评论 慢性乙型肝炎合并代谢相关性脂肪肝患者肝硬度的变化

StephenW

Comment
Dynamics of liver stiffness in chronic hepatitis B patients with concurrent metabolic-associated fatty liver disease
February 19, 2021

To the Editor:

We read with interest the article by Mak et al.1 and commend their work exploring the diverse relationship between hepatic steatosis and chronic hepatitis B (CHB). Through prospective follow-up of 330 patients with normal alanine aminotransferase (ALT) and low viraemia, Mak et al. showed persistent severe steatosis (controlled attenuation parameter ≥280 dB/m) was associated with progression of fibrosis category after three years. As modern nucleos(t)ide analogues are able to achieve effective long term viral/biochemical suppression and attenuate fibrosis development,2 the focus of CHB management has shifted to address non-viral risk factors such as concurrent steatosis—with approximately 30% prevalence amongst patients with CHB3 —and metabolic-associated fatty liver disease (MAFLD).4 Although Mak et al. provided useful insight into the effects of severe steatosis on virologically quiescent CHB, the broader relationship between these two conditions remains elusive. We aimed to provide additional insight by modelling serial liver stiffness measurements (LSM) over time and comparing their trajectories amongst patients with or without concurrent MAFLD.

We retrospectively identified all non-cirrhotic CHB patients at a tertiary Australian centre. Patients were followed up from first review between 01/01/2010–31/12/2016 until 31/08/2020 or loss-to-follow-up. Steatosis was diagnosed radiologically (diffusely increased echogenicity on ultrasound) and MAFLD was diagnosed using new criteria. 4 Transient elastography was performed by a certified operator in accordance with best clinical practice for quality and probe selection. 5
The median of ≥10 successful measurements was recorded. Multivariable general linear mixed-effects regression (random intercept at the patient level) was used to model LSM, BMI, ALT and viral load using optimal order polynomial time covariates (by Akaike’s information criterion) and time interaction terms. Each model was controlled for baseline age, sex, LSM, ALT, BMI, viral load, antiviral status, prior antiviral exposure and metabolic risk factors. Analysis was performed in Stata/IC 16.1 (StataCorp LP, USA, 2020).

Of 660 patients (median follow-up 6.0 years; IQR 4.1–8.3), 172 (26%) had concurrent MAFLD. Data comprised 1,997 LSM, 10,647 ALT and 8,223 DNA measurements. MAFLD patients were of similar age (median 45.5 vs 43.0 years, P=0.09), but were more commonly male (65% vs 44%, P<0.001). There was no significant difference (MAFLD vs non-MAFLD) in the proportion who were HBeAg positive (19% vs 25%, P=0.21), on antiviral therapy at baseline (7% vs 12%, P=0.18) or commenced on therapy during follow-up (25% vs 29%, P=0.49). Most (61%) were never on antiviral therapy. Interestingly, we found that although average LSM was 15% higher initially (95% CI 7–24%, P<0.001) amongst patients with concurrent MAFLD, this improved over time such that there was no significant difference after 2–3 years (Figure 1). Although LSM is known to be elevated in obesity, the trajectory of LSM in MAFLD patients did not appear to correlate with BMI, but instead mirrored the trajectory of HBV DNA and ALT, reflective of the underlying virological and biochemical response. On average, DNA was 35% lower in MAFLD patients (95% CI 14–51%, P=0.003), and this difference remained over time. ALT decreased in all patients over time but was 13% higher in MAFLD patients on entry (95% CI 4–23%, P=0.003), and remained higher throughout follow-up. Of note, a similar degree of improvement in LSM was not observed in patients without MAFLD, despite no difference in the rate of change in ALT or viral load between MAFLD and non-MAFLD patients.

Perhaps the most striking finding of these data is the lack of any apparent worsening of LSM on average over time—in fact, LSM improved in MAFLD patients, with similar findings when analysing only untreated patients (data not shown). However, our cohort was substantially different to the cohort by Mak et al. as we included all CHB patients, the majority of whom had elevated HBV DNA and ALT throughout follow-up. This perhaps suggests viraemia and/or raised ALT has a more pronounced influence on LSM, and that the effect of steatosis is unmasked only after viral and biochemical suppression. Another explanation could be the influence of improved lifestyle changes not captured in our data, however BMI did not substantially change over time. Although we were limited by the lack of CAP measurements to quantify steatosis degree, ultrasound is less sensitive for steatosis so the patients in our cohort were likely to have moderate-to-severe steatosis. Thus, our results are markedly different from Mak et al. who showed the rate of fibrosis progression appeared highest in patients with persistent severe steatosis (41%) and new onset severe steatosis (35%). However, data for milder degrees of steatosis were not provided. It remains speculative whether the negative effects of steatosis on liver fibrosis outweigh the apparent protective effects, since concurrent steatosis attenuates viraemia,6,7
accelerates HBsAg seroclearance,1and possibly even improves the rate of response to antiviral therapy.8  Additional prospective studies are required to further clarify the unique relationship between steatosis and CHB.

StephenW

评论
慢性乙型肝炎并发代谢相关性脂肪肝患者的肝硬度动态
2021年2月19日

致编辑：

我们感兴趣地阅读了Mak等人1的文章，并赞扬他们的工作探索了肝脂肪变性和慢性乙型肝炎（CHB）之间的多种关系。通过对330名丙氨酸转氨酶正常（ALT）和低病毒血症的患者进行前瞻性随访，Mak等。显示持续的严重脂肪变性（控制衰减参数≥280dB / m）与三年后纤维化类别的进展有关。随着现代核苷酸（t）ide类似物能够实现有效的长期病毒/生化抑制并减轻纤维化的发展，2 CHB管理的重点已转移到解决非病毒性危险因素，例如并发脂肪变性，其中大约30％的患病率CHB3-和代谢相关性脂肪肝疾病（MAFLD）的患者。4尽管Mak等。由于提供了关于严重脂肪变性对病毒学上静止的CHB的作用的有用见解，这两种情况之间的更广泛关系仍然难以捉摸。我们的目标是通过对随时间推移进行的系列肝硬度测量（LSM）建模并比较有或没有并发MAFLD的患者之间的轨迹进行比较，从而提供更多的见识。

我们在澳大利亚一家三级中心回顾性鉴定了所有非肝硬化性CHB患者。从2010年1月1日至2016年12月31日至2020年8月31日之间或首次失访后的首次复查中对患者进行随访。通过放射学诊断出脂肪变性（超声检查中回声的扩散性增加），并使用新的标准诊断出MAFLD。 4瞬态弹性成像是由合格的操作员根据质量和探针选择的最佳临床实践进行的。 5
记录≥10次成功测量的中位数。使用最佳顺序多项式时间协变量（根据Akaike的信息标准）和时间相互作用项，使用多变量一般线性混合效应回归（在患者水平随机拦截）对LSM，BMI，ALT和病毒载量进行建模。控制每个模型的基线年龄，性别，LSM，ALT，BMI，病毒载量，抗病毒状态，先前抗病毒暴露和代谢危险因素。分析在Stata / IC 16.1（StataCorp LP，美国，2020年）中进行。

在660例患者（中位随访6.0年； IQR 4.1-8.3）中，有172例（26％）患有并发MAFLD。数据包括1,997个LSM，10,647个ALT和8,223个DNA测量值。 MAFLD患者年龄相似（中位数45.5 vs 43.0岁，P = 0.09），但男性更常见（65％vs 44％，P <0.001）。基线时抗病毒治疗或HBeAg阳性的HBeAg阳性（19％vs 25％，P = 0.21）的比例（MAFLD与非MAFLD）无显着性差异（7％vs 12％，P = 0.18）。随访期间的治疗（25％vs 29％，P = 0.49）。大多数（61％）从未接受过抗病毒治疗。有趣的是，我们发现尽管并发MAFLD患者最初的平均LSM升高了15％（95％CI 7–24％，P <0.001），但随着时间的推移有所改善，因此在2-3年后无显着差异（图1）。尽管已知LSM在肥胖症中升高，但MAFLD患者的LSM轨迹似乎与BMI不相关，而是反映了HBV DNA和ALT的轨迹，反映了潜在的病毒学和生化反应。平均而言，MAFLD患者的DNA降低了35％（95％CI 14–51％，P = 0.003），并且随着时间的流逝，这种差异仍然存在。随着时间的推移，所有患者的ALT均降低，但入院的MAFLD患者的ALT升高了13％（95％CI 4–23％，P = 0.003），并且在整个随访期间均保持较高水平。值得注意的是，尽管MAFLD和非MAFLD患者之间的ALT或病毒载量变化率没有差异，但没有MAFLD的患者并未观察到LSM的类似改善。

这些数据中最引人注目的发现可能是平均而言，随着时间的推移，LSM并没有任何明显的恶化-实际上，MAFLD患者的LSM有所改善，仅分析未经治疗的患者时，类似的发现（数据未显示）。但是，我们的队列与Mak等人的队列实质上不同。因为我们纳入了所有CHB患者，其中大多数患者在整个随访过程中HBV DNA和ALT升高。这也许表明病毒血症和/或升高的ALT对LSM有更明显的影响，并且只有在病毒和生化抑制后才能揭示出脂肪变性的作用。另一个解释可能是我们的数据中没有记录到生活方式改善的影响，但是BMI并没有随着时间的推移发生实质性变化。尽管我们由于缺乏用于量化脂肪变性程度的CAP测量方法而受到限制，但是超声对脂肪变性的敏感性较低，因此我们队列中的患者可能患有中度至重度脂肪变性。因此，我们的结果与Mak等人的研究明显不同。 在持续性严重脂肪变性（41％）和新发严重脂肪变性（35％）患者中，显示纤维化进展速度最高的研究者。 但是，没有提供有关轻度脂肪变性的数据。 脂肪变性对肝纤维化的负面影响是否超过表面保护作用仍是推测性的，因为并发脂肪变性可减轻病毒血症[6,7]。
加速HBsAg血清清除，甚至可能提高抗病毒治疗的反应率。8还需要进行其他前瞻性研究，以进一步阐明脂肪变性和CHB之间的独特关系。