重型β地中海贫血眼部变化的研究现状

重型β地中海贫血(β-TM)是一种由珠蛋白合成缺陷引起的遗传性疾病。该病需要长期输血和服用祛铁剂药物治疗,可引起眼部组织的各种继发性变化。与正常同龄人相比,β-TM患者的眼部表现为角膜曲率更为陡峭、前房更浅、晶状体厚度增加、眼轴更短和泪液分泌减少等改变;同时,营养缺乏和使用铁螯合剂药物治疗会增加罹患并发性白内障及视网膜变性的风险,从而影响β-TM患者的生存质量。本文结合国内外相关文献,对β-TM患者眼部相关变化进行探讨和综述,旨在为临床实践提供有价值的见解。

Iron dysregulation in beta-thalassemia

Iron deficiency anemia and iron overload conditions affect more than one billion people worldwide.Iron homeostasis involves the regulation of cells that export iron into the plasma and cells that utilize or store iron.The cellular iron balance in humans is primarily mediated by the hepcidin-ferroportin axis.Ferroportin is the sole cellular iron export protein,and its expression is regulated transcriptionally,post-transcriptionally and posttranslationally.Hepcidin,a hormone produced by liver cells,post-translationally regulates ferroportin expression on iron exporting cells by binding with ferroportin and promoting its internalization by endocytosis and subsequent degradation by lysosomes.Dysregulation of iron homeostasis leading to iron deposition in vital organs is the main cause of death in betathalassemia patients.Beta-thalassemia patients show marked hepcidin suppression,ineffective eiythropoiesis,anemia and iron overload.Beta-thalassemia is common in the Mediterranean region,Southeast Asia and the Indian subcontinent,and the focus of this review is to provide an update on the factors mediating hepcidin related iron dysregulation in beta-thalassemia disease.Understanding this process may pave the way for new treatments to ameliorate iron overloading and improve the long term prognosis of these patients.

重型β-地中海贫血患儿生长发育异常及其与铁超负荷的关系

目的探讨重型β-地中海贫血患儿生长发育状态及其与铁超负荷的关系。方法于2007年7～8月对50例长期在该院儿科定期输血的重型β-地中海贫血患儿进行身高、体重和性发育评价,并与1995年中国0～18岁儿童体重、身高百分位数参考值比较,同时检测输血前血常规、肝功能和血清铁蛋白水平。结果24例(48%)重型β-地中海贫血患儿表现身材矮小,其中15例同时伴体重低下。≥10岁者21例,仅7例出现自发性青春期发育,TannerII～III期;≥14岁者8例,其中4例尚无性征发育。身高低于第10百分位者(n=31)与身高高于第10百分位者(n=19)分组比较,前者血清铁蛋白水平显著增高(8239.2±5865.5vs5028.1±3885.7mg/L,P<0.05),输血前Hb水平显著降低(68.2±12.3vs79.7±14.5g/L,P<0.05),肝脏显著增大(P<0.05)。而体重低于第10百分位者(n=20)与体重高于第10百分位者(n=30)分组比较,前者仅血清铁蛋白水平差异具有显著意义(9165.5±6042.5vs5567.3±4447.3mg/L,P<0.05)。结论接受中等量输血和不正规除铁治疗的重型β-地中海贫血患儿常伴有身材矮小、体重低下和性发育迟缓,其生长发育异常与体内铁严重超负荷有关。

小儿重型β地中海贫血肝活检63例临床分析

目的分析小儿重型β地中海贫血(β-thalassemia,β地贫)的肝脏病理特点,探讨肝活检的方法与安全性。方法对1998年10月—2006年10月住院的63例重型β地贫患儿行肝活检,观察肝脏病理改变,并结合临床资料进行分析。结果共作66例次肝活检,均1次成功,成功率100%。肝活检显示肝组织内有不同程度铁沉积,中重度占42例(66.7%),铁沉积程度与血清铁蛋白(SF)水平呈明显正相关(r=0.70,P<0.01)。检出肝纤维化54例(85.7%),年龄(7.3±3.2)岁,SF在纤维化患儿中明显升高(P<0.01),但纤维化分期与SF、肝脏铁沉积程度无相关性(r=0.12、0.21,P均>0.05)。结论我国小儿重型β地贫存在肝脏铁含量重、肝纤维化普遍且发生年龄早的特点,与不规范治疗有关。小儿地贫肝活检安全、可行,能为治疗提供重要指导。

重型β地中海贫血患者肝脾肿大原因探析

目的探讨重型β地中海贫血(thalassemia major,TM)患者肝脾肿大的影响因素。方法 2008-07/2010-03月,171例TM患者接受腹部超声检查,观察其肝脾肿大情况及胆囊结石的发生,并记录一般情况、输血和去铁状况,测量血清铁蛋白浓度。结果 171例患者中113例肝脏增大,89例脾脏增大,15例曾行切脾术,4例有胆囊结石。地贫基因类型、是否高量输血是影响脾脏增大的因素。结论 TM患者中肝脾增大较为普遍,需加强规范化输血治疗,以维持输血前血红蛋白大于90g/L,尤其是β0/β0纯合子TM患者。

珠海地区重型β-地中海贫血儿童甲减发生率及危险因素的分析

目的:分析珠海地区重型β-地中海贫血(β-thalassemia major,β-TM)儿童甲状腺功能减退的发生率及危险因素。方法:对2018年8月至2020年8月在中山大学附属第五医院儿科和珠海市妇幼保健院儿科就诊并长期随访的86例β-TM患儿进行临床特征分析,了解珠海地区β-TM患儿甲状腺功能减退发生率,分析影响甲减发生率的危险因素。结果:珠海地区β-TM患儿甲状腺功能减退发生率为17.4%,甲状腺功能减退患儿血清铁蛋白均值(4948.27±1225.33μg/L)明显升高(t=10.273,P<0.05)。年龄≥10岁、血清铁蛋白≥2 500μg/L和未进行规范去铁治疗的β-TM患儿甲减发生率均明显升高(P<0.05)。进一步Logistic回归分析结果显示,年龄≥10岁是甲减发生率升高的独立危险因素。不规范去铁组患儿有较高的血清铁蛋白(3880.60±1269.17μg/L)、TSH(4.43±1.52mIU/L)和甲减发生率(37.14%)(P<0.05)。结论:珠海地区β-TM患儿甲状腺功能减退发生率偏高,且与年龄≥10岁、血清铁蛋白≥2 500μg/L和未进行规范去铁治疗相关。

重型β地中海贫血异基因造血干细胞移植中不同剂量ATG-F的比较研究

目的探讨不同剂量的抗人T淋巴细胞兔免疫球蛋白(ATG-F)在重型地中海贫血造血干细胞移植中的应用。方法将重型β地贫患儿进行异基因造血干细胞移植的预处理方案ATG-F分为2个剂量组(低剂量15 mg/kg组和高剂量30 mg/kg组)进行比较分析。预处理方案主要包括环磷酰胺,白消安,氟达拉宾赛替哌,以及ATG-F。结果两组在中性粒细胞及血小板植入时间上无差别。II-IV的急性移植物抗宿主病发生率在低剂量组和高剂量组分别为12.5%,9.4%,低剂量组有更高的发生趋势,III-IV的急性移植物抗宿主病在低剂量和高剂量分别是12.5%和6.3%,但无统计学差异。高剂量的ATG-F组临床拟诊真菌感染患儿较低剂量组显著高(P<0.05)。低剂量组和高剂量组2年的总的生存率分别是90.6%、93.8%。结论两组不同剂量的ATG-F作为重型β地中海贫血造血干细胞移植的预处理是可行的。

重型β珠蛋白生成障碍性贫血输血治疗现状

目的了解重型β珠蛋白生成障碍性贫血(地贫)患者输血治疗现状。方法 2010-01-01/2010-06-30在作者医院定期输血的重型β地贫246例,男163例,女83例,分析患者的输血频次和输血量,检测输血前血红蛋白、网织红细胞及胆红素。结果所有患者中,51例(20.73%)间隔不足21天输血1次,122例(49.59%)每21～35天输血1次,73例(29.67%)超过35天输血一次。输血前平均血红蛋白(76.10±18.30)g/L,79例(32.11%)超过90g/L。输血前网织红细胞、胆红素、间接胆红素则与血红蛋白水平成负相关。结论多数重型β地贫患者能按时输血,但输血效果欠佳,只有部分达到高量输血的目的。

铁螯合剂治疗重型β-珠蛋白生成障碍性贫血安全性的Meta分析

目的:评价去铁胺和去铁酮联合治疗重型β-珠蛋白生成障碍性贫血(beta-thalassemia major,BTSM)的安全性。方法:检索1985-01-01至2012-09-30的Cochrane图书馆、PubMed、EMBASE、Springer、Ovid、中国期刊全文数据库、中国生物医学文献数据库和维普期刊数据库,收集有关去铁胺和去铁酮联合治疗BTSM安全性的随机对照试验。从胃肠道药物不良反应(ADRs)、关节ADRs、粒细胞减少症、皮肤ADRs四个指标分析药物治疗的安全性,采用RevMan 5.0软件进行Meta分析。结果:纳入10篇文献,共486名病人。各亚组均具有较好的同质性,采用固定效应模型。Meta分析结果:去铁胺和去铁酮联合治疗组胃肠道ADRs(P<0.000 01)、关节ADRs(P=0.009)和粒细胞减少症(P=0.02)发生率均高于单独治疗组;而单独治疗组的皮肤ADRs发生率高于联合治疗组(P=0.006)。合并分析结果显示,联合治疗组的ADRs发生率高于单独治疗组(P<0.000 01)。结论:去铁胺和去铁酮联合治疗的ADRs发生率总体上高于去铁胺或去铁酮单独治疗组,但皮肤ADRs的发生率低于单用组。受纳入文献质量的限制,此结论尚需进一步证实。

重型β地中海贫血的治疗进展

地中海贫血是β-珠蛋白基因缺陷导致血红蛋白中β-珠蛋白链合成减少或缺乏,红细胞寿命缩短的一种遗传性溶血性贫血。临床表现轻重不一,重型患者可因贫血、脓毒症和全身衰竭死亡。输血、袪铁、脾切除术等为既往常用的治疗方案。因铁过载、免疫功能低下和治疗效果欠佳等原因,新的治疗方案应运而生,包括药物诱导γ-珠蛋白基因活化、异基因造血干细胞移植以及基因治疗。文章综述重型β地中海贫血治疗的研究进展。

广西重型β地中海贫血患者贫血和铁超载现状调查

目的了解广西重型β地中海贫血(TM)患者的贫血及铁超载状况,为其临床治疗提供基础数据和依据,以改善患者生存质量。方法利用地贫管理系统,统计2011—2017年共7年间就诊于本医院的1029名TM患者资料,共测定输血前血红蛋白(Hb)12 119次、血清铁蛋白(SF)4834次,分析Hb、SF的整体情况;每1年的平均Hb、SF情况;不同年龄患者的Hb、SF情况,利用SPSS软件对相关数据进行分析处理。结果患者输血前Hb>90 g/L、(60—90)g/L、(30—60)g/L、<30 g/L分别为28.9%(297/1 029)、49.1%(505/1 029)、19.4%(200/1 029)和2.6%(27/1 029),Hb平均水平与年份及年龄均无明显相关性。87.3%(898/1 029)的TM患者铁超载,46.8%(482/1 029)为重度铁超载(SF>2 500 ng/mL);平均SF水平随着患者年龄的增长呈上升趋势。结论广西的TM患者治疗现状远低于预期,迫切需要加强输血和去铁治疗。

重型β地中海贫血造血干细胞移植排斥与受者细胞免疫功能的关系

目的研究重型β地中海贫血患儿造血干细胞移植预处理前后的细胞免疫功能变化,分析其与移植排斥之间的关系。方法测定25例次重型β地中海贫血患儿预处理前后外周血中CD3+、CD3+CD4+、CD3+CD8+、CD3-CD56+细胞比率,以同期进行异基因造血干细胞移植的11例急性白血病患儿作对照,研究移植排斥与细胞免疫功能之间的关系。结果重型β地中海贫血组植入率65.2%,排斥率34.8%,急性白血病组植入率100%;CD3+CD8+T细胞百分比,重型β地中海贫血组在预处理前、后均高于急性白血病组(P均<0.05);CD3-CD56+细胞比率,重型β地中海贫血组预处理后较预处理前升高(P<0.05),而急性白血病组预处理后较预处理前显著降低(P<0.05);预处理前CD3-CD56+NK细胞比率,重型β地中海贫血排斥组高于植入组(P<0.05)。结论CD3-CD56+NK细胞可能与重型β地中海贫血移植排斥有关,可做为预测排斥的指标之一;CD3+CD8+T细胞与β地中海贫血移植排斥的关系有待进一步探索。

The Prevalence of Adrenal, Parathyroid and Cardiac Dysfunction in Patients with Beta Thalassemia Major

Background: Adrenal and parathyroid insufficiency are uncommon in patients with transfusion dependent Beta Thalassemia (β-TM). Further, myocardial echocardiographic abnormalities are recognized but with a variable outcomes Aim: The aim is to determine the prevalence of adrenal and parathyroid insufficiency in patient with transfusion dependent β-TM. And to assess left ventricle systolic and diastolic function using Pulsed Doppler (PD) and Tissue Doppler (DT) echocardiogram. Methods:The study was conducted on patients with β-TM (n = 99, age 15.92 ± 8.92 years) and compared with an age-matched controls (n = 98 age 15.79 ± 8.94 years). In all participants echocardiographic indices of M mode and PD and TD were performed. Blood samples were withdrawn for measuring the serum cortisol, parathyroid and Ferritin. Correlation between the level of cortisol and ferritin level was evaluated. Results: Patients with β-TM compared with controls, had significantly thicker LV septal wall index of 0.65 ± 0.26 vs 0.44 ± 0.2190, p 0.001 and LV posterior wall of 0.65 ± 0.235 vs 0.43 ± 0.214, p ± 5.5 vs 5.0 ± 5.6, p = 0.23. Furthermore patients with β-TM had higher E/A ratio (1.54 ± 0.18 vs 1.23 ± 0.17, p 0.01) and shorter deceleration time (DT) (170.53 ± 13.3 vs 210.50 ± 19.20 m sec, p 0.01). The ratio of transmitral E wave velocity to the tissue Doppler E wave at the basal septal mitral annulus (E/Em) was significantly higher in β-TM group (19.68 ± 2.81 vs 13.86 ± 1.41, p 0.05). The tissue Doppler systolic wave (Sm) velocity and the early diastolic wave (Em) were significantly lower in β-TM group compared with controls with Sm, of 4.82 ± 1.2 vs 6.22 ± 2.1 cm/sec, p 0.05 and (Em) of 3.51 ± 2.7 vs 4.12 ± 2.5 cm/sec p 0.05, respectively). The tricuspid valve velocity was significantly higher in β-TM patients compared with controls (2.85 ± 0.56 vs 1.743 ± 0.47 m/sec, respectively, p 0.01). The prevalence of adrenal insufficiency in patients with β-TM was 16%, hypoparathyroidism of 4.5% weak negative correlation between serum level of cortisol and the serum Ferritin. Conclusion: Patients with β-thalassemia major had a high prevalence of subclinical adrenal insufficiency of 16%, hypoparathyroidism of 4.5% with weak negative correlation between the low level of cortisol ≤160 nmol/L and high serum ferritin. Echocardiographic Pulsed Doppler showed a restrictive LV diastolic pattern suggestive of advanced diastolic dysfunction but preserved left ventricle systolic function.

National Approach to Premarital Diagnosis of Trait Thalassemia and Silent Carriers

Background: Major β-thalassemia occurs when impaired genes received by a neonate from the parents. In most of the parents, there are no apparent clinical manifestation and they just show some impairments in hematological indices. This study was designed to determine prevalence of minor and silent carries parents that have children suffering from major β-thalassemia, compare it with national protocol about prevention of thalassemia. Methods: A blood sample was taken from parents of all major thalassemic patients covered by TaleghaniHospitalin Gorgan (n = 195), CBC and Hemoglobin electrophoresis were done. Data were analyzed using SPSS software. Results: Amongst 196 parents one case have normal level of MCV, MCH, RBC, HbA, HbF and mentzer = 22.05 (0.51%) that diagnosed as alpha triplication/N by real time PCR, RFLP informative. The means of hematological indices were based on the national protocol. Conclusion: Present results showed that there are a few cases of thalassemia disorders with normal MCV, MCH, RBC, Mentzer index and Hb electrophoresis which could be missed in routine and pre-marital screening tests, resulted in a thalassemia child that it is possible in every screening test. Generally, indices were according to range of the national guideline.

Genetic Polymorphisms of HBS1L-MYB (rs4895441 and rs9376090) in Egyptian Patients with Hemoglobinopathy

Objective: Study the HBS1L-MYB (rs4895441 and rs9376090) genetic polymorphisms in Egyptian patients with β-thalassemia major and sickle cell disease and its relation to Hb F and severity of the disease. Background: Hb F is a predominant modulator for the severity of β-thalassemia major & sickle cell disease. Genetic polymorphism in the intergenic region (HBS1L-MYB) between GTP-binding elongation factor HBS1L and myeloblastosis oncogene MYB on chromosome 6q is associated with high fetal hemoglobin levels. Subjects and Methods: 150 subjects were included in this study. For all studied groups: Complete blood picture and serum ferritin were evaluated. For patients, hemoglobin variants were separated by High-performance liquid chromatography. Genotyping of HBS1L-MYB (rs4895441 & rs9376090) was evaluated by real-time polymerase chain reaction technique using TaqMan probe. Results: AG, CT genotypes, and G, C alleles of HBS1L-MYB (rs4895441 & rs9376090) were significantly high in sickle cell patients [OR (3.400);95% C.I (1.482 - 7.799)], (p = 0.003) & [OR (4.522);95% C.I (1.854 - 11.029)], (p = 0.001) respectively. Also, a significant association was detected between polymorphisms and disease severity. However, in β-thalassemia major, no significant association was detected. Conclusion: In sickle cell disease patients, Genetic polymorphisms in HBS1L-MYB (rs9376090 & rs4895441) affect the level of Hb F which could improve the prognosis of these patients.

3′BASE-SPECIFIC PCR AND ITS APPLICATIONS IN THE DETECTION OF GENE MUTATIONS OF BETA-THALASSEMIA

I. INTRODUCTIONAlthough the PCR (polymerase chain reaction )combined with ASO (allele-specific oligonucleotide) probe hybridization has greatly facilitated the gene diagnosis and the prenatal diagnosis of beta-thalassemia, the methodology requires the use of radioactive probes, and it is rather time-consuming and still technically complex. To simplify

Hemoglobin E/beta-thalassemia with Massive Myelofibrosis

HbE is the most common hemoglobin variant in the world.In compound heterozygotes,the interaction of HbE with othermutations in the β-globin gene results in HbE/β-thalasse-mia disease,which shows great variation in severity,includingcases that require blood transfusions just like the β-thalasse-mia major patients.Many hematologic disease could developmyelofibrosis.However,HbE/β-thalassemia with myelofibro-

铁螯合剂治疗重型β-地中海贫血疗效的Meta分析

目的系统评价去铁胺与去铁酮治疗重型β-地中海贫血的临床疗效。方法检索Cochrane图书馆、PubMed、EMBASE、中国期刊全文数据库、中国生物医学文献数据库和维普期刊数据库。以血清铁蛋白、肝组织铁浓度、尿铁排出量、心室射血分数值和心肌铁含量5个指标评价去铁胺、去铁酮和联合治疗的疗效,采用RevMan 5.0软件进行Meta分析。结果纳入符合条件的9篇RCT文献,共654名患者。Meta分析结果显示,去铁胺与去铁酮联用在以下方面均优于单用二者之一,且差异有统计学意义:血清铁蛋白下降值[WMD=-215.37,95%CI(-395.35,-35.39),P=0.02]、肝组织铁浓度下降值[SMD=-1.06,95%CI(-1.54,-0.58),P<0.000 1]、尿铁排出量变化值[SMD=1.04,95%CI(0.61,1.47),P<0.000 01]与心室射血分数值[WMD=3.37,95%CI(0.79,5.95),P=0.01];而在心肌铁含量变化方面差异无统计学意义[WMD=1.70,95%CI(-2.78,6.18),P=0.46]。去铁胺组与去铁酮组单独疗效中血清铁蛋白下降值[WMD=133.45,95%CI(-48.92,315.82),P=0.15]、心室射血分数值变化程度[WMD=0.96,95%CI(-2.74,4.66),P=0.40]、心肌铁含量变化程度[WMD=1.50,95%CI(-1.70,4.70),P=0.36]均不具有统计学意义。结论本篇Meta分析结果提示,去铁胺与去铁酮联用疗效优于二者之一单用,从而为当前国内重型β-地中海贫血的治疗提供了一种新的治疗选择。但由于纳入研究样本量小且质量较低,上述结论尚需要高质量、大样本的双盲随机对照试验加以证实。

非亲缘HLA表型不全相合供者造血干细胞移植治疗重型β地中海贫血的临床研究

目的探讨非亲缘不全相合供者造血干细胞移植治疗重型β地中海贫血的疗效及安全性。方法回顾性分析2018年1月至2022年4月厦门大学附属中山医院收治的因重型β地中海贫血接受非亲缘不全相合异基因造血干细胞移植(allo-HSCT)15例儿童受者的临床资料。15例均有1~2个HLA位点不相合,其中男8例,女7例;年龄7岁(3~12)岁;铁蛋白水平3417.3(223~14485)μg/L。预处理采用,由氟达拉滨(Flu)、白消安(Bu)和环磷酰胺(CTX)组成的FBC方案。移植物抗宿主病(GVHD)防治方案由环孢素(CsA)、吗替麦考酚酯(MMF)、抗人胸腺细胞免疫球蛋白(ATG)联合低剂量后置环磷酰胺(PTCy)和间充质干细胞组成。结果共完成移植15例;截至2022年4月1日,随访时间为24.1个月(11~49)个月;干细胞植入均成功,植入分析为完全供者嵌合体。中性粒细胞和血小板植入时间分别是12 d(11~22)d和14 d(8~38)d。死亡2例,预期2年的总生存率(OS)和无地中海贫血生存率(TFS)为86.67%。其中,移植后发生Ⅱ度以下急性移植物抗宿主病(aGVHD)5例,Ⅲ~Ⅳ度aGVHD 2例,局限型慢性移植物抗宿主病(cGVHD)3例,无广泛型cGVHD发生。巨细胞病毒和EB病毒均有5例受者激活。结论非亲缘HLA表型不全相合供者HSCT用于重型β地中海贫血的治疗是安全可行的。