Nuclear medicine improves the sensitivity of conventional radiology when tumor site identification is problematic. OCT offers a good availability/reliability ratio, and FDG-PET was proven useful. 68Gallium-SSTR-PET/CT use was infrequent, despite offering the highest sensitivity.
Dyslipidemia seems to be less frequent than other metabolic comorbidities in human Cushing’s syndrome. Nevertheless, it plays an important role in determining the global cardiovascular risk in overt and subclinical Cushing’s syndrome. In Cushing’s syndrome, there is an increase of triglyceride and total cholesterol levels whereas HDL can be at variable levels. Overt and subclinical Cushing’s syndrome share many features with metabolic syndrome including insulin resistance, abnormal fasting glucose levels, hypertension, obesity and dyslipidemia. The pathogenetic mechanisms are multifactorial, including direct and indirect cortisol action on lipolysis, free fatty acid production and turnover, very-low-density lipoprotein synthesis and fatty accumulation in the liver. AMP-activated protein kinase mediates many of glucocorticoid-induced metabolic changes. Insulin resistance plays a key role in determining lipid abnormalities. Other hormonal changes are involved including growth hormone, testosterone in men and estrogen in women, catecholamines and cytokines. In vitro, cortisol increases lipoprotein lipase in adipose tissues and particularly in visceral fat where lipolysis is activated, resulting in the release of free fatty acids into the circulation. The increase of free fatty acids may enhance the accumulation of hepatic lipids reducing glucose uptake and activating various serine kinases which results in decreased insulin signaling. Moreover, mice with a liver-specific disruption of the glucocorticoid receptor had diminished hepatic triglycerides levels. In humans, a high prevalence (up to 20%) of hepatic steatosis was also reported in patients with Cushing’s syndrome. Genetic variations in the glucocorticoid receptors may also affect the activity of cortisol, lipid metabolism and cardiovascular risk.
Patients with CD showed a stronger response to HDDST and CRH, and the adopted cut-offs showed a good SE and SP in discriminating them from patients with EAS. Concordant tests indicated CD when positive, whereas no response to either test was highly suggestive of EAS. The DDAVP test was of limited utility in the diagnostic phase. In conclusion, the choice of tests may play an important part in the differential diagnosis of ACTH-dependent CS.
Cushing's syndrome (CS) is associated with an incidence of venous thromboembolism (VTE) about ten times higher than in the normal population. The aim of our study was to develop a model for identifying CS patients at higher risk of VTE. We considered clinical, hormonal, and coagulation data from 176 active CS patients and used a forward stepwise logistic multivariate regression analysis to select the major independent risk factors for thrombosis. The risk of VTE was calculated as a 'CS-VTE score' from the sum of points of present risk factors. VTE developed in 20 patients (4 pulmonary embolism). The group of CS patients with VTE were older (p < 0.001) and had more cardiovascular events (p < 0.05), infections and reduced mobility (both p < 0.001), higher midnight plasma cortisol levels (p < 0.05), and shorter APTT (p < 0.01) than those without. We identified six major independent risk factors for VTE: age ≥69 years and reduced mobility were given two points each, whereas acute severe infections, previous cardiovascular events, midnight plasma cortisol level >3.15 times the normality and shortened APTT were given one point each. A CS-VTE score <2 anticipated no risk of VTE; a CS-VTE score of two mild risk (10 %); a CS-VTE score of three moderate risk (46 %); a CS-VTE score ≥4 high risk (85 %). Considering a score ≥3 as predictive of VTE, 94 % of the patients were correctly classified. A simple score helps stratify the VTE risk in CS patients and identify those who could benefit from thromboprophylaxis.
Cushing's syndrome (CS) is a clinical condition resulting from chronic exposure to glucocorticoid excess. As a consequence, hypercortisolism contributes significantly to the early development of systemic disorders by direct and/or indirect effects. Complications such as obesity, hypertension, diabetes, dyslipidemia, and hypercoagulability cause premature atherosclerosis and increase cardiovascular mortality. Impairment of the skeletal system is a relevant cause of morbidity and disability in these patients especially due to the high prevalence of vertebral fractures. In addition, muscle weakness, emotional lability, depression, and impairment of quality of life are very common. Clinical management of these patients is complex and should be particularly careful in identifying global cardiovascular risks and aim at controlling all complications. Although the primary goal in the prevention and treatment of complications is the correction of hypercortisolism, treatment does not completely eliminate these comorbidities. Given that cardiovascular risk and fracture risk can persist after cure, early detection of each morbidity could prevent the development of irreversible damage. In this review we present the various complications of CS and their pathogenetic mechanisms. We also suggest the clinical management of these patients based on our extensive clinical experience and on the available literature.
Objective: Corticotropin releasing hormone (CRH) test does not reliably distinguish Cushing's disease (CD) from normality or pseudo-Cushing state (PC). We assessed whether this could be achieved with a novel approach while preserving the ability of the test to distinguish CD from ectopic ACTH syndrome (EAS). Design: Retrospective/prospective study. Subjects and methods: We studied 51 subjects with CD, 7 with EAS, 26 with PC, and 31 controls (CT). Human CRH (hCRH) test was performed at 0830 h by measuring plasma ACTH and serum cortisol at K15, 0, 15, 30, 45, 60, 90, and 120 min. Results: The area under the curve-ACTH exhibited a significant negative correlation with baseline serum cortisol in CT and PC, but not in CD or EAS patients. ACTH response to hCRH was blunted in PC compared with CT, whereas peak serum cortisol was higher in PC than in CT subjects. These findings suggested that ACTH-dependent Cushing's syndrome can be diagnosed by the presence of two hCRH test parameters and excluded if either or both are absent. Application of i) basal serum cortisol O12 mg/dl and peak plasma ACTH O54 pg/ml, or ii) peak serum cortisol O21 mg/dl and peak plasma ACTH O45 pg/ml, had 91.3% (95% confidence intervals (CI) 81-97.1) and 94.8% (CI 85.6-98.9) sensitivity and 98.2% (CI 90.6-99.9) and 91.2% (CI 80.7-97) specificity respectively, in diagnosing ACTH-dependent Cushing's syndrome. The O14% serum cortisol increase from mean baseline values to the mean of 15 and 30 min values in patients who were positive for the test completely discriminated between CD and EAS. Conclusions: Simultaneous plasma ACTH and serum cortisol analysis enables the hCRH test to distinguish CD from PC and from normality, while preserving its ability to discriminate CD from EAS.
Objective: Glucocorticoid receptor (GR) polymorphisms alter glucocorticoid (GC) sensitivity and have been associated with altered metabolic profiles. We evaluate the prevalence of the four GR (NR3C1) polymorphisms BclI, N363S, ER22/23EK, and A3669G in patients with Cushing's syndrome (CS) compared with healthy controls (HC) and we investigate their role in the development of metabolic abnormalities in patients with CS according to their hormonal profile. Patients and methods: Sixty-one patients with CS and 71 sex-and age-matched HC were genotyped. Results: BclI variant was markedly higher in patients with CS compared with HC (62 vs 41%, P!0.05) while no significant differences were found among other polymorphisms. A very low frequency of N363S and the ER22/23EK was observed. In CS patients, despite the significantly increased levels of morning serum cortisol in BclI carriers compared with wild type no clinical or metabolic differences were found. In contrast, A3669G GR carriers showed a significantly reduced prevalence of type 2 diabetes mellitus compared with wild type (19 vs 68%, PZ0.001) despite the higher levels of both serum morning (21.7G6 vs 27.3G8.6 mg/dl, PZ0.009) and midnight cortisol (18.8G5.8 vs 24.0G8.0 mg/dl, PZ0.01). The negative association between diabetes and A3669G GR polymorphism remained significant when data were adjusted for potential confounding factors. Conclusions: The A3669G polymorphism of the GR gene plays a protective role in patients with CS, attenuating the effects of GC excess on glucose metabolism as shown by their reduced risk of diabetes.
A hypercoagulable state and its consequent increased incidence of thromboembolic complications are reported in patients with Cushing’s syndrome (CS). These alterations are related to cortisol excess that induces prothrombotic changes in blood by several and complex mechanisms including increased levels of clotting factors, mainly factor VIII and von Willebrand factor (VWF) and impaired fibrinolytic capacity. However, it has recently been observed that the increase in VWF levels is not a constant feature of CS and that VWF response to glucocorticoids is genetically determined and depends on the presence of particular polymorphisms in the VWF gene promoter. The risk of venous thromboembolism is moreover enhanced in patients with CS by additional endogenous and exogenous risk factors such as obesity, bed rest, surgery and invasive diagnostic procedures like inferior petrosal sinus (IPS) sampling. In line with all these data, patients with active CS should be treated as having a prothrombotic disorder and undergo antithrombotic prophylaxis during IPS sampling. Special care should be taken in the immediate perioperative period in order to avoid thromboembolic events. In the absence of prospective randomized trials, preventive antithrombotic treatment (best with heparin) during IPS sampling and low-dose heparin treatment early after surgery should be suggested.
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