Toward a Diagnostic Score in Cushing's Syndrome

Cushing's syndrome (CS) is a classical rare disease: it is often suspected in patients who do not have the disease;at the same time, it takes a mean of 3 years to diagnose CS in affected individuals. The main reason is the extreme rarity (1-3/million/year) in combination with the lack of a single lead symptom. CS has to be suspected when a combination of signs and symptoms is present, which together make up the characteristic phenotype of cortisol excess. Unusual fat distribution affecting the face, neck, and trunk;skin changes including plethora, acne, hirsutism, livid striae, and easy bruising;and signs of protein catabolism such as thinned and vulnerable skin, osteoporotic fractures, and proximal myopathy indicate the need for biochemical screening for CS. In contrast, common symptoms like hypertension, weight gain, or diabetes also occur quite frequently in the general population and per se do not justify biochemical testing. First-line screening tests include urinary free cortisol excretion, dexamethasone suppression testing, and late-night salivary cortisol measurements. All three tests have overall reasonable sensitivity and specificity, and first-line testing should be selected on the basis of the physiologic conditions of the patient, drug intake, and available laboratory quality control measures. Two normal test results usually exclude the presence of CS. Other tests and laboratory parameters like the high-dose dexamethasone suppression test, plasma ACTH, the CRH test, and the bilateral inferior petrosal sinus sampling are not part of the initial biochemical screening. As a general rule, biochemical screening should only be performed if the pre-test probability for CS is reasonably high. This article provides an overview about the current standard in the diagnosis of CS starting with clinical scores and screenings, the clinical signs, relevant differential diagnoses, the first-line biochemical screening, and ending with a few exceptional cases

Influence of Antihypertensive Treatment on RAAS Peptides in Newly Diagnosed Hypertensive Patients.

(1) Background: Recently, influences of antihypertensive treatment on the renin-angiotensin-aldosterone system (RAAS) has gained attention, regarding a possible influence on inflammatory and anti-inflammatory pathways. We aimed to study the effects of newly initiated antihypertensive drugs on angiotensin (Ang) II and Ang (1-7) as representers of two counter-regulatory axes. (2) Methods: In this randomized, open-label trial investigating RAAS peptides after the initiation of perindopril, olmesartan, amlodipine, or hydrochlorothiazide, Ang II and Ang (1-7) equilibrium concentrations were measured at 8 a.m. and 12 a.m. at baseline and after four weeks of treatment. Eighty patients were randomized (1:1:1:1 fashion). (3) Results: Between the four substances, we found significant differences regarding the concentrations of Ang II (p < 0.0005 for 8 a.m., 12 a.m.) and Ang (1-7) (p = 0.019 for 8 a.m., <0.0005 for 12 a.m.) four weeks after treatment start. Ang II was decreased by perindopril (p = 0.002), and increased by olmesartan (p < 0.0005), amlodipine (p = 0.012), and hydrochlorothiazide (p = 0.001). Ang (1-7) was increased by perindopril and olmesartan (p = 0.008/0.002), but not measurably altered by amlodipine and hydrochlorothiazide (p = 0.317/ 0.109). (4) Conclusion: The initiation of all first line antihypertensive treatments causes early and distinct alterations of equilibrium angiotensin levels. Given the additional AT1R blocking action of olmesartan, RAAS peptides shift upon initiation of perindopril and olmesartan appear to work in favor of the anti-inflammatory axis compared to amlodipine and hydrochlorothiazide

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

Omega-3 Fatty Acids and Heart Rhythm, Rate, and Variability in Atrial Fibrillation.

Background Previous randomized control trials showed mixed results concerning the effect of omega-3 fatty acids (n-3 FAs) on atrial fibrillation (AF). The associations of n-3 FA blood levels with heart rhythm in patients with established AF are unknown. The goal of this study was to assess the associations of total and individual n-3 FA blood levels with AF type (paroxysmal versus nonparoxysmal), heart rate (HR), and HR variability in patients with AF. Methods and Results Total n-3 FAs, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and alpha-linolenic acid blood levels were determined in 1969 patients with known AF from the SWISS-AF (Swiss Atrial Fibrillation cohort). Individual and total n-3 FAs were correlated with type of AF, HR, and HR variability using standard logistic and linear regression, adjusted for potential confounders. Only a mild association with nonparoxysmal AF was found with total n-3 FA (odds ratio [OR], 0.97 [95% CI, 0.89-1.05]) and docosahexaenoic acid (OR, 0.93 [95% CI, 0.82-1.06]), whereas other individual n-3 FAs showed no association with nonparoxysmal AF. Higher total n-3 FAs (estimate 0.99 [95% CI, 0.98-1.00]) and higher docosahexaenoic acid (0.99 [95% CI, 0.97-1.00]) tended to be associated with slower HR in multivariate analysis. Docosapentaenoic acid was associated with a lower HR variability triangular index (0.94 [95% CI, 0.89-0.99]). Conclusions We found no strong evidence for an association of n-3 FA blood levels with AF type, but higher total n-3 FA levels and docosahexaenoic acid might correlate with lower HR, and docosapentaenoic acid with a lower HR variability triangular index

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

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Association of pulmonary vein isolation and major cardiovascular events in patients with atrial fibrillation.

BACKGROUND Patients with atrial fibrillation (AF) face an increased risk of adverse cardiovascular events. Evidence suggests that early rhythm control including AF ablation may reduce this risk. METHODS To compare the risks for cardiovascular events in AF patients with and without pulmonary vein isolation (PVI), we analysed data from two prospective cohort studies in Switzerland (n = 3968). A total of 325 patients who had undergone PVI during a 1-year observational period were assigned to the PVI group. Using coarsened exact matching, 2193 patients were assigned to the non-PVI group. Outcomes were all-cause mortality, hospital admission for acute heart failure, a composite of stroke, transient ischemic attack and systemic embolism (Stroke/TIA/SE), myocardial infarction (MI), and bleedings. We calculated multivariable adjusted Cox proportional-hazards models. RESULTS Overall, 2518 patients were included, median age was 66 years [IQR 61.0, 71.0], 25.8% were female. After a median follow-up time of 3.9 years, fewer patients in the PVI group died from any cause (incidence per 100 patient-years 0.64 versus 1.87, HR 0.39, 95%CI 0.19-0.79, p = 0.009) or were admitted to hospital for acute heart failure (incidence per 100 patient-years 0.52 versus 1.72, HR 0.44, 95%CI 0.21-0.95, p = 0.035). There was no significant association between PVI and Stroke/TIA/SE (HR 0.94, 95%CI 0.52-1.69, p = 0.80), MI (HR 0.43, 95%CI 0.11-1.63, p = 0.20) or bleeding (HR 0.75, 95% CI 0.50-1.12, p = 0.20). CONCLUSIONS In our matched comparison, patients in the PVI group had a lower incidence rate of all-cause mortality and hospital admission for acute heart failure compared to the non-PVI group. CLINICALTRIALS GOV IDENTIFIER NCT02105844, April 7th 2014

Supplementary data from: Steroid profiling using liquid chromatography mass spectrometry during adrenal vein sampling in patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH)

INTRODUCTION: Adrenal vein sampling (AVS) is not a routine procedure in patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH), but has been used to determine lateralization of cortisol secretion in order to guide decision of unilateral adrenalectomy. Our aim was to characterize the steroid fingerprints in AVS samples of patients with PBMAH and hypercortisolism and to identify a reference hormone for AVS interpretation. METHOD: Retrospectively, we included 17 patients with PBMAH from the German Cushing’s registry who underwent AVS. 15 steroids were quantified in AVS and peripheral blood samples using LC-MS/MS. We calculated lateralization indices and conversion ratios indicative of steroidogenic enzyme activity to elucidate differences between individual adrenal steroidomes and in steroidogenic pathways. RESULTS: Adrenal volume was negatively correlated with peripheral cortisone (r=0.62, p<0.05). 24-hour urinary free cortisol correlated positively with peripheral androgens (rDHEA=0.57, rDHEAS=0.82, rA=0.73, rT=0.54, p<0.05). DHEA was found to be a powerful reference hormone with high selectivity index, which did not correlate with serume cortisol and has a short half-life. All investigated steroids showed lateralization in single patients indicating the heterogenous steroid secretion pattern in patients with PBMAH. The ratios of corticosterone/aldosterone (catalyzed by CYP11B2), androstenedione/dehydroepiandrosterone (catalyzed by HSD3B2) and cortisone/cortisol (catalyzed by HSD11B2) in adrenal vein samples were higher in smaller adrenals (p<0.05). ARMC5 mutation carriers (n=6) showed lower androstenedione/17-hydroxyprogesterone and higher testosterone/androstenedione (p<0.05) ratios in peripheral blood, in line with lower peripheral androstenedione concentrations (p<0.05). CONCLUSION: Steroid profiling by LC-MS/MS led us to select DHEA as a candidate reference hormone for cortisol secretion. Lateralization and different steroid ratios showed that each steroid and all three steroidogenic pathways may be affected in PBMAH patients. In patients with germline ARMC5 mutations, the androgen pathway was particularly dysregulated

Supplementary data from: Adrenal venous sampling (AVS) in Primary Bilateral Macronodular Adrenocortical Hyperplasia (PBMAH): A study of 16 patients

Adrenal venous sampling in primary bilateral macronodular adrenocortical hyperplasi

Time to diagnosis in Cushing’s syndrome: A meta-analysis based on 5367 patients

The time from first symptom to diagnosis of Cushing's syndrome is considered relevant for the severity of phenotype at presentation and long-term outcome. We therefore performed a systematic literature search to investigate relevant factors associated with a short time to diagnosis. The meta-analysis of 45 studies with 5560 patients showed significant differences for adrenal Cushing’s syndrome, Cushing’s disease and the ectopic Cushing’s syndrome. We did not find difference for gender, age or time of publication