摘要
肝炎肝硬化是由于肝炎病毒长期作用于肝脏引起的一种慢性、进行性、弥漫性肝病的终末阶段,肝脏纤维组织增生,破坏正常肝小叶的结构,代之以再生结节和假小叶,使肝脏正常血液供应被破坏,临床表现为门静脉高压症及肝功能障碍等。根据中医理论,肝炎肝硬化的发生与发展过程存在肝主疏泄和藏血功能的异常,其中“肝藏血”功能异常主要表现为血瘀、阴虚等基本病机。本研究拟从分析肝炎肝硬化“肝藏血”功能异常表现与微观指标的相关性入手并由病理反推生理,为阐释“肝藏血”的现代科学内涵提供一定依据。
目的
1梳理“肝藏血”的理论与肝炎肝硬化的病理生理,分析中医对肝炎肝硬化病因病机的认识,构建探讨肝炎肝硬化“肝藏血”功能异常表现与微观指标相关性的研究思路。
2基于临床横断面调查数据,分析肝炎肝硬化常见证候要素的分布特点,在此基础上,了解其“肝藏血”功能异常相关的证候要素血瘀、阴虚等的表现特点。
3基于临床横断面调查数据,分析肝炎肝硬化“肝藏血”功能异常时微观指标的表现特点,为进一步探讨两者间的相关性提供参考依据。
4基于临床横断面调查数据,分析肝炎肝硬化“肝藏血”功能异常表现与微观指标的相关性,并由病理反推生理,为阐释“肝藏血”的现代科学内涵提供一定依据。
方法
1构建研究思路
通过梳理中医对“肝藏血”功能及功能异常表现和肝炎肝硬化病因病机的认识,以及西医对肝脏生理和肝炎肝硬化病理生理的认识,归纳肝炎肝硬化“肝藏血”功能异常表现的证候要素以及微观指标,构建探讨两者间相关性的研究思路。
2临床数据采集
采用前瞻性多中心的横断面流行病学调查方法,运用课题组统一制订的《肝炎肝硬化临床信息采集表》采集患者的中医症状、体征等临床表现以及实验室、影像学检查等微观指标。
3制订《肝炎肝硬化常见证候要素辨识标准》(供本课题研究使用)
参照现行的多个诊疗共识,结合前期文献回顾与临床调查结果,并经过二轮专家论证制订。
4制订《肝炎肝硬化常见症状与证候要素量化表》
根据信息采集表中对中医症状和体征的量化分级形成,证候要素量化得分为相关症状、体征得分的加和。
5数据处理
包括数据录入,数据清洗,数据类型转换等。
6统计学方法
应用SPSS13.0统计软件包进行。
6.1分析分布特点
计量资料采用独立样本t检验或Mann-Whitney秩和检验比较两组间的差异,采用单因素方差分析或Kruskal-Wallis H检验比较三组间的差异；计数资料采用卡方检验比较两组间的差异。统计推断以0.05作为检验水准。
6.2分析相关性
(1)线性趋势图：观察血瘀、阴虚的证候要素量化得分与微观指标水平均值的线性趋势。
(2)简单相关分析：连续、分类变量分别采用Pearson、Spearman相关分析方法。
(3)多元线性回归：以血瘀、阴虚的证候要素量化得分为因变量,微观指标水平为自变量,自变量筛选采用逐步回归法。
(4)二分类Logistic回归分析：以是、否判定为血瘀或阴虚合并血证为因变量,以微观指标是、否异常为自变量,采用进入法分别进行单自变量的模型拟合。
(5)逐步贝叶斯判别分析：以是、否判定为血瘀或(和)阴虚以及其是、否合并各血证作为因变量,以微观指标为自变量,自变量筛选采用Wilks' Lambda法。
结果
1肝炎肝硬化“肝藏血”功能异常表现与微观指标相关性的研究思路
肝炎肝硬化的发生发展过程与“肝藏血”功能异常的血瘀、阴虚等基本病机密切相关。以统计学方法为工具,探讨患者的血瘀、阴虚(或合并血证)与微观指标(血常规、凝血功能、肝功能、门静脉血流动力学、脾脏体积、胃镜检查、肝脏储备功能、血管活性物质等指标)的相关性。
2肝炎肝硬化常见证候要素的分布特点
2.1常见证候要素的分布
801例肝炎肝硬化患者中,血瘀503例,阴虚448例,湿热257例,气滞438例,气虚517例,阳虚428例,水停462例。
2.2血瘀、阴虚的分布
在代偿期与失代偿期患者中,血瘀分别占52.50%、69.60%,量化得分分别为4.97±2.41、5.96±2.61(P<0.05)；阴虚分别占55.40%、56.30%,量化得分分别为5.33±2.05、5.55±2.15(P>0.05)。
2.3血证的分布
吐血、便血、紫斑、齿衄、鼻衄患者在代偿期/失代偿期分别有5例/38例,5例/33例,7例/16例,72例/78例,43例/70例。齿衄多合并鼻衄,吐血多合并便血,前者两期均有分布,后者主要分布在失代偿期。
2.4血瘀、阴虚与血证组合的分布
67.40%的吐血、71.00%的便血、91.30%的紫斑、92.00%的齿衄及96.40%的鼻衄患者均合并血瘀或(和)阴虚。血瘀、阴虚得分在血瘀、阴虚与(血瘀合阴虚)分别合并各血证的三组间存在差异,在合并紫斑、吐血、便血时均较高。
3肝炎肝硬化“肝藏血”功能异常时微观指标的表现特点
3.1肝炎肝硬化患者血瘀出现或程度加重时微观指标的表现特点
分别比较患者血瘀组与非血瘀组、血瘀代偿期与失代偿期微观指标水平的差异以及血瘀在各微观指标是、否异常两组的分布和得分差异,在血瘀出现或程度加重时,微观指标的变化有：(1)红细胞、血红蛋白、红细胞压积、血小板计数、血小板平均体积降低；(2)凝血酶原时间延长、凝血酶原活动度降低、凝血酶原时间比值升高；(3)白蛋白、白球比、前白蛋白降低,球蛋白升高；(4)MELD、Child-Pugh评分升高；(5)脾脏长径增长、厚径增厚；(6)门静脉内径增宽、门静脉平均血流速度减低,等。
比较患者血瘀分别合并吐血、便血、紫斑、齿衄、鼻衄时在各微观指标是否异常两组的分布差异,在血瘀合并血证出现时,微观指标的变化有：(1)红细胞、血红蛋白、红细胞压积、血小板计数降低；(2)凝血酶原活动度降低、凝血酶原时间比值升高；(3)总蛋白、白蛋白、白球比降低；(4)肝固有动脉峰值流速升高,等。
以上差异均有统计学意义(P<0.05)。
3.2肝炎肝硬化患者阴虚出现或程度加重时微观指标的表现特点
分别比较患者阴虚组与非阴虚组、阴虚代偿期与失代偿期微观指标水平的差异以及阴虚在各微观指标是、否异常两组的分布和得分差异,在阴虚出现或程度加重时,微观指标的变化有：(1)凝血酶原活动度降低、凝血酶原时间比值升高、纤维蛋白原升高；(2)球蛋白升高、白球比降低；(3)红细胞、血红蛋白、红细胞压积、血小板平均体积降低；(4)脾脏厚径增厚；(5)肝固有动脉峰值流速升高、门静脉平均血流速度减低；(6)NO水平降低,等。
比较患者阴虚分别合并吐血、便血、紫斑、齿衄、鼻衄时在各微观指标是、否异常两组的分布差异,在阴虚合并血证出现时,微观指标的变化有：(1)中性粒细胞百分比、红细胞、血红蛋白、红细胞压积、血小板计数降低；(2)凝血酶原活动度降低、凝血酶原时间比值升高；(3)MELD评分升高；(4)肝固有动脉内径扩张,等。
以上差异均有统计学意义(P<0.05)。
3.3肝炎肝硬化患者血瘀、阴虚与(血瘀合阴虚)三组间微观指标的表现特点
比较血瘀组、阴虚组与(血瘀合阴虚)组及其分别合并吐血、便血、紫斑、齿衄、鼻衄时三组间指标水平的差异,微观指标的变化有：(1)血瘀或(血瘀合阴虚)与阴虚相比,白蛋白、白球比、总蛋白降低,MELD、Child-Pugh评分升高,门、脾静脉流速降低；(2)(血瘀合阴虚)与阴虚相比,红细胞降低、凝血酶原时间延长、凝血酶原活动度降低、凝血酶原时间比值升高；(3)阴虚或(血瘀合阴虚)与血瘀相比,5-HT、NO水平降低；(4)阴虚与血瘀相比,门静脉内径变窄、中性粒细胞百分比降低,等。以上差异均有统计学意义(P<0.05)。
4肝炎肝硬化“肝藏血”功能异常表现与微观指标的相关性
4.1肝炎肝硬化血瘀与微观指标的相关性
总结血瘀与微观指标的相关性在线性趋势、简单相关分析、多元线性回归分析的表现,与血瘀呈正相关的微观指标有：(1)血小板计数、血小板平均体积降低；(2)凝血酶原时间延长、凝血酶原活动度降低、凝血酶原时间比值升高；(3)球蛋白升高,白蛋白、白球比降低；(4)脾脏厚径增厚；(5)门静脉平均血流速度减低、门静脉内径增宽；(6)AT-Ⅱ水平升高；(7)MELD、Child-Pugh评分升高；(8)红细胞、血红蛋白、红细胞压积降低,等。
总结血瘀分别合并吐血、便血、紫斑、齿衄、鼻衄时与微观指标的相关性在简单相关分析和二分类Logistic回归分析的表现,与血瘀合并血证呈正相关的微观指标有：(1)凝血酶原活动度降低、凝血酶原时间比值升高；(2)红细胞、血红蛋白、红细胞压积降低；(3)肝固有动脉峰值流速升高,等。
以上结果均有统计学意义(P<0.05)。
4.2肝炎肝硬化阴虚与微观指标的相关性
总结阴虚与微观指标的相关性在线性趋势、简单相关分析、多元线性回归分析的表现,与阴虚呈正相关的微观指标有：(1)凝血酶原活动度降低、凝血酶原时间比值升高、纤维蛋白原升高；(2)白球比、前白蛋白降低,球蛋白升高；(3)门静脉内径变窄、肝固有动脉峰值流速升高、肝固有动脉内径扩张；(4)中性粒细胞百分比降低；(5)5-HT、TNF-α、NO水平降低,等。
总结阴虚分别合并吐血、便血、紫斑、齿衄、鼻衄时与微观指标的相关性在简单相关分析和二分类Logistic回归分析的表现,与阴虚合并血证呈正相关的微观指标有：(1)红细胞、血红蛋白、红细胞压积降低；(2)凝血酶原活动度降低、凝血酶原时间比值升高,(3)肝固有动脉内径扩张,等。
以上结果均有统计学意义(P<0.05)。
4.3肝炎肝硬化血瘀、阴虚与(血瘀合阴虚)三组间的判别分析
在判别血瘀、阴虚与(血瘀合阴虚)时有贡献的微观指标为红细胞、白蛋白、门静脉内径、5-HT和TNF-α。
在判别血瘀、阴虚与(血瘀合阴虚)分别合并吐血、便血、紫斑、齿衄、鼻衄时有贡献的微观指标为红细胞、白细胞、凝血酶原活动度、纤维蛋白原、Child-Pugh评分和NO。
结论
1随着肝炎肝硬化血瘀程度的加重,门静脉高压加重,脾肿大/脾功能亢进加重,肝脏储备功能降低,肝脏凝血功能障碍,等。(?)
2随着肝炎肝硬化阴虚程度的加重,肝脏合成凝血酶原功能障碍,肝脏合成血浆蛋白功能障碍,门静脉高压加重,等。
3从肝炎肝硬化的病理反推生理,初步表明,“肝藏血”与门静脉血流动力学、脾脏功能、肝脏合成血浆蛋白功能、肝脏合成凝血酶原功能、肝脏储备功能等有一定相关性。
Hepatitis cirrhosis is the end-stage of chronic, progressive and diffuse liver disease due to the long-term effects of hepatitis virus on the liver. Liver fibrous tissue proliferated, normal lobular structures was disrupted and replaced with regenerative nodules and false lobules, resulting in normal blood supply to the liver was damaged, and its clinical menifestation included liver dysfunction and portal hypertension,etc. According to traditioanal Chinese medicine(TCM), the occurrence and development of hepatitis cirrhosis was affected by the dysfunction of liver controlling dispersion and housing blood. The specific contents of dysfunction of liver housing blood included blood stasis, yin deficiency, etc. The study focused on analyzing the correlation between dysfunction of liver housing blood and indicators from lab findings and imaging of hepatitis cirrhosis, supplying evidence for interpreting the modern scientific connotation of liver housing blood by inferring physiology from pathology.
Objective
1To build the working hypothesis by combing the theory of hepatitis cirrhosis and liver housing blood.
2To understand the distribution features of common syndrome elements of hepatitis cirrhosis, and then understand the manifestation featres of blood stasis, yin deficiency, etc. based on the clinical cross-sectional survey data.
3To understand the manifestation features of indicators when liver housing blood was dysfunction based on the clinical cross-sectional survey data and supply evidence for further analysis.
4To supply evidence for interpreting the modern scientific connotation of dysfunction of liver housing blood by analyzing the correlation between the dysfunction manifestation of liver housing blood and indicators from lab findings and imaging based on the clinical cross-sectional survey data.
Methods
1Building the working hypothesis
The traditional Chinese medicine(TCM) theory of the dysfunction manifestation of liver housing blood and hepatitis cirrhosis pathogenesis and the western medicine theory of liver physiology and hepatitis cirrhosis pathophysiology was combed. The syndrome elements of the dysfunction manifestation of liver housing blood was established. The working hypothesis was built.
2Data collection
Nationwide multi-center cross-sectional epidemiological survey was conducted. TCM symptoms, signs and indicators from lab findings and imaging were collected by using the unified "hepatitis cirrhosis case survey form" formulated by research group.
3"Standards of hepatitis cirrhosis syndrome elements differentiation"
The standards were formulated based on current multiple clinic consensus, literature review, clinical survey data and experts evaluation.
4"Quantization form of hepatitis cirrhosis symptoms and syndrome elements"
The form was formulated based on the quantitative classification of symptoms and signs in the "hepatitis cirrhosis case survey form".
5Data processing
Including data entry, data cleaning and data type conversion.6Statistical methods
SPSS13.0statistical package was adopted.
6.1Analyzing the distribution features
(1) Independent sample t test or Mann-Whitney rank sum test was used to compare the difference between two groups and one-way ANOVA or Kruskal-Wallis H test was used to compare the differences among three groups when the data was measurement.
(2)The chi-square test was used to compare the difference between two groups when the data was count.
Statistical inference took0.05as the significance level.
6.2Analyzing the correlation
(1)Linear trend:a linear trend was used to observe the liner trend between syndrome elements quantized score of blood stasis or yin deficiency and indicators'average level.
(2) Simple correlation analysis:pearson and spearman correlation analysis were respectively used to analyze continuous and categorical variables.
(3)Multiple linear regression:syndrome elements quantized score of blood stasis or yin deficiency as the dependent variable, the indicators level as independent variable, the variable selection using stepwise regression method.
(4) Binary Logistic Regression Analysis:whether blood stasis or yin deficiency combined with bleeding syndrome being diagnosed as the dependent variable, whether indicators being abnormal as independent variables, single independent variable in fitting the model were respectively conducted using the enter method.
(5) Stepwise Bayes discriminant analysis:whether blood stasis or yin deficiency being diagnosed, and whether blood stasis or yin deficiency combined with bleeding syndrome being diagnosed as the dependent variables, indicators as the independent variables, variables selection using Wilks'Lambda method.
Results
1Building the working hypothesis of the study
The occurrence and development of hepatitis cirrhosis was affected by blood stasis and yin deficiency, which were the dysfunction manifestation of liver housing blood. The correlation between the syndrome elements of blood stasis, yin deficiency(or combined with bleeding syndrome) and indicators(routine blood test, clotting function, liver function, portal hemodynamics, liver ultrasound, endoscopy, liver reserve function, vasoactive substances, etc.) were explored by using statistical methods as the tools.
2The distribution features of syndrome elements of hepatitis cirrhosis
(1) The distribution of syndrome elements:503cases of patients were diagnosed blood stasis,448case of yin deficiency,257cases of damp heat,438cases of qi stagnation,517cases of qi deficiency,428cases of yang deficiency,462cases of water retention during all the801cases of hepatitis cirrhosis patients.
(2)The distribution of blood stasis and yin deficiency:In the compensated and decompensated stages, patients with blood stasis accounted for52.50%and69.60%and quantified score were4.97±2.41and5.96±2.61respectively (P<0.05); patients with yin deficiency accounted for55.40%and56.30%and quantified score were5.33±2.05and5.55±2.15respectively (P>0.05)
(3) The distribution of bleeding syndrome:In the compensated&decompensated stage, patients with hematemesis, melena, ecchymosis, gum bleeding and epistaxis accounted for5&38,5&33,7&16,72&78and43&70cases respectively. In addition, gum bleeding usually combined with epistaxis, which was most distributed in the two stages. Hematemesis combined with melena, which was distributed in the decompensated stage.
(4) The distribution of combination of blood stasis or yin deficiency with bleeding syndrome:67.4%of hematemesis patients,71%of melena patients,91.3%of ecchymosis patients,92%of gum bleeding patients and96.4%of epistaxis patients combined with blood stasis or(and) yin deficiency. The quantified score of blood stasis and yin deficiency exists difference among the three groups of blood stasis, yin deficiency and their combination and both the score was much higher when combined with ecchymosis, hematemesis or melena than other bleeding syndrome.
3The manifestation features of indicators when liver housing blood dysfunction3.1The manifestation features of indicators when blood stasis existed or aggravated
When blood stasis existed or aggravated, the changes of indicators contained:
(1) reduced erythrocytes, hemoglobin, hematocrit, platelets, mean platelet volume, etc.;(2)prolonged prothrombin time, reduced prothrombin time activity percentage, increased international normalized ratio;(3) reduced albumin, albumin/globulin and prealbumin, elevated globulin;(4) increased MELD, Child-Pugh score;(5)growed spleen diameter and thickness;(6)widened portal vein, reduced portal vein average flow velocity, etc. through comparing the difference of indicator level between blood stasis and not blood stasis groups, blood stasis in the compensated and decompensated stages, and the difference of blood stasis's distribution and quantified score between the normal and abnormal indicators groups.
When blood stasis combined with bleeding syndrome existed, the changes of indicators contained:(1) reduced erythrocytes, hemoglobin, hematocrit and platelets;(2) reduced prothrombin time activity percentage, increased international normalized ratio;(3) reduced total protein, albumin, and albumin/globulin;(4) elevated hepatic artery peak velocity, etc. through comparing the difference of distribution of blood stasis combined with hematemesis, melena, ecchymosis, gum bleeding and epistaxis respectively between the normal and abnormal indicators groups.
The above differences were statistically significant (P<0.05)3.2The manifestation features of indicators when yin deficiency existed or aggravated
When yin deficiency existed or aggravated, the changes of indicators contained:(1) reduced prothrombin time activity percentage, increased international normalized ratio, elevated fibrinogen;(2) elevated globulin, reduced albumin/globulin;(3) reduced erythrocytes, hemoglobin, hematocrit, and mean platelet volume, etc.(4)growed spleen thickness;(5)elevated hepatic artery peak velocity, reduced portal vein average flow velocity;(6) reduced NO level, etc. through comparing the difference of indicator level between yin deficiency and not yin deficiency groups, yin deficiency in the compensated and decompensated stages, and the difference of yin deficiency's distribution and quantified score between the normal and abnormal indicators groups.
When yin deficiency combined with bleeding syndrome existed, the changes of indicators contained:(1) reduced percentage of neutrophils, erythrocytes, hemoglobin, hematocrit, platelets, mean platelet volume;(2) reduced prothrombin time activity percentage, increased international normalized ratio;(3)increased MELD score;(4)widened hepatic artery, etc. through comparing the difference of distribution of yin deficiency combined with hematemesis, melena, ecchymosis, gum bleeding and epistaxis respectively between the normal and abnormal indicators groups.
The above differences were statistically significant (P<0.05)3.3The manifestation features of indicators among the three groups of blood stasis, yin deficiency and their combination
(1) albumin, albumin/globulin and total protein reduced, MELD, Child-Pugh score increased, portal vein and spleen vein average flow velocity reduced when blood stasis or their combination compared with yin deficiency group;(2) erythrocytes reduced, prothrombin time prolonged, prothrombin time activity percentage reduced, international normalized ratio increased when their combination compared with yin deficiency group;(3)5-HT, NO level reduced when yin deficiency or their combination compared with blood stasis group;(4) portal vein narrowed, percentage of neutrophils reduced when yin deficiency compared with blood stasis group. The above differences were statistically significant (P<0.05)
4The correlation between dysfunction manifestation of liver housing blood and indicators of hepatitis cirrhosis patients 4.1The correlation between blood stasis and indicators of hepatitis cirrhosis patients
The indicators that positively related with blood stasis included:(l)reduced platelets, mean platelet volume;(2) prolonged prothrombin time, reduced prothrombin time activity percentage, increased international normalized ratio;(3) reduced albumin, albumin/globulin, elevated globulin;(4) growed spleen thickness;(5)widened portal vein, reduced portal vein average flow velocity;(6) elevated AT-II level;(7) increased MELD, Child-Pugh score;(8) reduced erythrocytes, hemoglobin, hematocrit, etc. based on linear trend, simple correlation analysis and multiple linear regression.
The indicators that positively related with blood stasis combined with bleeding syndrome included:(1)reduced prothrombin time activity percentage, increased international normalized ratio;(2)reduced erythrocytes, hemoglobin, hematocrit;(3)elevated hepatic artery peak velocity, etc. based on the simple correlation analysis and binary logistic regression analysis between indicators and blood stasis combined with bleeding syndrome.
The above results were statistically significant (P<0.05)4.2The correlation between yin deficiency and indicators of hepatitis cirrhosis patients
The indicators that positively related with yin deficiency included:(1)reduced prothrombin time activity percentage, increased international normalized ratio, elevated fibrinogen;(2) reduced albumin/globulin and prealbumin, elevated globulin;(3) narrowed portal vein, elevated hepatic artery peak velocity, widened hepatic artery;(4)reduced percentage of neutrophils;(5)reduced5-HT, TNF-a, NO level, etc. based on linear trend, simple correlation analysis and multiple linear regression.
The indicators that positively related with yin deficiency combined with bleeding syndrome included:(1)reduced erythrocytes, hemoglobin, hematocrit;(2) reduced prothrombin time activity percentage, increased international normalized ratio;(3)widened hepatic artery, etc. based on the simple correlation analysis and binary logistic regression analysis between indicators and yin deficiency combined with bleeding syndrome.
The above results were statistically significant (P<0.05)4.3Discriminant analysis among the three groups of blood stasis, yin deficiency and their combination of hepatitis cirrhosis patients
The indicators that contributed to discriminate blood stasis, yin deficiency and their combination were erythrocytes, albumin, portal vein,5-HT and TNF-a.
The indicators that contributed to discriminate blood stasis, yin deficiency and their combination accompanied with5bleeding syndrome respectively were erythrocytes, leukocytes, prothrombin time activity percentage, fibrinogen, Child-Pugh score and NO level.
Conclusion
1With the severity of blood stasis in hepatitis cirrhosis patients, portal hypertension and splenomegaly/hypersplenism aggravated, liver reserve function decreased, liver coagulation dysfunctioned, etc.
2With the severity of yin deficiency in hepatitis cirrhosis patients, liver's synthesis of prothrombin dysfunctioned, liver's synthesis of plasma protein dysfunctioned, portal hypertension aggravated, etc.
3Inferring physiology from pathology of hepatitis corrihosis, the correlation preliminarily indicated that liver housing blood might associated with portal hemodynamics, spleen function, liver's synthesis function of plasma protein, liver's synthesis function of prothrombin, liver reserve function, etc.
引文
1. 张育轩,危北海.肝硬化临床诊断、中医辨证和疗效评定标准(试行方案)[J].中国中西医结合杂志,1994,14(4)：237-238.
2. 中国中西医结合学会消化系统疾病专业委员会.肝硬化中西医结合诊治方案[J].现代消化及介入诊疗,2005,10(2)：119-121.
3. 中国中西医结合学会消化系统疾病专业委员会.肝硬化中西医结合诊疗共识[J].中国中西医结合消化杂志,2011,19(4)：277-279.
4.郑筱萸.中药新药临床研究指导原则[M].北京：中国医药科技出版社,2002：143-150.
5. 中国中医药学会内科肝病委员会.病毒性肝炎中医辨证标准[J].中医杂志,1992,(5)：39-40.
6.朱梅,乔琦红,朱方石,等.对肝硬化临床证型Child分级评估的研究[J].中国校医,1999,13(6)：418-419.
7.焦栓林,欧阳洪,杜世奇,等.转化生长因子β1与肝炎后肝硬化中医证型及Child-Pugh分级的相关性[J].实用医药杂志,2012,29(5)：394-396.
8.冀爱英,任平,余晓珂,等.肝炎肝硬化中医证型与Child-pugh分级的相关性研究[J].中国中医基础医学杂志,2010,16(12)：1144,1147.
9.冀爱英,赵英红,杜明瑞.肝炎肝硬化中医证型与免疫学指标的相关性研究[J].中医药学报,2006,34(3)：39-40.
10.赵英红,孙和才,梁军.肝炎肝硬化中医证型与血清肝功能指标的相关性研究[J].四川中医,2011,29(11)：55-56.
11.刘玉品,池晓玲,周懂晶,等.肝硬化多层螺旋CT数量化诊断及其中医证候分析[J].实用医学杂志,2011,27(6)：1090-1092.
12.陈慧,陈培琼,黄穗平.肝硬化患者内分泌激素水平与中医证候及预后相关性研究[J].广东医学,2000,21(4)：341-342.
13.张琴,刘平,陈慧芬,等.肝炎后肝硬化中医证候特点的临床调查研究[J].中西医结合学报,2003,1(2)：108-112.
14.张琴,陈慧芬,陈良,等.肝炎后肝硬化中医证候与肝功能损伤关系的探讨[J].上海中医药杂志,2004,38(3)：8-11.
15.黄忠远,杨军平.乙肝后肝硬化Child-Pugh分级与PDCD5表达水平的关系[J].赣南医学院学报,2007,27(3)：371-373.
16.高丽芳,赵文霞.218例肝硬化患者中医证型、肝功能分级及食管静脉曲张分析[J].现代中医药,2012,32(1)：23-25.
17.袁虹,曹廷智,刘红,等.302例乙型肝炎肝硬化患者中医证候学探讨[J].中西医结合肝病杂志,2009,19(6)：346-349.
18.陈晓蓉,李桂明,王江蓉,等.不同证型肝硬化患者的门静脉血流动力学改变[J].中西医结合学报,2004,2(3)：178-181.
19.张北平,刘丰,谢庆平,等.肝炎肝硬化中医证型与TIMP-1、肝纤维化指标及肝功能分级相关性研究[J].新中医,2011,43(7)：16-18.
20.李岩,王垂杰.肝硬化的中医辨证分型研究[J].辽宁中医杂志,2009,36(2)：225-227.
21.谢芳,乔飞,隋云华.肝硬化中医辨证分型与Child-Pugh分级相关性研究[J].江苏中医药,2011,43(3)：27-28.
22.朱方石,卜平,朱海杭,等.肝硬化中医证型与Child-Pugh分类相关性的研究[J].中西医结合肝病杂志,1997,7(4)：198-200.
23.施卫兵,杨素霞.乙型病毒性肝炎肝硬化中医证型与客观检测指标相关性[J].安徽中医学院学报,2009,28(4)：28-30.
24.张寅,王新月,江宇泳.乙肝后肝硬化中医证型与肝功能Child-Turcotte-Pugh 分级和MELD评分的相关性研究[C].第二十四届全国中西医结合消化系统疾病学术会议专题报告及论文集：2012.
25.熊屏,李雪芹.乙肝肝硬化中医证型与门静脉血流动力学及肝功能分级相关性研究[J].浙江中医药大学学报,2008,32(5)：608-610.
26.萧焕明,施梅姐,池晓玲.373例乙肝肝硬化失代偿期患者证候与客观指标的相关性研究[J].辽宁中医杂志,2012,39(10)：1909-1012.
27.刘倩,王晓素.肝硬化证型与生物学指标相关性研究[J].辽宁中医药大学学报,2012,14(2)：113-116.
28.袁继丽,张华,王磊,等.乙型肝炎后肝硬化患者中医证候要素的生物化学特征[J].中西医结合学报,2011,9(4)：374-381.
29.张玲,潘虹,蒋桦,等.乙肝肝硬化失代偿期各证型肝功能特点的研究[J].辽宁中医杂志,2012,39(10)：1963-1964.
30.吴嘉赓,李尧坚.肝硬化患者透明质酸与辨证施治关系的探讨[J].中国中西医结合脾胃杂志,1995,3(2)：73-75.
31.吴嘉庚,张立煌.肝硬化患者中医”证”的实质研究[J].中国中西医结合杂志,1999,19(5)：279-281.
32.周建衡,赵军年.血小板、脾脏指数与乙型肝炎肝硬化中医证型的关系[J].福建中医学院学报,2008,18(3)：9-10.
33.陈培琼,金红艳,田广俊,等.不同中医证型肝硬化患者Hp感染与血氨水平的相关性研究[J].广州中医药大学学报,2008,25(2)：157-160.
34.冀爱英,杜明瑞,张晓伟,等.垂体甲状腺轴激素与肝炎肝硬化中医证型及Child-Pugh分级相关性的临床研究[J].中国实验方剂学杂志,2009,15(11)：101-103.
35.胡振斌,吕建林,邱华,等.肝硬化中医辨证分型与血浆内毒素水平的相关性研究[J].辽宁中医杂志,2012,39(1)：92-93.
36.李筠,汪承柏.慢性肝病60例血浆内毒素与生化、病理和中医证型关系的研究[J].新消化病学杂志,1995,3(1)：24-26.
37.丛志斌,杨世忠,贾丽娟.肝硬化中医证型与超声特征的相关性研究[J].中国中西医结合影像学杂志,2005,3(1)：5-8.
38.李雪芹,熊屏,张赤志,等.乙型肝炎肝硬化患者中医证型与超声影像学特征的关系[J].中西医结合肝病杂志,2007,17(3)：165-167.
39.张寅,王新月,江宇泳.乙肝后肝硬化中医证型与肝脾超声血流动力学参数的相关性研究[J].中国中医药信息杂志,2013,20(5)：21-22.
40.王江,侯键,谢明国,等.肝硬化中医证型与多层螺旋CT门静脉成像特点关系的研究[J].四川中医,2010,28(11)：22-24.
41.赖祥红.TGF-β1、PDGF与乙肝肝硬化肝功能分级及中医证型的相关性研究[J].江苏中医药,2012,44(4)：20-21.
1. 印会河.中医基础理论[M].上海：上海科学技术出版社,1984：37-38.
2.李德新.中医基础理论[M].北京：人民卫生出版社,2001：77-78.
3.孙广仁.中医基础理论[M].北京：中国中医药出版社,2002：89-90.
4.王蕾,试论肝藏血的机理[J].中医药研究,1999,15(6)：2-3.
5.房克英.“肝藏血”的国内外研究进展[D].北京：北京中医药大学,2013.
6.马月香.肝主藏血机理新探[J].中医药学刊,2005,23(1)：189.
7. 陈明.“肝藏血”小议[J].国医论坛,1995(6)：44.
8.钟飞.中医之“肝藏血”生化机理初探[J].中医药信息,1989,(5)：2-3.
9.徐鸿达,李萍.对中医肝藏血理论的初步探讨[J].甘肃中医学院学报,1987(3)：48,52.
10.张清怡.《临证指南医案》中“肝藏血主疏泄”的脏象理论研究[D].北京：北京中医药大学,2013.
11.张压西,李璇.从中医古籍“肝藏血、血舍魂”理论中探究不寐的内涵[J].中华中医药杂志,2011,26(10)：2211-2216.
12.谷丽敏,翟笑枫,凌昌全.“恶血归肝”伤科临证探析[J].安徽中医学院学报,2002,21(5)：29-30.
13.吴淑萍.安老汤治疗崩漏105例[J].安徽中医临床杂志,2000,12(6)：558.
14.张德超.崩漏治疗八法浅谈[J].北京中医杂志,1985,3：18-20.
15.陈超.崩漏验案二则[J].中医杂志,1979,(11)：33-34.
16.汪素卿,王惠珍.《傅青主女科》调经从肝论治浅析[C].第九次全国中医妇科学术研讨会论文集,2009：111-113.
17.哈荔田,罗元恺,韩百灵,等.功能性子宫出血(崩漏)证治[J].中医杂志,1985,(6)：4-10.
18.缑建华.略论肝与妇科疾病的关系[J].天津中医学院学报,1987,(1)：11-14.
19.许晓波,石玲.举元煎合二至丸加减治疗功能性子宫出血41例[J].中医药学刊,2003,21(6)：1005.
20.孙玉英,曹佩霞.费伯雄从心肝脾论治崩漏浅析[J].吉林中医药,2011,31(9)：919-920.
21.王玲,王采甫.略论崩漏与血瘀的关系[J].陕西中医,1998,19(12)：546-547.
22.贾文合,江永洪.叶天士治崩漏验案浅析[J].青海医药杂志,1993,(4)：6.
23.张华山.血崩治验三则[J].中国中医药信息杂志,1999,6(5)：70.
24.汪一江.汪墨斋治疗月经病经验[J].中医药临床杂志,2007,19(2)：107-108.
25.王开林,张淑元.调理肝气治疗血证的经验[J].成都中医学院学报,1988,11(4)：27-29.
26.程运文.《傅青主女科》月经病治肝特色.山西中医,1990,6(3)：30-31.
27.李燕翀,郭蕾,张俊龙.浅论肝于女子的作用[J].光明中医,2010,25(4)：591-593.
28.古学奎,丘和明.分期辨治难治性原发性血小板减少性紫癜57例疗效观察[J].新中医,2010,42(9)：68-69.
29.吴萸.辨证治疗血小板减少性紫癜[J].中国民族民间医药,2010,(5)：104-105.
30.张茂雷,刘萍,杜兆芬.春发肌衄治验1例[J].山西中医,1998,14(5)：23.
31.李达,代喜平,康颖,等.自拟怡血饮治疗成人慢性特发性血小板减少性紫癜 56例[C].第八届全国中西医结合血液病学术会议论文集,2007：191-194.
32.刘学彦,尹振东.小柴胡汤治疗特发性血小板减少性紫癜32例[J].中医研究,1998,11(5)：53.
33.蓝海,刘安平,古学奎,等.丘和明治疗原发性血小板减少性紫癜经验[J].中医杂志,2011,52(6)：462-463.
34.郭教礼,侯利孝.特发性血小板减少性紫癜从肝热论治[J].陕西中医函授,1991,(3)：13-14.
35.洪亚庆,常玉双,沈舒文.沈舒文教授从肝藏血治疗原发性血小板减少性紫癜临床经验[J].陕西中医,2010,31(1)：73-74.
36.常名空,侯德健.郭子光教授发挥肝主疏泄学说治疗血小板疾病[J].四川中医,2007,25(12)：3-4.
37.舒卫宏.肝藏血在治疗肝硬化门静脉高压中的应用[J].中国中医药现代远程教育,2011,9(2)：186.
38.陈福来,袁以红.肝硬化并发上消化道出血证治[J].吉林中医药,1990,(4)：13.
39.崔丽安,张俊富.从慢性肝炎、肝硬化出血倾向探讨中医“肝藏血”、“脾统血”理论的意义[J].中西医结合肝病杂志,2002,12(1)：48-49.
40.黄惠平.梁乃津辨治肝硬化失代偿期经验[J].新中医,1996,(4)：10-12.
41.王瑞起.孙剑璞老中医治疗出血证的经验[J].辽宁中医杂志,1984,(10)：4-5.
42.黄笑芳.姚芳蔚视网膜出血证治体会[J].中国社区医师,2011-12-2(20).
43.赵会芳,张义生,胡敏麟.肝不藏血之出血机理初探[J].中国医药学报,1991,6(4)：5-7.
44.魏广艺,汤杰英.中医内科疾病治疗中“治血先治肝”理论探讨.现代中西医结合杂志[J],2006,15(17)：2303-2304.
45.张海福.血证辨治[J].陕西新医药,1979,8(9)：28-30.
46.孙其新.血证关键在脾胃——李可学术思想探讨之四[J].中医药通报,2007,6(2)：9-12.
47.陈钢.小柴胡汤加减治疗血证经验[J].中国中医急症,1996,5(2)：92.
48.陈钢.试论肝统摄血液[J].贵州中医学院学报,1985,(1)：18-21.
49.江磊磊,张传永.试论治血先治肝[J].新中医,2009,41(4)：107-108.
50.周赛男,张荣华.从肝浅议血证[J],中医药导报,2007,13(10)：5-6,32.
51.方樟培.“肝体阴而用阳”对肝病治疗的指导意义[J].光明中医,2001,16(94)：2-4.
1.王家駹,李绍白.肝脏病学(第3版)[M].北京：人民卫生出版社,2013：28-36,281-290,298-316,630-645.
2.陈灏珠,林果为,王吉耀.实用内科学(第14版)[M].北京：人民卫生出版社,2013：1997-2007.
3.周仲瑛.中医内科学[M].北京：中国中医药出版社,2007：257-288.
4. 印会河.中医基础理论[M].上海：上海科学技术出版社,1984：37-38.
5.李德新.中医基础理论[M].北京：人民卫生出版社,2001：77-78.
6.孙广仁.中医基础理论[M].北京：中国中医药出版社,2002：89-90.
7.刘燕池,雷顺群.中医基础理论[M].北京：学苑出版社,2004：167-169.
8.李德新.李德新中医基础理论讲稿[M].北京：人民卫生出版社,2008：449-453.
9. 中国中西医结合学会消化系统疾病专业委员会.肝硬化中西医结合诊疗共识[J].中国中西医结合消化杂志,2011,19(4)：277-279.
10.刘绍能,陶夏平,王融冰,等.慢性乙型肝炎中医病因病机演变规律研究[J].中国中医药信息杂志,2007,14(12)：14-16.
11.邓鑫,文彬.肝硬化门静脉高压症的中医病机特点分析[J].辽宁中医杂志,2012,39(5)：816-818.
12.晏军,王煦.王绵之教授治疗早期肝硬化的经验[J].北京中医药大学学报,2001,24(4)：56-57.
13.单书健,陈子华.古今名医临证金鉴·黄疽胁痛脸胀卷石[M].北京：中国中医药出版社,1999：223.
14.张琴,刘平,章浩伟,等.900例肝炎后肝硬化中医证候判别模式的研究[J].中国中西医结合杂志,2006,26(8)：694-697.
15.黄贤樟.肝硬化的病机及临床治疗探讨[J].广州中医学院学报,1991,8(2,3)：150-154.
16.张云鹏.姜春华学术经验精粹[M].北京：中国中医药出版社,1994：96.
17.谭春雨,刘平.肝硬化“虚损生积”病机理论溯源及其临床意义[J].上海中医药大学学报,2010,24(4)：25-28.
18.郝朴,庄克莹.抗肝Ⅲ号片治疗肝炎肝硬化阴虚血瘀证94例[J].江苏中医,1999,20(8)：20.
19.刘树农.刘树农医论选[M].上海：上海科学技术出版社,1987：292.
20.史宇广,单书健.当代名医临证精华·肝炎肝硬化专辑[M].北京：中医古籍出版社,1988：208.
21.孔庆辉,刘春芳,隋杨.中西医结合治疗肝硬化腹水脾肾阳虚型30例[J].山东中医杂志,2008,27(4)：257-258.
22.杨艳娜.真武汤治疗脾肾阳虚型乙肝肝硬化腹水30例[J].亚太传统医药,2009,5(7)：37-38.
23.吴智兵,邹立华.彭胜权教授治疗肝硬化经验介绍[J].新中医,2004,36(5)：9-10.
24.刘震,陶夏平,姚乃礼.慢性乙型肝炎、早期肝硬化“毒损肝络”病机证候特点的研究[J].中国中医基础医学杂志,2011,17(2)：201-203.
25.姚泰,曹济民,樊小力,等.生理学[M].北京：人民卫生出版社,2010：46-68.
26.李桂源.病理生理学[M].北京：人民卫生出版社,2010：193,205.
27.季绍良,成肇智.中医诊断学[M].北京：人民卫生出版社,2004：2.
28.田代华.中医辨证要素分析[J].山东中医药大学学报,1998,22(2)：87-91.
29.朱文锋.中医辨证体系及“证”的规范化研究[J].天津中医,2002,19(5)：1-4.
30.朱文锋.创立以证素为核心的辨证新体系[J].湖南中医学院学报,2004,24(6)：38-39.
31.王永炎,张启明,张志斌.证候要素及其靶位的提取[J].山东中医药大学学报,2006,30(1)：1-4.
32.王永炎.完善中医辨证方法体系的建议[J].中医杂志,2004,45(10)：729-731.
33.王永炎,张志斌.再议完善辨证方法体系的几个问题[J].天津中医,2007,24(1)：1-4.
34.朱文锋,张华敏.“证素”的基本特征[J].中国中医基础医学杂志,2005,11(1)：17-18.
1.季绍良,成肇智.中医诊断学[M].北京：人民卫生出版社,2004：2.
2.王天芳,王庆国,薛晓琳,等.中医症状规范化研究的现状与思路[J].北京中医药大学学报,2005,28(4)：19-22.
3.王家良.临床流行病学[M].上海：上海科学技术出版社,2012：130-131.
1.王家駹,李绍白.肝脏病学(第3版)[M].北京：人民卫生出版社,2013：28-36,281-290,298-316,630-645.
2.季绍良,成肇智.中医诊断学[M].北京：人民卫生出版社,2004：126.
3.李桂源.病理生理学[M].北京：人民卫生出版社,2010：193.
4. 陈灏珠,林果为,王吉耀.实用内科学(第14版)[M].北京：人民卫生出版社,2013：1997-2007.
5. BATALER R, GINES P, NICOLAS JM, et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells[J]. Gastroenterology,2000,118:1149-1156.
6. ROCKEY D. The cellular pathogenesis of portal hypertension:stellate cell contractility, endothelin, and nitric oxide[J].Hepatology,1997,25:2-5.
7.黄献平,袁肇凯,谭光波,等.冠心病血瘀证患者血管紧张素转换酶基因多态性的检测分析[J].中医杂志,2007,48(1)：65-68.
8.王勇,李春,啜文静,等.血管紧张素Ⅱ-NADPH氧化酶-活性氧通路在慢性心肌缺血血瘀证中作用的实验研究[J].中华中医药杂志,2011,26(10)：2265-2268.
9.庞青,田峰,刘昌.血小板与肝纤维化的关系[J].实用肝脏病杂志,2011,14(4)：315-317.
10. RUDDELL RG, MANN DA, RAMM GA, et al. The function of serotonin within the liver[J]. J Hepatol,2008,48(4):666-675.
11.孙政,曹杰,杨镇,等.门静脉高压症性血管病变中局部肿瘤坏死因子-α、血管紧张素原与核因子-kappa B的相关研究[J].广州医药,2007,38(2)：1-5.