Subclinical Cushing’s syndrome and cardiovascular disease

Guido Di Dalmazi and colleagues1 reported that in patients with adrenal incidentalomas and either stable mild hypercortisolism or worsening of cortisol hypersecretion, all-cause and cardiovascular disease-specific mortality was higher compared with in those with adrenal incidentalomas that did not secrete cortisol, after a mean follow-up of 7·5 years. Moreover, cortisol concentrations measured after dexamethasone-suppression test were associated with all-cause mortality independent of the presence of traditional cardiovascular disease risk factors.
Subclinical Cushing’s syndrome is the most common hormonal abnormality in patients with adrenal incidentalomas (prevalence 1—29%).2 The proportion of adrenal incidentalomas that progress to subclinical Cushing’s syndrome is low (1·7%) and most are lesions of 3 cm or larger.2 Progression to overt Cushing’s syndrome is controversial (because both spontaneous normalisation of hypersecretion and stable disease have been reported during follow-up) and spontaneous normalisation of hypersecretion has been reported in 50% of cases.2 Results of the study by Di Dalmazi and co-workers1 are important because they show, for the first time, that patients with subclinical Cushing’s syndrome are at increased risk of cardiovascular disease and all-cause mortality (mainly attributable to cardiovascular disease). The association of cortisol with all-cause mortality might also be attributable to its potential role in the pathogenesis of metabolic syndrome.3
Findings of previous studies have shown an increased prevalence of cardiovascular disease risk factors in patients with subclinical Cushing’s syndrome, but data for optimum management are conflicting. Some criteria—such as large (>4—6 cm) adrenal incidentalomas, features suggestive of malignancy (eg, heterogeneity, irregular shape, calcification or necrosis, invasion to adjacent tissues), or potentially lethal hormonal hypersecretion (ie, pheochromocytomas)—support the need for adrenalectomy. However, universal surgical management of patients with subclinical Cushing’s syndrome has not been accepted.24 Uncertainty about the most effective management strategy for subclinical Cushing’s syndrome is attributable to the variable definitions used, and the small sample size and retrospective nature of most studies.4 Only one prospective study has been published so far showing that laparoscopic adrenalectomy is more beneficial than is conservative management for the normalisation or improvement of cardiovascular disease risk factors, such as diabetes, dyslipidaemia, hypertension, and obesity.5
Prospective studies and registries are needed to document the effect of different approaches on the incidence of cardiovascular disease events and mortality in patients with adrenal incidentalomas and subclinical Cushing’s syndrome. Until then, individualised treatment seems prudent. Surgical management of subclinical Cushing’s syndrome can be suggested in young patients (age <50 years) and in those with cardiovascular disease risk factors or bone disease associated with hypercortisolism that are of recent onset, difficult to control with drugs, or show progression over time.4
Another message from Di Dalmazi’s study1 is that hormonal deterioration might develop even after 4—5 years, which most studies reported as a reasonable and safe follow-up.2 This possibility should be kept in mind for the management of patients with adrenal incidentalomas, especially if clinical signs of Cushing’s syndrome develop or if cardiovascular disease risk factors become evident or increase in severity (ie, hormonal hypersecretion).
We declare that we have no competing interests.


1 Di Dalmazi GVicennati VGarelli S, et alCardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing’s syndrome: a 15-year retrospective studyLancet Diabetes Endocrinol 2014published online Jan 29
2 Anagnostis PKaragiannis ATziomalos KKakafika AIAthyros VGMikhailidis DPAdrenal incidentaloma: a diagnostic challengeHormones (Athens) 20098163-184PubMed
3 Anagnostis PAthyros VGTziomalos KKaragiannis AMikhailidis DPClinical review: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesisJ Clin Endocrinol Metab 200994:2692-2701PubMed
4 Terzolo MPia AReimondo GSubclinical Cushing’s syndrome: definition and managementClin Endocrinol (Oxf) 20127612-18PubMed
5 Toniato AMerante-Boschin IOpocher GPelizzo MRSchiavi FBallotta ESurgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized studyAnn Surg 2009249388-391PubMed
a Division of Endocrinology, Police Medical Centre, Thessaloniki, 54 640, Greece
b Department of Endocrinology and Metabolism, Agios Pavlos General Hospital, Thessaloniki, Greece
c Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
d Department of Clinical Biochemistry (Vascular Prevention Clinic) Royal Free Hospital Campus, University College London Medical School, University College London, London, UK
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