Adrenal Incidentaloma: Picking out the High-Risk Patients

Abstract

Patients with adrenal incidentalomas and autonomous cortisol secretion (ACS) have been recognized as a category at risk of developing cardiovascular and metabolic co-morbidities. Considering the increasing number of patients affected by this condition, it is important to perform an accurate subtyping of the patients, in the light of a tailored treatment. This review aims to identify the phenotypic characteristics of patients with adrenal incidentalomas and ACS who are at risk of developing severe cortisol-related co-morbidities. ACS has been associated with severe alteration of the cardiovascular profile, including hypertension, diabetes, and atherosclerosis. Moreover, ACS has been identified as a contributing factor to the development of cardiovascular events and related mortality. Patients with ACS are also at risk of incident bone fractures, which occur in half of the patients independently of the bone mass density, and infectious diseases. Severity and persistence of hypercortisolism are among the main contributing factors for cardiovascular diseases and bone fractures. Moreover, progression of hypercortisolism over time and altered circadian cortisol rhythm seem to be important additional factors. The role of potential novel biomarkers is also discussed in this review.

Key words

adrenal incidentalomas - non-functioning - subclinical hypercortisolism - autonomous cortisol secretion - fractures - osteoporosis - cardiovascular diseases

• References

• 1 Fassnacht M, Arlt W, Bancos I. et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2016; 175: G1-G34
• 2 Di Dalmazi G, Pasquali R, Beuschlein F. et al. Subclinical hypercortisolism: A state, a syndrome, or a disease?. Eur J Endocrinol 2015; 173: M61-M71
• 3 Omura M, Saito J, Yamaguchi K. et al. Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens Res 2004; 27: 193-202
• 4 Martins LC, Conceição FL, Muxfeldt ES. et al. Prevalence and associated factors of subclinical hypercortisolism in patients with resistant hypertension. J Hypertens 2012; 30: 967-973
• 5 Reimondo G, Allasino B, Coletta M. et al. Evaluation of midnight salivary cortisol as a predictor factor for common carotid arteries intima media thickness in patients with clinically inapparent adrenal adenomas. Int J Endocrinol 2015; 2015: 674734
• 6 Evran M, Akkus G, Berk Bozdoğan İ. et al. Carotid intima-media thickness as the cardiometabolic risk indicator in patients with nonfunctional adrenal mass and metabolic syndrome screening. Med Sci Monit 2016; 22: 991-997
• 7 Imga NN, Ucar Elalmis O, Muslum Tuna M. et al. The relationship between increased epicardial fat thickness and left ventricular hypertrophy and carotid intima-media thickness in patients with nonfunctional adrenal incidentaloma. Int J Endocrinol Metab 2016; 14: e37635
• 8 Lupoli R, Ambrosino P, Tortora A. et al. Markers of atherosclerosis in patients with Cushing's syndrome: a meta-analysis of literature studies. Ann Med 2017; 49: 206-216
• 9 Di Dalmazi G. Update on the risks of benign adrenocortical incidentalomas. Curr Opin Endocrinol Diabetes Obes 2017; 24: 193-199
• 10 Lopez D, Luque-Fernandez MA, Steele A. et al. “Nonfunctional” adrenal tumors and the risk for incident diabetes and cardiovascular outcomes: a cohort study. Ann Intern Med 2016; 165: 533-542
• 11 Pivonello R, Isidori AM, De Martino MC. et al. Complications of Cushing's syndrome: State of the art. Lancet Diabetes Endocrinol 2016; 4: 611-629
• 12 Świątkowska-Stodulska R, Sworczak K. Disorders of hemostasis in overt and subclinical hypercortisolism. Exp Clin Endocrinol Diabetes 2013; 121: 588-594
• 13 Di Dalmazi G, Vicennati V, Garelli S. et al. Cardiovascular 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 study. Lancet Diabetes Endocrinol 2014; 2: 396-405
• 14 Morelli V, Reimondo G, Giordano R. et al. Long-term follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol Metab 2014; 99: 827-834
• 15 Debono M, Bradburn M, Bull M. et al. Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas. J Clin Endocrinol Metab 2014; 99: 4462-4470
• 16 Di Dalmazi G, Vicennati V, Rinaldi E. et al. Progressively increased patterns of subclinical cortisol hypersecretion in adrenal incidentalomas differently predict major metabolic and cardiovascular outcomes: A large cross-sectional study. Eur J Endocrinol 2012; 166: 669-677
• 17 Sbardella E, Minnetti M, D’Aluisio D. et al. Cardiovascular features of possible autonomous cortisol secretion in patients with adrenal incidentalomas. Eur J Endocrinol 2018; 178: 501-511
• 18 Kumari M, Shipley M, Stafford M. et al. Association of diurnal patterns in salivary cortisol with all-cause and cardiovascular mortality: Findings from the Whitehall II study. J Clin Endocrinol Metab 2011; 96: 1478-1485
• 19 Ronaldson A, Kidd T, Poole L. et al. Diurnal cortisol rhythm is associated with adverse cardiac events and mortality in coronary artery bypass patients. J Clin Endocrinol Metab 2015; 100: 3676-3682
• 20 Ceccato F, Barbot M, Albiger N. et al. Daily salivary cortisol and cortisone rhythm in patients with adrenal incidentaloma. Endocrine 2018; 59: 510-519
• 21 Cornelissen G. Cosinor-based rhythmometry. Theor Biol Med Model 2014; 11: 16
• 22 Roelfsema F, van Heemst D, Iranmanesh A. et al. Impact of age, sex and body mass index on cortisol secretion in 143 healthy adults. Endocr Connect 2017; 6: 500-509
• 23 Debono M, Harrison RF, Chadarevian R. et al. Resetting the abnormal circadian cortisol rhythm in adrenal incidentaloma patients with mild autonomous cortisol secretion. J Clin Endocrinol Metab 2017; 102: 3461-3469
• 24 Arlt W, Lang K, Sitch AJ et al. Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI Insight 2017; 2: pii: 93136
• 25 Fallo F, Castellano I, Gomez-Sanchez CE. et al. Histopathological and genetic characterization of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion: A case series. Endocrine 2017; 58: 503-512
• 26 Eisenhofer G, Masjkur J, Peitzsch M. et al. Plasma steroid metabolome profiling for diagnosis and subtyping patients with cushing syndrome. Clin Chem 2018; 64: 586-596
• 27 Di Dalmazi G, Fanelli F, Mezzullo M. et al. Steroid profiling by LC-MS/MS in nonsecreting and subclinical cortisol-secreting adrenocortical adenomas. J Clin Endocrinol Metab 2015; 100: 3529-3538
• 28 Tóth M, Grossman A. Glucocorticoid-induced osteoporosis: Lessons from Cushing’s syndrome. Clin Endocrinol (Oxf) 2013; 79: 1-11
• 29 Chiodini I, Vainicher CE, Morelli V. et al. mechanisms in endocrinology: Endogenous subclinical hypercortisolism and bone: a clinical review. Eur J Endocrinol 2016; 175: R265-R282
• 30 Mazziotti G, Frara S, Giustina A. Pituitary diseases and bone. Endocr Rev 2018; [Epub ahead of print]
• 31 Tauchmanovà L, Pivonello R, Di Somma C. et al. Bone demineralization and vertebral fractures in endogenous cortisol excess: Role of disease etiology and gonadal status. J Clin Endocrinol Metab 2006; 91: 1779-1784
• 32 Valassi E, Santos A, Yaneva M. et al. The European Registry on Cushing's syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur J Endocrinol 2011; 165: 383-392
• 33 Morelli V, Eller-Vainicher C, Salcuni AS. et al. Risk of new vertebral fractures in patients with adrenal incidentaloma with and without subclinical hypercortisolism: A multicenter longitudinal study. J Bone Miner Res 2011; 26: 1816-1821
• 34 Genant HK, Delmas PD, Chen P. et al. Severity of vertebral fracture reflects deterioration of bone microarchitecture. Osteoporos Int 2007; 18: 69-76
• 35 Pothuaud L, Carceller P, Hans D. Correlations between grey–level variations in 2D projection images (TBS) and 3D microarchitecture: Applications in the study of human trabecular bone microarchitecture. Bone 2008; 42: 775-787
• 36 Chiodini I, Morelli V, Masserini B. et al. Bone mineral density, prevalence of vertebral fractures, and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: An Italian multicenter study. J Clin Endocrinol Metab 2009; 94: 3207-3214
• 37 Eller-Vainicher C, Morelli V, Ulivieri FM. et al. Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism. J Bone Miner Res 2012; 27: 2223-2230
• 38 Vinolas H, Grouthier V, Mehsen-Cetre N et al Assessment of vertebral microarchitecture in overt and mild Cushing's syndrome using trabecular bone score. Clin Endocrinol (Oxf) 2018 [Epub ahead of print]
• 39 Vestergaard P, Lindholm J, Jorgensen JO. et al. Increased risk of osteoporotic fractures in patients with Cushing's syndrome. Eur J Endocrinol 2002; 146: 51-56
• 40 Delivanis DA, Iñiguez-Ariza NM, Zeb MH. et al. Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas. Clin Endocrinol (Oxf) 2018; 88: 209-216
• 41 Berr CM, Stieg MR, Deutschbein T. et al. Persistence of myopathy in Cushing's syndrome: Evaluation of the German Cushing's Registry. Eur J Endocrinol 2017; 176: 737-746
• 42 Di Dalmazi G, Quinkler M, Deutschbein T. et al. Cortisol-related metabolic alterations assessed by mass spectrometry assay in patients with Cushing's syndrome. Eur J Endocrinol 2017; 177: 227-237
• 43 Kim JH, Kwak MK, Ahn SH et al. Alteration in skeletal muscle mass in women with subclinical hypercortisolism. Endocrine 2018 [Epub ahead of print]
• 44 Drey M, Berr CM, Reincke M. et al. Cushing's syndrome: A model for sarcopenic obesity. Endocrine 2017; 57: 481-485
• 45 Ohlsson C, Nethander M, Karlsson MK et al. Serum dhea and its sulfate are associated with incident fall risk in older men: The mros sweden study. J Bone Miner Res 2018 [Epub ahead of print]
• 46 Dekkers OM, Horvath-Puho E, Jorgensen JO. et al. Multisystem morbidity and mortality in Cushing’s syndrome: A cohort study. J Clin Endocrinol Metab 2013; 98: 2277-2284
• 47 Isidori AM, Venneri MA, Graziadio C. et al. Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): A single-blind, randomised controlled trial. Lancet Diabetes Endocrinol 2018; 6: 173-185