The thrombotic risk in Cushing's syndrome-questions, answers, and the algorithm to consider in its assessment: part I-thrombotic risk not related to surgery.

Introduction: Recently, it has been reported that there is a great diversity in strategies used for thromboprophylaxis in patients with Cushing's syndrome (CS). An aim of this review was to discuss these practices in light of the existing data on the thrombotic risk in patients with CS and guidelines for medically ill patients. Methods: The four relevant topics and questions on thrombotic risk in CS were identified. The current guidelines on prevention and diagnosis of venous thromboembolism (VTE) were reviewed for the answers. An algorithm to consider in the assessment of the thrombotic risk in patients with CS was proposed. Results: To address both generic and CS-specific risk factors for VTE, the algorithm includes the stepwise approach consisting of Padua Score, urine free cortisol, and CS-VTE score, with no indication for routine thrombophilia testing in the prediction of an index VTE episode. Having confirmed VTE, selected patients require thrombophilia testing to aid the duration of anticoagulant treatment. The separate part of the algorithm is devoted to patients with ectopic adrenocorticotropic hormone syndrome in whom exclusion of VTE precedes introducing routine thromboprophylaxis to prevent VTE. The cancer-related VTE also prompts thromboprophylaxis, with the possible vessel invasion. The algorithm presents a unifactorial and multifactorial approach to exclude high-bleeding risks and safely introduce thromboprophylaxis with low-molecular-weight heparin. Summary: Our article is the first to present an algorithm to consider in the thrombotic risk assessment among patients with Cushing's syndrome as a starting point for a broader discussion in the environment. A plethora of factors affect the VTE risk in patients with CS, but no studies have conclusively evaluated the best thromboprophylaxis strategy so far. Future studies are needed to set standards of care.

Follow-up care and assessment of comorbidities and complications in patients with primary aldosteronism: The clinical practice guideline of the Taiwan Society of aldosteronism.

Primary aldosteronism (PA) is the most common form of endocrine hypertension, characterized by excess aldosterone production that leads to an increased risk of cardiovascular events and target organ damage. Both adrenalectomy and medical treatment have shown efficacy in improving clinical outcomes and comorbidities associated with PA, including a specific subtype of PA with autonomous cortisol secretion (ACS). Understanding the comorbidities of PA and establishing appropriate follow-up protocols after treatment are crucial for physicians to enhance morbidity and mortality outcomes in patients with PA. Additionally, the screening for hypercortisolism prior to surgery is essential, as the prognosis of patients with coexisting PA and ACS differs from those with PA alone. In this review, we comprehensively summarize the comorbidities of PA, encompassing cardiovascular, renal, and metabolic complications. We also discuss various post-treatment outcomes and provide insights into the strategy for glucocorticoid replacement in patients with overt or subclinical hypercortisolism. This clinical practice guideline aims to equip medical professionals with up-to-date information on managing concurrent hypercortisolism, assessing treatment outcomes, and addressing comorbidities in patients with PA, thereby improving follow-up care.

Assessment of non-traumatic vertebral fractures in Cushing's syndrome patients.

PURPOSE: Hypercortisolism has detrimental effects on bone metabolism with the consequences of bone loss and bone fractures. We aimed to evaluate the frequency of vertebral fragility fractures and to determine the factors associated with Cushing's syndrome (CS). METHODS: A total of 135 patients diagnosed with Cushing's syndrome [108 patients with Cushing's disease and 27 patients with adrenocortical adenoma] and 107 healthy controls were included in this cross-sectional study. The available clinical, laboratory, and radiologic data of patients with CS were recorded, retrospectively. Lateral vertebral radiograms were evaluated for vertebral fragility fractures according to Genant's semi-quantitative method. Bone mineral density (BMD) was determined using a Dual-energy X-ray absorptiometry (DEXA). RESULTS: Vertebral fragility fractures (VFs) were observed in 75.3% (n = 61) of the patients. The median number of VFs was six (min-max: 2-12). All patients with vertebral fractures had thoracic VF, and 50.7% of the patients had lumbar fragility fractures. Thirty-three (40.7%) patients with vertebral fractures had normal bone densitometry values. Osteoporosis and osteopenia were observed in 16.2% and 40.7% of the patients, respectively. The duration of active disease, the presence of ACTH-secreting pituitary adenoma, and 24-h urinary cortisol did not influence the presence of vertebral fractures. Vertebral fractures were independently associated with age, FSH, LH levels, and lumbar BMD (R2 = 68.18%, p = 0.028). The femoral neck BMD (but not lumbar BMD) was independently associated with age, BMI, and PTH levels (R2 = 48.48%, p < 0.001). CONCLUSION: Vertebral fracture frequency was higher in CS patients. Most of the patients with vertebral fractures had multiple fractures. Although low lumbar BMD was associated with VF, patients with CS with normal bone densitometry could experience VF. Vertebral radiograph evaluations as a part of routine evaluation for silent vertebral fractures may help to prevent further fractures in patients with CS.

Hypercortisolism and altered glucose homeostasis in obese patients in the pre-bariatric surgery assessment.

AIMS: Hypothalamus-pituitary-adrenal (HPA) axis hyperactivity was suggested to be associated with the metabolic syndrome (MS), obesity and diabetes. The aim of this study was to test whether hypercortisolism was associated with altered glucose homeostasis and insulin resistance, hypertension and dyslipidemia in a homogeneous population of obese patients. MATERIALS/METHODS: In retrospective analysis of a set of data about obese patients attending the outpatient service of a single obesity centre between January 2013 and January 2020, 884 patients with BMI >30 kg/m2 were segregated in two subgroups: patients with urinary free cortisol (UFC) higher than normal (UFC+; n = 129) or within the normal range (UFC-; n = 755). RESULTS: The overall prevalence of UFC+ was 14.6% and double test positivity (morning cortisol >1.8 mcg/dL following overnight dexamethasone suppression test, ODST) was detected in 1.0% of patients. Prediabetes (OR 1.74; 95%CI 1.13-2.69; p = 0.012) and diabetes (OR 2.03; 95%CI 1.21-3.42; p = 0.008) were associated with higher risk of UFC+ when analysis was adjusted for confounding variables. Conversely, hypertension and dyslipidemia were not related to UFC+. Within the individuals with normal FPG and HbA1c, those with higher estimated insulin resistance (HOMA2-IR) maintained a higher risk of UFC+ (OR 2.84, 95%CI 1.06-7.63; p = 0.039) and this relationship was weakened only when the body fat percentage was included into the model. CONCLUSIONS: In obese patients, hypercortisolism was more frequent across the entire spectrum of altered glucose homeostasis including the very early stages; this relation could not be detected for the other criteria of the MS, as waist, hypertension and atherogenic dyslipidemia.

Adrenal Venous Sampling for Assessment of Autonomous Cortisol Secretion.

Context: Autonomous cortisol secretion (ACS) can be unilateral or bilateral irrespective of the presence of an adrenal tumor. A reliable method to distinguish between unilateral and bilateral ACS is lacking. Objective: Evaluate the use of adrenal venous sampling (AVS) to distinguish between unilateral and bilateral ACS. Design and Methods: This was a prospective study of AVS in patients with adrenal tumors who received a diagnosis of ACS or adrenal Cushing syndrome (CS). Unilateral secretion was defined as >2.3-fold difference in cortisol levels between the two adrenal veins. Metanephrine levels were used to ascertain correct catheter position. Results were correlated with findings on CT and iodine-131-cholesterol scintigraphy. Results: Thirty-nine patients underwent AVS; there were no complications. The procedure was inconclusive in six patients and repeated with success in one, giving a success rate of 85%, and leaving 34 procedures for evaluation (adrenal CS, n = 2; ACS, n = 32). Of 14 patients with bilateral tumors, 10 had bilateral and 4 had unilateral overproduction. Of 20 patients with unilateral tumors, 11 had lateralization to the side of the tumor and the remaining had bilateral secretion. Cholesterol scintigraphy findings were concordant with those of AVS in 13 of 18 cases (72%) and discordant in 5 (28%). Conclusion: Laterality of ACS does not always correspond to findings on CT images. AVS is a safe and valuable tool for differentiation between unilateral and bilateral cortisol secretion and should be considered when operative treatment of ACS is a possibility.

Psychiatric Symptoms in Patients with Cushing's Syndrome: Prevalence, Diagnosis and Management.

Cushing's syndrome (CS) results from chronic exposure to cortisol excess, produced by the adrenal cortex. Hypercortisolism predisposes to psychiatric and neurocognitive disorders, mainly to depression and anxiety disorders. Screening tools to identify psychiatric symptoms are available for clinicians in their daily practice, although a specific diagnosis should be performed by specialists. Even if psychiatric symptoms improve after remission of hypercortisolism, complete recovery may not be achieved. Given the burden of these symptoms, psychiatric or psychological monitoring and treatment should be offered through all phases of CS, with a multidisciplinary approach. The aim of this article is to review data on the prevalence, diagnosis and management of psychiatric symptoms seen in patients with CS and to propose therapeutic approaches that may be followed in clinical practice. The prevalence of different psychiatric disorders has been described in both the active phase and after CS remission. Patients may not talk spontaneously about psychiatric symptoms they present, thus clinicians should ask directly about them. We recommend the use of screening tools in clinical practice to detect and treat these symptoms promptly. Even if reference endocrinologists cannot perform a definite psychiatric diagnosis, it will be important to ask patients directly about the presence of symptoms and refer if necessary to a psychiatrist. Additionally, patient information and educational programmes could be useful to manage psychiatric symptoms and to improve quality of life in patients with CS.

A venous thromboembolism risk assessment model for patients with Cushing's syndrome.

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.

Fracture risk assessment before and after resolution of endogenous hypercortisolism: is the FRAX® 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(®) 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(®) 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(®) 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(®) algorithm to all active CS patients using a baseline FRAX(®) Major of 17 % as "intervention threshold".

Subclinical hypercortisol-assessment of bone fragility: experience of single osteoporosis center in Sicily.

AIM: Hypercortisolism is known to cause osteoporosis. Some evidence suggests that osteoporotic fractures may be the presenting manifestations of otherwise-asymptomatic hypercortisolism. The aim of our research was to investigate the prevalence of subclinical hypercortisolism (SH) in postmenopausal women evaluated for bone fragility. PATIENTS AND METHODS: One hundred consecutive postmenopausal women attending the Osteoporosis Centre in the Department of Internal Medicine of the University of Messina (Messina, Italy), for the first time, were screened and a total of 50 patients (age 58±5 years) were studied. Hypercortisolism was diagnosed by unsuppressed serum cortisol levels after 2 day low dose dexamethasone suppression test. RESULTS: Among the 50 postmenopausal women studied, 3 had SH. This prevalence was 6%. The three patients with SH had a normal bone mineral density (BMD) at lumbar spine and were osteopenic at femoral neck, and presented one or more vertebral fractures at spinal radiography. CONCLUSIONS: Physicians should always consider SH among the causes of bone fragility, especially in individuals with vertebral fractures and the presence of an only slightly reduced BMD.

An assessment of petrosal sinus sampling for localization of pituitary microadenomas in children with Cushing disease.

CONTEXT: Pituitary adenomas in Cushing disease (CD) are usually small and difficult to visualize. Bilateral inferior petrosal venous sampling (BIPSS) before and after ovine CRH stimulation is reserved for patients who have ACTH-dependent Cushing syndrome and negative magnetic resonance imaging (MRI) or positive MRI but inconsistent biochemical data. OBJECTIVE: The objective of the study was to evaluate the usefulness of BIPSS as a tool for localization of a pituitary adenoma in children with CD. DESIGN: The study was a retrospective review of the records of 141 children who were admitted for evaluation of CD from 1982 to 2004. SETTING: The study was conducted at a tertiary care center. INTERVENTIONS AND OUTCOME MEASURES: Lateralization of ACTH secretion during BIPSS was compared with MRI and surgical findings for the localization of a microadenoma. RESULTS: A total of 94 patients, 49 males and 45 females with an age range of 5.3 to 18.7 yr (13 +/- 3.2 yr), underwent BIPSS. Localization of a microadenoma by BIPSS agreed with surgical location in only 58% of the cases (95% confidence interval, 43-66). The combined use of information from the MRI and inferior petrosal venous sampling did not predict the location of the tumor more frequently than MRI alone (P > 0.1), which in this study localized a lesion in 39% of the patients (95% confidence interval, 28-50). The procedure was completed successfully in all patients, and no serious complications were recorded. CONCLUSIONS: Although BIPSS was safe and well tolerated in an experienced center, lateralization of the ACTH gradient during BIPSS was a poor predictor of the site of the adenoma in children with CD.

Cognitive function and cerebral assessment in patients who have Cushing's syndrome.

Cushing's syndrome (CS) is a relevant model to better understand the effects of glucocorticoid (GC) excess on the human brain. The importance of GC excess on the central nervous system is highlighted by the high prevalence of neuropsychiatric disorders such as depression and cognitive impairment in patients who have CS. In addition, there is a high incidence of apparent diffuse loss of brain volume in patients who have CS. Recent studies indicate at least partial reversibility of these abnormalities following correction of hypercortisolism.

Does dynamic testing have a place in the modern assessment of endocrine hypertension?

Hypertension is one of the most important public health problems, affecting 15-20% of the adult population. The so-called "essential" hypertension includes the majority of cases; however, endocrine hypertension should always be suspected and excluded by physicians for at least 2 important reasons: prevalence rates of primary aldosteronism (the most common cause of mineralocorticoid-based hypertension) among hypertensives seem to be much higher than < 1% of initial studies, and treatment of endocrine hypertension relies on specific drugs (1) or on surgery. Endocrine hypertension comprises a spectrum of diseases (Table 1).

Bedside assessment of skin-fold thickness. A useful measurement for distinguishing Cushing's disease from other causes of hirsutism and oligomenorrhea.

BACKGROUND: The known catabolic effects of glucocorticoid excess on protein metabolism prompted us to devise a method to assess this measure in reproductive-aged females with Cushing's disease. Since collagen protein is a major component of skin, decreased abundance of this protein should cause a reduction in skin-fold thickness. To determine whether skin-fold thickness is useful as an added tool in the diagnosis of Cushing's disease, we compared this value in female patients with Cushing's disease with those who presented with a similar set of symptoms. METHODS: This open prospective study was conducted in an endocrinology clinic at a tertiary care center. The study population consisted of 88 females in the reproductive age group who presented to the clinic with hirsutism, oligomenorrhea, and/or obesity. Measurement of skin-fold thickness, body mass index, Ferriman-Gallwey index, and serum testosterone were performed in all patients. RESULTS: Skin-fold thickness in the patients with Cushing's disease was 1.5 +/- 0.2 mm (range, 1.0 to 1.8 mm). This value was significantly (P < .01) lower than that in controls or subjects with other disorders that have a similar set of presenting symptoms. CONCLUSIONS: Bedside assessment of skin-fold thickness is an easy, low-cost, and noninvasive test for distinguishing Cushing's disease from disorders with similar presenting symptoms in females of reproductive age. Assessment of skin-fold thickness should be used as an adjunct to current physical and biochemical study of patients with symptoms suggestive of Cushing's disease.

Use of a radioreceptor assay in the assessment of cushingoid features in patients with juvenile rheumatic diseases.

A marked variation has been observed in severity of cushingoid appearance in patients with rheumatic diseases (RD) following steroid administration. We studied ten children with RD to determine if a relationship exists between cushingoid features and an individual's steroid activity as measured by prednisolone equivalents using a radioreceptor assay. Cushingoid features were clinically assessed by a "cushing score" according to the method of Bergrem. Patients were assigned to either the cushingoid (C) or noncushingoid (NC) group at study entry according to their cushing score. Blood was drawn prior to prednisone ingestion and then at 30, 60, 90, 120, 240, and 360 minutes and each sample was assessed for prednisolone equivalents and also for free and total cortisol. Group comparisons of dose-adjusted area under curve (AUC) and peak response are reported. Cushingoid patients had higher plasma prednisolone equivalents (PE) than noncushingoid patients as measured by peak PE and AUC. The PE.6 h/L average AUC for C patients was 248 micrograms PE.6 h/L versus 134 micrograms PE.6 h/L for NC patients. This nearly twofold difference was also noted between mean peak values (C 82 micrograms/L vs. NC 44 micrograms/L). Spearman correlations of Cushing scores with these two parameters indicated significant (p less than 0.05) relationships. A patient's Cushing score correlated best with peak response (rs = 0.78) and also with AUC (rs = 0.72). Measurement of plasma peak PE or AUC could be valuable for individualizing steroid dosing in children with RD.