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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.
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发表于 2012-9-30 01:07
