ECE2016 DEBATE Are we ready for pharmacological therapy of obesity? (2 abstracts)
The term subclinical Cushing syndrome arose at the turn of the millennium with the description of large Italian study of adrenal incidentalomas. Of 1096 patients from 26 centres, 9.2% had subclinical Cushings (JCEM, 2000; 85:637-644). Since then over 300 publications have detailed this newly discovered endocrine diagnosis, and herein lies the main issue. The definition of Cushings syndrome is not in doubt a constellation of symptoms and signs that reflect prolonged and inappropriately high exposure of tissues to glucocorticoids. No single test has 100% sensitivity or specificity, which is why the guidelines suggest numerous screening tests including urinary free cortisol (UFC), late night salivary cortisol (LNSC) or a 1mg overnight dexamethasone (DEXA). Sensitivity is high to avoid missing the killing disease at the expense of specificity so that a false positive result is 50× more commoner than a true positive. False positives are common in patients with physiological cortisol hypersecretion, such as those with diabetes, obesity and depression.
Adrenal incidentalomas have a prevalence rate of 7% in subjects over 70 years, where prevalence rates for diabetes are 25%, hypertension 65%, obesity 35% and osteoporosis 16% (male) and 47% (female). Papers describe abnormalities in a host of variable diagnostic tests that have included random cortisol, loss of circadian rhythm, DHAS, blunted ACTH response to CRF in addition to the guidelines screening tests of UFC, LNSC and o/n Dexa in variable doses. No wonder that 9% of such patients have abnormal results the specificity of these tests predicts exactly that!
Within the subclinical literature, and our own personal experiences there are undoubtedly patients with adrenal incidentalomas who do have inappropriate cortisol hypersecretion, the hallmark of which must be suppressed ACTH. With the current lack of evidence base for treating what is usually mild disease, in a patient who may lack many of the discriminatory features of Cushings syndrome, the physician will be guided by end organ effects of cortisol (BMI, BMD, glucose tolerance, lipids, BP) in deciding whether or not to proceed to laparoscopic adrenalectomy but in doing so must accept that there is nothing subclinical in this scenario.
Subclinical Cushing syndrome currently comprises a majority of patients with age related diseases and false positive abnormalities in HPA axis testing who DO NOT have inappropriate cortisol hypersecretion. A small number of cases with suppressed ACTH and inappropriate cortisol production causing low BMD, BP, CVS risk and diabetes may need therapy, but then by definition are very much clinical in nature.