Correlation of hepatocyte HBsAg expression with virus replication and liver pathology

Abstract

To elucidate the biologic significance of hepatocyte HBsAg, its expression patterns were correlated with virus replication and liver pathology in 578 liver biopsies taken from chronic HBsAg carriers aged 1 to 80 years. Five major patterns of hepatocyte HBsAg were identified: homogeneous [intense and discrete, (Pattern A), faint and discrete, (Pattern B) and faint and grouped (Pattern C)]; globular or spotty (Pattern D), and marginal (Pattern E). Pattern A was always associated with viremia and also very frequently with membrane HBsAg expression, but rarely with active liver disease. It occurred most commonly in HBeAg-positive carrier children and young adults, reflecting an early immune tolerance phase with active virus replication. Pattern B was also usually associated with viremia, but very commonly associated with active disease (70%), reflecting active virus replication with enhanced immune response. Pattern E (marginal HBsAg), which was always in group distribution resembling a clonal expansion, predominated the HBeAg-negative phase and was associated with absence of viremia and occurred mostly in older adults with inactive bipolar disease spectrum (normal liver/mild disease or cirrhosis/hepatocellular carcinoma); this reflects a late phase of inactive virus replication or integration. Patterns C and D did not correlate well with viremia, but also tended to have inactive diseases as did Pattern E. These findings suggest that hepatocyte HBsAg expression is closely related to the natural course of chronic hepatitis B virus infection.

Prevalence and significance of hepatitis B virus (HBV) pre-S mutants in serum and liver at different replicative stages of chronic HBV infection

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] At the early replicative stage or in patients with acute exacerbation of chronic HBV carriers, the expression of HBsAg manifests an inclusion-like pattern in classic GGH, which usually distribute singly in liver sections. [8][9][10] After the HBeAg seroconversion or at the nonreplicative stage, however, a novel expression pattern of marginal type HBsAg emerges and the HBsAg-expressing hepatocytes usually cluster in groups. 9,10 The molecular basis of the differential expression patterns of HBsAg at different replicative stages remains unexplored.…”

“…Contrary to that at the active replicative stage, the HBsAg-containing hepatocytes are inversely increased and clustered in groups at the late or nonreplicative stage, usually associated with an absence of intrahepatic HBcAg expression. [9][10][11] The underlying mechanism of the life-long persistence of serum HBsAg and the novel discrepancy between the levels of HBsAg in serum and liver have not yet been clarified. In the past years, many studies have documented the accumulation of pre-S1 or large surface antigen in the hepatocytes during chronic HBV infection.…”

“…The majority of acute HBV infection are usually self-limited, whereas patients with chronic HBV infection usually pursue a life-long course that can be categorized into 3 phases based on the replicative status of HBV in serum and liver. [1][2][3][4][5][6][7][8][9] In the early or high replicative phase, there are high levels of hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), and HBV DNA in serum and an active replication of HBV genome with nuclear expression of core antigen (HBcAg) in liver. 3,[8][9][10] The HBsAg-expressing hepatocytes or ground glass hepatocytes (GGH) are usually singly scattered in distribution.…”

“…[1][2][3][4][5][6][7][8][9] In the early or high replicative phase, there are high levels of hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), and HBV DNA in serum and an active replication of HBV genome with nuclear expression of core antigen (HBcAg) in liver. 3,[8][9][10] The HBsAg-expressing hepatocytes or ground glass hepatocytes (GGH) are usually singly scattered in distribution. In the intermediate or immune clearance phase, there is an HLA-restricted cytotoxic T lymphocyte (CTL) response to viral antigen-expressing hepatocytes, which may result in a decrease of HBeAg and HBV DNA in serum.…”

Hepatitis B virus infection and primary hepatocellular carcinoma

“…In transgenic mice making HBsAg, spleen cells from nontransgenic syngeneic mice previously immunized with purified HBsAg particles were capable of recognizing and destroying host HBsAg-positive hepatocytes (237). However, the facts that there is no correlation between HBsAg expression and liver abnormalities (3,152,283) and that HBsAg-specific T cells have not been detected in patients with CAH (75,76,385) suggest that HBsAg is not a target for cellular immune responses under most circumstances during infection. Alternatively, the finding that prolonged overproduction of HBsAg by transgenic mice results in massive hepatic necrosis, extensive cellular inflammatory responses, widespread hepatocellular regeneration, and, finally, PHC (50, 51) implies that high levels of antigen production could be directly cytotoxic and that the accompanying regeneration could be important to the creation and propagation of preneoplastic nodules.…”