liver cirrhosis and HE. It is concluded that pathogenetic mechanisms of HE deduced from cell culture and animal experiments, such as oxidative stress, altered Zn(2+) -homeostasis and microglia activation also apply to human brain from patients with liver cirrhosis and HE. The study also revealed a not yet recognized increased expression of genes antagonizing pro-inflammatory signalling and inflammatory cytokine expression.