Alessandro Prete1, Anuradhaa Subramanian2, Irina Bancos3, Vasileios Chortis1, Stylianos Tsagarakis4, Katharina Lang1, Magdalena Macech5, Danae A Delivanis6, Ivana D Pupovac7, Giuseppe Reimondo8, Ljiljana V Marina9, Timo Deutschbein10, Maria Balomenaki4, Michael W O'Reilly11, Lorna C Gilligan12, Carl Jenkinson12, Tomasz Bednarczuk5, Catherine D Zhang6, Tina Dusek7, Aristidis Diamantopoulos4, Miriam Asia13, Agnieszka Kondracka5, Dingfeng Li6, Jimmy R Masjkur14, Marcus Quinkler15, Grethe Å Ueland16, M Conall Dennedy17, Felix Beuschlein18, Antoine Tabarin19, Martin Fassnacht20, Miomira Ivović9, Massimo Terzolo8, Darko Kastelan7, William F Young6, Konstantinos N Manolopoulos12, Urszula Ambroziak5, Dimitra A Vassiliadi4, Angela E Taylor12, Alice J Sitch21, Krishnarajah Nirantharakumar22, Wiebke Arlt23. 1. The Institute of Metabolism and Systems Research, University of Birmingham, Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, and Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom (A.P., V.C., K.L.). 2. Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom (A.S.). 3. Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom, and Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota (I.B.). 4. Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece (S.T., M.B., A.D., D.A.V.). 5. Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland (M.M., T.B., A.K., U.A.). 6. Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota (D.A.D., C.D.Z., D.L., W.F.Y.). 7. Department of Endocrinology, University Hospital Centre Zagreb, Zagreb, Croatia (I.D.P., T.D., D.K.). 8. Division of Internal Medicine, University of Turin, San Luigi Hospital, Turin, Italy (G.R., M.T.). 9. Department for Obesity, Reproductive and Metabolic Disorders, Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia (L.V.M., M.I.). 10. Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital Würzburg, University of Würzburg, Würzburg, and Medicover Oldenburg MVZ, Oldenburg, Germany (T.D.). 11. Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom, and Department of Medicine, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Republic of Ireland (M.W.O.). 12. Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom (L.C.G., C.J., K.N.M., A.E.T.). 13. Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, and Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom (M.A.). 14. Department of Medicine III and Institute of Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany (J.R.M.). 15. Endocrinology in Charlottenburg, Berlin, Germany (M.Q.). 16. Department of Endocrinology, Haukeland University Hospital, Bergen, Norway (G.Å.U.). 17. Department of Endocrinology, University Hospital Galway, Newcastle, Galway, Republic of Ireland (M.C.D.). 18. Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitäts Spital Zürich (USZ) und Universität Zürich (UZH), Zurich, Switzerland, and Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany (F.B.). 19. Service d'Endocrinologie, Centre Hospitalier Universitaire de Bordeaux, Hôpital du Haut-Lévêque, Pessac, France (A.T.). 20. Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital Würzburg, University of Würzburg, Würzburg, Germany (M.F.). 21. Institute of Applied Health Research, University of Birmingham, and NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom (A.J.S.). 22. Institute of Metabolism and Systems Research, University of Birmingham, Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, and Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom (K.N.). 23. Institute of Metabolism and Systems Research, University of Birmingham, Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, and NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom (W.A.).
Abstract
BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.
BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.
Authors: Isadora P Cavalcante; Annabel Berthon; Maria C Fragoso; Martin Reincke; Constantine A Stratakis; Bruno Ragazzon; Jérôme Bertherat Journal: Nat Rev Endocrinol Date: 2022-08-03 Impact factor: 47.564