This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Affiliated Hospital of Kawasaki Medical School (Kurashiki, Japan; ID No. 3288). As it was a retrospective study, and the requirement for informed consent was waived by the Ethics Committee of Affiliated Hospital of Kawasaki Medical School (Kurashiki, Japan; ID No. 3288). This study initially included 58 consecutive patients who underwent AVS with adrenocorticotropic hormone (ACTH) for local diagnosis of the lesion because of suspected primary aldosteronism (PA) with hypertension and an aldosterone-renin ratio (ARR)>200 (average 992.3; range 200.0-5233.3) from January 2010 to February 2019. The following patients were excluded because AVS could not be technically completed or the final local diagnosis of the hormone-producing lesion was unclear: patients who could not complete blood sampling from the right AdV (n=9); patients who did not undergo surgery, despite being diagnosed with unilateral aldosterone-producing adenoma (UAPA) by AVS (n=2); patients whose ARR did not decrease to within the normal range (<200) after surgery (n=2); and patients whose postoperative course could not be followed-up (n=1). Finally, this study included 44 patients (21 men, 23 women; mean age 56.0 years, range 28-73 years) with technical success of AVS, and all patients who were diagnosed with UAPA by AVS underwent surgery, and the ARR decreased to the normal range. The resulting diagnosis was idiopathic hyperaldosteronism (IHA) (n=24) and unilateral aldosterone-producing adenoma (UAPA) (n=20) including right APA (n=8) and left APA (n=12).
AVS was always conducted by 2 or 3 senior radiology residents or a radiologist with supervision by one of four interventional radiologists, after the administration of anticoagulant therapy with 3000 units of heparin. Under local anesthesia, 4-Fr sheaths were percutaneously inserted in the femoral veins of both legs. Before and after (between 15 and 30 minutes) bolus injection of 0.20 mg of the adrenocorticotropic hormone (ACTH) cortrosyn (cosyntropin), at least 3 mL of venous blood were sampled from the following four sites: the lowest point of the inferior vena cava (IVC) and the left AdV, the right AdV, and the IVC at one vertebral level above its confluence with the right AdV (the substitute right AdV [S-rt. AdV]). For the S-rt. AdV, the tip of the catheter was positioned on the same side of the IVC as the right AdV. Figure 1 shows how the positions of the S-rt. AdV were determined. For cannulation of the left AdV, a 4-Fr catheter of Simons-type (Terumo, Japan) and a 1.7-Fr microcatheter (Boston Scientific, United States) were mainly used, and sampling from the main trunk of the left AdV was conducted via a 4-Fr sheath (Medikit, Japan) inserted into the left femoral vein. For cannulation of the right AdV, a 4-Fr Cobra-type (Medikit, Japan) or Hook-type (Medikit, Japan) catheter inserted into the right femoral vein via a 4-Fr sheath was used. The same microcatheter was used for the right AdV if blood could not be withdrawn from the 4-Fr catheter. Digital subtraction angiography (DSA) was performed using a Allura Xper FD20 (Philips Healthcare, Netherland) and a Infinix 8000v (Canon Medical Systems, Japan). For patients in whom it was difficult to determine whether the catheter had entered the right AdV, unenhanced or enhanced cone-beam CT was performed to confirm the locations of the catheters in the right AdV.
To evaluate successful catheterization of an AdV, the selectivity index (SI) was calculated as follows: SI = plasma cortisol concentrations of the AdV / plasma cortisol concentrations of the lowest point of the IVC. On the basis of guidelines in previous reports (17-19), an SI 5.0 was considered to indicate successful catheterization of each AdV.
The aldosterone/cortisol (A/C) ratio of each AdV was calculated to evaluate the hormone-producing local diagnostic ability for PA. The conventional lateralized index (LI) (A/C ratio larger) / (A/C ratio smaller) was calculated. On the basis of guidelines in previous reports (17-19), an LI 4.0 was diagnosed as IHA, and an LI 4.0 was diagnosed as UAPA. Our own modified lateralized index (modified LI) (Left AdV A/C ratio) / (S-rt.AdV A/C ratio) was also calculated, the cutoff value with the best diagnostic performance was determined, and the diagnostic performances of the conventional LI and modified LI were compared.
Principle of Local Diagnosis of PA by the Modified LI
To explain the modified LI in simple terms, assume that a hormone-producing lesion produces 10 units of hormones and a normal adrenal gland produces 1 unit. Taking no account of hormone dilution, if there is a hormone-producing lesion in the right adrenal gland, then the 1 unit secreted normally and the 10 units of oversecreted hormone produced by the lesion in that gland, making a total of 11 units, will be detected in the blood sampled from the S-rt. AdV (Fig.2a). If there are hormone-producing lesions in both adrenal glands, the 10 units oversecreted by the hormone-producing lesion in the left adrenal gland and the 10 units oversecreted by the hormone-producing lesion in the right adrenal gland, making a total of 20 units, will be detected (Fig.2b). If there is a hormone-producing lesion in the left adrenal gland, the 10 units oversecreted by the hormone-producing lesion in the left adrenal gland and the 1 unit secreted by the right adrenal gland, a total of 11 units, will be detected (Fig.2c). Substituting these values into the formula for calculating the modified LI [modified LI = (Lt. AdV A/C ratio) / (S-rt.AdV A/C ratio) gives the following results. If there is a hormone-producing lesion in the right adrenal gland (Rt. UAPA), the modified LI =1/11 = 0.1 (Fig.2a). If there are hormone-producing lesions in both adrenal glands (IHA), the modified LI = 10/20 = 0.5 (Fig.2b). If there is a hormone-producing lesion in the left adrenal gland (Lt.UAPA), the modified LI = 10/11 = 0.9 (Fig.2c). The results are thus different in these three cases. In fact the hormone is diluted in the bloodstream, but the location of the hormone-producing lesion(s) will nevertheless make some difference.
A nonparametric Mann–Whitney U test was used to compare and identify significant differences in the mean conventional LI and the modified LI between UAPA and IHA. Receiver operating characteristic (ROC) curve analysis was performed for the comparison of UAPA and IHA using the conventional LI and the modified LI. The area under the ROC curve (AUC) was calculated for each variable, and the optimal threshold for each variable was determined from its respective ROC analysis by evaluating the sensitivity, specificity, and accuracy at different cutoff points on the ROC curve. The cutoff values of the modified LI values were determined so that the sum of sensitivity and specificity was maximized. All statistical analyses were performed using SPSS software (v. 17.0J for Windows; Chicago, IL). All tests were two-sided, and P <.05 was considered significant.