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本帖最后由 StephenW 于 2013-1-9 16:37 编辑
Natural history
HBeAg positive chronic hepatitis B
In the initial 2–3 decades of life, HBV infection is characterized by an immune tolerance phase in which patients usually have positive HBeAg, very high HBV DNA, normal ALT levels and minimal histological damage [14]. This is followed by an immune-clearance phase, which may lead to HBeAg seroconversion. Based on the results of cross-sectional studies, serum HBsAg levels were generally higher in patients in the immune tolerance phase than in the immune-clearance phase [3, 6-8, 13] (Fig. 1).
Figure 1. Serum HBsAg levels during natural history of hepatitis B virus infection. Median values with 95% CI. Adapted from Nguyen et al. [6]. Serum HBsAg levels are higher in HBeAg-postive (immune-tolerant and immune-clearance) than in HBeAg-negative chronic hepatitis B.
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自然史
HBeAg阳性慢性乙型肝炎
在最初的2-3几十年的生活中,的特点是HBV感染的免疫耐受期患者通常在HBeAg阳性,HBV DNA非常高,ALT水平正常和最少的组织损伤[14]。其次是免疫清除期,这可能会导致HBeAg血清学转换。基于截面的研究的结果,在患者中的免疫耐受阶段血清HBsAg水平普遍较高比[3,6-8,13](图1)中的免疫清除期。
图1。 B型肝炎病毒感染的自然历史过程中的血清HBsAg水平。 95%CI的中间值。改编自Nguyen等人。 [6]。比HBeAg阴性慢性乙型肝炎血清HBsAg水平较高的HBeAg阳性(免疫宽容和免疫清除)
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HBeAg negative chronic hepatitis B
Later in life, most of the HBV-infected population progresses to the immune active phase, loses HBeAg and seroconverts to anti-HBe (with various degrees of activity and fibrosis). Then, most of this HBeAg (−) chronic hepatitis B (CHB) population enters the inactive or low replicative phase, (characterized by wide fluctuations in serum HBV DNA levels and transaminases [15]. The clinical spectrum of HBeAg (−) CHB ranges from ‘inactive carrier’ status to aggressive HBeAg (−) CHB that is generally differentiated from ‘inactive carriers’ by serial serum ALT and HBV DNA level determinations [16, 17]. However, in 45–65% of cases, ALT activity can fluctuate with long periods of normal ALT levels, resulting in misclassification (Fig. 2). Inactive carriers have no or mild histological lesions in the liver with an excellent prognosis for survival and a low incidence of cirrhosis and HCC, while patients with HBeAg (−) CHB with fluctuating activity have a more severe disease progression with frequent cirrhosis [17-19]. Differentiating the latter from inactive carriers is highly important as these patients could benefit from therapy. According to NIH and EASL guidelines [20, 21], the differentiation between inactive and active phases of HBeAg (−) CHB is based on an HBV DNA cut-off of 2000 IU/ml. This cut-off has led to several controversial studies [17, 22-25].
Figure 2. Kinetics of HBsAg, HBV DNA and ALT follow-up during the natural history of a chronic hepatitis B-negative patient. This patient with ‘an inactive carrier’ pattern at inclusion shows several reactivation episodes, ALT >2N and dramatically increase in serum HBV DNA during the follow-up, while HBsAg level remained steady and above 3.3 log IU/ml.
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HBeAg阴性慢性乙型肝炎
以后在生活中,大部分的HBV感染人群进行的免疫活性相,失去HBeAg阳性和抗-HBe seroconverts有不同程度的活动和纤维化。然后,最本的HBeAg( - )慢性乙型肝炎(CHB)的人口进入非活动或低复制期(血清HBV DNA水平和转氨酶[15]。临床频谱的HBeAg( - )CHB范围内大幅波动,特点从“非活动载体的地位积极的HBeAg( - )CHB,一般是区别于”非活动性携带者“系列血清ALT和HBV DNA水平测定[16,17]。然而,在45-65%的情况下,谷丙转氨酶活性可以波动与长时间的ALT水平正常,造成分类错误(图2)。非活动性携带者,无或轻度的肝组织学病变,预后良好生存和肝硬化和肝癌的发生率较低,而患者的HBeAg( - )CHB的起伏活动与经常性肝硬化[17〜19]。鉴别,后者从非活动性携带者是非常重要的,因为这些患者从治疗中获益。据美国国立卫生研究院和EASL指南[20,21],有更严重的疾病进展根据HBV DNA,截止2000 IU / ml的分化之间的无效和有效阶段的HBeAg( - )CHB。截止,导致几个有争议的研究[17,22〜25]。
图2。在自然史的慢性乙肝阴性患者的HBsAg,HBV DNA和ALT后续动力学。这名患者显示了几个“非活性载体”的模式,包容激活发作,ALT> 2N并显着提高血清中HBV DNA,而在后续HBsAg水平保持稳定,3.3日志IU /毫升以上。
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Based on longitudinal studies, HBsAg levels are higher in patients with active HBeAg (−) CHB than in ‘inactive carriers’ [22-26].
基于纵向研究,活动性的HBeAg( - )乙肝表面抗原的水平较高比在患者在“非活动性携带者[22〜26]。
A longitudinal Asian study in 68 HBeAg (−) CHB patients predominantly infected with genotype C reported that the patients with inactive disease tend to have lower HBsAg levels than those with active disease; 2.24 ± 1.61 log10 IU/ml vs. 2.98 ± 0.88 log10 IU/ml respectively (P = 0.054). No cut-off value can confidentially differentiate ‘inactive carriers’ [22]. During long-term follow-up (median 10 years), the authors report that HBsAg <1000 IU/ml predicts seroclearance (91% specificity: 75% sensitivity) [23]. A study performed by Brunetto et al. [24] in Italian genotype D patients reported that HBsAg levels are higher in patients with HBeAg (−) CHB than in ‘inactive carriers’ and that a single point quantification of HBV DNA <2000 IU/ml and HBsAg <1000 IU/ml identifies inactive carriers with a positive predictive value (PPV) of 88%. However, this observation must be validated across all HBV genotypes. Similar results were reported in a recent study from France [25] in 165 patients with HBeAg (−) CHB (genotypes A–E). HBsAg levels in this study were lower in the 76 ‘inactive carriers’ than in the 89 patients with an HBeAg (−) CHB; 3.25 ± 0.96 log10 IU/ml vs. 3.67 ± 0.70 log10 IU/ml respectively (P < 0.001). The combination of a single measurement of HBsAg <1000 IU/ml and HBV DNA <2000 IU/ml identifies ‘inactive carriers’ with a PPV of 86%. More recently, the authors reported that the combination of a single measurement of HBsAg >1000 IU/ml and HBV DNA >200 IU/ml identifies patients with a ‘high risk of reactivation’ with a negative predictive value (NPV) of 96%, and sensitivity 92% [26]. The authors conclude that combination of HBsAg and HBV DNA levels at a single time point may accurately indentify HBeAg (−) CHB patients, during remission with a high probability of reactivation and who are good candidates for treatment.
亚洲的纵向研究68的HBeAg( - )CHB患者主要感染C基因型活跃的疾病,患者往往有较低的HBsAg水平较活动性疾病; 2.24±1.61 LOG10 IU / ml比2.98±0.88 log10的国际单位/毫升(P = 0.054)。没有cut-off值可以保密区分“非活动性携带者”[22]。在长期(平均10年),作者报告说,乙型肝炎表面抗原(HBsAg)<1000 IU / ml的预测转阴(91%特异性:敏感性为75%)[23]。由布鲁涅托等人进行的一项研究。 [24]在意大利D基因型患者HBsAg水平较高的HBeAg( - )CHB患者比在“非活动性携带者,HBV DNA <2000 IU / ml和乙型肝炎表面抗原(HBsAg)<1000 IU / ml的识别,单点定量的非活动性携带者,阳性预测值(PPV)为88%。然而,这种观察必须在所有HBV基因型的验证。来自法国最近的一项研究报告了类似的结果[25]在165例HBeAg阳性( - )CHB(基因型A-E)。在这项研究中HBsAg水平低76'非活动性携带者“的89例患者的e抗原( - )CHB; 3.25±0.96 LOG10 IU / ml比3.67±0.70 log10的国际单位/毫升(P <0.001)。组合的单次测量的乙型肝炎表面抗原(HBsAg)<1000 IU / ml和HBV DNA <2000 IU / ml的识别与PPV为86%的“非活动性携带者”。最近,作者报告说,乙肝表面抗原相结合的单次测量> 1000 IU / ml和HBV DNA> 200 IU / ml的患者识别,激活了一个“高风险”的阴性预测值(NPV)为96%,敏感性92%[26]。作者的结论是在一个单一的时间点相结合的HBsAg和HBV DNA水平,可准确恒等式e抗原( - )CHB患者,缓解激活的几率非常高,是很好的候选人治疗。
HBsAg and liver histology
Seto et al. [27] found an association between higher HBsAg (≥25 000 IU/ml) serum levels and mild fibrosis (stage F ≤ 1) in a cohort of 140 Asian HBeAg (+) CHB patients (no indication of HBV genotype) with ALT ≤ 2 times the upper limit of normal. Similar results are reported in a cohort of 406 chronic hepatitis B patients with genotypes A–E [28]. A negative correlation was found between the level of HBsAg and the stage of fibrosis, so that patients with no or mild fibrosis (F 0–1 Metavir score) could be distinguished from those with moderate or severe fibrosis (≥ F2), in HBeAg (+) patients, with a high NPV (91%). Furthermore, the authors describe a specific serum HBsAg cut-off (3.85 log10 IU/ml) to identify moderate to severe fibrosis (≥ F2) in HBeAg (+) CHB patients infected with HBV genotypes B or C. This association was not observed in HBeAg (−) patients [28]. There was no association between HBsAg titre and histological grade found in either study.
乙肝表面抗原和肝组织学
濑户等。 [27]发现之间的关联较高的乙肝表面抗原(≥25 000 IU / ml)的血清水平和轻度纤维化(第二阶段F≤1)在一组140亚洲e抗原(+)慢性乙型肝炎患者的HBV基因型(无指示),ALT≤正常上限的2倍。类似的结果在一组报道的406例慢性乙型肝炎患者的基因型A-E [28]。发现HBsAg和纤维化分期之间的水平呈负相关,因此,患者无或轻度肝纤维化(F 0-1 METAVIR评分)可区别于那些中度或重度肝纤维化(≥F2),在HBeAg( +)患者中,与一个高NPV(91%)。此外,作者描述了一个特定的血清HBsAg(3.85 log10的国际单位/毫升),以确定截止中度至重度纤维化(≥F2),在HBeAg(+)慢性乙型肝炎患者感染HBV基因型B或C。该协会并没有观察到e抗原( - )患者[28]。没有任何一项研究中发现乙肝表面抗原滴度和组织学分级之间的关系。
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