Subclinical Cushing’s syndrome: lots of questions — little answers

The literature review provides a definition of the essence of subclinical Cushing’s syndrome. Subclinical Cushing’s syndrome (subclinical hypercortisolism) is a pathological condition of the body characterized by an autonomous, excessive secretion of glucocorticoids, most often an adrenal cortex adenoma, suppression of the adrenocorticotropic function of the pituitary gland and the functional state of the opposite adrenal gland. Such a condition may be clini-cally asymptomatic or be accompanied by some nonspecific signs of hypercortisolism (arterial hypertension, diabetes mellitus, obesity, osteoporosis). Noteworthy is the large variability in the frequency of its detection, which is possibly due to the use of various criteria for assigning individual cases to this category. As a basic screening test for the detection of subclinical hypercortisolism, most researchers consider the most acceptable and effective night suppressive test with 1.0 mg of dexamethasone. Modern tactical and technical approaches to the treatment of subclinical Cushing’s syndrome are quite diverse and are more often based on pragmatic principles than on reliably substantiated ones. The author raises the question: could subclinical Cushing’s syndrome be the result of hyperfunction of normal or diffusely enlarged (hyperplastic) adrenal glands as a result of some disturbances in the hypothalamic-pituitary-adrenal hierarchy. And, finally, are the disorders “accompanying” subclinical Cushing’s syndrome a consequence of the overproduction of cortisol, although often insignificant, or can they be the cause of the onset of subclinical hypercortisolism? For the treatment of subclinical hypercortisolism, adrenalectomy is currently proposed, with the aim of reducing the intake of excessive amounts of glucocorticoids into the patient’s body, leading to the development of these disorders. Known drug methods of suppressing the function of the adrenal cortex — drugs chloditan, mitotane, ketoconazole.

Differential Phenotype of Primary Bilateral Macronodular Adrenal Hyperplasia and Other Bilateral Adrenal Lesions With Associated Subclinical Hypercortisolism. Study of 98 Patients.

Purpose: To evaluate the prevalence of primary bilateral macronodular adrenal hyperplasia (PBMAH) in patients with adrenal incidentalomas (AIs) with subclinical hypercortisolism. Also to analyse the differential phenotype of patients with PBMAH compared to other bilateral adrenal lesions which do not meet PBMAH definition.Methods: Retrospective study of patients with AIs diagnosed in our centre between 2013 and 2019 (n=730). Patients with bilateral disease and associated subclinical hypercortisolism (possible ACS or ACS) were included (n=98). Possible ACS and ACS were defined as a cortisol post-1mg-dexamethasone suppression test (DST)>1.8µg/dl but ≤5.0µg/dl and >5.0µg/dl. without specific clinical signs of Cushing´s syndrome, respectively. PBMAH diagnosis was established in patients with subclinical hypercortisolism, hyperplasia and bilateral adrenal nodules >1cm.Results: PBMAH was confirmed in 31.6% of bilateral AIs with subclinical hypercortisolism. Patients with PBMAH presented a higher prevalence of ACS than non-PBMHA (OR 4.1, 95%CI 1.38-12.09, P=0.010), but differences disappeared after adjusting by tumour size and total adenomatous mass (adjusted OR 2.3, 95%CI=0.65-8.27 and 2.3, 95%CI 0.47-11.21, respectively). However, no significant differences in the cardiometabolic profile of both groups were observed. Tumour size and total adenomatous mass were significantly higher in PBMAH (30.2±12.16 vs 24.3±8.47, P=0.010 and 53.9±20.8 vs 43.3±14.62, P=0.023).Conclusion: PBMAH is common in patients with incidentally detected bilateral adrenals lesions with associated subclinical hypercortisolism. The higher prevalence of ACS in PBMAH compared to non-PBMAH is associated with a higher tumour size and total adenomatous mass in PBMHA, but no differences in the cardiometabolic profile were observed between both groups.

Presence of Subclinical Hypercortisolism in Clinical Aldosterone-Producing Adenomas Predicts Lower Clinical Success

The clinical characteristics and outcomes in patients with clinical aldosterone-producing adenomas harboring KCNJ5 mutations with or without subclinical hypercortisolism remain unclear. This prospective study is aimed at determining factors associated with subclinical hypercortisolism in patients with clinical aldosterone-producing adenomas. Totally, 82 patients were recruited from November 2016 to March 2018 and underwent unilateral laparoscopic adrenalectomy with at least a 12-month follow-up postoperatively. Standard subclinical hypercortisolism (defined as cortisol >1.8 μg/dL after 1 mg dexamethasone suppression test [DST]) was detected in 22 (26.8%) of the 82 patients. Intriguingly, a generalized additive model identified the clinical aldosterone-producing adenoma patients with 1 mg DST>1.5 μg/dL had significantly larger tumors ( P =0.02) than those with 1 mg DST<1.5 μg/dL. Multivariable logistic regression showed that the presence of KCNJ5 mutations (odds ratio, 0.22, P =0.010) and body mass index (odds ratio, 0.87, P =0.046) were negatively associated with 1 mg DST>1.5 μg/dL, whereas tumor size was positively associated with it (odds ratio, 2.85, P =0.014). Immunohistochemistry revealed a higher degree of immunoreactivity for CYP11B1 in adenomas with wild-type KCNJ5 ( P =0.018), whereas CYP11B2 was more commonly detected in adenomas with KCNJ5 mutation ( P =0.007). Patients with wild-type KCNJ5 and 1 mg DST>1.5 μg/dL exhibited the lowest complete clinical success rate (36.8%) after adrenalectomy. In conclusion, subclinical hypercortisolism is common in clinical aldosterone-producing adenoma patients without KCNJ5 mutation or with a relatively larger adrenal tumor. The presence of serum cortisol levels >1.5 μg/dL after 1 mg DST may be linked to a lower clinical complete success rate.

Mental Health in Patients With Adrenal Incidentalomas: Is There a Relation With Different Degrees of Cortisol Secretion?

Context Cushing’s syndrome frequently causes mental health impairment. Data in patients with adrenal incidentaloma (AI) are lacking. Objective We aimed to evaluate psychiatric and neurocognitive functions in AI patients, in relation to the presence of subclinical hypercortisolism (SH), and the effect of adrenalectomy on mental health. Design We enrolled 62 AI patients (64.8 ± 8.9 years) referred to our centers. Subclinical hypercortisolism was diagnosed when cortisol after 1mg-dexamethasone suppression test was &gt;50 nmol/L, in the absence of signs of overt hypercortisolism, in 43 patients (SH+). Interventions The structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders-5, and 5 psychiatric scales were performed. The Brief Assessment of Cognition in Schizophrenia (Verbal and Working Memory, Token and Symbol Task, Verbal Fluency, Tower of London) was explored in 26 patients (≤65 years). Results The prevalence of psychiatric disorders was 27.4% (SH+ 30.2% vs SH- 21.1%, P = 0.45). SH+ showed a higher prevalence of middle insomnia (by the Hamilton Depression Rating Scale) compared with SH- (51% vs 22%, P = 0.039). Considering the Sheehan Disability Scale, SH+ showed a higher disability score (7 vs 3, P = 0.019), higher perceived stress (4.2 ± 1.9 vs 2.9 ± 1.9, P = 0.015), and lower perceived social support (75 vs 80, P = 0.036) than SH-. High perceived stress was independently associated with SH (odds ratio [OR] = 5.46, confidence interval 95% 1.4–21.8, P = 0.016). Interestingly, SH+ performed better in verbal fluency (49.5 ± 38.9 vs 38.9 ± 9.0, P = 0.012), symbol coding (54.1 ± 6.7 vs 42.3 ± 15.5, P = 0.013), and Tower of London (15.1 vs 10.9, P = 0.009) than SH-. In 8 operated SH+, no significant changes were found. Conclusions Subclinical hypercortisolism may influence patients’ mental health and cognitive performances, requiring an integrated treatment.