Coursework

Consequences of Hepatitis B virus (HBV) infection on the histopathological appearance of the liver.

The Hepatitis B Virus (HBV) is believed to have infected approximately a third of the global population, causing 1-2 million deaths annually (Murray et al. 2002), although this number is in decline since the introduction of an effective vaccine. Part of the Hepadnaviridae, HBV has a partially double-stranded deoxyribonucleic acid genome (dsDNA).

It is highly infectious, and can be spread via blood, semen, vaginal secretions, saliva, milk and tears. Once infected, there is an incubation time of 4-26 weeks (average 8) before symptoms of acute disease are observed. Viral replication occurs in the hepatocytes of the liver and results in a number of outcomes, depending on the patient’s immunocompetence and viral load. The virus is not directly cytopathic; during replication viral antigens, such as HBsAg and HBcAg (surface and core antigens, respectively), are presented at the hepatocyte surface in association with MHC class I molecules. This leads to activation of cytotoxic T lymphocytes (CD8+), which initiate cell destruction and inflammation. Despite the damage caused to the liver this reaction is often adequate to remove the infection. If the response is inadequate, the virus will remain, leading to a carrier state, persistent infection or chronic hepatitis (Jung & Pape 2002). The histopathology of the possible outcomes is discussed below.

ACUTE HEPATITIS

Hepatocyte attack by the immune system results in widespread hydropic degeneration, observed as ‘ballooning’ of the cells, which appear swollen and rounded. This progresses to focal necrosis, which can be observed throughout the liver lobule. Loss of these cells, as well as regeneration and swelling, leads to disruption of the liver tissue architecture and is marked by aggregates of inflammatory cells, predominately macrophages, which scavenge the dead material. Apoptosis initiated by cytotoxic T lymphocytes causes cells to shrink and become highly eosinophilic ‘Councilman bodies’, which are the remains of the hepatocyte cytoplasm, following nuclear removal by pyknosis or karryorhexis. These are then cleared from the cell plate to leave a gap. This is sometimes referred to as ‘drop out’, and is not associated with a marked inflammatory response (Wight 1994). In severe cases bridging necrosis may occur as tracts of confluent cells between portal and central veins are destroyed.

Cholestasis is an inconsistent feature of acute disease, observed as discolouration of hepatocytes due to bile and bile plugs in the caniculi. Epithelial cells of the bile ducts may undergo a ductular reaction and begin to proliferate. Another inflammatory characteristic of acute hepatitis is the proliferation of Kuppfer cells, especially in the portal tracts. Extension of this infiltrate, which contains a mixture of inflammatory cells, into the adjacent periportal tissue leads to ‘interface hepatitis.’

FULMINANT HEPATITIS

A very small proportion of cases of acute disease will progress to fulminant hepatitis, which is characterised by massive hepatocyte necrosis and variable inflammation and has a poor prognosis. On histological section, the portal tracts and terminal hepatic veins are closer together, due to the loss of so much liver tissue. Some ductular regeneration is also usually evident, along with inflammatory cell infiltrate.

CHRONIC HEPATITIS

If the immune response during the acute hepatitis is insufficient to clear the infection, and the virus persists to cause inflammation for more than 6 months, the condition becomes chronic (Stevens et al. 2002). Some features of acute hepatitis continue in chronic hepatitis, such as portal infiltrates of predominately lymphocytes and macrophages, bile duct epithelial reaction, interface hepatitis and bridging necrosis, and are accentuated microscopically by the deposition of fibrous tissue. Fibrosis is irreversible and replacement of necrosed areas of lobular hepatocytes, in the portal tracts or within the septa between lobules will cause architectural disruptions and may eventually progress to cirrhosis.

A distinctive feature of chronic hepatitis caused by HBV is the presence of ‘ground-glass’ hepatocytes, which have a pale, granular cytoplasm with the nucleus displaced to the cell periphery. This is due to the endoplasmic reticulum, which has been shown by immunostaining to be engorged with viral surface proteins, such as HBsAg (Huang & Yen 1993), produced during viral replication. In cases of reactivation of viral replication of a chronic persistent infection with HBV, histopathological signs of acute hepatitis will be seen superimposed on top of changes resulting from chronic hepatitis. The severity of both is likely to vary between individuals.

CIRRHOSIS

Some cases of chronic hepatitis will progress to the end-stage condition of cirrhosis. This is characterised by nodules of regenerating hepatocytic tissue and fibrous dividing bands. HBV usually results in macronodular cirrhosis, with nodules of several centimetres in diameter. As well as reducing the amount and architecture of the remaining hepatic tissue, the fibrosis also affects blood flow through the liver. This can result in portal hypertension, with increased pressure in the portal vein leading to the formation of anastomoses, called varices. Many features of chronic hepatitis also continue to be observable, such as varying numbers of chronic inflammatory cells in the portal areas and in the hepatocyte nodules.

HEPATOCELLULAR CARCINOMA

HBV infection is associated with an increased risk of developing hepatocellular carcinoma, especially following neonatal infection. This is due to the ability of the viral genome to integrate itself into the host DNA, disrupting the function of adjacent oncogenes (Koike et al. 2002), which causes transformation of the cell. This does not initiate tumour formation directly, but increases the likelihood that secondary events, such as cumulative oxidation or alcohol damage, will lead to the cell becoming cancerous. Histologically, hepatocellular carcinomas (HCC) can be unifocal, mulifocal or diffusely infiltrative and can range from well-differentiated to anaplastic.

CONCLUSION

Infection with hepatitis B virus can result in a number of possible outcomes, from acute hepatitis, fulminant hepatitis, chronic hepatitis and cirrhosis, as well as increasing the likelihood of developing hepatocellular carcinoma. Each possible stage of the infection can be identified by characteristic histopathological features.

REFERENCES

Huang, Z. M. & Yen, T. S. 1993 Dysregulated surface gene expression from disrupted hepatitis B virus genomes. J Virol 67, 7032-40.

Jung, M. C. & Pape, G. R. 2002 Immunology of hepatitis B infection. Lancet Infect Dis 2, 43-50.

Koike, K., Tsutsumi, T., Fujie, H., Shintani, Y. & Kyoji, M. 2002 Molecular mechanism of viral hepatocarcinogenesis. Oncology 62 Suppl 1, 29-37.

Kumar, V., Abbas, A.K., Fausto, N. 2005. 2005 Pathologic Basis of Disease. 7th edition. Chapter 18. Pennsylvania, USA: Elsevier Saunders. pp.891-902, 924-925.

Stevens, A., Lowe, J.S., Young, B. 2002 Wheater’s Basic Histopathology: a colour atlas and text. 4th edition. Churchill Livingstone: London. pp.155-162.

Wight, D. G. D. 1994 Symmer’s Systemic Pathology. Vol. 11: Liver, Biliary Tract and Exocrine Pancreas. 3rd Ed. Churchill Livingstone: London. pp.24-26, 153-157.