Tài liệu The clinical research of the therapy zhengxuxielian combined with interferon for treating chronic hepatitis c

密级：公开 学号：20104010 博 士 学 位 论 文 益气清化法联合干扰素治疗慢性丙型肝炎 正虚邪恋证的临床研究 研究生 黎氏白贤 指导教师 薛博瑜教授 学科专业 中医内科学 肝胆科专业 所在学院 第一临床医学院 毕业时间 201 3 年 06 月 A Dissertation Submitted for the Doctor‟s Degree The Clinical Research of the Therapy Zhengxuxielian combined with interferon for Treating Chronic Hepatitis C Candidate：LE THI BACH HIEN Adviser：Prof. BOYU.XUE Nanjing University of Chinese Medicine, Nanjing, China 学号：20104010 博 士 学 位 论 文 益气清化法联合干扰素治疗慢性丙型肝炎 正虚邪恋证的临床研究 作者姓名 黎氏白贤 申请学位级别 博士学位 指导教师姓名 薛博瑜 职 教授、主任医师 学科专业 研究方向 中医内科学 称 肝胆疾病 学习时间自 2010 年 09 月 10 日起 至 2013 年 06 月 30 日止 论文提交日期 2013 年 03 月 25 日 论文答辩日期 2013 年 05 月 29 日 学位授予单位 南京中医药大学 学位类型 临床医学博士学位 原创性声明 本人郑重声明：所呈交的学位论文，是本人在导师的指导下，独立进行研究工作所 取得的成果。除文中已经注明引用的内容外，本论文不包含任何其他个人或集体已经发 表或撰写过的作品成果。对本文的研究做出重要贡献的个人和集体，均已在文中以明确 方式标明。本人完全意识到本声明的法律结果由本人承担。 学位论文作者（需亲笔）签名： 2013 年 月 日 学位论文版权使用授权书 本学位论文作者完全了解学校有关保留、使用学位论文的规定，同意学校保留并向国家 有关部门或机构送交论文的复印件和电子版，允许论文被查阅和借阅。本人授权南京中 医药大学可以将本学位论文的全部或部分内容编入有关数据库进行检索，可以采用影 印、缩印或扫描等复制手段保存和汇编本学位论文。 保密□，在 年解密后适用本授权书。本学位论文属于不保密 □。 （请在以上方框内打“√”） 学位论文作者（需亲笔）签名： 2013 年 导师（需亲笔）签名： 2013 年 月 月 日 日 南京中医药大学博士学位论文 目 录 中文摘要 ........................................................................................................................................ V ABSTRACT ............................................................................................................................... VIII 缩略语表 ....................................................................................................................................... XI 前 言 ............................................................................................................................................... 1 第一部分 课题理论研究 ............................................................................................................... 5 第一章：中医学对慢性丙型性肝炎的研究进展 ..................................................................... 5 I.中医对肝胆的认识 ............................................................................................................... 5 1.中医学中“肝脏”的含义和实质 ....................................................................................... 5 2.中医学对肝脏位置的认识及论述 ................................................................................... 5 3.中医肝脏的生理功能 ....................................................................................................... 6 4.肝与其他脏腑在生理上密切关系 ................................................................................... 7 II. 中医对胆腑的认识 ............................................................................................................. 9 1.中医对胆腑含义及位置的认识 ....................................................................................... 9 2.中医对胆的生理功能的认识 ........................................................................................... 9 III.中医学对慢性丙型肝炎的研究进展............................................................................... 10 1.中医学对慢性丙型肝炎的病名认识[46] ........................................................................ 10 2.中医学对慢性丙型肝炎的病因病机探讨 ..................................................................... 11 3.中医学对慢性丙型肝炎的辨证诊断 ............................................................................. 16 4.中医学对慢性丙型性肝炎的治疗研究进展 ................................................................. 19 5. 难治慢性丙型性肝炎的中医辨证论治 ........................................................................ 26 6. 丙型性肝炎中医药临床研究存在问题评价与展望 .................................................... 28 参考文献 ................................................................................................................................... 30 第二章 西医学对慢性丙型性肝炎的研究进展...................................................................... 33 I.慢性丙型性肝炎的流行病学 ............................................................................................. 33 1.传染源 ............................................................................................................................. 33 2.传播途径 ......................................................................................................................... 33 3.人群感染性 ..................................................................................................................... 34 i 目 录 4.流行特征......................................................................................................................... 34 II.慢性丙型性肝炎的病毒学 ................................................................................................ 35 1.HCV 分类 ....................................................................................................................... 35 2.HCV 形态结构与生理性质 ........................................................................................... 35 3.HCV 基因组结构 ........................................................................................................... 35 4.HCV 复制 ....................................................................................................................... 35 5.HCV 变异 ....................................................................................................................... 36 III.丙型病毒性肝炎病理形态学改变 .................................................................................. 38 IV.慢性丙型病毒肝炎的致病机制与自然史 ...................................................................... 39 1.致病机制......................................................................................................................... 39 2.自然史............................................................................................................................. 39 V.慢性丙型肝炎的诊断学 ................................................................................................... 41 1. 临床诊断 ........................................................................................................................ 41 2. 实验室检查 .................................................................................................................... 41 3. 血清生化学检测 ............................................................................................................ 43 VI.慢性丙型肝炎的西医治疗 .............................................................................................. 49 1. 基本治疗 ........................................................................................................................ 49 2. 药物治疗 ........................................................................................................................ 50 3. 难治性慢性丙型肝炎的西医治疗策略(59) ................................................................... 56 4. 丙型肝炎西医药临床研究存在问题评价 .................................................................... 57 参考文献 ................................................................................................................................... 59 第二部分 临床研究 ..................................................................................................................... 61 I.研究设计 ................................................................................................................................. 61 II.研究方案 ............................................................................................................................... 61 1.诊断标准 ............................................................................................................................ 61 1.1 西医诊断标准 .............................................................................................................. 61 1.2 中医证型诊断标准 ...................................................................................................... 61 2.病例纳入标准 .................................................................................................................... 62 3.排除标准 ............................................................................................................................ 62 4.研究病历的终止条件 ........................................................................................................ 62 ii 南京中医药大学博士学位论文 5.剔除标准............................................................................................................................. 62 6.病历脱落与处理[7] ............................................................................................................. 62 7.治疗方案............................................................................................................................. 63 7.1 研究方法 ...................................................................................................................... 63 7.2 治疗方法 ...................................................................................................................... 63 8.观察指标............................................................................................................................. 63 9.疗效判定：......................................................................................................................... 64 9.1. 综合疗效判定 ............................................................................................................ 64 9.2. 抗病毒疗效评定标准 ................................................................................................ 64 9.3. 证候疗效判定标准 .................................................................................................... 64 9.4. 临床综合疗效判定标准 ............................................................................................ 64 10. 安全性评价标准[10] ......................................................................................................... 65 11. 不良事件轻重程度判断标准.......................................................................................... 65 12. 统计学方法...................................................................................................................... 65 III.结果 ...................................................................................................................................... 66 1.治疗前两组基线比较......................................................................................................... 66 1.1 两组性别比较 ............................................................................................................. 66 1.2 两组年龄比较 ............................................................................................................. 66 1.3 两组症状分布治疗前比较 ......................................................................................... 67 1.4 肝功能指标治疗前比较 ............................................................................................. 67 1.5 病毒定量治疗前比较 ................................................................................................. 68 2. 治疗组、对照组具体疗效比较........................................................................................ 68 2.1 两组治疗后体征比较 ................................................................................................. 68 2.2 两组治疗后肝功能疗效比较 ..................................................................................... 69 2.3 两组治疗后病毒定量 HCV-RNA 比较 ..................................................................... 69 2.5 两组临床综合疗效评定比较 ..................................................................................... 70 3.安全性比较......................................................................................................................... 71 4. 小结.................................................................................................................................... 71 第三部分 研究讨论与结论 ......................................................................................................... 73 I .研究讨论 ................................................................................................................................ 73 iii 目 录 1. 研究的理论依据 ............................................................................................................... 73 2. 研究的治疗原则 ............................................................................................................... 74 3. 研究的中药基本方药物组成与意义 ............................................................................... 75 4. 西医聚乙二醇干扰素联合利巴韦林抗丙型病毒的临床应用 ....................................... 77 5. 研究的疗效分析 ............................................................................................................... 78 5.1 临床综合疗效评价 ...................................................................................................... 78 5.2 症候疗效的评价 .......................................................................................................... 79 5.3 肝功能指标的评价 ...................................................................................................... 80 5.4 病毒定量指标的评价 .................................................................................................. 81 II. 研究的结论........................................................................................................................... 82 参考文献 ................................................................................................................................... 85 附 录............................................................................................................................................. 86 攻读博士学位期间取得的学术成果 ........................................................................................... 93 致 谢............................................................................................................................................. 94 简 介............................................................................................................................................. 95 iv 南京中医药大学博士学位论文 中文摘要 丙型病毒性肝炎是由丙肝病毒感染引起的一种感染病。丙型病毒性肝炎流行范围之 广、发病率之高、危害性之大，居各种传染病之首、症状表现多种多样，现代医学应用 抗病毒药治疗取得了一定疗效，但长期疗效差、复发率高，因为病毒的变异性比较高， 而且抗病毒药的副作用也不少。近年来中医药对丙型性肝炎的机理研究及辨证治疗显示 了一定的优越性。 A.研究背景 慢性丙型肝发病率高，知晓率低，是引起肝硬化、肝癌主要原因之一，感染 25-30 年 后肝硬化发生率为 5%-25%，是影响重大传染病。临床治疗慢性丙型肝炎的西药主要是聚 乙二醇干扰素联合利巴韦林为标准方案，其适应征要求严格、且禁忌症和副作用较多等 局限性。中医药用于防治慢性丙型肝炎具有较大优势。在此背景下，本课题用中西医结 合治疗慢性丙型肝炎的临床研究，探讨安全、有效的临床治疗方案。 B.研究目的： 根据中医理论与临床观察，明确中药益气清化法联合干扰素治疗慢性丙型肝炎正虚 邪恋证能改善症状，恢复肝功能、抑制病毒复制、改善肝组织损伤、防治肝纤维化及癌 变，从而提高临床益气清化法治疗慢性丙型肝炎的疗效。 C.研究方法： 本研究以确诊为慢性丙型肝炎正虚邪恋证进行临床研究，通过随机对照，观察 60 例 患者，随机分 2 组，其中治疗组 30 例，对照组 30 例，疗程为 48 周。观察两组患者在治 疗前、治疗 12 周及治疗结束时的综合疗效、抗病毒疗效、症候疗效、中医症候积分、肝 功能、肝脾 B 超的变化及安全性指标，进行比较两组的治疗效果。 治疗组(中西医结合治疗组)： 聚乙二醇干扰素 180ug，皮下注射，每周一次。利巴韦 林，每天 900mg 分三次口服，早中晚各 300mg。中药基本方，每天 1 剂，每天两次 (中药 基本方组成：黄芪 15g、白术 15g、栀子 15g、苦参 15g、胡黄连 6g) 对照组(西医治疗组)： 聚乙二醇干扰素 180ug，皮下注射，每周一次。利巴韦林，每 天 900mg 分三次口服，早中晚各 300mg。 D.研究结果： 1. 治疗组有效率为 90%，对照组总有效率为 73.3%，治疗组整体疗效与对照组相比，治疗 组明显优于对照组（P<0.05）, 表明本研究中药结合干扰素治疗慢性丙型肝炎正虚邪恋证 的疗效比对照组单纯用干扰素疗效较佳。两组总体疗效比较明显著差：。 治疗组 30 例，有效 27 例（90%），无效 3 例（10%），总有效率 90% 对照组 30 例，有效 24 例（73.3%），无效 8 例（26.7%）， 总有效率为 73.3%。 v 中文摘要 2. 益气清化法结合干扰素治疗慢性丙型性肝炎正虚邪恋证能改善临床症状体征： 两组治疗前症状体征分布无明显差异，差异无统计学意义，具有可比性（P > 0.05）。 两组患者治疗后乏力、腹胀、黄疸、口干口苦、肝脾肿大、怯冷或热症状均有显著性 差异，差异有统计学意义 （P<0.05） ；纳差、便溏、胁痛、腰膝酸软症状有非常显著改 善，差异有统计学意义 （P<0.01）。 由治疗组的症状积分均数 0.6908 > 对照组的症状积分均数 0.6817，可以认为治疗组的 症状积分转化率数高于对照组的症状积分。 3. 益气清化法结合干扰素治疗慢性丙型性肝炎正虚邪恋证能改善肝脏炎症，恢复肝功能 治疗前两组肝功能数值经 t 检验，P>0.05，提示：两组肝功能无明显差异。 治疗后两组肝功能数值经 t 检验：ALT、AST、GGT P<0.05，提示：两组肝功能 ALT、AST、GGT 明显改善。 治疗后两组肝功能数值经 t 检验 ALB、GLB、TBlil、DBlil 均无明显改善，差异无统计 学意义（ P>0.05），提示：两组肝功能 ALB、GLB、TBlil、DBlil 无明显改善。 由治疗组的肝功能均数 28.416 < 对照组的肝功能均数 52.9814，可以认为治疗组的肝功 能转化率数低于对照组的肝功能。 4. 益气清化法结合干扰素治疗慢性丙型性肝炎正虚邪恋证能改善血常规指标： 治疗前两组血常规指标无明显差异，差异无统计学意义，具有可比性 （P>0.05）两组 治疗后白细胞、红细胞、血小板均有显著改善，有显著差异，差异有统计意义 （P< 0.05）。 提示：两组治疗后血常规指标有明显改善 （P<0.05） 5. 益气清化法结合干扰素治疗慢性丙型性肝炎正虚邪恋证能改善病毒定量HCV-RNA，抑 制病毒复制： 治疗前两组病毒定量数值经 t 检验，P>0.05，提示：两组的病毒定量无明显差异。 治疗后两组病毒定量数值经 t 检验， P<0.05，提示：两组的病毒定量明显差异。 由治疗组的病毒定量均数 1000 < 对照组的病毒定量均数 2018，可以认为治疗组的病 毒定量转化率数低于对照组的病毒定量。 两组在治疗过程中未发生任何过敏反应或严重不良事件者，治疗后血常规、尿常规检 测均无明显异常变化，过程中亦无研究对象失访，表明益气清化法结合干扰素治疗正虚 邪恋证的临床研究安全有效，无明显毒副作用，且依从性好。治疗中、治疗后未见任何 不良反应。 E.研究结论： 论文通过中药益气清化法联合干扰素治疗慢性丙型肝炎患者，以干扰素作为对照 组。结果表明能够明显改善患者的乏力、腹胀、纳差、黄疸、口干口苦、便溏、胁痛腰 膝酸软、怯冷或热症状，肝功能、病毒定量均有显著性差异P<0.05。因此，益气清化法联 合干扰素治疗慢性丙型肝炎正虚邪恋证的临床研究能够改善患者的症状、恢复肝功能、 抑制病毒复制、改善肝组织损伤、防止肝纤维化及肝癌，从而提高临床益气清化法治疗 vi 南京中医药大学博士学位论文 慢性丙型肝炎的疗效。益气清化法联合干扰素治疗慢性丙型肝炎正虚邪恋证的临床研究 获得较好的疗效，主要体现在改善临床症状体征方面，是一种方便、无毒、无副作用的 方法。 关键词：慢性病毒性肝炎，丙肝，正虚邪恋，临床研究，益气清化法，干扰素 vii Abstract Abstract Hepatitis C virus is an infectious disease caused by hepatitis C virus infection.The incidence of hepatitis C range, high, harmfulness of it, in a variety of infectious diseases, the first symptoms varied, modern medical application of antiviral therapy and achieved a certain effect, but the long-term effect is poor, the recurrence rate is high, because of the variability of the virus is relatively high, and the side effects of antiviral drugs also many.In recent years, research on the mechanism of Chinese medicine for hepatitis C hepatitis and dialectical treatment shows certain superiority. A. OBJECTIVE: To observe the clinical effects of the Chinese herb (The Clinical Research of the Therapy Zhengxuxielian combined with interferon for Treating Chronic Hepatitis C) in treating chronic hepatitis C.It is expected to improve the patients‟ signs and symptoms ,the liver function test ,inhibit viral replication , recover the liver tissue damage ,prevent progression to liver fibrosis and liver cancer. B. METHOD: 60 cases with chronic hepatitis are randomly divided into 2 groups ,there are 30 cases in each groups .The treatment group were given “Yiqiqinghua” for oral administration combine with oral INF once daily ; the control group were merely given ora IFN once daily . Both groups took for 12 months. C. RESULTS： 1. A total of 60 patients completed 48 weeks of treatment, the treatment group of 30 cases, control group 30 cases. 2. Two groups of clinical comprehensive therapeutic effect by P < 0.05, two groups of overall efficacy comparison, significant difference.The overall efficacy analysis: the treatment group of 30 cases, 0 cases were cured (0%), partially effective in 27 cases (90%), invalid in 3 cases (10%), the total effective rate was 90%; the control group of 30 cases, 0 cases were cured (0%), partially effective in 24 cases (73.3%), invalid in 8 cases (26.7%), the total efficiency of 73.3%.In the treatment, after treatment and no any adverse reaction. 3. The two groups before treatment, bloating, anorexia, fatigue, dry mouth, along with jaundice, hypochondriac pain, tongue, hepatosplenomegaly, Yaoxisuanruan, afraid of cold or heat symptoms showed no significant difference between P > 0.05. Two groups of patients before and after treatment of fatigue, bloating, anorexia, jaundice, dry mouth pain, loose stools, hypochondriac pain, hepatosplenomegaly, Yaoxisuanruan, afraid of cold or heat symptoms were significantly different P<0.05. viii 南京中医药大学博士学位论文 The treatment group symptoms integral average 0.6908 > controls symptoms integral average 0.6817, can be considered the treatment of symptom clusters integral conversion rate number higher than the control group the symptom score. 4. In two groups before treatment liver function numerical inspection by T, P>0.05, tips: two groups had no significant difference in liver function. The two groups after treatment of liver function numerical inspection by t ALT alanine aminotransferase (U/L), AST aspartate aminotransferase (U/L), GGT glutamyl transpeptidase (U/L) P>0.05, tips: two groups of liver function ALT, AST, GGT difference. The two groups after treatment of liver function numerical inspection by t ALB albumin (g/L), GLB globulin (g/L), TBlil (umol/L), total bilirubin bilirubin direct bilirubin (DBlil umol/L) P>0.05, tips: two groups of liver function ALB, GLB, TBlil, DBlil showed no significant difference. The treatment group of liver function were number 28.416 < control group of liver function were number 52.9814, can be considered the treatment group liver function conversion rate number lower than the control group on liver function. 5. In two groups before treatment virus quantitative inspection by T, t=-1.182, P= 0.242, P>0.05, tips: two groups had no significant difference in the virus quantitative. In two groups after the treatment virus quantitative inspection by T, t=-2.590, P= 0.012, P<0.05, tips: two groups of virus quantitative difference. The treatment group virus quantitative average 1000 < controls virus quantitative average 2018, can be considered the treatment group virus quantitative conversion rate number lower than the control group virus quantitative. 6. Two group during treatment did not produce any allergic reactions or serious adverse events after treatment, blood, urine routine test showed no abnormal changes in the process of study, nor as lost to follow-up, clearing heat and detoxicating method that is effective and safe in treatment of chronic hepatitis B, no obvious toxic side effect, and good compliance. D.CONCLUSION: The results of this study show that Qinghua method combined with interferon for chronic hepatitis C positive imaginary evil love card can significantly improve patients with fatigue, bloating, anorexia, jaundice, dry mouth pain, loose stools, hypochondriac pain, hepatosplenomegaly, Yaoxisuanruan, afraid of cold or heat symptoms were significantly different P<0.05.But the treatment group on liver function, viral quantitation of HCV-RNA were smaller than those in the control group of liver function, viral quantitation of HCV-RNA mean that treatment group, liver function, viral quantitative conversion rate number lower than the control group on liver function, viral quantitation.Therefore, Qinghua method combined with ix Abstract interferon for chronic hepatitis C positive imaginary evil love card is mainly reflected in the can improve the clinical symptoms and signs. The clinical trial process, a treatment group and a control group of patients were not any allergic reactions or serious adverse events after treatment, blood, urine routine test showed no abnormal changes, safety evaluation for Grade 1, at the same time the whole process and no research on as lost, without shedding case, indicated in combination with lamivudine Chinese herbal medicine is safe and effective, and has no obvious toxic side effect, good compliance.Because of the limited time, this study has many deficiencies, in follow-up clinical studies need to be improved.Such as: in the choice of sample size, no sample size, may affect the experimental rigor and feasibility; the small number of cases, in a relatively short time, the drugs on liver function, viral markers, hepatosplenomegaly clinical study is not fully, can enlarge the number of cases, prolong time of observation, further validate its clinical efficacy.Qinghua method combined with interferon for chronic hepatitis C positive imaginary evil love card in clinical studies to obtain better curative effect, mainly reflected in the improvement of clinical symptoms and signs, is a kind of convenient use, no toxic side effect method. KEY WORDS: chronic hepatitis C, Zhengxuxielian , Chinese medicine, clinical research , IFN x 南京中医药大学博士学位论文 缩略语表 缩略语 英文全称 中文全称 HCV viral hepatitis C 丙型肝炎病毒 ALT alanine aminotransterase 丙氨酸氨基转移酶 AST aspartate aminotransterase 天门冬氨酸氨基转移酶 TB total bilirubin 总胆红素 ALB albumin 白蛋白 GLB globulin 球蛋白 ALP alkaline Phosphatase 碱性磷酸酶 GGT γ-glutamyl transferase γ-谷氨酰转肽酶 xi