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Article Navigation >  Journal of Clinical Hepatology  > 2016  >  32(3): 472-475

Correlation of HBV DNA load with liver pathology,liver function,and serological markers of liver fibrosis in children with chronic hepatitis B

DOI: 10.3969/j.issn.1001-5256.2016.03.014

  • The Pediatric Academy of University of South China

  • Published Date: 2016-03-20
    Abstract
  • Objective To investigate the correlation of HBV DNA load with liver pathology,liver function,and serological markers of liver fibrosis in children with chronic hepatitis B( CHB). Methods A total of 79 children with a confirmed diagnosis of CHB who were admitted to Liver Research Center of Children's Hospital of Hunan Province from July 2010 to June 2015 were selected,and according to the serum HBV DNA load,they were divided into low load group( 103< HBV DNA load≤105copies / ml,n = 8),medium load group( 105< HBV DNA load ≤107copies / ml,n = 54),and high load group( HBV DNA load > 107 copies / ml,n = 17). The degree of liver pathological changes and serum levels of alanine aminotransferase( ALT),aspartate aminotransferase( AST),procollagen type Ⅲ( PC Ⅲ),laminin( LN),hyaluronic acid( HA),and type Ⅳ collagen( Ⅳ- C) were compared between the groups. The Kruskal- Wallis rank sum test was applied for comparison of continuous data between groups,and Kendall's tau- b rank correlation analysis was applied for correlation analysis. Results The three groups mainly had a liver inflammation grade of G1,which accounted for 75%,74. 1%,and 64. 7%,respectively,and the high load group had an increased proportion of G2 patients( 35. 5%). The three groups mainly had a fibrosis stage of S1,which accounted for 75. 0%,72. 2%,and 70. 6%,respectively,and there were S4 patients in the low load group( 12. 5%). HBV DNA load was not correlated with liver inflammation grade or fibrosis stage( r = 0. 069 and- 0. 047,both P > 0. 05). The medium load group had higher serum levels of ALT and AST than the low load group,and the high load group had higher serum levels of ALT and AST than the medium load group; serum ALT level showed a significant difference between the three groups( χ2= 5. 37,P = 0. 048). The medium load group had lower serum levels of HA,LN,PCⅢ,and Ⅳ- C than the low load group,and the high load group had lower serum levels of HA,LN,PCⅢ,and Ⅳ- C than the medium group; serum PCⅢ level showed a significant difference between the three groups( χ2= 6. 26,P = 0. 044).Conclusion In children with CHB,HBV DNA load is not significantly correlated with liver pathology. A comprehensive analysis of HBV DNA load,liver function,and serological markers of liver fibrosis in clinical practice in combination with liver biopsy can achieve an objective and accurate evaluation of the conditions of children with CHB.

     

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  • 尽管药物和内镜治疗是门静脉高压症导致的食管胃静脉曲张破裂出血的首选治疗，但在内镜下止血失败，同时不能进行下一步治疗的情况下，脾切除门奇静脉断流术仍然是治疗食管胃底静脉曲张破裂出血的主要方式之一[1]，脾切除门奇静脉断流术后肝脏血流动力学改变是研究热点之一，术后早期血流动力学研究较多[2]，而对于术后血流动力学的长期、动态变化规律未见报道，本研究对术后患者进行长期随访，观察肝固有动脉及门静脉血流动力学的动态变化特点，分析肝脏血流动力学变化规律，为进一步了解脾切除门奇静脉断流术后肝功能、肝硬化等变化提供血流动力学方面的支持。

    1.   资料与方法

    1.1   研究对象

    收集2014年4月—2019年2月首都医科大学附属北京佑安医院普外中心103例门静脉高压行脾切断流术患者的临床资料。

    1.2   纳入和排除标准

    纳入标准：(1)各种原因引起的肝硬化；(2)行脾切断流术；(3)有上消化道出血史或胃镜提示食管胃底静脉重度曲张，红色征阳性。排除标准：(1)合并肝癌或其他恶性肿瘤；(2)布加综合征、血液系统疾病、冠心病及其他需长期服用抗凝药物的疾病；(3)术后门静脉系统血栓形成。

    1.3   术后抗凝治疗方案

    所有行脾切断流术患者均于术后48~72 h开始给予低分子肝素皮下注射，0.3 mL/12 h，应用3~5 d，并口服华法林抗凝治疗，维持国际标准化比值(INR)在1.25~1.5，血小板计数＞100×109/L时加用阿司匹林肠溶片100 mg/d，当血小板计数＞300×109/L时加用噻氯匹定0.25 g/d抗血小板凝聚，直至血小板降至正常水平。术后2周内，每周常规行2次彩色多普勒超声监测肝脏血流变化。对于上述预防治疗后仍发生门静脉血栓患者给予静脉溶栓治疗，溶栓方案为：尿激酶持续泵入，200 000 U/30 min，维持量30 000~50 000 U/h，应用3~5 d，尿激酶停用后，继续抗凝治疗。

    1.4   随访

    随访截止到2021年2月，随访时间为24~82个月，中位随访时间42个月，随访数据来自门诊及住院病历记录以及电话随访。患者术后1~2周出院，术后2周至3个月，每2~4周检测1次血常规、PT、INR、门静脉血流超声(包括门静脉内径、流量、门静脉最大流速、门静脉平均流速、肝固有动脉内径、流量、最大流速、最小流速等)，术后3个月至6个月，1~3个月完善1次上述检查；6个月后，每6个月完善1次上述检查。

    1.5   统计学方法

    采用SPSS 21.0软件行数据分析，计量资料以x±s表示，符合正态分布时采用配对样本t检验分析术前、术后指标的差异。P＜0.05为差异有统计学意义。

    2.   结果

    2.1   一般资料

    103例患者，随访96例，失访7例，随访率93.2%，其中男67例，女29例，年龄27~74岁，平均(47.6±9.4)岁，其中乙型肝炎肝硬化66例、丙型肝炎肝硬化12例、酒精性肝硬化11例、原发性胆汁性胆管炎5例、自身免疫性肝硬化2例(表 1)。术后门静脉压力较术前明显降低(P＜0.001)，而术后Child-Pugh分级较术前无明显变化(表 2)。

    表  1  患者术前一般资料
    Table  1.  Patient demographic and baseline characteristics
    项目 数值
    年龄(岁) 47.6±9.4
    性别(例)
    男 67
    女 29
    病因(例)
    乙型肝炎肝硬化 66
    丙型肝炎肝硬化 12
    酒精性肝硬化 11
    原发性胆汁性胆管炎 5
    自身免疫性肝病 2
    Child-Pugh分级(例)
    A 68
    B 24
    C 4
    下载: 导出CSV 
    | 显示表格
    表  2  术前、术后门静脉压力及肝功能变化
    Table  2.  Comparison of portal vein pressure and liver function at baseline and postoperatively in liver cirrhosis patients
    项目 术前 术后 统计值 P值
    门静脉压力(cmH2O) 36.1±4.1 23.9±3.9 t=14.99 < 0.001
    TBil (μmol/L) 21.5±9.2 15.2±6.6 t=5.33 < 0.001
    Alb (g/L) 36.9±3.7 35.5±1.8 t=2.20 0.027
    PT (s) 13.9±2.0 16.2±5.7 t=-6.70 < 0.001
    Child-Pugh分级(A/B/C) 68/24/4 69/24/3 χ2=4.00 0.407
    下载: 导出CSV 
    | 显示表格

    2.2   术后1周肝血流情况

    患者门静脉内径、门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均＜0.05)。肝固有动脉内径、流量、最大流速及最小流速均较术前明显升高(P值均＜0.05)(表 3)。

    表  3  术前和术后1周肝血流情况比较
    Table  3.  Comparison of hepatic hemodynamics at baseline and 1 week postoperation in liver cirrhosis patients
    项目 例数 术前 术后1周 t值 P值
    门静脉内径(mm) 89 12.79±1.50 12.19±1.60 3.13 0.003
    门静脉流量(mL) 89 1 533.01±125.48 1 088.15±136.65 6.16 ＜0.001
    门静脉最大流速(cm/s) 89 24.65±4.33 18.92±4.67 4.62 ＜0.001
    门静脉平均流速(cm/s) 89 19.50±6.30 15.19±4.32 5.08 ＜0.001
    肝动脉内径(mm) 89 3.76±0.48 3.93±0.85 -2.35 0.019
    肝动脉流量(mL) 89 230.01±37.13 358.52±76.20 -4.23 ＜0.001
    肝动脉最大流速(cm/s) 89 62.32±18.47 94.30±22.16 -5.84 ＜0.001
    肝动脉最小流速(cm/s) 89 17.96±6.14 31.36±6.70 -5.78 ＜0.001
    下载: 导出CSV 
    | 显示表格

    2.3   术后1个月肝血流情况

    患者门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均＜0.05)。肝固有动脉流量、最大流速及最小流速均较术前明显升高(P值均＜0.05)。门静脉内径、肝固有动脉内径较术前无明显差异(P值均＞0.05)(表 4)。

    表  4  术前和术后1个月肝血流情况比较
    Table  4.  Comparison of hepatic hemodynamics at baseline and 1 month postoperation in liver cirrhosis patients
    项目 例数 术前 术后1个月 t值 P值
    门静脉内径(mm) 81 12.77±1.53 12.37±2.09 1.499 0.141
    门静脉流量(mL) 81 1 577.28±190.48 940.82±142.27 5.514 ＜0.001
    门静脉最大流速(cm/s) 81 25.49±8.96 16.58±5.43 5.490 ＜0.001
    门静脉平均流速(cm/s) 81 19.84±3.96 13.61±5.01 4.870 ＜0.001
    肝动脉内径(mm) 81 3.76±0.47 3.87±0.45 -1.055 0.298
    肝动脉流量(mL) 81 230.34±59.97 276.48±66.07 -2.691 0.028
    肝动脉最大流速(cm/s) 81 62.51±19.66 71.62±12.84 -2.199 0.042
    肝动脉最小流速(cm/s) 81 18.25±6.05 23.18±4.28 -3.393 0.002
    下载: 导出CSV 
    | 显示表格

    2.4   术后3个月肝血流情况

    患者门静脉内径、门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均＜0.05)。肝固有动脉内径、肝动脉流量、最大流速及最小流速均较术前无显著差异(P值均＞0.05)(表 5)。

    表  5  术前、术后3个月肝血流情况比较
    Table  5.  Comparison of hepatic hemodynamics at baseline and 3 month postoperation in liver cirrhosis patients
    项目 例数 术前 术后3个月 t值 P值
    门静脉内径(mm) 79 12.88±1.62 12.16±1.71 2.55 0.016
    门静脉流量(mL) 79 1 497.90±161.76 1 030.76±174.13 3.70 0.001
    门静脉最大流速(cm/s) 79 23.27±4.12 16.99±4.97 4.25 ＜0.001
    门静脉平均流速(cm/s) 79 18.15±4.85 14.27±4.67 -3.23 0.003
    肝动脉内径(mm) 79 3.79±0.47 3.85±0.43 -0.68 0.502
    肝动脉流量(mL) 79 230.90±47.13 201.68±36.45 1.27 0.213
    肝动脉最大流速(cm/s) 79 61.10±18.07 58.51±16.63 0.62 0.535
    肝动脉最小流速(cm/s) 79 18.60±6.36 17.09±5.29 1.07 0.292
    下载: 导出CSV 
    | 显示表格

    2.5   术后6个月肝血流情况

    患者门静脉内径、门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均＜0.05)。肝固有动脉内径较术前显著增加(P＜0.05)。肝动脉流量、最大流速及最小流速均较术前无统计学差异(P值均＞0.05)(表 6)。

    表  6  术前、术后6个月肝血流情况比较
    Table  6.  Comparison of hepatic hemodynamics at baseline and 6 month postoperation in liver cirrhosis patients
    项目 例数 术前 术后6个月 t值 P值
    门静脉内径(mm) 77 12.89±1.49 12.09±1.87 2.59 0.015
    门静脉流量(mL) 77 1 568.64±220.48 933.00±182.94 4.17 0.002
    门静脉最大流速(cm/s) 77 23.92±7.21 17.73±5.39 3.83 0.001
    门静脉平均流速(cm/s) 77 18.91±7.21 14.75±4.72 2.92 0.006
    肝动脉内径(mm) 77 3.65±0.47 3.95±0.49 -2.69 0.012
    肝动脉流量(mL) 77 218.33±17.13 219.05±46.11 -0.04 0.962
    肝动脉最大流速(cm/s) 77 63.15±8.50 66.86±20.83 -0.74 0.460
    肝动脉最小流速(cm/s) 77 17.82±5.65 18.90±7.92 -0.65 0.519
    下载: 导出CSV 
    | 显示表格

    2.6   术后12个月肝血流情况

    患者门静脉内径、门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均＜0.05)。肝固有动脉内径、流量、最大流速及最小流速均较术前无明显差异(P值均＞0.05)(表 7)。

    表  7  术前、术后12个月肝血流情况比较
    Table  7.  Comparison of hepatic hemodynamics at baseline and 12 month postoperation in liver cirrhosis patients
    项目 例数 术前 术后12个月 t值 P值
    门静脉内径(mm) 64 12.83±1.62 11.96±1.10 3.11 0.004
    门静脉流量(mL) 64 1 649.60±123.48 937.64±181.42 4.32 ＜0.001
    门静脉最大流速(cm/s) 64 25.63±4.17 18.19±4.73 4.14 ＜0.001
    门静脉平均流速(cm/s) 64 19.84±3.78 15.45±4.13 3.09 0.005
    肝动脉内径(mm) 64 3.71±0.44 3.73±0.50 -0.13 0.895
    肝动脉流量(mL) 64 210.82±55.06 202.97±71.50 0.35 0.729
    肝动脉最大流速(cm/s) 64 60.89±10.22 64.19±11.92 -0.88 0.386
    肝动脉最小流速(cm/s) 64 17.90±4.26 17.16±5.21 0.511 0.613
    下载: 导出CSV 
    | 显示表格

    2.7   术后24个月肝血流情况

    患者门静脉内径、门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均＜0.05)。肝固有动脉内径、流量、最大流速及最小流速均较术前无明显差异(P值均＞0.05)(表 8)。

    表  8  术前、术后24个月肝血流情况比较
    Table  8.  Comparison of hepatic hemodynamics at baseline and 24 month postoperation in liver cirrhosis patients
    项目 例数 术前 术后24个月 t值 P值
    门静脉内径(mm) 60 12.72±1.23 11.23±1.44 2.44 0.016
    门静脉流量(mL) 60 1 554.73±171.48 910.47±122.28 2.47 0.015
    门静脉最大流速(cm/s) 60 21.22±4.96 15.21±3.73 3.32 0.001
    门静脉平均流速(cm/s) 60 19.16±3.08 14.55±3.23 2.82 0.006
    肝动脉内径(mm) 60 3.70±0.45 3.66±0.44 0.12 0.906
    肝动脉流量(mL) 60 224.91±17.70 219.33±16.33 -0.08 0.934
    肝动脉最大流速(cm/s) 60 63.98±10.68 64.58±19.00 -0.37 0.706
    肝动脉最小流速(cm/s) 60 19.40±6.78 18.09±7.42 -0.46 0.651
    下载: 导出CSV 
    | 显示表格

    3.   讨论

    肝硬化通常合并门静脉高压症，这是门静脉血流阻力增加和门静脉流入增加的结果[3]，由于肝脏是肝固有动脉和门静脉双重供血，同时肝固有动脉和脾动脉均由腹腔干发出，因此肝固有动脉、门静脉、脾动脉的血流动力学之间存在密切联系。门静脉高压症患者的内脏血流动力学紊乱已经得到证实，Zeng等[4]报道肝硬化门静脉高压症患者脾动脉/肝固有动脉内径比值异常的发生率较高，可作为内脏血流动力学紊乱的重要指标。而脾动脉半径和门静脉压力以及脾切除术后门静脉压力降低的程度之间存在关联[5]，长时间的门静脉压力升高，可能引起上消化出血，显著减低患者生存率，部分患者会出现门静脉系统血栓，进一步加重门静脉高压症，使肝功能恶化，甚至死亡[6-7]，而脾切除门奇静脉断流术是治疗门静脉高压导致食管胃曲张静脉出血的主要选择之一[8]。

    在我国脾切除门奇静脉断流术多是限期或者急诊手术[9]，术后并发症低，而且对肝功能有改善作用[10]。本研究中有4例术前Child-Pugh C级患者，均为因门静脉高压症导致的食管胃底曲张静脉破裂出血而行急诊手术，术前肝功能较差，而患者术后Child-Pugh评分恢复至A级或B级。此外术后患者外周血中透明质酸升高，Ⅲ型前胶原氨基末端前肽、Ⅳ型胶原降低也提示肝硬化门静脉高压症患者在脾切除门奇静脉断流术后肝硬化得到了逆转[2, 11]，同时门静脉流量减少以及肝动脉流量增加也是术后内脏血流动力学改变之一[12]，但由于数据量少且缺少长期随访，对于其动态变化并不了解，本研究观察脾切除门奇静脉断流患者术前以及术后短期、长期的肝固有动脉及门静脉内径、流量、流速的改变，从而了解肝脏内血流的动态变化。

    Huang等[2]发现与健康对照组相比，因门静脉高压症行脾切除门奇静脉断流术患者术后1周其门静脉内径、流量均明显高于健康对照组，门静脉最大流速较低，而与术前相比，肝固有动脉的最大流速和血流量均较术前显著升高，与其不同的是，本研究对比行脾切除门奇静脉断流术患者术前及术后的内脏血流改变，而非与健康对照组比较，更有利于了解术后和术前的血流变化差异，在术后1周时，也发现肝固有动脉的内径、流量、最大流速及最小流速均较术前显著增加，这种变化仅仅维持到术后1个月，而到术后3个月后，肝固有动脉的流量、最大流速及最小流速则恢复至术前水平，该结果在其他研究中未见报道。

    曾道炳团队等[4, 13]也发现脾切除门奇静脉断流术能够降低门静脉血流量和门静脉压力，伴有肝固有动脉流速、流量增加，此外，与健康人群的脾动脉内径/肝固有动脉内径(脾动脉/肝固有动脉)的比值相比，门静脉高压症患者的比值明显升高，证实存在内脏动力学紊乱，同时也对门静脉高压症的并发症有预测作用，研究结果还显示脾切除术后肝功能改善，而这一改变可能与术后血流动力学改变有关。本研究结果显示肝固有动脉的血流动力学改变比较短暂，而门静脉血流改变很持久，门静脉流量、流速以及内径等指标在术后1周开始就明显降低，之后持续保持在较低的水平。

    本研究动态显示了行脾切除门奇静脉断流患者手术前、后肝固有动脉及门静脉的血流动力学变化，以患者术前的结果作为参考，比较术后血流变化，不仅呈现术后早期的及变化特点，而且发现了长期的变化规律，尤其是肝固有动脉的血流变化仅仅维持1个月，而在术后3个月后则恢复至术前水平，这一变化与术后门静脉血流量和流速持续降低不同，这种变化为临床更好的研究脾切除门奇静脉断流术后的肝功能变化、肝硬度变化、门静脉系统血栓形成等方面提供了血流动力学方面的支持，为提高患者生活质量、改善预后提供帮助。

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    1. 李芷西，黄少坚，贺卓，黄嘉明，张起帆，周杰，王恺. 乙肝肝硬化门静脉高压症脾切除术后腹腔积液预测模型. 肝胆胰外科杂志. 2023(12): 736-741+746 .

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