中医药治疗NASH的系统评价及健脾补肾、活血降浊方治疗NASH大鼠的实验研究

【作者】 李立；

【导师】 李军祥；

【作者基本信息】 北京中医药大学 ， 中医内科学， 2010， 博士

【摘要】 1中医药治疗非酒精性脂肪性肝炎临床研究的系统评价目的通过对中医药防治NASH的临床研究文献的系统评价,为中医药临床研究提供科学有力的循证医学试验证据,使中医药研究结果能够得到推广和应用。方法1.以非酒精性脂肪性肝炎、NASH、中医、中医药、中药为主题词进行电子检索；2.由2名研究者根据纳入、排除标准对文献进行筛选,获取符合要求的文献；3.对纳入文献进行资料提取；4.评价纳入研究的质量,并用Revman4.2软件对其进行Meta分析。结果1.共检索到152篇文献,最终纳入22篇；2.对文献进行质量评价后发现,中医药防治NASH的临床研究存在很多设计缺陷,如样本含量的估算、随机、盲法、远期疗效等都缺乏充实证据,根据国际质量评价标准,22个研究中,18个属于低质量研究,4个属于中质量研究；3.经系统评价和Meta分析后总结中医治疗NASH疗效特点如下：①从肝论治的中药无论是在痊愈率和总有效率方面还是在改善肝功能(ALT、AST、GGT)、血脂(TG、TG、LDL-C、HDL-C)方面均不能体现出比西药的治疗优势；②从肝脾两方面论治的中药在痊愈率、有效率和改善肝功能方面均明显优于西药治疗,其亦可以改善血脂,但在调节TG和HDL-C方面并不比西药具备优势；③从肝脾肾三个脏腑论治的中药无论是治愈率、总有效率,还是肝功能、血脂疗效均优于西药治疗,只是在提高HDL-C方面与西药疗效相当；④有2篇文献观察了从肝肾两方面防治NASH的疗效,分析提示,其较西药对照治疗,可以明显提高痊愈率、总有效率和改善肝功能同时调节LDL-C、HDL-C,但对TC、TG的疗效并不优于西药。结论1.中医药干预治疗非酒精性脂肪性肝炎有明显疗效；2.从肝脾肾辨证论治在痊愈率、有效率和改善肝功方面均明显优于西药治疗；3.中药干预未发现严重不良反应；但由于中医药治疗NASH临床研究还存在很多问题,所综合分析的研究总体质量不高,以上结论还需更多大样本多中心设计良好的RCT来验证。2健脾补肾、活血降浊方对NASH大鼠脂质代谢因子及线粒体修复酶调控作用的影响目的通过研究健脾补肾、活血降浊方对NASH大鼠脂质代谢因子及线粒体修复酶调控作用,探讨非酒精性脂肪性肝炎发病机制及健脾补肾、活血降浊方防治NASH大鼠的作用机理。方法高脂饲料喂养制备NASH大鼠模型,每日灌胃健脾补肾方、活血降浊方、综合方及易善复进行治疗,10周后观察大鼠肝脏病理形态学变化,检测各组大鼠肝功能、血脂四项,SYBR Green荧光定量PCR法测定肝组织脂质代谢因子及线粒体修复酶mRNA指标,并进行统计。结果1.肝脏脂肪变性程度：模型组与空白组比较有显著差异(P＜0.01)；治疗组与模型组比较有显著差异(P＜0.05)；空白组与易善复治疗组比较有显著性差异(P＜0.01)；中药治疗组与易善复治疗组比较无统计学差异(P＞0.05)；2.炎症活动度计分(HAI)：模型组与空白组比较HAI升高,有非常显著性差异(P＜0.01)；各治疗组与模型组相比HAI均明显降低(P＜0.01)；综合方组在降低HAI方面,较易善复有明显优势(P＜0.01)；各中药治疗组肝脏炎症活动度计分之间无明显差异(P＞0.05)；3.肝功能的比较：模型组较空白组比较肝功能(AST、ALT、GGT、ALP)明显升高(P＜0.01)；各治疗组与模型组相比均明显降低(P＜0.01)；活血降浊方组在降低ALT方面与空白组有明显差异(P<0.01),健脾补肾方组和综合方组在降低ALT方面与空白组无差异(P＞0.05)；三种中药方组在降低AST、GGT方面与空白组相比有明显差异(P<0.01),但在降低ALP方面无差异(P>0.05)；易善复组在降低GGT方面明显优于三种中药治疗组(P<0.01)；4.血脂四项的比较：模型组血脂四项(LDL-C、HDL-C、TG、TC)与空白组及治疗组比较明显升高(P＜0.01)；各治疗组与空白组组比较明显升高(P＜0.01)；健脾补肾方、活血降浊方和综合方与易善复组相比各项血脂指标有明显差异(P＜0.01)；5.对线粒体DNA修复酶的影响：模型组3种线粒体DNA修复酶含量明显高于空白组(P＜0.01)；健脾补肾方、活血降浊方和综合方组明显高于模型组(P＜0.01),易善复组明显低于模型组(P＜0.01)；健脾补肾方、活血降浊方和综合方组与易善复组比较明显升高(P＜0.01)；健脾补肾方、活血降浊方和综合方组间比较无差别(P>0.05)；6.对脂质代谢因子PPARα、PGC-1α的影响：模型组PPARα、PGC-1α较空白组组明显降低(P<0.01)；各治疗组与模型组相比明显升高(P＜0.01)；健脾补肾方、活血降浊方和综合方组明显优于易善复组(P<0.01)；健脾补肾方、活血降浊方和综合方组间比较无差别(P＞0.05)；7.对脂质代谢因子SREBP-1c、SCAP的影响：模型组SREBP-1c、SCAP较空白组明显升高(P＜0.01)；各治疗组与模型组相比明显降低(P＜0.01)；健脾补肾方组和活血降浊方组与易善复组相比有统计学意义(P＜0.01)；综合方组SREBP-1c明显高于易善复组(P<0.01),SCAP与易善复组相比亦有统计学差异(P<0.05)；各治疗组与空白组相比存在明显差异(P＜0.01)；健脾补肾方、活血降浊方和综合方组间比较无差别(P＞0.05)。结论1本研究采用高脂饲料喂养方法成功复制NASH大鼠模型,方法简便,配方简单,并与人类NASH相似；2健脾补肾方、活血降浊方和综合方能改善NASH大鼠一般状态、肝脏病理情况,降低转氨酶,调节NASH大鼠血脂；3健脾补肾方、活血降浊方和综合方一方面可以抑制NASH大鼠肝组织SREBP-1c、SCAP的表达,提高PPARα、PGC-1α的表达；另一方面,其可以增加线粒体修复酶OGGL、UDG、NTHL的含量,提示健脾补肾方、活血降浊方和综合方可从调节脂质代谢和增进肝脏自身修复两方面防治非酒精性脂肪性肝炎。更多还原

【Abstract】 1 Systematic Review for Traditional Chinese Medicine Treatment of Non-alcoholic Steatohepatitis Clinical ResearchObjective:Through the systematic review of Chinese medicine clinical research of NASH,to provide scientific evidence-based medical evidence for Chinese medicine clinical,so that the results of research can be promoted and applied.Methods:1.Non-alcoholic steatohepatitis, NASH, Chinese medicine, Chinese medicine for the electronic search keywords; 2.By the two researchers according to inclusion, exclusion criteria were screened, get to meet the requirements of the literature; 3. Data extraction of included literature; 4. Evaluate the quality of included studies and used software Revman4.2 to Meta-analysis.Results:1.There are 152 articles were retrieved,22 of them are included.2. After evaluateing the quality of the reserches, it is not difficult found that there are many design flaws in the traditional Chinese medicine clinical study of NASH,such as estimation of sample size, randomized, blinded, long-term effect and so on.Many of them lack of substantial evidence, according to international quality evaluation criteria, in the 22 studies,18 is a low quality studies,4 are medium-quality studies.3. After the systematic review and Meta analysis, summarized characteristics of Chinese treatment of NASH effect as follows:①The theory of Liver treatment in Chinese medicine is not better than the treatment of western medicine in the fact of the recovery rate,total efficiency,liver function(ALT,AST,GGT),lipid (TG, TG, LDL-C, HDL-C).②The theory of Liver and spleen treatment in Chinese medicine is better than the treatment of western medicine in the function of improving the recovery rate, total efficiency,liver function,lipid,but In aspects of TG and HDL-C, Chinese medicine does not have the advantage than Western medicine.③The theory of Liver and spleen and kidney treatment in Chinese medicine are better than the treatment of western medicine,nomatter in the aspects of the recovery rate,total efficiency,liver function,lipids.④Only 2 articles researched the theory of Liver and kidney treatment,the analysis suggested that,compare with western medicine,this treatment in Chinese medicine can enhance the recovery rate, total efficiency, and improve the liver function, regulate LDL-C、HDL-C,except the treatment of TCandTG.Conclusions:1.The treatment of Chinese medicine for non-alcoholic steatohepatitis have significant effects.2.The theory of liver and spleen and kidney treatment of Chinese medicine is better than reatment of western medicine.3. Chinese medicine no serious adverse reactions.However, Chinese medicine treatment of NASH still have many problems of clinical research,many of the reserches are low quality studies,so these conclusions need further large sample multi-center well-designed RCT to verify.2 The Influence of Traditional Chinese Medicine on lipid metabolic factors and Mitochondrion DNA RepairenzymesObjective:Through the research of the influence of traditional Chinese medicine on lipid metabolic factors and Mitochondrion DNA Repairenzymes in non-alcoholic Steatohepatitis(NASH)rats,To investigate the pathogenesy of NASH and the mechanism that JianPiBuShen herbs and HuoXueJiangZhuo herbs prevent and treat NASH rats.Methods:Give high fat diet to prepare the model of NASH,except the model group and blank group,the other rats were treated by different TCM prescriptions and Essentiale, All the rats were executed after the therapy of 10 weeks,detected the liver functions,lipids in blood,lipid metabolic factors and mitochondrion DNA repair enzymes in liver,finally we analysed data.Results:1. The hepatocellular fatty degeneration:There were obviously differences among the blank group and the model group(p<0.01).Compared with model group, the hepatocellular fatty degeneration in treatment group had significant diference (p<0.01). The hepatocellular fatty degeneratio of the Essentiale group were raised obviously compared to the blank group(p<0.01).There’s no significant difference between different theory of treatment of Chinese medicine(p>0.05).2. The hepatocellular scorces of the severity of inflammation:The model group were raised obviously compared to the group of the blank group (p<0.01). Compared with model group, the hepatocellular scorces of the severity of inflammation in treatment group were decreased (p<0.01). Compared with the Essentiale group,the combination herbs of JianPiBuShen herbs and HuoXueJiangZhuo herbs can decreased the hepatocellular scorces of the severity of inflammation obviously (p<0.01). There were no distinct differences among the treatment groups(p>0.05).3.The liver function:AS、ALT、GGT、ALP of the model group were raised obviously compared to the blank group (p<0.01); The treatment groups was lower than that of the model group (p<0.01); ALT of HuoXueJiangZhuo herbs group and the blank group has distinct difference(p<0.01); AST、GGT of the three Chinese medicine treatment group and the blank group has distinct difference(p<0.01),but they have no different in ALP(p<0.01);GGT of the Essentiale group is lower than the he three Chinese medicine treatment group(p<0.01).4.The lipids in the blood:The blood lipids of the model group were raised obviously compared to the blank group (p<0.01); Compared with the blank group,The blood lipids in each treatment group were incresced significantly(p<0.01); There were distinct differences among the three Chinese medicine treatment group and the Essentiale group(p<0.01);5.The expression of mitochondrion DNA repair enzymes mRNA in hepatic issue: The expression of three kinds of mitochondrion DNA repair enzymes in the model group were raised obviously compared to the blank group (p<0.01); The expression in the three Chinese medicine treatment group were raised obviously compared to the model group (p<0.01), the Essentiale group was lower compared to the model group (p<0.01); There were no distinct differences among the three Chinese medicine treatment group(p>0.05).6.The expression of PPARaand PGC-1αmRNA in hepatic issue:The expression of PPARaand PGC-lainthe model group were decreased obviously compared to the blank group (p<0.01); The expression in each treatment group were raised obviously compared to the model group (p<0.01); The expression in the three Chinese medicine treatment group were higher than the Essentiale group(p<0.01); There were no distinct differences among the three Chinese medicine treatment group(p>0.05).7.The expression of SREBP-1 c,SCAP mRNA in hepatic issue:The expression of SREBP-1c,SCAP inthe’model group were increased obviously compared to the blank group (p<0.01);The expression in each treatment group were decreased obviously compared to the model group (p<0.01);There were distinct differences among the JianPiBuShen herbs,HuoXueJiangZhuo herbs and the Essentiale group (p<0.01);The SREBP-1c in the combination herbs of JianPiBuShen herbs and HuoXueJiangZhuo herbs were increased obviously compared to the Essentiale group (p<0.01),The SCAP in the combination herbs of JianPiBuShen herbs and HuoXueJiangZhuo herbs were increased obviously compared to the Essentiale group(p<0.05); There were no distinct differences among the three Chinese medicine treatment group(p>0.05).Conclusions:1. In this study, high fat diet rat model of NASH was successfully copied,the method is simple, and similar to human NASH.2.The Chinese medicine can improve the general state of rats and liver pathology, decreased liver function, regulated blood lipids of NASH rats.3.On the one hand,the Chinese medicine restrained the expression of SREBP-1c、SCAP and increased the expression of PPARα、PGC-lain hepatic issue;On the other hand,it can increased the expression of mitochondrion DNA repair enzymes mRNA in hepatic issue. The Chinese medicine Can regulate lipids and enhance liver itself-repair to prevent and treat the non-alcoholic steatohepatitis.更多还原