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.
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. 作者: 肝胆速递 时间: 2012-8-28 15:17
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。作者: StephenW 时间: 2012-8-28 15:33