Cushing disease and unilateral primary aldosteronism confounded by a nonfunctioning contralateral adrenal incidentaloma

Abstract

The discovery of an adrenal incidentaloma should prompt an evaluation for the presence of malignancy and autonomous hormonal secretion. Concomitant adrenal nodule and hypercortisolism or primary aldosteronism does not inherently confirm the adrenal lesion as the source of excessive hormone. Localization studies are needed to ensure proper identification of the source of hormone oversecretion prior to consideration of surgical resection. We report a case in which a patient presented with an adrenal incidentaloma but was found through extensive hormonal testing and localization studies to have Cushing disease and primary aldosteronism, which was localized to the contralateral adrenal gland, whereas the adrenal incidentaloma that prompted the initial evaluation appeared to be nonfunctioning. Our case report highlights the importance of localizing the functioning lesion in the context of an adrenal incidentaloma.

Introduction

An adrenal incidentaloma is usually discovered on an imaging study that was obtained for an unrelated reason [1]. The incidence of adrenal nodule has been estimated to be approximately 2%; however, it increases with age with an estimated prevalence of 10% in patients older than 80 years of age [2]. Up to 10% of adrenal incidentalomas are thought to be hyperfunctioning, although if mild autonomous cortisol secretion is included, then the incidence of hormonal hyperfunction can be as high as 30% to 35% [1, 3]. Importantly, biochemically confirmed hypercortisolism and/or primary aldosteronism may not necessarily originate from the nodule that prompted the initial workup, and localization studies are often necessary to guide treatment, which may include adrenal venous sampling (AVS) in primary aldosteronism and measurement of corticotropin (ACTH) and dehydroepiandrosterone sulfate in hypercortisolism [4, 5].

Once a diagnosis of primary aldosteronism is confirmed, AVS is often needed to lateralize the source of the excess aldosterone and help determine treatment options of surgery vs medical therapy [6]. If endogenous hypercortisolism is confirmed, ACTH level can help to differentiate between ACTH-independence (adrenal source) and ACTH-dependence (pituitary or an ectopic source). Magnetic resonance imaging (MRI) of the pituitary and inferior petrosal sinus sampling (IPSS) can further aid in localization for ACTH-dependent hypercortisolism.

Here we describe a case in which the discovery of an adrenal incidentaloma prompted a cascade of biochemical and localization studies resulting in identification and successful treatment of both Cushing disease and primary aldosteronism, despite that the initially identified nodule was determined to be nonfunctioning.

Case presentation

A 53-year-old man with a history of obesity, hypertension, depression, and anxiety was referred to the endocrinology clinic for evaluation of a 2.4 × 1.4-cm right adrenal nodule that was incidentally discovered on an abdominal computed tomography (CT) to evaluate for pancreatitis (Fig. 1). His hypertension was diagnosed in his 30s without a history of hypokalemia. On presentation, he was taking amlodipine 10 mg daily, carvedilol 50 mg twice daily, and spironolactone 50 mg daily with adequate blood pressure control and normal potassium level. He denied prior exogenous steroid exposure, spells, and family history of adrenal or pituitary disorders.

Figure 1.

A 2.4 × 1.4-cm right adrenal nodule (black arrow) was incidentally discovered on abdominal CT and prompted initial hormone workup.

Diagnostic assessment

His initial examination showed a body mass index of 31.2 kg/m², subtle cushingoid features including central obesity, peripheral wasting, thin skin, facial plethora, supraclavicular fat pad, dorsocervical fat pad, and ecchymoses on extremities.

An adrenal CT showed a right nodule with a precontrast −9.5 Hounsfield units, consistent with an adenoma. Initial hormone testing showed a baseline morning cortisol of 19.3 μg/dL (535 nmol/L) (normal reference range: 5.0-25.0 μg/dL; 137.9-689.7 nmol/L) and an abnormal cortisol 8.7 μg/dL (240 nmol/L) (normal reference range: <1.8 μg/dL; <50 nmol/L) after 1-mg overnight dexamethasone with adequate dexamethasone level. Additional testing on a different day demonstrated plasma aldosterone concentration (PAC) 9 ng/dL (0.25 nmol/L) (normal reference range: 3-16 ng/dL; 0.08-0.45 nmol/L), plasma renin activity (PRA) 0.7 ng/mL/h (16.59 pmol/L/h) (normal reference range: 0.25-5.82 ng/mL/h; 5.9-137.9 pmol/L/h), potassium 3.8 mmol/L (normal reference range: 3.5-5.1 mmol/L), and normal plasma metanephrines. Although there was concern for both hypercortisolism and hyperaldosteronism based on initial laboratory tests, a subsequent workup initially focused on hypercortisolism based on his physical features, comorbidities, and well-controlled blood pressure. Further testing revealed elevated 24-hour urinary free cortisol 81.3 μg/24 hours (2242.8 nmol/24 hours) (normal reference range: 4-50 μg/24 hours; 110.3-1379.3 nmol/24 hours) and elevated late night salivary cortisol 0.10 and 0.13 μg/dL (2.8 and 3.6 nmol/L) (normal reference range: ≤0.09 μg/dL; ≤2.5 nmol/L). Baseline 8 Am ACTH was 16.3 pg/mL (3.6 pmol/L) (normal reference range: 7.2-63.6 pg/mL; 1.6-14 pmol/L), and dehydroepiandrosterone sulfate level was 40 μg/dL (1.1 μmol/L) (normal reference range: 34-569 μg/dL; 0.9-15.4 μmol/L). A pituitary MRI scan originally reported no sellar lesion. Given his significant anxiety and depression and nonsuppressed ACTH, a desmopressin (DDAVP) stimulation test was performed to rule out nonneoplastic hypercortisolism and showed baseline ACTH of 24.6 pg/mL (5.4 pmol/L) and a peak level of 106.0 pg/mL (23.3 pmol/L) at 15 minutes after DDAVP, consistent with Cushing disease (Table 1). On reexamination of the pituitary MRI scan, a 3.6-mm hypoenhancement left pituitary lesion was identified, suggestive of possible microadenoma (Fig. 2). The pituitary source of hypercortisolism was further confirmed by IPSS, during which DDAVP 10 μg (8.45 nmol) was given as an intravenous bolus at 0 minutes, demonstrating apparent central to peripheral gradient of ACTH (Fig. 3).

Table 1.

Desmopressin (DDAVP) stimulation test results

Hormone	Baseline, pre-DDAVP	+15 minutes	+30 minutes	+60 minutes
Cortisol	13.0 μg/dL (359 nmol/L)	Not assessed	53.0 μg/dL (1462 nmol/L)	40.7 μg/dL (1123 nmol/L)
ACTH	24.6 pg/mL (5.4 pmol/L)	106.0 pg/mL (23.3 pmol/L)	67.8 pg/mL (14.9 pmol)	34.1 pg/mL (7.5 pmol/L)

Values in parentheses are International System of Units (SI).

Figure 2.

A 3.6-mm pituitary microadenoma (white arrows) was shown on contrast-enhanced MRI.

Figure 3.

Inferior petrosal sinus sampling (IPSS) showing an elevated central:peripheral (C:P) gradient of ACTH corrected by prolactin at right inferior petrosal sinus (IPS) consistent with pituitary source of ACTH.

Treatment

The patient underwent transsphenoidal resection of the pituitary tumor. Pathology showed corticotroph adenoma, which was stained positive for pituitary-specific T-box transcription factor (T-PIT) and ACTH (Fig. 4). Cortisol nadir was 4.9 μg/dL (135.2 nmol/L) on postoperative day 1. The patient was started on a replacement dose of hydrocortisone 15 mg in morning and 5 mg in afternoon, which was tapered off by approximately 2 weeks after the surgery. The patient reported improvement of his Cushing symptoms after surgery.

Figure 4.

Corticotroph pituitary neuroendocrine tumor (PitNET), T-PIT, lineage. Representative hematoxylin and eosin (H&E)-stained section shows a relatively monomorphic population of faintly basophilic neuroendocrine neoplastic cells with desmoplasia and focal crush artifact (A). The neoplastic cells show diffuse immunoreactivity to synaptophysin (B), nuclear expression of T-PIT transcription factor (C), and diffuse cytoplasmic expression of ACTH (D). Scale bar: 1 mm.

One month after surgery, his blood pressure improved, with episodes of borderline hypotension. Spironolactone was discontinued because of frequent urination and facilitation for primary aldosteronism diagnosis. Amlodipine 10 mg daily was continued, and carvedilol was reduced to 25 mg twice daily. After 3 months off spironolactone, his blood pressure rose from 100-120/70-90 mm Hg to 160-170/100-100 mm Hg. Repeat testing showed PAC 14 ng/dL (0.39 nmol/L), PRA 0.58 ng/mL/h (13.74 pmol/L/h), and potassium 4.0 mmol/L. Primary aldosteronism was confirmed with an oral salt loading test, which demonstrated 24-hour urine sodium 247 mmol/24 hours (normal reference range: >200 mmol/24 hours) and aldosterone 14.4 μg/24 hours [39.7 nmol/24 hours]) (normal reference range: <12 μg/24 hours; <33.1 nmol/L). AVS lateralized to the left side despite a right adrenal nodule (Table 2). He underwent left adrenalectomy with subsequent significant improvement in blood pressure. Pathology showed adrenal gland with nodular hyperplasia and hemorrhagic cyst; no immunohistochemical staining of aldosterone synthase was completed due to lack of availability.

Table 2.

Adrenal venous sampling (AVS) results

Hormone	RAV	LAV	IVC	RAV: IVC ratio	LAV:IVC ratio
Cortisol	1376 μg/dL (37958 nmol/L)	391 μg/dL (10786 nmol/L)	33.5 μg/dL (924 nmol/L)	41.1	11.7
Aldosterone	390 ng/dL (1082 nmol/L)	1100 ng/dL (3052 nmol/L)	26 ng/dL (72 nmol/L)
Aldosterone: cortisol ratio	0.3	2.8	0.8
Lateralization index		9.3
Contralateral suppression index	0.4

Values in parentheses are International System of Units (SI).

Abbreviations: IVC, inferior vena cava; LAV, left adrenal vein; RAV, right adrenal vein.

Lateralization index: aldosterone, cortisol ratio; LAV/aldosterone: cortisol ratio RAV.

Contralateral suppression index: aldosterone:cortisol ratio; RAV/aldosterone: cortisol ratio IVC.

Outcome and follow-up

After adrenalectomy, the patient was able to achieve sufficient blood pressure control and normalization of PRA to 1.94 ng/mL/h (46.0 pmol/L/h) on carvedilol only 25 mg twice daily. At 2 years after his pituitary surgery, his cushingoid features including central obesity, bruising and facial plethora, and overall quality of life have improved.

A repeat pituitary MRI scan showed postsurgical changes without residual or recurrent tumor. His most recent biochemical evaluation showed a normal 1-mg dexamethasone suppression test (cortisol of 1.7 μg/dL [46.9 nmol/L], normal 24-hour urinary free cortisol of 34.5 μg/24 hours [951.7 nmol/L], and 2 normal late night salivary cortisol levels of 0.03 μg/dL, 0.06 μg/dL [1.1 nmol/L, 1.9 nmol/L]). The right adrenal nodule remains stable in size and appearance on follow up imaging three years after initial CT. Due to its benign features and stable size, the right adrenal nodule required no further imaging according to current guideline [2].

Discussion

We present a case with a unilateral adrenal incidentaloma in which comprehensive biochemical workup ultimately led to a diagnosis of Cushing disease as well as primary aldosteronism localized to the contralateral adrenal gland. The patient had a satisfactory clinical outcome after pituitary surgery and unilateral adrenalectomy.

Biochemical evaluation for an adrenal incidentaloma should include assessment of autonomous cortisol secretion in all cases and primary aldosteronism and pheochromocytoma in select cases depending on comorbidities and imaging characteristics [1]. In our case, although hypercortisolism was confirmed, a baseline nonsuppressed ACTH level suggested a possible pituitary source. It is estimated that 40% to 50% of Cushing disease can be caused by a pituitary microadenoma too small to be readily visualized on pituitary MRI [7]. In our patient, secondary review of the initially negative MRI scan did reveal a 3.6-mm microadenoma. Both DDAVP stimulation test and IPSS were required to ensure the diagnosis of Cushing disease before proceeding with pituitary surgery.

Primary aldosteronism is estimated to affect 5% to 14% of individuals with hypertension, and current guideline recommends that any patient with hypertension be screened for primary aldosteronism with morning PAC and plasma renin activity or concentration [6, 8]. Many medications may affect interpretation of the screening tests. Our patient notably had a suppressed PRA even while on spironolactone, which raised concern for autonomous aldosterone secretion. Of note, β blockers may also lower PRA. Based on the previous Endocrine Society guideline for primary aldosteronism, an oral salt load test was completed as a confirmatory test, followed by AVS to lateralize the source of excess aldosterone [5]. In AVS, cortisol is usually used to confirm successful catheterization and normalize aldosterone levels. However, AVS result may be unreliable if the patient has endogenous hypercortisolism. In our case, AVS was performed when the patient reached eucortisolemia to minimize potential interference with AVS interpretation. However, if AVS is performed in a state of hypercortisolemia, plasma metanephrines can be used as an alternative to cortisol to assist in lateralization determination [9].

Similarly, accurate localization of the source of hypercortisolism is also important for determination of treatment options, especially surgery. A recent case of a 2.7-cm adrenal incidentaloma and hypercortisolism revealed a nonsuppressed ACTH, a 5-mm pituitary lesion, and positive corticotropin-releasing hormone stimulation test that finally led to removal of a pituitary tumor [10]. In contrast, another patient with cushingoid features, low TSH and free thyroxine, and a 7-mm pituitary microadenoma was noted to have ACTH-independent hypercortisolism and a 3.3-cm left adrenal adenoma that was eventually resected [11]. These cases including ours highlight the importance of localization in the accurate diagnosis and management of hypercortisolism. Presence of either an adrenal or a pituitary tumor or both in the context of hypercortisolism does not establish causality. Proper evaluation should at least include baseline ACTH and possibly additional testing such as DDAVP stimulation test and IPSS. Moreover, while co-secretion of cortisol is estimated to affect 20% to 77% of patients with primary aldosteronism, there has been a report of coexistent ACTH-independent hypercortisolism, primary aldosteronism, and bilateral adrenal adenomas in which AVS (corrected by plasma epinephrine) localized the excess cortisol to the left side and the excess aldosterone to the right side; the patient eventually underwent bilateral partial adrenalectomy [12, 13].

Our patient's adrenal incidentaloma was initially discovered on a CT scan evaluating pancreatitis. Hypercortisolism can predispose an increased risk of pancreatitis in the setting of hypertriglyceridemia and/or hyperglycemia. The etiology of pancreatitis in our patient was thought to be idiopathic because his triglycerides were only mildly elevated and his diabetes was well controlled on metformin monotherapy. Additionally, our patient had been seen by several other medical providers but had not been screened for hypercortisolism despite his mild cushingoid features until after the adrenal incidentaloma was discovered. Because the signs and symptoms of mild hypercortisolism overlap with other conditions, there can be a diagnostic delay of Cushing syndrome with a mean time to diagnosis approximately 34 months [14].

In conclusion, we presented a case in which hypercortisolism was originally found in the presence of an adrenal nodule. A nonsuppressed baseline ACTH led to further workup including DDAVP stimulation test, IPSS and secondary review of initially negative MRI, and eventually a diagnosis of Cushing disease resulting from a pituitary microadenoma. After successful surgical treatment of Cushing disease, subsequent evaluation confirmed a diagnosis of primary aldosteronism and AVS lateralized to the contralateral side of the adrenal nodule and led to adrenalectomy and significant improvement in blood pressures and biochemical markers. The nodule that prompted the original biochemical evaluation appears to be a nonfunctioning adenoma. Our case highlighted the importance of dynamic biochemical testing and uses of localization studies in the hormonal workup of adrenal nodules.

Learning points

• A systematic approach using biochemical testing should be undertaken upon the discovery of an adrenal incidentaloma.

• Adrenal hypercortisolism in the presence of an adrenal nodule should be confirmed with a low baseline ACTH level.

• Cushing disease should be suspected in patients with an adrenal incidentaloma and hypercortisolism with a non-suppressed ACTH level. Additional studies including pituitary MRI, DDAVP stimulation test, and IPSS may be needed to confirm the diagnosis of Cushing disease.

• In patients with confirmed primary aldosteronism and adrenal nodule(s), AVS can help to lateralize the source of aldosterone excess prior to consideration of adrenalectomy.

Contributors

All authors made individual contributions to authorship. J.G.F. was involved in manuscript design, composition of initial draft, and preparation of tables and figures. W.H. was involved in clinical case management and manuscript review. P.J. was involved in comprehensive interpretation of pathology results and provision of immunostaining images. All authors reviewed and approved the final draft.

Funding

No public or commercial funding.

Disclosures

Honoraria from Consulting and Speaking received from Recordati Rare Diseases: WH.

Informed patient consent for publication

Signed informed consent obtained directly from the patient.

Data availability

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.