In this study, we demonstrated that patients with PCC exhibited low ARR compared with those with SCS or NFA. ARR provided substantial sensitivity and specificity to discriminate PCC from other AIs. Increased ARR has generally been used in the screening of primary aldosteronism in patients with hypertension or AIs. Therefore, both PAC and PRA are commonly measured in the routine diagnostic process in AIs and suspicion of secondary hypertension. The present data suggest that the application of ARR in the screening of PCC as in primary aldosteronism may be useful.
Measurement of plasma MN and uMN levels in the diagnosis of PCC shows excellent sensitivity (70.8–100.0% and 80.0–97.0%) and specificity (79.4–97.6% and 69.0–95.1%) [3, 4, 5, 6, 7]; therefore, it has been used as a gold standard. Indeed, in the present study, increased levels of uMN and uNMN provided the highest sensitivity (80% and 100%, respectively) and specificity (100% and 75%, respectively) in the diagnosis of PCCs with an area under the ROC curve of 0.875 and 0.950, respectively. Thus, our data supports that measurements of MN level are recommended to screen PCC as demonstrated in the guidelines [12].
However, in clinical practice, there are some atypical AIs, such as PCCs without an increase in MN level and NFAs with a marginal increase in MN level [15]. In our series, we encountered a patient with NFA who showed increased plasma NA and uNMN levels (plasma NA, 0.63 pmol/mL [reference range, 0.15–0.57 pmol/mL], uNMN, 0.186 µg/day [reference range, 0.029–0.120 µg/day]). Additionally, the patient had bilateral adrenal tumors (2.8 cm on the left, 1.9 cm on the right). 123I-MIBG scintigraphy demonstrated that accumulation was detected only in the left tumor. This patient underwent left adrenalectomy, and the final diagnosis was NFA. Preoperative endocrinological examination showed PRA of 0.2 ng/mL/h, PAC of 85 pg/mL, and ARR of 425, which revealed that it was appropriate to exclude PCC from our ARR criteria, suggesting the evaluation of ARR provided additional information for accurate diagnosis. Furthermore, PCCs with normal MN levels have also been reported [8, 16]. In such cases, ARR may be helpful in the diagnosis of PCC as an additional marker.
It is well known that increased CA secretion in PCC causes chronic vasoconstriction, resulting in low circulating volume, which increases PRA [9]. Moreover, CAs directly stimulate renin secretion via a β1-adrenergic receptor-mediated process [10] (Fig. 3), leading to increased PRA in PCCs (Fig. 1A). In contrast, there were no differences in PAC between the three groups (Fig. 1B). Interestingly, ROC curve analysis revealed that low ARR had higher sensitivity and specificity than increased PRA to discriminate PCC. These data suggest that aldosterone levels were relatively low despite the increased PRA in each case of PCC. Indeed, when PAC and PRA were plotted on the graph, the dots of PCC tended to present on the upper left part, suggesting that PAC was relatively lower than PRA in each case (Fig. 1C). There are several plausible explanations for this phenomenon. First, adrenomedullin (AM) is a peptide hormone that lowers blood pressure via vasodilation, which was originally isolated from PCC, and has been shown to induce renin resistance with ARR suppression [17]. Since plasma AM level is generally high in PCC [18], this could suppress ARR. Another possibility is atrial natriuretic polypeptide (ANP), whose plasma levels are generally increased in PCC [19]. ANP reduces angiotensin II-dependent aldosterone secretion that causes decreased ARR. Moreover, ANP-dependent renal sodium excretion also leads to suppression of aldosterone production [19, 20, 21] (Fig. 3).
Regarding preoperative preparation of PCC, it is critical to normalize circulating volume by α-blocker administration to prevent perioperative complications [22]. In this aspect, it is important to have multiple biomarkers in the diagnosis or exclusion of PCC in addition to CAs preoperatively. Computed tomography (CT) value < 10 HU is a useful marker to rule out PCC in AIs [23]. However, CT value is high in various pathological conditions, such as adrenocortical carcinoma and metastatic adrenal mass. 123I-MIBG scintigraphy is also quite useful in the diagnosis of PCC with sensitivity of 85–88% and specificity of 84–100% [24, 25, 26, 27]. However, the availability of this imaging equipment is limited especially in primary physicians. It is considered that the additional use of the convenient biomarker ARR in combination with the general information may help in obtaining a more accurate diagnosis.
There are several limitations in this study. This is a retrospective study, and the sample size is small, so it is necessary to validate these results in a large-scale cohort study. Additionally, because some patients with NFA did not undergo surgery, we cannot completely exclude the possibility that PCC may be present in the NFA group.
In conclusion, we demonstrated that patients with PCC exhibited low PAC/PRA than those with NFA or SCS, indicating that low ARR indicated the possibility of PCC. Further investigation is necessary to clarify whether this convenient index, “ARR,” will help in the diagnosis of PCC.