原发性醛固酮增多症.ppt

1、原发性醛固酮增多症（primary aldosteronism，PA）,福建省立医院内分泌科 黄惠彬 2011. 08. 14,PA定义与临床重要性 PA筛查 PA诊断 PA分型 PA治疗,PA定义与临床重要性,PA是什么? 醛固酮（ALD）不适当升高，相对的自主性，不被钠负荷所抑制的一组综合征。 结果： 钠潴留、高血压、钾排泄增加可导致低血钾、肾素（PR）抑制、心血管损害。 病因： 腺瘤、单侧或双侧肾上腺增生、遗传性糖皮质激素可治疗的醛固酮增多症（GRA）。,醛固酮激素的合成,球状带,束状带,网状带,PA定义与临床重要性,PA有多常见？ 过去认为：PA在轻中度EH中10%,Primary A

2、ldosteronism Prevalence in Hypertensives (PAPY) study,this study showed that primary aldosteronism was present in at least 11.2% of the 1,125 consecutive patients who were newly diagnosed with hypertension and were referred to hypertension centers. More importantly, the PAPY study showed that 4.8% o

3、f patients had a surgically curable subtype of primary aldosteronism,PA定义与临床重要性,低钾在PA中的概率？ 只有少数PA有低钾（9%37%）（Mulatero P ） 醛固酮腺瘤（APA）中50%，特发性醛固酮增多症 （IHA）中17%患者血钾3.5mmol/L。 低钾对PA：低敏感性、低特异性、低阳性预测值,PA定义与临床重要性,PA的重要性在于？ 高患病率 高心血管风险 有特效的治疗方法改善不良结局,醛固酮受体的分布,PA的危害,靶器官损害：脑、心脏、动脉壁、肾脏。 心房纤颤、中风（缺血性或出血性）、肺水肿、心肌梗塞

4、,醛固酮体内过多对心血管的损害,醛 固 酮 的损 伤 作 用,炎症，血管纤维化和损伤,血栓形成前效应和纤溶障碍,中心高血压效应,内皮功能紊乱,自主神经功能障碍，儿茶酚胺潜能减弱，HR变异能力下降,室性心律失常,钠潴留,钾和镁离子丢失,心肌纤维化和坏死,PA定义与临床重要性 PA筛查 PA诊断 PA分型 PA治疗,PA筛查,高血压合并以下情况应进行筛查： 2、3级高血压 对降压药抵抗 自发性或利尿剂诱导的低血钾 肾上腺偶发瘤 早发高血压或脑血管事件家族史（40岁） PA患者的一级亲属,PA筛查,Gian Paolo Rossi, A comprehensive review of the cli

5、nical aspects of primary aldosteronism,扩大筛查范围,Given the high risk of primary aldosteronism in patients with hypertension, some additional categories could be included in this list: patients with evidence of damage to their target organs that is disproportionate to their blood pressure levels, those

6、with obstructive sleep apnea syndrome and hypertension and patients who are hypertensive and overweight or obese.,扩大筛查范围？,However, other experts favor a wide screening strategy, such as screening for primary aldosteronism in patients presenting with newonset hypertension. Use of this strategy is sup

7、ported by the high prevalence of primary aldosteronism,46 as well as the possibility of preventing a high rate of cardiovascular complications with an early diagnosis followed by specific treatment,PA筛查,筛查的方法： plasma aldosterone-renin ratio（ARR）是目前最可靠有效的PA筛查方法 ARR明显优于血钾或ALD（低敏感性）或 （低特异性） 当ARR难以得出结论或

8、者与临床情况不符时应重复。,PA筛查：ARR的影响因素,PA筛查： ARR的影响因素（续）,PA筛查：对ARR影响较小的药物,PA筛查：注意事项（续）,PA筛查：注意事项,PA筛查：注意事项,The patients should be tested after they have been kept resting supine, or sitting quietly, for 1 h. A concomitant 24 h collection of urine to measure urinary sodium excretion provides an assessment of th

9、e electrolyte intake, which is crucial for a correct interpretation of the renin and aldo sterone values.,PA筛查,纠正低钾 ARR最敏感的时间：早上起床后至少2小时以上（坐，站，走均可），在抽血前保持坐位5-15分钟。 不要限制钠摄入，普食即可。 轻度高血压应洗脱及停用降压药，中重度洗脱影响药物，选用影响小的药物。,抗高血压药对ARR有影响时,When the patient needs a stronger treatment than these agents, some hints

10、 can assist in interpreting the ARR and making the correct diagnosis. For example, a high PAC (416 pmol/l; 15 ng/dl) in a patient on drugs that should lower aldosterone, and/or a reduced level of renin despite receiving agents that are expected to raise the level of renin, indicate that the patient

11、could have primary aldosteronism, which should be investigated further.,PA筛查：肾素两种测定方法比较,The DRA is becoming popular because the samples are handled at room temperature (reviewed elsewhere48,56). However, freezing or exposing samples to low temperatures during this assay can artificially raise the va

12、lue owing to cryoactivation. By contrast, when using the PRA assay, handling plasma at room temperature can lead to angiotensinogen consumption, angiotensin I generation and high blank values, which can result in underestimation of the levels of renin.,PA筛查：肾素最低值限定,to avoid overinflating the ARR whe

13、n levels of renin are very low, the lowest renin value that can be included in the ratio is often fixed at a minimum (which is 0.2 ng/ml per h for PRA and 0.36 ng/ml for DRA).28,46 This precaution is crucial in subgroups of patients who usually have low PRA values, such as the elderly and people of

14、African origin.,PA筛查： ARR切点,In the largest study published to date, the ARR optimal cutoff was 26. This value corresponded to a sensitivity of 80.5% and a specificity of 84.5%;46 as expected cutoff values 26 increased sensitivity at the expense of specificity,PA筛查,筛查只需ARR或者是ARR+PAC15ng/dl？,PA定义与临床重要

15、性 PA筛查 PA诊断 PA分型 PA治疗,PA确诊,对于ARR阳性者，选择下列四种试验之一进一步明确或排除诊断： 1.盐水负荷试验 2.口服高钠试验 3.氟氢可的松试验 4.开博通试验 四种试验没有哪一种更优，在敏感性、特异性、可靠性方面各不相同。,PA确诊,PA确诊,口服高钠实验的局限性,the oral sodium loading test gives inconsistent results because of poor standardization and variable adherence of the patients to the protocol,62 particu

16、larly if a urinary aldosterone test is used. Measurement of urinary aldosterone is preferred by some clinicians because it is held to provide an integrated estimate of aldosterone production. However, aldosterone is mainly metabolized to tetrahydroaldosterone and only 1520% of the aldosterone excret

17、ed in urine is 18glucuronide, which is the substance that is usually measured to assess the excretion of aldosterone in the urine.,口服高钠实验的局限性（续）,For these considerations, and for reasons of practicality, the most popular tests in Europe and Japan (the saline infusion test and the captopril test), cu

18、rrently make use of the measurement of PAC. These tests have moderate sensitivity and high specificity in patients on an adequate sodium intake, for example 133 mmol/l per day (6.3 g NaCl per day).67,68,确诊方法假阴性（漏诊）,Unfortunately, however, these tests are often not usable, as aldosterone secretion is

19、 dependent on angiotensin in most patients with idiopathic hyperaldosteronism, but also in many patients with APA. Hence, relying on these tests can lead to missing several patients with curable APA who show suppressible aldosterone excess after reductions in the levels of renin.,PA定义与临床重要性 PA筛查 PA诊

20、断 PA分型 PA治疗,PA分型,PA分型,肾上腺CT应为进行分型时的首要检查以排除肾上腺皮质癌。 醛固酮癌直径几乎均4cm,影像学检查：CT,原醛，肾上腺双侧增生,原醛， 肾上腺腺瘤,库欣， 肾上腺腺瘤,原醛，单侧肾上腺增生,PA分型（二）,PA的CT表现： 1.正常 2.单侧大腺瘤（1cm） 3.轻微的单侧肾上腺某一肢增厚 4.单侧小腺瘤（1cm） 5.双侧大腺瘤或小腺瘤（或一侧大、一侧小腺瘤） 这些表现需要结合AVS结果来指导治疗 IHA：CT可以正常或结节样改变,PA分型：CT的局限性,1、小的APA可能误判为IHA（CT表现为双侧正 常或双侧结节） 2、明显的小腺瘤样外观，行单侧肾上

21、腺切除， 而实际上是增生 3、无功能的单侧腺瘤并不少见，尤其大于40岁 者，CT上无法与APA鉴别 4、UAH在CT上表现为“正常”,PA分型：CT的局限性,研究表明： 1、111例手术证实的APA只有59例CT正确诊断。 2、1cm的APA，CT检出率25% 3、经CT+AVS确诊的203例PA患者中CT准确率只 有53% 4、以CT作为依据有22%应做手术而没做，25%不 应做手术却做了手术。 5、41例PA患者行AVS与CT之间的一致性只有54%,PA分型：CT的局限性源于PA的多样性,腺瘤与增生结节 增粗与正常 结节状与正常 增生可以单侧或双侧 双侧增生两侧表现不一 无功能瘤与APA,

22、PA分型：CT与MRI比较,敏感性、空间分辨率、伪影方面 MRI的反相位技术 CT与MRI总体上在PA分型上无特殊优势，但价格昂贵,PA分型,当病人能耐受并有手术意向时，应进行肾上腺静脉插管采血（AVS）鉴别单侧或双侧病变。AVS应由有经验的放射科医生进行操作（敏感性95%，特异性100%）,采血部位,PA分型,判断过多的ALD有无优势侧分泌至关重要： 有些中心所有PA患者均行AVS检查； 另一些中心主张有选择性地应用（如年龄40岁，CT扫描表现为单侧很明显孤立性的腺瘤样病变，一般无需AVS）,PA分型： AVS的判断标准,“cortisol-corrected aldosterone rat

23、io”（CCAR） CCAR=高CCA/低CCA 用a1-24促肾上腺皮质激素刺激： CCAR 4:1，有优势侧分泌 CCAR 3:1，无优势侧分泌,PA分型： AVS的判断标准,不用a1-24促肾上腺皮质激素刺激： CCAR2:1，有优势侧分泌 一侧肾上腺CCA/外周血CCA2.5，且另一侧肾上腺CCA不高于外周血CCA时，提示有优势侧分泌，单侧肾上腺切除术可治愈或改善高血压。,AVS注意事项,First, to minimize the chance of false results AVS should be undertaken after the withdrawal, if fea

24、sible, of all confounding drugs or tapering treatment that reduces the levels of aldosterone as indicated for the screening test (Table2).,AVS注意事项（续）,Second, AVS should only be performed after correction of hypokalemia, if present, as hypokalemia reduces aldosterone secretion and, therefore, can min

25、imize lateralization, thus increasing the chances of false results.,AVS注意事项（续）,Third, use of bilaterally simultaneous catheterization during AVS88 avoids generating artificial differences between the adrenal glands owing to the different timing of the blood sampling during AVS, which is a stressful

26、situation. Bilaterally simultaneous catheterization is essential when AVS is performed without adrenocorticotropic hormone (ACTH) stimulation (see below),AVS注意事项（续）,Fourth, a major source of variation in the interpretation of AVS results is the difficulty of catheterizing the right adrenal vein, whi

27、ch is short and sometimes shares an egress with inferior accessory hepatic veins. Superselective catheterization of the right adrenal vein after identification of the hepatic vein (by CT),89 or after rapid measurement of cortisol levels in the adrenal vein during AVS,90,91 can circumvent this proble

28、m.,PA分型,当AVS不成功时： 1. 重复AVS 2. 盐皮质激素受体拮抗剂治疗 3. 基于其他检查结果考虑手术（如肾上腺CT） 4. 进一步做体位刺激试验（PST）或碘化胆固醇 显像（IS）,PA分型: PST,原理 研究表明，246个手术证实APA患者PST准确率为85% 误诊的原因：一些APA对Ang敏感；一些IHA的ALD分泌具有昼夜节律 PST常用于AVS不成功且CT示肾上腺单侧占位,PA分型,18-羟皮质酮（18-OHB）：皮质酮羟化产物 APA：8:00 卧位 18-OHB100ng/dl， IHA：通常100ng/dl。 该方法准确性差。,PA分型,对于20岁以前确诊PA或

29、有PA家族史的，有早发中风的家族史者，应进行GRA基因遗传学检测。,PA分型,家族性高醛固酮血症-型（FH-） 常染色体显性遗传，占PA1% 临床表现差异很大：有些患者无高血压，有些则有ALD过多，PRA抑制，早发高血压且严重，对传统抗高血压的治疗无效。,PA分型,FH-也是常染色体显性遗传，但具有遗传异质性。 FH-比FH-常见，一项研究表明它至少占PA 7% 与FH-不同的是高ALD不被地塞米松抑制，GRA突变检测阴性。FH-家族病人可表现为APA、IHA或两者皆有，临床上很难与非家族性的PA鉴别，其分子学基础尚不明确。一些研究表明病变在染色体7P22区域。,PA定义与临床重要性 PA筛查

30、 PA诊断 PA分型 PA治疗,PA治疗,单侧病变的PA（APA、UAH）行腹腔镜下单侧肾上腺手术。如果患者不能或不愿意手术，建议用盐皮质激素受体拮抗剂（ MRa ）治疗。,PA治疗,术后血压改善相关的因素：一级亲属高血压人数（1人），术前降压药数量（2种），高血压病程（5年），ARR比值高，尿ALD水平高，术前对螺内酯有反应 术后血压持续升高最常见原因：并存其他未知原因的高血压如EH（2030% of patients with primary aldo steronism would be expected to have concurrent essential hypertension.109)，高龄和/或长病程高血压（长期的双侧APA ）。,PA治疗,术前：控制血压，纠正低钾 术后： 术后尽快检测血ALD和