艾滋病HAART相关高脂血症中医证候规律研究

【作者】 娄彦梅；

【导师】 李峰；

【作者基本信息】 北京中医药大学 ， 中医诊断学， 2010， 博士

【摘要】 目的：目前艾滋病HAART治疗相关高脂血症的中医药证候研究及治疗方面尚属空白,本研究在国家“十一五”重大专项,及国家重点基础研究发展计划专项资助下,通过对未感染HIV高脂血症患者及艾滋病HAART相关高脂血症患者不同人群的症状、体征、中医证候、客观指标及十年心血管疾病风险评估等特点进行研究、分析、总结,探讨艾滋病HAART相关高脂血症的流行病学特点、中医证候规律及与十年心血管疾病风险评估的相关性分析,为中医药治疗艾滋病HAART相关高脂血症及降低心血管风险性提供依据,也为艾滋病HAART相关高脂血症中医证候及辨证论证奠定基础。方法：1.文献综述：通过查阅1979年-2010年2月PubMed及中国期刊全文数据库(CNKI)、中国生物医学数据库(CBM)、中文科技期刊全文数据库(VIP)医学文献资料库中的艾滋病HAART相关高脂血症英文文献216篇,中文文献21篇及高脂血症的中医药研究文献,分析总结艾滋病HAART相关高脂血症目前现代医学及中医药研究进展。2.理论研究：(1)艾滋病患者在HAART治疗中出现相关的血脂异常等症状,使患者患心血管疾病的几率大大提高,因此艾滋病相关的血脂异常是艾滋病治疗中一个重要的方面。通过对非艾滋病人原发性高脂血症的研究分析,在查阅中西医相关艾滋病及高脂血症文献的基础上,结合中外现代文献的观点,对此类患者中医证候学规律与艾滋病HAART相关高脂血症的病因病机、中医证候、研究进展进行客观地评价分析和总结,进行初步比较并探讨两者的相关性。并通过流行病学调查与临床实践的方法,探讨中医药对艾滋病HAART相关高脂血症的认识,为中医证候研究及治疗方面,提供新的思路与方法。(2)HAART相关高脂血症在用药过程中通常出现比较晚,平均2～6年以上,因此治疗初期往往不能引起重视；其次,其中的脂肪异常分布往往是不可逆的；并且,脂肪代谢的异常是导致心血管病变重要病因；再加上它可能会影响HAART药物的治疗效果,所以对它的早期诊断和治疗是十分重要的。以中医治疗未病的理论思想初步探讨艾滋病HAART相关高脂血症中医证候与十年心血管风险评估相关性,为中医辨证提供客观依据,以更好的指导临床治疗。3.临床研究：(2)对366例未感染HIV高脂血症患者的流行病学资料、症状、体征、中医证候、十年心血管疾病(CVD)风险评估,血脂指标相关性进行统计分析,总结其证候规律及与客观指标,风险评估得分的相关性。应用SAS9.1统计软件进行因子分析,提取中医证候要素(公因子)。(2)对60例艾滋病HAART相关高脂血症患者的流行病学资料,症状,体征,中医证候,十年CVD风险评估,血脂指标相关性进行统计分析,总结其证候规律及与客观指标,风险评估得分的相关性。应用SAS9.1.3统计软件进行因子分析,提取中医证候要素(公因子)。(3)对以上两组患者群的症状、体征、中医证候进行比较研究,进一步分析艾滋病HAART相关高脂血症患者证候规律及病因病机,为中医药治疗艾滋病HAART相关高脂血症提供依据。(4)应用典则相关分析对以上两组患者群的症状、体征、中医证候、十年CVD风险评估,血脂指标相关性进行比较研究,分析两者的不同特点及之间的差异。结果：1.流行病学特征、症状、体征的研究(1)流行病学特征比较本次研究病例中艾滋病HAART相关高脂血症组低HDL-C血症所占比例最大(33.33%),其次是高TG血症(28.33%),混合型高脂血症(25%),高TC血症所占比例最小(13.33%)。而未感染HIV的原发性高脂血症主要以混合型高脂血症最为多见,其次是高TC血症,两者有明显的不同。伴发疾病中,艾滋病HAART相关高脂血症患者伴发脂肪肝者35例,高血压者9例,冠心病者5例。与未感染HIV原发性高脂血症患者主要伴发高血压相比,艾滋病HAART相关高脂血症其主要伴发疾病为脂肪肝,这可能与艾滋病HAART相关高脂血症主要是以血清TG的升高为主要表现有关。研究结果显示艾滋病HAART相关高脂血症患者脂肪分布中面颊消瘦占最大比例(58.11%),其次为腹围增加(18.92%)及四肢脂肪菲薄,血管暴露(8.11%)。未感染HIV原发性高脂血症患者约半数以上未出现脂肪异常分布情况,而在肥胖患者中的腹围增加亦为单纯的腹围增加并无同时存在向心性脂肪堆积。采用国内外医师普遍公认的来自Framingham’心脏病研究的ATPⅢ风险评估系统(ATP Risk Estimator)进行心血管病风险评估及危险等级分级。艾滋病HAART相关高脂血症患者中低危患者(十年危险性<5%)40例(66.67%),中危患者(十年危险性5～10%)10例(16.67%),高危患者(CHD或CHD等危症,或十年危险性10-15%)5例(8.33%),极高危患者(ACS或缺血性心血管病合并DM或十年危险性>15%)5例(8.33%)。与未感染HIV高脂血症患者的危险等级分布没有显著性差异。(2)症状、体征的比较研究从两组患者群的51项症状、体征的比较结果看,艾滋病HAART相关高脂血症患者出现频率在40%以上的有10项,依次为：疲乏(76.67%)、形体异常(76.67%)、口苦(50%)、腰酸(45%)、健忘(43.33%)、口渴(43.33%)、心中烦闷(42.37%)、面色苍白(41.67%)、腰膝无力(41.67%)、四肢麻木(41.67%)。而未感染HIV高脂血症患者症状、体征出现频率在30%以上的有9项,分别为：疲乏(66.39%)、腰膝无力(61.48%)、食欲不振(50%)、烦躁易怒(44.81%)、四肢麻木(38.52%)、胸闷(37.16%)、心中烦闷(36.34%)、头痛(32.79%)、形体肥胖(30.6%)。可见艾滋病HAART相关高脂血症组较未感染HIV组症状较为明显。2.366例未感染HIV的原发性高脂血症证候研究通过因子分析的方法得出12个公因子,结合专业知识,研究结果显示,原发性高脂血症主要证候以气滞血瘀证最为常见,依次为痰浊瘀阻证、脾气虚证、肝郁气滞兼有郁热证、气阴两虚证、阴虚痰湿证,脾胃虚弱证、肾阳虚证,心气虚证,显示原发性高脂血症中医病机重在肝脾肾功能失调,痰浊瘀血阻滞。3.66例艾滋病HAART相关高脂血症证候研究与未感染HIV的原发性高脂血症相比,艾滋病HAART相关高脂血症患者群中肾虚证所占比例最大,其次是脾虚痰阻证。而未感染组气滞血瘀证所占比例最大,其次为痰浊瘀阻证及脾气虚证。研究结果显示未感染HIV高脂血症组证候分布以实证的气滞血瘀证为主,而艾滋病HAART相关高脂血症组证候分布以虚证的肾虚证为主。4.艾滋病HAART相关高脂血症病因病机根据艾滋病HAART相关高脂血症患者群中医证候分布规律结合文献研究及临床研究结果显示,艾滋病HAART相关高脂血症的病机大多属于本虚标实,虚实夹杂之证,艾滋病患者肾气亏虚,肝脾肾的运化功能失常,是引起HAART相关高脂血症的重要病机。与非AIDS高脂血症患者相比,艾滋病HAART相关高脂血症患者的肾虚证较为明显,尤其是HAART治疗疗程较长的患者,与肾虚的程度明显相关。5.年龄、BMI、心血管危险评分及危险分级、血脂指标与中医证候的相关性分析艾滋病HAART相关高脂血症患者群与未感染HIV的原发性高脂血症患者群年龄、BMI、心血管危险评分及危险分级、血脂指标与中医证候的相关性分析研究,以典则相关分析对两组分别进行研究,结果显示,未感染HIV的原发性高脂血症患者群：X3(冠心病十年风险评估)与F9(痰浊瘀阻证),X1(年龄)与F1(心气虚证)的相关性最大,且都呈正相关。艾滋病HAART相关高脂血症患者群：X4(心血管疾病危险分级)与F2(脾虚痰阻证因子)的相关性最大,且呈正相关,说明脾虚痰浊瘀阻程度越重其心血管病风险等级越高,其发生心血管病并发症的危险性越大。结论1.艾滋病HAART相关高脂血症与未感染HIV的原发性高脂血症患者的流行病学特征,症状、体征存在某些差异。艾滋病HAART相关高脂血症组较未感染HIV组症状较为明显,原因可能是受艾滋病本身复杂病理改变的影响。2.与未感染HIV的原发性高脂血症相比,艾滋病HAART相关高脂血症患者肾虚证出现频率最高。而未感染组气滞血瘀证所占比例最大,其次为痰浊瘀阻证及脾气虚证。结果显示也间接说明艾滋病HAART相关高脂血症以虚证证候占大多数,也提示在临床治疗中中医药治疗要更加偏重于补虚益正,以提高治疗疗效。3.艾滋病HAART相关高脂血症属本虚标实之证,属痰、浊、瘀范畴,以正虚为本,痰瘀为标,属本虚标实证。肾气亏虚,肝脾肾的运化功能失常,是引起HAART相关高脂血症的重要病机。与非AIDS高脂血症患者相比,艾滋病HAART相关高脂血症患者的肾虚证较为明显,尤其是HAART台疗疗程较长的患者,与肾虚的程度明显相关,因此治疗更应加强健脾益肾、益气养心、活血化痰的治疗。4.目前,在AIDS,患者HAART治疗后出现的毒副作用中,高脂血症已经越来越多的受到关注,高脂血症的出现,使患者暴露于心血管并发症的概率在不断增加,而目前调节脂代谢最为有效的他汀类药物,又和蛋白酶抑制剂之间存在相互作用。本研究通过对此类患者中医证候研究,为中医药辨证治疗HAART后的高脂血症提供有利依据,对发挥中医药优势,减小HAART的毒副作用,提高HAART的依从性同时改善脂代谢,提高此类患者的生存质量有着重要的意义。5.从本研究的因子分析结果看,为艾滋病HAART相关高脂血症证候规律的进一步研究提供了重要的参考价值,但由于课题研究时间的限制,还需要更多大样本、多中心的临床试验在将来更多的验证。更多还原

【Abstract】 ObjectiveCurrent HAART treatment of AIDS associated hyperlipidemia syndromes in Chinese medicine research and treatment is still blank. This research is based on the national "Eleventh Five" major projects, and the State Key Basic Research Program of special funding. The researchers analyzed and summarized the characteristics of non-AIDS associated hyperlipidemia and HAART treatment of AIDS associated hyperlipidemia with different groups of symptoms, signs, syndromes, objective indicators and the assessment of the 10-year cardiovascular risk. The features of HAART treatment of AIDS associated hyperlipidemia of the Traditional Chinese Medicine syndromes and 10-year rule and cardiovascular disease risk assessment of the correlation were analyzed. The results will provide the scientific basis of Chinese Medicine treatment of HAART associated hyperlipidemia and reduction of cardiovascular risk and the analysis of Traditional Chinese Medicine syndromes of AIDS-related hyperlipidemia syndromes.Methods:1.Literature ReviewThe literature of AIDS HAART associated hyperlipidemia syndromes was obtained from CNKI and CBM and VIP. The research of Modern Medicine and Chinese Medicine in fields of HAART treatment of AIDS associated hyperlipidemia syndromes were analyzed and summarized.2.Theory research(1) AIDS patients in HAART treatment often appear symptoms such as lipid abnormalities, which greatly increases risk of cardiovascular disease of patients, so HIV-related dyslipidemia is an important aspect of treatment to AIDS. Through research and analysis to non-AIDS primary hyperlipidemia, based on searching related western medicine and TCM literature about AIDS and hyperlipidemia, combining Chinese and foreign contemporary literature’s view, to make objective analysis and conclusion on such patients’ TCM syndrome law and AIDS HAART-related hyperlipidemia pathogenesis, TCM syndrome and evaluation of research and make a preliminary comparison and correlation.With methods of the epidemiological investigation and clinical practice discussing Chinese medicine’s understanding on AIDS HAART-related hyperlipidemia which can provide new ideas and methods for TCM’s syndrome research and treatment. (2) HAART-related hyperlipidemia usually occurs late in the course of medication, about an average of 2 to 6 years, so it often can not be paid attention to in the beginning of the treatment; Second, abnormal distribution of fat is often irreversible; and abnormal lipid metabolism is an important cause leading to cardiovascular disease; plus it may affect the therapeutic effect of HAART, so it is important to make early diagnosis and treatment. With theory of "prevention of disease" discussing correlation of syndromes of AIDS HAART-related hyperlipidemia with years of cardiovascular risk assessment, can provide an objective basis for the syndrome differentiation of TCM in order to guide clinical treatment better.3. Clinical Research(1) Counting and analyzing 366 cases of NON-AIDS patients with hyperlipidemia’s epidemiological data, symptoms, signs, syndromes, years CVD risk assessment, lipids index correlation, summarizing syndromes law and its correlation with objective indicators and risk assessment of the relevance scores. Applicating SAS9.1.3 statistical software to make factor analysis and abstracting TCM syndrome factor (common factor).(2) Counting and analyzing 60 cases of AIDS patients with HAART-related hyperlipidemia’s epidemiological data, symptoms, signs, syndromes, years CVD risk assessment, lipids index correlation, summarizing syndromes law and its correlation with objective indicators and risk assessment of the relevance scores. Applicating SAS9.1 statistical software to make factor analysis and abstracting TCM syndrome factor (common factor).(3) Comparing the two patient groups on the symptoms, signs and syndrome of TCM to analyze AIDS patients with HAART-related hyperlipidemia’s syndromes regulation and pathogenesis further,it can provide the basis for TCM treatment of AIDS HAART-related hyperlipidemia.(4) Compare and study two patient groups on the symptoms, signs, TCM syndrome, years of CVD risk assessment and lipids index correlation applicating canonical correlation analysis, Analyze the differences and characteristics between the two groups.Results:1. Epidemiological characteristics, symptoms and syndromes(1) Epidemiological characteristicsBase on our current research, AIDS HAART-related hyperlipidemia cases, the percentage of low HDL-C hyperlipidemia is the highest (33.33%), followed by high TG hyperlipidemia (28.33%), and combined hyperlipidemia (25%); the last is high-TC hyperlipidemia (13.33%). Combined hyperlipidemia is most common in cases of primary hyperlipidemia without HIV infections, followed by high-TC hyperlipidemia, which results are different from above.Complications of AIDS HAART-related hyperlipidemia patients are fatty liver disease (FLD) in 35 cases,9 cases in hypertension, and 5 cases in coronary heart disease.Comparing with HIV uninfected cases, HIV uninfected patients with primary hyperlipidemia are mostly associate with hypertension, unlike AIDS HAART-related hyperlipidemia cases with FLD might mainly cause by the elevating in serum TG. Case studies on fat distribution in AIDS HAART-related hyperlipidemia patients, thin cheeks are the highest (58.11%), followed by abdominal circumference increased (18.92%) and limb fat meager vascular exposure (8.11%). In HIV uninfected primary hyperlipidemia patients, more then half of them don’t have anomalous fat distribution. And cases in obesity, abdominal circumference increasing patients don’t have the complication with centripetal fat accumulation.According to Framingham’s ATP III risk assessment system (ATP Risk Estimator) for cardiovascular disease risk assessment and risk rating classification. In AIDS HAART-related hyperlipidemia patients, low-risk patients (10 years risk< 5%) 40 cases (66.67%), medium-risk cases (10 years risk 5-10%) 10 cases (16.67%), high-risk patients (CHD or CHD risk equivalents, or 10-year risk 10-15%) 5 cases (8.33%). There is no significant difference on the risk rating between HIV and non-HIV hyperlipidemia patients.(2) Symptoms and syndromesComparing 51 symptoms and syndromes from two groups of patients, AIDS HAART-related hyperlipidemia patients have 9 symptoms which frequency appears more than 40%:fatigue (76.67%), bitterness taste in mouth (50%), back pain (45%), forgetfulness (43.33%), thirst (43.33%), and distress (42.37%), pale (41.67%), weakness in waist and knee (41.67%), limb numbness (41.67%). And in HIV uninfected patients there are 9 symptoms which frequency appears more than 30%:fatigue (66.39), weakness in waist and knee (61.48%), anorexia (50%), irritability (44.81%), limb numbness (38.52%), chest tightness (37.16%), distress (36.34%), headache (32.79%), and obesity (30.6%). Symptoms appear more obviously on AIDS HAART-related hyperlipidemia patients.2.366 case studies of HIV uninfected primary hyperlipidemia patients12 common divisor were gain through factor analysis, studies show Qi stagnation with blood stasis is most common in primary hyperlipidemia patients, followed by phlegm stasis, spleen Qi deficiency syndrome, liver Qi stagnation with stagnant heat, Qi and Yin deficiency, Yin deficiency with phlegm, spleen and stomach weakness syndromes, kidney Yang deficiency, heart Qi deficiency, indicating the pathogenesis of primary hyperlipidemia is link to liver and spleen renal disorders, phlegm stagnation of blood stasis.3.66 case studies of AIDS HAART-related hyperlipidemia patientsCompare with HIV uninfected primary hyperlipidemia patients; kidney deficiency is most common in AIDS HAART-related hyperlipidemia patients. In HIV uninfected group, Qi stagnation with blood stasis is most in common, followed by phlegm stasis and spleen Qi deficiency syndrome. The syndrome distribution results show that excess Qi and blood stagnation is the main syndrome in HIV uninfected primary hyperlipidemia patients, while kidney deficiency syndrome is to AIDS HAART-related hyperlipidemia patients.4. Pathogenesis of AIDS HAART-related hyperlipidemiaAccording to syndrome distribution and literature research, the pathogenesis of AIDS HAART-related hyperlipidemia is mainly root deficiency and branch excess and mixed excess-deficient conditions. AIDS patients are mostly kidney Qi deficiency and dysfunctional in liver, kidney and spleen. Comparing with HIV uninfected primary hyperlipidemia patients; kidney deficiency is more obvious in AIDS HAART-related hyperlipidemia patients, especially with patients in the longer course treatment with HAART, significantly correlated with the degree of kidney deficiency.5. Age, BMI, cardiovascular risk score and risk classification, serum lipids and related syndromes analysisCase study between AIDS HAART-related hyperlipidemia patients and HIV uninfected primary hyperlipidemia patients on age, BMI, cardiovascular risk score and risk classification, serum lipids and TCM related syndromes analysis.The canonical correlation analysis in order to separate the two groups, the results show that HIV uninfected primary hyperlipidemia patients:X3 (10 years coronary heart disease risk assessment) and F9 (phlegm stasis), X1 (age) and Fl (Heart Qi Deficiency Syndrome) is the most relevant, and positively correlated.AIDS HAART-related hyperlipidemia patients:X4 (cardiovascular disease risk classification) and F2 (spleen phlegm obstruction factor) the maximum correlation, and a positive correlation, indicating more severe deficiency phlegm stasis of cardiovascular disease. The higher level of risk, the incidence of cardiovascular disease the greater the risk of complications.Conclusions:1. The epidemiological characteristics, symptoms and syndromes of AIDS HAART-related hyperlipidemia patients and HIV uninfected primary hyperlipidemia patients are not quite the same, maybe cause by the complex pathological changes in AIDS.2. Comparing with HIV uninfected primary hyperlipidemia patients, kidney deficiency is more obvious in AIDS HAART-related hyperlipidemia patients. In HIV uninfected group, Qi stagnation with blood stasis is most in common, followed by phlegm stasis and spleen Qi deficiency syndrome. Results reveal deficiency syndromes appear in most AIDS HAART-related hyperlipidemia patients, also indicates, treatments of Chinese medicine should emphasis on tonifying Qi to improve the treatment efficacy.3. AIDS HAART-related hyperlipidemia is root deficiency and branch excess, associate with phlegm, turbidity and stasis. AIDS patients are mostly kidney Qi deficiency and dysfunctional in liver, kidney and spleen, which are the important pathogenesis of AIDS HAART-related hyperlipidemia patients. Comparing with HIV uninfected primary hyperlipidemia patients; kidney deficiency is more obvious in AIDS HAART-related hyperlipidemia patients, especially with patients in the longer course treatment with HAART, significantly correlated with the degree of kidney deficiency. Therefore, treatments should emphasis on strengthen spleen and kidney, tonify Qi and nourishing the heart, invigorate blood and expel phlegm.4. Doctors concern more and more on the side effects of HAART treatments on AIDS patients. Hyperlipidemia has become one of the main attention, rates of cardiovascular complications have been climbing. Statins, the most effective lipid metabolism medicine, interacts with protease inhibitors. In TCM syndromes research, TCM treatments reduce the side effects of HAART, and improve the compliance of HAART while improving lipid metabolism and the life quality for patients.5. Base on factor analysis, the study on AIDS HAART-related hyperlipidemia provides an important reference value, but because of time constraints, we still need larger samples and more clinical trials in the future.更多还原