Pitfalls in the diagnosis and management of Cushing's syndrome

2015 ◽  
Vol 38 (2) ◽  
pp. E4 ◽  
Author(s):  
Vivek Bansal ◽  
Nadine El Asmar ◽  
Warren R. Selman ◽  
Baha M. Arafah
Keyword(s):  
Cushing’S Syndrome ◽  
Cushing’S Disease ◽  
Salivary Cortisol ◽  
Clinical Symptoms ◽  
Cushing's Syndrome ◽  
Cushing's Disease ◽  
Biochemical Tests ◽  
Late Night ◽  
Late Night Salivary Cortisol ◽  
Free Cortisol

Despite many recent advances, the management of patients with Cushing's disease continues to be challenging. Cushing's syndrome is a complex metabolic disorder that is a result of excess glucocorticoids. Excluding the exogenous causes, adrenocorticotropic hormone–secreting pituitary adenomas account for nearly 70% of all cases of Cushing's syndrome. The suspicion, diagnosis, and differential diagnosis require a logical systematic approach with attention paid to key details at each investigational step. A diagnosis of endogenous Cushing's syndrome is usually suspected in patients with clinical symptoms and confirmed by using multiple biochemical tests. Each of the biochemical tests used to establish the diagnosis has limitations that need to be considered for proper interpretation. Although some tests determine the total daily urinary excretion of cortisol, many others rely on measurements of serum cortisol at baseline and after stimulation (e.g., after corticotropin-releasing hormone) or suppression (e.g., dexamethasone) with agents that influence the hypothalamic-pituitary-adrenal axis. Other tests (e.g., measurements of late-night salivary cortisol concentration) rely on alterations in the diurnal rhythm of cortisol secretion. Because more than 90% of the cortisol in the circulation is protein bound, any alteration in the binding proteins (transcortin and albumin) will automatically influence the measured level and confound the interpretation of stimulation and suppression data, which are the basis for establishing the diagnosis of Cushing's syndrome. Although measuring late-night salivary cortisol seems to be an excellent initial test for hypercortisolism, it may be confounded by poor sampling methods and contamination. Measurements of 24-hour urinary free-cortisol excretion could be misleading in the presence of some pathological and physiological conditions. Dexamethasone suppression tests can be affected by illnesses that alter the absorption of the drug (e.g., malabsorption, celiac disease) and by the concurrent use of medications that interfere with its metabolism (e.g., inducers and inhibitors of the P450 enzyme system). In this review, the authors aim to review the pitfalls commonly encountered in the workup of patients suspected to have hypercortisolism. The optimal diagnosis and therapy for patients with Cushing's disease require the thorough and close coordination and involvement of all members of the management team.

scholarly journals MON-172 Comparison of a Late-night Salivary Cortisol Immunoassay and a Cortisol and Cortisone LCMS Assay in Patients with Cushing’s Disease

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Joshua Kannankeril ◽  
Ty Brian Carroll ◽  
James W Findling ◽  
Bradley Richard Javorsky ◽  
Ian Gunsolus ◽  
...  
Keyword(s):  
Cushing’S Syndrome ◽  
Cushing’S Disease ◽  
Salivary Cortisol ◽  
False Negative ◽  
Pituitary Surgery ◽  
Cushing's Syndrome ◽  
Cushing's Disease ◽  
Newly Diagnosed ◽  
Late Night ◽  
Late Night Salivary Cortisol

Abstract Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA) is established as a reliable screening test and recommended as a first-line test for Cushing’s syndrome.1,2 However, liquid chromatography-tandem mass spectrometry (LCMS), validated to measure salivary cortisol (F) and cortisone (E), has been proposed to be superior diagnostically as well as helpful in detecting saliva contaminated with topical hydrocortisone (i.e. cortisol).3,4 We measured EIA-F, LCMS-F, and LCMS-E in 913 consecutive late-night saliva samples from patients suspected of Cushing’s syndrome. For the current report, we focus only on the patients with Cushing’s disease (CD) who had at least one elevated salivary result using cutoffs established previously [EIA-F ≥3.3 nmol/L, LCMS-F ≥2.8 nmol/L, and LCMS-E ≥8.7 nmol/L].5 We identified 27 patients who had newly diagnosed CD (n-CD) or had persistent/recurrent CD after pituitary surgery (r-CD). Data are shown as mean (SD). There were 19F/8M patients aged 50 (17) y; their BMI was 35 (11) kg/m2. 8 patients had n-CD and 19 had r-CD. In all 27 patients, EIA-F was 9.1 (6.0), LCMS-F was 5.1 (4.0), and LCMS-E was 19.6 (12.3) nmol/L. In n-CD, EIA-F was 14.3 (7.7), LCMS-F was 7.7 (4.6), and LCMS-E was 29.4 (12.8) nmol/L. In r-CD, EIA-F was 6.9 (3.6), LCMS-F was 4.0 (3.2), and LCMS-E was 15.5 (10.0) nmol/L. Mean EIA-F was greater than mean LCMS-F in all patients, and mean LNSC in n-CD patients was greater than mean LNSC in r-CD patients. The LCMS-F/E ratio was <0.8 in all subjects indicating that no saliva samples were contaminated with topical hydrocortisone.3 Furthermore, there was no difference in the LCMS-F/E ratio between n-CD [0.3 (0.1)] and r-CD [0.3 (0.2)] patients. Using previously identified cutoffs, 9 of the 27 CD patients had normal LCMS-F whereas only 1 patient had a normal EIA-F (P=0.011). The EIA-F results of patients with normal LCMS-F were significantly lower than patients with increased LCMS-F demonstrating that LCMS-F was more likely to provide false negative results with milder hypercortisolism. Most of these false-negative LCMS-F results occurred in the r-CD patients (8 out of 19) who had milder hypercortisolism compared to the n-CD patients (P=0.006). No differences in diagnostic performance were found between EIA-F and LCMS-E. In summary, EIA-F appears to be superior to LCMS-F in identifying CD patients with milder hypercortisolism using established diagnostic cutoffs.5 Neither LCMS-E nor F/E ratio improved the diagnostic sensitivity in newly diagnosed CD or persistent/recurrent CD after pituitary surgery. We suggest that late-night salivary cortisol measured by EIA provides the best sensitivity for CD diagnosis. 1J Clin Endocrinol Metab 2008;93:1526–1540. 2Clin Chem 2003;49:203–204. 3Clin Chem 2012;58:947–948. 4J Clin Endocrinol Metab 2010;95:4951–4958. 5J Endocr Soc 2019;3:1631–1640.

scholarly journals SAT-203 Misleading Diagnosis of Cushing’s Syndrome on Pramipexole

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Elizabeth Pahomov ◽  
Subarna Mani Dhital
Keyword(s):  
Cushing’S Syndrome ◽  
Salivary Cortisol ◽  
Clinical Symptoms ◽  
Brain Mri ◽  
Cushing's Syndrome ◽  
Dopamine Receptor Agonist ◽  
Late Night ◽  
Late Night Salivary Cortisol ◽  
Morning Cortisol ◽  
Free Cortisol

Abstract We present an intriguing case of a patient incorrectly diagnosed with Cushing’s disease secondary to pramipexole use for restless leg syndrome (RLS). 61-year-old male with symptoms of 55 lb weight gain, progressive fatigue, and subjective muscle weakness presented to endocrinology office for work-up of possible Cushing’s syndrome. Physical exam was significant for mild facial plethora, purple striae, and central obesity. Patient’s history includes diagnosis of prolactin-producing pituitary microadenoma 30 years ago treated with bromocriptine with normalization of prolactin and resolution of adenoma. Patient notes ten years ago, he was started on pramipexole 1 mg TID for severe RLS. Given patient’s clinical symptoms he underwent hormonal testing which was notable for an abnormal 1 mg ONDST with morning cortisol 2.44 mcg/dL (normal &lt 1.8 mg/dL) and two abnormal late night salivary cortisol 0.177 mcg/dL and 0.199 mcg/dL (normal &lt 0.122). Repeat MRI showed a 0.4 cm hypoenhancing lesion in the left side of the anterior pituitary gland. Patient was referred for IPSS. His central-to-peripheral plasma ACTH ratio was as follows: before CRH administration: left 5.8, right 1.2; after CRH administration: left 16.4, right 2.7. These results demonstrated positive IPSS indicating centralization or a pituitary source of ACTH excess. Patient was going to be referred to neurosurgery for left pituitary adenoma resection, but literature search revealed a study showing pramipexole causing an increase in cortisol levels in physiologic studies involving healthy subjects. Due to these findings, labs were repeated while holding pramipexole. His morning cortisol and ACTH levels were normal. Late night salivary cortisol x3 were normal: 0.038, 0.071, and 0.024 mcg/dL (normal &lt 0.090 mcg/dL). The 24 hour urine free cortisol x2 was also normal. These negative biochemical findings showed no evidence of hypercortisolism off of pramipexole. This further complicated the case as the patient had positive IPSS. In order to help exclude the diagnosis of an ACTH secreting pituitary tumor, a DDAVP stimulation test was performed showing a normal response. Based on these tests it was concluded he does not have Cushing’s and that his hypercortisolism was related to pramipexole use. Repeat brain MRI showed no structural evidence of any pituitary lesion. We report a very rare case of pramipexole use leading to a false diagnosis of Cushing’s syndrome. This was fortunately identified prior to patient undergoing unnecessary surgery. We recommend awareness of pramipexole use associated with hypercortisolism to prevent incorrect diagnosis of Cushing’s syndrome. Schilling, J. C., Adamus, W. S., & Palluk, R. (1992). Neuroendocrine and side effect profile of pramipexole, a new dopamine receptor agonist, in humans. Clinical Pharmacology & Therapeutics, 51(5), 541-548.

scholarly journals Screening and diagnosis of Cushing's syndrome

2007 ◽  
Vol 51 (8) ◽  
pp. 1191-1198 ◽  
Author(s):  
Margaret de Castro ◽  
Ayrton C. Moreira
Keyword(s):  
Cushing’S Syndrome ◽  
Salivary Cortisol ◽  
Linear Growth ◽  
Fat Distribution ◽  
Cushing's Syndrome ◽  
First Line ◽  
Late Night ◽  
Late Night Salivary Cortisol ◽  
Free Cortisol ◽  
Pituitary Adrenal Axis

Cushing's syndrome (CS) results from sustained pathologic hypercortisolism. The clinical features are variable and the most specific features for CS include abnormal fat distribution, particularly in the supraclavicular and temporal fossae, proximal muscle weakness, wide purple striae, and decreased linear growth with continued weight gain in a child. Clinical presentation of CS can be florid and in this case the diagnosis is usually straightforward. However, the diagnosis can be difficult particularly in states of mild or cyclical or periodical hypercortisolism. Several tests based on the understanding of the physiologic characteristics of the hypothalamic-pituitary-adrenal axis have been used extensively to confirm the diagnosis of Cushing's syndrome, but none has proven fully capable of distinguishing all cases of CS from normal and/or pseudo-Cushing individuals. Three first-line diagnostic tests are currently used to screen for CS: measurement of free cortisol in 24-hour urine (UFC), cortisol suppressibility by low doses of dexamethasone (DST), and assessment of cortisol circadian rhythm using late-night serum and/or salivary cortisol. This paper discusses the effectiveness regarding best cut-off values, the sensitivity and the specificity of these tests to screen for CS. Late-night salivary cortisol appears to be the most useful screening test. UFC and DST should be performed to provide further confirmation of the diagnosis.

scholarly journals Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease

2020 ◽  
Vol 182 (2) ◽  
pp. 207-217 ◽  
Author(s):  
John Newell-Price ◽  
Rosario Pivonello ◽  
Antoine Tabarin ◽  
Maria Fleseriu ◽  
Przemysław Witek ◽  
...  
Keyword(s):  
Cushing’S Disease ◽  
Salivary Cortisol ◽  
Clinical Signs ◽  
Urinary Free Cortisol ◽  
Phase Iii ◽  
Cushing's Disease ◽  
Late Night ◽  
Late Night Salivary Cortisol ◽  
Free Cortisol ◽  
Two Samples

Objective Monitoring of patients with Cushing’s disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing’s disease. Design Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing’s disease (clinicaltrials.gov: NCT01374906). Methods Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time. Results At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman’s correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN. Conclusion mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing’s disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.

scholarly journals A commentary on Diagnosing Cushing’s disease in the context of renal failure

2019 ◽  
Vol 181 (4) ◽  
pp. C9-C11
Author(s):  
Hershel Raff ◽  
Eric P Cohen ◽  
James W Findling
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Failure ◽  
Cushing’S Syndrome ◽  
Salivary Cortisol ◽  
Cushing's Syndrome ◽  
Late Night ◽  
Urine Free Cortisol ◽  
Late Night Salivary Cortisol ◽  
Free Cortisol ◽  
Pituitary Adrenal Axis

The diagnosis of endogenous hypercortisolism (Cushing's syndrome) is extremely challenging. Chronic kidney disease (CKD) increases the activity of the hypothalamic-pituitary-adrenal axis making the diagnosis of Cushing's syndrome even more challenging. This is particularly so since urine free cortisol (UFC) testing is not useful in CKD. The case report by Stroud et al. in this issue of the European Journal of Endocrinology highlights this problem by finding normal UFC in a patient with pituitary ACTH-dependent Cushing's syndrome. Elevated late-night salivary cortisol (LNSC) testing was diagnostic and pituitary adenomectomy was curative. LNSC measurement is the diagnostic test of choice in patients with suspected Cushing's syndrome, particularly in the presence of CKD..

Diagnostic value of the late-night salivary cortisol in the diagnosis of clinical and subclinical Cushing’s syndrome: results of a single-center 7-year experience

2018 ◽  
Vol 67 (1) ◽  
pp. 28-33 ◽  
Author(s):  
Nusret Yilmaz ◽  
Gokhan Tazegul ◽  
Humeyra Bozoglan ◽  
Ramazan Sari ◽  
Sebahat Ozdem ◽  
...  
Keyword(s):  
Sensitivity And Specificity ◽  
Cushing’S Syndrome ◽  
Salivary Cortisol ◽  
Diagnostic Performance ◽  
Cushing's Syndrome ◽  
Lower Sensitivity ◽  
Subclinical Cushing’S Syndrome ◽  
Late Night ◽  
Late Night Salivary Cortisol ◽  
Free Cortisol

Late-night salivary cortisol (LNSaC) is an easy-to-use test reflecting the free cortisol level in the serum and does not require hospitalization. Controlled studies reported that LNSaC has a high sensitivity and specificity, but have not set a clearly defined cut-off value to be used in the diagnosis of Cushing’s syndrome. In this study, we aimed to evaluate the diagnostic performance of LNSaC in patients with clinical Cushing’s syndrome (CCS) and subclinical Cushing’s syndrome (SCS). The data of 543 patients, whose LNSaC levels were assessed using electrochemiluminescence immunoassay method, were retrospectively evaluated. The study included a total of 324 patients: 58 patients with CCS, 53 patients with SCS, and 213 patients without Cushing’s syndrome (NoCS). The cause of the Cushing’s syndrome was hypophyseal in 26 patients (45%), adrenal in 24 patients (41%), and ectopic in 8 patients (14%) in the CCS group. Median LNSaC levels were 0.724 (0.107–33) µg/dL in CCS group, 0.398 (0.16–1.02) µg/dL in SCS group, and 0.18 (0.043–0.481) µg/dL in NoCS group (p=0.001). Accordingly, LNSaC had 89.6% sensitivity and 81.6% specificity at a cut-off value of 0.288 µg/dL in the diagnosis of CCS; and had 80.7% sensitivity and 85.1% specificity at a cut-off value of 0.273 µg/dL in the diagnosis of SCS. In the present study, a lower sensitivity and specificity than previously reported was found for LNSaC in the diagnosis of CCS. Moreover, the diagnostic performance of LNSaC in patients with SCS was close to its diagnostic performance in patients with CCS. Each center should determine its own cut-off value based on the method adopted for LNSaC measurement, and apply that cut-off value in the diagnosis of Cushing’s syndrome.

scholarly journals Differentiating between Cushing's disease and pseudo-Cushing's syndrome: comparison of four tests

2014 ◽  
Vol 170 (4) ◽  
pp. 477-486 ◽  
Author(s):  
R A Alwani ◽  
L W Schmit Jongbloed ◽  
F H de Jong ◽  
A J van der Lely ◽  
W W de Herder ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Cushing’S Syndrome ◽  
Cushing’S Disease ◽  
Predictive Value ◽  
Serum Cortisol ◽  
Cushing's Syndrome ◽  
Cushing's Disease ◽  
Late Night ◽  
Late Night Salivary Cortisol ◽  
Dexamethasone Suppression

ObjectiveTo evaluate the diagnostic performance of four different tests in order to differentiate between Cushing's disease (CD) and pseudo-Cushing's syndrome (PCS).MethodsIn this prospective study, a total of 73 patients with clinical features of hypercortisolism and insufficient suppression of serum cortisol after 1 mg overnight dexamethasone and/or an elevated excretion of cortisol in 24-h urine samples were included. The circadian rhythm of serum cortisol levels as well as midnight serum cortisol (MserC) levels were assessed in all 73 patients. Late-night salivary cortisol (LNSC) concentrations were obtained in 44 patients. The dexamethasone–CRH (Dex–CRH) test was performed in 54 patients.ResultsFifty-three patients were diagnosed with CD and subsequently treated. Twenty patients were classified as having PSC. Serum cortisol circadian rhythm: the diurnal rhythmicity of cortisol secretion was retained in PCS. A cortisol midnight:morning ratio of >0.67 is highly suggestive of CD (positive predictive value (PPV) 100% and negative predictive value (NPV) 73%). MserC concentration >243 nmol/l has a PPV of 98% in predicting true CD (NPV 95%). LNSC level >9.3 nmol/l predicted CD in 94% of patients (NPV 100%). Dex–CRH test: after 2 days of dexamethasone suppression, a CRH-stimulated cortisol level >87 nmol/l (T=15 min) resulted in a PPV of 100% and an NPV of 90%.ConclusionThe Dex–CRH test as well as a single measurement of cortisol in serum or saliva at late (mid-) night demonstrated high diagnostic accuracy in differentiating PCS from true CD.

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