广西重型β地中海贫血患者铁过载及其相关并发症和机制研究
摘要
第一部分
广西重型β地贫患者铁过载状况研究
目的调查广西重型β地贫患者铁过载发病率及铁过载严重程度
方法从2010年11月至2013年1月共收集重型β地贫患者310例,其中男性196例,女性114例。年龄为2～25岁,中位年龄8岁。均进行了血清铁蛋白检测。
结果310例患者中脾大的有80例(25.8%),肝大的有70例(22.6%),行脾脏切除术的有39例(12.6%)。输血总量中位数为134(2-960)单位。5例(1.6%)为规则祛铁治疗,256例(82.6%)不规则祛铁治疗,49例(15.8%)未行祛铁治疗。SF中位值为3917(范围453-23640) ng/ml。其中96.4%的患者SF>1000ng/ml,76.6%的患者SF>2500ng/ml。SF水平与年龄及输血总量呈正相关(r=0.261,p=0.000及r=0.271,p=0.000)。
结论广西大多数重型β地贫患者为年轻的、不规则祛铁治疗,铁过载严重。
第二部分
重型β地贫患者心铁过载状况研究
目的调查广西重型β地贫患者心铁过载发病率及严重程度。
方法从2010年11月至2013年1月共收集重型β地贫患者201例,进行了心脏核磁共振T2*检测心脏T2*值,及左室射血分数(LVEF)检测。其中192例儿童青少年患者,9例成人患者,年龄4-25岁,中位年龄9岁。
结果1.201例行MRI检测的患者SF为4536(525-23640) ng/ml。165例(82.1%)患者SF>2500ng/ml。心脏T2*值为25.5±12.5ms。在192例儿童青少年中,68例(33.3%)心脏T2*<20ms。9例成人中有4例(44.4%)心脏T2*<20ms。其中25例(13%)儿童青少年存在严重心铁过载(心脏T2* 2.在175例能进行LVEF分析的患者中LVEF中位值为64%(49-81%),其中6例患者LVEF<56%,6例中的5例患者其均存在心铁过载。心铁过载的患者其心脏事件发病率高于心铁正常组(8.1%VS0.9%)。10例有心脏合并症的患者中有8例是有心铁过载的。
结论广西大多数重型β地贫患者心铁过载严重。心铁过载发生时间比之前报道的要早,心铁过载导致LVEF异常及心脏合并症发生。我们的研究结果建议,对不规则祛铁治疗的患者最早开始心铁检测的时间可早至6岁。
第三部分
重型β地贫患者肝脏铁过载状况研究
目的探讨重型β地中海贫血患者肝脏铁过载状况,及其与心脏铁过载二者之间的关系。
方法对59例大于10岁的重型β地中海贫血患者,中位年龄13岁(10-25),采用核磁共振T2*检测患者心脏T2*值及左室射血分数(LVEF),核磁共振R2检测肝脏铁含量(LIC),电化学发光法检测血清铁蛋白(SF)。
结果1.59例患者SF均值为6016.5±3566.9ng/ml (1345-23640ng/ml)。
2.患者LIC平均值为35.8±10.6mg/g干重。心脏T2*值均值为20.5±13.4ms,LVEF均值为70±4.6%,所有患者LVEF均为正常。在59例患者中有30例(50.8%)发生心铁过载,其中轻中度15例,重度15例。59例患者均发生肝脏重度铁过载(LIC>7mg/g干重),其中有53例(89.8%)为极重度肝铁沉积(LIC>15mg/g干重)。
3.30例(50.8%)心脏T2*值<20ms的患者其LIC均大于15mg/g干重,而LIC<15mg/g干重的6例(10.2%)患者其心脏T2*值>20ms。心脏T2*值与SF\LVEF均未见相关性(p>0.05)。LIC与SF呈正相关(r=0.698,p=0.000),与心脏T2*值呈负相关(r=-0.345,p=0.009)。
LIC、心脏T2*值与输血开始时间、输血总量及祛铁开始时间都未显示相关性。AST、ALT则与LIC呈正相关(r=0.307, p=0.019; r=0.348, p=0.007)
结论1.重型β地贫患者肝脏铁过载严重。
2.肝脏铁含量与血清铁蛋白水平相关。
3.在肝脏重度铁过载时,心脏铁过载与肝脏铁过载程度相关,肝铁浓度可以作为预测心铁的指标。
4.肝脏铁过载导致肝脏损伤,肝功能异常。
第四部分
重型β地贫患者氨基末端脑钠肽前体与心铁的关系
目的探讨重型β地贫患者氨基末端脑钠肽前体(NT-ProBNP)水平与心铁过载及左室射血分数(LVEF)的相关性。观察其在预测心铁过载和诊断心衰的应用价值。
方法收集广西重型β-地贫患者140例,其中男性83例,女性57例；年龄5-25岁,中位年龄8岁。对140例重型β地贫患者电化学发光法测定SF、 NT-proBNP及心肌酶谱(CK、 CK-MB、 LDH、 LDH、 α-HBD),同时收集正常对照组30例,其中男性20例,女性10例。年龄5-9岁,中位年龄8岁,检测其NT-proBNP水平。109例患者进行了核磁共振检测心脏T2*值及LVEF。
结果1.重型β地贫患者的NT-proBNP均数为137.2±136.5pg/ml(范围9.62-822.2),正常对照组的NT-proBNP均数为62.5±55.1pg/ml(范围9.8-230.1),重型β地贫患者的NT-proBNP水平明显高于正常对照组(p<0.05)。
2.在48例存在心铁过载的患者中NT-proBNP均数为212.5±169.4pg/ml;61例无心铁过载患者中NT-proBNP均数为107.6加减109.3pg/ml。心铁过载组NT-proBNP水平明显高于心铁正常组,差异有统计学意义(p<0.05)。NT-proBNP水平与年龄呈正相关性(r=0.436,p=0.000),与心脏T2*值呈负相关(r=-0.416,p=0.000),与SF及LVEF未见相关性。
3.心脏核磁共振T2*值为22.8±12.5ms(中位值为23.9ms)。在109例行心脏核磁共振检测的患者中,48例(44%)存在心脏铁过载(T2*值<20ms),其中29例(26.6%)为轻中度心脏铁过载(T2*值10-20ms),19例(17.4%)为重度铁过载(T2*值 结论重型β地贫患者NT-proBNP水平显著高于正常对照组,且心铁过载组明显高于心铁正常组。NT-proBNP水平与心脏T2*值负相关,NT-proBNP可能可以作为心铁沉积的预测指标。
第五部分
重型β地贫患者hepcidin、GDF15水平与铁过载的关系
目的通过检测地贫患者血清Hepcidin、GDF15及铁负荷指标,探讨Hepcidin、GDF15二者之间、其与输血总量及SF的关系,及其在铁过载中的作用。
方法分别采用酶联免疫吸附试验、电化学发光法测定136例重型地贫患者、17例中间型地贫患者及30例正常对照组血清的hepcidin、GDF15及SF。
结果1.地贫组患者的hepcidin均值为34.0±36.5ng/ml,正常对照组的均值为146.4±70.8ng/ml。地贫患者的hepcidin水平显著低于正常对照组。在136例重型患者,其hepcidin均值为31.5±33.6ng/ml,17例中间型患者的hepcidin均值为54.5±51.7ng/ml。中间型、重型患者的hepcidin水平均显著低于正常对照组(p<0.05),中间型与重型患者之间差异无统计学意义(p>0.05)。
2.地贫组患者的GDF15水平均值为9960.1±6280.6pg/ml,正常对照组的均值为GDF15水平均值为70.9±15.2pg/ml。地贫患者的GDF15水平显著高于正常对照组。在136例重型患者GDF15水平均值为9962.4±6527.3Pg/ml,17例中间型患者的GDF15水平均值为9944.6±4506.7pg/ml.中间型、重型患者的GDF15水平均显著高于正常对照组(p<0.01),中间型与重型患者之间差异无统计学意义(p>0.05)。
3.17例中间型患者的SF均值为3315.6±2827.3ng/ml,心脏T2*值为32.4±15.2ms。136例重型患者SF均值为5076.5±2662.1ng/ml,心脏T2*值为23.3±12.1ms。hepcidin及GDF15水平在心脏T2*值<20ms的患者的与心脏T2*值>20ms的患者间无差异(分别为31.7±28.3VS32.0±35.8ng/m1:10650.5±5690.7VS9831.4±6550.8pg/ml,p均>0.05)。
4.在正常对照组及地贫组hepcidin及GDF15与年龄、性别均未见相关性。153例地贫患者的hepcidin及GDF15水平与输血量、心脏T2*值、LVEF无明显相关关系。Hepcidin与SF则呈负性相关(r=-0.364,p<0.01)。
结论：1.中间型、重型地贫患者hepcidin水平低于正常对照组而GDF15水平高于正常对照组。
2.我们的研究结果提示中间型及重型地贫患者存在较严重无效造血及铁过载,需要加强输血及祛铁治疗。关于hepcidin对铁平衡的调节作用及与GDF15间的关系还需进一步研究。
第六部分
重型β地贫患者氧化应激状态研究
目的检测重型β地贫患者血清氧化应激产物及抗氧化酶MDA, NO、 SOD值,评估重型地贫患者氧化应激及抗氧化应激状况,及其与铁过载、铁过载相关并发症的关系。
方法收集重型β地贫123例,正常对照组44例。分别采用硫代巴比妥酸比色法、Griss试剂显色法、黄嘌呤氧化酶法测定患者及正常对照组的血清丙二醛(MDA)、一氧化氮(N0)、超氧化物歧化酶(SOD)的含量。
结果1.重型β地贫患者的MDA.N0及SOD水平分别为7.2±2.0ng/ml.81.7±21.7ng/ml.264.5±56.2U/ml.正常对照组MDA.NO及SOD水平分别为5.4±1.9ng/mL.72.O±16.9ng/ml.238.8±46.1U/ml.重型地贫患者MDA、NO及SOD水平显著高于正常对照组,差异有统计学意义(p值分别为0.000、0.024、0.021)。
2.44例正常对照组的MDA、NO、SOD与年龄及性别均未见相关性。123重型β地贫患者的MDA、NO、SOD均与年龄及血清铁蛋白(SF)相关,与性别无关。MDA、NO与输血总量也成正相关。在98例行心脏MRI T2*检测的患者,与心脏T2*值均呈负性相关(分别为r=-0.465,p=0.000； r=-0.418,p=0.000).MDA及N0水平在心脏T2*<20ms的患者高于心脏T2*>20ms的患者,差异有统计学意义(p<0.001),而SOD在两组间未见差异。其在42例有LIC的患者中,MDA.NO与LIC均呈正性相关(分别为r=0.531,p=0.000； r=0.440,p=0.004).而SOD与心脏T2*值及肝铁含量均未见相关性。AST与N0呈正相关(r=0.309,p:0.012).MDA.N0及SOD之间也呈正相关。
结论1.重型β地贫患者中氧化应激产物MDA.N0及抗过氧化酶SOD水平均高于正常对照组。患者机体处在氧化反应应激状态。
2.重型β地贫患者中铁过载导致氧化应激,并损伤组织器官功能。提示铁催化的氧化应激是导致重型β地贫患者患者铁过载相关并发症的一个因素。进行祛铁治疗可以防止氧化损伤,减少对机体的损害。
THE FIRST PART OF THESIS
STUDY OF IRON OVERLOAD IN PATIENTS WITH THALASSEMIA MAJOR IN GUANGXI
Purpose This study aimed at investigating the prevalence and severity of iron overload in a young Guangxi population with beta thalassemia major (TM).
Methods We studied310patients (196males and114females) with beta TM from November2010to January2013. The median age was8(5-25) years. Serum ferritin was measured by electrochemiluminescence immunoassay (ECLIA) in all patients.
Results Hepatomegaly and splenomegaly were found in80patients (25.8%) and89patients (22.6%), respectively. Thirty-nine patients (12.6%) received splenectomy treantment. The median number of blood transfused was134(rang2-960)U. Five patients (1.6%) were well-chelated,256patients (82.6%) poorly-chelated and49(15.8%) patients didn't receive chelation therapy. The median SF value is3917ng/ml.95.4%of all patients had SF>1000ng/ml,76.6%patients had SF>2500ng/ml.
Conclusions Most beta-TM patients in Guangxi are younger, poorly-chelated, and have a high burden of iron overload.
THE SECOND PART OF THESIS
STUDY OF CARDIAC IRON OVERLOAD IN PATIENTS WITH THALASSEMIA MAJOR
Purpose This study aimed at investigating the occurrence, prevalence and severity of cardiac iron overload in a young Guangxi population with beta thalassemia major (TM).
Methods We analyzed T2*cardiac magnetic resonance (CMR), left ventricular ejection fraction (LVEF) and serum ferritin (SF) in201beta TM patients with192children and9adults. The median age was9(4-25) years old.
Results Five patients (2.5%) were well-chelated and196patients (97.5%) poorly-chelated. The median SF level was4536(525-23,640) ng/ml and165patients (82.1%) had SF>2500ng/ml. Myocardial iron overload (T2*<20ms) were detected in64children (33.3%) and4adults (44.4%). Severe myocardial iron overload (T2*<10ms) were detected in25children (13%) and1adult (11.1%). Twenty-two patients under10years old (21.4%) had myocardial iron overload, in which3patients were only6years old. No myocardial iron overload was detected in14patients under the age of6years. Cardiac T2*was negatively associated with age (r=-0.328, p=0.000) or SF (r=-0.319, p=0.000). Measured by CMR, the median of LVEF was64%(49%-81%) in175of the TM patients. Five of6patients with a LVEF<56%had myocardial iron overload. The incidence of impaired LVEF in patients with myocardial iron overload was higher than that in patients without myocardial iron overload (8.1%vs0.9%, p=0.021). Eight of10patients with cardiac diseases had myocardial siderosis.
Conclusions Most Chinese TM patients have a high burden of iron overload. Myocardial siderosis, which occurred in patients younger than previously reported, was strongly associated with impaired LVEF and cardiac diseases. For those poorly-chelated TM patients, our data suggests that there leaves great room for improvement of patient care and that the first assessment of cardiac T2*should be performed as early as6years old.
THE THIRD PART OF THESIS
STUDY OF LIVER IRON OVERLOAD IN BETA-THALASSEMIA MAJOR PATIENTS
Objective The aim of this study was to study the prevalence and severity of liver iron overload in β-thalassemia major (β-TM) patients, and the relationship of cardiac T2*and liver iron concentration with various clinical and serum biochemical parameters.
Methods Cardiac T2*(MRI T2*)、 left ventricle ejection fraction (LVEF) and liver iron concetratin(LIC, MRI R2) were measured in59patients with P-TM by magnetic resonance imaging technique. The median age was (13) years old. Serum ferritin was measured by electrochemiluminescence immunoassay (ECLIA).
Results1. The median SF level was6016.5±3566.9ng/(1345-23640 ng/ml) ng/ml and51patients (86.4%) had SF>2500ng/ml.
2. The mean value of myocardial T2*was20.5±13.4ms, and LVEF value was70±4.6%. Fifteen patients had mild-moderate cardiac iron overload, and15patients had severe cardiac iron overload. ALL of patients had normal LVEF.
3. The mean value of LIC was35.8±10.6mg/g dry weight. Cardiac T2*<20ms were detected in30patients (50.8%). All of59patients had severe liver iron overload, and53patients (89.9%) had LIC>15mg/g dw.
4.The30patients(50.8%) with cardiac T2*<20ms had LIC15mg/g dw. And the6patients(10.2%) with LIC<15mg/g dw had normal cardiac T2*.
5. LIC was positively correlated with SF(r=0.698,p=0.000) and inersely correlated with cardiac T2*(r=-0.345,p=0.009). There was a positive correlation between AST、 ALT and LIC(r=0.307,p=0.019; r=0.348,p=0.007).
6. No correlatian was found between cardiac T2*and SF、 LVEF. There was no correlation between LIC、 cardiac T2*and age of starting blood transfusion、 age of starting chelation therapy and numbet of total blood transfused.
Conclusion β-thalassemia major patients had a severe liver and cardiac iron overload status. Liver iron concentration had a positive correction with SF and cardiac T2*. AST and ALT had a positive correction with liver severe iron overload.
THE FOURTH PART OF THESIS
CORRELATION OF NT-PROBNP LEVEL AND CARDIAC IRON OVERLOAD IN PATIENTS WITH BETA-THALASSEMIA MAJOR
Objective The aim of this study was to investigate the correlation between N-terminal pro-brain natriuretic peptide (NT-proBNP) levels with cardiacT2*and LVEF in patients with β-thalassemia major(β-TM),and investigate the value of NT-proBNP levels in detecting cardiac iron overload and LVEF abnormal.
Methods We studied140patientswith beta TM (83males and57females) and30healthy controls (20males and10females). The median age of patiens was8(5-25) years old and the median age of controls was8(5-9) years. NT-proBNP and serum ferritin (SF) were measured by electrochemilumine-scence immunoassay (ECLIA). Cardiac T2*and left ventricle ejection fraction (LVEF) were measured in109patients by magnetic resonance imaging T2*(MRI T2*).
Results1, NT-proBNP level in β-TM patients was higher than that in normal controls (137.2±136.5pg/ml vs62.5±55.1pg/ml, p<0.05).
2. The mean of NT-proBNP level in48patients with cardiac iron overload was higher than that in61patients without cardiac iron overload (212.5±169.4pg/ml vs107.6±109.3pg/ml, p<0.05). NT-proBNP was negatively associated with cardiac T2*(r=-0.416, p=0.000), and positively correlated with age(r=0.436,p=0.000).
3.The mean of cardiac T2*value in109patients was22.8±12.5ms (median23.9ms) and48patients(44%)had cardiac T2*<20ms.29patients (26.6%) had cardiac T2*between10ms and20ms, and19patients (17.4%) had cardiac T2*<10ms.Cardiac T2*was inversely correlated with age and SF. The mean LVEF value was64.9±5.9%.Five patients had LVEF<56%. LVEF was positively correlated with age (r=0.314,p=0.001).No correlation was found between LVEF and SF、 cardiac T2*.
Conclusion NT-proBNP levels are significantly increased in P-thalassemia major patient. NT-proBNP was negatively associated with cardiac T2*. NT-proBNP is valuable in detecting cardiac iron overload in β-thalassemia major patients. THE FIFTH PART OF THESIS
REGULATION OF IRON METABOLISM THROUGH GDF15AND HEPCIDIN IN BETA-THALASSEMIA MAJOR PATIENTS
Objective The aim of this study was to assess the level of hepcidin and Growth differentiation factor15(GDF15) in patients with P-thalassemia (β-TM) and to study the correlationships of the serum hepcidin and GDF15levels, the blood transfused and the markers of iron overload.
Methods Serum hepcidin、 differentiation factor-15and serum ferritin were measured136patients with β-TM patients,17patients with β-thalassemia intermedia(β-TI) and30healthy controls by enzymelinked immunosorbent assay(ELIAS) and electrochemiluminescence immunoassay(ECLIA).
Results1. The level of hepcidin in thalassemia was significantly lower than that in control group (34.0±36.5ng/ml vs146.4±70.8ng/ml).The mean level of hepcidin in136β-TM patients and17β-TI patients were31.5±33.6ng/ml and54.5±51.7ng/ml, respectively. The mean level of hepcidin in patients with β-TM and β-TI was significantly lower than that in control group (p<0.05).No significant differences was found between the hepcidin level of P-TM and β-TI patients (p>0.05).
2. The mean level of GDF15in thalassemia patients was significantly higher than that in control group (9960.1±6280.6pg/ml vs70.9±15.2pg/ml).The mean level of GDF15in136β-TM patients and17β-TI patients was9962.4±6527.3pg/ml and9944.6±4506.7pg/ml, respectively. The GDF15level of β-TM and P-TI patients was significantly higher than that in control group (p<0.01). No significant differences was found between the GDF15level of β-TM and P-TI patients (p>0.05).
3. The mean level of SF in patients with β-TM and β-TI were5076.5±2662.1ng/ml and3315.6±2827.3ng/ml, respectively. The mean levels of cardiac T2*in patients with β-TM and β-TI were were32.4±15.2ms and23.3±12.1ms, respectively. The median of hepcidin and GDF15in patients with cardiac iron overload (T2*<20ms) were not significantly different with those in patients without cardiac iron overload (T2*>20ms).
4. There was no correlation between hepcidin and GDF15with age and gender in both thalassemai patients and normal controls. No other clear correlation was found between hepcidin、GDF15and cardiac T2*and LVEF. Hepcidin level showed a negative relationship with SF(r=-0.364, p<0.01).
Conclusion The mean level of GDF15was significantly elevated and the mean level of hepcidin was decreased in patients with β-TM and β-TI compared to the normal controls. Our results may indicate that thalassemia patients are in a state of serious ineffective erythropoiesis and need intensify blood transfusion and chelation therapy.
THE SIXTH PART OF THESIS
OXIDATIVE STRESS AND ANTIOXIDANT ENZYME IN p-THALASSEMIA MAJOR PATIENTS
Objective The aim of this study was to evaluate the status of lipid peroxidation and antioxidant in patients with p-thalassemia major (β-TM), and investigate the correlation between the status of lipid peroxidation, antioxidant and iron overload.
Methods We analyzed serum malondialdehyde (MDA), nitric oxide (NO), plasma superoxide dismutase (SOD) and serum ferritin in123patients with β-TM and44healthy controls. MDA was measured spectrophotometerically using thiobarbituric acid (TBA). NO was determined by the Griess reaction. Assay of SOD was measured with xanthine oxidase reation.
Results1.The mean level of MDA, NO and SOD in β-TM were significantly higher than those in in healthy controls (7.2±2.0ng/ml vs5.4±1.9ng/ml,p=0.000;81.7±21.7ng/ml vs72.0±16.9ng/ml,p=0.024;264.5±56.2U/ml vs238.8±46.1U/ml,p=0.021) respectively.
2. All the patients were SF>1000ng/ml and104patients (84.6%)had SF>2500ng/ml.The mean level of cardiac T2*was23.6±12.5ms in98patients with β-TM. The mean level of liver iron concentration (LIC) in42patients with β-TM was37.7±9.1mg/g dry weight. The median of MDA and NO in patients with cardiac T2*<20ms was higher than those in patients with cardiac T2*>20ms. The median of SOD of was not significantly different between the two group.
3.There was no correlation between the MDA、 NO、 SOD and the age or gender in patients and normal controls. The MDA, NO, SOD were significantly correlated with SF levels. Serum levels of MDA and NO were positively correlated with LIC, and inversely correlation with cardiac T2*.NO correlation was found between SOD values and LIC or cardiac T2*.
Conclusion Our study results suggest that iron overload causes peroxidative damage in P-TM and the antioxidant system reation is to compensate for reducing lipid peroxidation to avoid tissue damage.
广西重型β地贫患者铁过载状况研究
目的调查广西重型β地贫患者铁过载发病率及铁过载严重程度
方法从2010年11月至2013年1月共收集重型β地贫患者310例,其中男性196例,女性114例。年龄为2～25岁,中位年龄8岁。均进行了血清铁蛋白检测。
结果310例患者中脾大的有80例(25.8%),肝大的有70例(22.6%),行脾脏切除术的有39例(12.6%)。输血总量中位数为134(2-960)单位。5例(1.6%)为规则祛铁治疗,256例(82.6%)不规则祛铁治疗,49例(15.8%)未行祛铁治疗。SF中位值为3917(范围453-23640) ng/ml。其中96.4%的患者SF>1000ng/ml,76.6%的患者SF>2500ng/ml。SF水平与年龄及输血总量呈正相关(r=0.261,p=0.000及r=0.271,p=0.000)。
结论广西大多数重型β地贫患者为年轻的、不规则祛铁治疗,铁过载严重。
第二部分
重型β地贫患者心铁过载状况研究
目的调查广西重型β地贫患者心铁过载发病率及严重程度。
方法从2010年11月至2013年1月共收集重型β地贫患者201例,进行了心脏核磁共振T2*检测心脏T2*值,及左室射血分数(LVEF)检测。其中192例儿童青少年患者,9例成人患者,年龄4-25岁,中位年龄9岁。
结果1.201例行MRI检测的患者SF为4536(525-23640) ng/ml。165例(82.1%)患者SF>2500ng/ml。心脏T2*值为25.5±12.5ms。在192例儿童青少年中,68例(33.3%)心脏T2*<20ms。9例成人中有4例(44.4%)心脏T2*<20ms。其中25例(13%)儿童青少年存在严重心铁过载(心脏T2*
结论广西大多数重型β地贫患者心铁过载严重。心铁过载发生时间比之前报道的要早,心铁过载导致LVEF异常及心脏合并症发生。我们的研究结果建议,对不规则祛铁治疗的患者最早开始心铁检测的时间可早至6岁。
第三部分
重型β地贫患者肝脏铁过载状况研究
目的探讨重型β地中海贫血患者肝脏铁过载状况,及其与心脏铁过载二者之间的关系。
方法对59例大于10岁的重型β地中海贫血患者,中位年龄13岁(10-25),采用核磁共振T2*检测患者心脏T2*值及左室射血分数(LVEF),核磁共振R2检测肝脏铁含量(LIC),电化学发光法检测血清铁蛋白(SF)。
结果1.59例患者SF均值为6016.5±3566.9ng/ml (1345-23640ng/ml)。
2.患者LIC平均值为35.8±10.6mg/g干重。心脏T2*值均值为20.5±13.4ms,LVEF均值为70±4.6%,所有患者LVEF均为正常。在59例患者中有30例(50.8%)发生心铁过载,其中轻中度15例,重度15例。59例患者均发生肝脏重度铁过载(LIC>7mg/g干重),其中有53例(89.8%)为极重度肝铁沉积(LIC>15mg/g干重)。
3.30例(50.8%)心脏T2*值<20ms的患者其LIC均大于15mg/g干重,而LIC<15mg/g干重的6例(10.2%)患者其心脏T2*值>20ms。心脏T2*值与SF\LVEF均未见相关性(p>0.05)。LIC与SF呈正相关(r=0.698,p=0.000),与心脏T2*值呈负相关(r=-0.345,p=0.009)。
LIC、心脏T2*值与输血开始时间、输血总量及祛铁开始时间都未显示相关性。AST、ALT则与LIC呈正相关(r=0.307, p=0.019; r=0.348, p=0.007)
结论1.重型β地贫患者肝脏铁过载严重。
2.肝脏铁含量与血清铁蛋白水平相关。
3.在肝脏重度铁过载时,心脏铁过载与肝脏铁过载程度相关,肝铁浓度可以作为预测心铁的指标。
4.肝脏铁过载导致肝脏损伤,肝功能异常。
第四部分
重型β地贫患者氨基末端脑钠肽前体与心铁的关系
目的探讨重型β地贫患者氨基末端脑钠肽前体(NT-ProBNP)水平与心铁过载及左室射血分数(LVEF)的相关性。观察其在预测心铁过载和诊断心衰的应用价值。
方法收集广西重型β-地贫患者140例,其中男性83例,女性57例；年龄5-25岁,中位年龄8岁。对140例重型β地贫患者电化学发光法测定SF、 NT-proBNP及心肌酶谱(CK、 CK-MB、 LDH、 LDH、 α-HBD),同时收集正常对照组30例,其中男性20例,女性10例。年龄5-9岁,中位年龄8岁,检测其NT-proBNP水平。109例患者进行了核磁共振检测心脏T2*值及LVEF。
结果1.重型β地贫患者的NT-proBNP均数为137.2±136.5pg/ml(范围9.62-822.2),正常对照组的NT-proBNP均数为62.5±55.1pg/ml(范围9.8-230.1),重型β地贫患者的NT-proBNP水平明显高于正常对照组(p<0.05)。
2.在48例存在心铁过载的患者中NT-proBNP均数为212.5±169.4pg/ml;61例无心铁过载患者中NT-proBNP均数为107.6加减109.3pg/ml。心铁过载组NT-proBNP水平明显高于心铁正常组,差异有统计学意义(p<0.05)。NT-proBNP水平与年龄呈正相关性(r=0.436,p=0.000),与心脏T2*值呈负相关(r=-0.416,p=0.000),与SF及LVEF未见相关性。
3.心脏核磁共振T2*值为22.8±12.5ms(中位值为23.9ms)。在109例行心脏核磁共振检测的患者中,48例(44%)存在心脏铁过载(T2*值<20ms),其中29例(26.6%)为轻中度心脏铁过载(T2*值10-20ms),19例(17.4%)为重度铁过载(T2*值
第五部分
重型β地贫患者hepcidin、GDF15水平与铁过载的关系
目的通过检测地贫患者血清Hepcidin、GDF15及铁负荷指标,探讨Hepcidin、GDF15二者之间、其与输血总量及SF的关系,及其在铁过载中的作用。
方法分别采用酶联免疫吸附试验、电化学发光法测定136例重型地贫患者、17例中间型地贫患者及30例正常对照组血清的hepcidin、GDF15及SF。
结果1.地贫组患者的hepcidin均值为34.0±36.5ng/ml,正常对照组的均值为146.4±70.8ng/ml。地贫患者的hepcidin水平显著低于正常对照组。在136例重型患者,其hepcidin均值为31.5±33.6ng/ml,17例中间型患者的hepcidin均值为54.5±51.7ng/ml。中间型、重型患者的hepcidin水平均显著低于正常对照组(p<0.05),中间型与重型患者之间差异无统计学意义(p>0.05)。
2.地贫组患者的GDF15水平均值为9960.1±6280.6pg/ml,正常对照组的均值为GDF15水平均值为70.9±15.2pg/ml。地贫患者的GDF15水平显著高于正常对照组。在136例重型患者GDF15水平均值为9962.4±6527.3Pg/ml,17例中间型患者的GDF15水平均值为9944.6±4506.7pg/ml.中间型、重型患者的GDF15水平均显著高于正常对照组(p<0.01),中间型与重型患者之间差异无统计学意义(p>0.05)。
3.17例中间型患者的SF均值为3315.6±2827.3ng/ml,心脏T2*值为32.4±15.2ms。136例重型患者SF均值为5076.5±2662.1ng/ml,心脏T2*值为23.3±12.1ms。hepcidin及GDF15水平在心脏T2*值<20ms的患者的与心脏T2*值>20ms的患者间无差异(分别为31.7±28.3VS32.0±35.8ng/m1:10650.5±5690.7VS9831.4±6550.8pg/ml,p均>0.05)。
4.在正常对照组及地贫组hepcidin及GDF15与年龄、性别均未见相关性。153例地贫患者的hepcidin及GDF15水平与输血量、心脏T2*值、LVEF无明显相关关系。Hepcidin与SF则呈负性相关(r=-0.364,p<0.01)。
结论：1.中间型、重型地贫患者hepcidin水平低于正常对照组而GDF15水平高于正常对照组。
2.我们的研究结果提示中间型及重型地贫患者存在较严重无效造血及铁过载,需要加强输血及祛铁治疗。关于hepcidin对铁平衡的调节作用及与GDF15间的关系还需进一步研究。
第六部分
重型β地贫患者氧化应激状态研究
目的检测重型β地贫患者血清氧化应激产物及抗氧化酶MDA, NO、 SOD值,评估重型地贫患者氧化应激及抗氧化应激状况,及其与铁过载、铁过载相关并发症的关系。
方法收集重型β地贫123例,正常对照组44例。分别采用硫代巴比妥酸比色法、Griss试剂显色法、黄嘌呤氧化酶法测定患者及正常对照组的血清丙二醛(MDA)、一氧化氮(N0)、超氧化物歧化酶(SOD)的含量。
结果1.重型β地贫患者的MDA.N0及SOD水平分别为7.2±2.0ng/ml.81.7±21.7ng/ml.264.5±56.2U/ml.正常对照组MDA.NO及SOD水平分别为5.4±1.9ng/mL.72.O±16.9ng/ml.238.8±46.1U/ml.重型地贫患者MDA、NO及SOD水平显著高于正常对照组,差异有统计学意义(p值分别为0.000、0.024、0.021)。
2.44例正常对照组的MDA、NO、SOD与年龄及性别均未见相关性。123重型β地贫患者的MDA、NO、SOD均与年龄及血清铁蛋白(SF)相关,与性别无关。MDA、NO与输血总量也成正相关。在98例行心脏MRI T2*检测的患者,与心脏T2*值均呈负性相关(分别为r=-0.465,p=0.000； r=-0.418,p=0.000).MDA及N0水平在心脏T2*<20ms的患者高于心脏T2*>20ms的患者,差异有统计学意义(p<0.001),而SOD在两组间未见差异。其在42例有LIC的患者中,MDA.NO与LIC均呈正性相关(分别为r=0.531,p=0.000； r=0.440,p=0.004).而SOD与心脏T2*值及肝铁含量均未见相关性。AST与N0呈正相关(r=0.309,p:0.012).MDA.N0及SOD之间也呈正相关。
结论1.重型β地贫患者中氧化应激产物MDA.N0及抗过氧化酶SOD水平均高于正常对照组。患者机体处在氧化反应应激状态。
2.重型β地贫患者中铁过载导致氧化应激,并损伤组织器官功能。提示铁催化的氧化应激是导致重型β地贫患者患者铁过载相关并发症的一个因素。进行祛铁治疗可以防止氧化损伤,减少对机体的损害。
THE FIRST PART OF THESIS
STUDY OF IRON OVERLOAD IN PATIENTS WITH THALASSEMIA MAJOR IN GUANGXI
Purpose This study aimed at investigating the prevalence and severity of iron overload in a young Guangxi population with beta thalassemia major (TM).
Methods We studied310patients (196males and114females) with beta TM from November2010to January2013. The median age was8(5-25) years. Serum ferritin was measured by electrochemiluminescence immunoassay (ECLIA) in all patients.
Results Hepatomegaly and splenomegaly were found in80patients (25.8%) and89patients (22.6%), respectively. Thirty-nine patients (12.6%) received splenectomy treantment. The median number of blood transfused was134(rang2-960)U. Five patients (1.6%) were well-chelated,256patients (82.6%) poorly-chelated and49(15.8%) patients didn't receive chelation therapy. The median SF value is3917ng/ml.95.4%of all patients had SF>1000ng/ml,76.6%patients had SF>2500ng/ml.
Conclusions Most beta-TM patients in Guangxi are younger, poorly-chelated, and have a high burden of iron overload.
THE SECOND PART OF THESIS
STUDY OF CARDIAC IRON OVERLOAD IN PATIENTS WITH THALASSEMIA MAJOR
Purpose This study aimed at investigating the occurrence, prevalence and severity of cardiac iron overload in a young Guangxi population with beta thalassemia major (TM).
Methods We analyzed T2*cardiac magnetic resonance (CMR), left ventricular ejection fraction (LVEF) and serum ferritin (SF) in201beta TM patients with192children and9adults. The median age was9(4-25) years old.
Results Five patients (2.5%) were well-chelated and196patients (97.5%) poorly-chelated. The median SF level was4536(525-23,640) ng/ml and165patients (82.1%) had SF>2500ng/ml. Myocardial iron overload (T2*<20ms) were detected in64children (33.3%) and4adults (44.4%). Severe myocardial iron overload (T2*<10ms) were detected in25children (13%) and1adult (11.1%). Twenty-two patients under10years old (21.4%) had myocardial iron overload, in which3patients were only6years old. No myocardial iron overload was detected in14patients under the age of6years. Cardiac T2*was negatively associated with age (r=-0.328, p=0.000) or SF (r=-0.319, p=0.000). Measured by CMR, the median of LVEF was64%(49%-81%) in175of the TM patients. Five of6patients with a LVEF<56%had myocardial iron overload. The incidence of impaired LVEF in patients with myocardial iron overload was higher than that in patients without myocardial iron overload (8.1%vs0.9%, p=0.021). Eight of10patients with cardiac diseases had myocardial siderosis.
Conclusions Most Chinese TM patients have a high burden of iron overload. Myocardial siderosis, which occurred in patients younger than previously reported, was strongly associated with impaired LVEF and cardiac diseases. For those poorly-chelated TM patients, our data suggests that there leaves great room for improvement of patient care and that the first assessment of cardiac T2*should be performed as early as6years old.
THE THIRD PART OF THESIS
STUDY OF LIVER IRON OVERLOAD IN BETA-THALASSEMIA MAJOR PATIENTS
Objective The aim of this study was to study the prevalence and severity of liver iron overload in β-thalassemia major (β-TM) patients, and the relationship of cardiac T2*and liver iron concentration with various clinical and serum biochemical parameters.
Methods Cardiac T2*(MRI T2*)、 left ventricle ejection fraction (LVEF) and liver iron concetratin(LIC, MRI R2) were measured in59patients with P-TM by magnetic resonance imaging technique. The median age was (13) years old. Serum ferritin was measured by electrochemiluminescence immunoassay (ECLIA).
Results1. The median SF level was6016.5±3566.9ng/(1345-23640 ng/ml) ng/ml and51patients (86.4%) had SF>2500ng/ml.
2. The mean value of myocardial T2*was20.5±13.4ms, and LVEF value was70±4.6%. Fifteen patients had mild-moderate cardiac iron overload, and15patients had severe cardiac iron overload. ALL of patients had normal LVEF.
3. The mean value of LIC was35.8±10.6mg/g dry weight. Cardiac T2*<20ms were detected in30patients (50.8%). All of59patients had severe liver iron overload, and53patients (89.9%) had LIC>15mg/g dw.
4.The30patients(50.8%) with cardiac T2*<20ms had LIC15mg/g dw. And the6patients(10.2%) with LIC<15mg/g dw had normal cardiac T2*.
5. LIC was positively correlated with SF(r=0.698,p=0.000) and inersely correlated with cardiac T2*(r=-0.345,p=0.009). There was a positive correlation between AST、 ALT and LIC(r=0.307,p=0.019; r=0.348,p=0.007).
6. No correlatian was found between cardiac T2*and SF、 LVEF. There was no correlation between LIC、 cardiac T2*and age of starting blood transfusion、 age of starting chelation therapy and numbet of total blood transfused.
Conclusion β-thalassemia major patients had a severe liver and cardiac iron overload status. Liver iron concentration had a positive correction with SF and cardiac T2*. AST and ALT had a positive correction with liver severe iron overload.
THE FOURTH PART OF THESIS
CORRELATION OF NT-PROBNP LEVEL AND CARDIAC IRON OVERLOAD IN PATIENTS WITH BETA-THALASSEMIA MAJOR
Objective The aim of this study was to investigate the correlation between N-terminal pro-brain natriuretic peptide (NT-proBNP) levels with cardiacT2*and LVEF in patients with β-thalassemia major(β-TM),and investigate the value of NT-proBNP levels in detecting cardiac iron overload and LVEF abnormal.
Methods We studied140patientswith beta TM (83males and57females) and30healthy controls (20males and10females). The median age of patiens was8(5-25) years old and the median age of controls was8(5-9) years. NT-proBNP and serum ferritin (SF) were measured by electrochemilumine-scence immunoassay (ECLIA). Cardiac T2*and left ventricle ejection fraction (LVEF) were measured in109patients by magnetic resonance imaging T2*(MRI T2*).
Results1, NT-proBNP level in β-TM patients was higher than that in normal controls (137.2±136.5pg/ml vs62.5±55.1pg/ml, p<0.05).
2. The mean of NT-proBNP level in48patients with cardiac iron overload was higher than that in61patients without cardiac iron overload (212.5±169.4pg/ml vs107.6±109.3pg/ml, p<0.05). NT-proBNP was negatively associated with cardiac T2*(r=-0.416, p=0.000), and positively correlated with age(r=0.436,p=0.000).
3.The mean of cardiac T2*value in109patients was22.8±12.5ms (median23.9ms) and48patients(44%)had cardiac T2*<20ms.29patients (26.6%) had cardiac T2*between10ms and20ms, and19patients (17.4%) had cardiac T2*<10ms.Cardiac T2*was inversely correlated with age and SF. The mean LVEF value was64.9±5.9%.Five patients had LVEF<56%. LVEF was positively correlated with age (r=0.314,p=0.001).No correlation was found between LVEF and SF、 cardiac T2*.
Conclusion NT-proBNP levels are significantly increased in P-thalassemia major patient. NT-proBNP was negatively associated with cardiac T2*. NT-proBNP is valuable in detecting cardiac iron overload in β-thalassemia major patients. THE FIFTH PART OF THESIS
REGULATION OF IRON METABOLISM THROUGH GDF15AND HEPCIDIN IN BETA-THALASSEMIA MAJOR PATIENTS
Objective The aim of this study was to assess the level of hepcidin and Growth differentiation factor15(GDF15) in patients with P-thalassemia (β-TM) and to study the correlationships of the serum hepcidin and GDF15levels, the blood transfused and the markers of iron overload.
Methods Serum hepcidin、 differentiation factor-15and serum ferritin were measured136patients with β-TM patients,17patients with β-thalassemia intermedia(β-TI) and30healthy controls by enzymelinked immunosorbent assay(ELIAS) and electrochemiluminescence immunoassay(ECLIA).
Results1. The level of hepcidin in thalassemia was significantly lower than that in control group (34.0±36.5ng/ml vs146.4±70.8ng/ml).The mean level of hepcidin in136β-TM patients and17β-TI patients were31.5±33.6ng/ml and54.5±51.7ng/ml, respectively. The mean level of hepcidin in patients with β-TM and β-TI was significantly lower than that in control group (p<0.05).No significant differences was found between the hepcidin level of P-TM and β-TI patients (p>0.05).
2. The mean level of GDF15in thalassemia patients was significantly higher than that in control group (9960.1±6280.6pg/ml vs70.9±15.2pg/ml).The mean level of GDF15in136β-TM patients and17β-TI patients was9962.4±6527.3pg/ml and9944.6±4506.7pg/ml, respectively. The GDF15level of β-TM and P-TI patients was significantly higher than that in control group (p<0.01). No significant differences was found between the GDF15level of β-TM and P-TI patients (p>0.05).
3. The mean level of SF in patients with β-TM and β-TI were5076.5±2662.1ng/ml and3315.6±2827.3ng/ml, respectively. The mean levels of cardiac T2*in patients with β-TM and β-TI were were32.4±15.2ms and23.3±12.1ms, respectively. The median of hepcidin and GDF15in patients with cardiac iron overload (T2*<20ms) were not significantly different with those in patients without cardiac iron overload (T2*>20ms).
4. There was no correlation between hepcidin and GDF15with age and gender in both thalassemai patients and normal controls. No other clear correlation was found between hepcidin、GDF15and cardiac T2*and LVEF. Hepcidin level showed a negative relationship with SF(r=-0.364, p<0.01).
Conclusion The mean level of GDF15was significantly elevated and the mean level of hepcidin was decreased in patients with β-TM and β-TI compared to the normal controls. Our results may indicate that thalassemia patients are in a state of serious ineffective erythropoiesis and need intensify blood transfusion and chelation therapy.
THE SIXTH PART OF THESIS
OXIDATIVE STRESS AND ANTIOXIDANT ENZYME IN p-THALASSEMIA MAJOR PATIENTS
Objective The aim of this study was to evaluate the status of lipid peroxidation and antioxidant in patients with p-thalassemia major (β-TM), and investigate the correlation between the status of lipid peroxidation, antioxidant and iron overload.
Methods We analyzed serum malondialdehyde (MDA), nitric oxide (NO), plasma superoxide dismutase (SOD) and serum ferritin in123patients with β-TM and44healthy controls. MDA was measured spectrophotometerically using thiobarbituric acid (TBA). NO was determined by the Griess reaction. Assay of SOD was measured with xanthine oxidase reation.
Results1.The mean level of MDA, NO and SOD in β-TM were significantly higher than those in in healthy controls (7.2±2.0ng/ml vs5.4±1.9ng/ml,p=0.000;81.7±21.7ng/ml vs72.0±16.9ng/ml,p=0.024;264.5±56.2U/ml vs238.8±46.1U/ml,p=0.021) respectively.
2. All the patients were SF>1000ng/ml and104patients (84.6%)had SF>2500ng/ml.The mean level of cardiac T2*was23.6±12.5ms in98patients with β-TM. The mean level of liver iron concentration (LIC) in42patients with β-TM was37.7±9.1mg/g dry weight. The median of MDA and NO in patients with cardiac T2*<20ms was higher than those in patients with cardiac T2*>20ms. The median of SOD of was not significantly different between the two group.
3.There was no correlation between the MDA、 NO、 SOD and the age or gender in patients and normal controls. The MDA, NO, SOD were significantly correlated with SF levels. Serum levels of MDA and NO were positively correlated with LIC, and inversely correlation with cardiac T2*.NO correlation was found between SOD values and LIC or cardiac T2*.
Conclusion Our study results suggest that iron overload causes peroxidative damage in P-TM and the antioxidant system reation is to compensate for reducing lipid peroxidation to avoid tissue damage.
引文
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