【作者】 张丹；

【导师】 王金泉； 刘志红；

【作者基本信息】 南京大学 ， 临床医学， 2019， 硕士

【摘要】 目的:Fabry病(Fabry disease,FD)是一种以α-半乳糖苷酶A(α-galactosidase A,α-Gal A)活性下降为特征的罕见的X连锁隐性遗传溶酶体贮积病。α-GalA基因突变导致该酶活性部分或全部丧失,造成其代谢底物三己糖酰基鞘脂醇(globotriaosylceramide,Gb3)和相关的鞘糖脂沉积在人体各器官、组织,最终引起一系列脏器病变。本文回顾性分析汉族人群Fabry病的临床、肾脏病理及心脏受累特点,并阐述影响Fabry病远期预后的相关危险因素。方法:选取2004年-2016年于东部战区总医院国家肾脏疾病临床医学研究中心暨全军肾脏病研究所经肾活检确诊为Fabry病的患者31例纳入研究。以随访期间肾小球滤过率较基础值下降50%为观察终点,将其分为肾功能稳定组和肾功能恶化组,比较两组的临床、肾脏病理及心脏病变特征,并利用COX回归模型分析影响肾脏预后的危险因素。结果:31例汉族Fabry病患者中男性20例(64.5%),女性11例(35.5%),平均起病年龄27.7±14.2岁(5～53岁),确诊年龄35.9±9.2岁(21～54岁),延误诊断时间8.0±10.5年。8例患者行α-半乳糖苷酶A活性检测,其外周血粒细胞中α-半乳糖苷酶A活性显著下降(中位数0.38 nmol/mL/h;范围0.0～22.13 nmol/mL/h)。肾活检后中位随访时间62月(8～156月),23例患者肾功能稳定,8例出现肾功能恶化。肾功能恶化组起病年龄明显小于肾功能稳定组(17.0±12.2岁vs.31.5±13.1岁,P<0.05)。肢端疼痛为最常见的首发症状(58.1%),其次为浮肿(51.6%)、少汗或无汗(38.7%)、皮肤血管角质瘤(35.5%)。20例患者存在心电图异常,主要表现为左心室高电压(41.9%)、ST-T改变(38.7%)。9例患者根据超声心动图可诊断为左心室肥厚,其中肾功能恶化组5例,肾功能稳定组4例(62.5%vs.17.4%,P=0.03)。肾功能恶化组初始24h尿蛋白、血肌酐、血胱抑素C及尿NAG均明显高于肾功能稳定组,差异有统计学意义(p<0.05)。肾功能恶化组肾小球节段硬化、足细胞空泡变性程度显著大于肾功能稳定组。患者3年、5年、10年累计肾脏存活率分别为96.6%、80.6%、64.5%。多因素COX回归分析,肾活检时MSSI评分、血肌酐及肾小球节段硬化是影响Fabry病肾功能预后的独立危险因素。MSSI评分预测患者进入终点事件的ROC曲线下面积为84.5%,截断值为18分(敏感性100%,特异性56.52%),肾小球节段硬化预测患者进入终点事件的ROC曲线下面积为78.0%,截断值为3.9%(敏感性100%,特异性52.17%)。K-M曲线则更直观地反映MSSI评分和肾小球节段硬化对肾脏存活率的影响,即初始MSSI评分≥18分、肾小球节段硬化比例≥3.99%时,肾脏远期预后均较差。结论:汉族人群Fabry病临床表现具有多样性,累及皮肤、心脏、肾脏等多个器官。Fabry病10年肾脏生存率仅64.5%。初始MSSI评分及肾小球节段硬化比例是Fabry病患者肾功能恶化的独立危险因素,可作为Fabry病预后不良的早期检测指标。更多还原

【Abstract】 Objective:Fabry disease(FD)is an inherited X-linked lysosomal storage disorder,caused by the mutation in the GLA gene that encodes the enzyme α-galactosidase A,which leads to potentially life-threatening accumulation of globotriaosylceramides(Gb3)in lysosome-carrying tissues.This study retrospectively analyzed the clinic-pathologic features and risk factors that affected renal prognosis of FD in Chinese patients.Methodology:Data covering 2004 to 2016,obtained from Fabry clinical database at the National Clinical Research Center of Kidney Diseases,Jinling Hospital,were reviewed retrospectively.All patients had confirmed renal pathology diagnosis.Patients were classified into renal function stabilization group and renal function deterioration group.The clinicopathological features and outcome were analyzed and compared between groups.Results:Thirty-one patients were analyzed,20(64.5%)were male and 11(35.5%)were female.The age at initial onset of symptoms and diagnosis were 27.7±14.2(5～53 years)and 35.9±9.2 years(21～54 years).The average time of delay diagnosis is 8.0±10.5 years.Reduced α-gal A activity in leukocytes was observed in 8 patients(median,0.38 nmol/mL/h;range 0.0-22.13 nmol/mL/h).After median 62 months(8～156 months)follow-up,23 of them had stable renal function while 8 underwent renal function deterioration.Frequent presenting symptoms included acroparesthesia(58.1%),edema(51.6%),hypo-or anhidrosis(38.7%),and angiokeratoma(35.5%).20 patients had ECG abnormalities including left ventricular high voltage(41.9%)and ST-and T-alterations(38.7%).Left ventricular hypertrophy was present in 62.5%patients with renal function deterioration and 17.4%patients with stable renal function(p=0.03).The renal cumulative survival rate of all patients was 96.6%,80.6%,and 64.5%in 3,5,and 10 years,respectively.24h urinary protein,serum-creatinine,cystatin C and urinary N-acetyl-beta-glucosaminidase increased significantly in the renal function deterioration group compared with the renal function stable group.The patients in the renal function deterioration group had higher segmental sclerosis and vacuole severity score than those in the stable renal function group.Mainz Severity Score Index(MSSI)and segmental sclerosis are independent predictive factors for a more rapid progression of Fabry nephropathy.The receiver operating characteristic analysis demonstrated that the area under the curve for the prediction of renal function progression on the basis of MSSI and segmental sclerosis levels in patients with FD was 0.845 and 0.780,respectively.MSSI score ≥18 or segmental sclerosis ≥3.9%in patients with FD positively correlated with poor renal prognosis.The K-M curve revealed more directly that the MSSI score ≥18 or segmental sclerosis ≥3.9%positively correlated with poor long-term renal prognosis.Conclusion:FD’ s clinical manifestations are heterogeneous and nonspecific.The 10-year cumulative renal survival rate was 64.5%in Chinese patients.MSSI score and segmental sclerosis levels predict the renal prognosis of patients with FD sensitively.更多还原