Impact of Toll-like Receptors 2(TLR2) and TLR 4 Gene Variations on HCV Susceptibility, Response to Treatment and Development of Hepatocellular Carcinoma in Cirrhotic HCV Patients.

Background and Aims: Genetic polymorphisms of Toll-like receptors (TLRs) have been proposed to affect susceptibility to HCV infection and progression to end-stage liver disease. This study was conducted to clarify the association of SNPS of TLR2 and TLR4 with clinical outcome of hepatitis C, response to treatment and development of HCC.Methods: The current study examined 3295 individuals from 725 families that were categorized into groups comprising chronic HCV (CH), spontaneous viral clearance (SC) and control subjects. Treated patients were classified into responders (RT) and non-responders (NRT). In addition, patients with liver cirrhotic (LC), and hepatocellular carcinoma (HCC) were also included. All subjects were genotyped for five single nucleotide polymorphisms (SNPs) of TLR2 and four SNPs of TLR4 and their haplotypes using allelic discrimination real-time PCR.Results: Results demonstrated strong association with allele A of rs13105517 of TLR2 and allele C of rs10116253 of TLR4 with CH in comparison to SC group. However, The peak of risk of HCC was observed with allele C of rs3804099 of TLR2 and C allele of rs10116253 TLR4 (p < 0.001).A strong association was found with allele T of rs1816702 of TLR2 and allele A of rs5030728 of TLR4 in non responder group in comparison to responders (p < 0.001). Haplotypes CAGT of TLR4 and ATAC of TLR2 showed significant association with CH and HCC groups in comparison to other groups.Conclusions: This study shows an association of minor alleles of TLR2 and TLR4 with outcome of HCV infection, response to therapy and development of HCC in cirrhotic patients.

Interrelationship between Toll-like receptors and infection after orthotopic liver transplantation.

Early microbial recognition by the innate immune system is accomplished by Toll-like receptors (TLRs), with resultant initiation of a pro-inflammatory response against infecting organisms. In spite of presence of an abundance of Toll-like receptors on the surface of the liver, gut bacteria does not elicit an inflammatory reaction in healthy individuals due to tolerance to these TLRs, suggesting that the inflammatory responses seen in the liver are the result of breakdown of this tolerance. While orthotopic liver transplantation is often life saving in many instances, death following this procedure is most commonly due to infection that occurs in up to 80% of transplant recipients, most commonly due to microbial causes in up to 70% of cases and viral infections in 20%, while fungal infections affect only 8% of cases. The probability of acquiring infection following hepatic transplantation is heightened due to affection of the innate immune defense mechanisms of the host following this procedure. Single nucleotide polymorphisms of TLRs have been associated with increased likelihood of either development of post-transplant infection or eradication of infecting organism. However, conflicting reports from other studies reveal that prevalence of this single nucleotide polymorphism is not increased in infected patients.