24-h Urinary Free Cortisol Research Articles

SAT-370 Clinical Characteristics and Metabolic Features of Patients with Subclinical Cushing's Syndrome and Its Correlation with Cortisol Level

Objective The aim of this study was to examine the clinical characteristics and metabolic features of subclinical Cushing’s syndrome (SCS), and to investigate the association of the cortisol level with the metabolic features in patients with SCS. Methods 52 patients with non-functioning adenoma (NFA), 45 patients diagnosed with SCS and 61 patients with overt adrenal Cushing’s syndrome (CS) participated in this study. Clinical data and endocrine function of the patients as well as histological findings were all reviewed. Results 1) The average age of patients with SCS was 52.56±13.25 years, 68.9% patients were female. No difference was detected in age, gender and BMI between patients with SCS and NFA (P > 0.05). Compared to patients with SCS, CS was more common in younger and female patients (43.90±13.83, 83.6%). The prevalence of diabetes mellitus, hypertension, and osteopenia/osteoporosis were significantly higher in patients with SCS compared to those with nonfunctioning tumors (57.8% vs 32.7%, 73.3% vs 53.8%, 41.2% vs 19.2%; P < 0.05). No difference was detected between SCS and CS patients in the prevalence of metabolic disease. 2) Compared to patients with NFA, plasma ACTH level is lower in patients with SCS (P < 0.05). Whereas, the midnight cortisol level and cortisol level after 1mg overnight dexamethasone suppression is higher in SCS than NFA (P < 0.05). No difference was detected between SCS and NFA in 24h urinary free cortisol and early-morning cortisol level (P > 0.05). Compared to SCS, the derangement of ACTH-cortisol axis is more prominent in CS patients demonstrated as suppressed plasma ACTH level and elevated plasma and 24h urine cortisol level. 3) In SCS cohort, SBP, FBG and HbA1c correlated positively with 24h urinary free cortisol (r =0.394, P =0.021; r =0.426, P =0.011, r =0.398, P =0.015; respectively). When controlling for age and gender, the correlation was also significant (P < 0.05). No correlations were found between BMI, TG, HDL and 24h urinary free cortisol. Conclusion Patients with SCS showed slight derangement of the circadian rhythm of cortisol and cortisol excess, and increased prevalence of metabolic disease. Furthermore, the cortisol level was related closely to blood glucose and blood pressure. Our findings might suggestive in therapeutic decision making (conservative vs surgery approach) in patients with SCS.

SUN-356 The Effects of Selective Serotonin Reuptake Inhibitors on Urinary Free Cortisol in Patients with Carney Complex and Primary Pigmented Nodular Adrenocortical Disease

PPNAD is a rare cause of ACTH-independent Cushing syndrome mainly associated with Carney complex (CNC). It is diagnosed by histologic examination or a 6-day Liddle test (LT) showing a paradoxical increase of >50% in 24-h urinary free cortisol (UFC) on the 2nd day of high-dose dexamethasone administration (Day 6 [D6]). PPNAD tissue has neuroendocrine features and can overexpress the serotonin (5-HT) synthesizing enzyme tryptophan hydroxylase type 2 and the 5-HT receptors types 4, 6, and 7, with formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production [1]. SSRIs inhibit the reuptake of 5-HT and are used as 1st-line antidepressants. This is a retrospective cohort study of patients with CNC and PPNAD that underwent a LT with the objective to evaluate the effect of SSRIs on UFCs in these patients. Of the 34 patients (4-65 y) with CNC and PPNAD that had a LT at our institution between 2004 and 2018, 4 patients took an SSRI during testing. No statistically significant differences were demonstrated between the SSRI (S) group and the non-SSRI (NS) group in baseline UFCs and urine 17-hydroxycorticosteroids (17OHS) and the percent increase in UFC and 17OHS on D6. Specifically, the median (IQR) baseline UFC in the S group was 36 (13-252) mcg/24h (nl 4-56) vs 35 (13-98) mcg/24h in the NS group (P=0.95). Baseline 17OHS were 11 (8-18) mg/mg creatinine (Cr) (nl ≤6) in the S group vs 8 (5-11) mg/mgCr in the NS group (P=0.27). The percent change in UFC was 208 (93-683)% in the S group and 185 (28-364)% in the NS group (P=0.89), while the percent change in 17OHS was 56 (40-87)% in the S group and 67 (16-92)% in the NS group (P=0.91). On D6, the S group appeared to have higher UFC [118 (63-635) mcg/24h vs 112 (58-201) mcg/24h; P=0.64] and 17OHS [16 (10-39) mg/mgCr vs 13 (7-17) mg/mgCr; P=0.25] than the NS group, but these were not statistically significant. Though these data do not confirm an effect of SSRIs on UFC and ultimately cortisol production in PPNAD, and the percent change in UFC during the LT was similar between both groups, the higher D6 UFC in the S group, when the baseline UFCs between the 2 groups were similar may suggest a degree of increased cortisol production in the S group. The data are limited by the small number of patients in the S group (n=4). In addition, 50% of patients in the S group vs 77% in the NS group underwent adrenalectomy, which is indicative of more severe disease in the NS group. More data are needed from this cohort to determine if SSRI use affects cortisol production in vivo, as this may have significant diagnostic and therapeutic implications for patients with CNC and PPNAD. Reference: 1. Bram, Z., et al., PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease. JCI Insight, 2016. 1(15): p. e87958.

SUN-397 A Rare Case of Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome Due to Thymic Large Cell Neuroendocrine Carcinoma Presenting as Severe Hypokalemia in a Taiwanese Man

Background Ectopic ACTH syndrome (EAS) represented 5% of Cushing syndrome. EAS is rapid onset, severe, associated with hypercortisolism related life-threatening infections and hypokalemia. In 60% of cases, the tumor is located in intrathoracic organ (lung, bronchus and thymus). Large cell neuroendocrine tumor of thymus secreting ACTH is a high grade, aggressive, poor prognosis and only few case reports in literature. Here we report a case of thymic LCNEC related EAS, which presented as severe hypokalemia, metabolic alkalosis and muscle weakness. Clinical Case A 71-year-old man presented with 12-kg weight loss, progressive generalized weakness and bilateral legs edema for two months.He has medical histories of hypertension and diabetes mellitus. Physical examination revealed generalized weakness without Cushingoid appearance. Laboratory examination showed metabolic alkalosis and severe hypokalemia (1.7 mmol/L, range 3.4-4.7).Hypokalemia work-up showed high morning ACTH 497 pg/mL (normal <46.0), cortisol 87.8 μg/dL (range 3.7-19.4), and normal limits of other pituitary hormones. Cushing syndrome survey showed lack of ACTH/cortisol circadian rhythm, markedly increased 24h urinary free cortisol excretion on two consecutive days ( 21429, 17061 μg). Low-dose and high-dose dexamethasone suppression tests showed non-suppressible. Ovine corticotrophin-releasing hormone stimulation test and desmopressin (DDAVP) test showed ectopic ACTH source. Pituitary MRI revealed negative findings. Bilateral inferior petrosal sinus sampling showed no central-to-peripheral ACTH gradient. Ectopic ACTH syndrome was impressed. Etomidate continuous infusion was prescribed.Fournier gangrene of left scrotum occurred during hospitalization and antibiotic and surgical treatment were given. Chest CT scan revealed tiny lobulated nodule in left lower lung field and soft tissue nodule in prevascular of mediastium. In-111 Octreoscan revealed several nodular lesions with increased In-111 uptake in the paraortic and prevascular region considering neuroendocrine tumor. Anterior mediastinal tumor excision was performed and histopathological report showed large cell neuroendocrine carcinoma of thymus with mitotic count 13/10 HPF and positive immunohistochemical stain for synaptophysin, chromogranin, DD-56, SSTR2 and ACTH. Sandostain LAR injection was administered afterward. Unfortunately, tumor progression with hypercortisolemia occurred after 6 months . External radiation and systemic chemotherapy were performed later. Clinical Lessons Although rare, Cushing syndrome must be considered in differential diagnosis of hypokalemia like our case, a challenging case of EAS. Early diagnosis and treatment was important to avoid life-threatening infections and metabolic complications. Moreover recurrence free survival with Sandostain LAR alone was only 6 months for LCNEC.

Performance of LC–MS/MS and immunoassay based 24-h urine free cortisol in the diagnosis of Cushing's syndrome

24-h urine free cortisol (UFC) is an indicator of integrated cortisol secretion and established screening tool for Cushing’s syndrome (CS). Doubts have been raised regarding specificity of immunoassays, and mass spectrometric techniques have been proposed as an alternative. In the present study we compared diagnostic accuracy of UFC measured with LC–MS/MS vs. immunoassay in patient with CS and patients where CS has been excluded. We examined 24-h urine samples from patients with surgically confirmed CS (n = 77; Cushing’s disease (n = 44), ectopic CS (n = 5), adrenal CS (n = 28)) and patients in whom Cushing’s syndrome was excluded (n = 97) by long-term follow up. UFC was first measured by automated chemiluminescence immunoassays (ADVIA Centaur, Siemens; LIAISON, DiaSorin). Aliquots of all samples were also analyzed by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Statistics: Passing-Bablok Regression, Receiver operating characteristic (ROC) analysis with Youden’s index calculation. UFC of CS patients were higher with both immunoassays compared to LC–MS/MS (913 +/- 235 vs. 303 +/- 155 μg/24 h (ADVIA) and 898 +/-216 vs. 399 +/- 196 μg/24 h (LIAISON)). Similarly, UFC were higher with immunoassays than with LC–MS/MS in the control group (223 +/- 10 vs. 23 +/- 2 μg/24 h (ADVIA) and 105 +/- 6 vs. 27 +/- 4 ug/24 h for (LIAISON)). Passing-Bablok regression showed good correlation between LC–MS/MS and ADVIA as well as between LCMS/MS and LIAISON (r = 0.96 and r = 0.99, p < 000.1) but less correlation in controls (r = 0.83 and r = 0.74, respectively, p < 000.1). ROC calculation revealed the highest ROC AUC (0.89) for the LIAISON immunoassay, followed by LC–MS/MS (0.82) and the ADVIA (0.80). In direct comparison, AUCs from LC–MS/MS and immunoassays in the same patient were not statistically different (p < 0,001). Best cut-off concentration to identify patients with CS was 234 μg/24 h (LIAISON), 51 μg/24 h for LC–MS/MS and 330 μg/24 h (ADVIA Centaur).In summary, UFC values were measured substantially higher by both immunoassays compared to LC–MS/MS. This is most likely due to cross-reactivity from interfering glucocorticoid metabolites. Nevertheless, all three methods correlated well. ROC analysis revealed the highest AUC for one of the immunoassays, although differences between the three methods were not significant. Direct comparison with LC–MS/MS indicates that high diagnostic accuracy can be obtained with suitable immunoassays.

Exacerbation of Cushing's syndrome during pregnancy: stimulation of a cortisol-secreting adrenocortical adenoma by ACTH originating from the foeto-placental unit.

SummaryA 29-year-old G4A3 woman presented at 25 weeks of pregnancy with progressive signs of Cushing’s syndrome (CS), gestational diabetes requiring insulin and hypertension. A 3.4 × 3.3 cm right adrenal adenoma was identified during abdominal ultrasound imaging for nephrolithiasis. Investigation revealed elevated levels of plasma cortisol, 24 h urinary free cortisol (UFC) and late-night salivary cortisol (LNSC). Serum ACTH levels were not fully suppressed (4 and 5 pmol/L (N: 2–11)). One month post-partum, CS regressed, 24-h UFC had normalised while ACTH levels were now less than 2 pmol/L; however, dexamethasone failed to suppress cortisol levels. Tests performed in vivo 6 weeks post-partum to identify aberrant hormone receptors showed no cortisol stimulation by various tests (including 300 IU hLH i.v.) except after administration of 250 µg i.v. Cosyntropin 1–24. Right adrenalectomy demonstrated an adrenocortical adenoma and atrophy of adjacent cortex. Quantitative RT-PCR analysis of the adenoma revealed the presence of ACTH (MC2) receptor mRNA, while LHCG receptor mRNA was almost undetectable. This case reveals that CS exacerbation in the context of pregnancy can result from the placental-derived ACTH stimulation of MC2 receptors on the adrenocortical adenoma. Possible contribution of other placental-derived factors such as oestrogens, CRH or CRH-like peptides cannot be ruled out.Learning points:Diagnosis of Cushing’s syndrome during pregnancy is complicated by several physiological alterations in hypothalamic–pituitary–adrenal axis regulation occurring in normal pregnancy.Cushing’s syndrome (CS) exacerbation during pregnancy can be associated with aberrant expression of LHCG receptor on primary adrenocortical tumour or hyperplasia in some cases, but not in this patient.Placental-derived ACTH, which is not subject to glucocorticoid negative feedback, stimulated cortisol secretion from this adrenal adenoma causing transient CS exacerbation during pregnancy.Following delivery and tumour removal, suppression of HPA axis can require several months to recover and requires glucocorticoid replacement therapy.

The role of Crooke's changes in recurrence and remission after gamma knife radiosurgery.

The objective of this study is to evaluate the role of Crooke's changes (CC) in normal the peri-tumoral anterior pituitary gland, in patients with Cushing's disease (CD) with a histopathological confirmed corticotroph adenoma, and determine if there is any difference in the recurrence and remission rates in CD patients after treatment with Gamma Knife Radiosurgery (GKRS). All patients treated with GKRS for CD from 2005 to 2016at our institution were identified. Patients had a confirmed adrenocorticotropic (ACTH)-secreting adenoma, i.e. corticotroph adenoma, and normal pituitary gland included in the surgical specimen, and specimens were stained with hematoxylin and eosin and also immunostaining for cytokeratin and ACTH. Statistical analyses were performed in a total of 61 patients who met the inclusion criteria. Additionally, we analyzed 20 patients in each group, with and without CC, after they were matched in a propensity score fashion. Endocrine remission defined as, a normal 24h urine free cortisol while off suppressive medication, occurred in 48 patients (78.7%), with 76.9% in those with CC and 81.8% in those without CC. There was no statistical significant difference between the two groups in regarding remission (p = 0.312) or recurrence (p = 0.659) in either the unmatched or matched cohorts. The presence or absence of CC in normal pituitary gland does not appear to confer a lower rate of remission or a higher rate of recurrence after GKRS. Patients with pituitary corticotroph adenomas that present with CC features may be well served by Stereotactic radiosurgery (SRS).

Changes in glucose metabolism based on 75-g oral glucose tolerance tests before and after surgery for adrenal Cushing's syndrome.

Adrenal Cushing's syndrome (CS) is caused by cortisol-producing adrenal adenoma and is frequently accompanied by glucose metabolism disorders, which are characterized by increased insulin resistance and insufficient β-cell compensation. However, considering the rarity of CS, few studies have assessed whether the glucose metabolism disorders could be ameliorated by surgical treatment. In this case series, we evaluated glucose metabolism before and after surgery in 11 patients (10 women and 1 man) who underwent unilateral adrenalectomy for overt adrenal CS between 2005 and 2016. Patients with pre-diagnosed diabetes mellitus (DM) were excluded. Pre- and post-operative 75-g oral glucose tolerance tests were performed. Cortisol secretion decreased significantly after surgery (median 24-h urinary free cortisol: 582.0 μg/day [interquartile range: 321.0-743.0 μg/day] to 31.3 μg/day [23.6-40.6 μg/day], p = 0.001). The results of the OGTT generally improved after surgery (normal glucose tolerance/impaired glucose tolerance/DM: 2/8/1 to 8/3/0), with significant decreases in the immunoreactive insulin and glucose levels. We also found a decrease in the median homeostatic model assessment of insulin resistance (2.4 [1.4-2.8] to 1.0 [0.6-1.1], p = 0.002), and increases in the median Matsuda index (3.0 [2.3-4.5] to 8.2 [6.3-11.4], p < 0.001), median insulinogenic index (0.70 [0.22-1.51] to 1.22 [0.78-1.64], p = 0.08), and median disposition index (609.1 [237.8-1,095.2] to 1,286.0 [1,034.6-1,857.6], p = 0.002). These findings indicate that adrenalectomy for adrenal CS without overt DM may help ameliorate glucose metabolism disorders, and improve both insulin resistance and insulin secretion.

Hypercortisolism in Newly Diagnosed Type 2 Diabetes: A Prospective Study of 384 Newly Diagnosed Patients.

Cross-sectional studies in small and selected populations report a high prevalence of hypercortisolism in patients with type 2 diabetes (T2D), which could have therapeutic implications, if confirmed. We therefore estimated the prevalence of hypercortisolism in a large and unselected cohort of recently diagnosed T2D patients. Consecutive patients with recently diagnosed T2D first underwent an overnight dexamethasone (1 mg) suppression test (OD). Patients not suppressing serum cortisol ≤50 nmol/l proceeded with a 48-h low dose dexamethasone suppression test (LDDST) and 24-h urinary free cortisol collection (UFC). Patients with elevated cortisol levels according to LDDST and/or UFC underwent imaging guided by plasma ACTH levels, and assessment of bone mineral density. A total of 384 T2D patients (232male/152 females) with a mean age of 60±10 years were included. Eighty-five (22%) patients suppressed incompletely to OD of whom 20 (5%) failed to suppress after LDDST and/or had elevated UFC (=hypercortisolism). Patients with hypercortisolism did not differ as regards age, BMI, HbA1c, T-score or blood pressure, but a higher proportion of them received antihypertensive treatment (100% vs. 64%, p=0.001). Imaging revealed adrenal adenoma(s) in 9 cases and a pituitary macroadenoma in 1 case. We found a 5% prevalence of hypercortisolism in unselected, recently diagnosed T2D, which was not associated with a persuasive cushingoid phenotype. The clinical implications are therefore uncertain.

Factors predicting long-term comorbidities in patients with Cushing\u2019s syndrome in remission

PurposeIn Cushing’s syndrome, comorbidities often persist after remission of glucocorticoid excess. Here, we aim to identify factors predicting long-term comorbidities in patients with Cushing’s syndrome in remission.MethodsIn a retrospective cross-sectional study, 118 patients with Cushing’s syndrome in remission (52 pituitary, 58 adrenal, 8 ectopic) were followed for a median of 7.9 years (range 2–38) after the last surgery. Associations between baseline anthropometric, metabolic, hormonal parameters at diagnosis, and comorbidities (obesity, diabetes, hyperlipidemia, hypertension, osteoporosis, depression) at last follow-up, were tested by uni- and multivariate regression analysis.ResultsIn patients with manifest comorbidities at diagnosis, remission of Cushing’s syndrome resolved diabetes in 56% of cases, hypertension in 36% of cases, hyperlipidaemia in 23%, and depression in 52% of cases. In a multivariate regression analysis, age, fasting glucose, BMI, and the number of comorbidities at diagnosis were positive predictors of the number of long-term comorbidities, while baseline 24-h urinary free cortisol (UFC) negatively correlated with the persistence of long-term comorbidities. The negative relationship between baseline UFC and long-term comorbidities was also found when pituitary and adrenal Cushing’s cases were analyzed separately. Baseline UFC was negatively related to the time of exposure to excess glucocorticoids.ConclusionsLong-term comorbidities after remission of Cushing’s syndrome depend not only on the presence of classic cardiovascular risk factors (age, hyperglycemia, BMI), but also on the extent of glucocorticoid excess. Lower baseline UFC is associated with a higher number of long-term comorbidities, possibly due to the longer exposure to excess glucocorticoids in milder Cushing’s syndrome.

Abstract P383: High Sodium Intake is Independently Associated with Subclinical Hypercortisolism in Hypertensive Patients

The widely accepted notion of an increase in water intake to compensate for a similar increase in salt consumption has recently been challenged by evidence of long-term renal and metabolic mechanisms favouring endogenous water accrual and body fluid preservation. A glucocorticoid-driven catabolic state is instrumental to this aim and is prevented by increased food intake in rodents. Demonstration of these mechanisms in large human populations is lacking and their relevance for cardiovascular disease is therefore unknown. We explored the association between sodium intake (estimated by 24h urine sodium excretion; USE) and 24h urinary free cortisol (UFC) in 145 patients screened for secondary causes of hypertension in a tertiary referral centre, after washout from drugs affecting the renin-angiotensin-aldosterone system (63 males, 43.3%; age, 48 [38-56] years; BMI, 27.1 [24.3-31.0] kg/m 2 ). USE was directly associated with UFC (Spearman’s rho=0.407, p&lt;0.001), as well as male gender (r=0.381, p&lt;0.001), BMI (r=0.243, p=0.006), creatinine clearance (r=0.637, p&lt;0.001) and, borderline, to plasma glucose (r=0.268, p=0.065). Importantly, UFC increased across classes of sodium intake (Low &lt; 2.3g/d, Medium 2.3-5g/d and High &gt; 5g/d) in lean and overweight groups (n=41, ANOVA p = 0.005 and n= 49, ANOVA p &lt; 0.001, respectively), but not in obese subjects (n=35; p = 0.083). Linear regression analysis showed that (square root-transformed) USE was the strongest explanatory variable for UFC after correction for age, gender, BMI, eGFR and aldosterone:renin ratio (β = 0.04, p &lt; 0.0005). A regression model that also included (Log-transformed) BMI as a surrogate of excess food intake (β = -0.51, p = 0.042), explained 23% of UFC variability in the cohort. We conclude that sodium intake, as estimated by USE, is an independent predictor of subclinical hypercortisolism in lean and overweight but possibly not in obese subjects. These data, in a population at increased cardiovascular risk, suggest a link between sodium intake and subclinical metabolic derangement, which could further add to the overall risk profile.

Effect of cabergoline monotherapy in Cushing's disease: an individual participant data meta-analysis.

The primary treatment of choice for Cushing's disease (CD) is the removal of the pituitary adenoma by transsphenoidal surgery (TSS). The surgical failure is seen in up to 75% of cases depending on the experience of the surgeon in different studies. Medical therapy is one of the options for the treatment of recurrent or persistent CD. The primary outcome of this meta-analysis was to find the proportion of patients achieving normalisation of 24-h urinary free cortisol (remission of CD) following cabergoline monotherapy. Literature search was conducted in January 2018 in PubMed/MEDLINE database from its date of inception to 31st December 2017. The search strategy used was "[(cushing) OR Cushing's] AND cabergoline". Individual participant data were extracted from the included studies and risk of bias was analysed by review checklist proposed by MOOSE. The individual participant data of 124 patients from six observational studies were included in this meta-analysis. 92 patients (74.2%) had past pituitary surgery. The proportion of patients achieving remission of Cushing’s disease (CD) with cabergoline monotherapy was 34% (95% confidence interval 0.26–0.43; P = 0.001) [corrected]. The previous surgery [odds ratio (OR) 28.4], duration of cabergoline monotherapy (OR 1.31) and maximum cabergoline dose (OR 0.19) were predictors for remission of CD. Mild and severe side effects were reported in 37.3% and 5.6% of patients, respectively, during cabergoline monotherapy. This meta-analysis shows that cabergoline monotherapy is a reasonable alternative for subjects with persistent or recurrent CD after TSS. It can also be used in CD patients either as a bridge therapy while waiting for surgery or in those unwilling for surgery or have contraindication to it.

Screening Tests for Hypercortisolism in Patients With Adrenal Incidentaloma

Background: To compare the diagnostic performance of different first-line screening tests for subclinical hypercortisolism (SH) in patients with adrenal incidentaloma (AI). Methods: We studied a series of patients with AI, with no clinical evidence of hormonal hypersecretion. For screening for SH, all patients performed 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC) and 24-h urinary free cortisol (UFC). A control group of patients with confirmed Cushing’s syndrome (CS) was used to calculate the diagnostic performance of the screening tests. Results: In the 83 patients with AI, morning cortisol after 1-mg DST was ? 1.8 ?g/dL in 69.9%, 1.9 to 5 ?g/dL in 26.5% and > 5 ?g/dL in 3.6%. LNSC was elevated in 20.5% and all patients had normal UFC levels. In the control group, composed of 50 patients with confirmed CS, all patients who underwent 1-mg DST had cortisol levels > 1.8 ?g/dL (1.9 to 5 ?g/dL in 16.2% and > 5 ?g/dL in 83.3%); LNSC was elevated in 93.8% and the UFC was increased in 85.4% of patients tested. Overall, for the screening of SH, the 1-mg DST presented a sensitivity and specificity of 100% and 69.9% with its lowest threshold (? 1.8 ?g/dL) and 83.3% and 96.4% with its highest threshold (< 5 ?g/dL). LNSC showed a sensitivity and specificity of 93.8% and 79.5% and the UFC of 85.4% and 100%, respectively. Conclusions: The 1-mg DST at its lowest threshold presented the highest sensitivity in identifying SH, but its low specificity encourages us to consider UFC levels, to reduce false-positive test results. J Endocrinol Metab. 2018;8(4):62-68 doi: https://doi.org/10.14740/jem510w

RESISTANT HYPERTENSION IN MOOD DISORDERS AND SLEEP DISTURBANCES

Objective: A relationship between cardiovascular diseases and psychopathological symptoms has been described in the literature. However, few studies have reported mood disorders in patients with resistant hypertension (RH). We discuss a case of RH in a young otherwise healthy woman, and analyse the diagnostic and therapeutic approach followed.Design and method: A 52-year old woman referred to our Centre for hypertension (170/104 mmHg) uncontrolled by 10 mg/day amlodipine, 10 mg/day ramipril, 25 mg/day hydrochlorothiazide and 4 mg/day doxazozin. The 24h-ABPM showed a Reverse-Dipper profile of BP values (Figure 1). She referred a new onset diabetes, a rapid weight gain and new-onset personality disturbance with generalized anxiety, panic disorder, impairment of memory and asthenia for which she had been treated with sertraline 50 mg and alprazolam 1 mg daiy. She also had insomnia and alteration of dreams which became more bizarre and vivid. Physical examination showed central obesity, supraclavicular fat pads, moon facies with easy bruising and mild hirsutism. Results: Serum cortisol levels at the morning and at the evening and 24h-urinary free cortisol levels were increased (52.7/55.8 mcg/dL and 2450 μg respectively). Hypokalemia (2.6 mEq/L) was also found. A total-body TC scan (Figure 2) revealed a left adrenal gland mass (12 × 13 × 7.5 cm on size) and many nodular focal lesions in the liver suspected as replicating forms. A total body FDG-PET/CT scan (Figure 3) showed an increased uptake of the tracer (SUVmax 5.2) in the left adrenal gland with multiple liver metastases. Despite a therapy with ketoconazole and high doses of mitotane, 45 days after the admission the patient died for a cardio-circulatory arrest but autopsy was not performed by explicit family request. The clinical picture was suggestive for a primary adrenocortical carcinoma (ACC). Conclusions: ACC is a rare and aggressive malignant neoplasm often diagnosed at an advanced stage. The combination of Cushing's syndrome is frequently found, but psychopathological symptoms are rare at the onset of ACC. We suggest not to consider as «depressed» and not to treat with antidepressant agents a young hypertensive subject with resistant HT without having ruled out an organic cause of psychiatric disease.

Spontaneous adrenocorticotropic hormone (ACTH) normalisation due to tumour regression induced by metyrapone in a patient with ectopic ACTH syndrome: case report and literature review

BackgroundEctopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is caused by tumours releasing ACTH. Ectopic ACTH-producing tumour regression is rarely induced using steroidogenesis inhibitors. We presented a case of EAS in which ACTH production by a lung tumour was reduced by metyrapone (MTP) and also reviewed previous cases of ectopic ACTH production suppressed via steroidogenesis inhibition.Case presentationA 71-year-old female with general fatigue, central obesity and impaired glucose tolerance was diagnosed with Cushing’s syndrome due to elevated ACTH (192.9 pg/mL; normal range, 7.2–63.3 pg/mL), cortisol (73.1 μg/dL; 6.4–21.0 μg/dL) and 24-h urinary free cortisol (UFC) (6160 μg/day; 11.2–80.3 μg/day) levels. Chest computed tomography identified a solid 26.6 × 22.9 × 30.0 mm tumour with a cavity in the upper lobe of the left lung. There was no adrenal gland enlargement. Tumour markers were not significantly elevated; ACTH levels were not suppressed by 8-mg dexamethasone. A corticotropin-releasing hormone stimulation test revealed blunted ACTH response (basal ACTH, 204.6 pg/mL; highest ACTH level during the 120-min stimulation test, 214.0 pg/mL). She was diagnosed with EAS due to a lung lesion. MTP treatment was started to reduce cortisol production. ACTH levels and cortisol and UFC levels were normalised and the ACTH-producing lung tumour was ablated after MTP treatment. In several reported cases, plasma ACTH levels reduced during steroidogenesis inhibitor treatment for EAS. Among the 10 patients, three cases of pheochromocytoma, one of thymic carcinoid and one of islet cell carcinoma were reported. In four cases, the tumour was not detected. In our case, the pathology of the lung tumour was unknown because of lack of tumour cells in biopsy. The patients were treated with ketoconazole (KTZ) and/or MTP and exhibited ACTH and cortisol/UFC suppression, but tumour regression was observed only in our case.ConclusionMTP and/or KTZ may reduce ACTH and cortisol production. The tumour spontaneously regressed after MTP treatment, indicating that MTP may reduce the tumour size without surgery. The mechanisms of therapeutic effects of steroidogenesis inhibitors and prognosis of spontaneous remission should be elucidated further via molecular biology studies.

Utility of a Single Late-Night Plasma Cortisol and Acth for the Diagnosis of Cushing Syndrome

To evaluate the diagnostic efficacy of various screening tests for the diagnosis of Cushing syndrome (CS). Thirty-five patients with CS and 16 patients of pseudo-CS were enrolled. Assessment of 24-h urinary free cortisol (UFC), late-night salivary cortisol (LNSC), overnight dexamethasone suppression test (ONDST), late-night plasma cortisol (LNPC), and adrenocorticotropic hormone (ACTH) on outpatient basis, and during sleep as well as in awake state after 48 hours of hospital admission. We found that 24-h UFC performed the best among the screening tests with sensitivity, specificity and areas under the curve (AUCs) of 96.0%, 99%, and 0.988, respectively, at a cut-off of 144.6 μg/24 h. A cut-off of 10.5 nmol/L for LNSC had sensitivity 85.7%, specificity 88.2%, and an AUC of 0.897. A cut-off of 412.4 nmol/L for LNPC on outpatient basis had sensitivity 88.2%, specificity 91.2%, and an AUC of 0.957. Cut-offs of 215 and 243.3 nmol/L for LNPC during sleep and awake states after acclimatization had sensitivity, specificity, and an AUC of 94.1%, 88.2%, and 0.958, respectively. An ONDST cut-off of 94.6 nmol/L provided sensitivity, specificity, and an AUC of 96.0%, 99.03% and 0.995, respectively. A cut-off of 30.3 pg/mL for late-night ACTH on outpatient basis had sensitivity 67.6%, specificity 99.9%, and an AUC 0.796.A cut-off of 22.6 pg/mL for ACTH during sleep state after acclimatization had sensitivity, specificity, and an AUC of 73.5%, 99.2%, and 0.827, respectively. UFC is the best screening test for CS. Furthermore, single measurements of LNPC and ACTH help to establish the diagnosis and ACTH dependency of CS in the majority of patients with CS. ACTH = adrenocorticotropic hormone AUC = area under the curve CRH = corticotropin-releasing hormone CS = Cushing syndrome ECLIA = electrochemiluminescence immuno-assay LDDST = low-dose dexamethasone suppression test LNPC = late-night plasma cortisol LNSC = late-night salivary cortisol ONDST = overnight dexamethasone suppression test RIA = radio-immuno assay UFC = urinary free cortisol.

Characteristics of Adrenal Incidentalomas in a Large, Prospective Computed Tomography-Based Multicenter Study: The COAR Study in Korea.

PurposePrevious studies on adrenal incidentalomas (AIs) are limited by their retrospective design, small numbers of patients, Western populations, or use of an outdated imaging technique. We investigated the characteristics of AIs in Korean patients and compared them with those reported in the largest retrospective study in Italy to discover the effects of improved imaging techniques and ethnicity differences.Materials and MethodsThis was a prospective, multicenter, cross-sectional observational study including 1005 Korean patients. Levels of plasma adrenocorticotrophic hormone, 24-h urinary free cortisol (UFC), serum cortisol after a 1 mg-dexamethasone suppression test, 24-h urinary fractionated metanephrine, and plasma aldosterone and plasma renin activity were measured. All AIs were characterized using computed tomography (CT).ResultsCompared with the results of the Italian study, AIs in Korean patients were observed more frequently in men and predominantly on the left side. Korean patients with AIs were slightly younger, and fewer patients underwent surgery. Most AIs were nonfunctional in both studies, while fewer subclinical hypercortisolism and more primary aldosteronism (PA) cases were detected in Korean patients. In our study, high UFC levels showed very low sensitivity, compared to those in the Italian study. In pheochromocytoma or PA cases, there were no hormonal differences between the studies. AIs in Korean patients were smaller, such that a lower cutoff size for detecting adrenocortical carcinoma (ACC) could be warranted.ConclusionRecent advances in CT technology were leveraged to provide accurate characteristics of AIs and to detect smaller ACCs.

Screening Tests for Hypercortisolism in Patients With Adrenal Incidentaloma

Background: To compare the diagnostic performance of different first-line screening tests for subclinical hypercortisolism (SH) in patients with adrenal incidentaloma (AI). Methods: We studied a series of patients with AI, with no clinical evidence of hormonal hypersecretion. For screening for SH, all patients performed 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC) and 24-h urinary free cortisol (UFC). A control group of patients with confirmed Cushing’s syndrome (CS) was used to calculate the diagnostic performance of the screening tests. Results: In the 83 patients with AI, morning cortisol after 1-mg DST was &lt;= 1.8 ? g/dL in 69.9%, 1.9 to 5 ? g/dL in 26.5% and &gt; 5 ? g/dL in 3.6%. LNSC was elevated in 20.5% and all patients had normal UFC levels. In the control group, composed of 50 patients with confirmed CS, all patients who underwent 1-mg DST had cortisol levels &gt; 1.8 ? g/dL (1.9 to 5 ? g/dL in 16.2% and &gt; 5 ? g/dL in 83.3%); LNSC was elevated in 93.8% and the UFC was increased in 85.4% of patients tested. Overall, for the screening of SH, the 1-mg DST presented a sensitivity and specificity of 100% and 69.9% with its lowest threshold (&lt;= 1.8 ? g/dL) and 83.3% and 96.4% with its highest threshold (&lt; 5 ? g/dL). LNSC showed a sensitivity and specificity of 93.8% and 79.5% and the UFC of 85.4% and 100%, respectively. Conclusions: The 1-mg DST at its lowest threshold presented the highest sensitivity in identifying SH, but its low specificity encourages us to consider UFC levels, to reduce false-positive test results. J Endocrinol Metab. 2018;8(4):62-68 doi: https://doi.org/10.14740/jem510w

How useful is urinary-free cortisol in the clinic?

Measurement of 24-h urine-free cortisol is frequently employed as a first-line screening and disease-monitoring test in Cushing's syndrome (CS). The quest for 'cortisol specificity' has seen the emergence of mass spectrometry (MS) based assays, particularly liquid chromatography/tandem mass spectrometry. In contrast to traditional immunoassays, liquid chromatography/tandem mass spectrometry 'free cortisol' measurement is less susceptible to 'interference' from cortisol precursors and metabolites. However, detection of these conjugates is important in mild CS and therefore, missed by MS if cortisol alone is measured. MS assays nevertheless are capable of measuring broad steroid profiles, including the potential to distinguish benign from malignant adrenal-based CS and detection of exogenous glucocorticoids. Until this is routine practice, we recommend against abandoning immunoassays measurement of urine-free cortisol.

Circadian Plasma Cortisol Measurements Reflect Severity of Hypercortisolemia in Children with Different Etiologies of Endogenous Cushing Syndrome

Background: The utility of circadian cortisol variation in estimating the degree of hypercortisolemia in different forms of endogenous Cushing syndrome (CS) has not been evaluated in children yet. Methods: A retrospective cohort study, including children who underwent surgery due to CS (n = 115), was divided into children with a pituitary adenoma (Cushing disease) (n = 88), primary adrenal CS (n = 21), or ectopic adrenocorticotropin- or corticotropin-releasing hormone (ACTH-/CRH)-secreting tumors (n = 6). Circadian plasma cortisol measurements were obtained at 11: 30 p.m. and at midnight, and at 7: 30 and 8: 00 a.m. The ratios between the morning and late-night concentrations were calculated. Results: Plasma cortisol early-morning and midnight (AM/PM) ratios negatively correlated with 24-h urinary free cortisol (UFC) collections among the full study population and in each of the individual etiologies. Plasma ACTH concentrations positively correlated with plasma cortisol AM/PM ratios among patients with ACTH-independent CS. Finally, patients with primary pigmented nodular adrenocortical disease showed no correlation between UFC collections and the plasma cortisol AM/PM ratio, in contrast with other etiologies for primary adrenal CS, which showed a strong negative correlation between them. Conclusion: Our study shows the association between the plasma cortisol AM/PM ratio and the degree of hypercortisolemia in children with CS.

Measuring cortisol in serum, urine and saliva - are our assays good enough?

Cortisol is a steroid hormone produced in response to stress. It is essential for maintaining health and wellbeing and leads to significant morbidity when deficient or present in excess. It is lipophilic and is transported bound to cortisol-binding globulin (CBG) and albumin; a small fraction (∼10%) of total serum cortisol is unbound and biologically active. Serum cortisol assays measure total cortisol and their results can be misleading in patients with altered serum protein concentrations. Automated immunoassays are used to measure cortisol but lack specificity and show significant inter-assay differences. Liquid chromatography - tandem mass spectrometry (LC-MS/MS) offers improved specificity and sensitivity; however, cortisol cut-offs used in the short Synacthen and Dexamethasone suppression tests are yet to be validated for these assays. Urine free cortisol is used to screen for Cushing's syndrome. Unbound cortisol is excreted unchanged in the urine and 24-h urine free cortisol correlates well with mean serum-free cortisol in conditions of cortisol excess. Urine free cortisol is measured predominantly by immunoassay or LC-MS/MS. Salivary cortisol also reflects changes in unbound serum cortisol and offers a reliable alternative to measuring free cortisol in serum. LC-MS/MS is the method of choice for measuring salivary cortisol; however, its use is limited by the lack of a single, validated reference range and poorly standardized assays. This review examines the methods available for measuring cortisol in serum, urine and saliva, explores cortisol in disease and considers the difficulties of measuring cortisol in acutely unwell patients and in neonates.