The Utility of Preoperative ACTH/Cortisol Ratio for the Diagnosis and Prognosis of Cushing's Disease

ABSTRACT Purpose: Cushing's syndrome (CS) is a rare disease having diagnostic difficulties. Many diagnostic tests have been defined but none of these are diagnostic alone. Determination of the cause is another problem which sometimes requires more sophisticated and invasive procedures. Therefore, we aimed to evaluate the utility of pretreatment plasma adrenocorticotropic hormone (ACTH)/cortisol ratios in patients with confirmed endogenous CS for the diagnosis and differential diagnosis of CS. Materials and Methods: This retrospective evaluation included 145 patients with the diagnosis of CS, 119 patients with Cushing's disease (CD), and 26 patients with ACTH-independent CS (AICS), in a university hospital. Furthermore, 114 individuals in whom CS diagnosis was excluded with at least one negative screening test were enrolled to the study as control group. The clinical, laboratory, imaging, postsurgical pathologic records and also clinical follow-up data of all patients were evaluated. Results: The median basal ACTH/cortisol ratio of the patients with CD was significantly higher than AICS and controls. A cutoff ACTH/cortisol ratio >2.5 was found to be diagnostic for CD with 82% specificity and 63% sensitivity. Among CD group, patients with recurrent disease had higher preoperative ACTH levels and ACTH/cortisol ratio than patients with sustained remission. Furthermore, these patients had more invasive, atypical, and larger tumors. Conclusion: An ACTH/cortisol ratio >2.5 would be beneficial to diagnose CD together with other diagnostic tests. It is a simple test with no additional cost. Higher ratios might be related with larger, invasive, and atypical adenoma and also might be helpful to predict recurrence.

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Diagnosis and Multimodality Management of Cushing’s Disease: A Practical Review

International Journal of Endocrinology ◽

10.1155/2013/893781 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 10

Author(s):

Gabriel Zada

Keyword(s):

Pituitary Adenoma ◽

Cushing’S Disease ◽

Patient Survival ◽

Clinical Laboratory ◽

Management Strategies ◽

Serum Cortisol ◽

Cushing's Disease ◽

First Line ◽

Stepwise Approach

Cushing’s Disease is caused by oversecretion of ACTH from a pituitary adenoma and results in subsequent elevations of systemic cortisol, ultimately contributing to reduced patient survival. The diagnosis of Cushing’s Disease frequently involves a stepwise approach including clinical, laboratory, neuroimaging, and sometimes interventional radiology techniques, often mandating multidisciplinary collaboration from numerous specialty practitioners. Pituitary microadenomas that do not appear on designated pituitary MRI or dynamic contrast protocols may pose a particularly challenging subset of this disease. The treatment of Cushing’s Disease typically involves transsphenoidal surgical resection of the pituitary adenoma as a first-line option, yet may require the addition of adjunctive measures such as stereotactic radiosurgery or medical management to achieve normalization of serum cortisol levels. Vigilant long-term serial endocrine monitoring of patients is imperative in order to detect any recurrence that may occur, even years following initial remission. In this paper, a stepwise approach to the diagnosis, and various management strategies and associated outcomes in patients with Cushing’s Disease are discussed.

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Assessment of Vitamin D Metabolism in Patients with Cushing’s Disease in Response to 150,000 IU Cholecalciferol Treatment

Nutrients ◽

10.3390/nu13124329 ◽

2021 ◽

Vol 13 (12) ◽

pp. 4329

Author(s):

Alexandra Povaliaeva ◽

Viktor Bogdanov ◽

Ekaterina Pigarova ◽

Artem Zhukov ◽

Larisa Dzeranova ◽

...

Keyword(s):

Vitamin D ◽

Cushing’S Disease ◽

Serum Vitamin ◽

Urinary Free Cortisol ◽

Cushing's Disease ◽

Control Group ◽

Vitamin D Metabolites ◽

Vitamin D Metabolism ◽

Serum Vitamin D ◽

Free Cortisol

In this study we aimed to assess vitamin D metabolism in patients with Cushing’s disease (CD) compared to healthy individuals in the setting of bolus cholecalciferol treatment. The study group included 30 adults with active CD and the control group included 30 apparently healthy adults with similar age, sex and BMI. All participants received a single dose (150,000 IU) of cholecalciferol aqueous solution orally. Laboratory assessments including serum vitamin D metabolites (25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3), free 25(OH)D, vitamin D-binding protein (DBP) and parathyroid hormone (PTH) as well as serum and urine biochemical parameters were performed before the intake and on Days 1, 3 and 7 after the administration. All data were analyzed with non-parametric statistics. Patients with CD had similar to healthy controls 25(OH)D3 levels (p > 0.05) and higher 25(OH)D3/24,25(OH)2D3 ratios (p < 0.05) throughout the study. They also had lower baseline free 25(OH)D levels (p < 0.05) despite similar DBP levels (p > 0.05) and lower albumin levels (p < 0.05); 24-h urinary free cortisol showed significant correlation with baseline 25(OH)D3/24,25(OH)2D3 ratio (r = 0.36, p < 0.05). The increase in 25(OH)D3 after cholecalciferol intake was similar in obese and non-obese states and lacked correlation with BMI (p > 0.05) among patients with CD, as opposed to the control group. Overall, patients with CD have a consistently lower 25(OH)D3/24,25(OH)2D3 ratio, which is indicative of a decrease in 24-hydroxylase activity. This altered activity of the principal vitamin D catabolism might influence the effectiveness of cholecalciferol treatment. The observed difference in baseline free 25(OH)D levels is not entirely clear and requires further study.

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Cushing’s Disease: Assessment of Early Cardiovascular Hemodynamic Dysfunction With Impedance Cardiography

Frontiers in Endocrinology ◽

10.3389/fendo.2021.751743 ◽

2021 ◽

Vol 12 ◽

Author(s):

Agnieszka Jurek ◽

Paweł Krzesiński ◽

Grzegorz Gielerak ◽

Przemysław Witek ◽

Grzegorz Zieliński ◽

...

Keyword(s):

Blood Pressure ◽

Arterial Hypertension ◽

Cushing’S Disease ◽

Impedance Cardiography ◽

Left Ventricular ◽

Cushing's Disease ◽

Control Group ◽

Stroke Index ◽

Disease Group ◽

Hemodynamic Assessment

BackgroundCushing’s disease is a rare condition associated with a high cardiovascular risk and hypercortisolemia-related hemodynamic dysfunction, the extent of which can be assessed with a noninvasive method, called impedance cardiography. The standard methods for hemodynamic assessment, such as echocardiography or ambulatory blood pressure monitoring may be insufficient to fully evaluate patients with Cushing’s disease; therefore, impedance cardiography is being currently considered a new modality for assessing early hemodynamic dysfunction in this patient population. The use of impedance cardiography for diagnosis and treatment of Cushing’s disease may serve as personalized noninvasive hemodynamic status assessment and provide a better insight into the pathophysiology of Cushing’s disease. The purpose of this study was to assess the hemodynamic profile of Cushing’s disease patients and compare it with that in the control group.Material and MethodsThis observational prospective clinical study aimed to compare 54 patients with Cushing’s disease (mean age 41 years; with 64.8% of this population affected with arterial hypertension) and a matched 54-person control group (mean age 45 years; with 74.1% of this population affected with arterial hypertension). The hemodynamic parameters assessed with impedance cardiography included the stroke index (SI), cardiac index (CI), systemic vascular resistance index (SVRI), velocity index (VI), (ACI), Heather index (HI), and thoracic fluid content (TFC).ResultsThe Cushing’s disease group was characterized by a higher diastolic blood pressure and a younger age than the control group (82.9 vs. 79.1 mmHg, p=0.045; and 41.1 vs. 44.9 years, p=0.035, respectively). Impedance cardiography parameters in the Cushing’s disease group showed: lower values of SI (42.1 vs. 52.8 ml/m2; p ≤ 0.0001), CI (2.99 vs. 3.64 l/min/m2; p ≤ 0,0001), VI (42.9 vs. 52.1 1/1000/s; p=0.001), ACI (68.7 vs. 80.5 1/100/s2; p=0,037), HI (13.1 vs. 15.2 Ohm/s2; p=0.033), and TFC (25.5 vs. 27.7 1/kOhm; p=0.006) and a higher SVRI (2,515 vs. 1,893 dyn*s*cm-5*m2; p ≤ 0.0001) than those in the control group.ConclusionsCushing’s disease is associated with significantly greater vasoconstriction and left ventricular systolic dysfunction. An individual assessment with impedance cardiography may be useful in Cushing’s disease patients in order to identify subclinical cardiovascular complications of chronic hypercortisolemia as potential therapeutic targets.

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Cushing's disease: results of transsphenoidal microsurgery with emphasis on surgical failures

Journal of Neurosurgery ◽

10.3171/jns.1990.72.3.0363 ◽

1990 ◽

Vol 72 (3) ◽

pp. 363-369 ◽

Cited By ~ 87

Author(s):

George T. Tindall ◽

Carl J. Herring ◽

Richard V. Clark ◽

David A. Adams ◽

Nelson B. Watts

Keyword(s):

Cushing’S Disease ◽

Preoperative Diagnosis ◽

Adrenocorticotropic Hormone ◽

Remission Rate ◽

Cushing's Disease ◽

Sustained Remission ◽

Original Diagnosis ◽

Content Type ◽

Transsphenoidal Microsurgery

✓ From 1977 to 1988, 56 patients with a preoperative diagnosis of Cushingαs disease were treated by transsphenoidal microsurgical exploration of the pituitary gland. In 42 patients, a discrete tumor was found and a selective adenomectomy was performed. Total hypophysectomy was performed in nine patients. In an attempt to preserve pituitary function, a technique of subtotal hypophysectomy was utilized in the remaining five patients. Regular and adequate follow-up results were obtained in 53 patients. A sustained remission was obtained in 45 of these 53 patients for a remission rate of 84.9%. Eight patients were classified as therapeutic failures. The causes for failure included: 1) invasive tumor; 2) hyperplasia mistaken for an adenoma; 3) a presumed ectopic source of adrenocorticotropic hormone; 4) misdiagnosis; 5) atypical tumor; and 6) recurrence of disease after remission. In cases of therapeutic failure, the original diagnosis of Cushing's disease must be reevaluated and treatment continued until sustained remission is achieved. Necessary measures to help avoid surgical failures and an approach for further diagnostic and therapeutic maneuvers in these cases are discussed.

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SUN-305 Hair Cortisol Measurement: An Innovative Method for Diagnosis and Follow-Up in Patients with Cushing’s Disease

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.597 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Natalia Gabriela Deligiannis ◽

Soledad Sosa ◽

Diego Gonzalez ◽

Carolina Ibar ◽

Dario Gustavo Jacobsen ◽

...

Keyword(s):

Cushing’S Disease ◽

Reference Interval ◽

Urinary Free Cortisol ◽

Cushing's Disease ◽

Control Group ◽

Hair Cortisol ◽

Kappa Index ◽

Free Cortisol ◽

Pituitary Lesion

Abstract Diagnosis of endogenous Cushing’s syndrome entails corticotropic autonomy, lack of circadian rhythm and/or hypercortisolism, evaluated through 24h urinary free cortisol (UFC). Hair cortisol measurement (HCM) has been described as an alternative marker of cortisol exposure over the preceding three months. OBJECTIVES To evaluate HCM in Cushing’s disease (CD). To analyze the correlation between HCM and UFC. To compare HCM values in CD vs controls. PATIENTS AND METHODS 3 cm hair from posterior vertex in CD and in controls age- and gender-matched between May 2017 and May 2019. Controls were low level stressed individuals (Holmes-Rahe’s scale) without adrenal disease. Normal reference interval of HCM was defined (40-128 pg/mg hair). Measurement: Siemens Immulite 2000 (Gwynedd, UK) automated chemoluminiscent immunoassay (CLIA) UFC values within the 3 months previous to hair collection were considered. Controlled CD defined as UFC ≤1 upper normal limit (UNL) with or without treatment, remission as UFC ≤1 without pituitary lesion. Results are presented as median (m) and range. Kruskal-Wallis ANOVA used for median difference evaluation and Kappa index for concordance determination. Chi2 test for comparison of recategorized UFC and HCM. Statistical analysis performed with SPSS 23.0 RESULTS 23 CD patients recruited, median age 42 ± 11 years; 91% (n=21) female; 10 samples collected at diagnosis and 13 during follow-up. Control group composed of 50 individuals 45% (n=10) had controlled CD (mUFC 0.42 UNL, range 0.1-0.9) and a mHCM of 134.5 pg/mg (62-334) and 55% (n=12) did not have control (mUFC 2.2, 1.1-6) and a mHCM of 150.5 (75-459). After recategorization of UFC (> o ≤ 1 UNL) and HCM (> o ≤ 128 pg/mg), determinations were associated (Chi2, p= 0.18), however, the concordance was acceptable (Kappa index = 0.276). After dividing CD patients according to HCM, 35% (n=8) had normal HCM: mHCM 113.5 (62-126) and mUFC 0.45 (0.1- 4.4). Among them, 63% (n=5) had controlled CD (mHCM 110, 62-121; mUFC 0.39, 0.1-0.85); 25% (n=2) had active CD (mUFC 2.7, 1.1-4.4; mHCM 121, 75-126). 65% had high HCM (n=15): mHCM 167 (132-459) and mUFC 1.36 (0.1-6). Most of them had active CD (n=11, 73%): mHCM 160 (132-459) and mUFC 2.2 (1.1-6). Four patients with elevated HCM (m 248, 148-334) had normal UFC (m 0.61, 0.12-0.92): 2 were in remission, 1 had normal postsurgical UFC with active disease in the follow-up and 1 had normal UFC under medical treatment. Controls (n=50) had mHCM 62.5 (40-126), significantly different from CD. CONCLUSIONS We evaluated HCM in CD, proposing this method as an additional diagnostic test for hypercortisolism. The acceptable concordance between UFC and HCM is possibly due to the different duration of the evaluated periods. The difference in the HCM values observed between controlled or active CD patients and controls permits the consideration of the method as an alternative in the diagnosis and/or follow-up of CD.

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A Rare Entity in Cushing’s Disease: Severe Hypokalemia and Metabolic Alkalosis

Medical Science and Discovery ◽

10.36472/msd.v8i3.492 ◽

2021 ◽

Vol 8 (3) ◽

pp. 189-192

Author(s):

Seda Turgut ◽

Muzaffer Ilhan ◽

Rabia Soytas ◽

Murat Alay ◽

Rumeyza Kazancioglu

Keyword(s):

Case Report ◽

Cushing’S Disease ◽

Metabolic Alkalosis ◽

Final Diagnosis ◽

University Hospital ◽

Cushing's Disease ◽

Resonance Imaging ◽

Right Lobe ◽

The Right ◽

Severe Weakness

Introduction: This case report aimed to highlight the prominence of considering Cushing's disease in the differential diagnosis of severe hypokalemia and metabolic alkalosis. Case Report: A 63-year-old woman who admitted to the emergency room of Bezmialem Vakif University Hospital, Istanbul with fatigue and severe weakness of extremities. Biochemistry results indicated severe hypokalemia (potassium=1.2 mmol/L) and metabolic alkalosis (pH= 7.83) and based on further endocrinological investigations, the final diagnosis of Cushing’s disease was confirmed, and magnetic resonance imaging revealed a macroadenoma in the right lobe of the pituitary. Transsphenoidal surgery was performed and Cushing’s disease was cured without any treatment. Conclusions: Although hypokalemia can be present in Cushing’s disease, none of the previous studies have reported hypokalemia as severe as in this case.

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Distinct Late-Night Salivary Cortisol Cut-Off Values for the Diagnosis of Hypercortisolism

Hormone and Metabolic Research ◽

10.1055/a-1608-1720 ◽

2021 ◽

Vol 53 (10) ◽

pp. 662-671

Author(s):

Lukas van Baal ◽

Marc Wichert ◽

Denise Zwanziger ◽

Henning Dralle ◽

Frank Weber ◽

...

Keyword(s):

Cushing’S Disease ◽

Salivary Cortisol ◽

Cushing's Disease ◽

Control Group ◽

High Morbidity ◽

Reference Ranges ◽

Ectopic Acth ◽

Late Night ◽

Late Night Salivary Cortisol ◽

Ectopic Acth Production

AbstractDue to high morbidity and mortality of untreated hypercortisolism, a prompt diagnosis is essential. Measurement of late-night salivary cortisol provides a simple and non-invasive method. However, thresholds and reference ranges differ among studies. The goal of this study was to define a threshold of late-night salivary cortisol for the diagnosis of hypercortisolism based on the used assay. Moreover, the influence of different aetiologies of hypercortisolism and individual comorbidities were investigated. Prospective analyses of 217 patients, including 36 patients with proven hypercortisolism were carried out. A sum of 149 patients with suspicion of hypercortisolism but negative endocrine testing and 32 patients with hypercortisolism in remission served as control group. Late-night salivary cortisol was measured using an automated chemiluminescence immunoassay. Cut-off values were calculated by ROC analysis. The calculated cut-off value for the diagnosis of hypercortisolism was 10.1 nmol/l (sensitivity 94%; specificity 84%). Only slightly lower thresholds were obtained in patients with suspected hypercortisolism due to weight gain/obesity (9.1 nmol/l), hypertension or adrenal tumours (both 9.8 nmol/l) or pituitary adenomas (9.5 nmol/l). The late-night salivary cortisol threshold to distinguish between Cushing’s disease and Cushing’s disease in remission was 9.2 nmol/l. The cut-off value for the diagnosis of ectopic ACTH-production was 109.0 nmol/l (sensitivity 50%, specificity 92%). Late-night salivary cortisol is a convenient and reliable parameter for the diagnosis of hypercortisolism. Except for ectopic ACTH-production, thresholds considering different indications for evaluation of hypercortisolism were only slightly different. Therefore, they might only be useful if late-night salivary cortisol results near the established cut-off value are present.

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Use of a Hospital Database to Determine the Characteristics of Diagnostic Tests

Methods of Information in Medicine ◽

10.1055/s-0038-1634789 ◽

1990 ◽

Vol 29 (03) ◽

pp. 205-212 ◽

Cited By ~ 3

Author(s):

Johanna Zwetsloot-Schonk

Keyword(s):

Clinical Practice ◽

Diagnostic Tests ◽

Patient Population ◽

Clinical Laboratory ◽

University Hospital ◽

Test Results ◽

Hospital Database ◽

Routinely Collected Data ◽

Study Population ◽

Using Data

AbstractTest indices are often determined by comparing test results of healthy persons with test results of patients known to have the disease. However, the patient population for which the test is ordered in clinical practice often differs from the study population on which the test indices are based. Hence, these indices are not applicable to clinical practice and should be recalculated using data from daily clinical practice. Two major problems of using routinely collected data are discussed: the assessment of the final health status and tracing the reason for ordering the test. Prior considerations are given to the use of hospital information systems (HIS) to sample the patient population that is desired and to collect the necessary data for calculating test indices. We investigated whether the HIS of Leiden University Hospital (which is presented as an example) can be used to calculate the indices of clinical laboratory tests, histopathologic examinations and radiodiagnostic investigations. The results indicate that the registration of diagnoses must be improved and that a way must be found to capture the implicit reasoning for ordering diagnostic tests.

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“The Adrenal Gland: Central Relay in Health and Disease - Current Challenges and Perspectives 2018” – Cushing’s Disease

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-0664-7632 ◽

2018 ◽

Vol 127 (02/03) ◽

pp. 147-155 ◽

Cited By ~ 1

Author(s):

Günter Stalla ◽

Denis Ciato ◽

Christina Dimopoulou

Keyword(s):

Cushing’S Disease ◽

Diagnostic Tests ◽

Chronically Ill ◽

Cushing's Disease ◽

Targeted Drugs ◽

Recurrence Rates ◽

Pharmacological Agents ◽

Late Night ◽

Individualized Care ◽

Challenging Situation

Abstract Background Despite advances in diagnostic and therapeutic approach, Cushing’s disease (CD) presents a challenging situation for the treating physician. Aims To elucidate current challenges, present strengths and pitfalls of existing diagnostic tests, enlighten the need for new diagnostic approaches, appraise the effects of surgery and available pharmacological agents and identify future perspectives regarding CD. Materials and methods Systematic search to PubMed and Medline databases for publications mainly over the last five years. Results Mutations in the ubiquitin specific peptidase 8 gene have been recently identified in functional sporadic corticotroph adenomas causing CD. Since the prevalence of obesity and metabolic syndrome is rapidly increasing, new diagnostic tests are necessary to differentiate these conditions. Next to the traditional tests, a cutoff of preoperative ACTH/cortisol ratio, an ultrasensitive late night salivary cortisol assay and the desmopressin test have been suggested as valid tools for the diagnosis and differential diagnosis of CD. Transsphenoidal surgery with variable remission and recurrence rates presents the treatment of choice for CD. Medical therapy consists of adrenal-targeted drugs e. g. ketoconazole, metyrapone, etomidate and mitotane and pituitary-targeted drugs e. g. pasireotide, cabergoline and retinoic acid. Conclusions CD is associated to a significant clinical burden, since numerous comorbidities persist after long-term biochemical control. These chronically ill patients show an increased mortality despite disease remission. Clinicians should treat comorbidities aggressively and seek for appropriate consultations. Structured consultation hours and expert excellence networks are needed in order to allow optimal, individualized care for affected patients, reverse increased morbidity and mortality and identify tumor recurrence early.

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Wnt10b and Wnt3a AS BIOMARKERS OF CHANGES IN THE REGULATION OF BONE METABOLISM IN PATIENTS WITH CUSHING’S DISEASE

Annals of the Russian academy of medical sciences ◽

10.15690/vramn904 ◽

2018 ◽

Vol 73 (2) ◽

pp. 115-121

Author(s):

T. A. Grebennikova ◽

Z. E. Belaya ◽

A. G. Solodovnikov ◽

A. V. Ilyin ◽

L. V. Nikankina ◽

...

Keyword(s):

Bone Remodeling ◽

Cushing’S Disease ◽

Cushing's Disease ◽

Control Group ◽

Serum Samples ◽

Wnt Proteins ◽

Free Cortisol ◽

Turnover Markers ◽

Modern Technologies ◽

Anterior Posterior

Background: Endogenous hypercortisolism due to Cushing’s disease (CD) is complicated by low-traumatic fractures in 50% of cases. Modern technologies allow to study pathogenetic changes in the regulation of bone remodeling in hypercortisolism and to offer new serum biomarkers.Aims: To evaluate levels of Wnt proteins related to bone remodeling regulation in serum samples from patients with CD.Materials and methods: Fasting serum samples were taken and stored in aliquot at ≤-80 °C from 42 consecutive subjects with clinically evident and biochemically confirmed active CD and 42 healthy volunteers matched by age, sex and body mass index (BMI). Evaluation of the levels of Wnt proteins (Wnt3a, Wnt10b) was measured by immunochemiluminescence assay using the WNT3a SEL818Hu (USCN) and the WNT10b SEP553Hu (USCN). Twenty-four hours urine free cortisol (24hUFC) (60−413 nmol/24h) and bone turnover markers was measured by electrochemiluminescence assay on a Cobas 6000 Module e601 (Roche). At the time of enrollment all participants were questioned regarding any low traumatic fractures for the period of the disease. Patients underwent standard spinal radiographs in anterior-posterior and lateral positions of the vertebrae Th4−L4 (Axiom Icons R200 Siemens).Results: The median (Ме Q25; Q75) age of patients with CD was 33 (21; 43) years with no difference among the groups, p=0.936; BMI ― 29 (23; 34) kg/m2, p=0.094 and without differences by sex, p=0.254. The median 24hUFC in subjects with CD ― 825 (301; 2077) nmol/24h was significantly higher as compared to the control group (p0.001). We report increased levels of Wnt3a and Wnt10b in patients with CD: Wnt3а 0.15 (0.04; 0.23) ng/ml in patients with CD vs 0,04 (0.01; 0.13) ng/ml in control group (p=0.017) and Wnt10b 2621 (2226; 3688) pg/ml vs 1917 (1721; 2549) pg/ml (p=0.008).Conclusions: The serum level of Wnt3a and Wnt10b reflects the intensity of Wnt-signaling dysregulation, and therefore they may be considered as biomarkers of bone remodeling deterioration in hypercortisolism.

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