修回日期: 2012-09-10
接受日期: 2012-10-16
在线出版日期: 2012-10-28
目的: 分析比较慢性丙型病毒性肝炎(chronic hepatitis C, HCV)抗病毒治疗前、后血脂变化与治疗疗效的关系, 为评估预后、及时调整治疗方案提供依据.
方法: 选择74例慢性HCV, 给予聚乙二醇干扰素a-2a联合利巴韦林抗病毒治疗, 对其治疗前、治疗12、24、48 wk的HCV-RNA定量和甘油三酯(triglycerides, TG)、总胆固醇(total cholesterol, TC)、高密度脂蛋白胆固醇(low-density lipoprotein cholesterol, HDL-C)、低密度脂蛋白胆固醇(high-density lipoprotein cholesterol, LDL-C)的检测数据进行比较分析.
结果: 74例患者中获得持续病毒学应答(sustained virological response, SVR)者43例(58%), 非持续病毒学应答(non sustained virological response, Non-SVR)组31例(42%). 治疗前SVR组TG、TC、HDL-C、均低于Non-SVR组, LDL-C高于Non-SVR组, 但差异均无显著性. 治疗期间两组的TG、TC、HDL-C、LDL-C的变化趋势各有不同, 两组TG升高趋势基本相同; SVR组比Non-SVR组治疗前有较低的HDL-C水平, 治疗期间降低的程度明显增加, 但差异无显著性; 治疗初期两组患者LDL-C降低趋势基本相同, 治疗至12 wk后 Non-SVR组患者LDL-C出现回升, HCV-RNA检测值仍在检测线以上, 而SVR组LDL-C持续低水平直至治疗结束, 并伴有 HCV-RNA阴转; SVR组TC在治疗12、24、48 wk均处于低下水平, 与Non-SVR组相应指标比较, 差异均有显著性(P = 0.01, 0.01, 0.03).
结论: 慢性丙型肝炎抗病毒治疗疗效与机体血脂水平密切相关, 但相关程度不尽相同, LDL-C在抗病毒治疗前处低水平, 治疗期间出现回升, 预示着HCV清除效果不佳. TC在抗病毒治疗前、后持续低水平, 是获得SVR的明确信号.
引文著录: 李磊, 罗明, 杨二娜, 王瑞, 王会清, 曹武奎. 慢性丙型肝炎血脂变化与抗病毒疗效的关系. 世界华人消化杂志 2012; 20(30): 2961-2965
Revised: September 10, 2012
Accepted: October 16, 2012
Published online: October 28, 2012
AIM: To observe changes in blood lipid metabolism in patients with chronic hepatitis C (CHC) who have received antiretroviral treatment, and to investigate the relationship between efficacy of antiviral treatment and changes in blood lipid metabolism.
METHODS: Seventy-four patients with CHC who have received pegylated interferon α-2α and ribavirin for 48 wk were followed. HCV-RNA quantification and serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) at 0, 12, 24, and 48 wk were detected and analyzed.
RESULTS: Sustained virological response (SVR) was found in 43 (58%) patients with CHC, and 31 (42%) patients had non-sustained virological response (Non-SVR). Although the SVR group had lower serum levels of TG, TC, HDL-C and higher serum levels of LDL-C before antiviral treatment, there were no significant differences in these parameters between the two groups. The changes in serum levels of different parameters showed different trends during the treatment. TG levels showed an increasing trend in both groups. Serum levels of HDL-C decreased more visibly in the SVR group than in the non-SVR group, but there was no significant difference between them. The decreasing trend of LDL-C levels was the same between the two groups at the early stage of treatment; however, serum levels of LDL-C gradually increased after 12 wk in the non-SVR group, although serum levels of LDL-C at 48 wk were still lower than baseline level, and HCV-RNA was still detectable. Serum LDL-C was maintained at low levels in the SVR group until the end of treatment, although HCV-RNA was undetectable at this time. After 12 weeks of treatment, serum levels of TC significantly decreased in the SVR group compared to those in the non-SVR group.
CONCLUSION: Efficacy of antiviral treatment is closely associated with changes in blood lipid metabolism in patients with CHC. Our finding that serum levels of LDL-C were low before treatment and rebounded during treatment indicates that the efficacy was not good. Lower serum levels of TC are beneficial to the efficacy of antiviral treatment.
- Citation: Li L, Luo M, Yang EN, Wang R, Wang HQ, Cao WK. Relationship between efficacy of antiviral treatment and changes in blood lipid metabolism in patients with chronic hepatitis C. Shijie Huaren Xiaohua Zazhi 2012; 20(30): 2961-2965
- URL: https://www.wjgnet.com/1009-3079/full/v20/i30/2961.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i30.2961
丙型病毒性肝炎(chronic hepatitis C, HCV)感染会导致脂代谢紊乱, 为了探讨血脂的变化与抗病毒疗效的关系, 我们分析了74例慢性丙型肝炎患者在给予聚乙二醇干扰素α-2α联合利巴韦林抗病毒治疗过程中血脂的变化, 现将结果报道如下.
收集2009-01/2011-01于天津市传染病医院住院确诊为慢性丙型肝炎并接受聚乙二醇干扰素α-2α联合利巴韦林治疗的患者74例, 年龄(49.39岁±10.42岁), 男性34例(45.95%), 体质量指数(body mass index, BMI)(24.29 kg/m2±2.68 kg/m2), 基因型均为1b型, 除外合并高血压、糖尿病、脂肪肝等其他并发症, 诊断治疗标准参照《丙型肝炎防治指南》[1].
治疗结束至随访24 wk时, 定性检测HCV-RNA阴性, 分别监测患者治疗0、12、24、48 wk及治疗结束后24 wk的HCV-RNA定量(或定量检测小于最低检测下限)以评价疗效, 依据疗效将其分为持续病毒学应答(sustained virological response, SVR)组和Non-SVR(non sustained virological response, Non-SVR)组, Non-SVR指未达到SVR者包括复发和治疗无效者; 同时检测血脂血清甘油三酯(triglycerides, TG)、总胆固醇(total cholesterol, TC)、高密度脂蛋白胆固醇(low-density lipoprotein cholesterol, HDL-C)和低密度脂蛋白胆固醇(high-density lipoprotein cholesterol, LDL-C), 血常规, 生化等相关项目. 患者均给予乙二醇干扰素α-2α联合利巴韦林180 μg皮下注射, 1次/wk, 中性粒细胞计数<1.0×109/L或血小板者<50×109/L给予135 μg, 口服利巴韦林1 200 mg/d, 疗程48 wk, 白细胞计数<0.75×109/L临时给予粒细胞集落刺激因子肌肉注射治疗, 血红蛋白低于100 g/L时利巴韦林减量, 低于80 g/L时停药.
统计学处理 应用SPSS17.0处理所得数据, 两样本间的比较采用两独立样本t检验, 计数资料采用χ2检验, 血脂的变化采用重复测量方差分析, 以P<0.05为差异有统计学意义.
治疗前两组数据包括TG、TC、LDL-C、HDL-C等的相关指标比较均无统计学差异(P>0.05, 表1).
| SVR | Non-SVR | P值 | |
| n(男/女) | 43(20/23) | 31(14/17) | |
| 年龄(岁) | 48.84±11.07 | 50.16±9.55 | 0.59 |
| BMI(kg/m2) | 24.34±2.89 | 24.23±2.40 | 0.87 |
| 起始RNA(×105 copies/mL) | 18.23±76.16 | 8.18±11.84 | 0.47 |
| 炎症反应程度(0-2/3-4) | 33/10 | 27/4 | 1.00 |
| 纤维化程度(0-2/3-4) | 39/4 | 21/10 | 1.00 |
| 血糖(mmol/L) | 5.13±0.42 | 5.10±0.60 | 0.78 |
| 白蛋白(g/L) | 41.64±5.75 | 41.30±3.00 | 0.77 |
| 谷丙转氨酶(μ/L) | 89.54±72.36 | 84.68±71.18 | 0.78 |
| 谷草转氨酶(μ/L) | 72.97±41.00 | 59.28±36.71 | 0.14 |
| 总胆红素(μmol/L) | 20.11±7.19 | 19.96±10.91 | 0.95 |
| 白细胞(×109/L) | 4.87±1.23 | 4.45±1.23 | 0.15 |
| 中性粒细胞(×109/L) | 2.90±0.67 | 3.03±1.00 | 0.54 |
| 血小板(×109/L) | 150.95±47.19 | 163.81±44.80 | 0.24 |
| 甘油三酯(mmol/L) | 1.00±0.45 | 1.14±0.42 | 0.17 |
| 总胆固醇(mmol/L) | 4.46±1.00 | 4.66±0.77 | 0.35 |
| 高密度脂蛋白(mmol/L) | 1.06±0.29 | 1.08±0.21 | 0.74 |
通过重复测量数据的方差分析可见两组患者在抗病毒治疗过程中TG水平的变化是逐渐升高, 并且SVR组的升高较为明显, 从治疗前的1.00 mmol/L±0.45 mmol/L逐渐升高到48 wk时的1.71 mmol/L±0.47 mmol/L. Non-SVR组的TG升高不明显, SVR组和Non-SVR组的升高趋势相同, 两组间比较无统计学差异(P = 0.98, 表2).
| 检测时间 | TG | TC | LDL-C | HDL-C | ||||||||
| SVR | Non-SVR | P值 | SVR | Non-SVR | P值 | SVR | Non-SVR | P值 | SVR | Non-SVR | P值 | |
| 治疗起始 | 1.00±0.45 | 1.14± 0.42 | 0.17 | 4.46±1.00 | 4.66± 0.77 | 0.35 | 2.47±0.57 | 2.28± 0.48 | 0.13 | 1.06±0.29 | 1.08± 0.21 | 0.74 |
| 12 wk | 1.41±0.53 | 1.43± 0.45 | 0.85 | 3.91±0.79 | 4.39± 0.73 | 0.01a | 2.12±0.46 | 2.10± 0.44 | 0.85 | 0.91±0.21 | 0.97± 0.20 | 0.22 |
| 24 wk | 1.62±0.53 | 1.55± 0.47 | 0.57 | 3.91±0.79 | 4.35± 0.65 | 0.01a | 2.05±0.44 | 2.15± 0.42 | 0.34 | 0.87±0.21 | 0.92± 0.18 | 0.24 |
| 48 wk | 1.71±0.47 | 1.62± 0.43 | 0.41 | 3.96±0.91 | 4.41± 0.75 | 0.03a | 2.03±0.41 | 2.23± 0.53 | 0.08 | 0.87±0.17 | 0.94± 0.31 | 0.21 |
两组患者在抗病毒治疗过程中TC水平较治疗前均降低, SVR组从治疗前的4.46 mmol/L±1.00 mmol/L逐渐降低到治疗48 wk的3.96 mmol/L±0.91 mmol/L, Non-SVR组从治疗前的4.66 mmol/L±0.77 mmol/L逐渐降低到治疗48 wk的4.41 mmol/L±0.75 mmol/L, 两组间TC水平从治疗开始约12 wk至治疗结束相比有统计学差异(P = 0.01, 0.01, 0.03, 表2).
SVR组患者LDL-C水平在治疗过程中逐渐降低, 从治疗前的2.47 mmol/L±0.57 mmol/L逐渐降低至治疗48 wk的2.04 mmol/L±0.41 mmol/L; Non-SVR组在抗病毒治疗起始阶段降低即由治疗前的2.28 mmol/L±0.48 mmol/L降低至治疗12 wk的2.10 mmol/L±0.44 mmol/L, 然后又逐渐回升至48 wk的2.23 mmol/L±0.53 mmol/L, 两组间LDL-C的变化趋势不同, 但比较两组间LDL-C的水平变化无统计学差异(P = 0.84, 表2).
两组患者在抗病毒治疗后HDL-C水平均较治疗前降低, SVR组从治疗前的1.06 mmol/L±0.29 mmol/L逐渐降低到治疗48 wk的0.87 mmol/L±0.17 mmol/L, Non-SVR组从治疗前的1.08 mmol/L±0.21 mmol/L逐渐降低到治疗48 wk的0.94 mmol/L±0.31 mmol/L, 两组间HDL-C的变化趋势相同, 比较两组间HDL-C水平变化无统计学差异(P = 0.27, 表2).
近来大量研究证明丙型肝炎病毒(hepatits C virus, HCV)的感染会导致脂代谢紊乱, 基础研究证实HCV感染肝细胞的过程如进入、复制、分泌与机体的脂代谢密切相关从而扰乱机体的脂代谢引起低脂血症、肝细胞脂肪变、胰岛素抵抗[2]. 抗病毒治疗可使低脂血症等得到改善[3]. 一些研究认为治疗前LDL-C和TC较高的患者有较好的病毒学应答率[4]. 但也有学者认为血脂变化多发生在抗病毒治疗期间, 其报道结果不尽相同[5,6].
本文对74例慢性丙型肝炎患者给以聚乙二醇干扰素α-2α联合利巴韦林治疗, 并于治疗前、治疗12、24、48 wk进行TG、TC、HDL-C、LDL-C和HCVRNA的检测. 经对治疗满48 wk后SVR和Non-SVR两组检测数据比较显示, 治疗前SVR组TG、TC、HDL-C、均低于Non-SVR组, LDL-C高于Non-SVR组, 但统计学处理差异均无显著性, 因此推测治疗前患者TG、TC、HDL-C、LDL-C的水平高低与抗病毒疗效关系不紧密. 但在抗病毒治疗过程中SVR和Non-SVR两组患者的TG、TC、HDL-C、LDL-C的变化趋势各有不同, 两组TG水平均逐渐升高, 随着治疗时间的延长TG升高趋势基本相同, 差异无显著性. 有研究发现应用干扰素治疗可以导致患者TG水平升高[6,7], 亦有用干扰素治疗其他疾病导致TG水平升高的报道[8,9]. 综合分析TG升高可能与干扰素药物本身可以抑制脂蛋白脂肪酶和甘油三酯脂酶的活性有关[10,11], 而与抗病毒疗效无明显的相关性.
Ramcharran等[12]发现抗病毒疗效与HDL-C水平相关, Harrison等[13]也发现治疗前较低的HDL-C水平的患者临床上易获得SVR, 推测HDL-C可以调节HCV进入肝细胞的途径, HDL-C水平的降低有利于获得更好的抗病毒疗效[14]. 但本研究结果显示, 两组患者HDL-C水平在治疗期间逐渐降低的变化趋势相同, SVR组比Non-SVR组治疗前有较低的HDL-C水平, 并且在治疗过程中SVR组降低的程度也明显于Non-SVR组, 但统计学处理差异均无显著性, 即不能证明HDL-C水平与治疗疗效的相关关系, 需扩大观察病例进一步验证.
在抗病毒治疗初期SVR、Non-SVR两组患者LDL-C逐渐降低趋势相似, 但随着治疗时间延长至12 wk后, LDL-C变化趋势显示不同, 即Non-SVR组患者LDL-C出现回升, 此时HCV-RNA定量检测值仍在检测线以上; 而SVR组LDL-C持续低水平直至治疗结束, 并伴有HCV-RNA阴转. 提示LDL-C的动态变化与病毒的清除有关, 这可能与HCV在血液中是以脂病毒样颗粒(lipoviroparticles, LVP)的形式存在有关, 即HCV被清除的同时与之结合的LDL-C随之减低.
在抗病毒治疗过程中TC的变化与其他指标不同, 与Non-SVR组相比SVR组在治疗前TC即处于低水平, 治疗至12、24、48 wk时持续低下,在相同的时间截点与Non-SVR组相应指标比较,差异均有显著性. 这种血脂变化趋势与Christian等报道相一致[15]. 表明在抗病毒治疗前及治疗期间TC始终处于低水平, 是易获得SVR的预测指标之一.
总之, 通过观察74例慢性丙型肝炎抗病毒治疗前、后血脂变化提示, 抗病毒治疗疗效与机体血脂水平密切相关, 但各监测指标的相关程度不尽相同: 与TG、HDL-C关系不甚明显; LDL-C在抗病毒治疗前处低水平, 治疗期间出现回升, 预示着HCV清除效果不佳; TC在抗病毒治疗前、后持续低水平, 是获得SVR的明确信号. 如果在抗病毒治疗前、后人为控制血脂变化是否能促进SVR的提高, 有待进一步观察.
聚乙二醇干扰素联合利巴韦林是目前抗丙型肝炎病毒(HCV)标准治疗方案, 但治愈率不高, 既往对抗HCV疗效的预测多集中在病毒本身如病毒的基因型、病毒载量等, 近年来宿主因素对抗病毒疗效的影响也受到很大的关注,其中包括脂代谢、糖代谢等,但是究竟产生什么样的影响有待进一步探讨.
王凯, 教授, 山东大学齐鲁医院肝病科
基础研究证实HCV的感染与脂代谢密切相关, 本文通过观察干扰素对抗HCV的疗效与血脂变化的关系证明HCV的清除过程亦影响脂代谢.
Negro等详细的报道了HCV的感染扰乱机体的脂代谢, Kuo等报道抗HCV治疗可使患者的低脂血症等得到改善.
本文观察了抗HCV治疗的疗效与血脂变化的关系, 为临床预测抗病毒疗效提供依据, 并为进一步研究提高抗病毒疗效提出了新的研究方向和思路.
低密度脂蛋白胆固醇(LDL-C): 富含胆固醇的脂蛋白, 亦是动脉粥样硬化的危险因素之一, 基础研究证实他与HCV感染肝细胞相关.
本文研究了抗HCV疗效与甘油三酯、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇的关系, 发现丙型肝炎抗病毒疗效与血脂水平密切相关, 并为临床预测抗病毒疗效提供了依据, 学术价值较好.
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