Arterial Hypertension Under the Knife: The Promise of Adrenalectomy in MACS—Breaking News From the CHIRACIC Study

Over the past 3 decades, due to widespread abdominal imaging, the prevalence of incidental adrenal nodules is increasing, reaching up to 7% in adults and up to 10% in patients older than 70 years (1). In the majority of cases, incidentally discovered adrenal nodules are benign lesions, and 20% to 50% of cases are associated with a mild autonomous cortisol secretion (MACS).

The term MACS was coined to replace the condition formerly known as subclinical Cushing syndrome. Indeed, several issues were related to the term subclinical Cushing syndrome, implying an intrinsic risk of progression to overt Cushing syndrome (CS); however, this progression is reported in less than 1% of cases (1), which might lead to overtreatment. Moreover, experts recognized the need to introduce the term autonomous, to better reflect the non-suppressible cortisol levels after the overnight dexamethasone suppression test (DST), and the term mild to focus on measurable cortisol excess in the absence of clinical CS features (1). Therefore, the recent European Society of Endocrinology/European Network for the Study of Adrenal Tumors (ESE-ENSAT) guidelines (1) reported specific diagnostic criteria to confirm MACS in patients with adrenal incidentalomas, characterized by post overnight DST cortisol levels >1.8 µg/dL, and adrenocorticotropic hormone (ACTH) independency without overt signs of cortisol excess (1). Notably, for cortisol levels post overnight DST between 1.8 and 5 µg/dL, a more accurate evaluation of MACS should be performed to reduce the potential risk of false positive results.

However, MACS is characterized by an increased prevalence and incidence of cardiovascular risk factors, mainly arterial hypertension, together with diabetes mellitus, dyslipidemia, and obesity, compared with patients with non-functioning adrenal nodules, therefore leading to a higher morbidity and mortality (1).

Whether patients with MACS could benefit from adrenalectomy, potentially improving their cardiovascular risk, and especially arterial hypertension, is still matter of debate.

The latest ESE-ENSAT guidelines (1) remained conservative on this recommendation, suggesting adrenalectomy based only on individual factors, such as sex, age, general health, degree and persistence of non-suppressible DST-induced cortisol levels, severity of comorbidities, and patients’ preference. This recommendation is cautious due to the low to very low quality of evidence available in published literature so far, mainly characterized by paucity of rigorous clinical trials, retrospective study designs, missing data, recruitment bias, and limited study populations (1). Moreover, methodological limitations, especially due to various definitions of MACS and not standardized antihypertensive treatments, prevented definitive conclusions to support the benefit of adrenalectomy in improving or curing arterial hypertension in patients with MACS (1).

Recently, in the Lancet Diabetes & Endocrinology, Antoine Tabarin and coworkers reported the findings from their European, multicenter, open-label, prospective, superiority, randomized, controlled trial, the CHIRACIC (The Chirurgie des Adenomes Cortisoliques Infra-Cliniques as for surgery of subclinical cortisol-secreting adenomas) study, in which they evaluated whether adrenalectomy, as compared with conservative treatment, could benefit patients with MACS, associated with unilateral adrenal mass, and arterial hypertension (2).

In the CHIRACIC study, 52 hypertensive patients with MACS were enrolled and randomly assigned to adrenalectomy (26 patients [considered for the intention-to-treat, ITT analysis], of whom 23 definitively underwent adrenalectomy [considered for the per protocol, PP analysis]) or conservative treatment (26 patients [considered for the ITT analysis], of whom 25 completed the study [considered for the PP analysis]) (2). The primary endpoint of the study was the proportion of normotensive patients, defined as home blood pressure measurements (HBPM) < 135/85 mmHg, who had reduced by at least 1 step (reduction of dosage and/or type of drugs) their antihypertensive treatment at the end of the study (2). The authors demonstrated that, according to the ITT analysis, 12 (46%) of the 26 patients randomized to adrenalectomy reduced antihypertensive treatment for at least one step (reduction of dosage and/or type of drugs), while normalizing or maintaining blood pressure control based on HBPM despite treatment reduction, compared with only 4 (15%) of the 26 conservatively treated patients (2). According with the PP analysis, these percentages increased to 52% and 16%, respectively (2). Therefore, the data of Tabarin and coworkers from the CHIRACIC study (2) supported a benefit of adrenalectomy on maintaining controlled blood pressure in patients with MACS, associated with unilateral adrenal mass, and arterial hypertension, raising the possibility of withdrawing antihypertensive treatments (2). Impressively, the authors demonstrated that at the end of the study, more than half of patients, specifically, 13 (57%) of the 23 patients who definitively underwent adrenalectomy, stopped their antihypertensive treatment, while maintaining normal blood pressure, compared with less than 5% of patients, specifically, only 1 (4%) of the 25 patients treated conservatively (2). A shorter duration of arterial hypertension was identified as a predictive factor for the interruption of antihypertensive treatment after adrenalectomy (2).

To our knowledge, only 3 previous randomized controlled trials (3-5) have been published on this topic, showing the same trend in favor of adrenalectomy, although the lack of a rigorous methodology, the heterogeneity in the definition of MACS, and the absence of standardized approaches for blood pressure assessment, as well as the absence of standardized antihypertensive treatment burden, prevented a precise comparison of the benefits of adrenalectomy on arterial hypertension. Beyond these 3 randomized controlled trials (3-5), 2 systematic reviews and metanalyses (6, 7) have been published aimed at comparing the effects of surgical or conservative management of MACS on cardiovascular risk factors. In the first metanalysis of 2016 (6), improvement in arterial hypertension was assessed in 9 studies, considering 89 patients with MACS who underwent adrenalectomy and 84 patients with MACS managed conservatively. The adrenalectomy group experienced a statistically significant improvement in arterial hypertension as compared with the conservatively managed group (RR 11, 95% CI: 4.3-27.8). More recently, in the second metanalysis of 2023 (7), part of the recent ESE-ENSAT guidelines (1), change in arterial hypertension was assessed in 8 studies, 4 of which already included in the previous metanalysis (6), considering both 192 patients with MACS who underwent adrenalectomy and 162 patients with MACS managed conservatively (7). Similarly to the previous metanalysis (6), the adrenalectomy group experienced a statistically significant improvement in arterial hypertension as compared with the conservatively managed group (RR 8.8, 95% CI: 4.0-19.2) (7).

However, the results of both metanalyses (6, 7) are limited by several factors: the majority of the studies included were observational, either retrospective or prospective, and at risk of bias (6, 7). Many studies were characterized by small sample size and heterogeneous definitions of MACS, with different cortisol cutoffs at overnight DST, ranging from 1.8 to 5 µg/dL, variable assay methods and variable presence of further diagnostic criteria, mainly including CS features, 8 mg overnight DST, urinary cortisol and ACTH levels (6, 7). Moreover, the variable definitions of comorbidities and their improvement, as well as the unstandardized approach for conservative treatment comorbidities, ranging from pharmacotherapeutic interventions to watchful waiting, did not permit accurate estimations of the real benefits from treatments (6, 7). Lastly, many studies included in the metanalyses (6, 7) lacked a sufficient long period of follow-up for observing significant changes in the outcomes, whose assessment was not blinded in any of the studies (6, 7).

In an attempt to minimize the heterogeneity evident in the previous studies (3-7), the study reported by Tabarin and coworkers (2) showed many strengths. First, this was a multicenter, prospective, randomized, controlled study, characterized by a more rigorous methodology compared with the previous randomized controlled studies (3-5).

The definition of MACS was clearly stated and predefined in the inclusion criteria, limiting the heterogeneity of previous various definitions of MACS. Particularly, for post overnight DST cortisol levels between 1.8 and 5 µg/dL, the diagnosis of MACS was performed more rigorously, adding additional abnormalities of hypothalamic-pituitary-adrenal axis, including suppressed morning plasma ACTH (<2.2 pmol/L) or ACTH peak less than 6.6 pmol/L during a corticotrophin-releasing hormone test, midnight serum cortisol greater than 150 nmol/L, elevated late-evening salivary cortisol according to center-specific assays, and increased 24-hour urinary free cortisol not exceeding 2 times the upper limit of normal. Moreover, MACS diagnosis was evaluated 3 times: at screening, before randomization, to secure MACS persistence, and after adrenalectomy, to confirm MACS disappearance (2).

Notably, a precise assessment of blood pressure was performed using HBPM (2), a recommended tool for clinical research able to overcome the issues of the previous studies, related to office measurements and “white coat” effects (3-7). Moreover, the wash-out of previously prescribed antihypertensive drugs during the run-in phase, in patients already treated for arterial hypertension, permitted exclusion of patients displaying normal HBPM, strictly meeting the inclusion criterion of arterial hypertension (2). Lastly, a standardized stepped-care antihypertensive treatment protocol was applied, in accordance with the European Society for Hypertension recommendations (1), overcoming the lack of standardization of antihypertensive treatment protocols in the previous trials (3-7).

The study of Tabarin and coworkers (2) presented few limitations, mainly including the short follow-up period of 1 year and the potential heterogeneity in the biochemical evaluation assays related to the inclusion of 17 different centers. Therefore, further studies are needed to support the decision of performing adrenalectomy in patients with MACS and arterial hypertension, especially based on larger cohorts of patients, to strengthen the power of the analyses of the CHIRACIC study (2), on longer follow-up period, in order to better evaluate the long-term outcomes following surgery, as well on uniformity of biochemical assays to improve the quality of data.

Moreover, beyond the scope of the CHIRACIC study (2), a deeper analysis aimed at identifying predictive factors useful to clinicians whether to recommend adrenalectomy for a given patient with an incidentally discovered unilateral adrenal mass, complicated with MACS, and arterial hypertension, is needed. Therefore, future studies with this scope will allow identification of the best candidates for surgery, potentially expanding the indication for adrenalectomy also to patients suffering from MACS associated with diabetes mellitus, dyslipidemia, and obesity, confirming the benefits of adrenalectomy, beyond arterial hypertension, on the overall cardiovascular risk and life expectancy.

The authors of the CHIRACIC study (2) concluded that adrenalectomy is an effective and safe treatment for the management of arterial hypertension in patients with unilateral adrenal incidentalomas and MACS, which enables reduction or discontinuation of antihypertensive drugs.

Therefore, this study (2) provides compelling evidence that may serve as a catalyst for the future revision and expansion of current ESE-ENSAT recommendations. By demonstrating a tangible clinical benefit, namely improvement of arterial hypertension and potential cardiovascular risk reduction, following adrenalectomy in patients with MACS, these findings suggest that MACS should be more firmly recognized as a secondary and surgically approachable cause of arterial hypertension. If validated in larger, longer prospective cohort studies, these results could significantly influence clinical practice, contributing to a reduction in cardiovascular morbidity and mortality, and paving the way for more personalized, mechanism-based therapeutic strategies in endocrine arterial hypertension (2).

Lastly, it is worth noting that the number of patients diagnosed with adrenal incidentalomas and MACS continues to rise, alongside the growing availability of pharmacological agents (8). From a personalized medicine perspective, the potential role of medical therapy, aimed at lowering cortisol levels, should not be underestimated.

Although only small case series have reported the use of metyrapone, mifepristone, or osilodrostat in patients with MACS, and prospective clinical trials are still needed to assess the feasibility of long-term medical management, medical therapy may represent a promising alternative, particularly for patients with bilateral adrenal incidentalomas or when surgery is contraindicated or declined.

Abbreviations

ACTH

adrenocorticotropic hormone

CS

Cushing syndrome

DST

dexamethasone suppression test

ESE-ENSAT

European Society of Endocrinology/European Network for the Study of Adrenal Tumors

HBPM

home blood pressure measurement

ITT

intention to treat

MACS

autonomous cortisol secretion

PP

per protocol

Funding

No funding.

Author Contributions

R.P., C.S., N.D.P., and A.C. have made substantial contributions to the manuscript. R.P., C.S., and N.D.P. have been involved in the analysis and interpretation of literature, elaboration, and drafting of the manuscript. R.P. and A.C. have made substantial contributions in revising the content as well as the style and the English wording of manuscript critically. All authors read and approved the final manuscript.

Disclosures

R.P. has received research funding from Corcept Therapeutics, Neurocrine Biosciences, Recordati AG, Esteve, Spruce Bioscience and Xeris Pharmaceuticals (Strongbridge Biopharma), and has served as a consultant for Corcept Therapeutics, Crinetics Pharmaceuticals, H Lundbeck A/S and Recordati Rare Diseases, outside the submitted work. C.S. has served as a consultant for Recordati Rare Diseases and Neurocrine UK Limited, outside the submitted work. N.D.P. has nothing to disclose. A.C. has served as a consultant for Recordati Rare Diseases, outside the submitted work.