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Research Article
Originally Published 14 September 2020
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Presence of Subclinical Hypercortisolism in Clinical Aldosterone-Producing Adenomas Predicts Lower Clinical Success

Kang-Yung Peng, Hung-Wei Liao https://orcid.org/0000-0003-3090-1937, Chieh-Kai Chan, Wei-Chou Lin, Shao-Yu Yang https://orcid.org/0000-0001-9170-2566, Yao-Chou Tsai, Kuo-How Huang, Yen-Hung Lin, Jeff S Chueh https://orcid.org/0000-0002-0713-4904, and Vin-Cent Wu https://orcid.org/0000-0001-7935-0991 [email protected]Author Info & Affiliations
Hypertension
Volume 76, Number 5
https://doi.org/10.1161/HYPERTENSIONAHA.120.15328
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Graphical Abstract

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.

Introduction

Primary aldosteronism (PA) is the most common cause of secondary hypertension and is reportedly present in 5% to 10% or more of patients with hypertension.1 Despite the same degree of blood pressure elevation, patients with PA have higher cardiovascular morbidity and mortality than those without the disorder.2
KCNJ5 mutation is the most common somatic mutation identified thus far in aldosterone-producing adenomas (APAs).3 Choi et al4 discovered mutations in the KCNJ5 gene coding for G-protein–activated inward rectifier potassium channel 4 that resulted in a calcium-mediated increase in aldosterone secretion.4
A meta-analysis of 1636 patients with an APA showed that the overall prevalence of KCNJ5 mutation is 43%5: ≈30% to 40% in western countries, and 60% to 70% in Japan and Taiwan.6 Individuals with APA with KCNJ5 mutation tend to be younger and female. They also exhibit higher plasma aldosterone levels and larger tumors than those without the mutation; however, no differences were found in blood pressure or serum potassium levels.5 KCNJ5 mutations have also been found in aldosterone and cortisol coproducing adenomas (A/CPAs).7 This phenomenon raises the question of whether APAs with KCNJ5 mutation hypersecrete clinically significant amounts of glucocorticoids. Although APAs produce aldosterone, A/CPAs may be underdiagnosed in patients with clinical APA because low-dose dexamethasone suppression test (DST) is not universally recommended and utilized as a screening test for detection of subclinical hypercortisolism (SH) during PA/APA diagnosis.8
It is estimated that 5% to 21% of adrenal incidentalomas are A/CPAs.8–10 In a study of patients with PA, patients with an A/CPA with SH were older and exhibited larger tumors, higher serum potassium levels, and lower aldosterone and adrenocorticotropic hormone levels than those with pure APAs without SH.8 KCNJ5 mutation in patients with APA has been shown to be a predictor of significant postoperative improvement in blood pressure and left ventricular mass index, with less need for antihypertensive medications.11–13 However, to date, no study has investigated the postoperative outcomes and clinical characteristics in patients with clinical APA harboring KCNJ5 mutation and SH.
Here, we aimed to explore the features of patients diagnosed with clinical APA with or without SH. Additionally, we attempted to ascertain the clinical correlations of cortisol level post-DST and to analyze postoperative outcomes according to KCNJ5 mutation status in the presence or absence of SH.

Materials and Methods

The authors declare that all supporting data are available within the article and the Data Supplement.

Data Sources and Study Population

Patients aged >18 years who had undergone adrenalectomy for preoperatively diagnosed clinical APA were prospectively recruited from November 2016 to March 2018 and were followed up until May 2019. For quality affirmation, the Taiwan Primary Aldosteronism Investigators database was used to standardize data collection.6,14–17
Preoperative identification of APA, per clinical, biochemical, and image criteria according to Taiwan PA diagnosis guideline16 was referred to as clinical APA.

Measurements

Screening, confirmation, and subtype identification of PA were performed in patients with hypertension according to the standard Taiwan Primary Aldosteronism Investigators protocol and aldosteronism consensus in Taiwan.16
Despite multiple guidelines available, no agreement exists on the biochemical diagnosis of SH.18 An overnight 1 mg DST was performed for every clinical APA patient recruited; namely, 1 mg of dexamethasone was administered orally at 2300 h, and the next morning at 0800 h a fasting blood sample was taken to measure serum cortisol concentration. A screening criterion of serum cortisol >1.8 μg/dL after a 1 mg DST was used to make a tentative diagnosis of suspected SH.19 We also discussed a cutoff value of serum cortisol levels >1.5 μg/dL (1 mg DST>1.5) after an overnight 1 mg DST.

Outcome Measurements

Patients were evaluated monthly for the first 3 months postoperatively and every 3 months thereafter. The Primary Aldosteronism Surgery Outcome consensus on clinical and biochemical outcomes was applied.20

Statistical Analysis

Patients were categorized by the presence or absence of 1 mg DST>1.5 (Table 1) and by the presence of mutated or wild-type (WT) KCNJ5 (Table 2). The Fisher exact test was used for categorical variables and the Mann-Whitney U test for continuous variables. An interaction term, KCNJ5 mutation × 1 mg DST<1.5 was generated to test whether the clinical outcome of 1 mg DST<1.5 was modified by the presence of a KCNJ5 mutation.
Table 1. Baseline Characteristics of Patients With Clinical APA by Cortisol Status
CharacteristicsAPA Without 1 mg DST>1.5*APA With 1 mg DST>1.5*P Value
Case numbers, n (%)56 (68.3%)26 (31.7%) 
KCNJ5 mutation, n (%)28 (50.0%)7 (26.9%)0.06
Age, y51.8 [48.9–54.6]54.7 [50.8–58.6]0.30
Female, n (%)31 (55.4%)12 (46.2%)0.48
Body mass index, kg/m225.8 [21.9–29.3]24.1 [20.8–27.3]0.14
Duration of hypertension, y3.0 [2.0–10.0]8.0 [3.0–15.0]0.12
Systolic blood pressure, mm Hg153.5 [148.7–158.3]153.4 [144.7–162.0]0.94
Diastolic blood pressure, mm Hg92.1 [88.3–96.0]92.5 [87.3–97.8]0.82
No. of antihypertensive medications preoperatively1.8 [1.0–3.0]1.8 [1.0–3.0]0.98
Post-DST serum cortisol, μg/dL1.0 [0.9–1.2]3.5 [2.1–4.8]<0.001†
Plasma aldosterone level,‡ ng/dL39.6 [23.2–52.1]49.1 [30.8–75.2]0.06†
Plasma renin activity,‡ ng/mL per hour0.2 [0.1–0.5]0.2 [0.1–0.5]0.99†
Diabetes mellitus, n (%)9 (16.1%)3 (11.5%)0.74
Hyperlipidemia, n (%)12 (21.4%)9 (34.6%)0.28
Cerebrovascular disease, n (%)2 (3.6%)3 (11.5%)0.32
Tumor size (maximal diameter), cm1.3 [1.2–1.5]1.7 [1.4–2.0]0.02
eGFR, mL/min per 1.73 m2101.5 [94.0–109.0]94.6 [78.3–110.8]0.24
Serum potassium, mEq/L3.4 [3.3–3.6]3.5 [3.1–3.8]0.88
Postoperative outcome
 Complete clinical success, n (%)35 (62.5%)10 (38.5%)0.06
 Complete biochemistry success, n (%)43 (76.8%)19(73.1%)0.46
Data are presented as the mean [CI] for normally distributed data and median [IQR] for non-normally distributed data. APA indicates aldosterone-producing adenoma; DST, dexamethasone suppression test; eGFR, estimated Glomerular filtration rate IQR, interquartile range; and SH, subclinical hypercortisolism.
*
Serum cortisol levels >1.5 μg/dL for an overnight 1 mg DST.
†
Statistical tests were performed after log transformation for DST cortisol and plasma aldosterone and renin.
‡
Obtained after hold drug that will interfere the renin-angiotensin system.
Table 2. Baseline Clinical and Biochemical Characteristics of Patients With Aldosterone-Producing Adenomas by KCNJ5 Mutation Status
Biochemistry and Clinical DataWT KCNJ5KCNJ5-MutatedP Value
Case number, n47 (57.3%)35 (42.7%) 
Serum potassium, mmol/L3.6 [3.4–3.8]3.2 [3.0–3.4]<0.01
Plasma aldosterone level, ng/dL39.9 [27.8–60.5]42.4 [28.5–64.0]0.83*
Plasma renin activity, ng/mL per hour0.2 [0.1–0.6]0.1 [0.1–0.4]0.10*
Systolic blood pressure, mm Hg152.7 [146.7–158.6]154.5 [148.6–160.4]0.70
Diastolic blood pressure, mm Hg91.8 [87.9–95.7]92.9 [87.8–98.0]0.65
Serum cortisol after DST, μg/dL1.2 [0.9–2.7]1.0 [0.9–1.5]0.31*
1 mg DST>1.5, n (%)18 (39.1%)8 (22.2%)0.15
4 pm ACTH, μg/dL11.7 [9.3–16.3]18.8 [11.2–23.7]0.29
4 pm cortisol, μg/dL6.9 [5.1–9.0]6.0 [4.1–10.9]0.61
24-h urine cortisol, μg0.42 [0.25–0.57]0.39 [0.32–0.74]0.29
B1 H score80.4 [62.5–104.7]66.1 [21.5–92.0]0.02
B2 H score60.2 [33.1–90.3]82.1 [66.7–112.5]<0.01
Tumor size (maximal diameter), cm1.5 [1.3–1.6]1.4 [1.2–1.6]0.93
Postoperative outcome
 Complete clinical success, n (%)20 (42.6)25 (71.4)0.01
 Complete biochemistry success, n (%)33 (70.2)29 (82.9)0.21
Data are presented as the mean [CI] for normally distributed data and median [interquartile range] for non-normally distributed data. ACTH indicates adrenocorticotropic hormone; and DST, dexamethasone suppression test.
*
Statistical tests were performed after log transformation for 1 mg DST cortisol and plasma aldosterone and renin.
Multivariable regression analysis was performed to investigate the relationship between KCNJ5 mutation and 1 mg DST>1.5 (Table 3, Methods in the Data Supplement).
Table 3. Factors Associated With 1 mg DST>1.5* in Patients Who Underwent Adrenalectomy for Clinical Aldosterone-Producing Adenoma
CharacteristicsUnivariateMultivariate†
Odds Ratio (95% CI)P ValueOdds Ratio (95% CI)P Value
Gender (female)0.69 (0.27–1.76)0.438  
Age, y1.02 (0.97–1.06)0.493  
KCNJ5 (yes)0.37 (0.13–1.01)0.0530.22 [0.07–0.69]0.010
Body mass index, kg/m20.92 (0.82–1.03)0.1410.87 [0.74–0.99]0.046
Diabetes mellitus (yes)0.68 (0.17–2.76)0.591  
Systolic blood pressure, mm Hg0.99 (0.97–1.02)0.869  
Diastolic blood pressure, mm Hg1.01 (0.97–1.04)0.716  
Estimated glomerular filtration rate0.99 (0.98–1.01)0.524  
Potassium, mEq/L1.44 (0.68–3.04)0.338  
Log [Plasma aldosterone level], ng/dL154 (0.27–8.82)0.569  
Log [Plasma renin activity], ng/mL per hour0.77 (0.37–1.60)0.481  
Log aldosterone renin ratio, ng/dL per ng/mL per hour1.35 (0.68–2.70)0.393  
Tumor size, cm2.37 (1.12–5.00)0.0232.85 [1.24–6.58]0.014
Log (duration of hypertension), y2.05 (0.76–5.55)0.1583.60 [1.13–11.43]0.024
DST indicates dexamethasone suppression test.
*
Serum cortisol levels >1.5 μg/dL for an overnight 1 mg DST.
†
Adjusted with all the factors listed in Table 3.
A conditional effect plot was drawn based on the fitted results of the regression model to predict 1 mg DST>1.5. We chose the turning point with maximal the slope change of the tangent line.
A 2-sided P<0.05 was considered significant. Statistical analyses were performed using Stata 14.2 MP (Stata Corporation, College Station, TX) and R software, version 3.4.4 (Free Software Foundation, Inc, Boston, MA).
Additional detailed descriptions of materials and methods are available in the Data Supplement.

Results

Baseline Characteristics

Baseline characteristics of the 82 patients with clinical APA are summarized in Table 1 according to their serum cortisol levels after the 1 mg DST via using 1.5 μg/dL as a cutoff point. None of these patients showed any clinical signs of hypercortisolism (Table 1).
The prevalence of SH, when defined by serum cortisol level >1.8 μg/dL after 1 mg DST is 26.8% among clinical APA patients (Table S1 in the Data Supplement); while if it is defined by 1 mg DST>1.5, there is 31.7% (n=26). Tumor size was significantly larger in those with 1 mg DST>1.5 (1.7 cm [1.4–2.0]) than in those without 1 mg DST> 1.5 (1.3 cm [1.2–1.5]; P=0.02). Otherwise, no significant between-group differences were observed in baseline characteristics (Table 1).
Table 2 summarizes the clinical and biochemical parameters of patients with clinical APA based on their KCNJ5 mutation status. There were no significant differences in clinical parameters between the KCNJ5-mutated and WT KCNJ5 groups, except that serum potassium levels were lower in the former (P=0.003). No significant differences between groups regarding DST serum cortisol level were observed under crude comparison (P=0.31).

KCNJ5 Mutation Negatively Associated With 1 mg DST>1.5 in Clinical APA

Nonetheless, 1 mg DST>1.5 was negatively associated with adenoma harboring KCNJ5 mutation after adjusting for sex, age, tumor size, body mass index, and log-transformed adrenocorticotropic hormone (Table S1; Table 3). The negative association between KCNJ5 mutation and 1 mg DST>1.5 persisted even after including estimated Glomerular filtration rate and other disease variables in sensitivity analysis. In multivariate logistic regression, a significant negative association between KCNJ5 mutation and 1 mg DST>1.5 was observed after adjusting for the same confounders when body mass index was treated as a continuous variable (odds ratio, 0.37; P=0.010 [95% CI, 0.07– 0.69]). In further sensitivity analysis, we further used serum cortisol levels >1.8 μg/dL after 1 mg DST to define SH; the result was still in accordance with our main findings, showing that KCNJ5 mutation was negatively associated with SH (odds ratio, 0.23; P=0.024 [95% CI, 0.06–0.83]).

Immunohistochemistry

Figure 1A and 1B shows the H score for immunoreactivity in APA tissue. The H score for CYP11B1 was higher in the WT KCNJ5 group, whereas the H score for CYP11B2 was higher in the KCNJ5-mutated group. The representative histological images of both types are shown in Figure 1C.
Figure 1. The H score of immunoreactivity of an aldosterone-producing adenoma (APA). Immunoreactivity for CYP11B1 was more prominent in APAs with wild-type (WT) KCNJ5 rather than mutated KCNJ5 (A), whereas CYP11B2 immunoreactivity was detected more abundantly in APAs with mutated than WT KCNJ5 (B and C).

Factors Associated With 1 mg DST>1.5

A conditional effect plot of the estimated risk against tumor size or body mass index was drawn to demonstrate the probability of having subclinical cortisol excess in clinical APA patients with mutated or WT KCNJ5 (Figure 2A and 2B; P=0.015, mutated versus WT KCNJ5). Those with WT KCNJ5 had a higher probability of developing 1 mg DST>1.5 than those with mutated KCNJ5. Tumor size was positively correlated with 1 mg DST>1.5, whereas body mass index was negatively correlated with it. The turning point was defined as the maximum slope of the tangent line according to the curve. According to the turning point, the KCNJ5-mutated group had an increased risk of developing 1 mg DST>1.5 when the tumor was larger than 1.2 cm.
Figure 2. Conditional effect plots of the estimated risk of 1 mg dexamethasone suppression test (DST) >1.5 related to KCNJ5 mutation status against tumor size (A) and body mass index (B) were drawn after adjustment for age and gender. (P=0.015, mutated vs wild type KCNJ5.) According to the turning point, the KCNJ5-mutated group had an increased risk of developing 1 mg DST>1.5 when the tumor was larger than 1.2 cm. C, A generalized additive model (GAM) plot for the probability of complete clinical success after adrenalectomy based on DST serum cortisol levels. Log [cortisol]=0.176 was an independent factor predicting complete clinical success after adrenalectomy.

Cutoff Point for Serum Cortisol Level for Complete Clinical Success

Independent variables were applied to generate the generalized additive model graph (Figure 2C) in which log of the serum cortisol levels after 1 mg DST were plotted against the log of the odds of clinical failure probability (Tables 1 and 2). The cutoff value in the generalized additive model model was cortisol level=1.5 µg/dL (95% CI, 1.33–1.75 µg/dL, ie, Log [cortisol (μg/dL)]=0.176). Therefore, a biochemical test predicting lack of complete clinical success was identified as a serum cortisol >1.5 μg/dL in an overnight 1 mg DST.

One Milligram DST>1.5 and Complete Clinical Success

The percentage of patients with postoperative complete clinical success was highest (78.6%) among those with mutated KCNJ5 and without 1 mg DST>1.5, followed by those who had neither KCNJ5 mutation nor 1 mg DST>1.5 (46.4%; Table 4; Tables S2 through S4). Patients with WT KCNJ5 and 1 mg DST>1.5 exhibited the lowest success rate (36.8%), followed by those with mutated KCNJ5 and with 1 mg DST>1.5 (42.9%). In multivariable logistic regression, patients with 1 mg DST>1.5 were associated with a significant noncomplete success after adrenalectomy (odds ratio, 6.72 [95% CI, 1.61–28.0], P=0.01); when the cutoff value of cortisol level defining SH was defined by 1.8 μg/dL after 1 mg DST, its association with a lower possibility of clinical success became insignificant (P=0.144). There was no significant interaction between KCNJ5 mutation status and SH in terms of clinical success (P=0.46). Moreover, there was no significant between-group difference regarding the biochemistry profiles.
Table 4. Factors Associated With Noncomplete Clinical Success in Patients Who Underwent Adrenalectomy for Clinical Aldosterone-Producing Adenoma
CharacteristicsUnivariateMultivariate*
Odds Ratio (95% CI)P ValueOdds Ratio (95% CI)P Value
Gender (female)0.34 (0.14–0.83)0.018  
Age, year1.02 (0.98–1.06)0.396  
KCNJ5 (yes)0.30 (0.12–0.75)0.0110.30 [0.09–0.97]0.044
1 mg DST>1.5 (yes)†2.67 (1.02–6.95)0.0456.72 [1.61–28.0]0.009
Log (body mass index), kg/m21.17 (1.04–1.31)0.0081.18 [1.01–1.37]0.032
Cardiovascular disease (yes)1.23 (0.17–9.17)0.841  
Diabetes mellitus (yes)1.87 (0.54–6.46)0.324  
Systolic blood pressure, mm Hg1.05 (1.02–1.08)0.0011.06 [1.02–1.10]0.002
Diastolic blood pressure, mm Hg1.05 (1.01–1.09)0.720  
Estimated glomerular filtration rate0.98 (0.96–0.99)0.004  
Potassium, mEq/L0.98 (0.49–1.95)0.953  
Log [Plasma aldosterone level], ng/dL0.69 (0.19–2.50)0.569  
Log [Plasma renin activity], ng/mL per hour0.84 (0.42–1.68)0.616  
Log aldosterone renin ratio, ng/dL per ng/mL per hour1.53 (0.30–7.76)0.608  
Tumor size, cm0.57 (0.28–1.17)0.1230.35 [0.12–1.00]0.05
Log (duration of hypertension), y2.54 (0.99–6.55)0.053  
1 mg DST>1.5 × KCNJ5 (yes)1.70 (0.36–8.12)0.508  
DST indicates dexamethasone suppression test.
*
Adjusted with all the factors listed in Table 4.
†Serum cortisol levels >1.5 μg/dL for an overnight 1 mg DST.

Postadrenalectomy 1 mg DST Cortisol Levels Follow-Up

We also reviewed our results of repeating 1 mg DST in some of those clinical APA patients with SH after their adrenalectomy. We identified 14 among those 26 patients who had their preadrenalectomy 1 mg DST cortisol >1.5 μg/dL, and who had 1 mg DST tested and data available at 6 months after surgery—none had serum cortisol level >1.5 μg/dL.

Discussion

SH, defined as cortisol >1.8 μg/dL after DST, was detected in more than a quarter of the clinical APA patients. KCNJ5-mutated clinical APAs showed higher degree of immunoreactivity for CYP11B2, whereas CYP11B1 immunostaining activity is higher in WT KCNJ5 APAs. Our results demonstrate that patients with clinical APA with mutated KCNJ5 had a lower prevalence of 1 mg DST>1.5 than those with WT KCNJ5. Notably, tumor size was positively associated with 1 mg DST>1.5, with the tumor being significantly larger in the presence of 1 mg DST>1.5 without KCNJ5 mutation. Individuals with clinical APA and 1 mg DST>1.5 had a lower chance of blood pressure normalization after adrenalectomy. We further validated 1 mg DST>1.5 as the optimal cutoff value to predict complete clinical success according to a generalized additive model plot, where the log odds for the outcome equaled zero.
The exact prevalence and clinicopathological features of A/CPAs remain to be elucidated. In our cohort of clinical APA patients who underwent adrenalectomy, the prevalence of SH was 26.8% when the cutoff value of cortisol after 1 mg DST was set at 1.8, and 31.7% when 1 mg DST>1.5. In Japan, the prevalence of SH has been reported to be 20% to 30% in patients with PA,8,21 which is higher than that reported in Greece (12.1%).10 Our findings further showed that in the presence of mutated KCNJ5, clinical APAs larger than 1.2 cm on computed tomography scan are more likely to be associated with 1 mg DST>1.5. Consistent with our findings, previous studies have reported that an APA usually appears as a small nodule, <2 cm in diameter on computed tomography, whereas a larger, benign-appearing unilateral mass could indicate an A/CPA.8,22
We showed that the prevalence of KCNJ5 mutations was 30.8% among patients with a clinical APA and 1 mg DST>1.5. KCNJ5 mutations have been detected in a small number of reported cases of cortisol-producing adenomas.7,23 Our result showed that KCNJ5 mutation is significantly less associated with SH in clinical APA patients. Regarding immunohistochemistry, APAs with KCNJ5 mutations exhibited lower CYP11B1 expression. KCNJ5-mutated APAs display a zona fasciculata-like phenotype.24 Therefore, we hypothesized that in the adrenal glands of patients with an APA, cortisol synthesis in the normal zona fasciculata is impaired due to the presence of prominent zona fasciculata-like cells in KCNJ5-mutated APAs. Alternatively, KCNJ5-mutated APAs could be secondary to an increasing need for converting circulating cortisol to 18-oxocortisol. Increased synthesis of 18-oxocortisol could potentially decrease circulating cortisol levels. 18-oxocortisol is a hybrid steroid that structurally resembles both glucocorticoid and mineralocorticoid; it is usually converted from circulating cortisol by aldosterone synthase (CYP11B2) in the zona glomerulosa of a normal adrenal gland.25 However, peripheral levels of 18-oxocortisol are significantly correlated with circulating aldosterone rather than its normal precursor, circulating cortisol.26 Enhanced 18-oxocortisol synthesis was found in APAs with mutated KCNJ5 rather than with WT KCNJ5.24 Thus, clinical APAs with KCNJ5 mutation are less likely to be associated with biochemical hypercortisolism.
In adenomas with WT KCNJ5, APA-like lesions may arise from aldosterone-producing cell clusters and diffuse cortisol production may occur in the peripheral zona fasciculata area or in the possible aldosterone-producing cell cluster-to-APA transitional lesions, a continuous streak of transitional APA.27 Aldosterone-producing cell clusters are often heterogeneous, with zona glomerulosa cells intermingled with zona fasciculata cells expressing CYP11B1.28 CYP11B1/CYP17 and CYP11B2/CYP17 hybrid cells expressed in APAs have been suggested to synthesize cortisol.29 Further testing of the renin-angiotensin system and adrenocorticotropic hormone pathways are mandated to clarify this issue.

Tumor Size and SH

A/CPAs may be underdiagnosed because a DST to screen for SH is not routinely performed in patients with a clinical APA according to current various PA diagnosis guidelines.8 Depending on the size of the lesion and the status of APA-associated mutations, adenoma may be associated with SH. We found that 1 mg DST>1.5 is more likely to be present in patients with a WT KCNJ5 adenoma with tumor size >1.2 cm. It is possible that a heterogeneous steroid localization pattern appears in large clinical APAs even with mutated KCNJ5. This might be attributed to the impairment of steroidogenic enzymes and a shortage in precursor steroids in adenomatous cells.27

Postoperative Outcomes

Several factors could contribute to the partial success or failure after adrenalectomy for APA. The presence of KCNJ5 mutation, which increases serum aldosterone levels, has been reported to be a positive predictor of significant postoperative improvement in blood pressure with less need for antihypertensive medications.11–13 In our study, those individuals with a KCNJ5 mutation but without 1 mg DST>1.5 constituted the highest proportion (78.6%) that achieved clinical success postoperatively. Those with the lowest clinical success rate were clinical APA patients with 1 mg DST>1.5 with or without KCNJ5 mutation. The presence of 1 mg DST>1.5 may thus be a predictor of low clinical success rate. Nevertheless, altogether 45/82 (54.8%) of our all clinical APA patients were able to achieve clinical success; better than the 37% reported in an international cohort of patients who underwent unilateral adrenalectomy for PA/clinical APA.20
Postoperative adrenal insufficiency after an adrenalectomy for a clinical APA is possible and should be monitored for, as some patients may require glucocorticoid replacement despite the absence of preoperative overt hypercortisolism. Therefore, testing for biochemical evidence of clinical and SH in patients with PA should be performed preoperatively because of possible postoperative adrenal insufficiency.
Since our study deals with subtle cortisol autonomous secretion, the information after surgery is important to validate significance of the results.

Limitations

This study has several limitations. First, the sample size was relatively small and does not allow for a firm conclusion. Second, there has been lack of uniformity in cutoff values in the diagnostic protocols for SH. The American Endocrine Society proposed to use a serum cortisol level of ≥1.8 μg/dL in a 1 mg DST30 but controversies remain.18 Using a cutoff of 1.5 μg/dL for DST cortisol, we increased the sensitivity of detecting SH but euthanized some specificity. Although 1 mg DST>1.5 was fairly well-validated to be correlated with the outcomes in this clinical APA cohort, it may not necessarily be extrapolated to other clinical scenarios. Finally, the decision criteria for lateralization on AVS needs further verification since currently there is no established consensus when SH is present.

Perspectives

SH could be found in a quarter to 30% of patients with clinical APAs, depending on the cutoff criteria. Presence of SH based on cortisol level >1.5 μg/dL after a 1 mg DST may be linked to lower postoperative clinical success rate. Therefore, the consensus is needed to define SH in APA, as the guidelines differ on this topic. We demonstrated that in clinical APA patients, cortisol level >1.5 μg/dL after an overnight 1 mg DST is significantly correlated to various clinical outcomes.
There is disagreement regarding the best cutoff for cortisol level after DST because the definition of SH, especially in PA, is a very weak clinical criterion.31 An even higher variability in sensitivity and specificity was observed for cortisol after DST, when different cutoffs were set in a previous report 32.
Our IHC staining study showed that our clinical APA patients included a subgroup of patients with eventual negative or light CYP11B2 staining in adenomas (yet revealing positive staining for CYP11B1 and CYP17A1), together with subcapsular positive CYP11B2-staining aldosterone-producing cell clusters (Figure S2). Therefore, clinical APAs (per clinical, biochemical, and image criteria) include more heterogeneity than histological APAs under current various PA diagnosis guidelines.

Acknowledgments

We greatly appreciate technical support from the Second Core Lab in National Taiwan University Hospital for technical assistance. We also greatly appreciate English editing from Mr Eric B Chueh of Case Western Reserve University.

Novelty and Significance

What Is New?

•
Clinical aldosterone-producing adenomas (APA) patients with mutated KCNJ5 have a lower prevalence of subclinical hypercortisolism than those with wild-type KCNJ5.
•
Clinical APA patients with serum cortisol <1.5 µg/dL after 1 mg dexamethasone suppression test together with mutated KCNJ5) are associated with a better clinical success rate after adrenalectomy.

What Is Relevant?

•
KCNJ5 mutation and body mass index are inversely associated with subclinical hypercortisolism.
•
Among KCNJ5-mutated clinical APAs, subclinical hypercortisolism is more likely to be present when tumor size >1.2 cm.
•
KCNJ5-mutated clinical APAs show higher degree of immunoreactivity for CYP11B2, whereas CYP11B1 activity is higher in wild-type KCNJ5 APAs.

Summary

One milligram dexamethasone suppression test >1.5 is common in clinical APA patients without a KCNJ5 mutation or with a relatively larger adrenal tumor. The presence of 1 mg dexamethasone suppression test >1.5 may be linked to a lower clinical complete success rate.

Supplemental Material

File (hyp_hype202015328d_supp2.docx)
File (hyp_hype202015328d_supp2.pdf)

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Go to Hypertension
Go to Hypertension
Hypertension
Volume 76 • Number 5 • November 2020
Pages: 1537 - 1544
PubMed: 32921192

Copyright

© 2020 American Heart Association, Inc.

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History

Received: 21 April 2020
Revision received: 10 May 2020
Accepted: 16 August 2020
Published online: 14 September 2020
Published in print: November 2020

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Keywords

  1. aldosterone
  2. glucocorticoids
  3. hyperaldosteronism
  4. mineralocorticoids
  5. potassium channels

Subjects

  1. Hypertension
  2. Omics

Authors

Affiliations

Kang-Yung Peng*
From the Departments of Internal Medicine (K.-Y.P., S.-Y.Y., Y.-H.L., V.-C.W.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei
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Hung-Wei Liao https://orcid.org/0000-0003-3090-1937
Chinru Clinic, Taipei, Taiwan (H.-W.L.)
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Chieh-Kai Chan
Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu County (C.-K.C.)
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Wei-Chou Lin
Department of Pathology (W.-C.L.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei
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Shao-Yu Yang https://orcid.org/0000-0001-9170-2566
From the Departments of Internal Medicine (K.-Y.P., S.-Y.Y., Y.-H.L., V.-C.W.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei
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Yao-Chou Tsai
Department of Urology, Taipei Medical University Hospital, Taipei Medical University, Taiwan (Y.-C.T.)
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Kuo-How Huang
Department of Urology (K.-H.H.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei
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Yen-Hung Lin*
From the Departments of Internal Medicine (K.-Y.P., S.-Y.Y., Y.-H.L., V.-C.W.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei
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Jeff S Chueh https://orcid.org/0000-0002-0713-4904
Glickman Urological and Kidney Institute, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, OH (J.S.C.).
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Vin-Cent Wu* https://orcid.org/0000-0001-7935-0991 [email protected]
From the Departments of Internal Medicine (K.-Y.P., S.-Y.Y., Y.-H.L., V.-C.W.), National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei
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Notes

*
TAIPAI, Taiwan Primary Aldosteronism Investigation (TAIPAI) Study Group, Taipei, Taiwan.
The Data Supplement is available with this article at Supplemental Material.
Correspondence to Vin-Cent Wu, Department of Internal Medicine, National Taiwan University Hospital, Room 1555, Clinical Research Bldg, 7 Chung-Shan S Rd, Taipei 100, Taiwan. Email [email protected]

Disclosures

None.

Sources of Funding

This study was supported by grants from the Taiwan National Science Council (MOST 106-2314-B-002-166-MY3, 107-2314-B-002-026-MY3, 106-2321-B-182-002) and National Taiwan University Hospital (105-S3061, 107-S3809, UN103-082, UN106-014, 105-P05, 106-P02, 107-T02,107-A141).

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