2017, 64 (1), 65-73 Original ACTH stimulation test and computed tomography are useful for differentiating the subtype of primary aldosteronism Ayako Moriya1), Masaaki Yamamoto1), Shunsuke Kobayashi1), Tomoko Nagamine1), Naomi Takeichi-Hattori1), Mototsugu Nagao1), Taro Harada1), Kyoko Tanimura-Inagaki1), Shiro Onozawa2), Satoru Murata2), Hideki Tamura1), 3), Izumi Fukuda1), Shinichi Oikawa1), 4) and Hitoshi Sugihara1) 1) Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8603, Japan 2) Department of Radiology/Center for Advanced Medical Technology, Nippon Medical School, Tokyo 113-8603, Japan 3) Tamura Medical Clinic, Tokyo 132-0013, Japan 4) Department of Diabetes and Lifestyle Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association (JATA), Tokyo 204-8522, Japan Abstract. The diagnostic steps for primary aldosteronism (PA) include case screening tests, confirmatory tests, and localization. The aim of this study was to identify useful confirmatory tests and their cut-off values for differentiating the subtype of primary aldosteronism, especially in unilateral PA, such as aldosterone-producing adenoma, and bilateral PA, such as idiopathic hyperaldosteronism. Seventy-six patients who underwent all four confirmatory tests, the captopril-challenge test (CCT), furosemide upright test (FUT), saline infusion test (SIT), and ACTH stimulation test (AST), and who were confirmed to have an aldosterone excess by adrenal venous sampling (AVS) were recruited. Subjects were diagnosed as having unilateral aldosterone excess (n=17) or bilateral aldosterone excess (n=59) by AVS. The SIT-positive rate was significantly higher in the unilateral group (94.1%) than in the bilateral group (57.6%). Multivariable logistic regression analysis showed that tumor on computed tomography (CT) and plasma aldosterone concentration (PAC)max/cortisol on the AST were useful for differentiating the subtype of PA. Receiver operating characteristic (ROC) curve analysis for distinguishing the subtype of PA showed that a cut-off value of 18.3 PACmax/cortisol on the AST had a sensitivity of 83% and a specificity of 88%. The area under the ROC curve was 0.918 (95% confidence interval 0.7916–0.9708). These data suggest that abdominal CT and AST are useful for differentiating the subtype of PA and the indication for AVS. Key words: Primary aldosteronism, Subtype, ACTH stimulation test, Computed tomography, Saline infusion test PRIMARY ALDOSTERONISM (PA) is the most have shown that chronic aldosterone excess produces important cause of secondary hypertension and is asso- increased aortic stiffness, independent of blood pres- ciated with a higher risk of cardiovascular events and sure [5]. Therefore, the early diagnosis and treatment renal damage than essential hypertension [1–3]. It of PA are important to prevent vascular target organ has been shown that aldosterone excess may be asso- damage caused by aldosterone excess. In epidemio- ciated with endothelial dysfunction independent of logical studies, the incidence of PA in hypertensive blood pressure and produce microvascular inflam- patients ranged widely, from 3.2% to 21.7% [6]. The mation not only in the brain but also in the myocar- difference in the prevalence of PA among various stud- dium [4]. Furthermore, recent experimental studies ies is mainly caused by the different cut-off values Submitted Jun. 8, 2016; Accepted Aug. 29, 2016 as EJ16-0297 for the screening or confirmatory tests. The diagnos- Released online in J-STAGE as advance publication Oct. 1, 2016 tic guidelines for PA of the Japan Endocrine Society Correspondence to: Izumi Fukuda, Department of Endocrinology, (JES) recommend measuring the plasma renin activity Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, (PRA) (ng/mL/h) and plasma aldosterone concentra- Japan. E-mail: [email protected] tion (PAC) (pg/mL) and then calculating the PAC/PRA ©The Japan Endocrine Society 66 Moriya et al. ratio (ARR) in patients initially diagnosed as having endocrinological examinations such as confirmatory hypertension. If the ARR is over 200, the JES recom- tests (CCT, FUT, and SIT) and ACTH-stimulated AVS mends making a definitive diagnosis by performing at (ACTH-AVS). A definitive diagnosis of PA was based least 2 of 3 confirmatory tests, the captopril-challenge on at least one positive confirmatory test (CCT, FUT, test (CCT), the furosemide upright test (FUT), and the or SIT). AST and computed tomography (CT) were saline infusion test (SIT) [7]. On the other hand, the performed in all patients. Japanese Society of Hypertension (JSH) recommends that PA should be diagnosed by performing at least 1 Assays confirmatory test [8]. Furthermore, the ACTH stimu- Serum cortisol levels were measured by an enzyme lation test (AST) is also reported to be useful for diag- immunoassay (EIA) kit (Tosoh Corporation, Tokyo, nosing PA accurately [9]. Japan). PAC and PRA were measured by radioimmu- Once PA is diagnosed, a localized diagnosis is nec- noassay (Fujirebio Inc., Tokyo, Japan). essary. Aldosterone-producing adenoma (APA) (uni- lateral) and idiopathic hyperaldosteronism (IHA) Procedure of diagnosis in PA (bilateral) are the most common subtypes of primary Hypertensive patients with ARR over 200 were tar- aldosteronism [10, 11]. Adrenal venous sampling geted [7, 14]. All antihypertensive drugs except cal- (AVS) is the gold-standard test to differentiate unilat- cium channel blockers and α-blockers were stopped eral from bilateral disease, and it should be offered to at least 2 weeks before the examination [7]. Plasma patients who have been diagnosed with PA based on potassium concentrations of 3.5 mEq/L or less were confirmatory tests and wish to be treated surgically [7, corrected by oral supplementation. All tests were per- 11]. However, AVS is far from easy to perform for formed during morning hours in a quiet room. In par- all patients with PA because of some problems (e.g., ticular, PRA and PAC were measured in blood sam- high cost, adrenal phlebography-associated complica- ples obtained after 30 min of rest in a supine position tions, and the high level of technical skill and experi- in the morning. ence needed for successful cannulation of the (right) adrenal vein). Recent reports have shown that the Confirmatory tests ACTH stimulation test with 1-mg dexamethasone CCT, FUT, and SIT were performed after overnight is useful for determining the subtype of PA [12, 13]. fasting according to the JES guidelines [7]. However, little has been reported about which confir- CCT matory tests are useful in determining the subtype of Patients took captopril 50 mg (crushed orally). PA. Our objective was to determine the most useful Blood samples were obtained before and after taking confirmatory test and the cut-off value to distinguish captopril. ARR over 200 at 60 minutes after captopril the subtype of PA. administration was considered positive. FUT Subjects and Methods Patients were administered 40 mg of furosemide by an intravenous injection and maintained in a standing Patients position for two hours. PRA values less than 2.0 ng/ The medical records of patients diagnosed with mL/h at 60 and 120 minutes after loading were consid- PA by confirmatory testing and localization by AVS ered positive. were retrospectively analyzed. Ninety patients admit- SIT ted to Nippon Medical School Hospital for AVS from Patients were infused with 2 L of 0.9% saline over 4 January 2009 to March 2015 were examined. This hours. The test was considered positive when PAC was was a retrospective study without intervention that higher than 60 pg/mL after the saline infusion. was approved by the Nippon Medical School and AST Faculty of Medicine Ethics Committee and conducted Patients were administered 250 μg of synthetic in accordance with the principles of the Declaration of ACTH (tetracosactide acetate: Cortrosyn® (Daiichi Helsinki. This study was registered with the University Sankyo Company, Limited, Tokyo, Japan)) by intrave- Hospital Medical Information Network (UMIN) (No. nous injection. Blood samples were obtained before UMIN000022657). The diagnosis was confirmed by and every 30 minutes for 2 hours after ACTH injec- Usefulness of AST and CT for PA subtype 67 tion. A ratio of PAC to cortisol (F) over 8.5 at the time ratio was over 2.6, and the contralateral ratio was less of peak concentration of aldosterone after ACTH injec- than 1.0 [7, 16]. tion (PACmax/F) was considered positive [9]. Exclusion criteria CT scan The following patients were excluded from this All but one patient underwent CT of the adrenal study: one patient who had iodine allergy and used glands with contiguous 0.625, 1.25, 2.5, or 5-mm slice steroid during AVS; five patients who were diag- cuts. Only one patient underwent a 10-mm scan in nosed with subclinical Cushing’s syndrome; four another facility. All scans were reviewed by several patients taking antihypertensive drugs other than experienced radiologists. An adrenal tumor on CT was calcium channel blockers and α-blockers for refrac- defined as the presence of a solitary or clearly delin- tory hypertension; one patient with bilateral aldoste- eated nodule; “mild adrenal enlargement” and “a ques- rone-producing adenomas, confirmed by the clini- tionable nodule” were regarded as no nodule. cal course and pathology after surgery (left adrenal gland tumor segmental resection and right adrenalec- Adrenal venous sampling tomy); two patients with unsuccessful AVS; and one Expert radiologists performed AVS. To confirm patient who had unilateral aldosterone excess (PAC > that the catheter tip was inserted into the adrenal vein, 14,000 pg/mL) and LR over 2.6, but CR over 1.0 on CT venography with contrast media was performed AVS. The data of 76 of the 90 initial patients were [15]. After confirming that the catheter tip was inserted ultimately analyzed. into the adrenal vein, blood samples were collected, and tetracosactide acetate (synthetic ACTH) was Statistical analysis injected intravenously. Blood samples were obtained Fisher’s exact test was used for categorical vari- within 15 to 45 minutes after ACTH stimulation [15].