Rare Challenges in Diagnosing Cushing’s Syndrome and Primary Aldosteronism: A Case Report of a Female With a Negative Workup

Posted on September 18, 2023 by MaryO

Abstract

Cushing’s syndrome with concurrent primary aldosteronism (PA) is a rare presentation, and establishing an early diagnosis is imperative to preventing morbidity and long-term sequelae. The diagnosis is established by sequential lab work, showing an elevated cortisol and aldosterone level.

Taking the above into consideration, it is evident that repeatedly negative results on all three tests can present an extremely challenging case. In this report, we discuss a female who presented with an adrenal incidentaloma and features suggestive of primary hyperaldosteronism as well as Cushing’s syndrome but no elevations in serum, urine, or salivary cortisol.

In this study, we present a 37-year-old female with resistant hypertension and tachycardia. She had several features suggestive of Cushing’s syndrome including resistant hypertension, proximal muscle weakness, weight gain, easy bruising, hair loss, and a history of tachycardia and chest pain. Examination revealed an obese female with thin silvery abdominal striae. The patient’s labs revealed normal serum cortisol, urine-free cortisol (UFC), late-night salivary cortisol, and a normal dexamethasone suppression test. An abdominal computed tomography (CT) scan revealed a right adrenal mass measuring 2.1 x 1.5 x 2.5 cm. Due to a high index of suspicion, adrenal venous sampling was performed, which revealed high levels of cortisol and aldosterone in the right vein, confirming the diagnosis. The patient subsequently underwent a right adrenalectomy. She developed hypotension post-op, leading to the diagnosis of glucocorticoid-remediable aldosteronism.

Introduction

Primary aldosteronism (PA) is the excess production of aldosterone by the adrenal glands, despite a low serum renin level. The presentation of hyperaldosteronism can be vague and include symptoms such as muscle weakness, fatigue, headaches, numbness, and cramps. More specific findings include resistant hypertension, low serum potassium, and metabolic alkalosis. The etiologies are variable and can include an adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia [1].

Cushing’s syndrome is also caused by excess hormone secretion by the adrenal glands. The etiologies include a primary adrenal adenoma, hyperplasia, carcinoma, or exogenous corticosteroid use. It can also be caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma or as a result of paraneoplastic ACTH secretion. The clinical presentation is highly variable and leads to difficulties in establishing a diagnosis.

The concurrent existence of primary hyperaldosteronism and Cushing’s syndrome creates additional hindrances in diagnosis, yet further obscured in a patient with a repeatedly negative workup for both conditions.

Case Presentation

A 37-year-old female presented to her primary care physician with complaints of proximal muscle weakness, tachycardia, and chest pain. Repeated blood pressure readings revealed that she was hypertensive, and she was started on amlodipine and benazepril, which elevated her blood pressure further. A computed tomography (CT) scan (Figure 1) of the abdomen was performed due to resistant hypertension, which revealed an adrenal incidentaloma (right adrenal gland measuring 2.1 x 1.5 x 2.5 cm). Precontract density was 5 Hounsfield units, and a 15-minute delayed washout showed 11 Hounsfield units for a 72% washout. She was thus referred to endocrinology.

Abdominal-CT-scan-showing-a-nodule-in-the-right-adrenal-gland-measuring-2.1-x-1.5-x-2.5-cm
Figure 1: Abdominal CT scan showing a nodule in the right adrenal gland measuring 2.1 x 1.5 x 2.5 cm

She presented to the endocrinology clinic on March 12, 2021. A thorough physical examination was performed, which revealed a well-appearing obese female (BMI of 38.86 kg/m2) with no acute distress. Her blood pressure was 144/108 mmHg, her pulse was 95, and she was afebrile. Thin silvery striations were present on the abdomen, and alopecia was present on the crown. A review of all other systems was unremarkable. A detailed family history revealed early-onset hypertension in her brother (age: 35 years) and her mother (age: 30 years). Personal history included elevated anxiety, weight gain, headaches (frontal band distribution), increased thirst, easy bruising as well as delayed clearance of bruises, and proximal muscle weakness presenting as difficulty in climbing stairs and inability to lift heavy objects. She reported no change in menstrual cycles. There was no history of exogenous corticosteroid use.

Serum biochemistries were sent (Table 1), which showed normal levels of thyroid stimulating hormone (TSH), creatinine, liver function tests, and serum electrolytes. However, mildly elevated aldosterone (23 ng/dl), mild hypokalemia (3.3 mEq/L), and suppressed ACTH and dehydroepiandrosterone (DHEA) sulfate were discovered. The aldosterone to renin ratio was also elevated at 59.9 on spironolactone and was 71.4 three months later when spironolactone was discontinued. These findings lead to a preliminary diagnosis of primary hyperaldosteronism.

Test Result
Calcium 9.1 mmol/L
Sodium 137 mmol/L
Potassium 4.1 mmol/L
Chloride 106 mmol/L
CO2 27
BUN 15 mmol/L
Glucose 95 mmol/L
Creatinine 1.1 μmol/L
AST 24 U/L
ALT 20 U/L
Albumin 4.4 g/L
Total protein 7.0 g/L
Total bilirubin 0.4 μmol/L
Alkaline phosphatase 40 U/L
Renin 0.44
Table 1: Patient serum biochemistries

BUN: Blood urea nitrogen; AST: Aspartate transaminase; ALT: Alanine transaminase.

A workup for elevated cortisol was also performed as the patient was phenotypically Cushingoid, and the following biochemistries were sent sequentially: serum cortisol, 24-hour urine-free cortisol (UFC), salivary cortisol, and a low-dose dexamethasone suppression test (Table 2). The bloodwork was hence nonconfirmatory.

Endocrine workup
Serum cortisol 4.5 mcg/dL
Urine-free cortisol 1.57 g/24 h
Salivary cortisol <0.03 μg/dL
Dexamethasone suppression test 1.5 mcg/dL
Aldosterone <4.0
Table 2: Patient follow-up bloodwork

Despite a repeatedly negative workup for Cushing’s syndrome, adrenal venous sampling was performed due to a high index of suspicion. The results revealed an inferior vena cava (IVC) cortisol of 20, left adrenal venous (LAV) cortisol of 81, and right adrenal vein (RAV) cortisol of 1280. The results of the IVC aldosterone were 24, LAV aldosterone was 660 and RAV aldosterone was 1500. The elevated levels of cortisol in the RAV were in complete contradiction to the aforementioned workup. A diagnosis of Cushing’s syndrome and concurrent PA was determined.

Adrenal veinous sampling was instrumental in establishing the diagnosis but was equivocal and did not lateralize aldosterone and cortisol excess. However, the amount of aldosterone and cortisol were both significantly higher on the right side. After a panel discussion with doctors from several disciplines, a laparoscopic adrenalectomy was planned. The procedure was successful, and the patient was initially showing clinical improvement. The specimen was sent for pathological evaluation and revealed an adrenal cortical adenoma.

After initial improvement, the patient developed hypotension, which was likely due to adrenal insufficiency. The patient was supplemented with 1-mg dexamethasone tablets, which stabilized her condition, and a diagnosis of glucocorticoid-remediable-aldosteronism was made.

Based on a strong family history of early onset-resistant hypertension, a genetic component was suspected. Several genes associated with PA with autosomal dominant inheritance have been identified [2], such as CYP11B2, CLCN2, KCNJ5, CACNA1D, and CACNA1H. The patient was offered genetic testing but was unable to follow through due to financial reasons.

Discussion

This patient presented as an extremely rare example of PA and Cushing’s syndrome, with negative serum cortisol, 24-hour UFC, late-night salivary cortisol, and a dexamethasone suppression test. Despite repeatedly negative lab results, the patient presented with a markedly elevated cortisol on adrenal venous sampling. In our literature search, we found an instance of a patient with several negative UFCs [3]; however, to the best of our knowledge, there have been no reported instances of a completely negative workup in a patient who is positive for Cushing’s syndrome. In fact, in the practice guidelines published by the Journal of Clinical Endocrinology & Metabolism [4], it is recommended that patients with a suspected diagnosis of Cushing’s syndrome or an adrenal incidentaloma and two concordant negative test results need not undergo further investigations.

One proposed mechanism for the misleading workup could be assay interference. Interference occurs when a substance or process falsely alters an assay result [5]. This can lead to incorrect diagnosis and subsequent treatment and poses a threat to the patient. Another suggested mechanism causing false negative test results could be the hook effect [6]. The hook effect is described as a phenomenon that leads to falsely low results due to the presence of excessive analyte.

In a study by Friedman et al. [7], it was noted that patients with “episodic Cushing’s syndrome” or those with mild symptoms had a negative workup. The study recommended serial monitoring for the disease. The interesting fact is that our patient had several features suggestive of active Cushing’s syndrome, and the hypotension seen postoperatively was a testament to the fact that there was in fact a cortisol excess, which led to adrenal insufficiency. In light of the above, a consistently negative workup is perplexing.

Zhang et al. suggested performing a low-dose dexamethasone suppression test in individuals presenting with PA, prior to adrenal vein sampling (AVS) and surgery due to the high prevalence of Cushing’s syndrome in patients with PA [8]. A positive test result can lead to a straightforward diagnosis; however, in this rare case where the patient had severe negative tests, it can present as a challenge in diagnosis and treatment.

Conclusions

The presence of PA and concurrent Cushing’s syndrome can present as a diagnostic challenge. It is recommended to follow up on the signs of Cushing’s syndrome with preliminary tests and to presume its absence if two concordant tests are negative. Our patient, however, was an exceptional case.

This case highlighted the importance of maintaining a high index of suspicion for patients presenting with several signs and symptoms of the disease and a negative workup. More attention should be paid to the patient’s history, and a thorough physical examination should be conducted. In those with an uncertain diagnosis, adrenal venous sampling can provide a clearer picture and lead to a more accurate understanding of the case.

References

  1. Reincke M, Bancos I, Mulatero P, Scholl UI, Stowasser M, Williams TA: Diagnosis and treatment of primary aldosteronism. Lancet Diabetes Endocrinol. 2021, 9:876-92. 10.1016/S2213-8587(21)00210-2
  2. Dutta RK, Söderkvist P, Gimm O: Genetics of primary hyperaldosteronism. Endocr Relat Cancer. 2016, 23:R437-54. 10.1530/ERC-16-0055
  3. Moloney KJ, Mercado JU, Ludlam WH, Broyles FE: Diagnosis of Cushing’s disease in a patient with consistently normal urinary free cortisol levels: a case report. Clin Case Rep. 2016, 4:1181-3. 10.1002/ccr3.647
  4. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-40. 10.1210/jc.2008-0125
  5. Dimeski G: Interference testing. Clin Biochem Rev. 2008, 29:S43-8.
  6. The hook effect. (2014). Accessed: June 19, 2023: https://www.aacc.org/science-and-research/clinical-chemistry-trainee-council/trainee-council-in-english/pearls-of-lab….
  7. Friedman TC, Ghods DE, Shahinian HK, et al.: High prevalence of normal tests assessing hypercortisolism in subjects with mild and episodic Cushing’s syndrome suggests that the paradigm for diagnosis and exclusion of Cushing’s syndrome requires multiple testing. Horm Metab Res. 2010, 42:874-81. 10.1055/s-0030-1263128
  8. Zhang Y, Tan J, Yang Q, et al.: Primary aldosteronism concurrent with subclinical Cushing’s syndrome: a case report and review of the literature. J Med Case Rep. 2020, 14:32. 10.1186/s13256-020-2353-8

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Clinical Characterization of Patients With Primary Aldosteronism Plus Subclinical Cushing’s Syndrome

Posted on February 8, 2020 by MaryO

 

Published: 

BMC Endocrine Disorders volume 20, Article number: 9 (2020)

Abstract

Background

Primary aldosteronism (PA) plus subclinical Cushing’s syndrome (SCS), PASCS, has occasionally been reported. We aimed to clinically characterize patients with PASCS who are poorly profiled.

Methods

A population-based, retrospective, single-center, observational study was conducted in 71 patients (age, 58.2 ± 11.2 years; 24 males and 47 females) who developed PA (n = 45), SCS (n = 12), or PASCS (n = 14). The main outcome measures were the proportion of patients with diabetes mellitus (DM), serum potassium concentration, and maximum tumor diameter (MTD) on the computed tomography (CT) scans.

Results

The proportion of DM patients was significantly greater in the PASCS group than in the PA group (50.0% vs. 13.9%, p <  0.05), without a significant difference between the PASCS and SCS groups. Serum potassium concentration was significantly lower in the PASCS group than in the SCS group (3.2 ± 0.8 mEq/L vs. 4.0 ± 0.5 mEq/L; p <  0.01), without a significant difference between the PASCS and PA groups. Among the 3 study groups of patients who had a unilateral adrenal tumor, MTD was significantly greater in the PASCS group than in the PA group (2.7 ± 0.1 cm vs. 1.4 ± 0.1 cm; p <  0.001), without a significant difference between the PASCS and SCS groups.

Conclusions

Any reference criteria were not obtained that surely distinguish patients with PASCS from those with PA or SCS. However, clinicians should suspect the presence of concurrent SCS in patients with PA when detecting a relatively large adrenal tumor on the CT scans.

Peer Review reports

Background

Primary aldosteronism (PA), an adrenocortical disorder caused by an adrenal tumor that overproduces aldosterone, accounts for 5 to 15% of patients with hypertension [1]. Cushing’s syndrome (CS), an endocrinopathy resulting from the prolonged, excessive adrenocortical secretion of cortisol, falls roughly into the following 2 categories: adrenocorticotropic hormone (ACTH)-dependent CS and ACTH-independent CS; the former includes Cushing’s disease that is primarily caused by a pituitary ACTH-secreting tumor and ectopic ACTH syndrome resulting from extrapituitary ACTH-secreting tumors (eg, bronchial carcinoid) [2], while the latter is usually caused by unilateral adenomas or carcinomas that provoke the autonomous adrenal cortical secretion [3]. Subclinical Cushing’s syndrome (SCS), an ill-defined endocrine disorder leading to the ACTH-independent secretion of cortisol from an adrenal adenoma that is not fully restrained by pituitary feedback [4], is known to cause hypertension, glucose intolerance, and dyslipidemia [5].

The concurrence of clinically overt hyperaldosteronism and subclinical hypercortisolism is rare in PA patients [6]. To date, a few number of studies have examined the clinicopathological features of patients with PA plus SCS (PASCS), the incidences of which have ranged between about 10 and 20% [7, 8]. Lower plasma ACTH levels and a greater tumor size were found in patients with PASCS than in patients with PA alone [8]. In the clinical settings, we rarely encounter PASCS patients who show a small adrenal tumor on the computed tomography (CT) scans and/or do not have a low plasma ACTH level in blood samples collected in the early morning. To examine the clinical features of PASCS patients in the present study, we compared clinical, laboratory, and imaging characteristics among patients with PA, SCS, or PASCS.

Methods

Patients

We conducted a population-based, retrospective, single-center, observational study in 187 patients (119 with PA, 54 with SCS, and 14 with PASCS) at Saitama Medical University Hospital, Saitama, Japan, between January 1999 and December 2016. Hypertensive patients with suspected PA or SCS, as well as normotensive or hypertensive patients with an adrenal incidentaloma were referred to our hospital. A total of 116 patients were excluded from the study: 31 who were diagnosed with PA or SCS only because tests required to definitely diagnose these endocrinopathies were not conducted; 61 who failed to meet the new Japanese diagnostic criteria of SCS [9]; 1 who failed to meet the new Korean diagnostic criteria of subclinical hypercortisolism [10]; and 23 who failed to meet the Japanese [11] and United States [12] diagnostic criteria of PA. Therefore, we investigated 71 patients who were definitely diagnosed with PA and/or SCS (45 with PA, 12 with SCS, and 14 with PASCS). This study was approved by the institutional review board of Saitama Medical University. Patients provided written informed consent to the use of their clinical and laboratory data in the study.

Diagnosis of PA and SCS

Hormones required for the diagnosis of PA and SCS were assayed according to the procedures described in the pertinent guidelines [9, 11]. Serum cortisol and plasma ACTH levels were determined by electrochemiluminescence immunoassay, plasma aldosterone concentration (PAC) and plasma renin activity (PRA) by radioimmunoassay, and serum dehydroepiandrosterone sulfate (DHEAS) level by chemiluminescent enzyme immunoassay (SRL Inc., Tokyo, Japan). Blood samples were collected in the early morning (7 a.m. to 9 a.m.). PA was suspected when detecting elevated PAC (≥ 150 pg/mL), low PRA (≤ 1.0 ng/mL/hr), and/or the elevated aldosterone-to-renin ratio (> 200). We conducted the following 3 challenge tests in accordance with the Japanese guidelines of PA [11]: captopril challenge test, furosemide upright posture challenge test, and ACTH challenge test. PA was diagnosed when at least 1 of these 3 challenge tests afforded results compatible with the disease. Furthermore, we also referred to the American guideline of PA [12] for selecting only patients who met the diagnostic criteria for PA. Prior to the confirmatory tests, patients had not received any antihypertensive drugs for at least 2 weeks except for those with severe hypertension treated with calcium-channel blockers and/or α-blockers. Adrenal venous sampling (AVS), whose usefulness was well documented in the Japanese and United States guidelines [11,12,13], was conducted in all of patients who had PA or PASCS to make the differential diagnosis of uni- or bilateral aldosterone hypersecretion.

The low-dose (1-mg) dexamethasone suppression test (DST) and the corticotropin-releasing hormone (CRH) challenge test were conducted, and the diurnal rhythms of cortisol were also determined—all for the diagnosis of SCS. Moreover, the high-dose (8-mg) DST was also conducted to rule out ACTH-dependent CS. Test results were assessed in accordance with the diagnostic criteria advocated by the Japan Endocrine Society [9] to make the definite diagnosis of SCS. Concretely, patients were required to meet the requisites 1–3)—1) presence of an adrenal incidentaloma; 2) lack of characteristic features of Cushing’s syndrome; and 3) normal basal serum cortisol levels, as well as to have either of the requisites 4–6)—4) the cutoff value of serum cortisol level for the diagnosis of SCS was ≥ 5 μg/dL after the 1-mg DST, 5) the cutoff value of serum cortisol level for the diagnosis of SCS was ≥ 3 μg/dL after the 1-mg DST, and at least 1 of “Low plasma levels of ACTH in the early morning,” “No diurnal changes in serum cortisol levels,” “Unilateral uptake on adrenal scintigraphy,” “Low serum levels of DHEAS,” or the presence of “Transient adrenal insufficiency or atrophy of the attached normal adrenal cortex after removal of the adrenal tumor,” or 6) the cutoff value of serum cortisol level for the diagnosis of SCS was ≥ 1.8 μg/dL after the 1-mg DST, with the presence of “Low plasma levels of ACTH in the early morning” and “No diurnal changes in serum cortisol levels,” or the presence of “Transient adrenal insufficiency or atrophy of the attached normal adrenal cortex after removal of the adrenal tumor.” In the present study, we examined only patients who met the requisites 1–3) and either 1 of the requisites 4–6) as patients with SCS. All patients underwent 128-slice CT of the adrenal glands. 131I-adosterol adrenal scintigraphy was conducted in all of patients who had SCS or PASCS to specify the laterality of the adrenal tumor. Consequently, 7 of 12 patients with SCS and 8 of 14 patients with PASCS underwent adrenalectomy. Postsurgical histopathological examination confirmed cortisol hypersecretion based on the atrophy of the normal area adjacent to the adenoma of the removed adrenal gland [9].

Study outcome measures

At the initial visit, all patients were checked up for their age and sex. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and the outcome measures listed in Table 1 were examined in untreated patients. At the time of admission to the hospital for making the definite diagnosis, height and body weight were measured to calculate body mass index (BMI). In the early morning of the next day of admission to the hospital, blood pressures were measured. Blood samples were collected to determine PAC, PRA, as well as plasma ACTH, serum cortisol, and serum DHEAS levels. The laterality of the adrenal tumor was confirmed based on the results from AVS and/or CT. The Hounsfield number and MTD of adrenal tumors were determined on the CT scans.

Table 1 Clinical, laboratory, and imaging characteristics of untreated patients with PA, SCS, or PASCS

The following terms were defined for PASCS: hypertension, SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg [14]; diabetes mellitus (DM), an fasting plasma glucose (FPG) level ≥ 126 mg/dL, a 2-h plasma glucose level ≥ 200 mg/dL in the 75-g oral glucose tolerance test, and/or a serum hemoglobin A1c (HbA1c) level ≥ 6.5% in national glycohemoglobin standardization program [15]; and dyslipidemia, a serum triglyceride (TG) level ≥ 150 mg/dL, a serum high-density lipoprotein cholesterol (HDL-C) level < 40 mg/dL, or a serum low-density lipoprotein cholesterol (LDL-C) level ≥ 140 mg/dL [16]. To specify the source of aldosterone hypersecretion by AVS, the following diagnostic criteria were used: 1) the laterality ratio (LR) and the contralaterality ratio (CR) calculated before and after the ACTH challenge test in reference to the Japanese guidelines of PA [11]; 2) the absolute PAC value of ≥ 14,000 pg/mL in reference to the articles of Ohmura [17] and Makita [18]; and 3) the aldosterone ratio of the right and left adrenal veins. According to the Japanese guidelines of PA [11], an LR of > 4 and a CR of < 1 after the ACTH challenge test were used as the cutoff values. Tumor laterality was determined based on a CR of < 1 and the absolute PAC value of ≥ 14,000 pg/mL when the ACTH challenge test indicated an LR of 2 to 4 or a discrepancy occurred in tumor laterality before and after the ACTH challenge test. Since serum cortisol levels considerably differed in the adrenal veins of PASCS patients, the adrenal gland secreting cortisol predominantly was determined based on the aldosterone ratio and on the right-to-left ratio of aldosterone and cortisol in the adrenal veins in reference to the article of Hiraishi et al. [8]. Moreover, tumor laterality was determined based on the results from 131I-adosterol adrenal scintigraphy and on the absolute value of PAC in reference to the articles of Funder et al. [12] and Minami et al. [13]. We did not measure plasma metanephrine concentrations, although the measurement thereof is useful for determining the need for AVS [19] in patients with the suspected concurrence of aldosterone and cortisol hypersecretion.

Statistical analyses

Continuous and categorical variables were analyzed according to the one-way analysis of variance and Fisher’s exact test, respectively. Two of the 3 study groups were analyzed according to Student’s t-test. Bonferroni’s correction was applied to the p values from Student’s t-test or Fisher’s exact test in multiple comparisons between 2 among the 3 study groups. Blood steroid profiles were compared between 2 groups according to Student’s t-test or the Mann-Whitney U-test.

In addition, the multiple linear regression analysis adjusted for age, sex, and BMI was performed to examine differences in MTD and serum potassium concentration among the PA, SCS, and PASCS groups. MTD was not measured in 1 of 42 patients in the PA group who had a unilateral adrenal tumor. Therefore, the data from the patient were excluded as the missing data.

A value of p <  0.05 was considered statistically significant. The JMP software version 9.0 (SAS Institute, Cary, NC, USA) was used to make all statistical analyses except multiple linear regression analysis that was performed using the STATA software version 14 (Stata Corp, College Station, TX, USA).

Results

Study population

The clinical, laboratory, and imaging characteristics of 71 patients are shown in Table 1. Mean age was 58.2 ± 11.2 years, females (n = 47, 66.2%) were predominant, and mean BMI was 25.2 ± 4.5 kg/m2. No significant difference was found in age, sex, and BMI among the PA, SCS, and PASCS groups (Table 1). SBP and DBP of patients with untreated hypertension were 165.6 ± 26.1 mmHg and 96.0 ± 13.6 mmHg, respectively, in the PA group in contrast to 145.6 ± 26.9 mmHg and 80.0 ± 12.7 mmHg, respectively, in the SCS groups. DBP was significantly greater (p <  0.01) in the PA group than in the SCS group.

Comorbidities are shown in Table 1. Hypertension occurred in 45 (100%), 9 (75.0%), and 13 (92.9%) patients in the PA, SCS, and PASCS groups, respectively. The proportion of patients with hypertension was significantly greater (p <  0.05) in the PA group than in the SCS group; however, no significant difference was found between the PASCS group and the PA group. Notably, the incidence of hypertension was 100% in patients with PA. DM occurred in 6 (14.0%), 6 (50.0%), and 7 (50.0%) patients in the PA, SCS, and PASCS groups, respectively. The proportion of DM patients was significantly greater (p <  0.05) in the PASCS group than in the PA group. Dyslipidemia occurred in 25 (56.8%), 10 (83.3%), and 9 (64.3%) patients in the PA, SCS, and PASCS groups, respectively; however, no significant difference was found among these study groups.

Results from laboratory tests are shown in Table 1. FPG was greater not statistically but numerically in the PASCS group than in the PA group (131.6 ± 52.1 mg/dL vs. 103.8 ± 28.5 mg/dL; p = 0.09). On the other hand, FPG was statistically greater in the SCS group than in the PA group (150.0 ± 60.7 mg/dL vs. 103.8 ± 28.5 mg/dL; p <  0.01). HbA1c was greater not statistically but numerically in the PASCS group than in the PA group (6.5 ± 2.1% vs. 5.7 ± 0.9%; p = 0.21). On the other hand, HbA1c was significantly greater in the SCS group than in the PA group (7.3 ± 2.2% vs. 5.7 ± 0.9%; p <  0.01). Serum potassium concentration was significantly lower in the PA group than in the SCS group (3.3 ± 0.7 mEq/L vs. 4.0 ± 0.5 mEq/L; p <  0.01) and in the PASCS group than in the SCS group (3.2 ± 0.8 mEq/L vs. 4.0 ± 0.5 mEq/L; p <  0.01). No significant difference was found in serum potassium concentration between the PA group and the PASCS group. Serum alkaline phosphatase (ALP) level was significantly greater in the PASCS group than in the PA group (279.1 ± 105.4 U/L vs. 212.3 ± 46.3 U/L; p <  0.01). No significant difference was found in serum ALP level between the SCS group and the PASCS group.

Subsequently, differences in CT Hounsfield units and MTD of adrenal tumors among the 3 study groups were examined with respect to 65 patients who had a unilateral adrenal tumor (Table 2). MTD on the CT scans was significantly greater in the PASCS group than in the PA group (2.7 ± 0.1 cm vs. 1.3 ± 0.1 cm; p <  0.001) and was also greater in the SCS group than in the PA group (2.7 ± 0.2 cm vs. 1.3 ± 0.1 cm; p <  0.001). No significant difference was found in MTD between the SCS group and the PASCS group. MTD was significantly smaller in the PA group than in the other 2 groups, was second smallest in the SCS group, and was largest in the PASCS group (Table 2). MTD ranged as follows: 0.3–2.2 cm, 1.8–3.5 cm, and 1.1–5.0 cm in the PA, SCS, and PASCS groups, respectively (Fig. 1).

Table 2 Maximum tumor diameters and computed tomography Hounsfield units of adrenal tumors in patients who had a unilateral adrenal tumor
Full size table
Fig. 1
figure1

Maximum tumor diameters in patients with PA, SCS, or PASCS who had a unilateral adrenal tumor. PA, primary aldosteronism; SCS, subclinical Cushing’s syndrome, PASCS, primary aldosteronism plus subclinical Cushing’s syndrome

The blood steroid profiles of patients with PA or PASCS are shown in Table 3. PAC was significantly greater in the PASCS group than in the PA group (255.0 [713.3–153.5] vs. 208.0 [273.0–159.8]; p <  0.005). No significant difference was found in PRA in the morning, while the PAC/PRA ratio was significantly greater in the PASCS group than in the PA group (1450.0 [5010.0–529.4] vs. 1258.3 [1956.3–643.1]; p <  0.005). The PAC/PRA ratio in the captopril challenge test was significantly greater in the PASCS group than in the PA group (3028.5 ± 3648.9 vs. 730.7 ± 745.7; p <  0.001) as with PAC in the captopril challenge test (348.6 ± 340.1 vs. 149.0 ± 94.2; p <  0.005). Serum cortisol level was significantly greater in the PASCS group than in the PA group (16.4 ± 6.6 μg/dL vs. 12.4 ± 4.3 μg/dL; p <  0.05). The mean serum cortisol level was 17.8 ± 5.9 μg/dL in the SCS group and was not significantly greater in the SCS group than in the PASCS group (17.8 ± 5.9 μg/dL vs. 16.4 ± 6.6 μg/dL; p = 0.49). No significant difference was found in plasma ACTH and serum DHEAS levels in the early morning; however, these variables were not significantly lower in the PASCS than in the PA group (p = 0.29 for ACTH and p = 0.40 for DHEAS). On the other hand, the peak plasma ACTH levels in the CRH challenge test were significantly lower in the PASCS group than in the PA group (18.9 ± 8.9 vs. 57.1 ± 10.8; p <  0.005) (Table 3) and were not significantly greater in the SCS group than in the PASCS group (15.3 ± 5.6 μg/dL vs. 18.9 ± 8.9 μg/dL; p = 0.64).

Table 3 Blood steroid profiles of patients with PA or PASCS
Full size table

Multiple linear regression analysis on MTD and serum potassium concentration with respect to patients in the PA, SCS, and PASCS groups who had a unilateral adrenal tumor

MTD was significantly greater in the PASCS and SCS groups than in the PA group with respect to patients who had a unilateral adrenal tumor (Table 2). Therefore, we conducted a multiple linear regression analysis adjusted for age, sex, and BMI to examine differences in MTD among the PA, SCS, and PASCS groups. Consequently, MTD was significantly smaller in the PA group than in the PASCS group (difference, – 1.19 cm; 95% CI, – 1.66 to – 0.72 cm). However, no significant difference was found in MTD between the SCS group and the PASCS group (Table 4). Serum potassium concentration was significantly greater in the SCS group than in the PASCS group (difference, 0.97 mEq/L; 95% CI, 0.38 to 1.54 mEq/L). However, no significant difference was found in serum potassium concentration between the PASCS group and the PA group (Table 4).

Table 4 Multiple regression analysis on maximum tumor diameter and serum potassium concentration with respect to patients in the PA, SCS, and PASCS groups who had a unilateral adrenal tumor (n = 65)
Full size table

The cutoff value of 2.4 cm for tumor size seemed to produce the largest proportion of classified patients (91.0%). Patients with PA who had a tumor size of > 2.4 cm almost certainly had the elements of PASCS (specificity 100%). Namely, the sensitivity and specificity were calculated to be 58.0 and 100%, respectively, when the cutoff point for tumor diameter was set to 2.4 cm. The odds ratio for tumor diameter when comparing PA with PASCS was 0.06 (95% CI, 0.006–0.261).

Discussion

We found several clinical and laboratory differences between patients with PASCS and patients with either PA or SCS. Regarding the impact of PA and SCS on glucose metabolism, the risk of developing DM in SCS is enhanced by the overproduction of cortisol that leads to increased gluconeogenesis [20]. Moreover, the risk is also enhanced by PA through 1) a hypokalemia-induced decrease in initial pancreatic insulin release and 2) a reduction in insulin sensitivity [21,22,23]. Hypokalemia is caused by the mineralocorticoid receptor-mediated overexcretion of potassium from the kidneys in both hypercortisolism and hyperaldosteronism [12, 24, 25]. Serum potassium concentration decreased significantly in the PA group than in the SCS group (p <  0.01). Similarly, the concurrence of PA and SCS significantly decreased serum potassium concentration against the SCS group (p <  0.01), but not the PA group. Of special note was the fact that the PASCS group involving both hyperaldosteronism and hypercortisolism did not show any greater decrease in serum potassium concentration as compared with the PA group. The mineralocorticoid receptors (MRs) bind both mineralocorticoids and glucocorticoids with high affinity (deoxycorticosterone = corticosterone ≥ aldosterone = cortisol) [26]. On the other hand, a cortisol-degrading enzyme—11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)—is expressed in renal epithelial cells and regulates the binding of aldosterone to the MRs by impeding cortisol binding to the MRs through the inactivation of cortisol to cortisone [26, 27]. Namely, this physiological event explains the MR-mediated renal excretion of potassium that is enhanced by both cortisol and aldosterone. We hypothesize that the renal potassium excretion-enhancing activity is greater for aldosterone than for cortisol due to the 11β-HSD2-induced, extensive inactivation of cortisol and that the hyperaldosteronism-enhanced renal excretion of potassium in patients with PASCS becomes more apparent, with the less effect of hypercortisolism on renal potassium excretion. Zallocchi et al. [28] described that renal 11β-HSD2 activity is regulated by glucocorticoids, is downregulated following adrenalectomy, and is restored by corticosterone replacement. These findings lead us to hypothesize that 11β-HSD2 may suppress the binding of corticosteroids to the MRs almost completely in subclinical hypercortisolism or that the expression/activity of renal 11β-HSD2 may be increased in PA. However, these hypotheses require further research for its demonstration.

The proportion of DM patients increased significantly in the PASCS group than in the PA group (p <  0.05), which is in line with a previous study that described abnormal glucose metabolism in PA patients with cortisol hypersecretion [29]. Hyperaldosteronism found in patients with PA also induces abnormal glucose metabolism [21,22,23], although being less intense as compared with hypercortisolism found in patients with SCS. The proportions of DM patients in the PA and SCS groups increased, which resulted to nullify a statistically significant difference in the proportion of DM patients between the 2 study groups. The fact that the risk for DM is increased in PA patients with mild glucocorticoid excess has been reported [30,31,32]; the finding was also described in Japanese patients with PA and patients with PASCS [33].

Interestingly, patients with PASCS involving hypercortisolism- and hyperaldosteronism-induced hypokalemia showed neither additive or synergic impact on abnormal glucose metabolism contrary to our prediction. The proportion of DM patients was comparable between the PASCS group and the SCS group. However, the reason for these findings is unknown, awaiting the further accumulation of clinical evidence.

MTD was significantly smaller (p <  0.001) in the PA group than in the PASCS or SCS group, and multiple regression analysis on MTD revealed that MTD was significantly larger by 1.2 cm in the PASCS group than in the PA group (p <  0.001). Previous studies [8, 34] examined the clinical characteristics of patients with PA or PASCS and described significant differences in MTD between the 2 study groups. Their results were concordant with and support our results that indicated no significant difference in MTD between the PASCS group and the SCS group.

Most of previous clinical studies in patients with SCS have described adrenal tumors of ≥ 2 cm in diameter [35, 36]. In addition, an adrenal adenoma causing the overproduction of both cortisol and aldosterone is considered to have a ≥ 2.5 cm diameter [34]. In the present study, however, the adrenal tumor was smaller in both patients with SCS and patients with PASCS. Concretely, the smallest MTD was 1.1 cm in patients with PASCS (Fig. 1). None of patients, who had PA and an adrenal tumor < 1 cm in diameter, developed SCS. Therefore, the dexamethasone suppression test may not be required for them.

Regarding bone metabolism impairment in SCS, the risk of developing osteoporosis is enhanced by the overproduction of cortisol in SCS [37, 38]. On the other hand, hyperaldosteronism is also known to increase the risk for osteoporosis [39]. SCS and PA are the risk factors for a reduction in BMD and an increase in vertebral fracture [37,38,39]. In the present study, serum ALP level was significantly greater in the PASCS group than in the PA group (p <  0.01). No significant difference was found in serum ALP level between the SCS group and the PASCS group. If this ALP represents bone alkaline phosphatase (BAP), the deleterious effects of hyperaldosteronism on bone metabolism might be masked by the severe abnormalities of bone metabolism caused by hypercortisolism in patients with PASCS. However, the relevant effects are difficult to assess by means of bone metabolism markers [eg, BAP] in patients with hypercortisolism as found in SCS [37]. Unfortunately, we neither used bone metabolism markers, nor measured BMD. Therefore, we will intend to investigate these variables in the future.

Limitations

The present study has several limitations. First, the study was retrospective in design and had a relatively small number of patients. Therefore, selection bias and sampling bias cannot be discarded. Second, not all patients underwent AVS or had a histopathological diagnosis. Patients, to whom challenge tests for either PA or SCS were conducted, were not included in the present study. Hence, the number of patients resulted to be relatively small. Third, the lack of data in the present study impeded the analysis of BMD and bone metabolism markers. Fourth, 131I-adosterol adrenal scintigraphy is not only useful for the diagnosis of SCS, but also is a very important imaging modality to predict postsurgical hypoadrenalism [40]. However, we could not investigate the latter.

Conclusions

We could not obtain any reference criteria to surely distinguish patients with concurrent endocrinopathies from those with a single endocrinopathy. However, clinicians should suspect the presence of concurrent SCS in patients with PA when detecting an adrenal tumor (≥ 1 cm in diameter) on the CT scans.

Availability of data and materials

The datasets analyzed during the current study are available from the corresponding author on a reasonable request.

Abbreviations

ACTH:
Adrenocorticotropic hormone
ALP:
Alkaline phosphatase
BMI:
Body mass index;
CRH:
corticotropin-releasing hormone
CT:
computed tomography
DBP:
Diastolic blood pressure
DHEAS:
Dehydroepiandrosterone sulfate
FPG:
Fasting plasma glucose
HbA1c:
Hemoglobin A1c
HDL-C:
High-density lipoprotein cholesterol
HU:
Hounsfield unit
LDL-C:
Low-density lipoprotein cholesterol
MTD:
Maximum tumor diameter
NGSP:
National glycohemoglobin standardization program
PA:
Primary aldosteronism
PAC:
Plasma aldosterone concentration
PASCS:
Primary aldosteronism plus subclinical Cushing’s syndrome
PRA:
Plasma renin activity
SBP:
Systolic blood pressure
SCS:
Subclinical Cushing’s syndrome
TG:
Triglyceride
UA:
Uric acid

References

  1. 1.

    Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89:1045–50.

  2. 2.

    Kageyama K, Oki Y, Sakihara S, Nigawara T, Terui K, Suda T. Evaluation of the diagnostic criteria for Cushing’s disease in Japan. Endocr J. 2013;60:127–35.

  3. 3.

    Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006;367:1605–17.

  4. 4.

    Terzolo M, Pia A, Reimondo G. Subclinical Cushing’s syndrome: definition and management. Clin Endocrinol. 2012;76:12–8.

  5. 5.

    Iacobone M, Citton M, Scarpa M, Viel G, Boscaro M, Nitti D. Systematic review of surgical treatment of subclinical Cushing’s syndrome. Br J Surg. 2015;102:318–30.

  6. 6.

    Fallo F, Bertello C, Tizzani D, Fassina A, Boulkroun S, Sonino N, et al. Concurrent primary aldosteronism and subclinical cortisol hypersecretion: a prospective study. J Hypertens. 2011;29:1773–7.

  7. 7.

    Piaditis GP, Kaltsas GA, Androulakis II, Gouli A, Makras P, Papadogias D, et al. High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas. Clin Endocrinol. 2009;71:772–8.

  8. 8.

    Hiraishi K, Yoshimoto T, Tsuchiya K, Minami I, Doi M, Izumiyama H, et al. Clinicopathological features of primary aldosteronism associated with subclinical Cushing’s syndrome. Endocr J. 2011;58:543–51.

  9. 9.

    Yanase T, Oki Y, Katabami T, Otsuki M, Kageyama K, Tanaka T, et al. New diagnostic criteria of adrenal subclinical Cushing’s syndrome: opinion from the Japan Endocrine Society. Endocr J. 2018;65:383–93.

  10. 10.

    Lee SH, Song KH, Kim J, Park S, Ahn SH, Kim H, et al. New diagnostic criteria for subclinical hypercortisolism using postsurgical hypocortisolism: the co-work of adrenal research study. Clin Endocrinol. 2017;86:10–8.

  11. 11.

    Nishikawa T, Omura M, Satoh F, Shibata H, Takahashi K, Tamura N, et al. Task force committee on primary Aldosteronism, the Japan Endocrine Society guidelines for the diagnosis and treatment of primary aldosteronism—the Japan Endocrine Society 2009. Endocr J. 2011;58:711–21.

  12. 12.

    Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, et al. The management of primary aldosteronism: Case detection, diagnosis, and treatment: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101:1889–916.

  13. 13.

    Minami I, Yoshimoto T, Hirono Y, Izumiyama H, Doi M, Hirata Y. Diagnostic accuracy of adrenal venous sampling in comparison with other parameters in primary aldosteronism. Endocr J. 2008;55:839–46.

  14. 14.

    Ogihara T, Saruta T, Rakugi H, Fujimoto A, Ueshima K, Yasuno S, et al. CASE-J trial group, relationship between the achieved blood pressure and the incidence of cardiovascular events in Japanese hypertensive patients with complications: a sub-analysis of the CASE-J trial. Hypertens Res. 2009;32:248–54.

  15. 15.

    Committee of the Japan Diabetes Society on the Diagnostic Criteria of Diabetes Mellitus, Seino Y, Nanjo K, Tajima N, Kadowaki T, Kashiwagi A, Araki E, et al. Report of the committee on the classification and diagnostic criteria of diabetes mellitus. J Diabetes Investig. 2010;1:212–28.

  16. 16.

    Teramoto T, Sasaki J, Ueshima H, Egusa G, Kinoshita M, Shimamoto K, et al. Japan atherosclerosis society (JAS) Committee for Epidemiology and Clinical Management of atherosclerosis. Diagnostic criteria for dyslipidemia, executive summary of Japan atherosclerosis society (JAS) guideline for diagnosis and prevention of atherosclerotic cardiovascular diseases for Japanese. J Atheroscler Thromb. 2007;14:155–8.

  17. 17.

    Omura M, Saito J, Yamaguchi K, Kakuta Y, Nishikawa T. Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens Res. 2004;27:193–202.

  18. 18.

    Makita K, Nishimoto K, Kiriyama-Kitamoto K, Karashima S, Seki T, Yasuda M, et al. A novel method: super-selective adrenal venous sampling. J Vis Exp. 2017;127:55716.

  19. 19.

    Dekkers T, Deinum J, Schultzekool LJ, Blondin D, Vonend O, Hermus AR, et al. Plasma metanephrine for assessing the selectivity of adrenal venous sampling. Hypertension. 2013;62:1152–7.

  20. 20.

    Bancos I, Alahdab F, Crowley RK, Chortis V, Delivanis DA, Erickson D, et al. Therapy of endocrine disease: improvement of cardiovascular risk factors after adrenalectomy in patients with adrenal tumors and subclinical Cushing’s syndrome: a systematic review and meta-analysis. Eur J Endocrinol. 2016;175:R283–95.

  21. 21.

    Corry DB, Tuck ML. The effect of aldosterone on glucose metabolism. Curr Hypertens Rep. 2003;5:106–9.

  22. 22.

    Remde H, Hanslik G, Rayes N, Quinkler M. Glucose metabolism in primary aldosteronism. Horm Metab Res. 2015;47:987–93.

  23. 23.

    Watanabe D, Yatabe M, Ichihara A. Evaluation of insulin sensitivity and secretion in primary aldosteronism. Clin Exp Hypertens. 2016;38:613–7.

  24. 24.

    Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol. 2007;66:607–18.

  25. 25.

    Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BM, Colao A. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4:611–29.

  26. 26.

    Funder JW. Mineralocorticoid receptors: distribution and activation. Heart Fail Rev. 2005;10:15–22.

  27. 27.

    Ferrari P, Sansonnens A, Dick B, Frey FJ. In vivo 11beta-HSD-2 activity: variability, salt-sensitivity, and effect of licorice. Hypertension. 2001;38:1330–6.

  28. 28.

    Zallocchi ML, Matkovic L, Calvo JC, Damasco MC. Adrenal gland involvement in the regulation of renal 11beta-hydroxysteroid dehydrogenase 2. J Cell Biochem. 2004;92:591–602.

  29. 29.

    Gerards J, Heinrich DA, Adolf C, Meisinger C, Rathmann W, Sturm L, et al. Impaired glucose metabolism in primary aldosteronism is associated with cortisol co-secretion. J Clin Endocrinol Metab. 2019. https://doi.org/10.1210/jc.2019-00299 [Epub ahead of print].

  30. 30.

    Wu VC, Chueh SJ, Chen L, Chang CH, Hu YH, Lin YH, et al. Risk of new-onset diabetes mellitus in primary aldosteronism: a population study over 5 years. J Hypertens. 2017;35:1698–708.

  31. 31.

    Arlt W, Lang K, Sitch AJ, Dietz AS, Rhayem Y, Bancos I, et al. Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI Insight. 2017;2:e93136.

  32. 32.

    Beuschlein F, Reincke M, Arlt W. The impact of Connshing’s syndrome – mild cortisol excess in primary aldosteronism drives diabetes risk. J Hypertens. 2017;35:2548.

  33. 33.

    Akehi Y, Yanase T, Motonaga R, Umakoshi H, Tsuiki M, Takeda Y, et al. High prevalence of diabetes in patients with primary aldosteronism (PA) associated with subclinical hypercortisolism and prediabetes more prevalent in bilateral than unilateral PA: a large, multicenter cohort study in Japan. Diabetes Care. 2019;42:938–45.

  34. 34.

    Späth M, Korovkin S, Antke C, Anlauf M, Willenberg HS. Aldosterone- and cortisol-co-secreting adrenal tumors: the lost subtype of primary aldosteronism. Eur J Endocrinol. 2011;164:447–55.

  35. 35.

    Maehana T, Tanaka T, Itoh N, Masumori N, Tsukamoto T. Clinical outcomes of surgical treatment and longitudinal non-surgical observation of patients with subclinical Cushing’s syndrome and nonfunctioning adrenocortical adenoma. Indian J Urol. 2012;28:179–83.

  36. 36.

    Rockall AG, Babar SA, Sohaib SA, Isidori AM, Diaz-Cano S, Monson JP, et al. CT and MR imaging of the adrenal glands in ACTH-independent Cushing syndrome. Radiographics. 2004;24:435–52.

  37. 37.

    Chiodini I, Vainicher CE, Morelli V, Palmieri S, Cairoli E, Salcuni AS, et al. Mechanisms in endocrinology: endogenous subclinical hypercortisolism and bone: a clinical review. Eur J Endocrinol. 2016;175:R265–82.

  38. 38.

    Hardy RS, Zhou H, Seibel MJ, Cooper MS. Glucocorticoids and bone: consequences of endogenous and exogenous excess and replacement therapy. Endocr Rev. 2018;39:519–48.

  39. 39.

    Asbach E, Bekeran M, Reincke M. Parathyroid gland function in primary aldosteronism. Horm Metab Res. 2015;47:994–9.

  40. 40.

    Ricciato MP, Di Donna V, Perotti G, Pontecorvi A, Bellantone R, Corsello SM. The role of adrenal scintigraphy in the diagnosis of subclinical Cushing’s syndrome and the prediction of post-surgical hypoadrenalism. World J Surg. 2014;38:1328–35.

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Acknowledgments

The authors would like to express their gratitude Kazuyuki Inoue, MD and Takujiro Iuchi, MD for their role in the data collection. The authors also thank Satoshi Sakima, MD, for valuable discussions about the manuscript.

Funding

No funding was obtained for this study.

Author information

Affiliations

  1. Department of Endocrinology and Diabetes, Saitama Medical University, Morohongo 38, Moroyama, Iruma-gun, Saitama, 350-0495, Japan
    • Shigemitsu Yasuda
    • , Yusuke Hikima
    • , Shinichiro Iida
    • , Yoichi Oikawa
    • , Masashi Isshiki
    • , Ikuo Inoue
    • , Akira Shimada
    •  & Mitsuhiko Noda
  2. Department of Home Care Medicine, Sowa Hospital, Sagamihara, Kanagawa, Japan
    • Yusuke Kabeya
  3. Department of Diabetes, Metabolism and Endocrinology, Ichikawa Hospital, International University of Health and Welfare, Chiba, Japan
    • Mitsuhiko Noda

Contributions

SY analyzed and interpreted the data, drafted, and finalized the manuscript. YK performed statistical analyses, YH, YK, SI, YO, MI, II, AS, and MN contributed to the discussion and critically revised the manuscript, AS and MN are taking full responsibility for the work as a whole. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shigemitsu Yasuda.

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All participants gave written informed consent. The present study followed the recommendations of the Declaration of Helsinki and was approved by the ethics committee of Saitama Medical University (18049.01).

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Yasuda, S., Hikima, Y., Kabeya, Y. et al. Clinical characterization of patients with primary aldosteronism plus subclinical Cushing’s syndrome. BMC Endocr Disord 20, 9 (2020). https://doi.org/10.1186/s12902-020-0490-0

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Keywords

  • Primary aldosteronism
  • Subclinical Cushing’s syndrome
  • Adrenal tumor
  • Maximum tumor diameter
  • Diabetes mellitus
  • Serum potassium

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