Aldosterone-Cortisol co-secretion in different adrenal tumors: A case series

Abstract

Primary aldosteronism is the most common cause of endocrine hypertension. It commonly presents as refractory hypertension, carrying an elevated risk of cardiac and renal complications. Concurrent hypercortisolemia exacerbates the susceptibility to metabolic disorders, including obesity, dyslipidemia, abnormal blood glucose levels, and cardiovascular and renal diseases. Among the reported patients with co-secretion of aldosterone, the majority are aldosterone producing adenoma. Cases of bilateral adrenal hyperplasia secreting both aldosterone and cortisol are rarely reported. In this study, we conducted a comparative analysis of the clinical manifestations, laboratory tests, and imaging findings in two cases involving unilateral aldosterone-producing adenomas and bilateral macronodular adrenal hyperplasia respectively. Notably, our patients exhibited a cortisol circadian rhythm during the initial screening, complicating the diagnosis of Cushing's syndrome. The incorporation of early or routine low-dose dexamethasone suppression tests may prove beneficial in identifying co-secretory lesions promptly, assessing the risk of perioperative adrenal insufficiency, and guiding subsequent treatment and prognosis evaluation.

Introduction

In patients with hypertension, the prevalence of endocrine hypertension exceeds 10%. These patients often present with resistant hypertension and are associated with higher levels of cardiac and renal damage, among which primary aldosteronism (PA), with a prevalence of 5%-10% among hypertensive patients, is the most common cause. ¹ In recent years, there has been a gradual increase in reports of adrenal diseases that secrete both aldosterone and cortisol. The presence of Cushing's syndrome (CS) is associated with an increased risk of metabolic disorders such as obesity, dyslipidemia, and dysglycemia, thereby heightening the risk of cardiovascular and renal diseases in patients. Among reported cases involving co-secretion of aldosterone, the majority involve aldosterone-producing adenoma. Instances of bilateral adrenal hyperplasia secreting both aldosterone and cortisol are rarely documented. Herein we conducted a comparative analysis of the clinical presentation, laboratory testing, and imaging findings in two cases representing these distinct adrenal disease types. We describe primary aldosteronism with subclinical Cushing's syndrome (SCS) as the primary presentation in these patients. It is suggested that early or routine low-dose dexamethasone suppression testing may be helpful for early diagnosis and treatment.

Case description

Patient 1

The patient was a 60-year-old female who had been hypertensive for more than 10 years. She reported no symptoms such as palpitations, headaches, or limb weakness. Two years ago, a computerized tomography scan revealed that the bilateral adrenal glands were heterogeneously enlarged with nodular changes, the largest nodule measuring 1.3 cm (Figure 1A). Liver function, renal function, thyroid function, and levels of blood and urinary metanephrine and normetanephrine were all within the normal range. Her cortisol levels peaked in the early morning and were below 7.5μg/dl at midnight (Table 1), indicating the presence of normal cortisol rhythms. The diagnosis of primary aldosteronism was characterized by high aldosterone, low renin, and an elevated aldosterone-to-renin ratio and positive saline infusion test result (PA screening was performed using the criteria aldosterone-to-renin ratio ＞3.7 and aldosterone levels > 10 ng/dL after a saline infusion test) (Table 2). As the patient declined adrenal venous sampling and surgery, we utilized the Clinical Nomogram ² to classify the patient as having bilateral hyperaldosteronism. Consequently, the patient received treatment with spironolactone, amlodipine, and metoprolol, resulting in blood pressure control within the range of approximately 130–150/80–90 mmHg. One year later, the patient gradually developed abdominal obesity, and the lower limbs became thinner than before. Upon admission, the patient's pulse was 78 bpm, blood pressure was 142/80 mmHg, body mass index was 30.48 kg/m², and there were signs of mild moon face, a buffalo hump, central obesity, and purple striae. The assessment of cortisol circadian rhythm was still present, but further dexamethasone suppression testing revealed the presence of Adrenocorticotropic Hormone (ACTH)-independent Cushing's syndrome (ACTH-independent CS screening was performed using the criteria baseline ACTH ＜20 pg/ml and cortisol level remained greater than 1.8 μg/dL after the dexamethasone suppression test) (Table 1). Bilateral macronodular adrenal hyperplasia was considered, but the patient continued to refuse surgical treatment and was subsequently discharged.

Figure 1.

Computerized tomography imaging of the two cases. (A) heterogeneously enlarged bilateral adrenal glands with nodular changes, the largest nodule measuring 1.3 cm. (B) right adrenal adenoma, with dimensions 3.1 cm X 3.5 cm.

Table 1.

Day-night rhythm of plasma cortisol concentration and after the dexamethasone suppression test.

		8:00	24:00	1mg	2mg	8mg
Case 1	F(μg/dL)	18.95	6.96	8.63	8.51	8.88
	ACTH(pg/ml）	10.02	-	3.29	3.66	＜1.5
Case 2	F(μg/dL)	21.13	5.31	6.42	8.73	-
	ACTH(pg/ml）	10.30	-	＜1.5	＜1.5	-

F: cortisol; ACTH: Adrenocorticotropic Hormone; 1mg: after 1 mg overnight dexamethasone suppression Test; 2mg: after classic low-dose (2 mg/day) dexamethasone suppression Test; 8mg: after high-dose (8 mg/day) dexamethasone suppression Test.

Table 2.

The aldosterone and dynamic test for the diagnosis of primary aldosteronism.

		Supine position	Upright position	Normal saline	Captopril
Case 1	PAC (ng/dl)	17.75	14.30	16.08	16.77
	PRA (uIU/mL)	3.19	6.17	1.99	3.95
Case 2	PAC (ng/dl)	97.30	78.60	82.30	-
	PRA (uIU/mL)	0.53	0.93	＜0.50	-

PAC: plasma aldosterone concentration; PRA: plasma renin concentration; normal saline: after saline infusion test; Captopril: after captopril challenge test.

Patient 2

The 31-year-old female patient was admitted to the hospital with the chief complaint of elevated blood pressure persisting for 1 year. Her blood pressure upon admission was 179/125mmHg, heart rate was 82bpm. Her height was 151 cm, weight was 55.6 kg, body mass index was 24.4 kg/m². There were no apparent signs of moon face, buffalo hump, centripetal obesity, wide purple striae, or other features associated with CS. Laboratory test results revealed the following: blood potassium levels were 2.4–2.6 mmol/L (reference range 3.5–5.5 mmol/L). Liver function, renal function, blood glucose, thyroid function, and levels of blood and urinary metanephrine and normetanephrine were all within the normal range. Further investigations uncovered renal potassium loss, elevated aldosterone, low renin levels, high elevated aldosterone-to-renin ratio, and positive saline infusion test result (Table 2) leading to the diagnosis of PA. Meanwhile, her ACTH baseline levels and dexamethasone suppression testing result leading to the diagnosis of ACTH-independent Cushing's syndrome (Table 1). Contrast-enhanced computerized tomography of the adrenal gland revealed a right adrenal adenoma, with dimensions.1 cm X 3.5 cm (Figure 1B). The 2016 clinical guidelines for the diagnosis and treatment of primary aldosteronism recommend that patients under 35 years of age with spontaneous hypokalemia, markedly elevated aldosterone secretion, and a unilateral adenoma identified on computerized tomography scans can proceed directly to unilateral adrenalectomy. ³ The patient underwent laparoscopic right adrenalectomy, with complete excision of the right adrenal gland and the lesion measuring 4 × 3 cm. Postoperative pathology confirmed adrenocortical adenoma. Postoperative reassessment revealed a serum cortisol level of 3.7 μg/dL (reference range 4.3–22.2μg/dL) and a blood potassium level of 4.0 mmol/L. Hydrocortisone replacement was given during the perioperative period. The patient was prescribed oral prednisone postoperatively at a dose of 10 mg/day, which was gradually tapered. After one month, prednisone was discontinued at a dose of 2.5 mg/day when the patient's mental state, appetite, and blood electrolyte levels were normal. After the operation, the patient discontinued antihypertension medications, resulting in blood pressure stabilizing at around 120/80 mmHg.

Discussion

Primary aldosteronism (PA) denotes the spontaneous secretion of aldosterone by the adrenal cortex, unaffected by renin and angiotensin II inhibition, and resistant to full suppression by sodium loading or extracellular volume expansion. This dysregulation leads to sodium retention and potassium excretion, manifesting as hypertension and hypokalemia. Meanwhile, heightened plasma aldosterone concentrations correlate with left ventricular hypertrophy, fibrosis, increased intima-media thickening, arterial wall inflammation, and endothelial dysfunction. Additionally, PA is identified as a risk factor for renal hyperfiltration, albuminuria, and glomerulosclerosis. ⁴ Such patients often exhibit a higher risk of stroke, coronary artery disease, atrial fibrillation, and heart failure,^{5, 6} increased kidney damage, ⁷ and other significant concerns. The presence of CS also elevates the risk of metabolic disorders, including obesity, dyslipidemia, dysglycemia, and cardiorenal diseases. Patients who undergo unilateral adrenalectomy for CS is at risk of contralateral adrenal gland suppression, due to the chronically elevated pre-operative cortisol levels, which cause consequent ACTH suppression and contralateral adrenal atrophy. Peri- and postoperative stress-dose glucocorticoids are required, which are weaned down to oral maintenance therapy prior to discharge. ⁸ We conducted a comparative analysis, examining the similarities and differences in clinical manifestations, laboratory tests, and imaging findings between two patients with different adrenal diseases involving co-secretion.

PA combine with CS due to bilateral macronodular adrenal hyperplasia is rarely reported. Adrenal hyperplasia of the greater tuberosity is an uncommon endogenous cause of CS, accounting for less than 2% of cases. The imaging is characterized by the presence of adrenal glands containing nodules of 10 mm or more. Its pathogenesis involves abnormal expression of adrenal receptors or peptide hormone receptor activity, local production of ACTH in adrenal tissue, and gene mutations. As far as we know, only two patients have been reported. One involves a middle-aged man with SCS combined with PA; its histological findings revealed CYP11B2-positive small cells present in the adrenal cortex's nodule area. ⁹ The second patient involves a 35-year-old woman, where imaging suggested bilateral macronodular adrenal cortex hyperplasia, ¹⁰ However, no imaging or pathological results were provided. Different from bilateral adrenal nodular hyperplasia caused by PA and CS, patients with CS and PA adenoma, known as aldosterone-and cortisol-producing adenoma (A/CPA), are reported, with prevalence of more than 10%. ¹¹ In patients with A/CPA, it usually presents as SCS.^12–14 The tumor diameter of A/CPA patients was larger than that of PA adenoma patients [(2.7 ± 0.1) cm vs. (1.4 ± 0.1) cm, P ＜0.001]. When the tumor size was ≥2.4 cm, the sensitivity for the diagnosis of co-secretion was 58.0%-100%. ¹⁵ The phenomenon of PA and CS coexistence is gradually being recognized. In Arlt et al.'s study, PA patients’ adenoma tissue with CYP11B1 expression was associated with a significant corresponding increase in cortisol hormone excretion. ¹⁴ In cases carrying mutations in KCNJ5 PA adenoma, plasma steroids concentrations, specifically 18 - hydroxyl cortisol (18-oxocortisol and 18-hydroxycortisol), were 18 times higher than the sum of the concentration of all other PA adenoma and 16 times higher. ¹⁶ In summary, based on our case and previous literature reports, the majority of patients with co-secretory adrenal diseases present primarily with hyperaldosteronism, with SCS as the main presentation. In a minority of cases, clinical CS was observed. In our first patient, even a circadian rhythm was observed during the screening, presenting challenges for the detection of autonomous cortisol secretion. However, current guidelines for diagnosis of PA do not indicate routine hypercortisolism assessment. ¹⁷ Nevertheless, we believe that in the case of bilateral adrenal nodular hyperplasia or unilateral large adenomas (such as those with a length-to-diameter ratio > 2.4 cm), early or regular administration of low-dose dexamethasone suppression tests appears to be necessary. This approach aids in identifying early pathological changes indicative of A/CPA, assessing the perioperative risk of adrenocortical hypofunction, guiding follow-up treatment, and evaluating prognosis.

Conclusions

The recognition of aldosterone-cortisol co-secreting adrenal diseases has gradually increased in clinical practice. Such patients often face a higher risk of cardiovascular and metabolic complications, as well as postoperative adrenal insufficiency. However, due to the frequently subclinical nature of CS and the guidelines not mandating routine low-dose dexamethasone suppression tests in patients with PA, these individuals are often overlooked. We contend that it is crucial to conduct early-stage evaluations of adrenal disease characterized by bilateral adrenal nodular hyperplasia or large nodules (> 2.4 cm) through routine low-dose dexamethasone suppression tests. This approach aids in the early identification of co-secreting adrenal lesions, reducing the risk of postoperative adrenal insufficiency and benefiting patient outcomes.