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Cited by 100Pituitary Gland Disorders and TreatmentsAdrenal Hormones and DisordersAdrenal and Paraganglionic Tumors

Accuracy of laboratory tests for the diagnosis of Cushing syndrome

Open access
Galm, Brandon P, Qiao, Nidan, Klibanski, Anne, Biller, Beverly M K, Tritos, Nicholas A·2020·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgaa105
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Abstract

Context: The diagnosis of Cushing syndrome (CS) can be challenging. It remains to be determined which diagnostic tests are the most accurate. Objective: To summarize the accuracy of diagnostic tests for CS using contemporary meta-analytic techniques (hierarchical models). Data Sources: PubMed, Embase, Scopus, Web of Science, and the Cochrane Database of Systemic Reviews (inception until August 3, 2018). Study Selection: Studies performed in adults that determined the accuracy of one or more diagnostic tests: overnight 1-mg dexamethasone suppression test (DST), 2-day low-dose DST (2d DST), 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), midnight serum cortisol (MSC), and the dexamethasone-suppressed CRH (dex-CRH) and desmopressin (dex-DDAVP) tests. Data Extraction: Two authors independently extracted data and performed methodological assessments. Data Synthesis: One hundred thirty-nine studies (14 140 participants) were included in the analysis. The respective sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio (95% confidence interval [CI]) estimates include the following: DST 98.6% (96.9%-99.4%), 90.6% (86.4%-93.6%), 10.5 (7.2-15.3), and 0.016 (0.007-0.035); 2d DST 95.3% (91.3%-97.5%), 92.8% (85.7%-96.5%), 13.2 (6.47-27.1), and 0.051 (0.027-0.095); UFC 94.0% (91.6%-95.7%), 93.0% (89.0%-95.5%), 13.3 (8.47-21.0), and 0.065 (0.046-0.092); LNSC 95.8% (93.%-97.2%), 93.4% (90.7%-95.4%), 14.6 (10.3-20.7), and 0.045 (0.030-0.066); MSC 96.1% (93.5%-97.6%), 93.2% (88.1%-96.3%), 14.2 (7.96-25.2), and 0.042 (0.026-0.069); and dex-CRH 98.6% (90.4%-99.8%), 85.9% (67.6%-94.7%), 7.0 (2.80-17.6), and 0.016 (0.002-0.118). A single study evaluated dex-DDAVP. Meta-regression and a novel network meta-analytic approach suggest that DST is the most sensitive while UFC is the least sensitive. Conclusions: All of the included diagnostic tests for CS are highly sensitive and specific. It appears that the DST is the most sensitive while the UFC is less sensitive. The specificity of all first-line tests appears comparable.

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  • Late-night salivary cortisol measured by enzyme immunoassay has a reported sensitivity and specificity >90% for Cushing syndrome.

    “Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA-F) is a first-line screening test for Cushing syndrome (CS) with a reported sensitivity and specificity of >90%.”

    From Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome (2020) · cites this paper as [53]

    The Results report sensitivity of 95.9% and specificity of 93.0% for late-night salivary cortisol measured by immunoassay. They do not give separate accuracy estimates for enzyme immunoassay (EIA-F), so the assay-specific part of the claim is not established by those figures. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • The current study sample is more representative of the real world than studies from only tertiary referral centers because tests were ordered by a range of clinicians including primary care physicians.

    “These tests were ordered by endocrinologists, endocrine surgeons, advanced practice providers, and primary care physicians making it more representative of the real world, rather than studies from only tertiary referral centers with a focus on CS [47, 53, 54].”

    From Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome (2020) · cites this paper as [53]

    The Discussion says most studies in the review were performed in academic settings, supporting the contrast with less routine clinical settings. It does not say those studies were only from tertiary referral centers or establish that the citing study’s sample is more representative. The clinician mix describes the citing authors’ own study, not Galm et al.’s review. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Using relatively nonspecific immunoassays, the sensitivity and specificity of late-night salivary cortisol exceeds 90% and can be as high as 95% to 97%.

    “We and others have demonstrated that, using relatively nonspecific immunoassays, the sensitivity and specificity of this test exceeds 90% and is as high as 95% to 97% [47, 53].”

    From Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome (2020) · cites this paper as [53]

  • Meta-analyses of the diagnostic value of LNSC have shown excellent sensitivity and much better specificity than our data imply.

    “Meta-analyses of the diagnostic value of LNSC have shown excellent sensitivity and much better specificity than our data imply [47, 53]”

    From Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome (2020) · cites this paper as [53]

  • In a recent meta-analysis including 139 studies, the accuracy of laboratory tests for CS was investigated.

    “In a recent meta-analysis including 139 studies, the accuracy of laboratory tests for CS was investigated (24).”

    From The diagnostic value of salivary cortisol and salivary cortisone in patients with suspected hypercortisolism (2022) · cites this paper as [24]

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Cites

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6 of the 161 references couldn’t be matched to a known paper.

Research works printed but not linked: 13

  1. [26]26. Ambrosi B, Bochicchio D, Ferrario R, Colombo P, Faglia G. Screening tests for Cushing's syndrome. Clin Endocrinol (Oxf). 1990;33(6):809-811.
  2. [37]37. Boer AK, Van Den Heuvel D, Lentjes E. Improved salivary diagnostics of Cushing's syndrome by means of own UPLC MS/MS method that distinguishes between cortisone and cortisol. Nederlandse Vereniging voor Klinische Chemie. 2012;37(3):219-221.
  3. [59]59. Deck KA, Eberlein L, Vetter H, Hillen H. Estimation of free cortisol in urine (author's transl). Dtsch Med Wochenschr. 1976;101(21):818-821.
  4. [68]68. Elmlinger MW, Ranke MB, Weber MM. Detection of free urinary cortisol by means of immunoassays in the diagnosis of adrenocortical disorders: is extraction of urine necessary? Clin Lab. 1997;43(10):857-862.
  5. [75]75. Goncharov NP, Katsia GV, Marova YI, Kolesnikova GS, Aropova SD, Rozhinskaya LY. Use of the ultrasensitive tech- nique to determine biologically active salivary free cortisol for evaluating the glucocorticoid function of the adrenal cortex. Probl Endokrinol (Mosk). 2008;54(3):27-35.
  6. [84]84. Kanejohnson NJ, Kendall JW, Cook DM. Urinary cortisol levels in low dose dexamethasone suppression test distinguish Cushing's patients from normal controls. Clin Res. 1985;33(1):A27 (Abstract).
  7. [91]91. Lépez M, Caamaño E, Romero C, Fiedler J, Araya V. Salivary cortisol among subjects with and without Cushing syndrome. Rev Med Chil. 2010;138(2):168-174.
  8. [98]98. Luo L, Gao R, Xu T, Yan S. Clinical application of cortisol cir- cadian rhythm, overnight dexamethasone suppression test, and urine free cortisol. Tianjin Yi Yao. 1984;12(2):74-78.
  9. [103]103. McKeever E, Mc Cance DR, Hunter SJ, Courtney CH, Mullan KR, Graham UM. Nocturnal salivary cortisol in the diagnosis of Cushing's syndrome. Ir J Med Sci. 2016;185:394 (Abstract).
  10. [108]108. Mugnier M, De Boissezon C, Lupi N, Morange I, Jaquet P. Direct assay of urinary free cortisol: medical applications. Immuno- Anal Biol Spe. 1997;12(6):308-311.
  11. [118]118. Odagiri E. Use of radioimmunoassay of cortisol and deoxycortisol in plasma and urine for the diagnosis of the pi- tuitary adrenocortical axis. Journal of Tokyo Women's Medical College. 1975;45(6):494-508.
  12. [137]137. Schuijt MP, Wagenmakers M, Meinardi J, Hermus A, van den Ouweland JMW. Late-night salivary cortisol for diagnosing Cushing's syndrome, as measured by LC-MS/MS and automated immunoassay. Clin Chem Lab Med. 2011;49:S447 (Abstract).
  13. [139]139. Shapiro S, Prestifilippo J, Kirschner MA. Diurnal variation in urinary free cortisol: a rapid test for Cushing's syndrome. J Newark Beth Isr Hosp. 1972;22(3):147-157.

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Authors
Galm, B. P., Qiao, N., Klibanski, A., Biller, B. M. K., & Tritos, N. A.
Affiliations
  • Harvard University (US)
  • Shanghai Medical College of Fudan University (CN)
Corresponding author
  • Galm, Brandon P
  • Qiao, Nidan
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2020-03-05
Volume
105
Issue
6
Pages
2081-2094
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/clinem/dgaa105
OpenAlex
W3009332915
Cited by
100
References
161
Citations by year
2026: 10 · 2025: 18 · 2024: 18 · 2023: 18 · 2022: 19 · 2021: 12 · 2020: 5
FWCI
10.18
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Massachusetts General Hospital
  • Johns Hopkins University
  • Medical University Sofia
  • Università degli Studi di Milano
  • Millendo Therapeutics
  • Semmelweis Egyetem
  • Sun Yat-sen University
  • Technische Universität Dresden
  • Universitair Medisch Centrum Utrecht
  • Universidade Federal do Rio Grande do Sul
  • Universidad de Buenos Aires
  • Universidade de São Paulo
  • Universidad de Chile
  • University of the Philippines
  • Haukeland Universitetssjukehus
  • National Institutes of Health
  • School of Medicine, Stanford University
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
Keywords
Cushing's syndrome, diagnostic accuracy, dexamethasone suppression test, urinary free cortisol, late-night salivary cortisol, desmopressin, diagnostic test sensitivity and specificity
MeSH terms
Cushing Syndrome, Humans, Hydrocortisone, Prognosis, ROC Curve, Meta-Analysis as Topic, Biomarkers, Clinical Laboratory Techniques

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