Online first
Review paper
Published online: 2024-12-11

open access

Page views 78
Article views/downloads 62
Get Citation

Connect on Social Media

Connect on Social Media

Adrenal tumours and subclinical adrenal hyperfunction

Lucyna Siemińska1, Katarzyna Siemińska2, Bogdan Marek1, Beata Kos-Kudła3, Mariusz Nowak1, Joanna Głogowska-Szeląg1, Dariusz Kajdaniuk1

Abstract

There is a significantly higher prevalence of obesity, hypertension, impaired glucose metabolism, and dyslipidaemia in patients with adrenal incidentalomas. The role of excess adipose tissue in the pathogenesis of adrenal adenomas has not been explored in depth. The study reviews the knowledge about different mechanisms that are related to adrenal tumourigenesis and steroidogenesis. The next objective of this paper is to provide an overview of subclinical types of adrenal hormonal hyperfunction. Recent research has challenged the bimodal diagnosis of hypercortisolism and primary hyperaldosteronism as categorical diseases. Currently we know that milder and subclinical forms are very common, and their involvement in cardiovascular disease is well characterised. Mild autonomous cortisol secretion and mild primary aldosteronism lead to the development of hypertension and metabolic disturbances. The clinical picture of pheochromocytoma is extremely variable and depends on the synthesis and release of catecholamines. The term “subclinical” does not apply fully to pheochromocytoma.

In this case, it would be appropriate to describe the tumour as clinically silent. In addition, the term “biochemically silent” is used, based on biochemistry, when plasma and urinary metanephrine levels are below the upper cut-offs of the reference intervals.

 

Article available in PDF format

View PDF Download PDF file

References

  1. Sherlock M, Scarsbrook A, Abbas A, et al. Adrenal Incidentaloma. Endocr Rev. 2020; 41(6): 775–820.
  2. Reimondo G, Castellano E, Grosso M, et al. Adrenal Incidentalomas are Tied to Increased Risk of Diabetes: Findings from a Prospective Study. J Clin Endocrinol Metab. 2020; 105(4).
  3. 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(8): 533–542.
  4. Reincke M, Fassnacht M, Väth S, et al. Adrenal incidentalomas: a manifestation of the metabolic syndrome? Endocr Res. 1996; 22(4): 757–761.
  5. Peppa M, Boutati E, Koliaki C, et al. Insulin resistance and metabolic syndrome in patients with nonfunctioning adrenal incidentalomas: a cause-effect relationship? Metabolism. 2010; 59(10): 1435–1441.
  6. Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, et al. Human adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci U S A. 2003; 100(24): 14211–14216.
  7. Kargi AY, Iacobellis G. Adipose tissue and adrenal glands: novel pathophysiological mechanisms and clinical applications. Int J Endocrinol. 2014; 2014: 614074.
  8. Babinska A, Kmieć P, Sworczak K. The role of selected adipokines in tumorigenesis and metabolic disorders in patients with adrenal tumors. Arch Med Sci. 2023; 19(2): 467–477.
  9. Muscogiuri G, Sorice GP, Prioletta A, et al. The size of adrenal incidentalomas correlates with insulin resistance. Is there a cause-effect relationship? Clin Endocrinol (Oxf). 2011; 74(3): 300–305.
  10. Altieri B, Tirabassi G, Della Casa S, et al. Adrenocortical tumors and insulin resistance: What is the first step? Int J Cancer. 2016; 138(12): 2785–2794.
  11. Midorikawa S, Sanada H, Hashimoto S, et al. The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection. Clin Endocrinol (Oxf). 2001; 54(6): 797–804.
  12. Morelli V, Frigerio S, Aresta C, et al. Adrenalectomy Improves Blood Pressure and Metabolic Control in Patients With Possible Autonomous Cortisol Secretion: Results of a RCT. Front Endocrinol (Lausanne). 2022; 13: 898084.
  13. Bernini G, Moretti A, Iacconi P, et al. Anthropometric, haemodynamic, humoral and hormonal evaluation in patients with incidental adrenocortical adenomas before and after surgery. Eur J Endocrinol. 2003; 148(2): 213–219.
  14. Bonnet S, Gaujoux S, Launay P, et al. Wnt/β-catenin pathway activation in adrenocortical adenomas is frequently due to somatic CTNNB1-activating mutations, which are associated with larger and nonsecreting tumors: a study in cortisol-secreting and -nonsecreting tumors. J Clin Endocrinol Metab. 2011; 96(2): E419–E426.
  15. Kamilaris CDC, Hannah-Shmouni F, Stratakis CA. Adrenocortical tumorigenesis: Lessons from genetics. Best Pract Res Clin Endocrinol Metab. 2020; 34(3): 101428.
  16. Cyranska-Chyrek E, Szczepanek-Parulska E, Olejarz M, et al. Malignancy Risk and Hormonal Activity of Adrenal Incidentalomas in a Large Cohort of Patients from a Single Tertiary Reference Center. Int J Environ Res Public Health. 2019; 16(10).
  17. Elhassan YS, Alahdab F, Prete A, et al. Natural History of Adrenal Incidentalomas With and Without Mild Autonomous Cortisol Excess: A Systematic Review and Meta-analysis. Ann Intern Med. 2019; 171(2): 107–116.
  18. Sung H, Siegel RL, Torre LA, et al. Global patterns in excess body weight and the associated cancer burden. CA Cancer J Clin. 2019; 69(2): 88–112.
  19. Stepaniak U, Micek A, Waśkiewicz A, et al. Prevalence of general and abdominal obesity and overweight among adults in Poland. Results of the WOBASZ II study (2013-2014) and comparison with the WOBASZ study (2003-2005). Pol Arch Med Wewn. 2016; 126(9): 662–671.
  20. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults. Lancet. 2024; 403(10431): 1027–1050.
  21. Kinyua AW, Doan KV, Yang DJ, et al. Insulin Regulates Adrenal Steroidogenesis by Stabilizing SF-1 Activity. Sci Rep. 2018; 8(1): 5025.
  22. Angelousi A, Kyriakopoulos G, Nasiri-Ansari N, et al. The role of epithelial growth factors and insulin growth factors in the adrenal neoplasms. Ann Transl Med. 2018; 6(12): 253.
  23. Belfiore A, Malaguarnera R, Vella V, et al. Insulin Receptor Isoforms in Physiology and Disease: An Updated View. Endocr Rev. 2017; 38(5): 379–431.
  24. Swierczynska MM, Mateska I, Peitzsch M, et al. Changes in morphology and function of adrenal cortex in mice fed a high-fat diet. Int J Obes (Lond). 2015; 39(2): 321–330.
  25. Witt A, Mateska I, Palladini A, et al. Fatty acid desaturase 2 determines the lipidomic landscape and steroidogenic function of the adrenal gland. Sci Adv. 2023; 9(29): eadf6710.
  26. Janssen JA. New Insights into the Role of Insulin and Hypothalamic-Pituitary-Adrenal (HPA) Axis in the Metabolic Syndrome. Int J Mol Sci. 2022; 23(15).
  27. Ermetici F, Malavazos AE, Corbetta S, et al. Adipokine levels and cardiovascular risk in patients with adrenal incidentaloma. Metabolism. 2007; 56(5): 686–692.
  28. Kushlinskii NE, Britvin TA, Kazantseva IA, et al. Serum interleukin-6 in patients with adrenal tumors. Bull Exp Biol Med. 2004; 137(3): 273–275.
  29. Babinska A, Kaszubowski M, Sworczak K. Adipokine and cytokine levels in non-functioning adrenal incidentalomas (NFAI). Endocr J. 2018; 65(8): 849–858.
  30. Glasow A, Bornstein SR, Chrousos GP, et al. Detection of Ob-receptor in human adrenal neoplasms and effect of leptin on adrenal cell proliferation. Horm Metab Res. 1999; 31(4): 247–251.
  31. Babińska A, Pęksa R, Wiśniewski P, et al. Expression of adiponectin receptors 1 and 2 and the leptin receptor in human adrenal tumors. Arch Med Sci. 2019; 15(5): 1254–1260.
  32. Brown KA, Scherer PE. Update on Adipose Tissue and Cancer. Endocr Rev. 2023; 44(6): 961–974.
  33. Atasoy A, Çakır E, Ahbab S, et al. Visfatin levels in hormonally inactive adrenal adenoma and their association with metabolic parameters. Turk J Med Sci. 2018; 48(3): 548–553.
  34. Akkus G, Evran M, Sert M, et al. Adipocytokines in Non-functional Adrenal Incidentalomas and Relation with Insulin Resistance Parameters. Endocr Metab Immune Disord Drug Targets. 2019; 19(3): 326–332.
  35. Chwalba A, Machura E, Ziora K, et al. The role of adipokines in the pathogenesis and course of selected respiratory diseases. Endokrynol Pol. 2019; 70(6): 504–510.
  36. Can M, Kocabaş M, Karaköse M, et al. New biomarkers to predict cardiovascular risk in patients with adrenal incidentaloma; irisin and nesfatin-1. Acta Endocrinol (Buchar). 2022; 18(2): 150–155.
  37. Strickland J, McIlmoil S, Williams BJ, et al. Interleukin-6 increases the expression of key proteins associated with steroidogenesis in human NCI-H295R adrenocortical cells. Steroids. 2017; 119: 1–17.
  38. Huby AC, Antonova G, Groenendyk J, et al. Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis. Circulation. 2015; 132(22): 2134–2145.
  39. Vecchiola A, Lagos CF, Carvajal CA, et al. Aldosterone Production and Signaling Dysregulation in Obesity. Curr Hypertens Rep. 2016; 18(3): 20.
  40. Arruda M, Mello Ribeiro Cavalari E, Pessoa de Paula M, et al. The presence of nonfunctioning adrenal incidentalomas increases arterial hypertension frequency and severity, and is associated with cortisol levels after dexamethasone suppression test. J Hum Hypertens. 2017; 32(1): 3–11.
  41. Szychlińska M, Rzeczkowska M, Matuszewski W, et al. Could a nonfunctional adrenal incidentaloma be a risk factor for increased carotid intima-media thickness and 10-year cardiovascular mortality based on the SCORE algorithm? A study from a single centre in Poland. Endokrynol Pol. 2023; 74(6).
  42. Fassnacht M, Tsagarakis S, Terzolo M, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2023; 189(1): G1–G42.
  43. Kim JH, Kim MJ, Lee JH, et al. Nonfunctioning Adrenal Incidentalomas are not Clinically Silent: A Longitudinal Cohort Study. Endocr Pract. 2020; 26(12): 1406–1415.
  44. Araujo-Castro M, Parra Ramírez P, Martín Rojas-Marcos P, et al. Nonfunctioning adrenal incidentalomas with cortisol post-dexamethasone suppression test >0.9 µg/dL have a higher prevalence of cardiovascular disease than those with values ≤0.9 µg/dL. Endocrine. 2023; 79(2): 384–391.
  45. Delivanis DA, Hurtado Andrade MD, Cortes T, et al. Abnormal body composition in patients with adrenal adenomas. Eur J Endocrinol. 2021; 185(5): 653–662.
  46. Debono M, Newell-Price J. Subclinical hypercortisolism in adrenal incidentaloma. Curr Opin Endocrinol Diabetes Obes. 2015; 22(3): 185–192.
  47. Araujo-Castro M, García Cano AM, Escobar-Morreale HF, et al. Predictive model for autonomous cortisol secretion development in non-functioning adrenal incidentalomas. Hormones (Athens). 2023; 22(1): 51–59.
  48. Berlińska A, Świątkowska-Stodulska R, Sworczak K. Factors Affecting Dexamethasone Suppression Test Results. Exp Clin Endocrinol Diabetes. 2020; 128(10): 667–671.
  49. Olsen H, Olsen M. Associations of age, BMI, and renal function to cortisol after dexamethasone suppression in patients with adrenal incidentalomas. Front Endocrinol (Lausanne). 2022; 13: 1055298.
  50. Sharma RP, Pandey GN, Janicak PG, et al. The effect of diagnosis and age on the DST: a metaanalytic approach. Biol Psychiatry. 1988; 24(5): 555–568.
  51. Carafone LE, Zhang CD, Li D, et al. Diagnostic Accuracy of Dehydroepiandrosterone Sulfate and Corticotropin in Autonomous Cortisol Secretion. Biomedicines. 2021; 9(7).
  52. Patrova J, Kjellman M, Wahrenberg H, et al. Increased mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: a 13-year retrospective study from one center. Endocrine. 2017; 58(2): 267–275.
  53. Pelsma ICM, Fassnacht M, Tsagarakis S, et al. Comorbidities in mild autonomous cortisol secretion and the effect of treatment: systematic review and meta-analysis. Eur J Endocrinol. 2023; 189(4): S88–S8S101.
  54. Araujo-Castro M, Paja Fano M, Pla Peris B, et al. Autonomous cortisol secretion in patients with primary aldosteronism: prevalence and implications on cardiometabolic profile and on surgical outcomes. Endocr Connect. 2023; 12(9).
  55. Deutschbein T, Reimondo G, Di Dalmazi G, et al. Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study. Lancet Diabetes Endocrinol. 2022; 10(7): 499–508.
  56. Di Dalmazi G, Vicennati V, Garelli S, 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(4): 669–677.
  57. Araujo-Castro M, Reincke M, Lamas C. Epidemiology and Management of Hypertension and Diabetes Mellitus in Patients with Mild Autonomous Cortisol Secretion: A Review. Biomedicines. 2023; 11(12).
  58. Brown JM, Robinson-Cohen C, Luque-Fernandez MA, et al. The Spectrum of Subclinical Primary Aldosteronism and Incident Hypertension: A Cohort Study. Ann Intern Med. 2017; 167(9): 630–641.
  59. Kmieć P, Zalewska E, Kunicka K, et al. Autonomous Aldosterone Secretion in Patients with Adrenal Incidentaloma. Biomedicines. 2022; 10(12).
  60. Nanba K, Vaidya A, Williams GH, et al. Age-Related Autonomous Aldosteronism. Circulation. 2017; 136(4): 347–355.
  61. Adlin EV. Subclinical Primary Aldosteronism and Cardiometabolic Disorders. Am J Hypertens. 2019; 32(5): 445–446.
  62. Hundemer GL, Agharazii M, Madore F, et al. Subclinical Primary Aldosteronism and Cardiovascular Health: A Population-Based Cohort Study. Circulation. 2024; 149(2): 124–134.
  63. De Sousa K, Boulkroun S, Baron S, et al. Genetic, Cellular, and Molecular Heterogeneity in Adrenals With Aldosterone-Producing Adenoma. Hypertension. 2020; 75(4): 1034–1044.
  64. Williams TA, Gomez-Sanchez CE, Rainey WE, et al. International Histopathology Consensus for Unilateral Primary Aldosteronism. J Clin Endocrinol Metab. 2021; 106(1): 42–54.
  65. Scholl UI. Genetics of Primary Aldosteronism. Hypertension. 2022; 79(5): 887–897.
  66. Myśliwiec J, Górska M. Primary aldosteronism: a common and important problem. A practical guide to the diagnosis and treatment. Endokrynol Pol. 2012; 63(4): 324–336.
  67. Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016; 101(5): 1889–1916.
  68. Faconti L, Kulkarni S, Delles C, et al. Diagnosis and management of primary hyperaldosteronism in patients with hypertension: a practical approach endorsed by the British and Irish Hypertension Society. J Hum Hypertens. 2024; 38(1): 8–18.
  69. Constantinescu G, Preda C, Constantinescu V, et al. Silent pheochromocytoma and paraganglioma: Systematic review and proposed definitions for standardized terminology. Front Endocrinol (Lausanne). 2022; 13: 1021420.
  70. Canu L, Van Hemert JAW, Kerstens MN, et al. CT Characteristics of Pheochromocytoma: Relevance for the Evaluation of Adrenal Incidentaloma. J Clin Endocrinol Metab. 2019; 104(2): 312–318.
  71. Kim BC, Pak SJ, Kwon D, et al. Silent pheochromocytoma in adrenal incidentaloma: unveiling clinical and radiological characteristics. Ann Surg Treat Res. 2024; 106(1): 38–44.
  72. Soltani A, Pourian M, Davani BM. Does this patient have Pheochromocytoma? a systematic review of clinical signs and symptoms. J Diabetes Metab Disord. 2015; 15: 6.
  73. Geroula A, Deutschbein T, Langton K, et al. Pheochromocytoma and paraganglioma: clinical feature-based disease probability in relation to catecholamine biochemistry and reason for disease suspicion. Eur J Endocrinol. 2019; 181(4): 409–420.
  74. Falhammar H, Kjellman M, Calissendorff J. Initial clinical presentation and spectrum of pheochromocytoma: a study of 94 cases from a single center. Endocr Connect. 2018; 7(1): 186–192.
  75. Lenders JWM, Duh QY, Eisenhofer G, et al. Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014; 99(6): 1915–1942.
  76. Eisenhofer G, Walther MM, Huynh TT, et al. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab. 2001; 86(5): 1999–2008.
  77. Pacak K, Eisenhofer G, Ilias I. Diagnosis of pheochromocytoma with special emphasis on MEN2 syndrome. Hormones (Athens). 2009; 8(2): 111–116.
  78. Eisenhofer G, Lenders JWM, Goldstein DS, et al. Pheochromocytoma catecholamine phenotypes and prediction of tumor size and location by use of plasma free metanephrines. Clin Chem. 2005; 51(4): 735–744.
  79. Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab. 2003; 88(6): 2656–2666.