Volume 51 Issue 3
May  2020
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Update and Research Progress in the Diagnosis of Primary Aldosteronism

  • Primary aldosteronism (PA) is the most common cause of secondary hypertension. The diagnosis procedure of PA includes screening, confirmatory diagnosis and subtype classification. International and national guidelines recommended plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio (ARR) to detect possible cases of PA, and one or more tests (fludrocortisone suppression test, saline infusion test, oral sodium loading test, or captopril challenge test) to confirm ARR positive patients. Adrenal venous sampling (AVS) is also recommended as the best method to distinguish unilateral and bilateral adrenal disease when surgical treatment is feasible and desired by the patient. However, many studies find that each of the above diagnostic method has shortcomings. Recently, more and more studies are attempting to explore new methods with higher diagnostic efficiency and more conveniences, including new screening tests, new confirmatory diagnostic tests, new imaging and pathological histology methods. In our studies, the regression model, which included upright PAC, upright PRA, and lowest potassium, is superior to ARR for PA screening; the blood potassium and the ratio of blood potassium to blood sodium after the saline infusion test are not suitable for PA subtyping. This article will review the advances and progress in PA diagnosis.
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Update and Research Progress in the Diagnosis of Primary Aldosteronism

    Corresponding author: TIAN Hao-ming, hmtian999@126.com
  • 1. Adrenal Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China
  • 2. Department of Endocrine and Metabolic Diseases, Suining Central Hospital, Suining 629000, China

doi: 10.12182/20200560201

Abstract: Primary aldosteronism (PA) is the most common cause of secondary hypertension. The diagnosis procedure of PA includes screening, confirmatory diagnosis and subtype classification. International and national guidelines recommended plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio (ARR) to detect possible cases of PA, and one or more tests (fludrocortisone suppression test, saline infusion test, oral sodium loading test, or captopril challenge test) to confirm ARR positive patients. Adrenal venous sampling (AVS) is also recommended as the best method to distinguish unilateral and bilateral adrenal disease when surgical treatment is feasible and desired by the patient. However, many studies find that each of the above diagnostic method has shortcomings. Recently, more and more studies are attempting to explore new methods with higher diagnostic efficiency and more conveniences, including new screening tests, new confirmatory diagnostic tests, new imaging and pathological histology methods. In our studies, the regression model, which included upright PAC, upright PRA, and lowest potassium, is superior to ARR for PA screening; the blood potassium and the ratio of blood potassium to blood sodium after the saline infusion test are not suitable for PA subtyping. This article will review the advances and progress in PA diagnosis.

  • 醛固酮由肾上腺分泌,其主要生理作用是参与维持渗透压、血容量及血压稳定,而当醛固酮病理性增多时,则可引起血压升高、血钾降低等一系列病理生理改变[1]。过去普遍认为原发性醛固酮增多症(primary aldosteronism,PA)在高血压中占比不足2%[2-3]。2013年我国流行病学调查数据显示,11个省的1 656例难治性高血压患者的PA患病率为7.1%[4]。2016年,一项纳入了39项研究、42 510例患者的meta分析发现,在初级医疗人群中PA患病率为3.2%~12.7%,转诊医疗中心的患病率为1.0%~29.8% [5]。2017年意大利流行病学调查显示,PA在初级医疗单位未经选择的1 672例高血压患者中患病率为5.9%,在三级高血压患者中占比达11.8%[6]。由于研究的异质性,报道的PA患病率差异巨大,但这些研究均表明PA是继发性高血压的主要病因,值得临床高度重视。


1.   初筛
  • 过去认为高血压、低血钾及醛固酮升高是PA的特征性表现,对于诊断PA具有重要价值[7];后来CONN等[8]发现无论是否存在低血钾,醛固酮升高和肾素活性(plasma renin activity,PRA)受抑的独特结合可用于诊断醛固酮瘤(aldosterone-producing adenoma,APA),并估计可能高达20%的高血压患者为PA。此后,一项研究首次提出血浆醛固酮浓度与肾素活性之比(ARR)为APA可靠筛查指标,并推荐ARR>400 (pg/mL)/(ng/mL·h)作为初筛阳性标准[9]。随后,ARR作为一种合理而简便的筛查方法被逐渐采纳,从而筛查出大量处于病程早期阶段的患者(大多数患者血钾正常),PA患者数量进而增加了5~15倍,APA的年检出率提高了1.3~6.3倍[10-12]。2008年,美国内分泌学会指南推荐ARR为首选的PA筛查方法[13],ARR为血浆醛固酮浓度(PAC)与PRA的比值,PAC的单位为pg/mL,PRA的单位为ng/ (mL·h),至今仍广泛应用。然而,受药物作用等影响,ARR变异较大,研究报道的敏感性和特异性分别为66%~100%和61%~100%[14]。因此,指南建议在筛查前应停用盐皮质激素受体拮抗剂(MRA)、血管紧张素转换酶抑制剂(ACEI)、血管紧张素Ⅱ受体拮抗剂(ARB)、利尿剂、β受体拮抗剂、甘草等干扰药物,纠正低钾,并维持正常钠盐摄入[15]

    但在实际临床操作中,很难做到停用所有对ARR有影响的药物。因此,梅奥诊所的YOUNG教授[16]提出了不同观点:若患者在接受MRA治疗后仍有低钾血症,说明盐皮质激素受体(MR)并没有完全被阻断。大多数PA患者使用的MRA剂量不足,因此,临床医生可以对所有接受MRA治疗的患者进行筛查,如果PRA或血浆肾素浓度(PRC)被抑制,确诊试验或肾上腺静脉采血(adrenal venous sampling, AVS)也无需停用MRA;而如果PRA未被抑制,建议停药后再筛查[16]。规范化的诊断应尽量避免所有的干扰因素,但由于PA诊断受太多干扰因素影响,如若完全按照规范进行,将耗费较多的人力、物力及时间,同时增加患者风险。我们认为,在某些情况下,即使没有停用干扰药物,其结果也可通过综合分析明确。当醛固酮受体被MRA拮抗或使用利尿剂时,水钠排泄增多,血容量减少,从而升高PRA,因此如果患者在服用这些药物时PRA仍被抑制,则可以进行筛查,但如果PRA未受抑制,建议停药后再筛查。ACEI或ARB同样可升高PRA,如果患者在服用这些药物时PRA正常或升高,并不能排除PA,建议停药后再筛查,而如果PRA被抑制,则很可能为PA,可进一步筛查。β受体拮抗剂和甘草抑制肾素分泌,因此可引起ARR假阳性,建议停药后再筛查。但β受体拮抗剂和甘草引起的ARR假阳性患者,PAC通常偏低,因此如果筛查标准中加入PAC切点值,则可排除假阳性,但具体PAC切点值尚需进一步研究确定。


    此外,ARR切点值也一直是研究热点。目前指南推荐立位ARR切点值范围20~40 (ng/dL)/(ng/mL·h),其中最常用为30 (ng/dL)/(ng/mL·h)[15]。国内研究提示我国人群立位ARR最佳切点值13.01~27.2 (ng/dL)/(ng/mL·h)[17-19]。本专题中,李元美等[20]对四川大学华西医院978例患者的研究显示立位ARR的最佳切点值为20 (ng/dL)/(ng/mL·h),卧位ARR最佳切点值为41 (ng/dL)/(ng/mL·h)。这些研究提示我国人群PA筛查的立位ARR阳性切点值偏低,且在不同地区可能还有差异,因此ARR最佳切点值应根据不同地区和人群特点确定。

    ARR是一个分数,其大小更多由分母PRA决定,在PRA极低时(如0.1 ng/mL·h),即使PAC低(如4 ng/dL),ARR也可能升高,但几乎可以肯定这不符合PA诊断。为了避免这一问题,YOUNG[21]建议在筛查标准中加入PAC>15 ng/dL。但有研究发现74例ARR及氟氢可的松试验(FST)均阳性的PA患者中,36%的患者PAC<15 ng/dL;且与APA相比,PAC<15 ng/dL在特发性醛固酮增多症(idiopathic adrenal hyperplasia,IHA)患者中更常见[22]。另有一项研究报道在125例切除APA的患者中,20例(16%)立位PAC<15 ng/dL,5例(4%)<10 ng/dL[23]。虽然PAC<10 ng/dL时漏诊APA的可能性较低(4%),但漏诊IHA的风险较大。因此,一些研究者建议对所有ARR升高患者行确诊试验,除非PAC低于确诊试验的阳性切点值(如FST,PAC<6 ng/dL)[15]。2019年YOUNG [16]建议对所有高血压患者进行至少一次PA筛查,阳性标准为PAC≥10 ng/dL且PRA<1.0 ng/mL·h或PRC低于参考范围下限。同时,VAIDYA等[24]也提出对于有高血压和/或低血钾的患者,PRA被抑制且PAC>10 ng/dL认为初筛阳性,PAC在5~10 ng/dL之间则为潜在初筛阳性。但采用PRA和PAC(而非ARR)作为筛查指标的诊断价值还需进一步验证,目前指南中尚无相关推荐意见。结合已有研究结果及目前指南推荐的生理盐水输注试验(SIT)的阳性诊断标准,本研究认为,ARR阳性结合PAC>10 ng/dL可能优于单纯ARR阳性,临床可进一步开展相关研究明确中国人群的切点值,此外联合ARR之外的其他敏感指标的筛查研究也可在不同人群中进一步探索。例如,本专题的一篇研究显示纳入立位PAC、立位PRA和最低血钾的回归模型的诊断效能优于ARR[20]

    传统的醛固酮及肾素检测方法为放射免疫法,存在技术要求高、工作量大、使用放射性物质、结果等待时间长等缺点。一些研究也聚焦于如何改善醛固酮和肾素的检测方法。MORIMOTO等[25]开发了一种新的全自动化学发光酶免疫分析方法,可以在10 min内同时测定醛固酮和肾素的浓度,其结果与放射免疫法和质谱法结果显著相关。该方法测定肾素浓度的分析灵敏度为0.1 pg/mL,优于放射免疫法(2.0 pg/mL)。这一新方法有望替代传统放射免疫检测。质谱技术具有高通量、样本制备过程简单且所需标本量少等优点,还可同时测量类固醇激素谱,而类固醇谱能够区分几乎所有的类固醇相关疾病[26],具有较高的临床应用价值。有研究表明质谱法与放射免疫法对筛查PA的敏感性和特异性没有差异[27]。将质谱法引入临床实践会对PA诊断产生重大影响,但该方法前期设备投入费用高且方法摸索需要一定时间。此外,有研究显示PA患者的尿液外泌体中氯化钠协同转运蛋白(pNCC)比原发性高血压(EH)患者高2.6倍,前列腺蛋白高1.5倍[28]。另一项研究显示PA患者的尿前列腺蛋白高于EH患者,具有特异性,但不敏感,且不同PA亚型患者的前列腺蛋白浓度并无显著差异[29]。上述研究表明尿液外泌体可作为PA的生物标记,但其临床价值还需进一步研究。

2.   确诊
  • 目前指南推荐4种确诊试验:FST、SIT、卡托普利试验(CCT)、口服高钠饮食[15]。这4种试验均是PA的生化确诊标准,目前尚无证据表明哪一种最好。FST和口服高钠饮食由于试验过程繁琐、耗时较长或国内无药等原因,目前临床很少开展,常用的确诊方法为SIT和CCT。

  • 1967年的一项研究表明正常人在盐水输注后醛固酮分泌受抑,而PA患者受抑不明显,因此SIT可用于评估是否存在醛固酮自主分泌[30]。此外,PA患者盐负荷后血钾降低,而其他类型高血压患者血钾无明显变化,因此盐水负荷后血钾降低是醛固酮过量分泌的间接证据,有助于PA的诊断[31-32]。本专题杜涓等[33]的研究还发现SIT后血钾和钠钾比值对PA分型诊断的敏感性较低,诊断价值有限。通过扩张容量后醛固酮分泌是否受抑可以较好区分PA与其他类型高血压,并逐渐应用于PA的诊断[34-37]

    指南推荐卧位SIT后PAC<5 ng/dL可基本排除PA,PAC>10 ng/dL可基本确诊,5~10 ng/dL 时诊断不确定[15]。四川大学华西医院研究显示SIT后PAC最佳切点值为11.45 ng/dL,敏感性和特异性分别为88.2%和95.4%,但大多数EH和健康受试者SIT后PAC高于5 ng/dL[38]。该研究提示中国人群盐水负荷后的PAC水平可能高于指南推荐的切点值,若参考指南的切点值,假阳性率可能偏高。

    尽管卧位SIT对排除PA有特异性,但不能区分APA和IHA[39]。因此,有研究探索了坐位SIT的诊断效能及对分型的作用,显示坐位SIT的敏感性优于卧位SIT[40];另一项研究显示坐位SIT的诊断敏感性显著高于卧位SIT(87% vs. 38%),但特异性相似(94% vs. 94%),此外坐位SIT在鉴别单侧(93% vs. 68%)和双侧(85% vs. 20%)病变时比卧位SIT更敏感[41]。目前也有学者正在中国人群中进行坐位SIT诊断效能的研究,如能进一步证实坐位SIT的准确性优于卧位SIT,加之操作更简便,其有望替代卧位SIT,成为更为简便易行、依从性较高的确诊试验。

  • 卡托普利可直接阻断血管紧张素Ⅱ(AT-Ⅱ)的合成,因此服用卡托普利后的PAC水平可反映醛固酮的自主分泌情况。1983年LYONS等[42]发现正常血压受试者及EH患者CCT后PAC均降至15 ng/dL以下,而绝大多数PA患者CCT后PAC大于 15 ng/dL,因此认为CCT可作为PA的诊断试验。但随后MULATERO等[43]研究发现在36%的患者中CCT会出现误导性结果,因而认为在没有心脏或肾功能等禁忌症的情况下,仍应首选SIT或FST,而不是CCT。中国新近发表的一项meta分析显示CCT和SIT的诊断效能无显著差异[44]。此外,SIT时17.5%的受试者有副作用,而CCT只有1.5%的受试者出现副作用[45]。因此,与SIT相比,CCT副作用少,耗时短,操作简便,可在门诊进行。

    目前指南推荐CCT后PAC抑制率小于30%作为PA的诊断标准[15],而2018年国内研究表明CCT后PAC的准确性更高[46]。2018年四川大学华西医院研究显示CCT后的PAC最佳切点值为16.7 ng/dL,曲线下面积(AUC)为0.933,表明CCT后PAC对PA诊断是可靠的,但PA组和EH组CCT后PAC抑制率无显著差异[47]。综合上述研究,采用CCT后PAC水平作为诊断指标可能更适合中国人群。

  • 一项前瞻性队列研究探索了AT-Ⅱ受体拮抗剂抑制试验对PA的诊断价值,该研究显示氯沙坦试验比CCT准确性更高且对分型有一定价值[48],但尚需进一步验证。TSIAVOS等[49]探索了一种新的过夜试验—地塞米松、卡托普利和缬沙坦联合试验(DCVT),结果显示DCVT后ARR切点值为0.32 (ng/dL)/(μU/mL)、且PAC切点值为3 ng/dL时,敏感性和特异性分别为98%和100%。该研究表明DCVT有望替代传统方法用于门诊,但仍需更多研究数据支持。

3.   分型
  • PA的分型是临床诊断的关键和难点。近期研究显示单侧病变行手术治疗组的生活质量、临床结果和生化指标的改善均优于药物组[50-51],终末期肾病的进展和死亡的长期预后优于EH,但药物治疗对预后没有显著影响[52]。因此,正确鉴别出单侧病变患者进行手术可明显改善患者预后。目前用于分型诊断的方法包括:AVS、影像学检查、体位试验、促肾上腺皮质激素(ACTH)刺激试验和临床预测模型等,其中以AVS准确性最高[15]

  • 1972年SCOGGINS等[35]发现由于受膈下静脉血流稀释的影响,仅根据PAC判断优势分泌侧可能产生误导,而双侧肾上腺皮质醇的分泌不受APA的影响,因此双侧肾上腺静脉皮质醇水平可用于判断是否成功采集到肾上腺静脉血。1979年DUNNICK等[53]提出PAC很大程度上取决于导管尖端的位置和肾静脉或下腔静脉血液与肾上腺静脉血液混合的程度,若直接比较双侧PAC可能产生差错,而两侧肾上腺皮质醇分泌是相似的,且皮质醇的分泌不受过量PAC的影响。因此,可通过测定肾上腺静脉中醛固酮/皮质醇比值(A/C)来校正导管放置的差异和肾上腺静脉血与其他来源的血液混合带来的影响。这两项研究为AVS用于分型提供了优化方案,其推荐方法一直使用至今。目前常用的AVS方案包括三种:无ACTH刺激非同步AVS、ACTH1-24 持续静脉输注下非同步AVS和负荷剂量ACTH1-24推注入后非同步AVS[54]


  • 研究表明,由于在开始AVS时患者可能产生应激反应,引起双侧肾上腺皮质醇短暂释放增加,导致双侧非同步AVS时先采血侧皮质醇偏高,降低AVS的准确性[63-64]。而双侧同步AVS可避免应激对皮质醇的影响,但这种方式操作难度大,很多医院无法开展。因此,有研究探讨了在非同步AVS时给予ACTH刺激,可避免应激对皮质醇的影响及皮质醇本身脉动性分泌的影响;另有研究显示快速皮质醇检测技术可在术中直接测定皮质醇水平,协助肾上腺静脉插管定位,提高AVS的成功率[58,65-66]。然而目前指南并未建议在AVS期间是否使用ACTH。一项meta分析显示ACTH刺激下的AVS可显著降低插管失败数量,但未能显著减少错误的优势分泌判断[67]。日本研究显示ACTH刺激将AVS成功率从67%提高到89%,有优势侧比例从62%降低到28%[68];另一项研究发现在222名受试者中,无ACTH刺激和有ACTH刺激的AVS结果在76%患者中一致,而在24%患者中不一致[69]。ROSSITTO 等[70]研究表明使用ACTH并未能改善患者术后结果。因此,应权衡采用ACTH刺激的利弊,更多开展相关研究,特别是以长期预后作为评价指标的前瞻性研究,进一步评估ACTH刺激的AVS对分型诊断的效能。

  • 近年有研究者探索检测其他物质代替皮质醇判断AVS插管是否成功。如采用11-脱氧皮质醇确定导管位置时,AVS过程中无需给予ACTH[71];采用17-羟孕酮和雄烯二酮做校正的SI分别比采用皮质醇高1.6倍和12倍,表明采用这些激素对判断AVS是否成功优于皮质醇,能够提高AVS成功率[72]

  • 由于右侧肾上腺静脉穿刺失败率高,导致AVS的整体成功率偏低,有研究探索了在不使用右侧AVS数据时可否准确区分PA亚型,如一项回顾性研究发现左侧肾上腺静脉A/C与下腔静脉A/C比值≥5.5可准确预测左侧病变,≤0.5可准确预测右侧病变,且该结论在另一家医疗机构得到验证(阳性预测值100%)[73]。然而,另一项研究表明仅采用左侧肾上腺静脉A/C和下腔静脉A/C,24%的单侧患者将被诊断为双侧,而11%的双侧患者可能错误地接受手术治疗(阳性预测值70%),建议谨慎解释不完整的AVS数据,并在决定肾上腺切除术前重复AVS[74]。上述研究结果的不一致可能与不同中心AVS的实施步骤和诊断标准的差异有关,各医疗中心需结合自身数据特点进一步分析研究。

  • 自1976年以来,肾上腺CT扫描因其简便、准确、无创的优势成为肾上腺成像的主要方法[75-76]。然而,2009年一项meta分析发现37.8%的患者CT/MRI结果与AVS结果不一致,如果仅以CT/MRI来决定是否单侧病变,14.6%的患者将进行不恰当的肾上腺切除术(AVS显示无优势侧),19.1%应进行肾上腺切除术的患者被不适当的排除(AVS显示有优势侧),3.9%的患者将进行错误的肾上腺切除术(AVS显示醛固酮优势分泌在对侧)[77]。但此篇分析纳入的文章缺乏随访数据,因此无法确定AVS诊断是否正确。而2016年的一项多中心前瞻性研究将PA患者分别根据CT或AVS的结果进行治疗,随访一年后发现两组患者降压药物使用强度及临床疗效无显著差异[78],提示AVS这个一直被认为准确性最高的分型诊断方法,并不比CT更有优势。然而该研究存在样本量较小、随访时间仅1年等不足,也可能使得AVS的优势未能充分体现。



    然而,临床上还有另一类情况需要考虑。NANBA等[83]发现55例肾上腺切除术患者中,所有基于AVS结果进行全肾上腺切除术的患者均从手术中获益,有3例(CT结果与AVS结果一致,但根据CT结果进行了肾上腺部分切除)患者无明显改善,这3例中2例有免疫组化结果,均为醛固酮合成酶(CYP11B2)阴性结节,说明即使是AVS的优势侧与CT结果一致,影像学诊断的肾上腺结节可能并不分泌醛固酮。2018年的一项多中心回顾性研究显示,CT与AVS相比,术后生化完全缓解的可能性降低,临床缓解无显著差异[84]。一项国际多中心研究表明AVS组患者手术治疗后高血压的治愈率高于非AVS组(40.0% vs. 30.5%,P=0.027)[59]

    上述研究表明目前CT尚不能取代AVS,但可以辅助选择需要进行AVS的PA患者。UMAKOSHI 等[85]研究发现双侧肾上腺CT检查结果正常且血钾正常的PA患者,其AVS有优势侧的先验概率较低,可采取药物治疗;而CT提示单侧病变且血钾低的PA患者,其AVS有优势侧的先验概率较高,则有必要进行AVS从而决定是否手术治疗。综上,尽管AVS还不够理想,但仍是目前最准确的分型诊断方法。在探索其他更好的方法的同时,也应加强对医务人员的正式培训、采用标准化程序以及选择适当的切点值以提高AVS的成功率和准确性[80]

  • 有研究显示CT肾上腺肢体测量有助于鉴别APA与IHA[86]。近三年,四川大学华西医院内分泌代谢科肾上腺亚专业组对肾上腺肢体和体积测量在PA诊断中的价值进行了探索。其中一项研究发现,单侧PA患者的左肾上腺肢体宽度与右肾上腺肢体宽度之比(L/Rw)均值为1.22,双侧PA患者的L/Rw均值为1.11(P<0.05),因此较低的L/Rw比值可能是双侧PA的预测指标[87]。另一项研究根据AVS结果将患者分为左侧组、右侧组和双侧组,发现左侧组的左/右侧肾上腺体积之比(L/Rv)最佳切点值为1.908时,可以确定46.0%的左侧组的PA患者(特异性为100.0%);右侧组L/Rv最佳切点值为0.765时,可以确定27.3%的右侧组的PA患者(特异性100.0%)。因此,L/Rv>1.908或<0.765的PA患者术前可无需进行AVS[88]。上述研究表明肾上腺肢体及体积测量的研究可以从多维度对CT结果进行分析,从而得到更优的诊断结果。

  • 当AVS失败、结果不明确或无法进行时,影像学功能显像可以作为AVS的补充,是一种相对敏感、特异、无创的方法。目前研究报道的肾上腺功能显像方法主要包括:CYP11B2选择性显像剂11C-美托咪酯(MTO)、123I-IMTO、18F-CDP2230,CXC趋化因子受体4型(CXCR4)选择性显像剂68Ga-pentixafor[89-93]

    作为AVS的替代方法,应该满足对CYP11B2高选择性和高亲和力、对小腺瘤高敏感性、高分辨率、辐射少及通用性等条件。目前功能显像对识别直径<1 cm腺瘤的敏感性仍有待提高。开发新的无创功能成像技术将对PA的临床实践产生重要影响。

  • 从仰卧位到直立位时,正常人PAC升高达50%以上,IHA患者呈现正常升高,但APA患者的改变不明显甚至降低[34,94-95],因此PST对PA分型诊断可能有一定价值。研究发现APA对AT-Ⅱ的敏感性明显低于IHA,这种差异可能在一定程度上解释了PAC对直立姿势反应的差异[96-98]


  • 有研究发现APA患者输注少量ACTH后,PAC相对高于正常受试者或IHA患者[102],APA对血浆ACTH刺激的微小变化比对血管紧张素或血钾变化更敏感[103];与IHA和非PA患者相比,APA患者醛固酮分泌对内源性ACTH的依赖性更强[104]。PCR定量评估显示APA过表达ACTH受体mRNA,而皮质醇腺瘤和非分泌性腺瘤的表达与正常肾上腺组织相似[105]。因此,给予外源性ACTH可能有助于区别APA和IHA。目前几项研究表明ACTH刺激试验的敏感性76.8%~95.5%,特异性80.6%~88.9%,AUC可达0.918~0.956,因此该试验有助于选择确实需要AVS的高度怀疑为APA的患者[106-109]

  • Meta分析显示PTH和钙浓度与PA显著相关,高PTH、低血钙可作为PA的预测因子[110]。ROSSI等[111]的研究显示血清PTH升高是APA的特征之一。而另一项研究显示PTH升高与PA亚型无关,血钾和血钙是影响PA患者血浆PTH的主要因素,经过治疗后PTH恢复正常[112]。上述研究表明PTH升高可能是PA的特征,但是否可用于分型诊断还需进一步研究。

  • 研究发现18-氧皮质醇代谢产物的排泄量在双侧增生中为2~12 μg/d,在典型的APA为17~1203 μg/d;18-羟皮质醇的排泄也可将双侧增生(23~59 μg/d)与典型APA(60~2750 μg/d)区分开[113]。2015年SATOH等[114]发现质谱法测得的血浆18-羟皮质醇对于PA分型的敏感性62%,特异性96%,18-氧皮质醇的敏感性83%,特异性99%。虽然上述研究表明18-氧皮质醇和18-羟皮质醇对PA分型有一定价值,但目前国内能检测这两个指标的医院较少。

  • 研究发现AT1R-Ab可能在PA病理生理过程中发挥作用,对PA的分型可能具有重要意义[115-116]。此外,ROSSITTO等[117]发现APA患者的AT1R-Ab比IHA患者高2倍,SABBADIN等[118]则发现APA和IHA间的AT1R-Ab差异无统计学意义,而WILLIAMS等[119]的研究显示IHA患者的AT1R-Ab活性高于APA患者。这些矛盾的研究结果表明AT1R-Ab是否有助于分型诊断还需进一步探索。

  • 近年来关于PA分型临床预测模型的研究逐渐增多,其中应用最广泛的是Kupers评分。Kupers评分共纳入3个预测指标(影像学上表现为典型的Conn腺瘤、血钾、估算肾小球滤过率),当分值为5时预测单侧的敏感性为53%,特异性为100% [120]。此后,不断有学者开发了多种PA分型诊断预测模型,包括改良Kupers评分、Nanba评分、Kamemura评分、Kobayashi评分及中国瑞金医院列线图等[60,121-127]


4.   功能组织病理学检查:免疫组化
  • 近几年通过免疫组化检查发现在APA旁边无明显瘤变的区域存在一些表达CYP11B2的细胞簇,称为产醛固酮细胞簇(aldosterone-producing cell clusters,简称APCCs),提示APCCs可能是APA的来源[128-132]。OMATA等[133]从非高血压个体尸检中选择了107个单侧肾上腺进行检测,发现61个APCCs,且APCC评分(每例APCCs数量/肾上腺皮质面积)随年龄增长而增长,常伴有体细胞突变(CACNA1D突变占76%),提示APCCs在PA和非PA性高血压中的病理生理学作用值得进一步研究。


5.   总结
  • 从发现PA至今的60多年里,其诊断技术逐步发展,形成了目前相对固定的初筛-确诊-分型诊断模式。随着研究的进展,新的检测方法如化学发光法和质谱法有望彻底改变现有放射免疫法的不足,但新方法的准确性尚需进一步验证。ARR作为首选的筛查指标被广泛应用,但也存在不足,有研究者推荐直接采用醛固酮和肾素水平作为筛查标准,但孰优孰劣,或二者结合,还需前瞻性的研究证实。CCT和SIT为目前最常用的确诊试验。CCT较SIT更为安全、简洁、便利,临床推广和操作性可能更强;而其他一些新的确诊试验(如坐位SIT、缬沙坦试验、DCVT)仍在不断的探索中。分型诊断是PA诊断的难点,尽管目前AVS准确性最高,但因其技术要求高导致临床难以大范围推广。对于无法开展AVS的医院,可以采用临床预测模型、CT或影像学功能显像结果等综合评估患者单侧病变的可能性,对于高度怀疑单侧病变的患者,建议术前推荐其到有条件进行AVS的医院检查。



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