Influence of cortisol cosecretion on non-ACTH-stimulated adrenal venous sampling in primary aldosteronism: a retrospective cohort study

Abstract

Objective: Cortisol measurements are essential for the interpretation of adrenal venous samplings (AVS) in primary aldosteronism (PA). Cortisol cosecretion may influence AVS indices. We aimed to investigate whether cortisol cosecretion affects non-ACTH stimulated AVS results. Design: Retrospective cohort study at tertiary referral center. Methods: We analyzed 278 PA patients who underwent non-ACTH stimulated AVS and had undergone at least a 1-mg dexamethasone suppression test (DST). Subsets underwent additional late-night salivary cortisol (LSC) and/or 24-hour urinary free cortisol (UFC) measurements. Patients were studied from 2013-2020 with follow-up data of 6 months following adrenalectomy or mineralocorticoid antagonist therapy initiation. We analyzed AVS parameters including adrenal vein aldosterone/cortisol ratios, selectivity, lateralization (LI) and contralateral suppression indices and post-operative ACTH-stimulation. We classified outcome according to PASO criteria. Results: 18.9% had a pathological DST result (1.9-5 µg/dl: n=44 (15.8%); > 5 µg/dl: n=8 (2.9%)). Comparison of AVS results stratified according to the 1-mg DST (≤ 1.8 vs. >1.8 µg/dl: p=0.499; ≤ 1.8 vs. 1.8 ≤ 5 vs. > 5 µg/dl: p=0.811) showed no difference. Lateralized cases with post DST serum cortisol values > 5 µg/dL had lower LI (≤ 1.8 µg/dL: 11.11 [5.36; 26.76] vs. 1.9-5 µg/dL: 11.76 [4.9; 31.88] vs. > 5 µg/dL: 2.58 [1.67; 3.3]; p=0.008). PASO outcome was not different according to cortisol cosecretion. Conclusions: Marked cortisol cosecretion has the potential to influence non-ACTH stimulated AVS results. While this could result in falsely classified lateralized cases as bilateral, further analysis of substitutes for cortisol are required to unmask effects on clinical outcome.

Role of Adrenal Vein Sampling in Guiding Surgical Decision in Primary Aldosteronism

“…If clinically significant hypercortisolism and low morning ACTH levels are documented, we recommend removing the gland with the dominant source of cortisol excess, to treat Cushing's syndrome first and foremost, as residual aldosterone excess can be treated with a mineralocorticoid receptor antagonist; in case of PBMAH with combined Cushing's syndrome and primary aldosteronism, removing the largest adrenal on abdominal CT scan is recommended [97]. If the cortisol co-secretion is mild, removing the gland overproducing aldosterone, according to AVS results, is recommended, while being aware of its impact on AVS interpretation itself [87,88] and on post-surgical management [5]. We, along with other groups, advocate for unilateral adrenalectomy (UA) in some cases of severe PA with documented asymmetrical bilateral aldosterone source on AVS in light of the recent findings on clear clinical and biochemical benefits in patients with bilateral PA who underwent UA with or without partial contralateral adrenalectomy [98,99].…”

“…This may be beneficial to use in place of cortisol in patients with significant cortisol co-secretion, but extensive data on this issue are still scarce, and modest cortisol co-secretion has little impact on interpretation [87,88]. While there is some evidence that high cortisol co-secretion can increase the non-ACTH-stimulated LR contralateral to it and misclassify some cases as bilateral [88], another study suggests that the LR is not significantly influenced by cortisol co-secretion when performed only under ACTH perfusion [87]. Recently, LC-MS/ MS was shown to be superior to immunoassays for lateralization diagnosis, particularly for ACTH-stimulated samples where the discordance between the two methods was higher [89].…”

“…In addition, steroid profiling using liquid chromatography with tandem mass spectrometry (LC-MS/MS) for 15 different adrenal steroids during AVS reported higher AV to peripheral vein ratios, both before and after ACTH stimulation, compared to that for cortisol, with the exceptions of DHEAS, cortisone, and 18-hydroxycortisol 86 . This may be beneficial to use in place of cortisol in patients with significant cortisol co-secretion, but extensive data on this issue are still scarce, and modest cortisol co-secretion has little impact on interpretation 87 88 . While there is some evidence that high cortisol co-secretion can increase the non-ACTH-stimulated LR contralateral to it and misclassify some cases as bilateral 88 , another study suggests that the LR is not significantly influenced by cortisol co-secretion when performed only under ACTH perfusion 87 .…”

Steroid profiling using liquid chromatography mass spectrometry during adrenal vein sampling in patients with primary bilateral macronodular adrenocortical hyperplasia

“…According to the experience of AVS in PA, a successful adrenal vein cannulation is traditionally defined by a SI >2 when AVS is performed without ACTH stimulation ( 16 – 18 ). In PA, the selection of cortisol as reference hormone is based on the assumption that cortisol is entirely secreted by the normal zona fasciculata and not overproduced by the aldosterone-producing lesion, which however has limitations in case of pronounced aldosterone and cortisol co-secretion ( 17 , 27 ). Metabolites with long half-life are slowly cleared from circulation, and have decreasing adrenal to peripheral gradients, thus, this will impair the interpretation of AVS results.…”

The Entity of Connshing Syndrome: Primary Aldosteronism with Autonomous Cortisol Secretion

“…One retrospective case-control study of 144 adults with PA showed abnormal DXM suppression tests in 14.6% of them; the ACS group had an increased cortisol value at the level of inferior vein cave versus the non-ACS group ( p = 0.01), but the selectivity and lateralization index and adrenal vein cannulation rate were similar among ACS andnon-ACS patients [ 125 ]. A retrospective, single centric, cohort study (from 2022) of 278 subjects with PA who were referred for AVS showed that 18.9% of them had an abnormal 1 mg DXM suppression test (post-DXM cortisol levels between 1.9 and 5 µg/dL—15.8% of them, with more than 5 µg/dL—another 2.9%); lateralized cases from the second group had a lower lateralization index versus those with post-DXM cortisol levels below 5 µg/dL, suggesting that high cortisol may impair the accuracy of the left-right gradient [ 126 ].…”