结节性硬化症患儿体格生长状态调查及雷帕霉素治疗后的疗效、安全性及对其体格发育的影响研究

发布时间：2018-08-12 08:58

【摘要】：目的:结节性硬化症(Tuberous sclerosis complex TSC )是单基因常染色体显性遗传病,发病机制是基因缺陷导致mTOR信号通路过度活化,雷帕霉素靶蛋白(mTOR )通路在衰老过程中起重要作用,抑制mTOR通路可以改善与年龄有关的疾病如:认知能力下降、癌症、老年痴呆症、肾和心脏疾病等。雷帕霉素(Rapamycin)能特异性抑制mTOR信号通路,是延缓衰老和治疗衰老相关疾病的潜在性药物,同时也是结节性硬化症(Tuberous sclerosis complex TSC)的分子靶向治疗药物。对于雷帕霉素安全性的研究多集中在器官移植及癌症患者中,本研究主要通过回顾性调查研究及观察性研究,对TSC儿童体格发育状态进行调查,以及对长期服用雷帕霉素治疗的TSC儿童与健康儿童的体格发育情况、TSC儿童服药前后生化指标、血常规及药物副反应进行比较,从而评价雷帕霉素的疗效、安全性及对儿童体格发育的影响。第一部分结节性硬化症儿童体格发育状态调查方法:收集2012年10月-2016年10月在我院儿科门诊确诊为结节性硬化症未服用雷帕霉素的学龄前期患儿体格发育(身高、体重)的情况行回顾性调查研究。所收集的体格生长指标:身高、体重、体块指数与国家卫计委网站发表的《中国7岁以下儿童生长发育参照标准》进行比较,从而了解TSC患儿体格生长情况。结果:入组295例学龄前期TSC儿童,婴幼儿占研究人群的74.24%。在研究的病例中癫痫发生率为89.83%,颅内病变者(皮层钙化+室管膜下结节+ SEGA)占72.88%,智力障碍者占72.54%,心脏横纹肌瘤的发生率占13.9%,肾脏错构瘤发生率为7.46%。在入组的患儿中身高在正常范围的占91.86%,身高高于同年龄同性别正常儿童X+2SD的占4.75%,低于同年龄同性别正常儿童X-2SD的占3.39%。体重在正常范围的占94.24%,体重高于同年龄同性别正常儿童X+2SD的占5.7% (男童体重高于X+2SD的占5.41%,女童体重高于X+2SD的占5.04%),年龄大于3岁10人,小于3岁的7人。无体重低于同年龄同性别正常儿童X-2SD的患儿。BMI在正常范围的占83.39%,高于X+2SD的患儿占14.24% (男童10.9%,女童17.99%),低于X-2SD的占2.37%。在合并肾脏病变的患儿中BMI高于正常的比例是31.03%。结论:在我们研究的七岁以下TSC患儿中癫痫的发生率稍高于文献报道,颅内病变及智力障碍者明显高于文献报道,肾脏错构瘤的发生率明显低于文献报道。患儿身高生长与同年龄同性别正常儿童大致相同。体重生长与同年龄同性别儿童大致正常,BMI高于正常的TSC患儿较正常同龄儿偏高,且女童比例高于男童。在TSC合并癫痫、心脏病变、颅内病变的患儿中其身高、体重、BMI分布无明显差异,但合并肾脏病变的患儿中BMI高于正常的比例偏高。第二部分雷帕霉素治疗后的疗效、安全性及对其体格发育的影响研究方法:本研究是回顾性的开放性临床试验。病例来自2014年9月到2016年12月在我院门诊就诊的结节性硬化症儿童,根据纳入和排除标准纳入病人,入组后给予雷帕霉素治疗。测量用药前身高、体重、生化、血常规及随访治疗后1年、2年后患儿身高、体重、生化、血常规及药物副反应情况,分析雷帕霉素的疗效、安全性及对其体格发育情况的影响。结果:我们入组的122名TSC儿童用药前身高在正常范围的110人,占总人数的90.16%,高于同年龄同性别正常儿童x+2SD的为9人,占总人数的7.38%,低于同性别童年龄正常儿童身高的均值x-2SD的3人,占总人数的2.46%。应用雷帕霉素治疗1年后,TSC儿童身高在正常范围的115人,占总人数的94.26%,高于同年龄同性别正常儿童x+2SD的为7人,占总人数的5.74%,无低于x-2SD的患儿;体重评价:TSC儿童用药前体重在正常范围的114人,占总人数的93.44%,高于同年龄同性别正常儿童x+2SD的为8人,占总人数的6.56%,无低于x-2SD的患儿。应用雷帕霉素治疗1年后,TSC儿童体重在正常范围的116人,占总人数的95.08%,高于同年龄同性别正常儿童x+2SD的为6人,占总人数的4.92%,无低于x-2SD的患儿。身体匀称度评价:体块指数(BMI) : TSC儿童用药前BMI在正常范围的99人,占总人数的81.15%,高于同年龄同性别正常儿童x+2SD的为21人,占总人数的17.21%,低于同年龄同性别正常儿童x-2SD的为2人,占总人数的1.64%。应用雷帕霉素治疗1年后,TSC儿童BMI在正常范围的99人,占总人数的81.15%,高于同年龄同性别正常儿童x+2SD的为20人,占总人数的16.39%,低于同年龄同性别正常儿童x-2SD的为3人,占总人数的2.46%。生长速率评价:所有入组患儿身高年生长速率在正常范围的109人,占总人数的89.34%。22名TSC患儿用药1、2年后自身前后对照年生长速率比较:其中8人年生长速率减慢,14人年生长速率增加。应用雷帕霉素治疗过程中我们观察到的药物副作用主要有脂质代谢异常:总胆固醇升高8人(5.46-6.95mmo/L),占6.56%,其中5人在治疗3个月内升高;低密度脂蛋白升高13人(3.47-4.5 mmo/L),占10.66%,其中有6人在治疗3个月内发现升高;高密度脂蛋白增高22人(1.61-2.4mmol/L),占18.03%,其中14人在治疗半年后升高;甘油三脂增高1人(1.82mmol/L),占0.82%;其余副作用有:食欲减退(3.28%)、口腔溃疡(5.74%)、肝功能异常(4.92%),均为1-2级副反应,均为一过性,给予对症治疗后可恢复正常。无血小板减少症和中性粒细胞减少症的发生、无血糖异常及肾功能损害。应用雷帕霉素治疗1年前后对疗效进行评价分析:癫痫、心脏横纹肌瘤、心肌或腱索强回声、色素脱失斑、鲨鱼皮样斑、肾脏多发结节治疗前后的改变有统计学意义,余症状无统计学意义。结论:在TSC儿童中长期应用雷帕霉素可使患儿癫痫、心脏病变、色素脱失斑、鲨鱼皮样斑、肾脏多发结节的症状减轻,且对身高、体重、体块指数、身高年增长速率均无影响,无骨髓抑制、肾功能异常、血糖异常的发生。在我们的研究中发现应用雷帕霉素治疗后有脂质代谢异常的副作用,其中主要以总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇增高为主。在总胆固醇及低密度脂蛋白胆固醇升高的患儿中52.38%的患儿在治疗早期即出现升高,随着治疗时间的延长无累积效应。63.64%应雷帕霉素治疗的TSC患儿高密度脂蛋白胆固醇升高发生在治疗半年以上。其余的药物副反应多为一过性,对症治疗后可恢复正常,在婴幼儿中有一过性肝功能损害,无持续肝功能损害的发生。在婴幼儿中应用雷帕霉素治疗,需密切监测肝功能、血脂及其他副作用的发生。
[Abstract]:Objective: Tuberous sclerosis complex TSC (TSC) is a monogenic autosomal dominant inherited disease. The pathogenesis of TSC is overactivation of mTOR signaling pathway caused by genetic defects. Rapamycin target protein (mTOR) pathway plays an important role in the aging process. Inhibiting the mTOR pathway can improve age-related diseases such as cognitive impairment. Rapamycin can specifically inhibit the mTOR signaling pathway. Rapamycin is a potential drug for delaying aging and treating aging-related diseases. It is also a molecular targeted drug for tuberculosis sclerosis complex TSC. Concentrated on organ transplantation and cancer patients, this study investigated the physical development of TSC children through retrospective and observational studies, as well as the physical development of TSC children and healthy children treated with rapamycin for a long time, biochemical indicators of TSC children before and after taking drugs, blood routine and side effects of drugs. To evaluate the efficacy, safety and impact of rapamycin on physical development in children. Part I: Investigation of physical development in children with tuberous sclerosis Methods: Physical development (height, weight) of preschool children with tuberous sclerosis diagnosed in our pediatric clinic from October 2012 to October 2016 was collected. Results: 295 preschool TSC children were enrolled and 74.24% of them were infants. The incidence of epilepsy was 89.83%. Intracranial lesions (cortical calcification + subependymal nodules + SEGA) accounted for 72.88%. Mental retardation accounted for 72.54%. Cardiac rhabdomyoma accounted for 13.9%. Renal hamartoma accounted for 7.46%. Among the children enrolled in the study, 91.86% were in the normal range and the height was higher than that of the same age and sex. Children with X+2SD accounted for 4.75%, 3.39% were lower than normal children of the same age. 94.24% were in normal weight, 5.7% were higher than normal children of the same age (5.41% were in boys'weight higher than X+2SD, 5.04% were in girls' weight higher than X+2SD), 10 were older than 3 years old, 7 were younger than 3 years old. The incidence of epilepsy was slightly higher in children under 7 years of age with TSC than in those under 7 years of age. It was reported that the incidence of renal hamartoma was significantly lower in children with intracranial lesions and mental retardation than in the literature. The height growth of the children was roughly the same as that of normal children of the same age and sex. There was no significant difference in height, weight and BMI distribution among children with TSC complicated with epilepsy, heart disease and intracranial lesions, but the proportion of children with renal lesions with BMI higher than normal was higher. Open clinical trial. The cases were from children with tuberculous sclerosis who were admitted to our outpatient clinic from September 2014 to December 2016. According to inclusion and exclusion criteria, the patients were treated with rapamycin. The height, weight, biochemistry, blood routine and follow-up were measured before treatment. The height, weight, biochemistry, blood routine and blood routine of the children were measured after 1 year and 2 years of treatment. The side effects of rapamycin were analyzed, and the effects of rapamycin on the efficacy, safety and physical development were analyzed. Results: Among the 122 TSC children, 110 (90.16%) were in normal height, 9 (7.38%) were higher than that of the normal children of the same age, and 9 (7.38%) were lower than that of the normal children of the same sex. One year after rapamycin treatment, 115 (94.26%) of the TSC children were in the normal range, 7 (5.74%) were higher than that of the same age and sex normal children (x+2SD), and no lower than that of the x-2SD children. 114, accounting for 93.44% of the total, 8, accounting for 6.56% of the total, were higher than normal children of the same age and sex x + 2SD, and none was lower than x-2SD. Body mass index (BMI): Before treatment, 99 children with TSC had BMI in the normal range, accounting for 81.15% of the total, 21 children with higher BMI than those with same age and normal sex, accounting for 17.21% of the total, and 2 children with lower BMI than those with same age and normal sex, accounting for 1.64% of the total. One year after treatment, 99 children with TSC had BMI in the normal range, accounting for 81.15% of the total, which was higher than 20 children of the same age with normal sex, accounting for 16.39% of the total, and 3 children of the same age with normal sex, accounting for 2.46% of the total. Comparing the annual growth rate of 22 children with TSC before and after 1 or 2 years of treatment, the annual growth rate of 8 children slowed down and that of 14 children increased. Five patients were elevated within 3 months of treatment, 13 patients (3.47-4.5 mmo/L) had elevated LDL, accounting for 10.66%. Six of them had elevated HDL, 22 (1.61-2.4 mmol/L) had elevated HDL, accounting for 18.03%. Fourteen of them had elevated HDL after half a year of treatment, one (1.82 mmol/L) had elevated triglycerides, accounting for 0.82%. The other side effects were: loss of appetite (1.61-2.4 mmol/L). 3.28%, oral ulcer (5.74%) and abnormal liver function (4.92%) were all grade 1-2 side effects, which were transient and could be recovered after symptomatic treatment. Myoma, myocardial or chordae tendineae strong echo, depigmentation plaque, shark skin-like plaque, renal multiple nodules before and after treatment had statistical significance, the remaining symptoms were not statistically significant. Conclusion: Long-term use of rapamycin in children with TSC can alleviate the symptoms of epilepsy, heart disease, depigmentation plaque, shark skin-like plaque, renal multiple nodules, and There was no effect on height, body weight, body mass index, annual growth rate of height, no bone marrow suppression, renal dysfunction, and abnormal blood glucose. In our study, we found that lipid metabolism was abnormal after rapamycin treatment, and the main side effects were total cholesterol, low density lipoprotein cholesterol and high density lipoprotein cholesterol. MAIN. Among the children with elevated total cholesterol and low density lipoprotein cholesterol, 52.38% had elevated HDL cholesterol at the early stage of treatment. There was no cumulative effect with the prolongation of treatment time. 63.64% of TSC patients treated with rapamycin had elevated HDL cholesterol more than half a year after treatment. After treatment, the symptoms can be restored to normal, and there is a transient liver function damage in infants, without the occurrence of persistent liver function damage.
【学位授予单位】：中国人民解放军医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R725.9

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