Whatever the virus (hepatitis A, B, C, D or E virus: HAV, HBV, HCV, HDV, HEV), the hepatitis it causes is not produced by the virus destroying liver cells directly. Under ordinary circumstances none of the hepatitis viruses is cytopathic (directly damaging to the cells it infects) for hepatocytes, the liver cells: the damage is produced by the immune response to infected cells. Cytotoxic T cells and natural killer cells recognise viral antigens displayed on the surface of infected hepatocytes and kill them, and the cytokines (signalling proteins) they release recruit inflammation. This single fact explains a paradox at the centre of the topic: the amount of virus does not predict how sick the patient is, because the severity depends on the immune response, not on the viral load (the amount of virus in the blood) alone.
Why some infections clear and others persist
Because the immune response does the damage, it also decides the outcome. The five viruses sit at different points on a spectrum from complete clearance to lifelong persistence.
HAV and HEV are cleared completely. The virus enters through the gut, reaches the liver and replicates there, but the innate and adaptive immune responses eliminate it, so acute infection ends in recovery and lifelong immunity to that virus. Neither causes chronic hepatitis in immunocompetent people; the exception is HEV in immunosuppressed transplant recipients, in whom chronic infection has been reported.
HBV persists because its genome survives in the hepatocyte nucleus as covalently closed circular DNA (cccDNA), a stable template that current drugs suppress but cannot eradicate. Whether infection becomes chronic is decided largely by the age at which it is acquired, and therefore by the balance between immune control and immune tolerance (failure to mount an attack on the virus): the immature immune system of a neonate tolerates the virus, so about 90% of infants infected at birth become chronic carriers, whereas an adult mounts an effective response and clears the virus in about 95% of cases. Flares of hepatitis in chronic HBV are immune-mediated attacks on infected cells.
HCV persists in most people: it evades innate immunity and exhausts the virus-specific T cells that would clear it, so about 70% of infections (range 55-85%) become chronic. Recovery does not confer lasting immunity, so reinfection is possible.
HDV depends entirely on HBV, using the hepatitis B surface antigen as its envelope. It can be acquired at the same time as HBV (co-infection) or as an additional infection in someone already carrying HBV (superinfection). Superinfection is the more dangerous: it accelerates progression to cirrhosis and raises the risk of hepatocellular carcinoma.
When the response is overwhelming
At the far end of the spectrum, an overwhelming immune response produces widespread hepatocyte death, called fulminant hepatitis, with massive necrosis and rapid loss of liver function. It is the same process as ordinary acute hepatitis, but unregulated. Which viruses cause it, and how it presents, is the subject of Complications of Viral Hepatitis.