Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study

Deutschbein, Timo; Reimondo, Giuseppe; Dalmazi, Guido Di; Bancos, Irina; Patrova, Jekaterina; Vassiliadi, Dimitra Argyro; Nekic, A; Debono, Miguel; Lardo, Pina; Ceccato, Filippo; Petramala, Luigi; Prete, Alessandro; Chiodini, Iacopo; Ivović, Miomira; Pazaitou‐Panayiotou, Kalliopi; Alexandraki, Krystallenia; Hanzu, Felicia A.; Loli, Paola; Yener, Serkan; Langton, Katharina; Spyroglou, Ariadni; Kocjan, Tomaž; Zacharieva, Sabina; Valdés, Nuria; Ambroziak, Urszula; Suzuki, Mari; Detomas, Mario; Puglisi, Soraya; Tucci, Lorenzo; Delivanis, Danae A.; Margaritopoulos, Dimitris; Dušek, Tina; Maggio, Roberta; Scaroni, Carla; Concistrè, Antonio; Ronchi, Cristina L.; Altieri, Barbara; Mosconi, Cristina; Diamantopoulos, Aristidis; Iñiguez-Ariza, Nicole M.; Vicennati, Valentina; Pia, Anna; Kroiß, Matthias; Kaltsas, Gregory; Chrisoulidou, Alexandra; Marina, Ljiljana; Morelli, Valentina; Arlt, Wiebke; Letizia, Claudio; Boscaro, Marco; Stigliano, Antonio; Kaštelan, Darko; Tsagarakis, Stylianos; Athimulam, Shobana; Pagotto, Uberto; Maeder, Uwe; Falhammar, Henrik; Newell‐Price, John; Terzolo, Massimo; Fassnacht, Martin

doi:10.1016/s2213-8587(22)00100-0

Cited by 86 publications

(73 citation statements)

References 32 publications

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“…Despite the absence of typical Cushing's syndrome symptoms and signs, several but not all retrospective cross-sectional and follow-up studies demonstrated that ACS is associated with an increased cardiovascular and all-cause mortality proportional to the degree of cortisol excess [71,[80][81][82][83][84][85][86]. A higher prevalence of hypertension, impaired glucose tolerance and type 2 diabetes, dyslipidemia, osteoporosis, and vertebral fractures along with decline in the quality of life has also been described in comparison to the general population [87][88][89][90].…”

Section: (B) Adrenal Incidentaloma and Autonomous Cortisol Secretionmentioning

confidence: 99%

Diagnosis and management of hypertension in patients with Cushing's syndrome: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension

Fallo

Dalmazi

Beuschlein

et al. 2022

Journal of Hypertension

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Endogenous/exogenous Cushing's syndrome is characterized by a cluster of systemic manifestations of hypercortisolism, which cause increased cardiovascular risk. Its biological basis is glucocorticoid excess, acting on various pathogenic processes inducing cardiovascular damage. Hypertension is a common feature in Cushing's syndrome and may persist after normalizing hormone excess and discontinuing steroid therapy. In endogenous Cushing's syndrome, the earlier the diagnosis the sooner management can be employed to offset the deleterious effects of excess cortisol. Such management includes combined treatments directed against the underlying cause and tailored antihypertensive drugs aimed at controlling the consequences of glucocorticoid excess. Experts on endocrine hypertension and members of the Working Group on Endocrine Hypertension of the European Society of Hypertension (ESH) prepared this Consensus document, which summarizes the current knowledge in epidemiology, genetics, diagnosis, and treatment of hypertension in Cushing's syndrome.

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Section: (B) Adrenal Incidentaloma and Autonomous Cortisol Secretionmentioning

confidence: 99%

Diagnosis and management of hypertension in patients with Cushing's syndrome: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension

Fallo

Dalmazi

Beuschlein

et al. 2022

Journal of Hypertension

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“…In the last years, comprehensive genomics studies of benign and malignant tumours have identified alterations in signalling pathways involved in adrenocortical tumourigenesis (i.e.Wnt/β-catenin, Rb/p53 signalling and/or IGF system) and autonomous cortisol excess (i.e. cAMP/PKA pathway) [5][6][7][8][9][10][11] . However, the molecular mechanisms underlying the pathogenesis of a vast percentage of adrenocortical tumours remained largely unexplained.…”

Section: Introductionmentioning

confidence: 99%

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

Altieri

Secener

Sai

et al. 2022

Preprint

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The human adrenal gland is a complex endocrine tissue. Developmental studies on this tissue have been limited to animal models or human foetus. Here, we present a cell atlas analysis of the adult human normal adrenal gland, combining single-nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland development and tumourigenesis. We identified two populations of potential progenitor cells resident within the adrenal cortex: adrenocortical progenitors NR2F2+-ID1+ cells, located within and underneath the capsule, and medullary progenitors SYT1+-CHGA- cells, located in islets in the subcapsular region. Using pseudotime analyses, we provided evidence of the centripetal nature of adrenocortical cell development and of the essential role played by the Wnt/β-catenin pathway in the adrenocortical self-renewal. By comparing transcriptional profiles of cells of normal adrenal glands and adrenocortical adenomas we revealed a high heterogeneity with six adenoma-specific clusters. Overall, our results give insights into adrenal plasticity and mechanisms underlying adrenocortical tumourigenesis.

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“…Our analysis also included patients with adrenal incidentalomas and MACS [21]. Between 30% and 50% of patients with adrenal incidentalomas have biochemical evidence of possible, low-grade autonomous cortisol release [20], associated with a worsened cardiovascular risk (hypertension, diabetes and obesity), a higher prevalence of cardiovascular events, greater bone loss, and a higher mortality rate [21,24,[48][49][50]. However, very little attention has been paid to the infection risk in patients with MACS.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility and characteristics of infections in patients with glucocorticoid excess or insufficiency: the ICARO tool

Minnetti

Hasenmajer

Sbardella

et al. 2022

European Journal of Endocrinology

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Objective: Registry data show that Cushing’s syndrome (CS) and adrenal insufficiency (AI) increase mortality rates associated with infectious diseases. Little information is available on susceptibility to milder forms of infections, especially those not requiring hospitalization. This study aimed to investigate infectious diseases in patients with glucocorticoid disorders through the development of a specific tool. Methods: We developed and administered the ICARO (InfeCtions in pAtients with endocRinOpathies) questionnaire, addressing infectious events over a 12-month observation period, to 1017 outpatients referred to four University Hospitals. The ICARO questionnaire showed good test-retest reliability. The odds of infection (OR[95% confidence interval]) were estimated after adjustment for confounders and collated into the ICARO score, reflecting frequency and duration of infections. Results: 780 patients met the inclusion criteria: 43 with CS, 32 with adrenal incidentaloma and mild autonomous cortisol secretion (MACS), and 135 with AI, plus 570 controls. Compared to controls, CS was associated with higher odds of urinary tract infections (UTIs) (5.1[2.3-9.9]), mycoses (4.4[2.1-8.8]), and flu (2.9[1.4-5.8]). Patients with adrenal incidentaloma and MACS also showed an increased risk of UTIs (3.7[1.7-8.0]) and flu (3.2 [1.5-6.9]). Post-dexamethasone cortisol levels correlated with the ICARO score in patients with CS. AI was associated with higher odds of UTIs (2.5[1.6-3.9]), mycoses (2.3[1.4-3.8]), and gastrointestinal infections (2.2[1.5-3.3]), independently of any glucocorticoid replacement dose. Conclusions: The ICARO tool revealed a high prevalence of self-reported infections in patients with glucocorticoid disorders. ICARO is the first of its kind questionnaire, which could be a valuable tool for monitoring infections in various clinical settings.

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Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study

Cited by 86 publications

References 32 publications

Diagnosis and management of hypertension in patients with Cushing's syndrome: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension

Diagnosis and management of hypertension in patients with Cushing's syndrome: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension

Cell Atlas at Single-Nuclei Resolution of the Adult Human Adrenal Gland and Adrenocortical Adenomas

Susceptibility and characteristics of infections in patients with glucocorticoid excess or insufficiency: the ICARO tool

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