中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

Research advances in predictive markers for HBeAg seroconversion in chronic hepatitis B patients treated with nucleos( t) ide analogues

DOI: 10.3969/j.issn.1001-5256.2020.06.036
Research funding:

 

  • Received Date: 2020-01-15
  • Published Date: 2020-06-20
  • Nucleos( t) ide analogues( NAs) are effective inhibitors for HBV replication and have become the preferred antiviral regimen for most patients with chronic hepatitis B( CHB). HBeAg seroconversion is an important index used to evaluate the durability and efficacy of antiviral therapy in HBeAg-positive CHB patients. The search for biomarkers that can predict HBeAg clearance or seroconversion after NAs treatment plays an important role in the selection of antiviral drugs,the adjustment of treatment regimens,and the achievement of individualized treatment. This article reviews the value of related markers,including HBV DNA,HBV RNA,anti-HBc,and HBcrAg,in predicting HBeAg clearance or seroconversion in CHB patients treated with NAs.

     

  • 非酒精性脂肪性肝病(NAFLD)是指在影像学或组织学检查中存在肝脂肪变性,并排除大量饮酒及长期应用促脂肪形成药物、单基因遗传紊乱、自身免疫性肝病、慢性病毒性肝炎等引起肝脂肪变性竞争性病因的疾病1。据相关流行病学研究2报道,NAFLD的全球患病率为25.24%(95%CI:22.10%~28.65%)。NAFLD的全球负担与全球肥胖率的增加平行,随着肥胖和代谢综合征的全球化流行,预测2030年NAFLD的病例将达到1.01亿3-4。NAFLD的谱系疾病广泛,已成为21世纪第二大肝脏疾病,未来10年NAFLD可能逐渐成为终末期肝病、肝移植和原发性肝癌主要因素之一5

    铊(TL)是一种常见的天然微量金属,黄铁矿开采和相关炼钢业是环境中TL污染的主要来源6。高水平的TL可诱导不良的抗氧化反应,降低还原型谷胱甘肽和超氧化物歧化酶(Mn-SOD)的水平,并产生高水平的活性氧(ROS)7。虽然NAFLD的发病机制尚未明确,但是ROS的产生,氧化应激、炎症对NAFLD的发病至关重要8。TL对人类的毒性比汞、镉、铅、铜、锌更大,但人们对它的研究程度远低于汞、镉、铅等其他有毒金属9。当TL从人体缓慢释放后,它可以积聚在头发和指甲中,而尿液中的TL水平比头发、指甲中TL水平能更好地作为中毒指标10。目前,美国食品和药物监督管理局尚未批准针对NAFLD安全有效的治疗药物,生活方式(饮食和锻炼)的改变是治疗的主要方式,NAFLD的预防极其重要11。本研究通过探讨尿液TL与NAFLD疾病进展的风险相关性,旨在从不同角度探索NAFLD发展的生物标志物,以便在个人和人群水平上制订预防策略。

    国家健康与营养检查调查(NHANES)是一项评估美国人口健康和营养状况的横断面调查,主要收集参与者的人口统计学数据、生活方式以及健康和营养状况信息12。本研究中,选取NHANES 2017—2020年数据。纳入标准:NHANES数据库中2017—2020年18岁及以上的注册参与者(n=9 693)。排除标准:(1)缺乏肝脏瞬时弹性成像数据的人群(n=1 376);(2)患有乙型肝炎、丙型肝炎人群(n=128);(3)饮酒量显著的人群(男>30 g/d,女>20 g/d)(n=456);(4)缺乏尿液TL指标的人群(n=5 222)。最终共有2 511例受试者纳入分析。详细筛选流程见图1

    图  1  筛选流程图
    Figure  1.  Filter flow chart

    肝脏瞬时弹性成像已被广泛用于普通人群中检测NAFLD13。受控衰减参数(CAP)对NAFLD检测的可靠性可与肝活检(金标准)相比,以CAP≥238 db/m,同时排除患有乙型肝炎、丙型肝炎及饮酒量显著的人群(男>30 g/d,女>20 g/d)确诊为NAFLD14

    采用高效液相色谱-电喷雾电离-串联质谱和在线固相萃取联合同位素稀释等方法定量检测尿液TL水平15。本研究尿液TL的检出限为0.02 μg/L,低于检测限的值被替换为检测限除以2的平方根。

    采用R4.2.2软件,计量资料若符合正态分布用x¯±s表示,若是偏态分布用MP25P75)表示,两组间比较采用成组t检验或Wilicoxon秩和检验;计数资料两组间比较采用χ2检验。通过描述性分析、多因素Logistic回归、限制性三次样条回归分析、亚组分析、交互作用,探究尿液TL与NAFLD的风险关联。将尿液TL分为连续变量和分类变量(根据四分位数分为四组,第一个四分位数为参考)并计算3个模型中的比值比(OR)和95%CI。在Model 1中未调整变量,在Model 2中调整年龄、性别、种族、教育、婚姻状况、家庭收入与贫困比比值(FMPIR)、体质量指数(BMI)、社会人口学变量,Model 3在Model 2的基础上调整吸烟、喝酒、糖尿病(DM)、高血压(HTN)、高脂血症(HL)相关健康因素变量。使用限制性三次样条回归分析,以检验尿液TL与NAFLD是否存在非线性关联,并可视化两者之间的剂量-反应关系。此外,在亚组分析中以年龄、性别、种族、教育、婚姻状况、FMPIR、BMI、吸烟、喝酒、DM、HTN、HL分类,并采用相加模型和相乘模型来估计患病风险的交互作用,以检测尿液TL与NAFLD关系可能的差异。考虑到尿液的稀释,尿液TL采用尿肌酐进行校准。P<0.05为差异有统计学意义。

    本研究符合条件的研究对象共2 511例(NAFLD组1 612例,Non-NAFLD组899例)。NAFLD组尿液TL水平明显高于Non-NAFLD组(0.18 μg/L vs 0.16 μg/L),差异具有统计学意义(Z=-2.76,P=0.01)。与Non-NAFLD组相比,NAFLD组的年龄、BMI较高,且主要集中在40~59岁、BMI≥30 kg/m2的肥胖人群。此外,两组比较,NAFLD组更倾向于男性、墨西哥裔美国人、丧偶/离婚/分居、喝酒、患有DM、HTN、HL的人群,差异均具有统计学意义(P值均<0.01)(表1)。

    表  1  研究对象基本特征
    Table  1.  Basic characteristics of research objects
    变量 总人数(n=2 511) Non-NAFLD组(n=899) NAFLD组(n=1 612) 统计值 P
    年龄(岁) 51(34~64) 42(28~61) 54(40~65) Z=-4.55 <0.01
    年龄分组[例(%)] χ2=23.22 <0.01
    18~39岁 822(32.74) 419(46.61) 403(25.00)
    40~59岁 806(32.10) 220(24.47) 586(36.35)
    ≥60岁 883(35.17) 260(28.92) 623(38.65)
    性别[例(%)] χ2=10.63 <0.01
    1 262(50.26) 491(54.62) 771(47.83)
    1 249(49.74) 408(45.38) 841(52.17)
    种族[例(%)] χ2=20.94 <0.01
    墨西哥裔美国人 326(12.98) 88(9.79) 238(14.76)
    非西班牙裔黑人 672(26.76) 279(31.03) 393(24.38)
    非西班牙裔白人 828(32.97) 288(32.04) 540(33.50)
    其他 685(27.28) 244(27.14) 441(27.36)
    教育[例(%)] χ2=1.85 0.26
    大专或以上学历 1 371(54.60) 501(55.73) 870(53.97)
    高中或同等学历 666(26.52) 241(26.81) 425(26.36)
    高中以下 474(18.88) 157(17.46) 317(19.67)
    吸烟[例(%)] χ2=0.08 0.82
    一生吸烟<100支 1 502(59.82) 541(60.18) 961(59.62)
    一生吸烟≥100支 1 009(40.18) 358(39.82) 651(40.38)
    婚姻状况[例(%)] χ2=24.41 <0.01
    已婚/与伴侣同居 1 450(57.75) 485(53.95) 965(59.86)
    从来没有结过婚 527(20.99) 237(26.36) 290(17.99)
    丧偶/离婚/分居 534(21.27) 177(19.69) 357(22.15)
    喝酒[例(%)] χ2=10.66 <0.01
    277(11.03) 120(13.35) 157(9.74)
    2 234(88.97) 779(86.65) 1 455(90.26)
    FMPIR 2.26(1.17~4.14) 2.19(1.16~4.14) 2.32(1.17~4.15) Z=-0.99 0.34
    BMI(kg/m2 28.40(24.55~33.75) 24.60(21.60~27.90) 30.85(27.10~35.80) Z=-24.99 <0.01
    BMI分组[例(%)] χ2=76.56 <0.01
    BMI<25 kg/m2 685(27.28) 477(53.06) 208(12.90)
    BMI≥30 kg/m2 1 031(41.06) 138(15.35) 893(55.40)
    25 kg/m2≤BMI<30 kg/m2 795(31.66) 284(31.59) 511(31.70)
    HTN[例(%)] χ2=18.44 <0.01
    2 077(82.72) 770(85.65) 1 307(81.08)
    434(17.28) 129(14.35) 305(18.92)
    HL[例(%)] χ2=51.83 <0.01
    2 223(88.53) 851(94.66) 1 372(85.11)
    288(11.47) 48(5.34) 240(14.89)
    DM[例(%)] χ2=67.38 <0.01
    2 163(86.14) 852(94.77) 1 311(81.33)
    348(13.86) 47(5.23) 301(18.67)
    尿液TL(μg/L) 0.17(0.10~0.26) 0.16(0.09~0.25) 0.18(0.11~0.26) Z=-2.76 0.01
    下载: 导出CSV 
    | 显示表格

    构建多元Logistic回归模型,探究尿液TL与NAFLD的关系。首先将尿液TL作为连续性指标分析,在Model 1、Model 2、Model 3中,尿液TL每上升一个四分位数,NAFLD的患病风险分别增加13%(OR=1.13,95%CI:1.02~1.25)、29%(OR=1.29,95%CI:1.15~1.44)、30%(OR=1.30,95%CI:1.16~1.46)。

    将尿液TL作为四分位数指标分析,在Model 3中与尿液TL最低组Q1相比,尿液TL Q2、Q3、Q4组患NAFLD的风险分别增加29%(OR=1.29,95%CI:1.02~1.63)、52%(OR=1.52,95%CI:1.20~1.94)、90%(OR=1.90,95%CI:1.48~2.44)(表2)。

    表  2  尿液TL与NAFLD的Logistic分析
    Table  2.  Logistic analysis of urinary TL and NAFLD
    变量 Model 1 P Model 2 P Model 3 P
    OR(95%CI OR(95%CI OR(95%CI
    尿液TL 1.13(1.02~1.25) 0.03 1.29(1.15~1.44) <0.01 1.30(1.16~1.46) <0.01
    尿液TL(人数/构成比)
    Q1(682/27.16%)
    Q2(631/25.13%) 1.21(0.97~1.50) 0.10 1.29(1.03~1.62) 0.03 1.29(1.02~1.63) 0.03
    Q3(648/25.81%) 1.28(1.02~1.61) 0.03 1.48(1.17~1.87) <0.01 1.52(1.20~1.94) <0.01
    Q4(550/21.90%) 1.36(1.08~1.71) 0.01 1.86(1.46~2.39) <0.01 1.90(1.48~2.44) <0.01
    下载: 导出CSV 
    | 显示表格

    调整年龄、性别、种族、教育、婚姻状况、FMPIR、BMI、吸烟、喝酒、DM、HTN、HL后进一步使用限制性三次样条回归分析,尿液TL与患NAFLD的风险存在正向剂量-反应关系(P<0.01)且为非线性关系(P<0.01),尿液TL<0.17 μg/L时,尿液TL为NAFLD的保护因素且随含量升高保护降低,当尿液0.17 μg/L≤TL≤0.44 μg/L时,尿液TL为NAFLD的危险因素且随含量升高危险度升高,然而当TL>0.44 μg/L时,其与NAFLD的患病风险无关(图2)。

    图  2  尿液TL与NAFLD之间的剂量-反应关系
    Figure  2.  Dose-response relationship between urinary TL and NAFLD

    调整年龄、性别、种族、教育、婚姻状况、FMPIR、BMI、吸烟、喝酒、DM、HTN、HL多个协变量,本研究发现尿液TL与吸烟、BMI之间存在显著的交互作用,差异有统计学意义(P交互作用<0.05)。进一步开展尿液TL与吸烟、BMI之间的亚组分析发现,一生吸烟≥100支的人群尿液TL每上升一个四分位数患NAFLD的风险增加50%(OR=1.50,95%CI:1.24~1.80),一生吸烟<100支的人群尿液TL每上升一个四分位数患NAFLD的风险增加20%(OR=1.20,95%CI:1.03~1.40),BMI≥30 kg/m2的人群尿液TL每上升一个四分位数患NAFLD的风险增加30%(OR=1.30,95%CI:1.05~1.70),差异具有统计学意义(P<0.05)(表3)。

    表  3  尿液TL与NAFLD的亚组分析及交互作用
    Table  3.  Subgroup analysis and interaction effect of urinary TL and NAFLD
    变量 OR(95%CI P 交互作用P
    年龄分组 0.58
    18~39岁 1.22(1.09~1.36) <0.01
    40~59岁 1.44(1.15~1.81) <0.01
    ≥60岁 1.09(0.91~1.31) 0.36
    性别 0.34
    1.35(1.13~1.60) <0.01
    1.28(1.09~1.50) <0.01
    种族 0.25
    墨西哥裔美国人 1.44(1.01~2.06) 0.04
    非西班牙裔黑人 1.33(1.07~1.66) 0.01
    非西班牙裔白人 1.41(1.15~1.72) <0.01
    其他 1.12(0.89~1.41) 0.34
    教育 0.74
    高中以下 1.45(1.09~1.93) 0.01
    高中或同等学历 1.22(0.99~1.51) 0.06
    大专或以上学历 1.32(1.13~1.54) <0.01
    婚姻状况 0.90
    已婚/与伴侣同居 1.30(1.12~1.51) <0.01
    从来没有结过婚 1.42(1.08~1.88) 0.01
    丧偶/离婚/分居 1.22(0.95~1.57) 0.11
    FMPIR 0.14
    <1.30 1.40(1.14~1.73) <0.01
    1.30≤FMPIR<3.50 1.31(1.08~1.59) 0.01
    ≥3.50 1.18(0.97~1.44) 0.10
    BMI分组 0.02
    <25 kg/m2 1.00(0.78~1.27) 0.37
    ≥30 kg/m2 1.30(1.05~1.70) 0.04
    25 kg/m2≤BMI<30 kg/m2 1.20(0.97~1.48) 0.09
    吸烟 0.03
    一生吸烟≥100支 1.50(1.24~1.80) <0.01
    一生吸烟<100支 1.20(1.03~1.40) 0.02
    喝酒 0.65
    1.30(1.15~1.47) <0.01
    1.28(0.91~1.80) 0.15
    DM 0.16
    1.64(1.01~2.64) 0.04
    1.29(1.15~1.46) <0.01
    HTN 0.37
    1.23(0.94~1.62) 0.14
    1.32(1.16~1.50) <0.01
    HL 0.14
    1.36(0.86~2.14) 0.19
    1.30(1.15~1.46) <0.01
    下载: 导出CSV 
    | 显示表格

    已有相关研究证明血清镉16、铜17、硒18、锰19、铅20、汞21、TL22及其他金属23,尿液锰19、砷24、镉25、钠26与NAFLD显著相关。肝功能受损与儿童尿液TL浓度升高有关27。在大鼠肝损伤实验28中,TL可导致大鼠肝细胞线粒体膜电位塌陷继而导致肝细胞死亡。暴露于TL(Ⅰ)和TL(Ⅲ)的小鼠肝脏HE染色显示肝窦充血和肝细胞坏死,肝脏/体质量比显著降低20。TL可诱导大鼠肝细胞中ROS形成,还原谷胱甘肽氧化,膜脂质过氧化和线粒体膜电位崩溃,致使线粒体膜电位塌陷和细胞色素C释放显著增加,破坏肝细胞的正常结构29。尿液TL浓度与肝损伤标志物ALT、AST、GGT和ALP呈显著正相关30。以上研究均表明尿液TL与肝细胞损伤密切相关,基于尿液TL与肝细胞损伤的相关性研究,本研究首次创造性探讨了尿液TL与患NAFLD的风险关联性,通过对NHANES 2017—2020年纳入NAFLD患者尿液TL水平进行评估,发现尿液高水平的TL是NAFLD患病风险增高的危险因素。燃煤、采矿和冶炼厂的工人是接触TL的高危人群,在NAFLD的预防和临床实践中,检测尿液TL水平有利于NAFLD的早期预防和高危人群筛查。

    目前尿液TL与NAFLD之间的关联研究较少,还需要进一步的研究来证实本次研究的结论。

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