灰色地带慢性乙型肝炎病毒感染者抗病毒治疗适应证变化对

StephenW

灰色地带慢性乙型肝炎病毒感染者抗病毒治疗适应证变化对识别显着肝损伤的影响
任山 1、王文静 2、陆俊峰 1、王可飞 1、马丽娜 1、郑艳红 1、郑素军 1、陈新月 1
隶属关系
隶属关系

    1个
    【作者单位】： 首都医科大学附属北京佑安医院肝病中心一科;
    2个
    北京肝病研究所，首都医科大学北京佑安医院，中国北京。

    PMID：36389814 PMCID：PMC964714​​1 DOI：10.3389/fimmu.2022.1035923

抽象的

目的：在临床实践中，很大一部分不符合任何常见免疫状态的慢性乙型肝炎病毒 (HBV) 感染被认为处于“灰色地带 (GZ)”。本研究旨在调查抗病毒治疗适应症的变化对识别 GZ 患者显着肝损伤的影响。

方法：对接受超声引导下经皮肝活检的慢性 HBV 感染和丙氨酸氨基转移酶 (ALT) 水平持续正常 (PNALT) 的患者进行回顾性检查。有证据的肝损伤 (EHI) 定义为炎症等级≥2 (≥G2) 和/或纤维化阶段≥2 (≥F2)。收集完整的临床资料、肝脏炎症和纤维化分级，并通过Luminex技术检测细胞因子水平，并进行分析以研究肝脏的免疫和组织病理学状态。

结果：共有 347 例慢性 HBV 感染和 PNALT 患者被分为免疫耐受（IT，n = 108）、非活性 HBV 表面抗原（HBsAg）携带者（IHC，n = 61）、GZ-1（GZ 中 HBeAg 阳性） ，n = 92）和 GZ-2（GZ 中的 HBeAg 阴性，n = 68）相。其中GZ期51.3%，EHI期50.1%。 EHI 组的 IL-6 水平高于非 EHI 组（2.77 对 1.53 pg/ml，Z = -13.32，p = 0.028）。单核细胞趋化蛋白 1 (MCP-1) 水平与 HBV DNA (R = 0.64, p < 0.001) 和 HBeAg (R = 0.5, p < 0.001) 呈正相关，但与纤维化程度呈负相关 (R = -0.26, p = 0.048）。 GZ期EHI比例为60.55%，显着高于IT期（39.8%）和IHC期（37.7%）（χ2=10.4，p=0.006）。共有 46.69% 的患者超过新的 ALT 抗病毒治疗阈值（男性 30 U/L，女性 19 U/L）。低于新 ALT 阈值的 IT 和 IHC 阶段的 EHI 值分别为 32.6% 和 37.8%，而 GZ-1 和 GZ-2 患者的 EHI 值分别为 67.4% 和 68.4%，超过新的ALT 阈值，差异有统计学意义（χ2 = 11.13，p < 0.001；χ2 = 14.22，p = 0.002）。我们队列中的中位年龄为 38.91 岁，只有 21.03% 的人不到 30 岁。 <30 岁的 IT 和 IHC 患者的 EHI 值分别为 32.4% 和 35.8%，而当患者年龄超过 30 岁但仍处于 IT 和 IHC 阶段时，EHI 的比率增加到 43.2%。

结论：以 30 岁为分界点并降低 ALT 阈值有助于筛查是否存在显着肝损伤，尤其是对于 GZ 患者。 IL-6是EHI的良好指标，MCP-1与HBV DNA呈显着正相关，与肝纤维化呈负相关。

关键词：丙氨酸转氨酶（ALT）；抗病毒治疗；慢性乙型肝炎（CHB）；灰色地带（GZ）；适应症；肝活检；严重的肝损伤。

版权所有 © 2022 任、王、陆、王、马、郑、郑和陈。
利益冲突声明

作者声明，该研究是在没有任何可能被解释为潜在利益冲突的商业或财务关系的情况下进行的。处理编辑在审阅时声明与作者有共同的父从属关系。

StephenW

Effect of the change in antiviral therapy indication on identifying significant liver injury among chronic hepatitis B virus infections in the grey zone
Shan Ren  1 , Wenjing Wang  2 , Junfeng Lu  1 , Kefei Wang  1 , Lina Ma  1 , Yanhong Zheng  1 , Sujun Zheng  1 , Xinyue Chen  1
Affiliations
Affiliations

    1
    First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing, China.
    2
    Beijing Institute of Hepatology Beijing Youan Hospital, Capital Medical University, Beijing, China.

    PMID: 36389814 PMCID: PMC9647141 DOI: 10.3389/fimmu.2022.1035923

Abstract

Objective: In clinical practice, a substantial proportion of chronic hepatitis B virus (HBV) infections that do not fit into any of the usual immune states are considered to be in the "grey zone (GZ)". This study aimed to investigate the effect of the change in antiviral therapy indication on identifying significant hepatic injury among GZ patients.

Methods: Patients with chronic HBV infections and a persistent normal alanine aminotransferase (ALT) level (PNALT) who underwent ultrasonography-guided percutaneous liver biopsy were examined retrospectively. Evidenced hepatic injury (EHI) was defined as an inflammation grade ≥2 (≥G2) and/or fibrosis stage ≥2 (≥F2). Complete clinical data, liver inflammation, and fibrosis grades were collected, and the levels of cytokines were detected by the Luminex technique, all of which were analysed to investigate the immune and histopathology states of the liver.

Results: A total of 347 patients with chronic HBV infections and PNALT were categorized into immune tolerant (IT, n = 108), inactive HBV surface antigen (HBsAg) carrier (IHC, n = 61), GZ-1 (HBeAg positive in GZ, n = 92), and GZ-2 (HBeAg negative in GZ, n = 68) phases. Among them, 51.3% were in the GZ phase, and 50.1% presented with EHI. The IL-6 levels were higher in the EHI group than in the non-EHI group (2.77 vs. 1.53 pg/ml, Z = -13.32, p = 0.028). The monocyte chemoattractant protein 1 (MCP-1) level was positively correlated with HBV DNA (R = 0.64, p < 0.001) and HBeAg (R = 0.5, p < 0.001) but negatively correlated with fibrosis grade (R = -0.26, p = 0.048). The ratio of EHI in the GZ phase was 60.55%, which was significantly higher than that in patients in the IT (39.8%) and IHC phases (37.7%) (χ2 = 10.4, p = 0.006). A total of 46.69% of all patients exceeded the new ALT antiviral treatment threshold (30 U/L for men and 19 U/L for women). The EHI values in the IT and IHC phases below the new ALT threshold were 32.6% and 37.8%, respectively, whereas higher EHI values of 67.4% and 68.4% were seen in GZ-1 and GZ-2 patients, respectively, exceeding the new ALT threshold, and the difference was statistically significant (χ2 = 11.13, p < 0.001; χ2 = 14.22, p = 0.002). The median age in our cohort was 38.91 years, and only 21.03% were less than 30 years old. The EHI values in the IT and IHC patients <30 years old were 32.4% and 35.8%, respectively, while the ratio of EHI increased to 43.2% once patients were older than 30 years but still in the IT and IHC stages.

Conclusion: Setting 30 years old as a cut-off and lowering the ALT threshold could facilitate screening for the presence of significant liver injury, especially for GZ patients. IL-6 was a good indicator of EHI, and MCP-1 was significantly positively correlated with HBV DNA but negatively correlated with liver fibrosis.

Keywords: alanine aminotransferase (ALT); antiviral therapy; chronic hepatitis B (CHB); grey zone (GZ); indication; liver biopsy; significant liver injury.

Copyright © 2022 Ren, Wang, Lu, Wang, Ma, Zheng, Zheng and Chen.
Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared parent affiliation with the authors at the time of review.