Incidentally discovered adrenal masses and subclinical Cushing syndrome

The frequency of incidental discovery of adrenal masses (adrenal incidentaloma) is increasing due to widespread use of computerized abdominal imaging — adrenal incidentalomas are encountered in approximately 5 percent of imaging studies.

Irina Bancos, M.D., a consultant with Endocrinology, Diabetes, Metabolism and Nutrition at Mayo Clinic's campus in Rochester, Minnesota, explains: "Tumors of the adrenal cortex or medulla can result in hormonal excess, which includes catecholamine excess, mineralocorticoid excess and glucocorticoid excess (Cushing syndrome). Cushing syndrome (CS) is associated with clinically significant morbidity and mortality. Such patients may present with weight gain, altered fat redistribution, skin fragility, easy bruisability and purple striae, muscle loss and proximal myopathy, osteoporosis and fractures, diabetes mellitus, dyslipidemia, and hypertension."

While CS is quite rare, much more commonly, patients with adrenal tumors present with bio-chemical evidence of mild autonomous cortisol production without development of overt cush-ingoid features. Dr. Bancos highlights: "This condition is frequently labeled as subclinical CS (SCS). The definition of SCS varies, but mainly relies on demonstration of nonsuppressible morning cortisol with the overnight 1-mg dexamethasone suppression test (DST).

"The 1-mg DST is considered the most valuable test in SCS despite the ongoing debate on the optimal dose of dexamethasone (for example, 1, 2 or 8 mg), the most accurate cortisol cutoff (for example, 1.8, 2.2 or 5 mcg/dL), and a wide range of reported sensitivity (44 to 100 percent) and specificity (24 to 100 percent).

"As shown in a study published by Melvin M. Grumbach, M.D., and others in Annals of Internal Medicine in 2003, around 30 percent of patients with adrenal incidentaloma fulfill the criteria of SCS. Though patients with SCS lack symptoms and signs of overt CS, several reports, including studies published by Maurizio Iacobone, M.D., and others in Surgery in 2012 and Valentina Morelli, M.D., Ph.D., and others, published in The Journal of Clinical Endocrinology & Metabolism in 2014, have shown that SCS is associated with a high prevalence of hypertension, obesity, diabetes mellitus, dyslipidemia and osteoporosis.

"As a group, patients with SCS have higher rates of cardiovascular risk factors and events. However, management of an individual patient with SCS is controversial as the contribution of mild hypercortisolism toward the development of otherwise prevalent hypertension, weight gain, dyslipidemia, diabetes mellitus and cardiovascular events is unknown. Indeed, while some studies reported partial improvement of cardiometabolic risk factors in certain patients, the degree of improvement was unpredictable.

"The current classification of patients with adrenal tumors and glucocorticoid excess fails to accurately predict the individual harmful metabolic effect of hypercortisolism. Although it is well-known that glucocorticoids have a wide range of metabolic actions, it remains to be determined how exactly mild hypercortisolism affects metabolic parameters and whether any metabolic markers could identify individuals with SCS who would be more likely to benefit from the surgery. Currently, such patients usually undergo follow-up with targeted testing to identify any (possibly cortisol induced) metabolic abnormalities. And referral for adrenalectomy is largely dependent on the endocrinologist's comfort level with SCS and the patient's preference."

A team of investigators at Mayo Clinic is currently attempting to better understand differences in steroid production in patients with SCS as well as tie in measured abnormalities with cortisol-induced metabolic changes. Dr. Bancos says: "Our team has recently developed a novel assay that measures 26 urinary steroid metabolites by high-resolution liquid chromatography-mass spectrometry (LC-MS). We are in the process of developing a serum steroid assay aimed to discern false-positives from true clinically significant abnormalities in steroid production of patients with SCS. Such in-depth adrenal steroid profiling allows us to better characterize adrenal tumor glucocorticoid production other than cortisol.

"In addition, we have an active trial for patients with adrenal tumors referred for adrenalectomy in whom we are able to combine in-depth steroid profiling with testing of beta cell function and insulin sensitivity before and after adrenalectomy. We are hopeful that identifying biomarkers of hypercortisolism's influence on metabolism in the future will allow us to intervene in a timely manner and prevent irreversible complications that occur in select patients with SCS," says Dr. Bancos.

For more information

Grumbach MM, et al. Management of the clinically inapparent adrenal mass (incidentaloma). Annals of Internal Medicine. 2003;138:424.

Iacobone M, et al. Adrenalectomy may improve cardiovascular and metabolic impairment and ameliorate quality of life in patients with adrenal incidentalomas and subclinical Cushing's syndrome. Surgery. 2012;152:991.

Morelli V, et al. Long-term follow-up in adrenal incidentalomas: An Italian multicenter study. The Journal of Clinical Endocrinology & Metabolism. 2014;99:827.