HBsAg定量测量作为一种新的替代标记+慢性乙肝大三阳肝纤维

StephenW

Focus: Quantitative HBsAg measurement as a new surrogate marker for assessment of hepatic fibrosis in HBeAg+ chronic hepatitis B



    Liver Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel

    http://dx.doi.org/10.1016/j.jhep.2013.03.002, How to Cite or Link Using DOI



Refers To

        Michelle Martinot-Peignoux, Roberto Carvalho-Filho, Martine Lapalus, Ana Carolina Ferreira Netto-Cardoso, Olivier Lada, Richard Batrla, Friedemann Krause, Tarik Asselah, Patrick Marcellin
        Hepatitis B surface antigen serum level is associated with fibrosis severity in treatment-naïve, e antigen-positive patients
        Journal of Hepatology, Volume 58, Issue 6, June 2013, Pages 1089-1095
        PDF (700 K)         

Referred to by

        Michelle Martinot-Peignoux, Roberto Carvalho-Filho, Martine Lapalus, Ana Carolina Ferreira Netto-Cardoso, Olivier Lada, Richard Batrla, Friedemann Krause, Tarik Asselah, Patrick Marcellin
        Hepatitis B surface antigen serum level is associated with fibrosis severity in treatment-naïve, e antigen-positive patients
        Journal of Hepatology, Volume 58, Issue 6, June 2013, Pages 1089-1095
        PDF (700 K)         

Since its discovery in 1967 [1], qualitative hepatitis B surface antigen (HBsAg) has been widely used for diagnosis of hepatitis B virus (HBV) infection. It took almost four decades until the development of an automated reliable, specific and sensitive quantitative HBsAg assay (Architect™, Abbott Diagnosis, USA) with a dynamic range of 0.05–250.0 IU/ml, and which is capable of detecting as low as 0.05 IU/ml HBsAg, corresponding to around 0.2 ng/ml [2]. Another commercially available assay with comparable properties has recently been licensed (Elecsys HBsAg II quant assay, Roche Diagnostics, USA) [3]. These assays detect the intact, wild type infectious virus as well as the two non-infectious forms of the envelope protein, including the small, spheric surface protein (produced in excess of 104–105 over the infectious virion) and the filamentous-tubular particles containing the small, middle and large envelope proteins. The rising interest of the hepatology community in HBsAg quantification is reflected in over 60 reports, which appeared since the publication of Deguchi et al. in 2004 [2], [4], [5], [6], [7], [8] and [9]. Such assays have been used to study the pathophysiology, natural history, and response to therapeutic interventions in chronic hepatitis B (CHB). Indeed, HBsAg serum levels correlate with HBV replication and with intrahepatic cccDNA in HBeAg+ CHB patients. Furthermore, HBsAg levels have been shown to correlate, although not completely, with serum HBV-DNA concentration. Thus, HBsAg derived from cccDNA has been suggested as low cost marker for follow-up of HBV replication as compared to the significantly more expensive HBV-DNA assays. It should be remembered in this context that HBsAg can also be synthesized by integrated HBV-DNA into the host genome and this form of HBsAg is undistinguishable, by current methods, from cccDNA encoded envelope protein(s). Regardless of this reservation, quantification of HBsAg serum levels as a marker for viral burden and response to anti-viral therapy is progressively being used, mainly in HBeAg + CHB patients. In such patients treated with pegylated interferon with or without lamivudine, declining HBsAg levels may predict anti-HBe and the less frequent anti-HBs seroconversion. In contrast, although HBsAg levels tend to decline following seroconversion from HBeAg to anti-HBe, the correlation between cccDNA, viral load and HBsAg levels in HBeAg negative patients is unpredictable, especially in view of the abundance of defective HBV particles in such patients.

Recently Seto et al. have suggested a novel application for quantification of serum HBsAg for the assessment of hepatic fibrosis in HBeAg+ CHB patients [10].They studied 140 patients in Hong-Kong (65% male, median age 32.7 years) of whom 56 (40%) had ALT ⩽2 × ULN. Seventy-two (51.4%) and 42 (30%) had an Ishak fibrosis score ⩽1 and 87.9% were classified as in the immune clearance phase of persistent HBV infection. Patients with fibrosis score ⩽1, when compared to patients with fibrosis score >1, had significantly higher median HBsAg levels (50,320 and 7820 IU/ml, respectively, p <0.001). Among patients with ALT ⩽2 × ULN, serum HBsAg levels achieved an ROC analysis of 0.869 in predicting fibrosis score ⩽1. HBsAg ⩾25,000 IU/ml was independently associated with fibrosis score ⩽1 (p = 0.025, odds ratio 9.042). Using this cut-off, HBsAg level in patients with ALT ⩽2 × ULN, positive and negative predictive values (NPP) for predicting a fibrosis score ⩽1 were 92.7% and 60.0% respectively. For an unidentified reason, HBV DNA levels had no association with degree of fibrosis established through a liver biopsy. The investigators concluded that “Among HBeAg-positive patients with ALT ⩽2 × ULN, high serum HBsAg levels can accurately predict fibrosis score ⩽1, and could potentially influence decisions concerning treatment commencement and reduce the need for liver biopsy”.

In the present issue of the Journal of Hepatology, Martinot-Peignoux and co-workers from France have studied a larger, and ethnically more diverse cohort of 406 Caucasian, Asian, African and Mediterranean CHB patients [11], extending and confirming the preliminary observations of Seto et al. regarding the inverse correlation between HBsAg levels and degree of fibrosis [10]. Both studies employed an identical quantitative HBsAg assay (Elecsys®, Roche Diagnostics). However, while the report of Seto et al. included only HBsAg+/HBeAg+ CHB patients of unidentified genotype, the study of Martinot-Peignoux and co-workers recruited both HBeAg positive (25%) and HBeAg negative (75%) patients. Of the 406 patients, 30% were of HBV genotype E, 26% genotype A, 24% genotype D, and 11–9% of genotype B and C, respectively.

The main findings of the French study include: (1) a strong inverse correlation between HBsAg levels and degree of fibrosis. In contrast, no such correlation was present in the HBeAg negative group. Thus, HBeAg+ CHB patients with moderate or severe fibrosis as assessed by the Metavir score, had significantly lower serum HBsAg and HBV-DNA levels compared to patients with no or little fibrosis. (2) A strong correlation was found between HBsAg and HBV-DNA levels in the HBeAg+ group, but not in the HBeAg− group. (3) Interestingly, lower HBsAg levels and increased severity of fibrosis were greater in patients with normal ALT levels as compared to patients with elevated ALT. (4) Importantly, 50% of the overall study population with cirrhosis and 69% of the HBeAg+ cohort with cirrhosis belonged to genotype A. (5) Genotype B patients had the highest HBsAg levels. (6) Using ROC analysis, the overall ability of serum HBsAg levels to differentiate HBeAg+ patients into low (F0–F1) or moderate to advanced fibrosis (F2–F4) was calculated as 0.77 rising 0.89 in patients with normal ALT. (7) HBeAg+ patients infected with genotype B or C could be separated into moderate and severe fibrosis as compared to no or mild fibrosis, using serum HBsAg levels alone without ALT. Thus, an overall cut-off value (irrespective of ALT) for serum HBsAg levels of 3.85 log IU/ml was calculated for these genotypes at a theoretical specificity of 86% and an NPP of 100%.

Comment: the study by Martinot-Peignoux and co-workers [11] indeed confirms the association between lower serum levels of HBsAg and the presence of moderate to severe fibrosis in HBeAg+ CHB patients as initially reported by Seto et al.[10]. The report is adding new information generated in a relatively large cohort of patients who also underwent genotyping for HBV. An in-depth comparison between the two studies can be found in the discussion in the report by Martinot-Peignoux et al.[11]. At present, the mechanism, leading to a decreased HBsAg level in HBeAg+ patients with advanced fibrosis is not understood. It was hypothesized that enhanced immune clearance of HBsAg or intracellular block of HBsAg secretion may be involved in such a process [10]. Regardless of the mechanism involved, the knowledge that high HBsAg levels may predict insignificant fibrosis in HBeAg+ patients is reassuring. However, despite its putative advantage and before embracing another method for assessment of hepatic fibrosis, further validation of these data is recommended. In particular, a comparison with already available means for assessment of fibrosis (i.e., elastography) is warranted in a larger cohort of HBeAg+ CHB patients with adequate representation of the individual genotypes and ethnic groups. Finally, Tseng and co-workers have recently suggested that in HBeAg- patients, high HBsAg levels can predict disease progression [12]. This observation stands in contrast to the reports of Seto et al and Martinot-Peignoux et al [10] and [11]. The different role of HBsAg quantification in these two risk groups awaits further confirmation and clarification.
Conflict of interest

The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

StephenW

于1967年发现以来[1]，定性的B型肝炎表面抗原（HBsAg）已被广泛使用的B型肝炎病毒（HBV）感染的诊断。花了近四十年，直到自动化可靠，特异性和敏感性HBsAg定量检测的动态范围0.05-250.0 IU /毫升（建筑师™，雅培诊断，USA）的发展，并能检测低至0.05国际单位/毫升乙肝表面抗原，对应约0.2纳克/毫升的[2]。另一种市售的检测与可资比较物业最近被准许（第二ELECSYS乙肝表面抗原定量法检测，罗氏诊断，美国）[3]。这些检测方法检测完好，野生型感染性的病毒，以及两个非感染性的包膜蛋白的形式，包括小的，球形的表面蛋白的（超过104-105中产生的感染性病毒粒子）和的丝状管状颗粒含小，中，大信封蛋白。肝病乙肝表面抗原定量社区体现在利率上升超过60份报告，出现自出版的DEGUCHI等。在2004年[2]，[4]，[5]，[6]，[7]，[8]和[9]。这样的分析已经被用来研究的病理生理，自然历史，和干预治疗慢性乙型肝炎（CHB）。事实上，乙肝表面抗原血清HBV复制与与肝内cccDNA的HBeAg阴性慢性乙型肝炎患者。此外，HBsAg水平已显示关联，虽然不能完全与血清HBV-DNA浓度。因此，HBsAg的cccDNA的是来自于已被建议作为低成本的标记为后续HBV复制的相比，明显更昂贵的HBV-DNA检测。应当记住在此背景下，乙肝表面抗原也可以被集成HBV-DNA合成到宿主基因组，这种形式的乙肝表面抗原是无法区分的，由目前的方法，从cccDNA的编码包膜蛋白（次）。不管这一保留，量化的HBsAg血清作为标记病毒的抗病毒治疗的负担和响应正逐渐使用，主要是在大三阳+ CHB患者。在这样的聚乙二醇干扰素治疗的患者有或无拉米夫定，下降HBsAg水平可以预测抗-HBe和抗-HBs阳转不太频繁。与此相反，尽管HBsAg水平往往下降以下从HBeAg到抗-HBe血清转换，cccDNA的病毒载量和HBeAg阴性患者的HBsAg水平之间的相关性是不可预测的，特别是考虑到在这些患者中有缺陷的HBV颗粒的丰度。

最近濑户等。已经提出了一个新颖的应用血清HBsAg定量评估大三阳肝纤维化+ CHB患者[10]。他们研究140例患者在香港，香港（65％男性，平均年龄32.7岁），其中56人（40％）有ALT⩽2×ULN。有72个（51.4％）和42（30％）Ishak纤维化评分⩽1，被列为HBV持续感染的免疫清除期和87.9％。患者纤维化评分⩽1，当患者纤维化评分> 1相比，有显着较高的平均HBsAg水平（50,320和7820 IU /毫升，分别为P <0.001）。在患者ALT⩽2×ULN，血清HBsAg水平达到0.869 ROC分析预测纤维化评分⩽1。乙肝表面抗原⩾25,000 IU / ml的是独立与纤维化评分⩽1（P = 0.025，比值比为9.042）。使用这个截止，HBsAg水平的患者ALT⩽2×ULN，预测纤维化评分⩽1的阳性和阴性预测值（NPP）分别为92.7％和60.0％。对于不明原因，HBV DNA水平，通过建立肝活检纤维化程度没有关联。研究者的结论，其中HBeAg阳性患者ALT⩽2×ULN，血清HBsAg水平高“可以准确预测纤维化评分⩽1，并可能影响决定有关治疗开始，减少肝活检”的需要。

在目前发行的杂志“肝脏病杂志，马丁诺德Peignoux和他的同事从法国406白人，亚洲，非洲和地中海CHB患者的一个更大的，和种族更加多样化的队列研究[11]，延伸和确认的初步意见濑户等。关于逆HBsAg水平和纤维化程度之间的相关性[10]。这两项研究都采用相同的HBsAg定量检测（®ELECSYS，罗氏诊断）。然而，虽然濑户等人的报告。只包括乙肝表面抗原+ / e抗原+ CHB患者不明基因型，该研究马天瑞Peignoux的和他的同事招募了两个（25％）HBeAg阳性和HBeAg阴性患者（75％）。的406名患者中，30％的乙肝病毒基因型E，A基因型的26％，24％D基因型，B，C基因型和11-9％，分别。

法国研究的主要结论包括：（1）强大的HBsAg水平和纤维化程度的负相关关系。相反，没有这样的相关性目前在HBeAg阴性组。大三阳+ CHB患者，中度或重度纤维化METAVIR得分评估，因此，没有或很少纤维化患者相比有显着降低血清HBsAg和HBV-DNA水平。 （2）较强的相关性，发现HBsAg和HBV-DNA水平之间的HBeAg +组，但不是在e抗原组。 （3）有趣的是，HBsAg水平较低和纤维化程度增加更大的ALT水平正常的患者相比，患者ALT升高。 （4）更重要的是，整体研究人口与肝硬化的50％和69％的HBeAg +队列肝硬化属于基因型（5）基因型乙肝患者HBsAg水平最高。 （6）使用ROC分析，血清HBsAg水平的整体能力，区分大三阳+患者分为低（F0-F1）或中度至晚期肝纤维化（F2-F4）计算为0.77上升0.89 ALT正常的患者。 （7）大三阳患者感染B型或C可以分为中度和重度纤维化相比无或轻度纤维化，无ALT单独使用血清HBsAg水平。因此，整体的cut-off值（不论的ALT）3.85日志的血清的HBsAg水平IU /毫升这些基因型计算为86％和100％的NPP的理论特异性。

评论：马天瑞Peignoux的和同事的研究[11]，确实印证降低血清HBsAg和存在的中度至严重纤维化大三阳+ CHB患者最初报道的濑户等之间的关联。[10]。报告中产生一个比较大的谁也进行了基因分型，HBV患者队列添加新的信息。在深入的比较，可以发现两者之间的研究报告中讨论马天瑞Peignoux等人[11]。目前，该机制在HBeAg（+）患者晚期肝纤维化的乙肝表面抗原水平下降，导致不理解。据推测，在这样的过程中，可能会涉及增强免疫清除乙肝表面抗原HBsAg的分泌或细胞块[10]。不管涉及的机制，在HBeAg（+）患者的知识，HBsAg水平高可能预测微不足道纤维化是令人欣慰的。然而，尽管其公认的优势和拥抱另一种方法评估肝纤维化，这些数据进一步验证之前建议。特别是，比较评估肝纤维化（即弹性）已经可用的手段保证足够代表性的个体的基因型和族群对HBeAg + CHB患者在更大的一队。最后，曾和他的同事最近指出大三阳患者，乙肝表面抗原水平可以预测疾病的进展[12]。此观察矗立在濑户等人的报告和马天瑞Peignoux等人[10]和[11]。不同的角色在这两个高危人群的HBsAg定量等待进一步的确认和澄清。
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作者宣称，他没有任何披露有关资金或有利益冲突就这个手稿。