E抗原阳性慢性乙肝患者高HbsAg提示肝纤维化轻微

肝胆速递

PLoS One. 2012;7(8):e43087. Epub  2012 Aug 20.

High Hepatitis B Surface Antigen Levels Predict Insignificant Fibrosis in Hepatitis B e Antigen Positive Chronic Hepatitis B.
E抗原阳性慢性乙肝患者高HbsAg提示肝纤维化轻微

肝胆速递：慢性乙肝患者中，低HBsAg比高HbsAg患者更易肝纤维化

Seto WK, Wong DK, Fung J, Ip PP, Yuen JC, Hung IF, Lai CL, Yuen MF.
SourceDepartment of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong.

AbstractINTRODUCTION: There is no data on the relationship between hepatitis B surface antigen (HBsAg) levels and liver fibrosis in hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B (CHB).
METHODS: Serum HBsAg and HBV DNA levels in HBeAg-positive CHB patients with liver biopsies were analyzed. The upper limit of normal (ULN) of alanine aminotransferase (ALT) was 30 and 19 U/L for men and women respectively. Histologic assessment was based on Ishak fibrosis staging for fibrosis and Knodell histologic activity index (HAI) for necroinflammation.
RESULTS: 140 patients (65% male, median age 32.7 years) were recruited. 56 (40%) had ALT ≤2×ULN. 72 (51.4%) and 42 (30%) had fibrosis score ≤1 and necroinflammation grading ≤4 respectively. Patients with fibrosis score ≤1, when compared to patients with fibrosis score >1, had significantly higher median HBsAg levels (50,320 and 7,820 IU/mL respectively, p<0.001). Among patients with ALT ≤2×ULN, serum HBsAg levels achieved an area under receiver operating characteristic curve of 0.869 in predicting fibrosis score ≤1. HBsAg levels did not accurately predict necroinflammation score. 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 for predicting fibrosis score ≤1 were 92.7% and 60.0% respectively. HBV DNA levels had no association with liver histology.
CONCLUSION: 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.

肝胆速递

PLoSOne。 2012年7（8）：e43087。 EPUB 2012年8月20日。
B型肝炎表面抗原水平预测无意义的B型肝炎e抗原阳性慢性乙型肝炎纤维化的
濑户WK红，黄DK，IP PP，源丰J，JC，IF，赖CL，元MF。
源

医学系，香港玛丽医院，香港，香港的大学。
抽象
简介：

B型肝炎表面抗原（HBsAg）水平和肝纤维化的B型肝炎e抗原（HBeAg）阳性慢性乙型肝炎（CHB）患者之间的关系没有任何数据。
方法：

血清HBsAg和HBV DNA水平，HBeAg阳性CHB患者肝活检进行了分析。正常的上限（ULN），丙氨酸氨基转移酶（ALT）分别为30和19 U / L，男性和女性。组织学评估是根据Ishak纤维化分期肝纤维化和Knodell组织学活动指数（HAI），坏死性炎症。
结果：

招募140名患者（65％为男性，平均年龄32.7年）。有56人（40％）ALT≤2×ULN。有72（51.4％）和42（30％）纤维化评分≤1，坏死性炎症分级≤4。与纤维化评分≤1，当患者纤维化评分> 1，患者HBsAg水平有显着较高的中位数（50,320和7,820 IU /毫升，P <0.001）。 ALT≤2×ULN的患者中，血清HBsAg水平达到下面积受试者工作特征曲线的0.869预测纤维化评分≤1。 HBsAg水平并不能准确地预测坏死性炎症评分。乙型肝炎表面抗原（HBsAg）≥25,000 IU / ml的独立与纤维化评分≤1（P = 0.025，比值比9.042）。使用这个截止患者的HBsAg水平ALT≤2×ULN，阳性和阴性预测值，预测纤维化评分≤ 1分别为92.7％和60.0％。 HBV DNA水平与肝组织学无关联。
结论：

其中HBeAg阳性患者ALT≤2×ULN，血清HBsAg水平可以准确地预测纤维化评分≤1，并有可能影响决策的关于治疗的开始和减少肝活检的需要。

肝胆速递

Discussion

An elevated ALT level classically differentiates immune clearance from immune tolerance in HBeAg-positive CHB. Nevertheless, studies have shown ALT to be an inaccurate marker of liver injury [7], [9]. Although HBsAg staining patterns in liver histology [29] and antibody to the hepatitis B core antigen IgM titers [30] could assist in differentiating the two HBeAg-positive disease phases, the assessment of fibrosis remains an essential step in deciding treatment commencement [5]. Current non-invasive methods are unable to accurately identify patients with severe histologic abnormalities. Our present study showed serum HBsAg levels can play an important role in identifying HBeAg-positive patients with insignificant fibrosis and potentially reduce the need for liver biopsies. Although there had been preliminary analysis linking HBsAg levels with histologic severity [31], our study to our knowledge was the first to formally use liver histology as an outcome measure to assess the role of HBsAg titers in distinguishing insignificant and significant fibrosis.

The present study identified two serum HBsAg cut-off levels useful for predicting insignificant fibrosis among HBeAg-positive patients with ALT ≤2×ULN. Serum HBsAg ≥100,000 IU/mL was 100% predictive of insignificant fibrosis. Prior studies also found similarly high serum HBsAg levels in immune tolerant patients defined by normal ALT levels [24], [25], [32]. HBeAg-positive patients with HBsAg ≥100,000 are likely to have insignificant fibrosis even if ALT levels are minimally elevated.

The present study also found the optimal serum HBsAg cut-off level to predict insignificant fibrosis to be of ≥25,000 IU/mL. Among HBeAg-positive patients with ALT ≤2×ULN, serum HBsAg ≥25,000 IU/mL had a positive predictive value of 92.7% of predicting insignificant fibrosis. In addition, serum HBsAg ≥25,000 IU/mL was the best factor independently associated with insignificant fibrosis (p = 0.025, odds ratios 9.042). Our results suggest that HBeAg-positive patients with ALT ≤2×ULN and serum HBsAg ≥25,000 IU/mL can be observed without the need of liver biopsies. If serum HBsAg levels are below 25,000 IU/mL, other forms of assessment of fibrosis are necessary to decide for the commencement of therapy.

Our study failed to establish any association between serum HBV DNA levels and liver histology in HBeAg-positive patients. A possible explanation is that in these patients, the immune-mediated response during immune clearance may lead to fluctuating viremic levels with varying degrees of abnormalities in histology [33]. Several non-invasive predictive indices involving HBeAg-positive patients proposed in recent studies have also not included serum HBV DNA as a factor for prediction [13], [14]. Serum HBV DNA levels are of greater predictive value in HBeAg-negative patients [34].

While the exact mechanism for the inverse relationship between the HBsAg levels and the degree of fibrosis remains to be examined, it may be related to the different stages of immune clearance. HBsAg is found extensively in immunohistochemical staining of liver histology in the immune tolerance phase [29]. With the transition from immune tolerance to early immune clearance, the immune system starts to increase its magnitude of immune control on the HBV. Serum HBsAg levels still remain high at the transition from immune tolerance to early immune clearance phase (ALT level may be at the high normal range) and it is to be expected that there will be minimal fibrosis because immune mediated attack is still of low magnitude. Upon entering into a more full-blown stage of immune clearance with repeatedly greater immune mediated damage, more fibrosis develops, and viral control is achieved with decreasing HBsAg levels. HBsAg production could also be influenced by the development of preS/S mutants during immune clearance [35].

Intriguingly, high HBsAg levels are not always favorable in CHB, as shown by recent studies demonstrating high HBsAg levels to be associated with the development of HCC [36], [37]. Hence, further longitudinal studies should be performed to examine the exact relationship between severity of fibrosis, disease progression and HBsAg levels by serial HBsAg measurement. Studies including non-Asian CHB patients would also be important, since such patients are infected later in life, with the classical immune tolerant phase absent or very short, and could well demonstrate different results.

Our study employed the lowered ULN for ALT (30 U/L for men, 19 U/L for women) as recommended by current treatment guidelines. Therefore, our cohort of patients with ALT ≤2×ULN accurately represents the HBeAg-positive population in which assessment of histologic severity is essential before deciding on treatment. In addition, the assay used for serum HBsAg measurement in our study has a broad dynamic range, minimizing the potential errors related to manual dilution in the measurement of high levels. Our study is limited by the lack of non-Asian CHB patients. In addition, HBV genotyping was not performed in our study, although prior studies have shown genotypes B and C, the two common genotypes in Hong Kong, have a similar risk of advanced fibrosis and histologic progression [38], [39]. Future studies involving different CHB populations with different genotypes are required to validate our findings. The comparison of the predictive value of HBsAg levels (including for HBeAg-negative histology) with different non-invasive predictive indices (e.g. the asparate aminotransferase/platelet ratio index) and transient elastography are also needed. In additional, future clinical and cost-effectgive studies with larger cohorts, after the adjustment of HBV genotype, could consider fitting HBsAg levels and other available non-invasive markers as an algorithm for practical clinical usage.

In conclusion, serum HBsAg ≥25,000 IU/mL was independently associated with insignificant fibrosis. This level accurately predicted insignificant fibrosis in HBeAg-positive CHB patients with ALT ≤2×ULN (AUROC 0.869, positive predictive value 92.7%), the group of patients in which histologic evaluation is recommended. Measurement of serum HBsAg levels can thus assist treatment decisions among HBeAg-positive patients and potentially reduce the need for liver biopsies.

肝胆速递

讨论

一个经典的ALT水平升高的区别从HBeAg阳性慢性乙型肝炎的免疫耐受，免疫清除。然而，有研究表明ALT以一个不准确的标记的肝损伤[7]，[9]。虽然乙肝表面抗原，肝组织学染色模式抗体，乙肝核心抗原IgM抗体滴度[30] [29]，可以协助区分两个HBeAg阳性的疾病阶段，评估肝纤维化仍然是一个重要的步骤，以决定治疗的开始[5] 。目前的非侵入性的方法是无法准确地确定患者患有严重的组织学异常。我们目前的研究表明，血清HBsAg水平确定微不足道纤维化的HBeAg阳性患者，可以发挥重要的作用，并有可能减少肝活检的需要。虽然曾有过初步的分析，将HBsAg水平与病理严重程度[31]据我们所知，我们的研究是第一个正式使用作为衡量的结果评估的作用的HBsAg滴度区别微不足道，显着纤维化的肝组织学。

本研究发现血清HBsAg截止水平与ALT≤2×ULN的HBeAg阳性患者中预测无关紧要纤维化的有用的。血清HBsAg≥100,000 IU / mL的100％预测无关紧要纤维化的。此前的研究也发现了同样高的血清HBsAg水平中所定义的ALT水平正常的免疫耐受的患者[24]，[25]，[32]。 HBeAg阳性患者与乙肝表面抗原≥10万，即使ALT水平轻度升高，可能有微不足道的纤维化。

目前的研究还发现，血清HBsAg截止水平的最佳预测微不足道的纤维化是≥25000 IU / mL的。在HBeAg阳性患者ALT≤2×ULN，血清HBsAg≥2.5 IU / mL时的预测无关紧要纤维化的92.7％，阳性预测值。此外，血清HBsAg≥2.5 IU / mL时，最好微不足道纤维化（P = 0.025，比值比9.042）独立相关的因素。我们的研究结果表明，HBeAg阳性患者ALT≤2×ULN，血清HBsAg≥25000 IU /毫升，可观察有无肝活检的需要。如果血清HBsAg水平低于25,000 IU / mL时，其他形式决定开始治疗肝纤维化的评估是必要的。

我们的研究没，建立血清HBV DNA水平和HBeAg阳性患者的肝脏组织学之间有任何关系。一种可能的解释是，在这些患者中，免疫介导的免疫清除反应过程中可能会导致波动的病毒血症水平有不同程度的异常组织学[33]。涉及HBeAg阳性患者，在最近的研究中提出的的几种非侵入性的预测指数也血清HBV DNA不包含作为预测的一个因素[13]，[14]。血清HBV DNA水平，HBeAg阴性患者[34]的预测值。

虽然仍然要检查的HBsAg水平和纤维化程度的反比关系的确切机制，它可能与免疫清除的不同阶段。乙型肝炎表面抗原（HBsAg）是广泛存在于肝脏组织学免疫组化染色，免疫耐受阶段[29]。从免疫耐受的早期免疫清除与过渡，免疫系统开始，以增加其对HBV的免疫控制的幅度。血清HBsAg水平仍然很高，在免疫耐受，免疫清除期早期（ALT水平在正常范围内）的过渡，将是最小的纤维化，因为免疫介导的攻击仍然是低程度的，它是可以预期的。后进入一个更加成熟的阶段，免疫清除反复更大的免疫介导的损伤，肝纤维化的发展，病毒控制与HBsAg水平下降。乙肝表面抗原生产也受到前S / S突变体的发展，在免疫清除[35]。

有趣的是，高HBsAg水平并不总是有利的CHB所示，最近的研究表明HBsAg水平高的发展与HCC [36]，[37]。因此，应进行进一步的纵向研究，研究严重程度的肝纤维化，病情恶化和测量通过串行乙肝表面抗原HBsAg水平之间的确切关系。包括非亚洲慢性乙肝患者的研究也很重要，因为这类病人感染以后的生活中，与传统的免疫耐受期不存在或很短，并且有可能表现出不同的结果。

我们的研究采用降低ULN ALT（30 U / L，男性，19 U / L为女性）的建议，目前的治疗准则。因此，我们的研究中，患者ALT≤2×ULN准确地反映HBeAg阳性的人口中，在决定治疗前的病理严重程度的评估是必不可少的。此外，该法用于测量血清HBsAg在我们的研究中有一个宽的动态​​范围内，最大限度地减少手动稀释高水平测量有关的潜在错误。我们的研究是有限的非亚洲慢性乙型肝炎患者缺乏。此外，HBV基因分型，在我们的研究中，尽管此前的研究表明基因型B和C两种常见的基因型，在香港，有一个类似的先进的肝纤维化和组织学进展的风险[38]，[39]。未来的研究涉及不同基因型的不同CHB人群的需要来验证我们的研究结果。 HBsAg水平（包括HBeAg阴性组织学）与不同的非侵入性的预测指标（如天门冬氨酸氨基转移酶/血小板比值指数）和瞬时弹性成像的预测值的比较也是必要的。另外，未来的临床和成本effectgive的研究有较大同伙，调整后的HBV基因型，可以考虑配件HBsAg水平及其他非侵入性的标记，实用临床使用的算法。

总之，血清HBsAg≥25,000 IU / mL的独立相关性与微不足道纤维化。这个级别准确地预测微不足道纤维化的HBeAg阳性CHB患者ALT≤2×ULN（AUROC 0.869，阳性预测值92.7％），组的患者中，组织评估，建议。测量血清HBsAg水平可以HBeAg阳性患者辅助治疗的决定，并有可能减少肝活检的需要。

StephenW

这是一个非常有意思的的论文。
它揭示了一些有关免疫清除期。

完整的文章可以在这个环节看:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423440/?tool=pubmed

咬牙硬挺

感谢分享。