原发性醛固酮增多症李江源.ppt

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1、原发性醛固酮增多症（Primary Aldosteronism）,李江源解放军总医院内分泌科,原发性醛固酮增多症的发现,OCT 29，1954 Conn JW在美国中部临床研究学会第27次年会的主席致词中首次报告了一例APA患者34y,F，间歇抽搐，肌无力和麻痹7a，Bp170/100mmHg,Na 151,K 1.6，Cl 102（mEq/L）,尿Aldo排量增高，手术切除右肾上腺腺瘤（直径4cm）后，血压和生化指标恢复正常Conn JW,J Lab Clin Med 1955,45:3,原发性醛固酮增多症,定义：是一组独立或半独立于肾素血管紧张素系统（PAS）的原发于肾上腺皮质的慢性Ald

2、o分泌过多性疾病。发病率：约占全部高血压患者的0.5%-2.2%,醛固酮分泌的调节因子,兴奋性调节因子：RAS，K，ACTH，POMC的N端片段，ET ASF（Aldosterone-stimulating factor),Serotoin抑制性调节因子：Dopamine(DA),Atrial Natriuretic Peptide(ANP),Somatostatin,ProreninReninAngiotensinogen ATI ATII(1q 42.3,485AA)(10肽，-His-Leu)(Asp.Arg.Val.Tyr.Ile.His.pro.phe),ACE,AminoPepti

3、dase,ATIII(7肽）ATIV（6肽）,ATIIPIP2 CalmdulinIP3 Ca+Pro-P Pro-PAldo Aldo快速分泌 持久分泌PIP2=磷脂酰肌醇=磷酸；Pro-P=蛋白磷酸化,DG,PKC,10-11 10-10 10-9 10-8 10-7,FIG.3.Angiotensin II does-response curves for aldosterone produciton by rat zona glomerulosa cells at differing calcium concentrations.Cells prepared in media cont

4、aining no calcium(),0.2 mM calcium(),0.5 mM calcium(),or 1.2mM calcium()were incubated angiotensin II at the concentrations indicated.,ALDOSTERONE(ng/105 cells),2.01.0,肾K排泄,K平衡,Aldo释放,肾钠潴留,ATII,ATI,循环血容量,肾浣泣压,肾小球旁器,肾素,AT原,钾对Aldo释放和RAS调节的关系,1.00.5,5 10 15,ALDOSTERONE(ng/105 cells),POTASSIUM CONCENTRA

5、TION(Mm),FIG.4.Aldosterone production by dog zona glomerulosa cells in response to potassium as a function of extracellular calcium concentration.Cells prepared in media containing 0.2 mM calcium(-),0.5 mM calcium(),or 1.2mM calcium()were incubated with potassium chloride at the concentrations indic

6、ated,K的作用机理,K 肾上腺球状带细胞迅速除极 电压依赖性钙通道开放 Ca+内流 调钙蛋白 PKC Aldo释放,Figure 4.Stimulation by angiotensin II,ET-1 and ET-3 of aldoste-rone secretion by calf zona glomerulosa cells in culture.A representative experiment is shown(n=3).Each point is the meanSEM of four wells.The increase of aldosterone secretion

7、 was significant(P0.05)with all doses.,Aldosterone ng/well/2h,Endothelin Log Molar,ET-1,ET-3,Aldosterone-Stimulating Factor(ASF),是一种糖蛋白，MW.26000，在人垂体前叶、血浆和尿中均可检出大鼠实验：ASF刺激Aldo分泌和血压升高作用机制：依赖K与cAMP无关，不被DXM 或ACTH 拮抗剂或ATII拮抗剂所抑制,嗜铬细胞瘤的定位诊断（俄）,儿茶酚胺的代谢效应,与pheo有关的疾病,低肾素高醛固酮的常见原因,原发性醛固酮增多症先天性肾上腺皮质增生（CYP11B和

8、CYP17A）缺乏症Liddle综合征其他：甘草、异位ACTH分泌过多,原发性醛固酮增多症的临床表现,低钾症状：无力、周期性麻痹、抽搐或搐搦低钾性浓缩功能障碍：多尿、夜尿多高血压：18428/112 16mmHg，可表现为恶性或轻度高血压或血压正常。可有高血压眼底改变。血钠：轻度增高（继醛则降低），但无水肿糖代谢（低钾引起）：可有IGT或显性糖尿病,原发性醛固酮增多症的诊断,高血压、低血钾（少数患者例外）PRA：几乎全部患者25(可疑）（试验期间停用降压药、补钾立位2h后采血）,高血压低血钾,可能是原醛,高血压病或继醛,原醛确诊,高血压病,APA,IHA,25 Aldo/PRA 比值25,钠负

9、荷 试验,Aldo未被抑制,Aldo受 抑制,CT 18-OHB,CT(+),100ng/dL,CT(-)100ng/dL,Liddle综合征,与原醛相似：高血压，低血钾，低肾素活性与原醛区别：低醛固酮；低血钾用氨苯喋啶或阿米洛利有效，安体舒通无效。病 因：肾钠上皮通道亚单位基因突变。阿米洛利敏感性上皮通道，三个亚单位，突变造成通道持续激活，远曲小管回吸收钠过多和容量扩张。遗 传 方 式：常染色体显性遗传。,盐水输注试验（Saline Infusion Test）,摄入钠120meq/日饮食至少3天；卧床过夜；次晨8时测PRA、Aldo、18-OHB和F作为对照；从8时-10时，均匀滴注生理盐

10、水1250ml；在输液结束时再次采血测定上述4种激素有心血管疾病患者，输液速度可减慢，试验时间适当延长。,Subtypes of Primary Hyperaldosleronism,体位试验（Posture Test）,摄入钠120meq/日饮食至少3天卧床过夜次晨8时采血测定PRA、Aldo和F立位走动4小时和/或口服速尿80mg；12时再次采血测定上述3种激素,2010864210.50.1,P0.001,P=NS,CONTROL SI,CONTROL SI,Figure 2.Valation of the aldosterone/cortisol ratio during saline

11、 infusion(Sl)in 14 patients with aldosterone-producing adenoma(APA)and six with idiopathic hyperaidosteronism(IHA).The ratios were calculated by dividing the actual values of aldosterone(ng/dl)by those of cortisol(ug/dl).Statistical analysis was performed by the paired Student test comparing the Val

12、ues before(control)and after saline infusion in each group.,各型原醛醛固酮水平(mg/dl)对体位和Spl试验的反应,安体舒通试验（Spironolactone Test）,摄入钾50-70meq/日和钠120mEq/日饮食口服安体舒通150-300mg/日，历时4-6周；对照期和服药后分别采血测定Aldo、18-OHB和PRA.,50403020100,120,APA,PAH,AP-RRA,IHA,BEFORE,AFTER,PLASMA ALDOSTERONE（ng/dl）,Figure 9.Plasma aldosterone(n

13、g/dl)response to treatment with spironolactone,150/200 mg/day for six weeks,in 43 patients with APA,four patients with PAH,four patients with AP-RRA,and 17 patients with IHA.From Biglieri,Irony,Kater.54,血清18-OHB水平测定,APA患者100ng/dlIHA患者100ng/dl,Figure 10.Plasma 18 OHB levels(ng/dl)in 34 patients with

14、primary aldosteronism,nine patientswith essential hypertension(SHBP),and ten normal subjects(NL).From Kem et al.69,GSHA诊断试验,地塞米松 1mg 0AM 0.5mg 8AM立位2小时，如血浆Aldo5nd/100ml有诊断意义，与IAH或APA无重叠。,胆固醇（腺粒体外）,胆固醇（腺粒体内）,孕烯醇酮,17-OH孕烯醇酮,孕酮,17-OH孕酮,11-去氧皮质酮,11-去氧皮质醇,皮质酮,皮质醇,醛固酮,StAR,CPY11B1,CPY17,HSD3B2,CPY17,CPY21

15、,CPY21,CPY11A1,CPY11B1,CPY11B2,GSHA的分子病因（同源基因重组错误）,CYP11B1,Promoter,CYPB2,束状带,ACTH依赖性,球状带,醛固酮合成,不同类型原醛的生化改变,NV=normal Values,根据Aldo的反应鉴别各型原醛,肾上腺CT扫描,最新一代机器，能发现直径0.7cm的腺瘤；直径3cm的醛固酮瘤应考虑是癌瘤的可能性。,Scintigraphy in primary Aldosteronism,碘胆固醇肾上腺闪烁扫描,氟美松1mg 4/日，连服12天；从第5天开始卢戈氏液3滴，2/日，连服14天；第7天注射131碘-19-胆固醇1-

16、2mci；APA：48-72 h双侧不对称显影；IHA：72-120 h双侧轻度显影；正常人：120h以后显影。,肾上腺静脉采血,插入导管，分别于两侧肾上腺静脉采血测定Aldo和F，比较两侧定结果；注射ACTH后再采血更准确，腺瘤Aldo/F10。,原醛的治疗,APA：手术（首选），药物IHA：药物PAH：单侧或次全肾上腺切除，药物AP-RRA：同上GSHA：药物APC：手术+化疗,APA的治疗,手术切除腺瘤，约2/3的患者完全缓解，其余1/3的患者需除压药治疗。单侧背部切口入路，几乎无并发症和死亡率。,1例原醛患者肾上腺静脉插管结果,原醛的药物治疗（一）,醛固酮拮抗剂：安体舒通钠转移抑制剂：

17、咪吡嗪，氨苯喋啶钙通道阻滞剂：异搏定，心痛定转换酶抑制剂：Captopril,enalapril,Amiloride(20-40mg/日）和SPL（200-400mg/日6W）治疗原醛的比较,*自身对照（SPL-placebo-Aml各6W）,氨苯喋啶（50mg）+双克（25mg）治疗原醛,心痛定（30-50mg/日）治疗原醛（6例）4周的疗效,原醛的药物治疗（二）,类固醇合成抑制剂：睛环氧雄烷血清素能拮抗剂：赛庚啶多巴胺拮抗剂：溴隐停,Trilostane（睛环氧雄烷）,（4，5-环氧-17-羟-3-氧代5-雄烷-2-睛）作用：竞争性抑制3 羟脱氢异构酶治疗增生或腺瘤型原醛，剂量120-90

18、0/日副作用：轻度腹泻,(n=9)(n=9),赛庚啶*治疗APA和IHA,*8mg单剂8-9Am口服，每30min采血一次，共4次，计算平均值。,+20+100,+20+100-10,(a)2h UPPIGHT POSTUREP0.01,(b)60min CAPTOPRIL 25mg,P0.05,IAH APA DSH(n=10(n=6)(n=3),.,.,.,IAH APA DSH(n=28)(n=28)(n=3),CHANGE IN PL.ALDOSTERONE(ng/dl),Figure 4a,4b.Plasma aldosterone change from basal values

19、after two hours of upright posture(a)and 60minutes after the administration of 25 mg captopril(b)in patients with IAH,APA,and DSH.For the captopril test,the patients were evaluated at 10AM while maintaining a comfortably sitting Dosition two hours before and for the duration of the study.Data for IA

20、H and APA are expressed as meanSEM;comparison beteen values was made using the unpaired t-test.,Nact 0.9%,ng/kg/min,0.5 1 2 4,PL ALDOSTERONE ng/dl,Fig.2.Plasma aldosterone response to angiotensin II infusion in three siblings with DSH.Asp1-Val5 angiotensin(Hyperten-sin,Ciba-Geigy)was infused at the rate of 0.5,1.0,2.0,4.0ng/kg/min in four consecutive 30-min periods,followed by another period of saline 8,MINUTES,