多发性骨髓瘤中医证型及相关因素多元统计分析
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摘要
背景
多发性骨髓瘤(MM)是恶性浆细胞病中最常见的一种类型,属祖国医学“骨痹”“虚劳”、“腰痛”、“骨蚀”等范畴。目前中医药治疗MM已取得较好的疗效,但查阅近十年国内文献,各家采用的MM辨证分型方法各异,观点繁多,持论不一,大多数以主观经验推理为主,辨证标准不统一,缺乏大规模、多中心循证医学研究。这些问题导致虽然中医辨证论治在改善MM临床症状、缓解病情方面具有独特的优势,但由于缺乏客观化、标准化,难以总结推广,不利于中医学术交流和发展。
本研究重点放在探索MM辨证的客观化、规范化、标准化方面。拟从循证医学及微观辨证角度,借助数学多元统计方法,对MM的辨证分型规律及相关因素进行探讨,为中医建立和完善MM的规范化辨证治疗体系,提供客观的依据。
目的
研究初诊MM中医证型分布规律,观察初诊MM患者相关因素(包括年龄、性别、病程、西医分期、西医类型)与中医证型分布的关系,重点观察血清肿瘤负荷指标及预后指标[血β2-微球蛋白(β2-MG)、血乳酸脱氢酶(LDH)、血C-反应蛋白(CRP)、血清白蛋白(ALB)]与中医证型的相关性,从微观辨证角度总结中医证型的规律。
方法
本研究为临床研究,分循证医学回顾性研究和临床前瞻性研究两部分进行。
1、MM的循证医学回顾性研究
联合北京中医药大学附属东直门医院、上海中医药大学附属曙光医院、广州中医药大学第一附属医院、广东省中医院、广州市中医医院五家中医医院为合作单位,采用循证医学回顾性调查研究的方法,以各医院1997年1月至2007年12月入院符合标准的初诊MM患者病历为调研对象,对调研病历的数据进行统计：运用病例聚类分析与临床专家认证相结合的方法总结初诊MM中医证型分布规律,归纳初诊MM的基本中医证型。应用主成分分析,找出各证型的主要及次要症状,优化初诊MM辨证的诊断标准。在确定中医证型分布规律的前提下,采用Spearman相关性分析、单因素方差分析及卡方检验,研究其相关因素(包括年龄、性别、病程、西医分期、西医类型)、血清肿瘤负荷指标及预后指标(血β2-MG、LDH、CRP、ALB)与中医证型分布的关系。
2.、MM的前瞻性研究
临床观察广州市中医医院、广东省中医院、江苏省中医院血液内科2008年1月一2010年1月门诊就诊及住院、符合诊断标准和纳入标准的初诊MM患者,根据临床经验进行证型判别,采用频数分析,观察中医正虚证、邪实证分布情况；观察中医正虚证与邪实证兼挟情况；采用Spearman相关性分析、单因素方差分析及卡方检验,观察患者病程、西医分期及类型、血清肿瘤负荷指标及预后指标(血β2-MG、LDH、CRP、ALB)等与中医证型分布的相关性。并与回顾性调查研究结果相比较,总结其内在规律。
结果
1.MM的循证医学回顾性研究结果
1.1一般资料：
共调研1997年1月至2007年12月入院符合标准的初诊MM患者病历128例,包括广州中医药大学第一附属医院26例,广东省中医院40例,广州市中医医院11例,北京中医药大学附属东直门医院24例、上海中医药大学附属曙光医院27例。其中男72例(56.25%),女56例(43.75%),年龄最小16岁,最大88岁,平均年龄62.77±12.9岁；病程最长120个月,最短3天,平均病程8.17±16.86(月)。
128例中,ⅢA期57例(44.53%),ⅢB期41例(32.03%),ⅡA期14例(10.94%),ⅡB期6例(4.69%),ⅠA期2例(1.56%),ⅠB期8例(6.25%)。93例病历进行了西医分型,其中IgG-κ型29例(31.2%),IgG-λ型11例(11.8%),λ型8例(8.6%),IgA-κ型5例(5.4%),IgA-λ型12例(12.9%)IgA型7例(7.5%),κ型8例(8.6%),IgA-IgG-K型1例(1.1%),IgG型9例(9.7%),不分泌型3例(3.2%)。
1.2.初诊的MM证型分布规律：
1.2.1通过病例聚类分析,归纳出MM五种临床证型：脾肾两虚、脾肾阳虚、脾肾阴虚、水湿内蕴、痰毒瘀阻。
1.2.2与此同时,通过中医专家组逐一对128例病历进行辨证,总结出临床五种常见类型：①脾肾两虚；②脾肾两虚、痰瘀毒滞；③脾肾阳虚,痰湿内阻；④脾肾阴虚,湿热蕴毒；⑤脾肾阴虚,痰瘀互结。
1.2.3比较上述两者异同及优缺点,认为病例聚类的结果分散性较好,证型分布清晰,特征突出,能画龙点睛地阐明辨证要素,但不能完全覆盖临床实践；中医专家组的意见贴合临床实际,符合临床需要,但由于临床证型种类繁多,最终只能选取占总病例数94%的五大证型作为常见证型,层次感和分散性不强。究其两者的关系是相互补充、相辅相成的,两者结合体现了临床的虚实夹杂,前者是后者内在规律的体现。故确立聚类分析结果：脾肾两虚、脾肾阳虚、脾肾阴虚、水湿内蕴、痰毒瘀阻五种类型,为MM临床基本证型。其中前三者为正虚证,后两者为邪实证。
1.2.4在确定中医基本证型分布规律的前提下,通过主成分分析,归纳出各证型的主症及次症：
脾肾两虚：主症：腰膝酸软、倦怠乏力、食少纳呆、骨痛、少气懒言。次症：面色萎黄、面色少华、自汗、心悸、舌淡苔白、脉弱。
脾肾阳虚：主症：畏寒肢冷、大便不实、面色晄白、脘腹胀满、面肢浮肿。次症：小便清长、口淡不渴、夜尿频多、舌淡胖苔白、脉沉。
脾肾阴虚：主症：口干咽燥、五心烦热、发热、烦渴、盗汗。次症：舌红苔少,脉弦细数。
水湿内蕴：主症：脘腹胀满、面肢浮肿、食少纳呆、口淡不渴、苔白。次症：大便不实、心悸、恶心呕吐、肢体麻木、舌淡胖苔腻、脉沉细。
痰毒瘀阻：主症：眩晕耳鸣、恶心呕吐、溲赤、发热、面色晦暗。次症：肌肤甲错、肢体麻木、大便干结、烦渴、失眠、舌暗红苔黄腻、脉滑。
1.2.5参照上述五种基本证型标准再对128例病历进行辨证,并通过频数分析表明,脾肾两虚占32.03%,脾肾阳虚11.72%,脾肾阴虚6.25%,水湿内蕴16%,痰毒瘀阻34%。正虚证中以脾肾两虚类型分布最广,邪实证中以痰毒瘀阻类型多见。
1.2.6调研中出现频率最高的临床表现依次为腰膝酸软、食少纳呆、倦怠乏力、少气懒言,舌淡白,脉沉。舌紫暗的几率为41.4%。初诊病人骨痛的几率占40.6%,面色少华(25%)、萎黄(18.75%)、晄白(14.06%)的总几率占57.81%。
1.3.各因素相关性分析：
1.3.1年龄：年龄与中医证型分布有一定的相关性。卡方检验,痰毒瘀阻的P<0.05,表明痰毒瘀阻在各年龄段有显著性差异。纵观年龄与证型分布,痰毒瘀阻的证型在40-49岁期间最多见,在80岁以上最少见。
1.3.2性别：性别与中医证型基本不相关。卡方检验,在各个证型,男女性别上均无显著性差异。
1.3.3病程：病程和中医证型分布存在明显相关性。单因素方差分析,各个证型间的病程指标有显著差异。水湿内蕴型和脾肾两虚型病程相对较短,脾肾阳虚型病程相对较长。
1.3.4西医分期：分期和中医证型分布没有明显相关性。但单因素方差分析,在ⅢA期、ⅢB期各个证型分布有显著差异。ⅢA期痰毒瘀阻型多见；ⅢB期脾肾两虚型多见。
1.3.5西医类型：西医类型和中医证型分布没有明显相关性。卡方检验,IgG-κ型中脾肾两虚、痰毒瘀阻型为多。
1.3.6血β2-MG：血β2-MG和中医证型分布有微弱的相关性。单因素方差分析,各个证型间的血β2-MG指标没有显著差异。且两两证型比较也无显著差异。
1.3.7血LDH：血LDH和中医证型分布有微弱的相关性。单因素方差分析,各个证型间的血LDH指标没有显著差异。但两两证型比较有显著差异。血LDH值脾肾阳虚>脾肾阴虚>脾肾两虚,痰毒瘀阻>水湿内蕴。
1.3.8血CRP：血CRP和中医证型分布有微弱的相关性。但单因素方差分析,各个证型间的血CRP指标没有显著差异。两两比较,脾肾两虚和痰毒瘀阻、脾肾阳虚和水湿内蕴、脾肾阳虚和痰毒瘀阻有显著差异。痰毒瘀阻型血CRP最高,脾肾阳虚型血CRP最低。
1.3.9血ALB：血ALB和中医证型分布基本没有相关性。单因素方差分析,各个证型间的血ALB指标没有显著差异。但两两比较,脾肾阳虚型血ALB最低,痰毒瘀阻型血ALB最高。
2.MM的前瞻性临床研究结果
2.1.一般资料：
共调研2008年1月—2010年1月门诊就诊及住院的符合诊断标准和纳入标准的初诊MM患者23例,其中广州市中医医院3例,广东省中医院10例,江苏省中医院10例。男15例(65.21%),女8例(34.79%),年龄最小51岁,最大82岁,平均年龄64.39±10.44岁；病程最长36个月,最短15天,平均病程9.85±9.67(月)。
23例中ⅢA期6例(26.09%),ⅢB期13例(56.52%),ⅡA期3例(13.04%),ⅡB期1例(4.35%)。IgG-κ型5例(21.7%),IgG-λ型4例(17.4%),λ型2例(8.7%),IgA-κ型1例(4.35%),IgA-λ型4例(17.4%),IgA型2例(8.7%),IgG型1例(4.35%),κ型2例(8.7%),IgD型1例(4.35%),不分泌型1例(4.35%)。
2.2.初诊的MM证型分布规律：
2.2.1临床23例中脾肾两虚5例(21.7%),脾肾两虚夹痰瘀9例(39.1%),脾肾阴虚夹痰瘀4例(17.4%),脾肾阳虚兼湿毒瘀阻3例(13.1%),痰瘀毒蕴2例(8.7%)。
2.2.2临床纯虚无邪实、纯实无正虚的证型所占比例不高(7／23,30.4%),大多数仍为虚实夹杂证。
2.3.各因素相关性分析：
2.3.1病程：病程和中医证型分布存在弱相关性。虽无统计学意义上的差异,但通过统计数值仍可以看出脾肾阳虚兼湿毒瘀阻病程相对较长。
2.3.2西医分期、类型：西医分期、类型和中医证型分布没有明显相关性。通过卡方检验,各个证型分布在西医分期、类型上也没有显著差异。
2.3.3血β2-MG、血LDH：血β2-MG、LDH和中医证型分布没有明显相关性。卡方检验也提示各个证型间的血β2-MG、LDH指标没有显著差异。两两证型比较也无显著差异。
2.3.4血CRP：通过相关系数,表明血CRP和中医证型分布无明显相关性。卡方检验表明,各个证型间的血CRP指标无显著差异。但两两比较,脾肾两虚和痰瘀毒蕴、脾肾两虚和脾肾两虚夹痰瘀型有显著差异。痰瘀毒蕴型血CRP较脾肾两虚型、脾肾两虚夹痰瘀型为高。
2.3.5血ALB：相关系数表明血ALB和中医证型分布基本没有相关性。卡方检验表明各个证型间的血ALB指标没有显著差异。但脾肾阳虚兼湿毒瘀阻型和痰瘀毒蕴型两两比较有显著差异。脾肾阳虚兼湿毒瘀阻型血ALB较痰瘀毒蕴型血ALB低。
结论
1.初诊MM证型分布规律及病因病机总结
1.1本回顾性研究中通过病例聚类分析,归纳出MM五种临床证型：脾肾两虚、脾肾阳虚、脾肾阴虚、水湿内蕴、痰毒瘀阻。通过中医专家组总结出临床五种常见类型：①脾肾两虚；②脾肾两虚、痰瘀毒滞；③脾肾阳虚,痰湿内阻；④脾肾阴虚,湿热蕴毒；⑤脾肾阴虚,痰瘀互结。究其两者的关系是相互补充、相辅相成的,两者结合体现了临床的虚实夹杂,前者是后者内在规律的体现。故依据中医教材《中医内科学》的辨证论治撰写模式,确立了聚类分析的结果：脾肾两虚、脾肾阳虚、脾肾阴虚、水湿内蕴、痰毒瘀阻五种类型为初诊MM临床基本证型。前瞻性研究中观察到脾肾两虚、脾肾两虚夹痰瘀、脾肾阴虚夹痰瘀、脾肾阳虚兼湿毒瘀阻、痰瘀毒蕴五种临床证型的存在,揭示了回顾性研究聚类分析的结果可以作为初诊MM的临床基本证型,但其结果只为我们提供了基本要素及原则,临床运用仍需根据实际情况灵活把握兼夹。
1.2回顾性及前瞻性研究均阐明了初诊MM的中医病因病机是以脾肾虚为本,痰瘀湿毒为要。由于六淫、饮食、情志等因素使阴阳气血失调,脾肾亏损,风寒湿或风湿热邪侵袭机体,导致气血运行不畅,痰瘀内生,痰瘀湿毒相互胶结,内搏于骨,深入于髓,痹阻经络,经脉筋骨失于濡养或蚀骨伤髓而致骨痹。其中肾虚为本病发病主要内在因素,痰瘀湿毒为主要病理关键。邪实中毒邪极少单独致病,常有挟痰挟瘀挟虚之特点。并注意整个疾病过程中不能忽视瘀的存在。
1.3提示了初诊的MM首发症状以骨痛、贫血为多。临床上出现骨痛及贫血应警惕本病。
2.初诊MM微观辨证的建立
回顾性研究中表明MM各相关因素(包括年龄、性别、病程、西医分期、西医类型)、血清肿瘤负荷指标及预后指标(血β2-MG、LDH、CRP、ALB)在疾病不同证型上有各自的相关性和差异性。前瞻性研究中由于收集样本数相对较少,上述大多数指标与中医证型分布之间未能做出相关性和差异性,但分析其具体结果大体符合回顾性研究的结论,基本能在客观上论证回顾性调查研究结果的确切性、实用性。通过这些指标,能帮助客观把握中医辨证、建立微观辨证。
3.数学多元统计方法与中医标准化、客观化的关系
3.1回顾性研究显示了、前瞻性研究验证了数学多元统计方法——聚类分析运用于中医虽能综合反映证候的临床信息特征、对样本证候特征做出高度概括——分为虚证和实证两大类,但实际上临床疾病复杂多变,往往会出现证型与证型之间的不同组合,形成兼证。故虚实夹杂的证型兼顾不全,不能涵盖临床所有证型。其基本证型的确立只为我们提供了初诊MM的基本辨证要素,临床需根据中医辨证思维综合考虑、灵活夹杂才能客观反映实际情况。提示单纯依靠聚类算法一般不会得到圆满的结果,聚类分析结果必须与该领域的经验结合才能切实可行。
3.2主成分分析运用于中医辨证标准的确立,虽然在不丢失原来主要信息的前提下,用简单的几个证候要素反应总体的信息,简化及明确了证候标准。但目前仍有诸多问题,如初级症候要素筛选、主成分要素提取的最佳路径、样本数量为多少最科学、经济、合理等等,需要在日后的不断研究中结合临床经验进一步探索。
3.3需要大量、均衡的样本数才能充分保证实验结果的完善性。但由于MM发病率较低,加之我们收集的为初诊病例,获得符合标准的病例数相对较少,收集病例数有限,对结果的统计意义有一定的影响。
以上提示了中医临床证候纷繁复杂,具有复合性和复杂性等特点,面对如此复杂的理论体系,不能刻板地运用数学方法来替代灵活的辨证施治,单纯数理统计知识得出的结论运用于临床实践是不全面的,机械采用单纯的数理统计知识来研究、剖析中医是不合适的。只有在保持原有中医辨证方法特色和优势的基础上,结合现代数学研究方法,找到两者的交融点、平衡点,使中医传统经验技术与数学客观依据有机结合,才能有效指导临床实践,实现有中医特色的辨证客观化、规范化。
4.回顾性病历调查与前瞻性临床研究优缺点比较
回顾性病历调查虽能在短时间内获取大量样本资料,但也有自身难以克服的缺点,如临床医生书写原始病历时,对中医证候信息的采集侧重点不同、表达信息不规范；部分有意义的信息及数据由于当时医疗条件的限制而致缺失等问题,可能会影响部分结果的准确性。前瞻性临床研究由于有目的地采集临床信息,故减少了原始指标包含信息的损失,从而实现对相关证候信息、西医客观指标等资料全面而有效的分析处理,保证了结果的真实性、可靠性,遗憾的是短时间内难以获得满意数量的样本资料。
综上所述,本研究的初衷是借助数学的方法实现中医辨证的客观化、标准化。诚然,通过临床数据表明运用数学多元统计的方法帮助中医辨证实现客观化、规范化、微观化是切实可行的,但发现数学多元统计方法运用于中医药研究显示出某些不完善性,这是由于中医自身特点决定的。如何找到两者的切入点,达到既能有效地应用于临床实践,又便于总结、交流、推广的目的,也是标准化研究的难点、重点。本研究属于初始阶段,有一定的局限性,寻找到完全适应中医证候复杂性特点的方法任重道远,尚待更多、更大样本、多种学科联合的后续研究。相信通过我们不懈地努力,中医现代证候研究必然会取得实质性的突破。
Research background
Multiple Myeloma(MM) is the most common type of hematologic tumor worldwide. it belongs to bone Bi-Syndrome、consumptive disease、lumbago and Erosion of bone in Traditional Chinese Medicine(TCM). But through consulting recent ten years'domestic literature, We have found that TCM syndrome differentiation of MM have many disadvantages, such as experiential inference, not unified standard, and lack of multicenter、large-scale evidence-based research. These are the obstacles in the development of TCM. So this study focuses on the objectification and standardization of TCM syndrome differentiation. From the perspective of Evidence-Based Medicine (EBM) and microcosmic syndrome differentiation, this study will make a discussion on the distribution of TCM syndrome type and related factors of MM by means of multivariate statistical method. It will supply an objective basis of TCM's standardization of syndrome differentiation.
Objective
To investigate newly diagnosed MM's distribution of TCM syndrome type, observe the relationship between distribution of TCM syndrome type and related factors (including age、gender、course of disease、clinical stage and types of Western Medicine); Emphasis on indexes of tumor burden and prognosis (such asβ2-MG、LDH、CRP、ALB in blood). From the perspective of microcosmic syndrome differentiation, the rule of TCM syndrome differentiation is summarized.
Method
This research includes two parts, one is the clinical retrospective study, the other is the prospective clinical study.
1.The clinical retrospective study of MM based on evidence-based medicine
Combined with Dongzhimen Hospital Attached to Beijing TCM University, Affiliated Shuguang Hospital of Shanghai University of TCM, the First Affiliated Hospital of Guangzhou University of TCM, Guangzhou's TCM Hospital and Guangdong Provincial Hospital of TCM, From January 1997 to December 2007, the patients'cases were collected, who meet the inclusion and diagnostic criteria, and the statistical analysis has been made based on the data. By applying cluster analysis, and with clinical practice, distribution of TCM syndrome type was summarized. By means of Principal Component Analysis (PCA), the main and accessory symptoms were found. By means of correlation analysis, one-way anova, and chi-square test, we studied the relationship between distribution of TCM syndrome type and related factors (including age、gender、course of disease、clinical stage and types of Western Medicine), indexes of tumor burden and Prognosis.
2. Prospective clinical study on MM
Investigating newly diagnosed MM cases during January 2008-January 2010, combined with Guangzhou's TCM Hospital, Guangdong Provincial Hospital of TCM and Jiangshu Provincial Hospital of TCM, we make differentiation according to clinical experience, Using frequency analysis, observing the distribution of asthenia and sthenia syndrome. By means of correlation analysis, one-way anova, and chi-square test, we observe relationship between distribution of TCM syndrome type and related factors (including course of disease、clinical stage and types of Western Medicine), Indexes of tumor burden and prognosis after the cases are diagnosed according to distribution of TCM syndrome type. We sum up the inherent laws through comparing the results of the retrospective and prospective clinical study.
Result
1.The clinical retrospective study of MM based on evidence-based medicine
1.1 General data of patients:
128 MM cases have been investigated, who meet the inclusion and diagnostic criteria. Including 26 cases in the First Affiliated Hospital of Guangzhou University of TCM,40 cases in Guangdong Provincial Hospital of TCM,11 cases in Guangzhou's TCM Hospital,24 cases in Dongzhimen Hospital attached to Beijing TCM University,27 cases in Affiliated Shuguang Hospital of Shanghai University of TCM. And male 72 examples(56.25%), female 56 cases (43.75%), Among the patients, the youngest was 16 years old, and the eldest was 88 years old, of the128 cases average age was 62.77±12.9 years old, The longest course was 120 months, and shortest course was three days, the average duration was 8.17±16.86 (month).
Of the 128 cases,57 patients (44.53%) were at stageⅢA,41 patients (32.03%) were at stageⅢB,14 patients (10.94%) were at stageⅡA,6 patients (4.69%) were at stageⅡB,2 patients (1.56%) were at stageⅠA, 8 patients (6.25%) were at stageⅠB.93 examples were given types.29
cases (31.2%) were IgG-κtype,11 cases (11.8%) were IgG-λtype,8 cases (8.6%) wereλtype,5 cases (5.4%) were IgA-κtype,12 cases (12.9 %) were IgA-λtype,7 cases (7.5%) were IgA type,8 cases (8.6%) wereκtype, 1 cases (1.1%) were IgA-IgG-κtype,9 cases (9.7%) were IgG type, 3 cases (3.2%) were unsecretarial type.
1.2. MM's distribution of TCM syndrome type
1.2.1 By applying cluster analysis, the five clinic syndrome types of MM can be summarized:deficiency of spleen and kidney、spleen-kidney yang deficiency、spleen-kidney yin deficiency、dampness-fluid accumulating in the interior、stagnation of phlegm、poison and blood stasis.
1.2.2 Meanwhile, The experts summarized the five common clinic syndrome types of MM:①deficiency of spleen and kidney;②deficiency of spleen and kidney holding blood stasis、sputum and toxin;③spleen-kidney yang deficiency accompanying sputum-wetness;④spleen-kidney yin deficiency accompanying damp-heat-toxin。⑤spleen-kidney yin deficiency with sputum and blood stasis.
1.2.3 By comparing their difference、advantages and disadvantages, We believe that the results of cluster analysis have many advantages, such as good dispersion、syndromes clear、bright lines、feature highlights、clarifying the differentiation factor, but can not fully cover the clinical practice; The views of the expert group were in accordance with clinical practice, meet the clinical need, but because of the clinical syndromes was very complex. we only could select the five clinic syndrome types as the common syndrome, the common syndrome occupied 94% of the total number of cases, the level and dispersion were not strong. it was considered that the relationship between them was mutual complemented。The former was the embody of the latter. So almost all specialists considered that the results of the cluster analysis could used as the basic clinic syndrome types of MM. And the first three were the positive asthenia syndrome, the rest two were the evil sthenia syndrome.
1.2.4 By means of PCA, the main and accessory symptoms were summarized:
deficiency of spleen and kidney:
main symptoms:lassitude in loin and knee, lassitude, poor appetite, bone pain, weak pulse.
accessory symptoms:little qi and lazy to talk, sallow complexion, (?)sterless complexion, spontaneous sweating, palpitation, pale tongue with whitish fur.
yang deficiency of spleen and kidney:
main symptoms:aversion to cold, and cold limbs, loose stool, pale complexion, abdominal distention, edema.
accessory symptoms:weak taste and not thirsty, clear and long urine or urinating frequently at night, pale and enlarged tongue with whitish fur, deep Pulse.
spleen-kidney yin deficiency:
main symptoms:dry mouth and throat, feverish sensation over five centers, fever, polydipsia, night sweating.
accessory symptoms:red tongue with less fur, stringy、thin and fast Pulse.
dampness-fluid accumulating in the interior:
main symptoms:abdominal distention, edema, poor appetite, weak taste and not thirsty, whitish fur.
accessory symptoms:loose stool, palpitation, nausea, vomiting, limb numbness, pale and enlarged tongue with greasy fur, thin and deep Pulse.
stagnation of phlegm、poison and blood stasis:
main symptoms:dizziness, tinnitus, nausea, vomiting, little and yellow urine, fever, dim complexion.
accessory symptoms:scaly skin, limb numbness, dry stool, polydipsia, insomnia, dark red tongue with yellow greasy fur, slippery pulse.
1.2.5 The result of frequency analysis showed that deficiency of spleen and kidney accounted for 32.03%, yang deficiency of spleen and kidney accounted for 11.72%, Spleen-Kidney Yin Deficiency was 6.25%, dampness-fluid accumulating in the interior was 16%, stagnation of phlegm、poison and blood stasis occupied 34%. deficiency of spleen and kidney is most in deficiency Syndromes, stagnation of phlegm、poison and blood stasis is most in excess Syndromes.
1.2.6 The symptoms with the highest frequency were lassitude in loin and knee、poor appetite、lassitude、little qi and lazy to talk、pale tongue with whitish fur, deep Pulse. Probability of dark red tongue was 41.4%. In 128 cases, probability of bone pain was 40.6%, probability of Pale、sallow and lusterless complexion was 57.81%.
1.3. Correlation analysis of each factor
1.3.1 Age:MM's distribution of TCM syndrome type has correlation with age. Through chi-square test, stagnation of phlegm, poison and blood stasis has significance differences in various age stage. Stagnation of phlegm、poison and blood stasis type was the most in 40-49th period, and the rarest above 80 years old.
1.3.2 Gender:gender and distribution of TCM syndrome type was not related basically. Through chi-square test, there was no significant difference in sex.
1.3.3 Course of disease:course of disease showed significant correlation with distribution of TCM syndrome type. Through one-way anova, the comparison of course of disease in all TCM syndromes showed that type of dampness-fluid accumulating in the interior and deficiency of spleen and kidney type were shorter, yang deficiency of spleen and kidney type was longer.
1.3.4 Clinical stage:clinical stage was basically unrelated to Distribution of TCM syndrome type. There was significant statistical difference in clinical stage over the distribution of the five TCM syndromes. stagnation of phlegm, poison and blood stasis was found inⅢA, deficiency of spleen and kidney was found inⅢB.
1.3.5 Type of western medicine:type of western medicine was basically unrelated to distribution of TCM syndrome type. deficiency of spleen.and kidney and stagnation of phlegm、poison and blood stasis were found on IgG-кtype.
1.3.6 Bloodβ2-MG:Bloodβ2-MG was little inversely correlated with distribution of TCM syndrome type, But there was no significant statistical difference in them. Multiple comparisons showed no significant difference also.
1.3.7 Blood LDH:Blood LDH was little inversely correlated with distribution of TCM syndrome type. There was no significant statistical difference in distribution of TCM syndrome type. Multiple comparisons showed significant difference. The blood LDH in yang deficiency of spleen and kidney was higher than those in the other two deficiency Syndromes. The blood LDH in stagnation of phlegm、poison and blood stasis was higher than dampness-fluid accumulating in the interior.
1.3.8 Blood CRP:There was a positive correlation between blood CRP and distribution of TCM syndrome type. There was no significant statistical difference in distribution of TCM syndrome type. multiple comparisons showed the CRP in stagnation of phlegm、poison and blood stasis was the highest, but in yang deficiency of spleen and kidney was the lowest.
1.3.9 Blood ALB:Blood ALB was positive correlated with distribution of TCM syndrome type. There was no significant statistical difference in distribution of TCM syndrome type.multiple comparisons showed the ALB in stagnation of phlegm、poison and blood stasis was the highest, but in yang deficiency of spleen and kidney was the lowest.
2. Prospective clinical study on MM
2.1. General data of patients:
23 cases, Including 10 cases in Guangdong Provincial Hospital of TCM, 10 cases in Jiangsu Provincial Hospital of TCM,3 cases in Guangzhou's TCM Hospital. And male 15 examples (65.21%), female 8 cases (34.79%), Among the patients, the youngest is 51 years old. And the eldest 82, of the 23 cases Average age is 62.77±12.9 years old, the longest course is 36 months, and shortest course is 15 days. average duration is 9.85±9.67 (month).
Of the 23 cases,6 patients (26.09%) are at stageⅢA,13 patients (56.52 %) are at stageⅢB,3 patients (13.04%) are at stageⅡA,1 patients (4.35 %) are at stageⅡB.5 cases (27.1%) are IgG-кtype,4cases (17.4%) are IgG-λtype,2 cases (8.7%) areλtype, 1 cases (4.35%) are IgA-кtype, 4 cases (17.4%) are IgA-λtype,2 cases (8.7%) are IgA type,2 cases (8.7 %) areкtype, lcases (4.35%) are IgD type,1 cases (4.35%) are IgG type,
1 cases (4.35%) are unsecretarial type.
2.2. Distribution of TCM syndrome type of MM
2.2.1 Of the 23 cases,5 patients (21.7%) are deficiency of spleen and kidney,9 patients (39.1%) are deficiency of spleen and kidney holding sputum and blood stasis,4 patients (17.4%)are spleen-kidney yin deficiency accompanying sputum and blood stasis,3 patients (13.1%) are spleen-kidney yang deficiency accompanying damp-blood stasis-toxin。2 patients (8.7%) are stagnation of phlegm、poison and blood stasis.
2.2.2 In clinical, the asthenia and sthenia syndrome account for the proportion are not high (7/23,30.4%), Syndrome of intermingled deficiency and excess is the most in clinical.
2.3. Correlation Analysis of each factor
2.3.1 Course of disease:course of disease shows little correlation with distribution of TCM syndrome type. There'is no statistical difference between them, but the course of spleen-kidney yang deficiency accompanying damp-stasis-toxin is longer.
2.3.2 Clinical stage and type of western medicine:clinical stage and type of western medicine are basically unrelated to distribution of TCM syndrome type. There is no significant statistical difference in clinical stage and type of western medicine over the distribution of the five TCM syndromes.
2.3.3 Bloodβ2-MG and LDH:Bloodβ2-MG and LDH are positive correlated with distribution of TCM syndrome type. There is no significant statistical difference in distribution of TCM syndrome type. Multiple comparisons show no significant differences also.
2.3.4 Blood CRP:There is no correlation between blood CRP and distribution of TCM syndrome type. There is no significant statistical difference in distribution of TCM syndrome type. multiple comparisons show the CRP in stagnation of phlegm、poison and blood stasis is higher than in deficiency of spleen and kidney and deficiency of spleen and kidney holding sputum and blood stasis.
2.3.5 Blood ALB:Blood ALB is positive correlated with distribution of TCM syndrome type. There is no significant statistical difference in distribution of TCM syndrome type. multiple comparisons show the ALB in spleen-kidney yang deficiency accompanying damp-blood stasis-toxin is lower than stagnation of phlegm、poison and blood stasis.
Conclusion
1. newly diagnosed MM's distribution of TCM syndrome type, the etiology and pathogenesis
1.1 In the clinical retrospective study,by applying cluster analysis, the five clinic syndrome types of MM could be summarized:deficiency of spleen and kidney、spleen-kidney yang deficiency、spleen-kidney yin deficiency、dampness-fluid accumulating in the interior、stagnation of phlegm、poison and blood stasis. Meanwhile, the experts summarized the following five common clinic syndrome types of MM:①deficiency of spleen and kidney;②deficiency of spleen and kidney holding blood stasis and toxin;③spleen-kidney yang deficiency accompanying sputum-wetness;④spleen-kidney yin deficiency accompanying damp-heat-toxin。⑤spleen-kidney yin deficiency with sputum and blood stasis。By comparing their difference、advantages and disadvantages, it was considered that the relationship between them was mutual complemental。The former was the embody of the latter。So according to the write mode of syndrome differentiation and treatment in "Chinese Internal Medicine", almost all specialists considered that the results of the cluster analysis could be used as the basic clinic syndrome types of MM。In prospective clinical study on MM, there are the following five clinic syndrome types of MM, including deficiency of spleen and kidney、deficiency of spleen and kidney holding sputum and blood stasis、spleen-kidney yin deficiency accompanying sputum and blood stasis、spleen-kidney yang deficiency accompanying damp-blood stasis-toxin、stagnation of phlegm、poison and blood stasis. It shows the results of cluster analysis are the basic clinic syndrome types of MM, they reflect the basic elements of differentiation, we must use them flexibly according to the actual situation.
1.2 The retrospective and prospective study show that etiology and pathogenesis of MM in TCM are asthenia of spleen and kidney, also closely correlated with phlegm coagulation, blood stasis、dampness and toxin. Because of six exogenous pathogens, emotional frustration, improper diet, misbalance of qi/blood and yin/yang、asthenia of spleen and kidney are easy to be made, wind cold dampness and Pathogenic toxin will take advantage of the body's weak points and attack organism, Noxious blood stasis and phlegm accumulate near channels、meridians、muscle and joint, which lead to insufficient nourishment for tendon. So bone Bi-Syndrome is induced. In the etiology and pathogenesis, The key point of its pathogenesis is asthenia of kidney, also closely correlated with phlegm coagulation, blood stasis、dampness and toxin. Pathogenic toxin appears together with stasis、phlegm and asthenia frequently. And the importance of the blood stasis should not be ignored in the whole course of the disease.
1.3 The first symptom Is bone pain、anemia frequently. In clinic, when bone ache or anemia occurs, we should be alert of the existence of the disease.
2. The bulding of microcosmic syndrome differentiation
The clinical retrospective study shows that each influence factor is correlated with distribution of TCM syndrome type. And there are statistical differences in distribution of TCM syndrome type. Using these Indexes can achieve the syndrome differentiation objectively. In the prospective study, because of the few MM's samples, most of the above indexes have not been able to show the correlation and difference, the results are approximately same as the clinical retrospective study. These show that the results are practical. Using these indexes can help to achieve the syndrome differentiation of TCM
objectively.
3.The relationship between mathematical statistics method, objectification and standardization of TCM syndrome differentiation
3.1 Although using the cluster analysis in TCM can comprehensively reflect the clinical information characteristic and the basic elements of differentiation, it can not give dual attention to syndrome of intermingled deficiency and excess. Because of the TCM's complexity, the results of cluster analysis are the basic clinic syndrome types of MM only, we must use them flexibly according to the actual clinical situation. These show that the simply mathematical statistics method isn't fully suitable for the complex TCM. It should be considered comprehensively on clinical. The expert group opinion is still needed to reflect the clinic fact. The conclusion must connect with clinical practice.
3.2 By means of PCA, We established the standard of TCM, without losing the original premise of the main information, used a few simple elements of response syndrome to reflect the general information, simplify and clarify the standard syndrome. Bur there are still many problems when applying PCA to TCM, such as Filtering elements of primary symptoms, reducing symptoms of elements, the best ways and means to extract the most convincing of the number of samples, etc. It is needed to continue research in the future to further explore clinical experience.
3.3 Massive balanced sample numbers is needed to be able to guarantee the experimental result perfect. Because the incidence of MM is relatively low and the MM cases we collected are initially diagnosed, medical record which met the inclusion criteria is few, so the statistical significance is limited.
The above shows TCM compound and complex characteristics, the simply mathematical statistics method isn't completely suitable for the complex TCM. The conclusions of mathematical statistics applying to the clinical practice don't cover all the aspects. Only supported by mathematics and experience simultaneously, can the TCM realize the objectification and standardization of TCM syndrome differentiation.
4. compare with advantages and disadvantages of the retrospective and prospective clinical study.
Although the retrospective study can gain the massive sample data within a short time, but some information and data maybe be ignored because of medical condition limit at that time, it will affect the accuracy of the partial results possibly. In the prospective clinical study, the information manifests completely, it has guaranteed the result's authenticity. Unfortunately, it's hard to get enough samples within a short time.
In summary, The original intention of this study is to set up of TCM's standardization of syndrome differentiation by means of multivariate statistical method. Indeed, The application of mathematical statistics method for the TCM objective syndrome differentiation is feasible. But because of the TCM's complexity, the simply mathematical statistics method is not suitable for the complex TCM. It should be combined with the expert group opinion. And how to find the joint point for them which can be effectively applied to clinical practice, and easy to sum up, exchange, spread is the importat and difficult. point. This research belongs to the preliminary stage, it has certain limitation. Exploring the modern methodology on the study of TCM syndrome needs more endeavors.
多发性骨髓瘤(MM)是恶性浆细胞病中最常见的一种类型,属祖国医学“骨痹”“虚劳”、“腰痛”、“骨蚀”等范畴。目前中医药治疗MM已取得较好的疗效,但查阅近十年国内文献,各家采用的MM辨证分型方法各异,观点繁多,持论不一,大多数以主观经验推理为主,辨证标准不统一,缺乏大规模、多中心循证医学研究。这些问题导致虽然中医辨证论治在改善MM临床症状、缓解病情方面具有独特的优势,但由于缺乏客观化、标准化,难以总结推广,不利于中医学术交流和发展。
本研究重点放在探索MM辨证的客观化、规范化、标准化方面。拟从循证医学及微观辨证角度,借助数学多元统计方法,对MM的辨证分型规律及相关因素进行探讨,为中医建立和完善MM的规范化辨证治疗体系,提供客观的依据。
目的
研究初诊MM中医证型分布规律,观察初诊MM患者相关因素(包括年龄、性别、病程、西医分期、西医类型)与中医证型分布的关系,重点观察血清肿瘤负荷指标及预后指标[血β2-微球蛋白(β2-MG)、血乳酸脱氢酶(LDH)、血C-反应蛋白(CRP)、血清白蛋白(ALB)]与中医证型的相关性,从微观辨证角度总结中医证型的规律。
方法
本研究为临床研究,分循证医学回顾性研究和临床前瞻性研究两部分进行。
1、MM的循证医学回顾性研究
联合北京中医药大学附属东直门医院、上海中医药大学附属曙光医院、广州中医药大学第一附属医院、广东省中医院、广州市中医医院五家中医医院为合作单位,采用循证医学回顾性调查研究的方法,以各医院1997年1月至2007年12月入院符合标准的初诊MM患者病历为调研对象,对调研病历的数据进行统计：运用病例聚类分析与临床专家认证相结合的方法总结初诊MM中医证型分布规律,归纳初诊MM的基本中医证型。应用主成分分析,找出各证型的主要及次要症状,优化初诊MM辨证的诊断标准。在确定中医证型分布规律的前提下,采用Spearman相关性分析、单因素方差分析及卡方检验,研究其相关因素(包括年龄、性别、病程、西医分期、西医类型)、血清肿瘤负荷指标及预后指标(血β2-MG、LDH、CRP、ALB)与中医证型分布的关系。
2.、MM的前瞻性研究
临床观察广州市中医医院、广东省中医院、江苏省中医院血液内科2008年1月一2010年1月门诊就诊及住院、符合诊断标准和纳入标准的初诊MM患者,根据临床经验进行证型判别,采用频数分析,观察中医正虚证、邪实证分布情况；观察中医正虚证与邪实证兼挟情况；采用Spearman相关性分析、单因素方差分析及卡方检验,观察患者病程、西医分期及类型、血清肿瘤负荷指标及预后指标(血β2-MG、LDH、CRP、ALB)等与中医证型分布的相关性。并与回顾性调查研究结果相比较,总结其内在规律。
结果
1.MM的循证医学回顾性研究结果
1.1一般资料：
共调研1997年1月至2007年12月入院符合标准的初诊MM患者病历128例,包括广州中医药大学第一附属医院26例,广东省中医院40例,广州市中医医院11例,北京中医药大学附属东直门医院24例、上海中医药大学附属曙光医院27例。其中男72例(56.25%),女56例(43.75%),年龄最小16岁,最大88岁,平均年龄62.77±12.9岁；病程最长120个月,最短3天,平均病程8.17±16.86(月)。
128例中,ⅢA期57例(44.53%),ⅢB期41例(32.03%),ⅡA期14例(10.94%),ⅡB期6例(4.69%),ⅠA期2例(1.56%),ⅠB期8例(6.25%)。93例病历进行了西医分型,其中IgG-κ型29例(31.2%),IgG-λ型11例(11.8%),λ型8例(8.6%),IgA-κ型5例(5.4%),IgA-λ型12例(12.9%)IgA型7例(7.5%),κ型8例(8.6%),IgA-IgG-K型1例(1.1%),IgG型9例(9.7%),不分泌型3例(3.2%)。
1.2.初诊的MM证型分布规律：
1.2.1通过病例聚类分析,归纳出MM五种临床证型：脾肾两虚、脾肾阳虚、脾肾阴虚、水湿内蕴、痰毒瘀阻。
1.2.2与此同时,通过中医专家组逐一对128例病历进行辨证,总结出临床五种常见类型：①脾肾两虚；②脾肾两虚、痰瘀毒滞；③脾肾阳虚,痰湿内阻；④脾肾阴虚,湿热蕴毒；⑤脾肾阴虚,痰瘀互结。
1.2.3比较上述两者异同及优缺点,认为病例聚类的结果分散性较好,证型分布清晰,特征突出,能画龙点睛地阐明辨证要素,但不能完全覆盖临床实践；中医专家组的意见贴合临床实际,符合临床需要,但由于临床证型种类繁多,最终只能选取占总病例数94%的五大证型作为常见证型,层次感和分散性不强。究其两者的关系是相互补充、相辅相成的,两者结合体现了临床的虚实夹杂,前者是后者内在规律的体现。故确立聚类分析结果：脾肾两虚、脾肾阳虚、脾肾阴虚、水湿内蕴、痰毒瘀阻五种类型,为MM临床基本证型。其中前三者为正虚证,后两者为邪实证。
1.2.4在确定中医基本证型分布规律的前提下,通过主成分分析,归纳出各证型的主症及次症：
脾肾两虚：主症：腰膝酸软、倦怠乏力、食少纳呆、骨痛、少气懒言。次症：面色萎黄、面色少华、自汗、心悸、舌淡苔白、脉弱。
脾肾阳虚：主症：畏寒肢冷、大便不实、面色晄白、脘腹胀满、面肢浮肿。次症：小便清长、口淡不渴、夜尿频多、舌淡胖苔白、脉沉。
脾肾阴虚：主症：口干咽燥、五心烦热、发热、烦渴、盗汗。次症：舌红苔少,脉弦细数。
水湿内蕴：主症：脘腹胀满、面肢浮肿、食少纳呆、口淡不渴、苔白。次症：大便不实、心悸、恶心呕吐、肢体麻木、舌淡胖苔腻、脉沉细。
痰毒瘀阻：主症：眩晕耳鸣、恶心呕吐、溲赤、发热、面色晦暗。次症：肌肤甲错、肢体麻木、大便干结、烦渴、失眠、舌暗红苔黄腻、脉滑。
1.2.5参照上述五种基本证型标准再对128例病历进行辨证,并通过频数分析表明,脾肾两虚占32.03%,脾肾阳虚11.72%,脾肾阴虚6.25%,水湿内蕴16%,痰毒瘀阻34%。正虚证中以脾肾两虚类型分布最广,邪实证中以痰毒瘀阻类型多见。
1.2.6调研中出现频率最高的临床表现依次为腰膝酸软、食少纳呆、倦怠乏力、少气懒言,舌淡白,脉沉。舌紫暗的几率为41.4%。初诊病人骨痛的几率占40.6%,面色少华(25%)、萎黄(18.75%)、晄白(14.06%)的总几率占57.81%。
1.3.各因素相关性分析：
1.3.1年龄：年龄与中医证型分布有一定的相关性。卡方检验,痰毒瘀阻的P<0.05,表明痰毒瘀阻在各年龄段有显著性差异。纵观年龄与证型分布,痰毒瘀阻的证型在40-49岁期间最多见,在80岁以上最少见。
1.3.2性别：性别与中医证型基本不相关。卡方检验,在各个证型,男女性别上均无显著性差异。
1.3.3病程：病程和中医证型分布存在明显相关性。单因素方差分析,各个证型间的病程指标有显著差异。水湿内蕴型和脾肾两虚型病程相对较短,脾肾阳虚型病程相对较长。
1.3.4西医分期：分期和中医证型分布没有明显相关性。但单因素方差分析,在ⅢA期、ⅢB期各个证型分布有显著差异。ⅢA期痰毒瘀阻型多见；ⅢB期脾肾两虚型多见。
1.3.5西医类型：西医类型和中医证型分布没有明显相关性。卡方检验,IgG-κ型中脾肾两虚、痰毒瘀阻型为多。
1.3.6血β2-MG：血β2-MG和中医证型分布有微弱的相关性。单因素方差分析,各个证型间的血β2-MG指标没有显著差异。且两两证型比较也无显著差异。
1.3.7血LDH：血LDH和中医证型分布有微弱的相关性。单因素方差分析,各个证型间的血LDH指标没有显著差异。但两两证型比较有显著差异。血LDH值脾肾阳虚>脾肾阴虚>脾肾两虚,痰毒瘀阻>水湿内蕴。
1.3.8血CRP：血CRP和中医证型分布有微弱的相关性。但单因素方差分析,各个证型间的血CRP指标没有显著差异。两两比较,脾肾两虚和痰毒瘀阻、脾肾阳虚和水湿内蕴、脾肾阳虚和痰毒瘀阻有显著差异。痰毒瘀阻型血CRP最高,脾肾阳虚型血CRP最低。
1.3.9血ALB：血ALB和中医证型分布基本没有相关性。单因素方差分析,各个证型间的血ALB指标没有显著差异。但两两比较,脾肾阳虚型血ALB最低,痰毒瘀阻型血ALB最高。
2.MM的前瞻性临床研究结果
2.1.一般资料：
共调研2008年1月—2010年1月门诊就诊及住院的符合诊断标准和纳入标准的初诊MM患者23例,其中广州市中医医院3例,广东省中医院10例,江苏省中医院10例。男15例(65.21%),女8例(34.79%),年龄最小51岁,最大82岁,平均年龄64.39±10.44岁；病程最长36个月,最短15天,平均病程9.85±9.67(月)。
23例中ⅢA期6例(26.09%),ⅢB期13例(56.52%),ⅡA期3例(13.04%),ⅡB期1例(4.35%)。IgG-κ型5例(21.7%),IgG-λ型4例(17.4%),λ型2例(8.7%),IgA-κ型1例(4.35%),IgA-λ型4例(17.4%),IgA型2例(8.7%),IgG型1例(4.35%),κ型2例(8.7%),IgD型1例(4.35%),不分泌型1例(4.35%)。
2.2.初诊的MM证型分布规律：
2.2.1临床23例中脾肾两虚5例(21.7%),脾肾两虚夹痰瘀9例(39.1%),脾肾阴虚夹痰瘀4例(17.4%),脾肾阳虚兼湿毒瘀阻3例(13.1%),痰瘀毒蕴2例(8.7%)。
2.2.2临床纯虚无邪实、纯实无正虚的证型所占比例不高(7／23,30.4%),大多数仍为虚实夹杂证。
2.3.各因素相关性分析：
2.3.1病程：病程和中医证型分布存在弱相关性。虽无统计学意义上的差异,但通过统计数值仍可以看出脾肾阳虚兼湿毒瘀阻病程相对较长。
2.3.2西医分期、类型：西医分期、类型和中医证型分布没有明显相关性。通过卡方检验,各个证型分布在西医分期、类型上也没有显著差异。
2.3.3血β2-MG、血LDH：血β2-MG、LDH和中医证型分布没有明显相关性。卡方检验也提示各个证型间的血β2-MG、LDH指标没有显著差异。两两证型比较也无显著差异。
2.3.4血CRP：通过相关系数,表明血CRP和中医证型分布无明显相关性。卡方检验表明,各个证型间的血CRP指标无显著差异。但两两比较,脾肾两虚和痰瘀毒蕴、脾肾两虚和脾肾两虚夹痰瘀型有显著差异。痰瘀毒蕴型血CRP较脾肾两虚型、脾肾两虚夹痰瘀型为高。
2.3.5血ALB：相关系数表明血ALB和中医证型分布基本没有相关性。卡方检验表明各个证型间的血ALB指标没有显著差异。但脾肾阳虚兼湿毒瘀阻型和痰瘀毒蕴型两两比较有显著差异。脾肾阳虚兼湿毒瘀阻型血ALB较痰瘀毒蕴型血ALB低。
结论
1.初诊MM证型分布规律及病因病机总结
1.1本回顾性研究中通过病例聚类分析,归纳出MM五种临床证型：脾肾两虚、脾肾阳虚、脾肾阴虚、水湿内蕴、痰毒瘀阻。通过中医专家组总结出临床五种常见类型：①脾肾两虚；②脾肾两虚、痰瘀毒滞；③脾肾阳虚,痰湿内阻；④脾肾阴虚,湿热蕴毒；⑤脾肾阴虚,痰瘀互结。究其两者的关系是相互补充、相辅相成的,两者结合体现了临床的虚实夹杂,前者是后者内在规律的体现。故依据中医教材《中医内科学》的辨证论治撰写模式,确立了聚类分析的结果：脾肾两虚、脾肾阳虚、脾肾阴虚、水湿内蕴、痰毒瘀阻五种类型为初诊MM临床基本证型。前瞻性研究中观察到脾肾两虚、脾肾两虚夹痰瘀、脾肾阴虚夹痰瘀、脾肾阳虚兼湿毒瘀阻、痰瘀毒蕴五种临床证型的存在,揭示了回顾性研究聚类分析的结果可以作为初诊MM的临床基本证型,但其结果只为我们提供了基本要素及原则,临床运用仍需根据实际情况灵活把握兼夹。
1.2回顾性及前瞻性研究均阐明了初诊MM的中医病因病机是以脾肾虚为本,痰瘀湿毒为要。由于六淫、饮食、情志等因素使阴阳气血失调,脾肾亏损,风寒湿或风湿热邪侵袭机体,导致气血运行不畅,痰瘀内生,痰瘀湿毒相互胶结,内搏于骨,深入于髓,痹阻经络,经脉筋骨失于濡养或蚀骨伤髓而致骨痹。其中肾虚为本病发病主要内在因素,痰瘀湿毒为主要病理关键。邪实中毒邪极少单独致病,常有挟痰挟瘀挟虚之特点。并注意整个疾病过程中不能忽视瘀的存在。
1.3提示了初诊的MM首发症状以骨痛、贫血为多。临床上出现骨痛及贫血应警惕本病。
2.初诊MM微观辨证的建立
回顾性研究中表明MM各相关因素(包括年龄、性别、病程、西医分期、西医类型)、血清肿瘤负荷指标及预后指标(血β2-MG、LDH、CRP、ALB)在疾病不同证型上有各自的相关性和差异性。前瞻性研究中由于收集样本数相对较少,上述大多数指标与中医证型分布之间未能做出相关性和差异性,但分析其具体结果大体符合回顾性研究的结论,基本能在客观上论证回顾性调查研究结果的确切性、实用性。通过这些指标,能帮助客观把握中医辨证、建立微观辨证。
3.数学多元统计方法与中医标准化、客观化的关系
3.1回顾性研究显示了、前瞻性研究验证了数学多元统计方法——聚类分析运用于中医虽能综合反映证候的临床信息特征、对样本证候特征做出高度概括——分为虚证和实证两大类,但实际上临床疾病复杂多变,往往会出现证型与证型之间的不同组合,形成兼证。故虚实夹杂的证型兼顾不全,不能涵盖临床所有证型。其基本证型的确立只为我们提供了初诊MM的基本辨证要素,临床需根据中医辨证思维综合考虑、灵活夹杂才能客观反映实际情况。提示单纯依靠聚类算法一般不会得到圆满的结果,聚类分析结果必须与该领域的经验结合才能切实可行。
3.2主成分分析运用于中医辨证标准的确立,虽然在不丢失原来主要信息的前提下,用简单的几个证候要素反应总体的信息,简化及明确了证候标准。但目前仍有诸多问题,如初级症候要素筛选、主成分要素提取的最佳路径、样本数量为多少最科学、经济、合理等等,需要在日后的不断研究中结合临床经验进一步探索。
3.3需要大量、均衡的样本数才能充分保证实验结果的完善性。但由于MM发病率较低,加之我们收集的为初诊病例,获得符合标准的病例数相对较少,收集病例数有限,对结果的统计意义有一定的影响。
以上提示了中医临床证候纷繁复杂,具有复合性和复杂性等特点,面对如此复杂的理论体系,不能刻板地运用数学方法来替代灵活的辨证施治,单纯数理统计知识得出的结论运用于临床实践是不全面的,机械采用单纯的数理统计知识来研究、剖析中医是不合适的。只有在保持原有中医辨证方法特色和优势的基础上,结合现代数学研究方法,找到两者的交融点、平衡点,使中医传统经验技术与数学客观依据有机结合,才能有效指导临床实践,实现有中医特色的辨证客观化、规范化。
4.回顾性病历调查与前瞻性临床研究优缺点比较
回顾性病历调查虽能在短时间内获取大量样本资料,但也有自身难以克服的缺点,如临床医生书写原始病历时,对中医证候信息的采集侧重点不同、表达信息不规范；部分有意义的信息及数据由于当时医疗条件的限制而致缺失等问题,可能会影响部分结果的准确性。前瞻性临床研究由于有目的地采集临床信息,故减少了原始指标包含信息的损失,从而实现对相关证候信息、西医客观指标等资料全面而有效的分析处理,保证了结果的真实性、可靠性,遗憾的是短时间内难以获得满意数量的样本资料。
综上所述,本研究的初衷是借助数学的方法实现中医辨证的客观化、标准化。诚然,通过临床数据表明运用数学多元统计的方法帮助中医辨证实现客观化、规范化、微观化是切实可行的,但发现数学多元统计方法运用于中医药研究显示出某些不完善性,这是由于中医自身特点决定的。如何找到两者的切入点,达到既能有效地应用于临床实践,又便于总结、交流、推广的目的,也是标准化研究的难点、重点。本研究属于初始阶段,有一定的局限性,寻找到完全适应中医证候复杂性特点的方法任重道远,尚待更多、更大样本、多种学科联合的后续研究。相信通过我们不懈地努力,中医现代证候研究必然会取得实质性的突破。
Research background
Multiple Myeloma(MM) is the most common type of hematologic tumor worldwide. it belongs to bone Bi-Syndrome、consumptive disease、lumbago and Erosion of bone in Traditional Chinese Medicine(TCM). But through consulting recent ten years'domestic literature, We have found that TCM syndrome differentiation of MM have many disadvantages, such as experiential inference, not unified standard, and lack of multicenter、large-scale evidence-based research. These are the obstacles in the development of TCM. So this study focuses on the objectification and standardization of TCM syndrome differentiation. From the perspective of Evidence-Based Medicine (EBM) and microcosmic syndrome differentiation, this study will make a discussion on the distribution of TCM syndrome type and related factors of MM by means of multivariate statistical method. It will supply an objective basis of TCM's standardization of syndrome differentiation.
Objective
To investigate newly diagnosed MM's distribution of TCM syndrome type, observe the relationship between distribution of TCM syndrome type and related factors (including age、gender、course of disease、clinical stage and types of Western Medicine); Emphasis on indexes of tumor burden and prognosis (such asβ2-MG、LDH、CRP、ALB in blood). From the perspective of microcosmic syndrome differentiation, the rule of TCM syndrome differentiation is summarized.
Method
This research includes two parts, one is the clinical retrospective study, the other is the prospective clinical study.
1.The clinical retrospective study of MM based on evidence-based medicine
Combined with Dongzhimen Hospital Attached to Beijing TCM University, Affiliated Shuguang Hospital of Shanghai University of TCM, the First Affiliated Hospital of Guangzhou University of TCM, Guangzhou's TCM Hospital and Guangdong Provincial Hospital of TCM, From January 1997 to December 2007, the patients'cases were collected, who meet the inclusion and diagnostic criteria, and the statistical analysis has been made based on the data. By applying cluster analysis, and with clinical practice, distribution of TCM syndrome type was summarized. By means of Principal Component Analysis (PCA), the main and accessory symptoms were found. By means of correlation analysis, one-way anova, and chi-square test, we studied the relationship between distribution of TCM syndrome type and related factors (including age、gender、course of disease、clinical stage and types of Western Medicine), indexes of tumor burden and Prognosis.
2. Prospective clinical study on MM
Investigating newly diagnosed MM cases during January 2008-January 2010, combined with Guangzhou's TCM Hospital, Guangdong Provincial Hospital of TCM and Jiangshu Provincial Hospital of TCM, we make differentiation according to clinical experience, Using frequency analysis, observing the distribution of asthenia and sthenia syndrome. By means of correlation analysis, one-way anova, and chi-square test, we observe relationship between distribution of TCM syndrome type and related factors (including course of disease、clinical stage and types of Western Medicine), Indexes of tumor burden and prognosis after the cases are diagnosed according to distribution of TCM syndrome type. We sum up the inherent laws through comparing the results of the retrospective and prospective clinical study.
Result
1.The clinical retrospective study of MM based on evidence-based medicine
1.1 General data of patients:
128 MM cases have been investigated, who meet the inclusion and diagnostic criteria. Including 26 cases in the First Affiliated Hospital of Guangzhou University of TCM,40 cases in Guangdong Provincial Hospital of TCM,11 cases in Guangzhou's TCM Hospital,24 cases in Dongzhimen Hospital attached to Beijing TCM University,27 cases in Affiliated Shuguang Hospital of Shanghai University of TCM. And male 72 examples(56.25%), female 56 cases (43.75%), Among the patients, the youngest was 16 years old, and the eldest was 88 years old, of the128 cases average age was 62.77±12.9 years old, The longest course was 120 months, and shortest course was three days, the average duration was 8.17±16.86 (month).
Of the 128 cases,57 patients (44.53%) were at stageⅢA,41 patients (32.03%) were at stageⅢB,14 patients (10.94%) were at stageⅡA,6 patients (4.69%) were at stageⅡB,2 patients (1.56%) were at stageⅠA, 8 patients (6.25%) were at stageⅠB.93 examples were given types.29
cases (31.2%) were IgG-κtype,11 cases (11.8%) were IgG-λtype,8 cases (8.6%) wereλtype,5 cases (5.4%) were IgA-κtype,12 cases (12.9 %) were IgA-λtype,7 cases (7.5%) were IgA type,8 cases (8.6%) wereκtype, 1 cases (1.1%) were IgA-IgG-κtype,9 cases (9.7%) were IgG type, 3 cases (3.2%) were unsecretarial type.
1.2. MM's distribution of TCM syndrome type
1.2.1 By applying cluster analysis, the five clinic syndrome types of MM can be summarized:deficiency of spleen and kidney、spleen-kidney yang deficiency、spleen-kidney yin deficiency、dampness-fluid accumulating in the interior、stagnation of phlegm、poison and blood stasis.
1.2.2 Meanwhile, The experts summarized the five common clinic syndrome types of MM:①deficiency of spleen and kidney;②deficiency of spleen and kidney holding blood stasis、sputum and toxin;③spleen-kidney yang deficiency accompanying sputum-wetness;④spleen-kidney yin deficiency accompanying damp-heat-toxin。⑤spleen-kidney yin deficiency with sputum and blood stasis.
1.2.3 By comparing their difference、advantages and disadvantages, We believe that the results of cluster analysis have many advantages, such as good dispersion、syndromes clear、bright lines、feature highlights、clarifying the differentiation factor, but can not fully cover the clinical practice; The views of the expert group were in accordance with clinical practice, meet the clinical need, but because of the clinical syndromes was very complex. we only could select the five clinic syndrome types as the common syndrome, the common syndrome occupied 94% of the total number of cases, the level and dispersion were not strong. it was considered that the relationship between them was mutual complemented。The former was the embody of the latter. So almost all specialists considered that the results of the cluster analysis could used as the basic clinic syndrome types of MM. And the first three were the positive asthenia syndrome, the rest two were the evil sthenia syndrome.
1.2.4 By means of PCA, the main and accessory symptoms were summarized:
deficiency of spleen and kidney:
main symptoms:lassitude in loin and knee, lassitude, poor appetite, bone pain, weak pulse.
accessory symptoms:little qi and lazy to talk, sallow complexion, (?)sterless complexion, spontaneous sweating, palpitation, pale tongue with whitish fur.
yang deficiency of spleen and kidney:
main symptoms:aversion to cold, and cold limbs, loose stool, pale complexion, abdominal distention, edema.
accessory symptoms:weak taste and not thirsty, clear and long urine or urinating frequently at night, pale and enlarged tongue with whitish fur, deep Pulse.
spleen-kidney yin deficiency:
main symptoms:dry mouth and throat, feverish sensation over five centers, fever, polydipsia, night sweating.
accessory symptoms:red tongue with less fur, stringy、thin and fast Pulse.
dampness-fluid accumulating in the interior:
main symptoms:abdominal distention, edema, poor appetite, weak taste and not thirsty, whitish fur.
accessory symptoms:loose stool, palpitation, nausea, vomiting, limb numbness, pale and enlarged tongue with greasy fur, thin and deep Pulse.
stagnation of phlegm、poison and blood stasis:
main symptoms:dizziness, tinnitus, nausea, vomiting, little and yellow urine, fever, dim complexion.
accessory symptoms:scaly skin, limb numbness, dry stool, polydipsia, insomnia, dark red tongue with yellow greasy fur, slippery pulse.
1.2.5 The result of frequency analysis showed that deficiency of spleen and kidney accounted for 32.03%, yang deficiency of spleen and kidney accounted for 11.72%, Spleen-Kidney Yin Deficiency was 6.25%, dampness-fluid accumulating in the interior was 16%, stagnation of phlegm、poison and blood stasis occupied 34%. deficiency of spleen and kidney is most in deficiency Syndromes, stagnation of phlegm、poison and blood stasis is most in excess Syndromes.
1.2.6 The symptoms with the highest frequency were lassitude in loin and knee、poor appetite、lassitude、little qi and lazy to talk、pale tongue with whitish fur, deep Pulse. Probability of dark red tongue was 41.4%. In 128 cases, probability of bone pain was 40.6%, probability of Pale、sallow and lusterless complexion was 57.81%.
1.3. Correlation analysis of each factor
1.3.1 Age:MM's distribution of TCM syndrome type has correlation with age. Through chi-square test, stagnation of phlegm, poison and blood stasis has significance differences in various age stage. Stagnation of phlegm、poison and blood stasis type was the most in 40-49th period, and the rarest above 80 years old.
1.3.2 Gender:gender and distribution of TCM syndrome type was not related basically. Through chi-square test, there was no significant difference in sex.
1.3.3 Course of disease:course of disease showed significant correlation with distribution of TCM syndrome type. Through one-way anova, the comparison of course of disease in all TCM syndromes showed that type of dampness-fluid accumulating in the interior and deficiency of spleen and kidney type were shorter, yang deficiency of spleen and kidney type was longer.
1.3.4 Clinical stage:clinical stage was basically unrelated to Distribution of TCM syndrome type. There was significant statistical difference in clinical stage over the distribution of the five TCM syndromes. stagnation of phlegm, poison and blood stasis was found inⅢA, deficiency of spleen and kidney was found inⅢB.
1.3.5 Type of western medicine:type of western medicine was basically unrelated to distribution of TCM syndrome type. deficiency of spleen.and kidney and stagnation of phlegm、poison and blood stasis were found on IgG-кtype.
1.3.6 Bloodβ2-MG:Bloodβ2-MG was little inversely correlated with distribution of TCM syndrome type, But there was no significant statistical difference in them. Multiple comparisons showed no significant difference also.
1.3.7 Blood LDH:Blood LDH was little inversely correlated with distribution of TCM syndrome type. There was no significant statistical difference in distribution of TCM syndrome type. Multiple comparisons showed significant difference. The blood LDH in yang deficiency of spleen and kidney was higher than those in the other two deficiency Syndromes. The blood LDH in stagnation of phlegm、poison and blood stasis was higher than dampness-fluid accumulating in the interior.
1.3.8 Blood CRP:There was a positive correlation between blood CRP and distribution of TCM syndrome type. There was no significant statistical difference in distribution of TCM syndrome type. multiple comparisons showed the CRP in stagnation of phlegm、poison and blood stasis was the highest, but in yang deficiency of spleen and kidney was the lowest.
1.3.9 Blood ALB:Blood ALB was positive correlated with distribution of TCM syndrome type. There was no significant statistical difference in distribution of TCM syndrome type.multiple comparisons showed the ALB in stagnation of phlegm、poison and blood stasis was the highest, but in yang deficiency of spleen and kidney was the lowest.
2. Prospective clinical study on MM
2.1. General data of patients:
23 cases, Including 10 cases in Guangdong Provincial Hospital of TCM, 10 cases in Jiangsu Provincial Hospital of TCM,3 cases in Guangzhou's TCM Hospital. And male 15 examples (65.21%), female 8 cases (34.79%), Among the patients, the youngest is 51 years old. And the eldest 82, of the 23 cases Average age is 62.77±12.9 years old, the longest course is 36 months, and shortest course is 15 days. average duration is 9.85±9.67 (month).
Of the 23 cases,6 patients (26.09%) are at stageⅢA,13 patients (56.52 %) are at stageⅢB,3 patients (13.04%) are at stageⅡA,1 patients (4.35 %) are at stageⅡB.5 cases (27.1%) are IgG-кtype,4cases (17.4%) are IgG-λtype,2 cases (8.7%) areλtype, 1 cases (4.35%) are IgA-кtype, 4 cases (17.4%) are IgA-λtype,2 cases (8.7%) are IgA type,2 cases (8.7 %) areкtype, lcases (4.35%) are IgD type,1 cases (4.35%) are IgG type,
1 cases (4.35%) are unsecretarial type.
2.2. Distribution of TCM syndrome type of MM
2.2.1 Of the 23 cases,5 patients (21.7%) are deficiency of spleen and kidney,9 patients (39.1%) are deficiency of spleen and kidney holding sputum and blood stasis,4 patients (17.4%)are spleen-kidney yin deficiency accompanying sputum and blood stasis,3 patients (13.1%) are spleen-kidney yang deficiency accompanying damp-blood stasis-toxin。2 patients (8.7%) are stagnation of phlegm、poison and blood stasis.
2.2.2 In clinical, the asthenia and sthenia syndrome account for the proportion are not high (7/23,30.4%), Syndrome of intermingled deficiency and excess is the most in clinical.
2.3. Correlation Analysis of each factor
2.3.1 Course of disease:course of disease shows little correlation with distribution of TCM syndrome type. There'is no statistical difference between them, but the course of spleen-kidney yang deficiency accompanying damp-stasis-toxin is longer.
2.3.2 Clinical stage and type of western medicine:clinical stage and type of western medicine are basically unrelated to distribution of TCM syndrome type. There is no significant statistical difference in clinical stage and type of western medicine over the distribution of the five TCM syndromes.
2.3.3 Bloodβ2-MG and LDH:Bloodβ2-MG and LDH are positive correlated with distribution of TCM syndrome type. There is no significant statistical difference in distribution of TCM syndrome type. Multiple comparisons show no significant differences also.
2.3.4 Blood CRP:There is no correlation between blood CRP and distribution of TCM syndrome type. There is no significant statistical difference in distribution of TCM syndrome type. multiple comparisons show the CRP in stagnation of phlegm、poison and blood stasis is higher than in deficiency of spleen and kidney and deficiency of spleen and kidney holding sputum and blood stasis.
2.3.5 Blood ALB:Blood ALB is positive correlated with distribution of TCM syndrome type. There is no significant statistical difference in distribution of TCM syndrome type. multiple comparisons show the ALB in spleen-kidney yang deficiency accompanying damp-blood stasis-toxin is lower than stagnation of phlegm、poison and blood stasis.
Conclusion
1. newly diagnosed MM's distribution of TCM syndrome type, the etiology and pathogenesis
1.1 In the clinical retrospective study,by applying cluster analysis, the five clinic syndrome types of MM could be summarized:deficiency of spleen and kidney、spleen-kidney yang deficiency、spleen-kidney yin deficiency、dampness-fluid accumulating in the interior、stagnation of phlegm、poison and blood stasis. Meanwhile, the experts summarized the following five common clinic syndrome types of MM:①deficiency of spleen and kidney;②deficiency of spleen and kidney holding blood stasis and toxin;③spleen-kidney yang deficiency accompanying sputum-wetness;④spleen-kidney yin deficiency accompanying damp-heat-toxin。⑤spleen-kidney yin deficiency with sputum and blood stasis。By comparing their difference、advantages and disadvantages, it was considered that the relationship between them was mutual complemental。The former was the embody of the latter。So according to the write mode of syndrome differentiation and treatment in "Chinese Internal Medicine", almost all specialists considered that the results of the cluster analysis could be used as the basic clinic syndrome types of MM。In prospective clinical study on MM, there are the following five clinic syndrome types of MM, including deficiency of spleen and kidney、deficiency of spleen and kidney holding sputum and blood stasis、spleen-kidney yin deficiency accompanying sputum and blood stasis、spleen-kidney yang deficiency accompanying damp-blood stasis-toxin、stagnation of phlegm、poison and blood stasis. It shows the results of cluster analysis are the basic clinic syndrome types of MM, they reflect the basic elements of differentiation, we must use them flexibly according to the actual situation.
1.2 The retrospective and prospective study show that etiology and pathogenesis of MM in TCM are asthenia of spleen and kidney, also closely correlated with phlegm coagulation, blood stasis、dampness and toxin. Because of six exogenous pathogens, emotional frustration, improper diet, misbalance of qi/blood and yin/yang、asthenia of spleen and kidney are easy to be made, wind cold dampness and Pathogenic toxin will take advantage of the body's weak points and attack organism, Noxious blood stasis and phlegm accumulate near channels、meridians、muscle and joint, which lead to insufficient nourishment for tendon. So bone Bi-Syndrome is induced. In the etiology and pathogenesis, The key point of its pathogenesis is asthenia of kidney, also closely correlated with phlegm coagulation, blood stasis、dampness and toxin. Pathogenic toxin appears together with stasis、phlegm and asthenia frequently. And the importance of the blood stasis should not be ignored in the whole course of the disease.
1.3 The first symptom Is bone pain、anemia frequently. In clinic, when bone ache or anemia occurs, we should be alert of the existence of the disease.
2. The bulding of microcosmic syndrome differentiation
The clinical retrospective study shows that each influence factor is correlated with distribution of TCM syndrome type. And there are statistical differences in distribution of TCM syndrome type. Using these Indexes can achieve the syndrome differentiation objectively. In the prospective study, because of the few MM's samples, most of the above indexes have not been able to show the correlation and difference, the results are approximately same as the clinical retrospective study. These show that the results are practical. Using these indexes can help to achieve the syndrome differentiation of TCM
objectively.
3.The relationship between mathematical statistics method, objectification and standardization of TCM syndrome differentiation
3.1 Although using the cluster analysis in TCM can comprehensively reflect the clinical information characteristic and the basic elements of differentiation, it can not give dual attention to syndrome of intermingled deficiency and excess. Because of the TCM's complexity, the results of cluster analysis are the basic clinic syndrome types of MM only, we must use them flexibly according to the actual clinical situation. These show that the simply mathematical statistics method isn't fully suitable for the complex TCM. It should be considered comprehensively on clinical. The expert group opinion is still needed to reflect the clinic fact. The conclusion must connect with clinical practice.
3.2 By means of PCA, We established the standard of TCM, without losing the original premise of the main information, used a few simple elements of response syndrome to reflect the general information, simplify and clarify the standard syndrome. Bur there are still many problems when applying PCA to TCM, such as Filtering elements of primary symptoms, reducing symptoms of elements, the best ways and means to extract the most convincing of the number of samples, etc. It is needed to continue research in the future to further explore clinical experience.
3.3 Massive balanced sample numbers is needed to be able to guarantee the experimental result perfect. Because the incidence of MM is relatively low and the MM cases we collected are initially diagnosed, medical record which met the inclusion criteria is few, so the statistical significance is limited.
The above shows TCM compound and complex characteristics, the simply mathematical statistics method isn't completely suitable for the complex TCM. The conclusions of mathematical statistics applying to the clinical practice don't cover all the aspects. Only supported by mathematics and experience simultaneously, can the TCM realize the objectification and standardization of TCM syndrome differentiation.
4. compare with advantages and disadvantages of the retrospective and prospective clinical study.
Although the retrospective study can gain the massive sample data within a short time, but some information and data maybe be ignored because of medical condition limit at that time, it will affect the accuracy of the partial results possibly. In the prospective clinical study, the information manifests completely, it has guaranteed the result's authenticity. Unfortunately, it's hard to get enough samples within a short time.
In summary, The original intention of this study is to set up of TCM's standardization of syndrome differentiation by means of multivariate statistical method. Indeed, The application of mathematical statistics method for the TCM objective syndrome differentiation is feasible. But because of the TCM's complexity, the simply mathematical statistics method is not suitable for the complex TCM. It should be combined with the expert group opinion. And how to find the joint point for them which can be effectively applied to clinical practice, and easy to sum up, exchange, spread is the importat and difficult. point. This research belongs to the preliminary stage, it has certain limitation. Exploring the modern methodology on the study of TCM syndrome needs more endeavors.
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