Mild autonomous cortisol secretion in benign adrenal tumors increases cardiometabolic risk
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Mild autonomous cortisol secretion is prevalent in nearly half of adults with benign adrenal tumors and can increase the risk for hypertension and type 2 diabetes, according to study data published in the Annals of Internal Medicine.
In an analysis of data from participants in the ENSAT EURINE-ACT study, about 45% had possible or definitive mild autonomous cortisol secretion, with most cases found in women.
“Based on our findings and the high prevalence of adrenal tumors, we estimate that over 2 million adults in the U.S. could have mild autonomous cortisol secretion,” Alessandro Prete, MBBS, MD, the Diabetes UK Sir George Alberti Research Fellow at the Institute of Metabolism and Systems Research at the University of Birmingham College of Medical and Dental Sciences, U.K., told Healio. “Only a minority of people with incidentally discovered adrenal tumors are referred to an endocrinologist and undergo optimal workup to exclude mild autonomous cortisol secretion. If left undiagnosed, people with mild autonomous cortisol secretion are at risk of developing adverse cardiometabolic consequences and present with poorly controlled hypertension and type 2 diabetes.”
Prete and colleagues analyzed data from 1,305 participants (67% women) with benign adrenal tumors in the ENSAT EURINE-ACT study, which recruited adults with newly diagnosed adrenal tumors of more than 1 cm from 2011 to 2016. Participants were defined as having mild autonomous cortisol secretion if their morning serum cortisol concentration was not suppressed to less than 50 nmol/L after administration of 1 mg of dexamethasone at 11 p.m. the preceding night and they did not have clinical features of Cushing’s syndrome. Possible mild autonomous cortisol secretion was defined as a serum cortisol between 50 nmol/L and 138 nmol/L and definitive as a serum cortisol greater than 138 nmol/L. The prevalence of hypertension, prediabetes, type 2 diabetes and dyslipidemia were determined based on clinical data at adrenal tumor diagnosis. Participants with hypertension or type 2 diabetes were also part of a subgroup analysis of outcomes based on the number of antihypertensives prescribed or insulin therapy, respectively.
Mild cortisol secretion increases hypertension, diabetes risk
Of the study cohort, 49.7% had a nonfunctioning adrenal tumor, 34.6% were diagnosed with possible mild autonomous cortisol secretion, 10.7% with definitive mild autonomous cortisol secretion and 5% with clinically overt adrenal Cushing’s syndrome. Women were 73.6% of those diagnosed with definitive mild autonomous cortisol secretion and 86.2% of those with Cushing’s syndrome. Adults with mild autonomous cortisol secretion were more likely to present with bilateral tumors than those with a nonfunctioning adrenal tumor (30.1% vs. 16.5%).
“It surprised us just how common mild autonomous cortisol secretion was in our study,” Prete said. “Previous smaller studies reported a prevalence of mild autonomous cortisol secretion of up to 30% in people with adrenal tumors. Conversely, we found that mild autonomous cortisol secretion, defined as the failure to suppress serum cortisol sufficiently during the 1 mg dexamethasone suppression test, is much more prevalent.”
Participants with definitive mild autonomous cortisol secretion had a higher prevalence of hypertension than those with a nonfunctioning adrenal tumor (adjusted prevalence ratio [aPR] = 1.15; 95% CI, 1.04-1.27). A higher prevalence of hypertension was also observed in those with Cushing’s syndrome compared with a nonfunction adrenal tumor (aPR = 1.37; 95% CI, 1.16-1.62). The prevalence of requiring three or more antihypertensive medications was higher for those with definitive mild autonomous cortisol secretion (aPR = 1.31; 95% CI, 1.02-1.68) and Cushing’s syndrome (aPR = 2.22; 95% CI, 1.62-3.05).
Those with Cushing’s syndrome had a higher prevalence for type 2 diabetes compared with those with a nonfunctioning adrenal tumor (aPR = 1.62; 95% CI, 1.08-2.42). Of those with type 2 diabetes, insulin was required more often in adults with definitive mild autonomous cortisol secretion (aPR = 1.89; 95% CI, 1.01-3.52) and Cushing’s syndrome (aPR = 3.06; 95% CI, 1.6-5.85) compared with those with a nonfunctioning adrenal tumor. There were no differences observed in dyslipidemia prevalence.
Adults with mild autonomous cortisol secretion and bilateral adrenal tumors were more often prescribed three or more hypertension medications than those with unilateral tumors (aPR = 1.28; 95% CI, 1.01-1.62) and were more frequently diagnosed with dysglycemia (aPR = 1.2; 95% CI, 1.01-1.41).
More studies on cardiometabolic risk needed
Prete said more studies are needed to examine the association between cardiometabolic risk and mild autonomous cortisol secretion in greater detail.
“First, it is imperative to establish how mild autonomous cortisol secretion is linked to the increased cardiometabolic risk by investigating how cortisol excess affects human metabolism,” Prete said. “Second, researchers should investigate the prognostic risk stratification of people with mild autonomous cortisol secretion, in order to identify early on those who carry a higher risk of developing adverse cardiometabolic consequences. Third, new treatment strategies should be tested to mitigate this risk in affected individuals.”
In a related editorial, Andre Lacroix, MD, FCAHS, professor of medicine at the University of Montreal Teaching Hospital, said the study supports European Society of Endocrinology guidelines recommending that providers determine the cardiometabolic consequences of mild autonomous cortisol secretion in adults with benign adrenal tumors. However, he questioned the use of a single 1 mg dexamethasone test to diagnose mild autonomous cortisol secretion.
“There are potential pitfalls in relying on a single serum cortisol value after the 1 mg dexamethasone test, which can be influenced by several factors including alterations in corticosteroid-binding globulin levels, various cortisol assays with less precision in low values, and drug interference with dexamethasone metabolism,” Lacroix wrote in the editorial.
Lacroix wrote that future studies are needed to examine the effects of modest cortisol excess on other target tissues and the effects of treating mild cortisol excess with steroidogenesis inhibitors, glucocorticoid receptor antagonists or surgery.
Reference:
For more information:
Alessandro Prete, MBBS, MD, can be reached at a.prete@bham.ac.uk.
Perspective
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Ricardo Correa, MD, EsD, FACE, FACP, CMQ
Adrenal masses discovered by chance are known as adrenal incidentalomas. Their prevalence has increased significantly in recent decades due to the more frequent use of imaging, such as CT, MRI and ultrasound. These findings are made during emergency room visits, outpatient imaging or hospitalization in clinical conditions related to the chest or abdomen. Incidentally discovered adrenal tumors are recorded in about 5% of adults undergoing cross-sectional imaging. Adrenal incidentaloma can be classified as malignant or benign, depending on the imaging characteristics.
A benign adrenal incidentaloma can cause some adrenal cortex hormonal production that can go from overt hypercortisolism and hyperaldosteronism to mild autonomous cortisol secretion (up to 35% reported) to no production at all (nonfunctioning adrenal tumor). Several studies have reported an increased prevalence of cardiometabolic comorbidities in patients with adrenal incidentaloma and mild autonomous cortisol secretion in the last years.
The study by Prete and colleagues aimed to investigate the clinical characteristics, cardiometabolic burden and urinary steroid excretion in persons with benign adrenal tumors. To date, this has been the most extensive prospective study with patients with benign adrenal tumors.
The researchers included 1,305 patients with adrenal tumors more than 1 cm from 2011 to 2016. They found that persons with benign adrenal tumors and mild autonomous cortisol secretion have increased prevalence and severity of hypertension and diabetes compared with persons with nonfunctioning adrenal tumor. In contrast, a non-significant difference was found between the two groups regarding dyslipidemia. Furthermore, the mild autonomous cortisol secretion group carries an increased cardiometabolic burden as in overt hypercortisolism.
Even though there are some limitations to this study, including cross-sectional design, the finding reinforces the knowledge that we should consider a more aggressive individualized approach (surgery) for patients with adrenal incidentaloma and mild autonomous cortisol secretion considering age, comorbidities and patient preference due to elevated cardiovascular risk.
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