Reduced hepatic injury in Toll-like receptor 4-deficient mice following D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure.

Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), D-galactosamine (GalN)-induced FHF is a well established model of liver injury in mice. Toll-Like Receptor 4 (TLR4) has been identified as a receptor for LPS. The aim of this study was to investigate the role of TLR4 in FHF induced by D-GalN/LPS administration in mice. Wild type (WT) and TLR4 deficient (TLR4ko) mice were studied in vivo in a fulminant model induced by GalN/LPS. Hepatic TLR4 expression, serum liver enzymes, hepatic and serum TNF-α and interleukin-1ß levels were determined. Apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor-kappaß (NF-κ ß) and phosphorylated c-Jun hepatic expression were studied using Western blot analysis. All WT mice died within 24 hours after administration of GalN/LPS while all TLR4ko mice survived. Serum liver enzymes, interleukin-1ß, TNF-α level, TLR4 mRNA expression, hepatic injury and hepatocyte apoptosis all significantly decreased in TLR4ko mice compared with WT mice. A significant decrease in hepatic c-Jun and IκB signaling pathway was noted in TLR4ko mice compared with WT mice. In conclusion, following induction of FHF, the inflammatory response and the liver injury in TLR4ko mice was significantly attenuated through decreased hepatic c-Jun and NF-κB expression and thus decreased TNF-α level. Down-regulation of TLR4 expression plays a pivotal role in GalN/LPS induced FHF. These findings might have important implications for the use of the anti TLR4 protein signaling as a potential target for therapeutic intervention in FHF.

Spontaneous hepatic rupture: 13-year experience of a single center.

BACKGROUND: Spontaneous hepatic rupture is a rare clinical event associated with various pathologies of the liver. Most series to date reported the incidence and characteristics of a single etiology. METHODS: Data were collected for all patients admitted with spontaneous hepatic rupture from 1995 to 2007. RESULTS: Ten patients met the study criteria. Hepatocellular adenoma was the cause of the rupture in six female patients, in their second to fourth decade. In the remaining patients, the ruptures were because of hepatocellular carcinoma in two, metastatic gastrointestinal stromal tumor in one, and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) in one. Nine out of 10 patients were treated surgically. CONCLUSION: Spontaneous hepatic rupture requires a high index of suspicion for a correct and timely diagnosis. Outcome is potentially grave and greatly depends on the underlying condition.

p73 overexpression and nuclear accumulation in hepatitis C virus-associated hepatocellular carcinoma.

p73 is the first identified homolog of p53, but its function has not been established. Our study investigated the expression of p73 in liver tissue of patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC). RT-PCR was performed on RNA extracted from tumorous and nontumorous liver tissue of HCV-associated HCC, and control tissue and the cDNA were sequenced. Anti-p73 polyclonal antibodies were used for protein analysis and immunohistochemistry, and patients' sera were analyzed for anti-p73 antibodies by radioimmunoassay. Analysis of the p53 gene was performed by SSCP and RFLP-PCR. The p73 mRNA and protein were highly expressed and accumulated in HCC tissues. Immunohistochemical studies revealed significant immunoreactivity in the nuclei of HCC cells. No mutations were detected in the p73 gene or in p53, and no loss of heterozygosity of the p53 gene was found. Anti-p73 antibodies were detected in sera of HCC patients, but were not significantly different from that occurring in non-HCV or non-HCC patients. In conclusion, p73 protein is overexpressed and accumulates in the nuclei of HCV-associated HCCs and may play a role in HCC development.