A new role for an old marker, HBsAg

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A new role for an old marker, HBsAg
  Jnl of Hepatology
Volume 52, Issue 4, Pages 475-477 (April 2010)

Maurizia Rossana Brunetto
Liver Unit, University Hospital of Pisa, Italy

published online 01 February 2010.
Refers to article:
Hepatitis B surface antigen levels during the natural history of chronic
hepatitis B: A perspective on Asia , 17 February 2010
Tin Nguyen, Alexander J.V. Thompson, Scott Bowden, Catherine Croagh, Sally Bell, Paul V. Desmond, Miriam Levy, Stephen A. Locarnini
Journal of Hepatology
April 2010 (Vol. 52, Issue 4, Pages 508-513)
Abstract | Full Text | Full-Text PDF (758 KB)

Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: A European perspective , 15 February 2010
Jerzy Jaroszewicz, Beatriz Calle Serrano, Karsten Wursthorn, Katja Deterding, Jerome Schlue, Regina Raupach, Robert Flisiak, C.-Thomas Bock, Michael P. Manns, Heiner Wedemeyer, Markus Cornberg
Journal of Hepatology
April 2010 (Vol. 52, Issue 4, Pages 514-522)
Abstract | Full Text | Full-Text PDF (1061 KB)

Detection in the serum of the "Australia antigen", namely hepatitis B surface antigen (HBsAg), was the Nobel prize discovery that identified hepatitis B virus (HBV) about 40years ago; to this day HBsAg remains the hallmark of overt HBV infection [1], [2]. HBsAg circulates in a wide array of particulate forms: competent virions (42nm, Dane particles), 20nm diameter filaments of variable length, and 20-22nm spherical defective particles, corresponding to empty viral envelopes [3]. Serum HBsAg results from the different combinations of three proteins (small, medium and large), either glycosylated or not, that are specified by a single open reading frame providing 3 carboxy-terminal colinear HBsAg proteins of different length. The small (S) protein (226 amino acids) is expressed at the highest levels, predominates in both virions and subviral particles and is secreted without cleavage of amino acid residues during translocation because of its self-assembling capacity with host-derived lipids in the cell ER [4]. The middle (M) protein (containing 55 extra residues of the pre-S2 domain) is regulated by the same promoter and is similarly secreted, whereas the transcription of the large protein (L) is regulated by a specific but weaker promoter (pre-S1) [5]. Hepatitis B virus large surface protein (L-HBs) containing both the pre-S2 region and the 108-119 additional residues of the pre-S1 domain, is an essential component of both virions and filaments, and represents 10-20% of their envelope proteins. In contrast, the L-HBs represents only 2% of the 22nm spherical particles [6], [7]. The complexity of HBsAg production and secretion is known since the early studies that showed a larger excess of both filaments and spherical subviral particles was present in highly viremic HBeAg positive carriers as compared to low viremic anti-HBe positive carriers, in whom the decline of filaments paralleled that of virions whereas spherical particles remained in moderate excess [8], [9]. Thus, subviral HBsAg particles exceed virions by a variable factor of 102-105 and can accumulate up to concentrations of several hundred micrograms per milliliter of serum [3].

Quantification of HBsAg was introduced more than 20years ago, but only recently has it been significantly improved by new automated quantitative assays [10]. Several studies suggest a new potential role of quantitative serum HBsAg in the prediction of virological response to antiviral therapy, at least in Peg-interferon treated patients [11], [12], [13]. HBsAg appears useful to identify non-responders as early as 12-24weeks after the beginning of treatment and to tailor treatment duration in responders [12], [13]. The correlations between HBsAg and HBV-DNA kinetics are complex and variable in the different treatment settings; the kinetics of the two parameters are dissociated in lamivudine treated patients and relapsers to Peg-interferon, but parallel in sustained responders to Peg-interferon [12], [13]. Preliminary reports on HBsAg and HBV-DNA serum levels in untreated acute and chronic hepatitis B cases confirm such a discrepancy, and little is known about their relative variations along the highly dynamic chronic HBV infection [14].

In this issue of the Journal, two manuscripts provide new insights into serum HBsAg levels during chronic HBV infection in Asian and European cohorts of HBV carriers. The novelty of the works of Nguyen et al. [15] and Jaroszewicz et al. [16] stems from their study on the correlations between HBsAg serum levels and the clinical and virologic features of chronic HBV carriers analysed in different phases of infection according to the most recent criteria. Overall, 434 chronic carriers were studied: 62 immune-tolerant carriers (IT), 103 HBeAg positive patients in the immune-clearance phase (IC), 118 HBeAg negative carriers in the non-/low replicative phase (LC), and 151 patients with HBeAg negative hepatitis (ENH). Two major findings are common in the two studies: (1) median HBsAg levels differ significantly during the 4 phases of HBV infection and decline progressively from IT (4.5-4.96log10IU/ml in Asian and European carriers) to LC (2.86-3.09log10IU/ml in Asian and European carriers); (2) HBsAg/HBV-DNA ratios are significantly higher in LC (1.05 Asian-1.17 European) as compared to all the others patients (ratios range 0.55-0.64). These findings entail that HBsAg secretion is highly dynamic and varies along chronic HBV infection both quantitatively and qualitatively. Accordingly, one intriguing and complex issue remains the correlation between HBsAg and HBV-DNA serum levels. In spite of an overall correlation in the European cohort (R=0.75, p<0.001), the two parameters show weaker or absent correlations when the different phases of HBV infection are analysed separately or by HBV genotype. A negative correlation is reported in genotype A HBeAg positive (IC, R=-0.24) and negative (ENH, R=-0.07) patients, a positive relation in genotype B, C and D ENH, in genotype B and C IT and in genotype A and D LC, but all the correlation coefficients are poor (R ranging from 0.29 to 0.57). On the contrary, in genotype B and C HBeAg positive patients (IC) HBsAg and HBV-DNA serum levels correlate significantly (p=0.0001) and with better coefficient (R=0.77), as well as in 12 European patients with acute hepatitis B (R=0.79). These data suggest direct interactions between HBV genotype, HBsAg serum level and viral load. Accordingly, genotype-specific patterns of expression of intracellular and extracellular viral DNA and antigens were shown by transfection of Huh7 [17]. In vitro, genotype A showed a sharp dissociation between HBsAg and HBV-DNA production, with the highest HBsAg secretion combined with the lowest HBV-DNA production in the culture medium [17]. Larger studies are needed to address the correlations between HBV genotypes and the dynamics of HBsAg serum levels during the different phases of HBV infection. In spite of the possible limitation of genotype interference, it is interesting to note that HBsAg and HBV-DNA serum levels showed their highest correlation in the early phases of immune clearance, namely in acute hepatitis B and in HBeAg positive CHB (IC) [15], [16]. These findings, together with the parallel kinetics of HBsAg and HBV-DNA in patients responding to Peg-IFN treatment [12], [13], suggest that virion and HBsAg antigen production correlate better when they are concordantly inhibited by a strong immune-response resulting in the efficient control of viral replication, namely HBeAg/anti-HBe or HBsAg/anti-HBs seroconversion. If the immune clearance does not succeed in the complete control of HBV infection, leading to HBsAg clearance and anti-HBs seroconversion, HBV infection evolves into the low replicative phase or HBeAg negative CHB. In both conditions, the discrepancy between HBV-DNA and HBsAg production may increase for several reasons but it is primarily due to the production of defective particles that outnumber the virions during the low replicative phase, as already shown in the older studies, where lower amounts of serum L-HBs (the hallmark of the surface protein of the virion and filaments) were found in non-viremic as compared to viremic HBV carriers [8], [9]. The higher HBsAg/HBV-DNA ratios found by Nguyen and Jaroszewicz in LC are consistent with the previous data, suggesting a relatively lower production of virions versus subviral HBs antigens in this subset of carriers. This might depend on a stronger inhibition of pre-genome transcription from intrahepatic cccDNA as compared to the envelope protein mRNAs, or to the defective secretion of virions as a consequence of the emergence of HBV mutants, which are selected by the long lasting immune pressure on the HBsAg gene that may deregulate HBsAg expression with an asymmetric production of S, M and L proteins [18], [19]. Indeed an inverse relationship was reported between serum HBsAg levels and the intrahepatic cytoplasmic storage of HBsAg (ground glass cells) [14]. In fact, overexpression of L-HBs can cause S protein to accumulate in the Golgi complex and to inhibit the secretion of HBsAg particles, as a proper stoichiometry between L and S proteins is required for the secretion of HBsAg and virions [18], [19]. Finally a role of integrated HBV-DNA in the alteration of HBsAg secretion was also advocated [20].



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In conclusion, HBsAg serum levels are the resultant of the complex equilibrium between the virus and the host's immune system as well as the product of the transcription of specific mRNAs rather than viral replication. Thus, we may speculate that serum HBsAg is the indirect expression of transcriptionally active cccDNA rather than total intrahepatic cccDNA. Of course, we cannot exclude a role of integrated HBV-DNA in HBsAg synthesis; however, the evidence that HBsAg serum levels decline significantly with the duration of HBV infection, when the amount of integrated HBV-DNA is supposed to increase, weakens such a hypothesis. The substantial variations of total serum HBsAg in the different phases of HBV infection proposes quantitative HBsAg as a new diagnostic tool for the characterization of the HBV carrier in combination with HBV-DNA. The two HBV markers providing complementary information on the status of HBV infection (Fig. 1) may be very useful in clinical practice to define the specific condition of the single HBV carrier during the highly dynamic phases of chronic HBV infection, just as latitude and longitude allow to define the ship's position in the ocean. This will be of paramount importance to avoid the misclassification of an asymptomatic HBeAg negative CHB patient as an inactive carrier because of a single point serum test with normal transaminases and negative HBV-DNA caused by the typical intermittent disease profile of HBeAg negative CHB.

总之，乙肝表面抗原血清水平是之间的病毒与宿主的免疫系统，以及具体的mRNA转录产物复杂的平衡，而不是病毒的复制造成的。因此，我们可以推测，血清乙肝表面抗原，是不是总肝内转录活跃的cccDNA的cccDNA间接表达。当然，我们不能排除在乙肝表面抗原合成的综合HBV - DNA的作用，但是，有证据表明，乙肝表面抗原血清水平下降与乙肝病毒感染，会期时，综合HBV - DNA的数量应该大大增加，削弱了这种假说。总的HBV感染血清乙肝表面抗原的不同阶段提出的重大变化作为一种新的为乙型肝炎病毒携带者与HBV - DNA的结合HBsAg定量定性诊断工具。乙肝病毒标志物提供了2对乙型肝炎病毒感染（图1）可在临床实践中非常有用的定义在慢性乙肝病毒感染的高动态阶段的单乙肝病毒携带者的具体情况，只是作为补充资料地位经度和纬度允许定义的船舶在海洋中的地位。这将是非常重要，以避免一无症状HBeAg的误判，因为单点转氨酶正常和消极的HBV - DNA的血清试验阴性慢性乙型肝炎患者作为无效承运人典型的HBeAg阴性慢性乙型肝炎间歇性病症引起的。

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