原发性醛固酮增多症分型定侧诊断进展

原发性醛固酮增多症 (原醛 )临床分型不仅具有理论意义 ,更重要的是有助于指导治疗。目前所知原醛至少有 7种类型 ,其中以醛固酮腺瘤 (APA)和特发性醛固酮增多症 (IHA)两型为多见。鉴别腺瘤和增生的方法中以双侧肾上腺静脉采样检查 (AVS)法最为可靠 ,但由于其本身具有局限性而难以广泛开展。CT应用最为广泛 ,对于单侧大结节腺瘤CT诊断的结论可靠 ,不必考虑AVS检查 ;对于其它病例 ,特别是IHA ,CT检查的结论不可靠 ,必需进行AVS检查以及早作出分型诊断和相应治疗。     

醛固酮合酶基因多态性与原发性高血压及血浆醛固酮水平的关系

目的　探索武汉地区汉族人群中醛固酮合酶 (CYP11B2 )基因 3 44C/T多态性与原发性高血压 (EH)的相关性 ,及高血压人群醛固酮合酶CYP11B2基因 3 44C/T多态性与血浆醛固酮(pAldo)水平的相关性。方法　应用PCR RELP技术对 2 0 4例CYP11B2基因 3 44C/T多态性进行分析 ,应用放射免疫法测定 10 6例EH组的血浆醛固酮水平。结果　CYP11B2基因 3 44C/T多态性以TT和CT为主要基因型 ,与EH无明显相关性 (P >0 .0 5 )。高血压患者血浆醛固酮水平在CYP11B2基因 3 44C/T的 3个不同基因型组比较差异有显著性 (P <0 .0 1)。结论　武汉地区汉族人群CYP11B2基因 3 44C/T多态性频率与EH没有明显相关性。高血压人群的血浆醛固酮水平与CYP11B2基因 3 44C/T多态性相关     

原发性醛固酮增多症25例临床分析

回顾性分析、总结了25例PA的临床资料.结果APA19例,占76%;特发性醛固酮增多症(IHA)6例,占24%;66.67%IHA患者立位后醛固酮上升大于33%,氨体舒酮试验阳性率达80%;B超、CT检查结果与PA的诊断符合率为72%、92%.结论血、尿醛固酮、肾素活性测定与氨体舒通试验是PA的主要诊断方法;血醛固酮立位试验有助于肾上腺皮质肿瘤和增生的鉴别;双侧肾上腺静脉采样,是PA分型定侧的重要方法;PA的定侧主要依靠B超、CT;外科手术是治疗APA的重要方法;IHA多采用药物治疗.     

原发性醛固酮增多症25例临床分析

回顾性分析、总结丁25例PA的临床资料。结果：APA19例，占76％；特发性醛固酮增多症（IHA）6例，占24％；66．67％IHA患者立位后醛固酮上升大于33％，氨体舒酮试验阳性率达80％；B超、CT检查结果与PA的诊断符合率为72％、92％。结论：血、尿醛固酮、肾素活性测定与氨体舒通试验是PA的主要诊断方法；血醛固酮立位试验有助于肾上腺皮质肿瘤和增生的鉴别；双侧肾上腺静脉采样，是PA分型定侧的重要方法；PA的定侧主要依靠B超、CT；外科手术是治疗APA的重要方法；IHA多采用药物治疗。     

640例高血压患者中原发性醛固酮增多症患病率及临床特点

目的　探讨高血压患者中原发性醛固酮增多症（PA）的患病率,并分析PA患者的临床特点。方法　选择就诊于东莞市中医院内科门诊高血压患者640例,于清晨9∶30～10∶30患者起床2小时后,取坐位5～15　min后采血测定血浆醛固酮（ALD）水平和肾素活性（PRA）,计算血浆醛固酮/血浆肾素活性比值（ARR）。ARR≥30且ALD水平≥15　ng／dL的患者接受开博通试验,服开博通后2小时血浆醛固酮水平抑制程度≤30%,则试验结果为阳性,诊断为原发性醛固酮增多症^［1］。进一步分型时,PA患者均进行肾上腺薄层增强CT检查,诊断为特发性醛固酮增多症（IHA）的患者加用盐皮质激素受体拮抗剂（螺内酯）治疗,诊断为醛固酮瘤（APA）患者予以在腹腔镜下行单侧肾上腺切除术。结果　640例患者中112例（17.5%）ARR≥30,其中87例（13.59%）ARR≥30且ALD水平≥15　ng／dL的患者接受开博通试验。服用开博通2　h后血ALD水平抑制≤30%者32例,确诊为PA（5%）,其中20例诊断为APA（3.125%）,另外12例（1.875%）诊断为IHA。诊断为IHA的患者加用螺内酯治疗,醛固酮瘤患者予以在腹腔镜下行单侧肾上腺切除术。结论　高血压人群中原发性醛固酮增多症的患病率较高,要重视高血压患者中原发性醛固酮增多症的筛查,原发性醛固酮增多症患者临床具有高血压、低血钾、高尿钾、高醛固酮、低肾素、高ARR的典型临床特点。     

CYP11B2基因多态性与原发性高血压患者血浆ALD浓度的关系及氢氯噻嗪的影响

目的　研究CYP11B2 ( - 344C/T)基因多态性与原发性高血压患者血浆ALD浓度的关系及氢氯噻嗪对血浆醛固酮浓度的影响。方法　应用聚合酶链反应技术 (PCR)检测 6 85例原发性高血压患者CYP11B2基因型同时测定其血浆ALD浓度 ,然后均服用HCTZ 12 5mg/d ,6周后资料完整的 6 5 9例患者按TT、CT、CC 3种基因型分组 ,观察不同基因型患者血浆ALD浓度的变化。结果　CC基因型患者基线血浆ALD浓度为 ( 173 96± 5 7 0 8)pg/mL ,高于TT、CT型者 ,差别有统计学意义。服 6周HCTZ后 3组患者血浆醛固酮水平均增高 ,增高幅度分别为 ( 90 71± 88 5 7) pg/mL ,( 6 5 4 5± 73 71)pg/mL ,( 5 8 17± 98 97) pg/mL。TT、CT基因型患者治疗前后血浆醛固酮水平有统计学差异 ,CC基因型患者治疗前后血浆醛固酮水平无统计学差异。ΔALD在 3组基因型间有统计学差异。结论　CC基因与患者血浆ALD浓度高与其他两型 ;服HCTZ后血浆ALD水平上升 ,CC基因型患者上升幅度小于TT、CT基因型者     

CYP11B2基因多态性与原发性高血压患者血浆ALD浓度的关系及氢氯噻嗪的影响

目的研究CYP11B2(-344C/T)基因多态性与原发性高血压患者血浆ALD浓度的关系及氢氯噻嗪对血浆醛固酮浓度的影响.方法应用聚合酶链反应技术(PCR)检测685例原发性高血压患者CYP11B2基因型同时测定其血浆ALD浓度,然后均服用HCTZ 12.5 mg/d,6周后资料完整的659例患者按TT、CT、CC 3种基因型分组,观察不同基因型患者血浆ALD浓度的变化.结果 CC基因型患者基线血浆ALD浓度为(173.96±57.08)pg/mL,高于TT、CT型者,差别有统计学意义.服6周HCTZ后3组患者血浆醛固酮水平均增高,增高幅度分别为(90.71±88.57)pg/mL,(65.45±73.71)pg/mL,(58.17±98.97)pg/mL.TT、CT基因型患者治疗前后血浆醛固酮水平有统计学差异,CC基因型患者治疗前后血浆醛固酮水平无统计学差异.ΔALD在3组基因型间有统计学差异.结论 CC基因与患者血浆ALD浓度高与其他两型;服HCTZ后血浆ALD水平上升,CC基因型患者上升幅度小于TT、CT基因型者.     

原发性高血压患者醛固酮合酶基因-344C/T多态性与血浆醛固酮浓度的关系

目的探讨汉族原发性高血压人群醛固酮合酶(CYP11B2)基因-344C/T多态性频率分布特点及其与血浆醛固酮浓度的关系。方法应用PCR-RELP技术对103例原发性高血压患者的CYP11B2基因-344C/T多态性进行分析。结果汉族原发性高血压人群CYP11B2基因-344C/T多态性以TT和CT为主要基因型,C等位基因较少见。与携带TT基因型的高血压患者比较,CT CC基因型携带者的血浆醛固酮浓度明显增高(148．52±55．63 ng/ml vs 122．85±38．22 ng/ml,P=0．015)。结论汉族原发性高血压人群CYP11B2基因-344C/T多态性与血浆醛固酮浓度有关。     

原发性高血压伴肥胖患者血浆RAAS激素水平和CYP11B2－344C/T基因多态性的相关性

目的 通过检测原发性高血压伴肥胖患者血浆肾素-血管紧张素-醛固酮系统（RAAS）激素水平和醛固酮合成酶CYP11B2－344C/T基因多态性,探讨原发性高血压伴肥胖患者CYP11B2－344C/T易患基因型以及基因多态性与RAAS的关系。方法 随机选取1～2级原发性高血压患者60例,其中高血压伴肥胖者30例,单纯高血压者30例;同期体检中心体检者60例,其中单纯肥胖者30例,健康者30例。采用PCR-RFLP和琼脂糖凝胶电泳等方法检测CYP11B2－344C/T基因多态性,用放射免疫法检测血浆RAAS水平。结果 TT基因型例数与TC+CC基因型例数进行多重比较,有显著差异（P<0.05）,其中以原发性高血压伴肥胖组差异最为显著;T与C等位基因例数进行多重比较,有显著差异（P<0.05）,其中以原发性高血压伴肥胖组差异最为明显。按基因型分组统计分析各组血浆肾素、血管紧张素Ⅱ及醛固酮水平,TT基因型组显著高于TC、CC基因型组（P<0.05）。结论 原发性高血压伴肥胖患者CYP11B2－344C/T基因型以TT基因型为主,等位基因以T等位基因为主。TT基因型血浆RAAS激素水平各组份比TC、CC基因型显著升高,TT基因型可能为原发性高血压伴肥胖患者易感基因型。     

CYP11B2基因多态性与原发性高血压患者血浆ALD浓度的关系及氢氯噻嗪的影响

目的研究CYP11B2(-344C/T)基因多态性与原发性高血压患者血浆ALD浓度的关系及氢氯噻嗪对血浆醛固酮浓度的影响.方法应用聚合酶链反应技术(PCR)检测685例原发性高血压患者CYP11B2基因型同时测定其血浆ALD浓度,然后均服用HCTZ 12.5 mg/d,6周后资料完整的659例患者按TT、CT、CC 3种基因型分组,观察不同基因型患者血浆ALD浓度的变化.结果 CC基因型患者基线血浆ALD浓度为(173.96±57.08)pg/mL,高于TT、CT型者,差别有统计学意义.服6周HCTZ后3组患者血浆醛固酮水平均增高,增高幅度分别为(90.71±88.57)pg/mL,(65.45±73.71)pg/mL,(58.17±98.97)pg/mL.TT、CT基因型患者治疗前后血浆醛固酮水平有统计学差异,CC基因型患者治疗前后血浆醛固酮水平无统计学差异.ΔALD在3组基因型间有统计学差异.结论 CC基因与患者血浆ALD浓度高与其他两型;服HCTZ后血浆ALD水平上升,CC基因型患者上升幅度小于TT、CT基因型者.     

Genetic alterations in patients with primary aldosteronism.

The syndrome of primary aldosteronism is characterized by hypertension with excessive production of aldosterone, potassium loss, and suppression of the renin-angiotensin system. The most common clinical subtypes of primary aldosteronism are aldosterone-producing adrenocortical adenoma (APA) and bilateral adrenal cortical hyperplasia (idiopathic hyperaldosteronism, or IHA). It has been reported that renin suppression and aldosterone levels are lower and hypokalemia milder in patients with IHA than in patients with APA. In the present study, we investigated the genetic analysis of aldosterone synthase gene, CYP11B2 in patients with primary aldosteronism and review the recent studies. The chimeric CYP11B1/CYP11B2 gene, which is a candidate gene for glucocorticoid-remediable hyperaldosteronism, was not found in either the DNA from aldosteronoma or in the genomic DNA from patients with APA or IHA. Mutations in the CYP21 or CYP11B1 gene were not present in patients with APA. No mutations in the coding region of the CYP11B2 gene were found in patients with IHA or APA. The level of CYP11B2 messenger RNA (mRNA) was much higher in the aldosteronoma portion than in nonadenomatous portion. The overexpression of CYP11B2 mRNA seen in the mononuclear leukocytes of patients with IHA suggests that unidentified aldosterone-stimulating factors or abnormalities of the CYP11B2 promoter region may cause the overproduction of aldosterone characteristic of IHA. The variants of the CYP11B2 gene may also contribute to dysregulation of aldosterone synthesis and lead to susceptibility to IHA.     

CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism

Primary aldosteronism is characterized by autonomous production of aldosterone and arterial hypertension, and it occurs in 2 principal forms: aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). APA can be cured through removal of the adenoma, whereas IHA leads to hypertension that must be treated with medication. The origin of the autonomous aldosterone production in IHA is poorly understood, but genetic factors may contribute to its cause. To test the hypothesis that variants of the aldosterone synthase gene may contribute to susceptibility to IHA, we compared genotypes at 3 polymorphic sites in the CYP11B2 gene in patients with IHA (n=90) with those found in patients with APA (n=38), in patients with essential hypertension (n=72), and in normotensive individuals (n=102). We observed significant linkage disequilibrium among the 3 polymorphisms with 2 frequent haplotypes in all groups studied. One haplotype (C2R) was found to be increased in frequency in the IHA group (47%) compared with the other groups, which had a similar haplotype frequency (36%). The 3 polymorphisms studied have been implicated in either essential hypertension or excess aldosterone production in previous studies. Because of the strong linkage disequilibrium, the observed results could be due to the action of any 1 of the 3 alleles or to another allele in linkage disequilibrium with them. Our results suggest that variations in the CYP11B2 gene may contribute to dysregulation of aldosterone synthesis and lead to susceptibility to IHA.     

原发性醛固酮增多症的分型诊断

目的 探讨用于原发性醛固酮增多症(原醛症)分型诊断检查方法的价值.方法 收集本院近7年来57例临床确诊的原醛症患者[醛固酮瘤22例,特发性醛固酮增多症(特醛症)26例,原发性肾上腺增生9例],检测患者的血电解质、血浆肾素活性及血、尿醛固酮,将结果与19例原发性高血压患者对照.再通过肾上腺CT、体位激发试验及肾上腺静脉采血检查对原醛症患者分型并随访.结果 (1)醛固酮瘤患者血压及血、尿醛固酮较特醛症患者高,血钾及血浆肾素活性则低,而原发性肾上腺增生患者临床及生化改变介于两者之间.肾上腺CT检查在原醛症分型诊断中的符合率为醛固酮瘤86.4%,特醛症73.1%,原发性肾上腺增生22.2%;肾上腺静脉采血检查以两侧醛固酮之比作为判定标准时符合率为86.4%、80.8%和77.8%,以醛固酮与皮质醇之比为判定标准则符合率分别为95.5%、92.3%及100.0%.(2)醛固酮瘤及原发性肾上腺增生患者术后随访血醛固酮均下降,血压恢复正常者分别为22.7%及44.9%,血钾恢复正常者为83.3%及100.0%,而特醛症患者随访中各项测值无明显变化,另有33.3%诊断时血钾正常的患者随访中出现低血钾.结论 原醛症的分型诊断需依靠多种检查手段综合分析,单纯依赖影像学检查或体位激发试验并不可靠,肾上腺静脉采血检查可作为影像学检查的补充,用两侧醛固酮与皮质醇的比值分析较单纯比较两侧醛固酮之比更为可靠;醛固酮瘤及原发性肾上腺增生患者术后临床及生化测值均得以明显改善,而特醛症患者随访中无明显变化.     

Genetic analysis of aldosterone synthase in patients with idiopathic hyperaldosteronism.

Idiopathic hyperaldosteronism (IHA) is characterized by hypertension with excessive production of aldosterone, potassium loss, and suppression of the renin-angiotensin system. We compared activity of aldosterone synthase and expression of CYP11B2 messenger RNA (mRNA) in mononuclear leukocytes (MNL) from patients with IHA to findings in leukocytes from patients with aldosterone-producing adenoma and normal controls. Aldosterone synthase activity was estimated from conversion of [14C]deoxycorticosterone to [14C]aldosterone. Levels of CYP11B2 mRNA were determined by competitive PCR. In the same subjects, we sought the chimeric CYP11B1/CYP11B2 that is candidate gene for glucocorticoid-remediable hyperaldosteronism. Southern blot analysis and a long PCR method were used to detect the chimeric gene. Direct sequencing of the CYP11B2 also was performed. No chimeric genes or mutations in the coding region of the CYP11B2 were found in genomic DNA from these patients. However, both aldosterone synthase activity and CYP11B2 mRNA expression were greater in mononuclear leukocytes of patients with IHA than those of patients with aldosterone-producing adenoma or controls. These results suggest that regulatory factors of the CYP11B2 gene, e.g. unidentified aldosterone-stimulating substances or abnormalities in the promoter region of the CYP11B2 gene in patients with IHA resulting in oversecretion, may cause overexpression of mRNA of CYP11B2.     

Dissociation of Plasma Atrial Natriuretic Peptide Responses to Upright Posture and Furosemide Administration in Patients with Normal-, Low Renin Essential Hypertension and Primary Aldosteronism

Plasma levels of atrial natriuretic peptide (ANP) were measured in patients with normal renin essential hypertension (n = 12), low renin essential hypertension (n = 11) and primary aldosteronism due to aldosterone producing adenoma (APA, n = 8) and idiopathic hyperaldosteronism (IHA, n = 3) after overnight rest in the supine position and after 4 h upright posture and furosemide administration. Plasma renin activity (PRA) and aldosterone (Aldo) levels were also determined. Compared to normal renin essential hypertension (33.6± 2.2 pg/ml), basal plasma ANP was significantly higher in low renin essential hypertension (66.8± 6 pg/ml), IHA (54.1± 6.3 pg/ml) and APA before (62.4± 4.9 pg/ml) but not after adrenal surgery (22± 3 pg/ml). After upright posture and furosemide administration plasma ANP was decreased (p < 0.01) in patients with low renin and, less markedly, with normal renin essential hypertension, however not in IHA and APA. In about half of the patients with low renin essential hypertension, unchanged PRA after upright posture and furosemide administration was associated with increased plasma Aldo and decreased ANP levels. We conclude that (i) the relatively high basal plasma ANP levels in low renin essential hypertension, IHA and APA may reflect the presence of volume expansion in these patients; (ii) the hormonal responses to upright posture and furosemide administration in patients with normal and low renin essential hypertension may indicate a counterregulatory role of ANP during activation of the renin-angiotensin-aldosterone system; (iii) the high plasma ANP, which is unresponsive to upright posture and furosemide administration, in patients with APA and IHA may be a potentially interesting new finding whose pathophysiological significance remains to be established.     

Pathophysiological roles of the adrenal renin-angiotensin system in patients with primary aldosteronism.

The mechanism of overproduction of aldosterone in primary aldosteronism is unclear. The intraadrenal renin-angiotensin system (RAS) has been suggested to possess the functional role of the synthesizing aldosterone and regulating blood pressure. In order to clarify the pathophysiological roles of adrenal RAS in aldosterone-producing adenoma (APA), we studied the expressions of the messenger RNAs (mRNAs) of renin, angiotensinogen, type 1 (AT1R) and type 2 angiotensin II receptor (AT2R), CYP11B1 (11 beta-hydroxylase gene) and CYP11B2 (aldosterone synthase gene) in 8 patients with angiotensin II-responsive (ATII-R) APA and compared them with the expressions of the same mRNAs in 8 patients with angiotensin II-unresponsive (ATII-U) APA. Quantification of the mRNA of each gene was done using a real-time polymerase chain reaction with specific primers. There were no significant differences between ATII-R APA and ATII-U APA in the mRNA levels of renin, angiotensinogen, AT1 R, CYP11B1 and CYP11B2. The amount of AT2R mRNA was significantly higher in the patients with ATII-R APA than in those with ATII-U APA (p<0.05). These results may suggest that AT2R partially contributes to the overproduction of aldosterone in ATII-R APA.     

Acute and Chronic Effect of Nifedipine in Primary Aldosteronism

Since calcium entry blocker drugs can interfere with aldosterone secretion in vitro, a similar effect in vivo, in man, has been suggested and partially confirmed. The data available in primary aldosteronism are more controversial. Therefore, we have studied the acute and chronic effect of nifedipine in 7 patients with idiopathic hyperaldosteronism (IHA) and 8 with aldosterone producing adenoma (APA). On 2 different days, 10 mg of nifedipine or placebo were given sublingually to the patients and blood pressure and heart rate were recorded every 5 min. for 60 min. Plasma aldosterone, cortisol, PRA and serum K were measured at 0, 30 and 60 min. 5 patients with IHA and 6 with APA received nifedipine 20 mg per os bid for 3 months; the same parameters were evaluated on days 0, 30, 60 and 90; urinary aldosterone was measured on days 0, 30, 60 and 90. BP decreased in both groups both after acute and chronic administration of nifedipine. Plasma aldosterone showed a similar trend either after acute nifedipine or placebo; however, during chronic treatment it was slightly decreased in IHA patients. Cortisol, PRA, urinary aldosterone and K⁺ remained unchanged. In conclusion, nifedipine is an effective antihypertensive agent also in primary aldosteronism; its aldosterone inhibiting properties are minimal and seem to be present only during long-term therapy in IHA.     

Renal damage in primary aldosteronism: results of the PAPY Study

Primary aldosteronism (PA) has been associated with cardiovascular hypertrophy and fibrosis, in part independent of the blood pressure level, but deleterious effects on the kidneys are less clear. Likewise, it remains unknown if the kidney can be diversely involved in PA caused by aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Hence, in the Primary Aldosteronism Prevalence in Italy (PAPY) Study, a prospective survey of newly diagnosed consecutive patients referred to hypertension centers nationwide, we sought signs of renal damage in patients with PA and in comparable patients with primary hypertension (PH). Patients (n = 1180) underwent a predefined screening protocol followed by tests for confirming PA and identifying the underlying adrenocortical pathology. Renal damage was assessed by 24-hour urine albumin excretion (UAE) rate and glomerular filtration rate (GFR). UAE rate was measured in 490 patients; all had a normal GFR. Of them, 31 (6.4%) had APA, 33 (6.7%) had IHA, and the rest (86.9%) had PH. UAE rate was predicted (P < 0.001) by body mass index, age, urinary Na+ excretion, serum K+, and mean blood pressure. Covariate-adjusted UAE rate was significantly higher in APA and IHA than in PH patients; there were more patients with microalbuminuria in the APA and IHA than in the PH group (P = 0.007). Among the hypertensive patients with a preserved GFR, those with APA or IHA have a higher UAE rate than comparable PH patients. Thus, hypertension because of excess autonomous aldosterone secretion features an early and more prominent renal damage than PH.     

Evaluation of angiotensin II type‐1 receptor antibodies in primary aldosteronism and further considerations about their possible pathogenetic role

Angiotensin II type‐1 receptor autoantibodies (AT1RAb) have been involved in the genesis of primary aldosteronism (PA), both in aldosterone‐producing adenoma (APA) and in idiopathic hyperaldosteronism (IHA). In this study, we evaluated the titer of AT1RAb in 44 PA patients (15 with APA and 29 with IHA) compared with 18 normotensive healthy controls who were matched for gender and age. In 17 PA patients (6 APA and 11 IHA) the titer was evaluated under mineralocorticoid receptor (MR) antagonist treatment. We found that PA patients had a significantly higher titer of AT1RAb compared with controls (median values 33 [IQR 15.6] IU/mL vs 17.5 [IQR 10.8] IU/mL, respectively; P < 0.0001). No significant difference of the AT1RAb titer was reported among PA patients, subdivided according to the subtypes and the concomitant MR antagonist therapy. No significant correlation was detected between age, gender, BMI, blood pressure values, baseline aldosterone, ARR, and the AT1RAb titer of all patients enrolled. Our data confirm an increased titer of AT1RAb in both subtypes of PA, independently from the concomitant use of MR antagonists and clinical/biochemical characteristics of PA patients. The small sample of patients and the relatively short time of treatment could have influenced these results. Moreover, the ELISA assay fails to evaluate the bioactivity of AT1RAb. Further studies should evaluate if the subtype, the clinical/biochemical recovery of PA, or both, influence the pathogenetic role of AT1RAb. The possible autoimmune pathogenesis and reversal effect with AT1R blocker treatment in PA patients with AT1RAb positivity is intriguing and requires further study.