Cushing's Syndrome Patients Research Articles

Limitations of Basal Cortisol in the Diagnosis of Cushing Syndrome

Cushing syndrome (CS) is one of the most challenging diseases to diagnose due to the difficulties that may arise during laboratory test interpretations. A random serum cortisol level is often obtained by a general practitioner as a first step in the work-up of suspected CS patients. In this respect, it is rarely useful and has limitations. We report an extremely unusual case of a female patient who presented with adrenocorticotropic hormone-independent CS and corticosteroid-binding globulin (CBG) deficiency. The patient was initially misdiagnosed with and treated for adrenal insufficiency because of persistently low basal cortisol levels, in detriment of her exacerbated Cushing features and symptoms. We describe the limitations of using basal cortisol in the diagnosis of CS and review the differential diagnosis of patients with CS who have low basal cortisol. CBG variants may explain the findings of high urinary and salivary cortisol, in the absence of increased serum cortisol.

Differences of brain functional alterations between subtypes of Cushing's syndrome patients

Objective: To compare the differences of brain functional damage of subtypes of patients with Cushing's syndrome (CS). Methods: A total of 11 adrenocorticotropic hormone (ACTH)-dependent CS patients and 29 ACTH-independent CS patients were recruited from Chinese PLA General Hospital between September 2015 and March 2017 with confirmed CS. The psychiatric scales and brain task functional magnetic resonance imaging (fMRI) were evaluated. Results: A total of 40 patients (34 females, 6 males) with a mean age of (39.20±12.10) years and a median education level of 12 (9, 16) years were enrolled. ACTH-dependent patients had significantly worse performance than the ACTH-independent patients in response to the depression evaluation (64.6±6.1 vs 56.2±12.8, P=0.008), positive emotion (17.8±4.2 vs 24.3±7.2, P=0.008) and CS life quality [31(29,33) vs 42(29,51), P=0.040]. In the reaction to positive target pictures, ACTH-dependent CS patients showed stronger activation in left superior temporal gyrus compared with patients in ACTH-independent group, while the activation degree of their bilateral dorsal anterior cingulate cortex, bilateralsuperior frontal gyrus and left middle frontal gyrus was much worse. In the reactions to negative target pictures, ACTH-dependent CS patients had weaker activation in bilateral cerebellum, left superior frontal gyrus, left middle frontal gyrus, left precuneus and right postcentral gyrus, compared with patients in the ACTH-independent CS group (P<0.01, AlphaSim corrected). The activation degree of some regions whose brain function was different between the two groups was correlated to the cortisol level, ACTH level, 24 h urinary free cortisol (UFC) level, depression evaluation and negative emotion assessment (all P<0.05). Conclusions: The severity of the depression and the life quality of patients in ACTH-dependent group are worse than ACTH-independent CS patients. The brain function of ACTH-dependent CS patients is much weaker.

Demographic Characteristics, Etiology, and Comorbidities of Patients with Cushing's Syndrome: A 10-Year Retrospective Study at a Large General Hospital in China.

Purpose To investigate the demographic characteristics, etiology, and comorbidities of Cushing's syndrome (CS) patients at a large medical center in China. Methods Records on CS patients discharged from 2008 to 2017 were retrieved from the hospital discharge abstract database (DAD) using ICD-10 codes. Demographic characteristics, etiology, and comorbidity data were analyzed. Results Cushing's disease (CD) accounted for 63.0% of CS patients, followed by adrenocortical adenoma (ACA) (20.9%), primary bilateral macronodular adrenal hyperplasia (BMAH) (6.2%), ectopic ACTH syndrome (EAS) (5.9%), primary pigmented nodular adrenocortical disease (PPNAD) (1.8%), and adrenocortical carcinoma (ACC) (1.0%). CD, ACA, ACC, and PPNAD presented marked preponderances in women (4.1 : 1, 10.5 : 1, 4.3 : 1, and 2.3 : 1, respectively), while BMAH (59.8%) and EAS (51.0%) showed slightly higher preponderances in men. CD patients were younger than ACA and EAS patients (36.1 ± 12.9 years vs. 39.4 ± 12.7 years and 36.1 ± 12.9 years vs. 41.0 ± 15.8, P < 0.001); PPNAD patients were the youngest (24.2 ± 10.8 years, P < 0.001), and BMAH patients were the oldest (51.3 ± 9.9 years, P < 0.001). Hypertension, diabetes mellitus, osteoporosis without fractures, osteoporotic fractures, dyslipidemia, and fatty liver occurred more frequently in CD patients than in ACA patients (P < 0.001 for all). Osteoporotic fractures were observed more frequently in PPAND than in ACA (26.7% vs. 9.0%, P < 0.001) and BMAH (26.7% vs. 4.9%, P < 0.001) patients. EAS patients had more severe and diverse comorbidities, with higher prevalences of hypokalemia (52.0%), diabetes mellitus (61.2%), and osteoporotic fractures (28.6%). When adjusted for age, male CD patients were associated with hypertension (OR = 2.266, 95% CI: 1.524–3.371, and P < 0.001), osteoporotic fractures (OR = 2.274, 95% CI: 1.568–3.298, and P < 0.001), fatty liver (OR = 1.435, 95% CI: 1.028–2.003, and P = 0.034), and hypokalemia (OR = 1.944, 95% CI: 1.280–2.951, and P = 0.002). Conclusions The proposed method efficiently evaluates CS patients' epidemiological profiles using hospital DADs with ICD-10 codes and thus may enrich the limited epidemiological data and contribute to clinical practice for CS.

Hair Glucocorticoids as a 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 cortisol levels over longer periods of time. 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 the sum of both (sumHairF+E), as measured by a state-of-the-art LC-MS/MS technique, in untreated patients with confirmed endogenous CS (n = 89) as well as in community controls (n = 295) from the population-based Lifelines cohort study. Results: Both glucocorticoids were significantly elevated in CS patients when compared to controls. A high diagnostic efficacy was found for HairF (area under the curve 0.87 [95% CI: 0.83–0.92]), HairE (0.93 [0.89–0.96]), and sumHairF+E (0.92 [0.88–0.96]) (all p < 0.001). The participants were accurately classified at the optimal cutoff threshold in 86% of the cases (81% sensitivity, 88% specificity, and 94% negative predictive value [NPV]) by HairF, in 90% of the cases (87% sensitivity, 90% specificity, and 96% NPV) by HairE, and in 87% of the cases (86% sensitivity, 88% specificity, and 95% NPV) by the sumHairF+E. HairE was shown to be the most accurate in differentiating CS patients from controls. Conclusion: Scalp hair glucocorticoids, especially hair cortisone, can be seen as a promising biomarker in screening for CS. Its convenience in collection and workup additionally makes it feasible for first-line screening.

Hypercoagulability and Risk of Venous Thromboembolic Events in Endogenous Cushing's Syndrome: A Systematic Meta-Analysis.

Background: Hypercortisolism has been implicated in the development of venous thromboembolic events (VTE). We aimed to characterize VTE risk in endogenous Cushing's syndrome (CS) patients, compare that risk to other pathologies, and determine if there are any associated coagulation factor changes.Methods: Medline and Scopus search for “hypercortisolism” and “thromboembolic disease” from January 1980 to April 2017 to include studies that reported VTE rates and/or coagulation profile of CS patients. A systematic review and meta-analysis were performed.Results: Forty-eight studies met inclusion criteria. There were 7,142 CS patients, average age was 42 years and 77.7% female. Odds ratio of spontaneous VTE in CS is 17.82 (95%CI 15.24–20.85, p < 0.00001) when comparing to a healthy population. For CS patients undergoing surgery, the odds ratio (both with / without anticoagulation) of spontaneous VTE is 0.26 (95%CI 0.07–0.11, p < 0.00001)/0.34 (0.19–0.36, p < 0.00001) when compared to patients undergoing hip fracture surgery who were not treated with anticoagulants. Coagulation profiles in patients with CS showed statistically significant differences compared to controls, as reflected by increases in von Willebrand factor (180.11 vs. 112.53 IU/dL, p < 0.01), as well as decreases in activated partial thromboplastin time (aPTT; 26.91 vs. 30.65, p < 0.001) and increases in factor VIII (169 vs. 137 IU/dL, p < 0.05).Conclusion: CS is associated with significantly increased VTE odds vs. general population, but lower than in patients undergoing major orthopedic surgery. Although exact timing, type, and dose of anticoagulation medication remains to be established, clinicians might consider monitoring vWF, PTT, and factor VIII when evaluating CS patients and balance advantages of thromboprophylaxis with risk of bleeding.

Autoimmune Diseases in Patients with Cushing’s Syndrome after Resolution of Hypercortisolism: Case Reports and Literature Review

Introduction Cushing's syndrome (CS) is a clinical condition characterized by excessive cortisol production, associated with metabolic complications, such as diabetes mellitus, dyslipidemia, metabolic syndrome, hypertension, and cardiovascular diseases. Nowadays, the occurrence of autoimmune diseases in CS have not been completely evaluated in the previous studies. Objective The aim of this study was to evaluate the occurrence of autoimmune diseases in CS patients after successfully treated. Materials and Methods From January 2001 to December 2017, in our Secondary Hypertension Unit, we evaluated 147 CS patients (91 with ACTH-independent disease, 54 with ACTH-dependent disease, and 2 patients with ectopic ACTH production. Results 109 CS patients (74.1%) were surgically treated (67 ACTH-independent CS patients (61.5%) undergone adrenalectomy and 42 ACTH-dependent CS (38.5%) undergone transsphenoidal surgery) and evaluated after 6, 12, and 24 months after clinical and biochemical remission of disease. In 9 (8.3%) of overall treated CS patients (8.3%), during follow-up, we observed the onset of some manifestations of autoimmune diseases. In particular, one patient had a systemic lupus erythematosus, one patient had rheumatoid arthritis, 4 patients reported autoimmune thyroiditis (Basedow-Graves' disease and Hashimoto's thyroiditis), one patient had clinical features of psoriasis, one patient showed myasthenia gravis, and one patient had giant cell arteritis. Conclusions Our results demonstrate that patients successfully treated for CS could develop autoimmune diseases. Therefore, after treatment, CS patients need to be strictly monitored in order to evaluate the possible onset of autoimmune diseases.

Active cushing syndrome patients have increased ectopic fat deposition and bone marrow fat content compared to cured patients and healthy subjects: a pilot 1H-MRS study.

Glucocorticoid excess is one of the most important causes of bone disorders. Bone marrow fat (BMF) has been identified as a l new mediator of bone metabolism. Cushing syndrome (CS), is a main regulator of adipose tissue distribution but its impact on BMF is unknown. The objective of the study was to evaluate the effect of chronic hypercortisolism on BMF. This was a cross-sectional study. Seventeen active and seventeen cured ACTH-dependent CS patients along with seventeen controls (matched with the active group for age and sex) were included. the BMF content of the femoral neck and L3 vertebrae were measured by 1H-MRS on a 3-Tesla wide-bore magnet. BMD was evaluated in patients using dual-energy X-ray absorptiometry. Active CS patients had higher BMF content both in the femur (82.5±2.6%) and vertebrae (70.1±5.1%) compared to the controls (70.8±3.6%, p=0.013 and 49.0±3.7% p=0.005, respectively). In cured CS patients (average remission time of 43 months), BMF content was not different from controls at both sites (72.3±2.9% (femur) and 46.7%±5.3% (L3)). BMF content was positively correlated with age, fasting plasma glucose, HbA1c, triglycerides and visceral adipose tissue in the whole cohort and negatively correlated with BMD values in the CS patients . Accumulation of BMF is induced by hypercortisolism. In remission patients BMF reached values of controls. Further studies are needed to determine whether this increase in marrow adiposity in CS is associated with bone loss.

Abstract P333: Effect of Autonomous Cortisol Secretion on Cerebrovasuclular Events in Patients With Primary Aldosteronism

Background: Primary aldosteronism (PA) display a higher risk of cerebrovascular events (CVE) compared with essential hypertension (EH).On the one hand, it was also reported that the PA patients associated with autonomous cortisol secretion had high incidence of CVE. Objective: Our objective was to investigate the effect of autonomous cortisol secretion on the prevalence of CVE in the patients with PA and/or Cushing syndrome (CS). Design and Setting: This was a retrospective cross-sectional study from Tohoku University Hospital between 2008 and 2017. Patient: 291 patients were analyzed. In the patients with PA, the recent continuous cases performed adrenal venous sampling (AVS) were extracted. They were divided into four groups. Group A: 32 CS patients, Group B: 34 PA patients with autonomous cortisol secretion, Group C:121 PA patients with aldosterone producing adenoma (APA) and Group D: 104 PA patients with idiopathic hyperaldosteronism (IHA). They were also performed and analyzed MRI brain scans during a hospitalization and examined 1-mg dexamethasone suppression test . The patients in Group A, B and C were underwent adrenalectomy. Results: In Group A and Group B, the female-to-male ratio was significantly high (about 4:1). The prevalence of symptomatic stroke prevalence of symptomatic stroke before the confirmed diagnosis in each group were as follows: Group A:2/32, Group B: 0/34, Group C:13/121 and Group D: 3/104. The unruptured cerebral aneurysms were detected in Group A:1/32, Group B: 0/34,Group C:2/121 and Group D: 3/104. Aside from this results, 3 patients underwent surgical clipping for unruptured cerebral aneurysms. During this follow-up period, 5 patients had new onset of CVE(cerebral infarction: 1, cerebellar hemorrhage: 4) in Group C albeit carried out adrenalectomy. In comparison with MRI findings between Group A and B, we found no significant difference in the prevalence of Cerebral microbleeds (CMBs:5.8-9.3%) and High grade white matter hyperintensities (HWHs:43-50%). Conclusion: In this study, we could not demonstrate that the patients with PA associated with autonomous cortisol secretion had high incidence of CVE. Nevertheless, we demonstrate that the patients with APA had relatively high incidence of CVE.

Metyrapone treatment in Cushing's syndrome: a real-life study.

Medical treatment is increasingly used in patients with Cushing's syndrome (CS). Metyrapone (MET) is an inhibitor of 11β-hydroxylase: retrospective studies reported a decrease of cortisol secretion in 50% of cases. We evaluated the effectiveness of MET in an observational study, considering the normalization of urinary-free cortisol (UFC) and late-night salivary cortisol (LNSC) levels. We enrolled 31 patients with CS, treated with MET for at least 1 month (16 for primary treatment and 15 after surgical failure). A planned dose-titration regimen considering baseline UFC levels was adopted; MET dose was uptitrated until UFC normalization, surgery, or side effect occurrence. UFC and LNSC levels were routinely measured by liquid chromatography-tandem mass spectrometry. Patients were treated with a median dose of 1000 mg for 9 months. UFC and LNSC decreased quickly after the first month of treatment (-67 and -57% from baseline), with sustained UFC normalization up to 12 and 24 months (in 13 and 6 patients, respectively). UFC and LNSC normalized later (after 3-6 months) in patients with severe hypercortisolism (>5-fold baseline UFC). Regarding the last visit, 70 and 37% of patients normalized UFC and LNSC, respectively. Body weight reduction (-4 kg) was observed after UFC normalization. Severe side effects were not reported, half of the female patients complained of hirsutism, and blood pressure was not increased. MET therapy is a rapid-onset, long-term effective, and safe medical treatment in CS patients, achieving UFC normalization (in 70% of patients) more than cortisol rhythm recovery (in 37% of subjects).

Increased Serpina3n release into circulation during glucocorticoid-mediated muscle atrophy.

BackgroundGlucocorticoids (GC) play a major role in muscle atrophy. As skeletal muscle is a secretory organ, characterization of the muscle secretome elicited by muscle atrophy should allow to better understand the cellular mechanisms and to identify circulating biomarkers of this condition. Our project aimed to identify the changes in the muscle secretome associated with GC‐induced muscle atrophy and susceptible to translate into circulation.MethodsWe have identified the GC‐induced changes in the secretome of C2C12 muscle cells by proteomic analysis, and then, we have determined how these changes translate into the circulation of mice or human subjects exposed to high concentrations of GC.ResultsThis approach led us to identify Serpina3n as one of the most markedly secreted protein in response to GC. Our original in vitro results were confirmed in vivo by an increased expression of Serpina3n in skeletal muscle (3.9‐fold; P < 0.01) and in the serum (two‐fold; P < 0.01) of mice treated with GC. We also observed increased levels of the human orthologue Serpina3 in the serum of Cushing's syndrome patients compared with healthy controls matched for age and sex (n = 9/group, 2.5‐fold; P < 0.01). An increase of Serpina3n was also demonstrated in muscle atrophy models mediated by GC such as cancer cachexia (four‐fold; P < 0.01), sepsis (12.5‐fold; P < 0.001), or diabetes (two‐fold; P < 0.01). In contrast, levels of Serpina3n both in skeletal muscle and in the circulation were reduced in several models of muscle hypertrophy induced by myostatin inhibition (P < 0.01). Furthermore, a cluster of data suggests that the regulation of muscle Serpina3n involves mTOR, an essential determinant of the muscle cell size.ConclusionsTaken together, these data suggest that Serpina3n may represent a circulating biomarker of muscle atrophy associated to GC and, broadly, a reflection of dynamic changes in muscle mass.

Contralateral adrenal width predicts the duration of prolonged post-surgical steroid replacement for subclinical Cushing syndrome.

To identify pre-treatment factors affecting the duration of post-surgical steroid replacement in patients undergoing adrenalectomy for subclinical Cushing syndrome. The present retrospective analysis included 64 patients who underwent unilateral laparoscopic adrenalectomy for subclinical Cushing syndrome. Adrenal tumor and contralateral adrenal sizes together with various clinical factors were studied in association with the duration of post-surgical steroid replacement. Adrenal tumor and contralateral adrenal size were measured at the level of the maximum transverse plane of the adrenal glands using computed tomography scan or magnetic resonance imaging. Cox's proportional hazards model was used for the statistical analysis. All 64 patients were treated with post-surgical steroid replacement after adrenalectomy. The median duration of the steroid treatment was 6 months. When assessing the duration of post-surgical steroid replacement, contralateral adrenal volume <0.745 cm3 , contralateral adrenal width <6.15 mm and serum cortisol after a 1-mg dexamethasone suppression test >2.65 μg/dL were significant predictors of prolonged post-surgical steroid treatment on univariate analysis. On multivariate analysis, contralateral adrenal width <6.15 mm was the only independent predictive factor for the prolonged post-surgical steroid replacement. Contralateral adrenal width seems to represent a significant predictive factor for the duration of post-surgical steroid replacement in subclinical Cushing syndrome patients. Pre-surgical assessment of image findings might help clinicians determine the total duration of steroid therapy after adrenalectomy.

Differences in skin lesions of endogenous and exogenous Cushing's patients.

IntroductionCushing’s syndrome is a rare condition characterized by increased glucocorticoid levels. Dermatologically, it causes a variety of skin conditions such as atrophy, striae, acne, plethora, hypertrichosis, hirsutism, acanthosis nigricans, hyperpigmentation, alopecia, purpura and fragile skin. Although skin lesions of Cushing’s syndrome have been described, exogenous and endogenous types have not been studied in detail.AimTo determine differences in possible skin lesions depending on the cause of Cushing’s syndrome.Material and methodsA total of 35 patients – 16 iatrogenic Cushing’s syndrome patients and 19 endogenous Cushing’s syndrome patients – who were diagnosed in Erciyes University and 15 healthy individuals were included in this study.ResultsThere was at least one skin finding in 34 (97.1%) of the patients with Cushing’s syndrome and 9 (60%) in the control group (p = 0.001). Comparison regarding skin findings in patient and control groups revealed that hypertrichosis, hyperpigmentation, and fungal infections were significantly more frequent in the patient group than the control group. Hirsutism was found more frequently in the endogenous group whereas stria, hypertrichosis and fungal infections were more frequent in the exogenous group.ConclusionsSince Cushing’s syndrome is a rare disease and it is often diagnosed later in life, data on the frequency of skin findings are limited and sparse in the literature. In the comparison of endogenous Cushing’s and exogenous Cushing’s groups, acne, hypertrichosis, and fungal infections were found more frequently in the exogenous Cushing’s group and hirsutism more frequently in the endogenous Cushing’s group.

Preoperative medical treatment in Cushing's syndrome: frequency of use and its impact on postoperative assessment: data from ERCUSYN.

Surgery is the definitive treatment of Cushing's syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial. (1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS). 1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS). Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups. PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results.

Metabolic Syndrome in Cushing's Syndrome Patients.

Cushing's syndrome (CS), including visceral obesity, dyslipidemia, hypertension and diabetes among its many manifestations, is "a model" of metabolic syndrome. Glucocorticoid (GC) excess, through a combination of effects on liver, muscle, adipose tissue and pancreas, increases gluconeogenesis and impairs insulin sensitivity, leading to carbohydrate abnormalities. Dyslipidemia is a common finding in CS as a consequence of GC-related increased lipolysis, lipogenesis and adipogenesis. CS patients experience typical changes in body composition, with fat redistribution resulting in accumulation of visceral adipose tissue. Hypertension, myocardial and vascular abnormalities along with the metabolic changes and the characteristic coagulopathy increase cardiovascular morbidity and mortality. Metabolic syndrome features can persist long after normalisation of cortisol levels.

Bone Health in Patients with Cushing's Syndrome.

Introduction:Osteoporosis is a well-recognized complication of Cushing's syndrome (CS). Data on bone health in patients with CS from south Asian countries, which are vitamin D deficient, are scarce.Aims:We assessed bone mineral density (BMD) in patients with CS in comparison to controls. We also looked into how BMD differs in different types of endogenous CS.Materials and Methods:Thirty-seven cases of CS and 48 matched controls were studied for clinical, biochemical, hormonal, and bone densitometry parameters.Results:BMD (both total lumbar spine (LS) and hip) as well as Z scores were significantly lower in CS patients as compared to controls. Neither LS nor hip BMD was significantly different among different etiological groups of CS. The difference in BMD was also not significant between eumenorrhoeic and oligo-/amenorrhoeic patients with CS.Conclusion:Patients with CS are at increased risk of having fracture secondary to osteopenia and osteoporosis. There is no significant association of vitamin D and intact parathormone with low BMD in patients with CS.

TSH ratio as a novel diagnostic method for Cushing's syndrome.

Circadian variations impact thyrotropin (TSH) secretion; in Cushing's syndrome (CS) patients, the nocturnal serum TSH surge is abolished. The aim of this prospective study is to examine whether serum TSH surge may be a useful diagnostic method for CS. This prospective study recruited 136 inpatients for differential diagnosis of CS or subclinical CS (SCS), and 21 inpatients with depression at Osaka University Hospital. Serum TSH surge was assessed by the midnight-to-morning serum TSH ratio (2300-2400 h to 0800-0900 h). The diagnostic accuracy (sensitivity and specificity) between TSH ratio and ordinary screening tests [low-dose dexamethasone suppression test (LDDST), late-night serum cortisol and urine free cortisol (UFC)] were compared. Twenty-two patients were diagnosed as CS (12 overt CS and 10 SCS) and the remaining 120 patients were excluded for CS. The diagnostic accuracy of TSH ratio (cutoff value 1.0) yielded sensitivity 90.9% [95% confidence interval (CI) 70.8-98.9], specificity 95.0% (95% CI 89.4-98.1), and a high positive and low negative likelihood ratio [18.2 (95% CI 8.2-40.1) and 0.096 (95% CI 0.026-0.359), respectively]. The specificity of TSH ratio was significantly higher than LDDST and midnight serum cortisol test. The sensitivity of TSH ratio was significantly higher than UFC. TSH ratio showed more than 1.0 in all patients with depression and CYP3A4 inducer users. TSH ratio is a novel supportive diagnostic method with higher specificity than the current diagnostic methods for CS.

Decreased lymphocytes and increased risk for infection are common in endogenous pediatric Cushing syndrome.

ObjectiveHypercortisolemia results in changes of the immune system and elevated infection risk, but data on the WBC changes in pediatric Cushing syndrome (CS) are not known. We describe the changes of the WBC lineages in pediatric endogenous hypercortisolemia, their associations with the markers of disease severity, and the presence of infections.Study designWe identified 197 children with endogenous CS. Clinical and biochemical data were recorded. Sixty-six children with similar age and gender, and normocortisolemia served as controls.ResultsThe absolute lymphocyte count of CS patients was significantly lower than that of controls, while the total WBC and the absolute neutrophil counts were significantly higher. These changes correlated with several markers of CS severity and improved after resolution of hypercortisolemia. Infections were identified in 35 patients (17.8%), and their presence correlated to elevated serum morning cortisol, midnight cortisol, and urinary free cortisol levels, as well as with the decrease in absolute lymphocyte count.ConclusionsChildren with endogenous CS have abnormal WBC counts, which correlate with the severity of CS, and normalize after cure. Infections are common in this population; clinicians should be aware of this complication of CS and have low threshold in diagnosis and treating infections in CS.

Predictability of hypoadrenalism occurrence and duration after adrenalectomy for ACTH-independent hypercortisolism.

To evaluate if the parameters of hypothalamic-pituitary-adrenal (HPA) axis activity could predict the occurrence and duration of post-surgical hypocortisolism (PSH) in patients with Cushing's syndrome (CS) and with adrenal incidentaloma (AI). We studied 80 patients (54 females, age 53.3±11years), who underwent adrenalectomy for CS (17 patients) or for AI (53 patients). Before surgery, we measured adrenocorticotroph hormone (ACTH), urinary free cortisol (UFC) and serum cortisol after 1mg dexamethasone suppression test (1mg-DST) levels. After surgery, all patients were given a steroid replacement therapy, and PSH was searched after 2months by a low-dose (1µg, iv) corticotropin stimulation test, that was repeated every 6months in PSH patients for at least 4years. The PSH occurred in 82.4 and 46% of CS and AI patients, respectively. In the whole sample and in AI patients separately considered, the PSH was independently predicted by the preoperative cortisol levels after 1mg-DST, however, with a low (<70%) accuracy. In AI patients the PSH occurrence was not ruled out even by the cortisol levels after 1mg-DST lower than 1.8μg/dL (50nmol/L). In the 50% of CS patients and in 31% of AI patients the PSH lasted more than 18months and in 35.7% of CS patients it persisted for more than 36months. In AI patients, the PSH duration was not predictable by any parameter. However, a PSH duration of at least 12months was significantly predicted before adrenalectomy (sensitivity 91.7%, specificity 41.2%, positive predictive value 52.4%, negative predictive value 87.5%, p=0.05) by the presence of at least 2 out of low ACTH levels, increased UFC levels and cortisol levels after 1mg-DST≥3.0µg/dL (83nmol/L). The PSH occurrence and its duration are hardly predictable before surgery. All patients undergoing unilateral adrenalectomy should receive a steroid substitutive therapy.

A polymorphism in the CYP17A1 gene influences the therapeutic response to steroidogenesis inhibitors in Cushing's syndrome.

Steroidogenesis inhibitors, such as ketoconazole (KTZ) and metyrapone (MTP), are used to lower hypercortisolism in patients with Cushing's syndrome (CS). Cortisol normalization is not reached in all patients taking these medications. To test the hypothesis that variants in genes affecting steroidogenesis contribute to different responses to KTZ and/or MTP in patients with CS. Fifty-four CS patients (46 women; mean [±SD] age, 39.7±12.7; 83% with Cushing's disease [CD] and 17% with an adrenal adenoma) preoperatively treated with KTZ (20%), MTP (37%) or a combination of both (43%). Thirty-nine of these (72%) were described in a previous study investigating the outcome of preoperative treatment with KTZ or MTP in CS patients. Following single-nucleotide polymorphisms (SNPs) were analysed: rs6410 (CYP11B1 gene), rs1799998 and rs4546 (CYP11B2 gene), and rs6163 (CYP17A1 gene). The associations between SNPs and cortisol levels at the end of medical treatment were evaluated. Normalization of urinary free cortisol (UFC) was achieved in 50% of patients after 5months of treatment. Patients carrying the CC genotype of SNP rs6163 were more likely to be controlled than AC/AA (OR 0.25 [95%CI, 0.075-0.88]; P=.031). When only patients reaching eucortisolism after medical treatment were analysed, median interquartile range (IQR) duration of treatment was shorter in patients carrying the CC genotype of SNP rs6163 as compared to AA/AC carriers (4 [4.57]months vs 5.2 [6.1]months; P=.026). A polymorphism in the CYP17A1 gene was associated with the response to steroidogenesis inhibitors in CS. Genetic differences in the steroidogenic enzymes might account for inter-individual variations in the responsiveness to adrenal-blocking agents.

Cushing’s syndrome: a model for sarcopenic obesity

Obesity and its metabolic impairments are discussed as major risk factors for sarcopenia leading to sarcopenic obesity. Cushing's syndrome is known to be associated with obesity and muscle atrophy. We compared Cushing's syndrome with matched obese controls regarding body composition, physical performance, and biochemical markers to test the hypothesis that Cushing's syndrome could be a model for sarcopenic obesity. By propensity score matching, 47 controls were selected by body mass index and gender as obese controls. Fat mass and muscle mass were measured by bioelectrical impedance analysis. Muscle function was assessed by chair rising test and hand grip strength. Biochemical markers of glucose and lipid metabolism and inflammation (hsCRP) were measured in peripheral blood. Muscle mass did not differ between Cushing's syndrome and obese controls. However, Cushing's syndrome patients showed significantly greater chair rising time (9.5 s vs. 7.3 s, p = 0.008) and significantly lower hand grip strength (32.1 kg vs. 36.8 kg, p = 0.003). Cushing's syndrome patients with impaired fasting glucose have shown the highest limitations in hand grip strength and chair rising time. Similar to published data in ageing medicine, Cushing's syndrome patients show loss of muscle function that cannot be explained by loss of muscle mass. Impaired muscle quality due to fat infiltration may be the reason. This is supported by the observation that Cushing's syndrome patients with impaired glucose metabolism show strongest deterioration of muscle function. Research in sarcopenic obesity in elderly is hampered by confounding comorbidities and polypharmacy. As Cushing's syndrome patients are frequently free of comorbidities and as Cushing's syndrome is potentially curable we suggest Cushing's syndrome as a clinical model for further research in sarcopenic obesity.