TLR4 and chronic hepatitis B virus infection: Given the constant stimulation of hepatic TLR4 with gut-derived LPS the liver is thought to have developed tolerance mechanisms to limit hyperactivation of the immune system.21 However, recent studies demonstrate a loss of TLR tolerance in macrophages from chronic hepatitis B and C-infected patients, reporting an association between LPS-induced macrophage activation and progression to endstage liver disease.22,23 It is interesting to note that alcohol24 and HIV coinfection25 are both associated with increased levels of plasma LPS.