Presence of Subclinical Hypercortisolism in Clinical Aldosterone-Producing Adenomas Predicts Lower Clinical Success

Abstract

The clinical characteristics and outcomes in patients with clinical aldosterone-producing adenomas harboring KCNJ5 mutations with or without subclinical hypercortisolism remain unclear. This prospective study is aimed at determining factors associated with subclinical hypercortisolism in patients with clinical aldosterone-producing adenomas. Totally, 82 patients were recruited from November 2016 to March 2018 and underwent unilateral laparoscopic adrenalectomy with at least a 12-month follow-up postoperatively. Standard subclinical hypercortisolism (defined as cortisol >1.8 μg/dL after 1 mg dexamethasone suppression test [DST]) was detected in 22 (26.8%) of the 82 patients. Intriguingly, a generalized additive model identified the clinical aldosterone-producing adenoma patients with 1 mg DST>1.5 μg/dL had significantly larger tumors ( P =0.02) than those with 1 mg DST<1.5 μg/dL. Multivariable logistic regression showed that the presence of KCNJ5 mutations (odds ratio, 0.22, P =0.010) and body mass index (odds ratio, 0.87, P =0.046) were negatively associated with 1 mg DST>1.5 μg/dL, whereas tumor size was positively associated with it (odds ratio, 2.85, P =0.014). Immunohistochemistry revealed a higher degree of immunoreactivity for CYP11B1 in adenomas with wild-type KCNJ5 ( P =0.018), whereas CYP11B2 was more commonly detected in adenomas with KCNJ5 mutation ( P =0.007). Patients with wild-type KCNJ5 and 1 mg DST>1.5 μg/dL exhibited the lowest complete clinical success rate (36.8%) after adrenalectomy. In conclusion, subclinical hypercortisolism is common in clinical aldosterone-producing adenoma patients without KCNJ5 mutation or with a relatively larger adrenal tumor. The presence of serum cortisol levels >1.5 μg/dL after 1 mg DST may be linked to a lower clinical complete success rate.

Cortisol Co-Secretion and Clinical Usefulness of ACTH Stimulation Test in Primary Aldosteronism: A Systematic Review and Biases in Epidemiological Studies

“…Lastly, some studies have investigated the genetic mutation of APA with cortisol cosecretion. A recent study based on a Taiwanese database showed that the presence of KCNJ5 mutations was significantly lower among APA patients with subclinical hypercortisolemia than those without ( 15 ). Their immunohistochemistry analysis revealed the lower CYP11B1 expression among KCNJ5 mutated APAs, which generally display a ZF-like phenotype ( 43 ).…”

“…We restricted studies to those with a sample size ≥10 (to avoid case reports) and written in English. Flow of studies through review and summary of the identified 16 studies are shown in Figure 1A and Table 1 (6,(10)(11)(12)(13)(14)(15)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”

“…In 2009, Piaditis et al reported 12.1% of patients with adrenal incidentalomas had PA with hypercortisolemia (36). Since then, several studies from the Asian cohort have reported a 5%-27% prevalence of subclinical hypercortisolemia among patients with PA or APA (11)(12)(13)(14)(15). A recent multicenter cohort study in Germany showed even 77.6% of subclinical hypercortisolemia among 161 patients with PA (10).…”

“…A recent study using a mass spectrometrybased analysis in Europe showed that cortisol cosecretion in PA was associated with adverse metabolic risk factors (6), indicating the role of glucocorticoid on an increased risk of metabolic disorders among patients with PA (7)(8)(9)(10)(11). Moreover, while the actual prevalence of this phenotype is not clear, some studies have suggested a relatively high prevalence of PA with hypercortisolism than expected (6,(10)(11)(12)(13)(14)(15). Therefore, it is imperative to understand the current state of knowledge about cortisol cosecretion in PA, and consider whether the evaluation of cortisol excess needs be recommended in general PA screening or not.…”

MANAGEMENT OF ENDOCRINE DISEASE: The role of surgical adrenalectomy in primary aldosteronism

“…The longstanding dogma for targeted therapy for primary aldosteronism has been to pursue curative adrenalectomy for unilateral primary aldosteronism and to prescribe lifelong MR antagonist therapy for bilateral primary aldosteronism (2). It should be noted, that in addition to resolving aldosterone excess, surgical adrenalectomy for primary aldosteronism has the additional advantage of potentially resolving the cortisol excess that is now recognized as a prevalent, and potentially clinically relevant, risk factor (27,46,47,48,49). Below, we discuss the indications and ramifications of surgical adrenalectomy for unilateral, and bilateral, primary aldosteronism, and how these compare to medical therapy.…”