The degree of urinary hypercortisolism is not correlated with the severity of cushing’s syndrome

Cushing syndrome (CS) is characterized by increased morbidity and mortality compared to the general population. However, there are patients who have moreclinical aggressive forms than others. Aim of the study is to evaluate whether the degree of hypercortisolism, defined by the number of times urinary free cortisol (UFC) levels exceed the upper limit of the normal range (ULN), is related to the worsening of phenotypic features, as well as metabolic and cardiovascular parameters, in a cohort of CS patients. A cross-sectional study was conducted on 192 patients with active CS, consecutively presenting at the outpatients’ clinic of the University Hospitals of Ancona, Naples, and Palermo. Patients were grouped into mild (UFC not exceeding twice the ULN), moderate (2–5 times the ULN), and severe (more than 5 times the ULN) hypercortisolism. Thirty-seven patients (19.3 %) had mild, 115 (59.8 %) moderate, and 40 (20.9 %) severe hypercortisolism. A significant trend of increase among the three groups was demonstrated for 8-, 16-, and 24-h serum cortisol levels (p.001) and serum cortisol after low dose of dexamethasone suppression test (p = 0.001). No significant trend of increase was found regarding phenotype and comorbidities. The degree of hypercortisolism by itself does not appear to be a sufficient parameter to express the severity of CS. Therefore, estimating the severity of CS according to biochemical parameters remains a challenge, while the clinical phenotype and the associated comorbidities might be more useful to assessing the severity of the CS

Advances in the epidemiology, pathogenesis, and management of Cushing's syndrome complications

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

Advances in the epidemiology, pathogenesis, and management of Cushing's syndrome complications.

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

Fracture risk assessment before and after resolution of endogenous hypercortisolism: Is the FRAX(\uae) algorithm useful?

Purpose Fracture risk data following curative treatment of Cushing's syndrome (CS) are scarce and the role of bisphosphonates in bone recovery after remission is controversial. We evaluated the effects of hypercortisolism remission in bone recovery in CS. Then, we assessed if the FRAX (R) algorithm calculated before the cure can predict fracture risk after cure. Methods Thirty-six patients with CS were retrospectively investigated. Bone turnover markers, bone mineral density (BMD) at the lumbar spine (L1-L4) and left femur (both neck and total hip were considered), and fracture risk using FRAX (R) algorithm with femoral neck BMD were evaluated at diagnosis and after a median follow-up of 24 months (range 12-108 months) from hypercortisolism remission. Data about bone active therapy were analyzed. Results Hypercortisolism remission was associated with the improvement of all densitometric parameters and with the reduction of fracture risk. The percentage change in BMD and the fracture risk were not significantly different in bisphosphonate-treated vs. untreated patients. During follow-up, three fractured patients at baseline exhibited a new vertebral fracture. A baseline 10-year probability of major osteoporotic fractures (FRAX (R) Major) of 17 % was able to predict the occurrence of a new vertebral fracture during follow-up after cure with 100 % sensitivity, 77 % specificity, 81 % positive predictive value and 100 % negative predictive value. Conclusions Osteoporosis and fracture risk may be reversible after curative treatment of CS, regardless of bisphosphonate therapy. We suggest applying the FRAX (R) algorithm to all active CS patients using a baseline FRAX (R) Major of 17 % as "intervention threshold"

Up-to 5-year efficacy of pasireotide in a patient with Cushing's disease and pre-existing diabetes: literature review and clinical practice considerations.

Purpose Pasireotide is a multi-receptor-targeted somatostatin analogue approved in the EU and in the US for the treatment of adults with Cushing's disease (CD). Pasireotide has a safety profile similar to other somatostatin analogues with the exception of hyperglycemia. In this report and literature review, the current understanding of predicting a positive treatment response to pasireotide in CD and the management of diabetes mellitus (DM) during pasireotide treatment are discussed and analyzed. Case presentation We report a case of a 55-year-old woman with CD and DM who benefitted from long-term pasireotide. The patient, who was enrolled in a phase III trial of the drug, showed early clinical improvements with pasireotide [900 \u3bcg subcutaneously twice daily (bid)] but was classified as a non-responder as urinary free cortisol (UFC) levels, were not normalized. Continuation of pasireotide for 12 months at an increased dose (1,200 \u3bcg bid) normalized UFC levels and restored cortisol rhythm. The initial deterioration in her blood glucose was managed with insulin and metformin; however, after 12 months' treatment with pasireotide her DM was well controlled with oral hypoglycemic agents. Five years later, the patient is still receiving pasireotide (300 \u3bcg bid) with no loss of clinical or biochemical efficacy and with continued glycemic control. Conclusions This case presentation indicates that uncontrolled UFC levels during the first few months of pasireotide treatment as well as worsening of glycemic control in patients with CD and DM are not always predictive of the efficacy and tolerability and appears to support the long-term continuation of pasireotide

Pathophysiology of dyslipidemia in Cushing's syndrome.

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

Coagulopathy in Cushing's syndrome.

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