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CV risk elevated in patients with adrenal incidentalomas, mild hypercortisolism
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Patients with adrenal incidentalomas and mild hypercortisolism have an increased risk for cardiovascular events and mortality. This risk was evident even when clinical signs of overt hypercortisolism were not present, according to data published in The Lancet Diabetes & Endocrinology.
“Our findings are important because they add to the previously scant information about adrenal incidentalomas, which will be of use to doctors who are seeing an increasing number of patients with these masses,” Renato Pasquali, MD, of the S. Orsola-Malpighi Hospital in Bologna, Italy, said in a press release.
The retrospective study by Pasquali and colleagues assessed the adrenal incidentalomas of 198 outpatients treated every 18 to 30 months, with a mean follow-up of 7.5 years. At the time of follow-up, 114 patients demonstrated stable non-secreting adrenal incidentalomas (<50 nmol/L), 61 had either a stable intermediate phenotype (50 nmol/L-138 nmol/L) or subclinical Cushing’s syndrome (>138 nmol/L), and 23 patients had worsening pattern of secretion.
The incidence of CV events appeared higher in patients with a stable intermediate phenotype or subclinical Cushing’s syndrome (6.7% vs. 16.7%; P=.04) and in those with worsened secreting patterns (6.7% vs. 28.4%; P=.02) compared with patients with stable non-secreting adrenal incidentalomas, according to data.
In addition, CV events were independently related to changes in cortisol concentrations after the 1-mg dexamethasone suppression test (DST; HR=1.13; 95% CI, 1.05-1.21) from baseline to follow-up.
Patients with stable intermediate phenotype adrenal incidentalomas (57%) or subclinical Cushing’s syndrome (91.2%) tended to have lower survival rates for all-cause mortality (P=.005), researchers wrote. The main risk factors for all-cause mortality were age (HR=1.06; 95% CI, 1.01-1.12) and mean concentrations of cortisol after DST (HR=1.1; 95% CI, 1.01-1.19).
The unadjusted survival for CV-related mortality was lower in patients with either a stable intermediate phenotype (97.5%) or subclinical Cushing’s syndrome (78.4%; P=.02) vs. those with stable non-secreting adrenal incidentalomas (97.5%), and patients with worsened secreting patterns (60%; P=.01).
In an accompanying comment, Rosario Pivonello, MD, PhD, Maria Cristina De Martino, PhD, and Annamaria Colao, MD, PhD, of the Federico II University of Naples, Italy, wrote that the study supports the importance of long-term hormonal follow-up for clinical management of patients with adrenal incidentalomas.
“Furthermore, clinical monitoring of cardiometabolic risks seems to be important in these patients, particularly in those with subclinical Cushing’s syndrome and intermediate phenotype adrenal incidentalomas, for whom medical or surgical intervention could be needed,” they wrote.
They suggest long-term prospective studies to determine the frequency of new CV events and mortality in this patient population.
For more information:
Di Dalmazi G. Lancet Diabetes Endocrinol. 2014;doi:10.1016/S2213-8587(13)70211-0.
Pivonello R. Lancet Diabetes Endocrinol. 2014;doi:10.1016/S2213-8587(13)70190-6.
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Alice C. Levine, MD
The article from Dalmazi and colleagues published in The Lancet, adds to the growing body of literature from centers worldwide implicating mild hypercortisolism as a significant and independent risk factor for cardiovascular and all-cause mortality.
The findings were striking in that cardiovascular events were higher and survival rates for all-cause mortality were lower in patients with either stable intermediate phenotype or subclinical Cushing’s syndrome compared to those patients with stable non-secreting adrenal masses. Cardiovascular events were associated independently with a change in cortisol concentrations post dexamethasone 1 mg (DST). Finally the two factors that were positively associated with mortality were age and mean concentrations of cortisol post DST. There are obvious limitations to the study, including the retrospective nature of the design, the relatively small numbers of patients and the inability to draw conclusions about causality.
However, taken together with other large cross-sectional and prospective trials demonstrating increased cardiovascular risk and reduction of that risk with adrenalectomy for patients with hypercortisolism, this latest report further establishes the need to revise and refine our definitions. Firstly, subclinical Cushing’s syndrome is not-so-subclinical. Emerging data indicates that the “slow-burn” of mild hypercortisolism may be even more deleterious to the cardiovascular system than a quickly diagnosed and treated severe case of hypercortisolism. Secondly, we need to redefine (or, rather, come to a consensus on the definition) of mild hypercortisolism due to adrenal adenomas. It appears than any degree of hypercortisolism is associated with adverse outcomes and therefore it might be prudent to use the same definition for the mild cases as we currently use for clinically-apparent Cushing’s: failure to suppress AM serum cortisol to <1.8 mcg/dl (<50 nmol/L) after DST. Finally, although florid Cushing’s syndrome is a rare disease, mild hypercortisolism due to adrenal adenomas is not; endocrinologists must not only be aware of this growing problem but be prepared to treat it proactively.
Definitions change with time, based on the available data. It is quite telling that during the 15-year time period of the current study from The Lancet, the criteria for the diagnosis of hypertension changed from BP >160/90 mmHg (prior to 1999) to BP >140/90 mmHg after that date and the authors needed to alter their criteria for diagnosing hypertension. Glucose parameters and cholesterol definitions and treatment guidelines have, likewise, been refined significantly based on outcomes data over the past 15 years. Our definition of mild hypercortisolism and our threshold for treating this disorder is in need of an update.
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