【作者】 王萍；

【导师】 唐旭东；

【作者基本信息】 中国中医科学院 ， 中医内科学， 2008， 博士

【摘要】 【背景】慢性萎缩性胃炎(Chronic atrophic gastritis,CAG)是临床常见难治性胃病,发病率高,病情缠绵反复,伴肠化、异型增生时癌变危险性增加。迄今尚缺乏公认有效的干预措施,中医治疗本病的优势和特色已逐渐为人们所认识,但在辨证诊治及疗效评价上还存在一定问题,影响优势与特色的发挥,也阻碍临床和科研工作的开展。【目的】总结慢性萎缩性胃炎中医证候特征及辨证用药规律,为临床、科研提供参考;整理挖掘导师治疗CAG思维模式、用药经验等,有利于其学术思想推广;对中医治疗CAG临床疗效进行客观评价,分析活血化瘀治疗CAG的作用和疗效特点,探索形成符合疾病特点的综合疗效评价方法,分析当前疗效评价存在的问题。【方法】通过对中医辨证治疗CAG文献的收集整理和计量分析,对病机、证候要素、证候类型、用药及配伍规律等进行科学总结;秉承“人机结合、以人为本”的理念,运用“名老中医临床诊疗信息采集系统”、“名老中医经验智能分析平台”和关联规则等方法,结合导师本人指导,对其治疗CAG的思维模式、用药经验等进行总结;通过临床对照试验系统评价,与西医阳性药物、常规对症治疗等多种对照比较,客观评价中药治疗CAG临床疗效,通过文献筛选和质量评价明确当前疗效评价存在的问题;通过辨证治疗CAG65例临床观察,从病理组织学、胃镜下病变、症状、基于患者报告临床结局(PRO)评价量表四个方面客观评价疗效,并分析活血化瘀治疗CAG的作用,总结疗效优势和特点。【结果】(一)萎缩性胃炎中医证候特征及辨证用药规律分析共纳入文献137篇。常见证型为脾胃虚弱(占34.2%)、肝胃不和(21.3%)、胃阴不足(18.6%)、胃络瘀血证(18.1%)和脾胃湿热(15.6%)证;证候要素分虚实两方面,虚以气虚(23.3%)、阴虚(23.5%)为主,多于阳虚(11.5%);实以气滞(26.7%)和血瘀(18.6%)为主,多于湿热(14.3%)及郁热(4.3%);常用药分为健脾、理气、化湿、清热、养阴、活血及消导7类,包括白芍、白术、半夏、陈皮、茯苓、丹参、黄芪、香附、枳壳、黄连等;脾胃虚弱证治以香砂六君子汤加减,以党参、白术、黄芪、茯苓等为主药,配桂枝、生姜、吴萸等温中阳,配砂仁、陈皮、木香等理气,配莪术、丹参等活血,配神曲、内金、麦芽、山楂等消导助运;肝胃不和证以四逆散、柴胡疏肝散合金铃子散加减,以柴胡、香附、枳壳为主疏肝理气,配元胡、香附、川芎等活血理气,配白芍等防辛燥伤阴;脾胃湿热证以黄芩滑石汤、藿朴夏苓汤或香砂平胃散加减,用药以半夏、黄连、黄芩、佩兰、苍术、蔻仁为主,配合芳香化湿和运脾化湿药,配厚朴、陈皮、苏梗、砂仁等调气机,配茯苓、炒白术等健脾促纳运;胃阴不足证以一贯煎、沙参麦冬汤加减,以沙参、麦冬、石斛、白芍等为主药,佐半夏、佛手、香附、陈皮、砂仁、枳壳、谷麦芽、内金等理气消导,佐黄芪、肉桂等从阳引阴;胃络瘀血证以丹参饮、失笑散加减,以丹参、元胡、当归、莪术、蒲黄、五灵脂等药为主,常与黄芪、白术、茯苓等健脾药及檀香、砂仁等理气药配伍。(二)导师唐旭东教授治疗萎缩性胃炎经验总结与数据挖掘共收集病例113人次,中医诊断为“痞满”和“胃脘痛”者各占40.70%和41.59%;治法以理气(131频次)、活血(56频次)、健脾(51频次)为主;常用香苏饮、四逆散、小陷胸汤理气通降(共计116频次),金铃子散、丹参饮、失笑散活血理气(125频次),半夏泻心汤、黄芩滑石汤、黄连温胆汤清化湿热(54频次),香砂六君子汤、四君子汤健脾扶中(33频次),左金丸清肝泄热(32频次),益胃汤或一贯煎养阴(4频次);共用药110味,常用黄连、陈皮、清半夏、苏梗、乌贼骨、元胡、砂仁、川楝子、炒白术、香附、枳壳、黄芩、滑石等;理气通降配合柔润之品防温燥伤阴,选用健脾理气之品或配合益气健脾药,攻补兼施,配伍活血药或选用理气活血药物气血同治;正确选用不同作用的活血化瘀药,配合其他治法保证疗效,注意顾护脾胃正气;化湿理气并用,化湿兼顾健脾;养阴配伍理气及健脾运脾药防滋腻碍胃。常用药对为川楝子=＞元胡、清半夏=＞黄连、苏梗&香附=＞陈皮、黄芩&清半夏=＞滑石等。(三)中医辨证治疗萎缩性胃炎临床疗效评价研究1中药治疗萎缩性胃炎临床疗效的系统评价:(1)病理疗效:从病变例数和积分变化两方面比较,中药组与对照组萎缩改善有统计学差异(P=0.004和0.008),其中中药组优于维酶素、猴头菌和空白对照(P=0.0001、0.0002和0.01),西药对症治疗优于中药(P=0.03);中药组肠化改善优于对照组(P=0.02和P＜0.00001),其中与猴头菌、空白对照、西药常规比较(P=0.02、0.007和0.02),与维酶素比较(P=0.69)。中药组与对照组异型增生改善有统计学差异(P=0.006和0.004),其中与西药常规、空白对照比较(P=0.11和0.09),与维酶素比较(P=0.0004)。(2)胃镜疗效:中药组与对照组比较粘膜颗粒样、胆汁反流改善均有统计学差异(P=0.05和0.005),与维酶素、猴头菌比较血管透见改善均无差异(P=0.25和0.83),与维酶素比较粘膜白相改善有统计学差异(P=0.0002)。(3)Hp根除率:中药组与对照组Hp根除率有统计学差异(P=0.009),其中与维酶素、空白对照和枸橼酸铋钾颗粒比较(P=0.02、0.009和0.009),与猴头菌、西药常规比较(P=0.70和0.74)。(4)症状疗效:中药组与对照组总体症状改善有统计学差异(P=0.008),其中与枸橼酸铋钾颗粒、西药对症治疗比较(P=0.64和0.13),与维酶素、空白对照比较(P=0.04和0.008)。中药与对照组胃痛改善有统计学差异(P＜0.00001),其中与维酶素、猴头菌比较(P=0.0002和0.002);与维酶素比较胃痛积分改善有统计学差异(P＜0.00001,);中药与对照组胃胀痞闷改善有统计学差异(P＜0.00001),其中与维酶素和猴头菌比较(均P＜0.00001);中药与维酶素胃胀痞闷积分改善有统计学差异(P＜0.00001)。中药与维酶素比较嗳气改善无差异(P=0.18和0.22)。中药改善纳呆优于对照组(P=0.0007),其中与维酶素、猴头菌比较(P=0.03和0.02);与维酶素比较纳呆积分改善有统计学差异(P＜0.00001)。与维酶素、猴头菌比较大便异常改善均有统计学差异(P=0.002和0.03);与猴头菌比较嘈杂改善无差异(P=0.34);与维酶素比较嘈杂与反酸积分改善均有统计学差异(P＜0.00001)。2辨证治疗慢性萎缩性胃炎65例临床观察:(1)血瘀组患者较非血瘀组病程长(P=0.044)、病理组织学病变重(P=0.026),非血瘀组女性较多(P=0.013)、症状总分及PRO量表总分较血瘀组高(P=0.030和0.003);(2)PRO量表积分:治疗后消化不良、全身症状、心理、反流和排便异常5个维度及总分均有明显改善(P＜0.05),而社会功能无改善(P=0.089);各维度对总分贡献依次为消化不良(标化回归系数为0.423)＞全身症状(0.362)＞心理功能(0.353)＞反流(0.238)＞社会功能(0.141)＞排便异常(0.106)。各辨证组间各维度及总分改善无差异(P＞0.05);非血瘀组全身症状及总分改善优于血瘀组(P=0.002和0.004);(3)临床症状:治疗后各主症及总分均有明显改善(P＜0.05),总积分改善中以胃脘堵闷(0.397)和胀满(0.330)作用最大,其次为嘈杂(0.292)、胃痛(0.283)、纳差(0.273)、嗳气(0.189)。各辨证组间主症及总积分改善均无差异(P=0.113和0.150);血瘀组与非血瘀组主症及总积分改善有统计学差异(P=0.039和0.021)、纳差和嗳气改善有统计学差异(P=0.040和0.034);(4)胃镜病理:治疗后胃镜下主要病变积分、总积分和病理主要病变积分、总积分改善均有统计学差异(P＜0.05),各辨证组间以上各项改善均无差异(P＞0.05);血瘀组和非血瘀组病理主要病变及总积分改善有统计学差异(P=0.028和0.036),而胃镜主要病变及总积分改善无差异(P=0.387和0.207)。【结论】1慢性萎缩性胃炎中医证候特征及辨证用药规律慢性萎缩性胃炎临床表现以胃脘胀满、疼痛、堵闷、嗳气、纳差等消化不良症状为主,伴疲乏、消瘦等全身症状以及紧张、焦虑、恐癌等心理症状。CAG病机为虚实夹杂,虚以气虚、阴虚为主,实以气滞、血瘀为主,常见证型为脾胃虚弱、肝胃不和、脾胃湿热、胃阴不足及胃络瘀血;治疗侧重健脾、理气、活血。常在主方基础上,综合本证型病机特点、药物间相互作用及胃腑喜润恶燥、喜通降恶郁滞的生理特性,适当佐用其他类药物,使兼顾病机更全面,提高主药疗效。脾胃虚弱证治以甘温补益、健脾扶中为法,以香砂六君子汤(脾胃虚寒用黄芪建中汤)加减,常配伍理气、活血及消导药;肝胃不和证以辛香理气、和胃通降为法,用四逆散或柴胡疏肝散合金铃子散加减,常与活血、健脾、清热、养阴药配伍。脾胃湿热证以清热化湿为法,以黄芩滑石汤或藿朴夏苓汤或香砂平胃散加减,佐以芳香化湿及健脾淡渗药,配伍理气药以疏理气机、健脾药以助纳运。胃阴不足证以甘凉濡润、滋养胃阴为法,以一贯煎或益胃汤加减,少佐理气、醒脾消导药,防呆滞气机,少佐黄芪、肉桂等甘温之品从阳引阴。胃络瘀血证以活血理气通络为法,丹参饮或失笑散加减,此法贯穿治疗始终,常配合其他方法使用。应用时须区别血瘀程度、病变趋势,酌情选用和血、活血或破血等不同活血化瘀药物。兼气血不足者,配合党参、当归、白芍等益气养血;配伍理气药,首选活血兼有理气作用的药物,以通利血分之滞。2导师唐旭东教授治疗慢性萎缩性胃炎思维模式与用药经验(1)病机及辨证:认为CAG中医诊断以“痞满”、“胃脘痛”为宜;病机为虚实夹杂,脾胃虚弱是病理基础,气机阻滞、胃失和降是主要病机及重要环节,血瘀普遍存在,是疾病发生、发展甚至恶变的关键环节,单纯血瘀证并不多见,常伴发于其他证候,诊断时可不必拘泥于瘀血证的全部症状和体征。强调宏微观辨证结合、兼顾地域、气候、年龄等因素综合辨证。(2)治则治法:治疗重视调理气血,以气血为线贯穿各种治法。处方用药坚持攻补兼施,以补为主,寓通于补的原则,补,主要是补气、温阳,滋阴、补血;攻,重在理气活血通降导滞。(3)处方用药:理气通降常用香苏饮、四逆散、柴胡疏肝散、丹参饮等。常配伍滋阴柔和之品防温燥伤阴,理气兼顾健脾,理气配伍活血,气血同治;活血化瘀常用失笑散、丹参饮、金铃子散等,强调根据虚实主次、标本缓急选用不同作用程度的活血化瘀药,配合其他治法及药物,注意顾护脾胃正气;益气健脾常用四君子汤、香砂六君子汤,反对壅补,主张通补,即在运用理气、活血等药物保持脾胃通降功能基础上调补;清热化湿常用黄芩滑石汤、藿朴夏苓汤、半夏泻心汤及温胆汤等,常化湿理气并用,化湿兼顾健脾;养阴常用益胃汤或一贯煎,常配伍理气及健脾药防滋腻碍胃。此外,注意药物间配伍和对症治疗,调理大便以助通降。(4)强调用药平和、科学选择服药时间、足疗程治疗、强调应个人养生与药物治疗结合,强调长期随访、定期复查,强调定位活检和规范病理诊断;重视胃癌前病变,对肠化尤其异型增生进行针对性用药。3中医治疗CAG临床疗效评价中医治疗CAG在临床症状、基于患者报告临床结局(PRO)量表5个维度及总积分、胃镜下粘膜病变、病理组织学均有不同程度的改善。其中非血瘀组患者嗳气、纳差等消化不良症状改善优于血瘀组;血瘀组病理积分改善尤其肠化、萎缩优于非活血化瘀组,说明活血化瘀对于改善萎缩,防止病变进展具有重要作用。临床症状和PRO量表中,以消化不良、心理和全身症状改善最大,对社会功能影响尚待进一步研究验证。当前中医治疗CAG疗效评价还存在很多问题,建议今后研究:(1)定位活检、规范病理诊断,加强质量控制。(2)严格科研设计,遵循随机化原则,做好分配方案隐藏,可实行盲态评价;选择空白对照或西药常规治疗对照,避免疗效不确定的中成药;保证足够样本量;采用新近公认的疾病诊断标准,保证病例的可比性。(3)疗效指标选择:避免将病理、胃镜、症状混淆,建议各指标采用积分方法做前后比较,合理划分主、次病变(症状),参考新的悉尼分类系统对病理组织学病变进行规范分级和赋分,对于癌变意义大的异型增生进行深入评价;合理而实用的镜下病变分级有待进一步研究;症状分级及赋分要统一,主症可从频率和程度两方面综合评价,并予以较高权重;进行长期随访和疗效观测,观察死亡率、癌变率等终点指标;重视生活质量及患者自我报告临床结局的评价。(4)疗程须3个月以上,做好辨证分型和症状、舌、脉等术语规范。更多还原

【Abstract】 Chronic atrophic gastritis(CAG) as a commonest gastrointestinal disease, has higher prevalence and threatens healthy seriously. To date, general-accepted effective therapy remains absent. TCM may exert a promising option. But problems exist in therapeutic effect evaluation impair the progress of clinical research.Aim To conclude and analyze the differentiation-prescription rules of CAG; to evaluate the therapeutic effect of TCM for the treatment of CAG, to explore the evaluating methods and raise current problems.Method To analyze the rules of pathogenesis, differentiation and prescription of CAG, by literature analysis and dinning the experience of professor Tang ; to evaluate the therapeutic effect of CAG treated with TCM, and to address the characteristics, advantage and current problem by conducting systematic review and observing efficacy of 65 cases with CAG treated by TCM based on syndrome differentiation.Result1. Differentiation-prescription rules of CAG:(1) Results from literatures analysis: Spleen-stomach deficiency (34.2%) , disharmony between liver and stomach (21.3 %) , stomach-yin deficiency (18.6%) , spleen-stomach damp-heat (15.6%) and blood stasis in stomach collaterals (18.1 %) are the commonest syndromes. Qi and yin deficiency (23.3 % VS 23.5 %) dominate at deficient aspect, qi stagnation and blood stasis (26.7 % VS 18.6%) dominate at excess aspect. Common-used drugs include invigorating spleen, regulating qi, eliminating damp, nourishing yin, promoting blood circulation and promoting digestion, including Bai-shao, Bai-zhu, Ban-xia, Chen-pi, Fu-ling, and etc. Spleen-stomach deficiency syndrome treated with Xiang-sha-liu-jun-zi-tang, combined with drugs of regulating qi, warming interior, promoting blood circulation and nourishing yin; disharmony between liver and stomach syndrome treated with Si-ni-san or Chai-hu-shu-gan-san and Jin-ling-zi-san, spleen-stomach damp-heat syndrome treated with Huang-qin-hua-shi-tang or Huang-lian-wen-dan-tang combined with drugs of regulating qi and invigorating spleen; stomach-yin deficiency treated with Yi-guan-jian or Yi-wei-tang, matched drugs of regulating qi, promoting blood circulation and promoting digestion; blood stasis in stomach collaterals syndrome treated with Shi-xiao-san or Dan-shen-yin, combinded with drugs of regulating qi, invigorating spleen and nourishing yin.(2) Differentiation-prescription experience of professor Tang: Major treating method is regulating qi to promote stomach empting and descending, added drugs of promoting blood circulation, invigorating spleen, eliminating damp; common-used prescriptions includes Xiang-su-yin, Si-ni-san, Xiao-xian-xiong-tang, Jin-ling-zi-san, Dan-shen-yin,Shi-xiao-san and Zuo-jin-wan; drugs include Huang-lian, Chen-pi, Ban-xia, Su-geng, Wu-zei-gu, Yuan-hu, Chuang-lian-zi, and etc;common used drug pairs like Chuang-lian-zi=>Yuan-hu,Xiang-fu=>Chen-pi, Ban-xia=>Huang-lian, and etc.2. Evaluation of therapeutic effect of TCM for the treatment of CAG based on syndrome differentiation(1) Systematic review on TCM for the treatment of CAG: The efficacy was evaluated from both number and score changes. The atrophy improvement of TCM group is more significant than controls (P=0.004 VS 0.008 ), compared with vitacoenzyme, hericium and blank control (P=0.0001, 0.0002 VS 0.01), while symptomatic treatment superior to TCM (P=0.03); For improving IM, TCM is superior to controls (P=0.02 VS P<0.00001), compared with hericium, blank and symptomatic medication (P=0.02, 0.007 VS 0.02), with vitacoenzyme (P=0.69) .For improvement DYS of TCM group is more significant than controls (P=0.006 VS 0.004), compared with symptomatic medication and blank control (P=0.11 VS 0.09), with vitacoenzyme (P=0.0004) .For improving granula-like mucosa and bile reflux, TCM is superior to controls (P=0.05 VS 0.005) ,compared with vitacoenzyme and hericium for visible vessel change (P=0.25 VS 0.83). For Hp eradicative rate, there are significance between TCM and control (P=0.009), with hericium, blank control and bismuth potassium citrate (P=0.02, 0.009 VS 0.009), with hericium and symptomatic medication (P=0.70 VS 0.74) ;for overall symptomatic improvement, TCM is more significant than control (P=0.008) ,for stomach pain (P<0.00001) , epigastric distension and fullness (P < 0.00001) ,belching (P=0.18 VS 0.22) , poor appetite (P=0.0007), for disordered stool (P=0.002 VS 0.03) , heart burn (P<0.00001) , acid reflux (P<0.00001).(2) Clinical observation on 65 cases with CAG treated with TCM based on syndrome differentiation: patient of blood stasis with longer course (P=0.044) , more severe pathological lesions (P=0.026) ,non-blood stasis group with female dominance (P=0.013) ,more severe symptoms and PRO scores (P=0.030 VS 0.003) . After treatment the total symptom score, PRO score, endoscopic findings and pathological lesions were improved significantly (P<0.05); dimensions of PRO attribute to overall improvement as dyspepsia ( 0.423 ) >general symptoms (0.362)> Psychological function(0.353) >reflux (0.238) >social function (0.141)> disordered stool (0.106), the social status remains unchanged (P=0.089) .Total symptom scores improvement of non blood stasis group is superior (P=0.004) , especially belching and poor appetite(P=0.040 VS 0.034 ) ,symptoms attribute to overall improvement as gastric fullness (0.397) ,distention (0.330), heart bum (0.292), gastric pain (0.283) ,poor appetite (0.273) ,belching (0.189) . the pathological improvement of blood stasis group is superior (P=0.036) .Conclusion1. Differentiation-prescription rules:CAG manifests as non-specific dyspeptic symptoms like gastric fullness and distention, pain, belching, poor appetite, disordered defecation, general symptoms like lassitude, anorexia and psychological ones like nervous, anxiety and fear of carcinogenesis. The pathogenesis characterized by qi and yin deficiency dominance in deficient aspect, with qi stagnation and blood stasis dominance in excess aspect. Spleen-stomach deficiency is the basic pathogenesis, qi stagnation and blood stasis play a key role in occurrence and development. Commonest syndromes include disharmony and stagnating heat of liver-stomach, spleen-stomach deficiency, damp-heat in middle-Jiao, stomach yin deficiency. Blood stasis of stomach collateral developed in the long course of the disease, accompanied with other syndrome. Main treating method is regulating qi to promoting stomach soothing and descending, matched promoting blood circulating, invigorating spleen, eliminating damp; Each syndrome treated by major prescription, which modified with drugs of other functions, to prevent intense function or adverse effect of major drugs, by comprehensively considering the pathogenic character of the syndrome, drug interaction and the physiological nature of stomach. 2. Therapeutic effect evaluation of TCM for the treatment of CAGThe TCM was superior to controls in improving symptoms, five dimensions of PRO scale, endoscopic findings and pathological changes. Non blood stasis group is superior t in improving dyspeptic symptoms like belching and poor appetite; blood stasis group has more severe pathological lesions and exhibits more significant improvement after treatment. It is concluded that promoting blood circulation plays an important role in improving atrophy, IM and preventing carcinogenesis, which should be used careful for patient with digestion disorder. The phenomena of no change in social status still need further research.Some problems encountered in effect evaluation, which should be improved from following aspects: (1) Making biopsy from constant location, standardizing pathological operations, strengthening qualify control. (2) Strengthening research design, including randomization and allocation conceal, blind evaluation, choosing blank or conventional treatment as control, avoiding controls without recognized efficacy, sufficient sample size, applying recognized diagnostic criteria. (3) Selection of effect evaluating method: Intermingle of symptom, endoscopic and pathological changes should be avoided, scores of above items of pre and after treatment is recommended, differentiate the major and other lesion. The grade and scoring of pathological lesions should refer to updated Sydney system, and make further evaluation for DYS; rational and practical grading method still need further study. The classification and scoring of symptoms should be unify, the major ones should be evaluated from both frequency and intensity, longer duration and follow-up study to observe mortality and gastric cancer incidence rate, pay more attention to evaluation of the health related quality of life and patient reported outcome. (4) Treatment duration should be longer than 3 months, standardizing the Traditional Chinese Medicine Terms of CAG.更多还原