PATHOGENESIS OF INFECTION — The pathogenesis of HBV-related liver disease is largely due to immune-mediated mechanisms. In some circumstances, HBV can also cause direct cytotoxic liver injury.
Immune-mediated liver injury — Both innate and adaptive immune responses contribute to immune control of HBV infection, although the T cell response is a double-edge sword playing a role in both immune control as well as liver injury [2,4-7]. HBV-related liver disease is generally thought to be related to cytotoxic T cell-mediated lysis of infected hepatocytes. However, the noncytolytic T cell immune response is also important. The following observations are consistent with this hypothesis:
●Events associated with immune clearance, such as spontaneous or interferon-induced HBeAg seroconversion, are often accompanied by exacerbations of liver disease as evidenced by an elevated serum ALT [8,9]. ●Patients with chronic hepatitis B who clear HBeAg have more vigorous cytotoxic T lymphocyte responses to HBV antigens than those who remain HBeAg positive [10]. However, in HBeAg-positive patients the T cell response to HBV among those in the immune tolerance phase is not necessarily weaker than the T cell response among those in the immune active phase. Thus, the difference between these two phases is in the inflammatory response and not the T cell response [11]. ●Fulminant hepatitis B is believed to be due to massive immune-mediated lysis of infected hepatocytes. This explains why many patients with fulminant hepatitis B have no evidence of HBV replication at presentation. In addition to promoting hepatic injury, both the T cell and antibody responses to HBV help to control the infection. In one study, for example, HBV-specific cytotoxic T cells from patients studied up to 23 years after clinical and serologic recovery expressed activation markers indicating recent contact with HBV antigens [12]. This observation suggests that complete eradication of HBV rarely occurs after recovery from acute hepatitis and that traces of virus can maintain the T cell response for decades following clinical recovery, which in turn keeps the virus under control [12,13].
In a study of five patients who were identified during the incubation phase of acute HBV infection, NK cell activation was detected first followed by HBV-specific T cell response [14]. The presence of HBV-specific CD8+ and CD4+ cells during the incubation phase suggests that these cells play an important role in the control of infection and in the initiation of events that lead to liver damage. Maximal reduction in HBV-DNA levels occurred prior to peak increase in serum ALT levels, suggesting that viral control is mediated through noncytolytic as well as cytolytic mechanisms.
Direct cytotoxic liver injury — HBV is generally not a cytopathic virus. In most patients with chronic hepatitis B, for example, there is no direct correlation between viral load and the severity of liver disease. This is particularly true during the early phase of perinatally acquired HBV infection in which there is high serum HBV DNA but normal serum ALT concentrations [15]. Nevertheless, direct cytopathic liver injury can occur when the viral load is very high as in fibrosing cholestatic hepatitis, an unusual form of liver disease seen in some patients with recurrent hepatitis B following liver transplantation [16].
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Date: 2017-08-01 08:26 pm (UTC)PATHOGENESIS OF INFECTION — The pathogenesis of HBV-related liver disease is largely due to immune-mediated mechanisms. In some circumstances, HBV can also cause direct cytotoxic liver injury.
Immune-mediated liver injury — Both innate and adaptive immune responses contribute to immune control of HBV infection, although the T cell response is a double-edge sword playing a role in both immune control as well as liver injury [2,4-7]. HBV-related liver disease is generally thought to be related to cytotoxic T cell-mediated lysis of infected hepatocytes. However, the noncytolytic T cell immune response is also important. The following observations are consistent with this hypothesis:
●Events associated with immune clearance, such as spontaneous or interferon-induced HBeAg seroconversion, are often accompanied by exacerbations of liver disease as evidenced by an elevated serum ALT [8,9].
●Patients with chronic hepatitis B who clear HBeAg have more vigorous cytotoxic T lymphocyte responses to HBV antigens than those who remain HBeAg positive [10]. However, in HBeAg-positive patients the T cell response to HBV among those in the immune tolerance phase is not necessarily weaker than the T cell response among those in the immune active phase. Thus, the difference between these two phases is in the inflammatory response and not the T cell response [11].
●Fulminant hepatitis B is believed to be due to massive immune-mediated lysis of infected hepatocytes. This explains why many patients with fulminant hepatitis B have no evidence of HBV replication at presentation.
In addition to promoting hepatic injury, both the T cell and antibody responses to HBV help to control the infection. In one study, for example, HBV-specific cytotoxic T cells from patients studied up to 23 years after clinical and serologic recovery expressed activation markers indicating recent contact with HBV antigens [12]. This observation suggests that complete eradication of HBV rarely occurs after recovery from acute hepatitis and that traces of virus can maintain the T cell response for decades following clinical recovery, which in turn keeps the virus under control [12,13].
In a study of five patients who were identified during the incubation phase of acute HBV infection, NK cell activation was detected first followed by HBV-specific T cell response [14]. The presence of HBV-specific CD8+ and CD4+ cells during the incubation phase suggests that these cells play an important role in the control of infection and in the initiation of events that lead to liver damage. Maximal reduction in HBV-DNA levels occurred prior to peak increase in serum ALT levels, suggesting that viral control is mediated through noncytolytic as well as cytolytic mechanisms.
Direct cytotoxic liver injury — HBV is generally not a cytopathic virus. In most patients with chronic hepatitis B, for example, there is no direct correlation between viral load and the severity of liver disease. This is particularly true during the early phase of perinatally acquired HBV infection in which there is high serum HBV DNA but normal serum ALT concentrations [15]. Nevertheless, direct cytopathic liver injury can occur when the viral load is very high as in fibrosing cholestatic hepatitis, an unusual form of liver disease seen in some patients with recurrent hepatitis B following liver transplantation [16].