Chemosensory dysfunction in Cushing's syndrome

PURPOSE Cushing's syndrome (CS) can lead to structural changes in the brain and cognitive impairment, but chemosensory function has not been investigated yet. The aim was to analyze sense of smell and taste in patients with CS and explore the effect of therapy. METHODS The study cohort comprised 20 patients with florid CS treated between 2018 and 2020 in the outpatient clinic of the LMU Munich. We compared these 20 patients with CS to 40 healthy subjects matched for age, sex, and smoking status. Patients' sense of smell and taste was examined at diagnosis and 3 months after successful therapeutic surgery leading to clinical and biochemical remission. Odor threshold, discrimination, and identification were measured with \textquotedblSniffin' Sticks\textquotedbl, taste was measured with \textquotedblTaste Strips\textquotedbl. Perceived sense of smell and taste was retrieved via a questionnaire. RESULTS Patients with florid CS had significantly reduced smell (total smell score 30.3 vs. 34.4, p < 0.0005) and taste scores (9.5 vs. 12.0, p < 0.0005) compared to controls and significantly more frequently hyposmia (55 vs. 2.5%, p < 0.0005), hypogeusia (40 vs. 0%, p < 0.0005), and self-reported chemosensory impairment (60 vs. 0%, p < 0.0005). Three months after successful surgery, CS patients showed significant improvement of odor threshold (8.1 vs. 7.0, p < 0.0005), odor discrimination (12.0 vs. 11.0, p = 0.003), total smell score (33.4 vs. 30.3, p < 0.0005), and taste (11.5 vs. 9.5, p = 0.003). CONCLUSIONS Chemosensory dysfunction is a novel and clinically relevant feature of CS

Whom Should We Screen for Cushing Syndrome? The Endocrine Society Practice Guideline Recommendations 2008 Revisited

CONTEXT Cushing syndrome (CS) is a rare and serious disease with high mortality. Patients are often diagnosed late in the course of the disease. OBJECTIVE This work investigated whether defined patient populations should be screened outside the at-risk populations defined in current guidelines. METHODS As part of the prospective German Cushing registry, we studied 377 patients with suspected CS. The chief complaint for CS referral was documented. Using urinary free cortisol, late-night salivary cortisol, and the 1-mg dexamethasone suppression test as well as long-term clinical observation, CS was confirmed in 93 patients and ruled out for the remaining 284. RESULTS Patients were referred for 18 key symptoms, of which 5 were more common in patients with CS than in those in whom CS was ruled out: osteoporosis (8% vs 2%; P = .02), adrenal incidentaloma (17% vs 8%, P = 0.01), metabolic syndrome (11% vs 4%; P = .02), myopathy (10% vs 2%; P < .001), and presence of multiple symptoms (16% vs 1%; P < .001). Obesity was more common in patients in whom CS was ruled out (30% vs 4%, P < .001), but recent weight gain was prominent in those with CS. A total of 68 of 93 patients with CS (73%) had typical chief complaints, as did 106 of 284 of patients with ruled-out CS status (37%) according to the Endocrine Society practice guideline 2008. CONCLUSION The 2008 Endocrine Society Practice guideline for screening and diagnosis of CS defined at-risk populations that should undergo testing. These recommendations are still valid in 2022

Whom should we screen for Cushing syndrome? The Endocrine Society practice guideline recommendations 2008 revisited

CONTEXT: Cushing syndrome (CS) is a rare and serious disease with high mortality. Patients are often diagnosed late in the course of the disease. OBJECTIVE: This work investigated whether defined patient populations should be screened outside the at-risk populations defined in current guidelines. METHODS: As part of the prospective German Cushing registry, we studied 377 patients with suspected CS. The chief complaint for CS referral was documented. Using urinary free cortisol, late-night salivary cortisol, and the 1-mg dexamethasone suppression test as well as long-term clinical observation, CS was confirmed in 93 patients and ruled out for the remaining 284. RESULTS: Patients were referred for 18 key symptoms, of which 5 were more common in patients with CS than in those in whom CS was ruled out: osteoporosis (8% vs 2%; P = .02), adrenal incidentaloma (17% vs 8%, P = 0.01), metabolic syndrome (11% vs 4%; P = .02), myopathy (10% vs 2%; P < .001), and presence of multiple symptoms (16% vs 1%; P < .001). Obesity was more common in patients in whom CS was ruled out (30% vs 4%, P < .001), but recent weight gain was prominent in those with CS. A total of 68 of 93 patients with CS (73%) had typical chief complaints, as did 106 of 284 of patients with ruled-out CS status (37%) according to the Endocrine Society practice guideline 2008. CONCLUSION: The 2008 Endocrine Society Practice guideline for screening and diagnosis of CS defined at-risk populations that should undergo testing. These recommendations are still valid in 2022

Long-term outcome of primary bilateral macronodular adrenocortical hyperplasia after unilateral adrenalectomy

CONTEXT Unilateral adrenalectomy has been proposed in selected patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH), but its long-term outcome is unclear. OBJECTIVE The aim of this study was to analyze long-term clinical and biochemical outcome of unilateral adrenalectomy versus bilateral adrenalectomy in patients with PBMAH in comparison to outcome of cortisol-producing adenoma (CPA) treated by unilateral adrenalectomy. DESIGN Retrospective observational study in three German and one Italian academic tertiary care center. PATIENTS AND METHODS 25 PBMAH patients after unilateral adrenalectomy (unilat-ADX-PBMAH), 9 patients with PBMAH and bilateral adrenalectomy (bilat-ADX-PBMAH) and 39 patients with CPA and unilateral adrenalectomy (unilat-ADX-CPA) were included. RESULTS Baseline clinical and biochemical parameters were comparable in unilat-ADX-PBMAH, bilat-ADX-PBMAH and unilat-ADX-CPA. Directly after surgery, 84% of the unilat-ADX-PBMAH patients experienced initial remission of Cushing's syndrome. In contrast, at last follow-up (median 50 months) 32% of the unilat-ADX-PBMAH patients were biochemically controlled compared to nearly all patients in the other two groups (p=0.000). Adrenalectomy of the contralateral side had to be performed in 12% of the initially unilat-ADX-PBMAH patients. 3 of 20 unilat-ADX-PBMAH patients (15%) died during follow-up presumably of Cushing's syndrome related causes whereas no deaths occurred in the other two groups (p=0.008). Deaths occurred exclusively in patients who were not biochemically controlled after unilateral ADX. CONCLUSIONS Our data suggest that unilateral adrenalectomy of PBMAH patients leads to clinical remission and a lower incidence of adrenal crisis, but less sufficient biochemical control of hypercortisolism potentially provoking a higher mortality

Recurrence after pituitary surgery in adult Cushing's disease: a systematic review on diagnosis and treatment

PURPOSE Recurrence after pituitary surgery in Cushing's disease (CD) is a common problem ranging from 5% (minimum) to 50% (maximum) after initially successful surgery, respectively. In this review, we give an overview of the current literature regarding prevalence, diagnosis, and therapeutic options of recurrent CD. METHODS We systematically screened the literature regarding recurrent and persistent Cushing's disease using the MESH term Cushing's disease and recurrence. Of 717 results in PubMed, all manuscripts in English and German published between 1980 and April 2020 were screened. Case reports, comments, publications focusing on pediatric CD or CD in veterinary disciplines or studies with very small sample size (patient number < 10) were excluded. Also, papers on CD in pregnancy were not included in this review. RESULTS AND CONCLUSIONS Because of the high incidence of recurrence in CD, annual clinical and biochemical follow-up is paramount. 50% of recurrences occur during the first 50 months after first surgery. In case of recurrence, treatment options include second surgery, pituitary radiation, targeted medical therapy to control hypercortisolism, and bilateral adrenalectomy. Success rates of all these treatment options vary between 25 (some of the medical therapy) and 100% (bilateral adrenalectomy). All treatment options have specific advantages, limitations, and side effects. Therefore, treatment decisions have to be individualized according to the specific needs of the patient

The Effect of Biochemical Remission on Bone Metabolism in Cushing's Syndrome: A 2‐Year Follow‐Up Study

Endogenous Cushing's syndrome (CS) is a rare cause of secondary osteoporosis. The long‐term consequences for bone metabolism after successful surgical treatment remain largely unknown. We assessed bone mineral density and fracture rates in 89 patients with confirmed Cushing's syndrome at the time of diagnosis and 2 years after successful tumor resection. We determined five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. The bone turnover markers osteocalcin, intact procollagen‐IN‐propeptide (PINP), alkaline bone phosphatase, CTX‐I, and TrAcP 5b were measured in plasma or serum by chemiluminescent immunoassays. For comparison, 71 sex‐, age‐, and body mass index (BMI)‐matched patients in whom Cushing's syndrome had been excluded were studied. None of the patients received specific osteoanabolic treatment. At time of diagnosis, 69% of the patients had low bone mass (mean T‐score = −1.4 ± 1.1). Two years after successful surgery, the T‐score had improved in 78% of patients (mean T‐score 2 years postoperatively −1.0 ± 0.9). The bone formation markers osteocalcin and intact PINP were significantly decreased at time of diagnosis (p ≤ 0.001 and p = 0.03, respectively), and the bone resorption marker CTX‐I and TrAcP 5b increased. Postoperatively, the bone formation markers showed a three‐ to fourfold increase 1 year postoperatively, with a moderate decline thereafter. The bone resorption markers showed a similar but less pronounced course. This study shows that the phase immediately after surgical remission from endogenous CS is characterized by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients

Plasma steroid profiles in subclinical compared to overt adrenal Cushing's syndrome

CONTEXT Diagnosis of subclinical adrenal hypercortisolism is based on several tests of the hypothalamic-pituitary-adrenal axis to establish mild alterations of cortisol secretion and dysregulated cortisol physiology. OBJECTIVE This study assessed whether plasma steroid profiles might assist diagnosis of subclinical Cushing's syndrome (SC). DESIGN Retrospective cross-sectional study. SETTING Two tertiary medical centers. PATIENTS Two hundred and eight patients were tested for hypercortisolism among whom disease was excluded in 152 and confirmed in 21 with overt clinical Cushing's syndrome due to adrenal tumors (AC) compared to 35 with SC. Another 277 age- and gender-matched hypertensive and normotensive volunteers were included for reference. MAIN OUTCOME MEASURES Panel of 15 plasma steroids measured by mass spectrometry with classification by discriminant analysis. RESULTS Patients with SC showed lower (P<0.05) plasma concentrations of dehydroepiandrosterone and dehydroepiandrosterone-sulfate than subjects without SC. The largest increases (P<0.001) in plasma steroids among patients with SC were observed for 11-deoxycortisol and 11-deoxycorticosterone. Nevertheless, concentrations of 11-deoxycorticosterone, 11-deoxycortisol and pregnenolone in patients with AC were higher (P<0.05) than in those with SC. Patients with SC or AC could be distinguished from subjects without disease using the above combination of steroids as precisely as with use of measurements of serum cortisol after dexamethasone. The steroid combination provided superior diagnostic performance compared to each of the other routine biochemical tests. CONCLUSIONS Distinct plasma steroid profiles in patients with SC may provide a simple and reliable screening method for establishing the diagnosis

Hair glucocorticoids as biomarker for endogenous Cushing's syndrome: validation in two independent cohorts

Background/Aims: The current diagnostic workup of Cushing’s syndrome (CS) requires various tests which only capture short-term cortisol exposure, whereas patients with endogenous CS generally have elevated long-term cortisol levels. Scalp hair assessment has emerged as a convenient test in capturing glucocorticoid concentrations over long periods of time. The aim of this multicenter, multinational, prospective, case-control study was to evaluate the diagnostic efficacy of scalp hair glucocorticoids in screening of endogenous CS. Methods: We assessed the diagnostic performances of hair cortisol (HairF), hair cortisone (HairE), and sum of both (sumHairF+E), as measured by state-of-the-art LC-MS/MS technique, in untreated patients with confirmed endogenous CS (n=89), and community controls (n=295) from the population-based Lifelines cohort study. Results: Both glucocorticoids were significantly elevated in CS patients when compared to controls. High diagnostic efficacy was found for HairF (area under the curve (AUC), 0.87 [95% CI, 0.83 to 0.92]), HairE (0.93 [0.89 to 0.96]) and sumHairF+E (0.92 [0.88 to 0.96]; all P<.001). Participants were accurately classified at optimal cut-off threshold in 86% of cases (81% sensitivity, 88% specificity, 94% negative predictive value (NPV)) for HairF, in 90% of cases (87% sensitivity, 90% specificity, 96% NPV) for HairE, and 87% of cases (86% sensitivity, 88% specificity, 95% NPV) for the sum. HairE was shown to be most accurate in differentiating CS patients from controls. Conclusion: Scalp hair glucocorticoids, especially hair cortisone, can be seen as a promising biomarker in screening of CS. Its convenience in collection and workup additionally makes this feasible for first-line screenin

Supplementary data from: The gut microbiome in patients with Cushing’s syndrome is severely altered

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