Diagnosis of Cushing's disease in a patient with consistently normal urinary free cortisol levels: a case report.
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ABSTRACT:
SUBMITTER: Moloney KJ
PROVIDER: S-EPMC5134332 | biostudies-literature | 2016 Dec
REPOSITORIES: biostudies-literature
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Diagnosis of Cushing's disease in a patient with consistently normal urinary free cortisol levels: a case report.
Moloney Kelley J KJ Mercado Jennifer U JU Ludlam William H WH Broyles Frances E FE
Clinical case reports 20161109 12
The urinary free cortisol (UFC) test is widely used for the screening of Cushing's syndrome. This case study illustrates the potential failure of the UFC test to correctly diagnose Cushing's disease (CD), indicating that the use of other complementary tests may be necessary to diagnose this disease in some cases. ...[more]
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Project description:BackgroundTwenty-four-hour urinary free cortisol (UFC) measurement is the initial diagnostic test for Cushing's syndrome (CS). We compared UFC determination by both direct and extraction immunoassays using Abbott Architect, Siemens Atellica Solution, and Beckman DxI800 with liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, we evaluated the value of 24-hr UFC measured by six methods for diagnosing CS.MethodsResidual 24-hr urine samples of 94 CS and 246 non-CS patients were collected. A laboratory-developed LC-MS/MS method was used as reference. UFC was measured by direct assays (D) using Abbott, Siemens, and Beckman platforms and by extraction assays (E) using Siemens and Beckman platforms. Method was compared using Passing-Bablok regression and Bland-Altman plot analyses. Cut-off values for the six assays and corresponding sensitivities and specificities were calculated by ROC analysis.ResultsAbbott-D, Beckman-E, Siemens-E, and Siemens-D showed strong correlations with LC-MS/MS (Spearman coefficient r=0.965, 0.922, 0.922, and 0.897, respectively), while Beckman-D showed weaker correlation (r=0.755). All immunoassays showed proportionally positive bias. The areas under the curve were 0.975 for Abbott-D, 0.972 for LC-MS/MS, 0.966 for Siemens-E, 0.948 for Siemens-D, 0.955 for Beckman-E, and 0.877 for Beckman-D. The cut-off values varied significantly (154.8-1,321.5 nmol/24 hrs). Assay sensitivity and specificity ranged from 76.1% to 93.2% and from 93.0% to 97.1%, respectively.ConclusionsCommercially available immunoassays for measuring UFC show different levels of analytical consistency compared to LC-MS/MS. Abbott-D, Siemens-E, and Beckman-E have high diagnostic accuracy for CS.
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Project description:Mutations in the protein kinase A (PKA) regulatory subunit type 1A (PRKAR1A) and armadillo repeat-containing 5 (ARMC5) genes cause Cushing's syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD) and primary bilateral macronodular adrenocortical hyperplasia (PBMAH), respectively. Between the two genes, ARMC5 is highly polymorphic with several variants in the population, whereas PRKAR1A has very little, if any, non-pathogenic variation in its coding sequence. We tested the hypothesis that ARMC5 variants may affect the clinical presentation of PPNAD and CS among patients with PRKAR1A mutations. In this study, 91 patients with PPNAD due to PRKAR1A mutations were tested for abnormal cortisol secretion or CS and for ARMC5 sequence variants. Abnormal cortisol secretion was present in 71 of 74 patients with ARMC5 variants, whereas 11 of 17 patients negative for ARMC5 variants did not have hypercortisolemia. The presence of ARMC5 variants was a statistically strong predictor of CS among patients with PRKAR1A mutations (P < 0.001). Among patients with CS due to PPNAD, ARMC5 variants were associated with lower cortisol levels at baseline (P = 0.04) and after high dose dexamethasone administration (P = 0.02). The ARMC5 p.I170V variant increased ARMC5 protein accumulation in vitro and decreased viability of NCI-H295 cells (but not HEK 293T cells). PPNAD tissues with ARMC5 variants showed stronger ARMC5 protein expression than those that carried a normal ARMC5 sequence. Taken together, our results suggest that ARMC5 variants among patients with PPNAD due to PRKAR1A defects may play the role of a genetic modifier for the presence and severity of hypercortisolemia.
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Project description:There are conflicting data on whether variations of physiologic cortisol levels associated with cardiovascular risk. We hypothesize that prior discordant findings are related to problems associated with varying sample size, techniques for assessing cardiovascular risk and failure to adequately account for environmental factors. To address these issues, we utilized a large sample size, selected the Framingham risk score to compute cardiovascular risk and performed the study in a highly controlled setting. We had two main objectives: determine whether higher, yet physiologic, cortisol levels associated with increased cardiovascular risk and determine whether caveolin-1 (rs926198) risk allele carriers associated with increased cardiovascular risk. This was a cross-sectional study of 574 non-diabetic individuals who completed a common protocol. Data collection included fasting blood samples, blood pressure measurements and a 24-h urine-free cortisol collection. Five hundred seventeen of these participants also completed caveolin-1 genotyping. Subjects were classified as belonging to either the low-mode or high-mode urine-free cortisol groups, based on the bimodal distribution of urine-free cortisol. In multivariate analysis, Framingham risk score was statistically higher in the high-mode cortisol group (10.22 (mean) ± 0.43 (s.e.m.)) compared to the low-mode cortisol group (7.73 ± 0.34), P < 0.001. Framingham risk score was also statistically higher in the caveolin-1 risk allele carriers (8.91 ± 0.37) compared to caveolin-1 non-risk allele carriers (7.59 ± 0.48), P = 0.034. Overall, the estimated effect on Framingham risk score of carrying the caveolin-1 risk allele was 1.33 ± 0.61, P = 0.029. Both urinary cortisol and caveolin-1 risk allele status are independent predictors of Framingham risk score.
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Project description:OBJECTIVE:To explore the association of hypothalamic-pituitary-adrenal activity with ovarian functioning in women with and without chronic abdominal pain (CAP). DESIGN AND SETTING:A secondary data analysis was performed with data from female participants in a natural history protocol at the National Institutes of Health. PARTICIPANTS:A total of 36 women (age range = 19-39 years, mean = 27.11 years) were included in the study. METHODS:This pilot study was conducted with a subset of participants enrolled in a natural history protocol conducted in the Hatfield Clinical Research Center at the National Institutes of Health. The parent study included participants with and without CAP who provided a 5-hour urine sample for determination of cortisol levels and serum samples for determination of circulating levels of cortisol, luteinizing hormone, and follicle-stimulating hormone. CAP was defined as presence or absence of chronic pain for at least 6 months and was determined via self-report. RESULTS:Anti-Müllerian hormone (AMH) concentrations declined significantly with age as expected. When AMH levels were dichotomized as normal or abnormal (defined as higher or lower than age-specific normative ranges, respectively), there were significant associations between abnormal AMH levels and CAP and urine cortisol levels. Participants with CAP or low urine cortisol levels were significantly more likely to have abnormal AMH levels. CONCLUSION:Results suggest that chronic abdominal pain and hypothalamic-pituitary-adrenal dysregulation may be associated with abnormal AMH levels.
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Project description:BackgroundPheochromocytoma and paraganglioma (PPGL) is diagnosed through biochemical confirmation of excessive catecholamines in urine and plasma. Recent technological developments have allowed us to measure urinary free metanephrines; however, the diagnostic accuracy of these new methods and the diagnostic cutoff values have not been evaluated.MethodsThis is a retrospective study of 595 subjects, including 71 PPGL cases and 524 controls. PPGL was based on pathological confirmation. Subjects with no evidence of PPGL over 2 years were included in the control group.ResultsUrinary free metanephrines yielded similar area under the curve (AUC) to urinary fractionated metanephrines and plasma free metanephrines. However, urinary free normetanephrine yielded a better AUC than did urinary fractionated normetanephrine. The optimal cutoff for urinary free metanephrine and normetanephrine corrected for urinary creatinine yielded 97.2% sensitivity and 98.1% specificity.ConclusionUrinary free metanephrines are a reliable method for diagnosing PPGL in Asian populations compared with existing biochemical methods.
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Project description:BackgroundVertebroplasty is a procedure most commonly used for vertebral compression fractures. Although it is a relatively safe procedure, complications have been reported. Cement embolism is seen in 2.1%-26% of patients after percutaneous vertebroplasty.Case presentationa 38-year-old male who was diagnosed with cushing's syndrome, underwent percutaneous vertebroplasty for his thoracic osteoporotic compression fractures. 24-hours following vertebroplasty, he presented to emergency department with acute-onset dyspnea and chest pain. Chest radiography showed an opaque linear lesion in left pulmonary artery which was suggestive of cement embolism. Pulmonary spiral CT-scan further confirmed the diagnosis. The patient's symptoms improved over time, and warfarin was started with close cardiopulmonary assessments for indicators of cement embolus removal.Conclusionin patients with pulmonary cement embolism, conservative treatment may be recommended rather than a surgical removal except when the obstruction is extensive enough to cause hemodynamic changes. Given that all the related studies have suggested that pulmonary thromboembolism can occur as a complication due to bone cement leakage, discovering new cement alternatives and/or injection devices, seems beneficial.
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Project description:Acute hepatic porphyria (AHP) is a family of rare, serious, and potentially life-threatening metabolic disorders caused by mutations in genes encoding enzymes involved in hepatic heme biosynthesis. AHP is characterized by accumulation of neurotoxic heme intermediates, δ-aminolevulinic acid (ALA), and porphobilinogen (PBG), which are thought to be causal for the disease manifestations. Novel therapeutic treatments such as givosiran, an RNA interference therapeutic that was recently approved for treatment of adults with AHP, are focused on reducing the levels of ALA and PBG in patients toward levels observed in a healthy population. While there are two published reports on the distribution of urinary ALA and PBG levels in healthy subjects, these lacked the required details to enable the calculation of reference limits for ALA and PBG. Therefore, urinary ALA and PBG levels were quantified in 150 healthy subjects using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method that is highly sensitive, specific, accurate, and reproducible. These data were used to establish the upper limit of normal (ULN) values for ALA and PBG as 1.47 and 0.137 mmol/mol Cr, respectively. Relative to these ULN values, baseline urinary ALA and PBG levels in AHP patients were found to be 9.3- to 12-fold, and 238- to 336-fold higher, respectively. Results from this study can serve as a guide to assess the effectiveness of therapeutic interventions in lowering ALA and PBG.
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Project description:The occurrence of different subtypes of endogenous Cushing's syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing's disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background.
| S-EPMC8417750 | biostudies-literature
Project description:PurposeReport the efficacy and safety of pasireotide sc in patients with Cushing's disease during an open-ended, open-label extension to a randomized, double-blind, 12-month, Phase III study.Methods162 patients entered the core study. 58 patients who had mean UFC ≤ ULN at month 12 or were benefiting clinically from pasireotide entered the extension. Patients received the same dose of pasireotide as at the end of the core study (300-1,200 μg bid). Dose titration was permitted according to efficacy or drug-related adverse events.Results40 patients completed 24 months' treatment. Of the patients who entered the extension, 50.0% (29/58) and 34.5% (20/58) had controlled UFC (UFC ≤ ULN) at months 12 and 24, respectively. The mean percentage decrease in UFC was 57.3% (95% CI 40.7-73.9; n = 52) and 62.1% (50.8-73.5; n = 33) after 12 and 24 months' treatment, respectively. Improvements in clinical signs of Cushing's disease were sustained up to month 24. The most frequent drug-related adverse events in patients who received ≥1 dose of pasireotide (n = 162) from core baseline until the 24-month cut-off were diarrhea (55.6%), nausea (48.1%), hyperglycemia (38.9%), and cholelithiasis (31.5%). No new safety issues were identified during the extension.ConclusionsReductions in mean UFC and improvements in clinical signs of Cushing's disease were maintained over 24 months of pasireotide treatment. The safety profile of pasireotide is typical for a somatostatin analogue, except for the frequency and degree of hyperglycemia; patients should be monitored for changes in glucose homeostasis. Pasireotide represents the first approved pituitary-targeted treatment for patients with Cushing's disease.
| S-EPMC4560758 | biostudies-literature
Project description:BackgroundThe purposes of the study were to compare serum total cortisol (STC), salivary cortisol (SaC) and calculated free cortisol (cFC) levels at baseline and after the adrenocorticotrophic hormone (ACTH) stimulation test in patients with severe sepsis (SS) and determine the suitability of use of SaC and cFC levels instead of STC for the diagnosis of adrenal insufficiency (AI) in patients with SS. And secondary aims of this study were to compare these parameters in patients with SS with healthy controls and check their effects on survival status of the patients.MethodsThirty patients with SS (15 men and 15 women) were compared with 16 healthy controls. Low-dose (1 μg) ACTH stimulation test was performed to the patients on the first, seventh and 28th days of diagnosis of SS, but in control group, 1 μg ACTH stimulation test was performed only once. STC, SaC and cFC levels were measured during ACTH stimulation test.ResultsPatients were categorized as having low or high baseline STC according to a cut-off level of 10 μg/dL. In high STC group, baseline and peak SaC levels were found to be 2.3 (0.2-9.0) and 3.4 (0.5-17.8) μg/dL on D1 and 1.1 (0.8-4.6) and 2.6 (1.3-2.9) μg/dL on D7, respectively. In the control group, baseline and peak SaC levels were 0.4 (0.1-1.4) and 1.1 (0.4-2.5) μg/dL, respectively. Baseline and peak SaC levels after ACTH stimulation were found to be higher in high STC group than in controls, but they were found to be similar in low STC and control groups. In high STC group, cFC levels were 0.3 (0.1-0.3) and 0.4 (0.3-0.7) μg/dL on D1 and 0.2 (0.1-0.3) and 0.4 (0.1-0.7) μg/dL on D7, respectively. In the control group, baseline and peak cFC levels were 1.7 (0.4-1.9) and 1.8 (1.0-6.6) μg/dL, respectively. cFC levels were found to be lower in patients with SS subgroups than in the control group. Baseline and stimulated STC, SaC and cFC levels did not differ according to the survival status. SaC, cFC and STC levels were found to be correlated with each other.ConclusionsSS is associated with increased SaC, but decreased cFC levels when baseline STC is assumed to be sufficient. When STC level is assumed to be insufficient, SaC levels remain unchanged, but cFC levels are decreased. Lower STC levels is not associated with increased mortality in patients with SS. More data are needed in order to suggest the use of SaC and cFC instead of STC.Trial registrationClinicalTrials.gov No: NCT02589431.
| S-EPMC4706674 | biostudies-literature