E-Poster Presentation 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

A 40 year old woman was referred to our Endocrinology service following the incidental finding of bilateral adrenal adenomas on a CT scan performed to investigate back pain. Dedicated CT imaging of the adrenal glands showed a left adrenal nodule measuring 23x23x23mm, and a right adrenal nodule measuring 17x12x11mm; the nodules had pre-contrast Hounsfield unit values of 31 and 23, and absolute contrast washouts of 76.8% and 80%, respectively. The patient was from a Korean background with no significant medical history, took only over-the-counter vitamins, and did not consume alcohol or smoke. Systems review revealed two years of symptoms including generalised aches and pains, fatigue, weight gain (9kg over 12 months, up to 61kg), chronic constipation, thinning of the hair and skin, easy bruising, and oligomenorrhoea (three menstrual periods over 12 months). The patient had no history of fractures. On examination she had a body mass index of 20.32kg/m² (height 163cm, weight 54kg), blood pressure of 120/80, and no other clinical features of Cushing’s syndrome.

Morning plasma cortisol was normal at 498nmol/L (ref. range 145-619), with ACTH suppressed at 0.4pmol/L (ref. range 1.6-13.9). Hormonal evaluation demonstrated cortisol excess on two 24-hour urine cortisol assessments and low-dose (1mg) overnight dexamethasone suppression test (Table 1). Other hormonal evaluation, including aldosterone-renin ratio and plasma metanephrines, were normal. HbA1c was 5.2% (33.3mmol/mol). Bone mineral density assessment via dual-energy X-ray absorptiometry was unable to be performed due to COVID-19 restrictions; however CT imaging of the spine did not show any fractures or evidence of osteopaenia.

We made a diagnosis of ACTH-independent Cushing’s syndrome in the context of bilateral adrenal pathology. Autonomous cortisol secretion (ACS), whether associated with overt Cushing’s syndrome or otherwise, is seen in 5-30% of patients with incidentally-found adrenal lesions (1-3). The management of ACTH-independent Cushing’s syndrome is relatively straightforward where unilateral adrenal pathology is seen on imaging, with unilateral adrenalectomy being the usual recommendation (4). However, this decision is made more complicated in the setting of bilateral adrenal pathology, which carries with it a number of differential diagnoses, including bilateral macronodular adrenal hyperplasia, primary pigmented nodular adrenal disease, and bilateral adrenal adenomas (whereby one or both lesions may be autonomous). The distinction between functioning and non-functioning adrenal lesions cannot be made solely based on radiology findings, and although adrenal venous sampling (AVS) may aid in the lateralisation of cortisol excess, the current data are weak (1). Given our patient’s young age, symptom profile (including oligomenorrhoea and weight gain) and potential for future morbidity secondary to cortisol excess, we undertook a literature review for the use of AVS to guide further management. Although there is no currently accepted standard approach for the use of AVS for this indication, a number of alternative methods were identified in the literature, both for confirmation of catheter placement and for lateralisation of excess cortisol production.

Young et al (5) examined the use of AVS in 10 patients with bilateral adrenal lesions and ACS. An adrenal:peripheral adrenaline gradient was used to confirm catheter placement. The authors also used an adrenal:peripheral cortisol gradient cut-off of 6.5 to confirm the presence of a cortisol-secreting adenoma, with a high:low side adrenal vein cortisol gradient >2.3 sufficient to lateralise excess cortisol production to one side. All of the patients in this study had adrenalectomy guided by their AVS results; of the six patients who received unilateral adrenalectomy, none had recurrence of ACS (as shown by morning cortisol levels following overnight dexamethasone suppression test) at a mean follow-up of 36.1 months.

In a prospective study, Ueland et al (6) examined the use of AVS in 39 patients with adrenal lesions on CT imaging (both uni- and bilateral) and ACS.  A metanephrine gradient was used to confirm catheter placement, and a high:low side adrenal vein cortisol gradient >2.3 was again used to confirm lateralisation. The results of AVS testing were also correlated with iodocholesterol scintigraphy in 18 patients, a method of imaging which has been utilised previously to demonstrate cortisol secretion from adrenal lesions. 11 of the 12 patients who underwent AVS-guided unilateral adrenalectomy in this study had resolution of excess cortisol production based on post-operative dexamethasone suppression testing during the 24-month follow-up period. In addition, iodocholesterol scintigraphy was concordant with AVS in 72% of cases.

The cortisol:aldosterone ratio has been used in an attempt to determine lateralisation in case reports by Wei et al (7) and Domino et al (8), although lateralisation was not demonstrated in these cases; it was also used successfully in a case series (9) which used a ratio of >2.0 to confirm lateralisation. In the setting of a normal aldosterone/renin profile, aldosterone may serve as a correction factor to account for dilutional differences between the adrenal veins.

Due to the lack of availability of the isotope required for iodocholesterol scintigraphy, we referred the patient to Monash Health for AVS. Results demonstrated bilateral ACS (adrenal:peripheral cortisol gradients >6.5 bilaterally). All high:low adrenal vein cortisol gradients were <2.0; the results were inconsistent, with the greatest lateralisation ratio (1.86, table 2) shown between the right and left common adrenal veins. When aldosterone was used as a correction factor for the lateralisation index, the maximal cortisol:aldosterone ratio was 6.5 (left:right common adrenal veins, table 2). Lateralisation results based on cortisol:metanephrine ratio were inconsistent. A decision was made to refer the patient for unilateral left adrenalectomy due to the larger size of the left-sided lesion and the greater cortisol:aldosterone ratio on the left.

In patients with ACS and bilateral adrenal lesions, using AVS to measure adrenal vein cortisol normalised to either aldosterone or metanephrines may help to lateralise the source of cortisol excess; however, a standard approach is lacking and the results may be inconsistent.

Key learning points:

• Autonomous cortisol secretion is not an uncommon finding in patients with incidentally identified adrenal adenomas, with the optimal management made more challenging by the finding of bilateral adrenal pathology on imaging.

• Adrenal venous sampling has been described as a method for lateralisation of excess cortisol production in this context, analogous to the procedure’s use in evaluation of primary hyperaldosteronism.

• Challenges pertaining to the use of adrenal venous sampling for this indication include the lack of a standardised approach to biochemical confirmation of catheter placement, and the absence of an accepted correction factor to account for dilutional differences in cortisol between adrenal veins.

• Iodocholesterol scintigraphy is a potentially useful tool in this clinical scenario, however its use is precluded by limited availability in many centres.