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Natural History of Hepatitis B Infection
Submitted by Dr.bisho on Wed, 29/04/2009 - 10:26pm.
Natural History of Hepatitis B Infection
Chronic hepatitis B infection can be divided into 4 distinct phases:
(1) the immune-tolerance phase;
(2) the immune-clearance or immune-active phase;
(3) the inactive carrier phase; and
(4) reactivation. Clinical course is variable, however, and not all patients will experience every phase of infection.
Schematic of different phases of HBV infection.
The immune-tolerance phase is a latent period that typically occurs in individuals from HBV-endemic areas, where infection is most often acquired at birth or during early childhood. Due to incomplete development of the immune system at the time of infection, there is minimal host response to HBV despite high rates of viral replication. As a result, liver inflammation is minimal or absent. Liver disease is rarely progressive during this period and treatment is not effective.In this phase, serum HBV DNA is elevated, hepatitis B e antigen (HBeAg) is present, and alanine aminotransferase (ALT) levels are normal. The immune-tolerance phase can last for as long as 2-3 decades.
In most patients, a more vigorous cytotoxic T-cell response eventually occurs, heralding the immune-clearance phase. Viral replication remains high, and apoptosis and necrosis of hepatocytes occur, leading to elevated serum ALT, liver inflammation, and fibrosis. HBeAg seroconversion can occur during this period, resulting in the appearance of antibodies to HBeAg (anti-HBe) and suppression of viral replication.
In nonendemic areas such as the United States, HBV infection is most often acquired during adulthood, when the immune system is fully constituted. In these areas, the immune-tolerance phase is therefore very short or nonexistent, and immune clearance occurs shortly after infection.
HBeAg seroconversion is usually followed by clinical remission (the inactive carrier phase). This is characterized by normal serum ALT, low HBV DNA, and improvement in liver histology. Treatment is therefore not indicated in this patient group. A minority of inactive carriers will eventually lose hepatitis B surface antigen (HBsAg), resulting in resolution of infection
Conversely, it is not uncommon for patients in the inactive phase to experience reversion to HBeAg positivity or reactivation of disease, either spontaneously or as a result of immune suppression (eg, chemotherapy). This is likely due to the integration of HBV DNA into hepatocyte DNA in the form of covalently closed circular DNA (cccDNA). This can occur despite low or undetectable levels of serum HBV DNA and explains why inactive carriers are still at risk for the development of HCC.
In addition, approximately one third of inactive carriers go on to develop HBeAg-negative chronic hepatitis B.In these patients, mutations in the precore or core promoter regions of viral DNA result in downregulation of HBeAg production despite ongoing viral replication. As a result, high levels of HBV DNA and increased serum ALT are seen even though HBeAg is absent. This mutation occurs most frequently in patients with viral genotypes B, C, and D. HBeAg-negative chronic hepatitis B is associated with a lower rate of spontaneous remission and a poorer long-term prognosis than is HBeAg-positive chronic hepatitis B.
In patients with chronic hepatitis B, either HBeAg-positive or HBeAg-negative, repeated disease flares over time lead to fibrosis, cirrhosis, and carcinogenesis.Treatment is therefore essential in these individuals
