DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome)

Abstract

Endogenous hypercortisolism (Cushing's syndrome) usually implies the presence of a pathologic condition caused by either an ACTH-secreting neoplasm or autonomous cortisol secretion from a benign or malignant adrenal neoplasm. However, sustained or intermittent hypercortisolism may also accompany many medical disorders that stimulate physiologic/nonneoplastic activation of the HPA axis (formerly known as pseudo-Cushing's syndrome); these two entities may share indistinguishable clinical and biochemical features. A thorough history and physical examination is often the best (and sometimes only) way to exclude pathologic/neoplastic hypercortisolism. The presence of alcoholism, renal failure, poorly controlled diabetes and severe neuropsychiatric disorders should always raise suspicion that the presence of hypercortisolism may be related to physiologic/non-neoplastic Cushing's syndrome. As late-night salivary cortisol and low-dose dexamethasone suppression have good sensitivity and negative predictive value, normal studies exclude Cushing's syndrome of any form. However, these tests have imperfect specificity and additional testing over time with clinical follow-up is often needed. When there is persistent diagnostic uncertainty, secondary tests such as the DDAVP stimulation test and the dexamethasone-CRH test may provide evidence for the presence or absence of an ACTH-secreting tumor. This review will define and characterize the numerous causes of physiologic/non-neoplastic hypercortisolism and provide a rational clinical and biochemical approach to distinguish it from pathologic/neoplastic hypercortisolism (true Cushing's syndrome).

Significant prevalence of NR3C1 mutations in incidentally discovered bilateral adrenal hyperplasia: results of the French MUTA-GR Study

“…Altogether, our data indicate that the generalized glucocorticoid resistance syndrome seems to be relatively mild in patients harboring GR loss-of-function mutations, compared to the first cases described to date. The main differential diagnosis of mild glucocorticoid resistance could be the pseudo-Cushing syndrome, whose diagnostic relies on moderately elevated UFC (below twice the ULN) and partial failure of 1 mg DST in obese, poorly controlled diabetic, depressed or alcoholic patients (37). Four out of five mutated patients, reported in the present study, presented with these clinical and biochemical features suggesting that NR3C1 sequencing should be performed in some atypical pseudo-Cushing patients to comfort glucocorticoid resistance.…”

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

“…These observations support the hypothesis that clinical diagnosis or other variables not considered in this study can result in varied effects of Dex-treatment on the tumor microenvironment. 51 …”

“…51 To determine if the observed variations in Dex-mediated effects between tumor grade can be attributed to cortisol levels, we performed ELISA analysis on serum collected from healthy donors, or from Dex-treated or Dex-naïve glioma patients. While serum from grades I and II Dex-naïve patients trended lower for cortisol levels, there was no significant difference between groups (Supp Figure 2B).…”

Paediatric Cushing’s disease — a literature review of epidemiology, pathogenesis, clinical symptoms, and diagnostics

“…The ovine (o)CRH test has equal or even greater diagnostic value than HDDST in differentiating between CD and ectopic ACTH secretion [38,53,54]. The patient should be fasting and lying in bed.…”