Introduction

Primary aldosteronism (PA) is the most common cause of secondary hypertension, with an incidence rate of 5% to 10% [1,2]. Furthermore, compared with essential hypertension, PA is associated with a higher prevalence of cardiovascular and renal diseases, making early diagnosis and definitive treatment of PA crucial. Autonomous cortisol secretion (ACS), observed in 5% to 20% of cases with adrenal masses, increases cardiovascular morbidity and mortality [3]. The reported prevalence of concurrent PA and ACS varies widely, ranging from 10%–30% to 77% of all PA cases [3,4]. In most cases, aldosterone and cortisol are secreted simultaneously from a single adrenal mass. However, cases of bilateral adrenal adenomas in which aldosterone and cortisol are independently or asymmetrically secreted by the adrenal glands are rare [5-7]. Herein, we report a case of bilateral adrenal adenomas in which aldosterone and cortisol were asymmetrically secreted by the adrenal glands, which was confirmed by adrenal venous sampling (AVS) and postoperative outcomes.

Case

Ethics statement: This case report was reviewed and approved by the Institutional Review Board (IRB) of Jeju National University Hospital (IRB No: JEJUNUH 2024-12-008). The requirement for patient informed consent was waived by the IRB.

A 50-year-old female previously diagnosed with hypertension at a local clinic 2 months earlier, was referred to our outpatient clinic in the Endocrinology Department for further evaluation because of abnormal serum aldosterone levels and plasma renin activity (PRA). Test results from the local clinic revealed the following: serum potassium, 3.4 mmol/L; aldosterone, 33.55 ng/dL; PRA, <0.07 ng/mL/hour; and aldosterone-renin ratio (ARR), 504.7.

Upon presentation to our department, the patient had a blood pressure of 139/84 mmHg and a pulse rate of 70 beats per minute. The patient was receiving angiotensin receptor blocker (ARB) therapy and showed no other remarkable findings on physical examination. The patient was switched from antihypertensive ARB therapy to a calcium channel blocker for the diagnostic evaluation of PA. The patient’s serum aldosterone level and PRA were remeasured 2 weeks later. The follow-up tests showed a serum potassium level of 3.4 mmol/L (range, 3.5–5.3 mmol/L), an aldosterone level of 22.04 ng/dL (range: supine, 4.17–20.89 ng/dL; upright, 6.74–33.51 ng/dL), PRA <0.07 ng/mL/hour (range: supine, 0.32–1.84 ng/mL/hour; upright, 0.60–4.18 ng/mL/hour), and an ARR of 314.8, which were suggestive of PA. Therefore, dynamic endocrine tests for PA were performed to confirm the diagnosis.

During hospitalization, a saline load test revealed an aldosterone level of 25 ng/dL after loading. A captopril challenge test showed an increase in aldosterone rather than suppression, and a furosemide upright walking test demonstrated persistent suppression of PRA to <0.07 ng/mL/hour, confirming PA (Table 1). A computed tomography scan revealed two adrenal masses suspected to be adenomas, measuring 2.5 cm and 1.8 cm on the right and left adrenal glands, respectively (Fig. 1). To determine which adrenal gland was responsible for the autonomous aldosterone secretion confirmed by the saline load, captopril challenge, and furosemide upright walking tests, AVS was performed while continuously infusing adrenocorticotropic hormone (ACTH; cosyntropin) at 50 μg/hour. The selectivity index (SI), calculated as the ratio of cortisol levels in the adrenal veins to those in the inferior vena cava (IVC), was 19.8 on the right and 33.3 on the left, confirming successful catheterization of both adrenal veins. The lateralization index (LI) was 0.1 on the right and 16.1 on the left, indicating excessive aldosterone secretion from the left adrenal gland (Table 2). To exclude functional tumors other than PA, an overnight dexamethasone suppression test and 24-hour urinary catecholamine/metabolite measurements were performed. The serum cortisol level at 8:00 AM after 1-mg dexamethasone administration the night before was 4.8 μg/dL, which was suggestive of Cushing syndrome. Urinary tests revealed the following: metanephrine, 0.04 mg/day (range, ≤0.32 mg/day); normetanephrine, 0.12 mg/day (range, ≤0.39 mg/day); epinephrine, 2.83 μg/day (range, ≤40 μg/day); norepinephrine, 14.07 μg/day (range, ≤80 μg/day); and creatinine, 0.75 g/day (range, 0.8–2.0 g/day), which helped exclude pheochromocytoma. Further evaluations, including ACTH levels, diurnal variations in cortisol, and low- and high-dose dexamethasone suppression tests, were conducted for definitive and differential diagnoses of Cushing syndrome. Baseline ACTH levels were low and physiological diurnal variations in ACTH and cortisol levels were absent (Table 3). Low-dose dexamethasone suppression resulted in a cortisol level of 4.7 μg/dL, confirming Cushing syndrome. High-dose dexamethasone suppression resulted in a cortisol level of 4.3 μg/dL with persistently low ACTH levels, leading to the diagnosis of ACTH-independent Cushing syndrome (Table 4). According to published data, when ACS occurs in the presence of bilateral adrenal masses, a cortisol ratio between the adrenal veins of ≤2.0 indicates bilateral cortisol secretion [8]. The AVS findings in the present case demonstrated a cortisol ratio of 1.68 (Table 2), indicating bilateral cortisol secretion. In summary, the hormonal evaluation of the patient indicated autonomous aldosterone secretion from the left adrenal gland, causing PA, and ACS from both adrenal glands, thus causing Cushing syndrome.

The definitive treatment for these hormonal imbalances is bilateral adrenalectomy, which can lead to lifelong adrenal insufficiency. Therefore, a unilateral adrenalectomy of the left adrenal gland was performed. Laparoscopic adrenalectomy revealed a well-demarcated, 1.8-cm yellow-tan nodule in the left adrenal gland. Microscopic examination confirmed the presence of an adenoma (Fig. 2), with the remaining tissue showing a normal adrenal cortex and medulla. Postoperatively, serum potassium and aldosterone levels, PRA, and ARR normalized; however, ACTH levels remained suppressed (Table 5). The postoperative overnight dexamethasone suppression test showed a serum cortisol level of 10.3 μg/dL, indicating persistent cortisol hypersecretion. The patient’s blood pressure normalized after surgery without antihypertensive medication.

Therefore, the patient had bilateral adrenal adenomas with autonomous aldosterone secretion from the left adrenal gland and ACS from both adrenal glands. Left adrenalectomy resolved aldosterone but not cortisol hypersecretion.

Discussion

The asymmetric autonomous secretion of aldosterone and cortisol from bilateral adrenal adenomas has been reported in few cases [9-11]. A case of aldosterone secretion from the right adrenal gland and cortisol secretion from the left adrenal gland has also been reported in South Korea [12]. However, to our knowledge, there have been no reports of bilateral adrenal adenomas in which aldosterone is autonomously secreted from the left adrenal gland and cortisol is autonomously secreted from both adrenal glands, as observed in the present case.

In this case, the patient exhibited ACS, but there were no observed physical characteristics or symptoms of Cushing syndrome, leading to a diagnosis of subclinical Cushing syndrome (SCS). Patients with SCS have a higher prevalence of hypertension, dyslipidemia, osteoporosis, diabetes, obesity, and cardiovascular diseases and a reduced long-term survival rate [13]. As PA itself increases cardiovascular risk, the coexistence of SCS is associated with an even higher incidence of cardiovascular diseases [14]. Considering that the coexistence of PA and SCS is more common than previously expected, all patients diagnosed with PA should undergo active diagnostic testing for Cushing syndrome. If the coexistence of PA and SCS is confirmed, continuous and meticulous follow-up is essential to monitor the development of cardiovascular disease development [15]. In this case, symptoms of Cushing syndrome were not observed, and due to concerns about permanent adrenal insufficiency, only unilateral adrenalectomy was initially performed. However, if signs or complications related to Cushing syndrome develop in the future, additional contralateral adrenalectomy or medical treatment to suppress cortisol secretion may be considered.

In this patient, the lateralization of aldosterone and cortisol secretion was determined based on the AVS results and hormonal changes after surgery (left adrenalectomy). Additionally, AVS was performed under ACTH stimulation, and catheterization of the adrenal veins was considered successful because the SI was >4 (33.4 and 19.9 in the left and right adrenal veins, respectively) [16]. The LI used to determine the lateralization of aldosterone secretion was 16.1 and 0.1 for the left and right adrenal veins, respectively, indicating hypersecretion of aldosterone from the left adrenal gland. Lateralization of cortisol secretion can also be determined using AVS, where a ratio of cortisol levels between both adrenal veins of ≥2.3 indicates unilateral secretion and a value of ≤2.0 indicates bilateral secretion, as suggested by Young et al. [8]. The ratio of cortisol levels between the left and right adrenal veins in this patient was 1.68, which was below the threshold of 2.0. Additionally, reports suggest that a cortisol-to-peripheral vein (or IVC) ratio of ≥6.5 indicates a cortisol-secreting adenoma, while a ratio of ≤3.3 indicates a nonfunctioning adenoma [8]. In this patient, the results for the left and right adrenal veins were 33.4 and 19.9, respectively (identical to the SI), suggesting hypersecretion of cortisol from both adrenal glands.

Postsurgical findings also support the hypothesis that aldosterone hypersecretion occurred in the left adrenal gland, since blood pressure and potassium levels normalized and PRA recovered after the left adrenalectomy. Postoperatively, the lack of suppression of cortisol levels in the overnight dexamethasone suppression test and the continued decrease in basal ACTH levels further support the hypothesis that cortisol hypersecretion occurred in both adrenal glands.

The limitations of our case report are as follows. First, steroidogenic enzyme immunohistochemical staining and KCNJ5 mutation testing were not performed on the excised tissue, and postsurgical diagnostic testing for PA was not conducted. Because the morphological features of adrenal tumors alone do not reveal the type of hormone secreted, staining for steroidogenic enzymes could help understand the functional state and origin of the tissue [17]. KCNJ5 mutations are the most common genetic mutations in aldosterone-producing adenomas in East Asian patients [18]. However, in this case, the localization of aldosterone and cortisol secretion was achievable based solely on the AVS results, clinical course, and hormonal changes after surgery, without these two tests. Second, although the persistence of cortisol hypersecretion was confirmed by an overnight dexamethasone suppression test postoperatively, no diagnostic tests were conducted to confirm PA remission. However, considering the normalization of blood pressure, potassium, and ARR levels, as well as the recovery of PRA postoperatively, it was determined that the PA had entered remission, unlike Cushing syndrome. Third, the rationale for concluding that bilateral cortisol hypersecretion was present before surgery was based on AVS findings: the cortisol ratio between the left and right adrenal veins was <2, and the ratio of cortisol in the adrenal vein to that in the peripheral vein (or IVC) was >6.5. However, in the study by Young et al. [8], which formed the basis for these criteria, the investigators performed AVS without ACTH stimulation, unlike in our case. Therefore, applying the lateralization criteria proposed by Young et al. [8] to our case, in which AVS was performed with ACTH stimulation, may have been inappropriate. Nevertheless, because ACS persisted even after resection of the left adrenal gland, which showed a high cortisol level in the adrenal vein, we can conclude that bilateral cortisol hypersecretion was present before surgery. We believe that further research is needed to establish criteria for determining the lateralization of ACS in AVS performed with ACTH stimulation.

In conclusion, this case report details the autonomous secretion of aldosterone from the left adrenal gland and ACS from both adrenal glands, the diagnosis of which was confirmed through detailed endocrine evaluations, AVS, and postoperative clinical and hormonal changes. Given that the coexistence of SCS with PA is more common than previously suggested and significantly increases the risk of cardiovascular diseases, it is advisable to conduct diagnostic tests for Cushing syndrome in all patients with PA. Furthermore, in cases of bilateral adrenal adenomas with hormone overproduction, accurate AVS can confirm lateralization, thereby avoiding unnecessary bilateral adrenalectomies that can result in permanent adrenal insufficiency.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This work was supported by the 2025 education, research, and student guidance grant funded by Jeju National University.

Author contributions

Conceptualization: all authors; Data curation, Funding acquisition, Methodology, Project administration, Visualization: GK; Formal analysis: SY, SAL, GK; Supervision: SY, SAL; Investigation: JEH, GK; Writing-original draft: JEH, GK; Writing-review & editing: SY, SAL, GK.

Fig. 1.

Axial computed tomography images of the abdomen demonstrating bilateral adrenal adenomas (arows). The right adrenal mass was measured 2.5 cm with a pre-contrast Hounsfield unit (HU) of –4, which is consistent with a lipid-rich adenoma. The left adrenal mass measured 1.8 cm with a pre-contrast HU of –12, which is also consistent with a lipid-rich adenoma. Both lesions are well-circumscribed, with no evidence of local invasion or metastatic disease.

Fig. 2.

Histopathological findings of the resected left adrenal mass. The tumor cells are polygonal-shaped and have abundant clear cytoplasm with a nested and trabecular pattern (hematoxylin and eosin stain, ×100).

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Figure & Data

References

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