Tehran University Medical Journal

Hepatitis B virus (HBV) is an etiological agent of hepatitis B infection. Hepatitis B is a life-threatening disease that affects the liver. The clinical outcomes of the disease are varied from asymptomatic disease to serious complication such as cirrhosis and hepatocellular carcinoma (HCC). Despite availability of the vaccine and appropriate treatment, hepatitis B infection still remains a major public health problem worldwide. Based on WHO reports, over 887.000 people die annually from hepatitis B complication including cirrhosis and hepatocellular carcinoma. Hepatitis B is very contagious and spreads through infected blood, body fluids, mother to baby during birth, contaminated needle and between sexual partners. HBV uses sodium taurocholate cotransporting polypeptide (NTCP) receptor to enter hepatocytes and by replicating in these cells interferes with liver functions. In fact liver damage is as result of virus multiplication and activation of immune responses especially virus-specific cytotoxic T lymphocytes (CTLs) against infected cells. CTLs and CD4Th1 cells by killing infected cells and releasing antiviral cytokines control virus replication in infected individuals. Also, the functions of these cells in patients who successfully clear the infection are potentially strong. In contrast to acute self-limited HBV infection in persistent HBV infection, these cells are exhausted. Several studies have showed that the great challenge in clearance of the HBV infection is related to stability of covalently closed circular DNA (cccDNA). cccDNA produce in viral life cycle and remains inside the infected cells for a long time and act as a template for generating new pre-genomic RNA and virus propagation. So far, no antiviral treatment has been effective in the complete elimination of this structure. Prevention of the disease can be achieved by using effective vaccine. Previous studies indicated that neutralizing antibodies against surface antigen of the virus known as S antigen have protective properties. Therefore, a subunit vaccine containing S antigen is available. Currently S antigen is produced in recombinant form and WHO recommended the first dose should be given within a day of birth. Pegylated IFN-γ and nucleotide-nucleoside analogues are effective drugs against HBV infection, but they may have severe side effects. Ineffectiveness of the vaccine on premature infants and immunocompromised people and also drug side effects has made HBV infection a great trouble.
 

Background: Hepatic encephalopathy is defined as a neuropsychiatric brain dysfunction in acute or chronic liver failure. Infection and inflammation have crucial role in its pathophysiology. The purpose of our study was to demonstrate the relationship between toll-like receptor 4 (TLR4) expression and the encephalopathy induced with endotoxin in biliary cirrhotic rats.
Methods: The present study was conducted experimentally on male adult Wistar albino rats from May to January 2018 at the Pharmacology Department of Medical Faculty, Tehran University of Medical Sciences, Tehran, Iran. The animals were divided into two groups, cirrhotic vs sham-operated. Cirrhosis was induced by surgical ligation of the bile duct in male Wistar rats but in sham group the bile duct was not ligated during abdominal surgery (control). The animals in each group were divided to two subgroups that half of them were given intraperitoneally saline or low dose of endotoxin (0.1 mg/kg) on day 29. Then animal behavior study was done on the clinical sign of hepatic encephalopathy. Also, the histopathology of brain cortex and the expression of brain cortex toll-like receptor four protein were evaluated.
Results: Our results showed that endotoxin treatment decreased the patient's level of alertness and produced hepatic encephalopathy signs in cirrhotic rats and control groups. Cirrhosis increases toll-like receptor four expression in brain and acute endotoxin treatment increases toll-like receptor four expression in this group still more. It means that acute endotoxin treatment-induced clinical signs of acute encephalopathy in sham and cirrhotic rats and significant toll-like receptor four overexpression in cirrhotic animals. The histopathological assessment did not show a significant difference between the groups and did not show any changes after induction of cirrhosis and/or acute endotoxin treatment.
Conclusion: Cirrhosis and acute low dose endotoxin injection in cirrhotic rats induced hepatic encephalopathy signs that parallels with significant increased toll-like receptor 4 protein expression in brain cortex. Since the severity of the signs of encephalopathy was the same as intact animals, based on the definitions in pharmacology, in the cells of cirrhotic groups endotoxin tolerance has developed.