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Cited by 18Pituitary Gland Disorders and TreatmentsAdrenal Hormones and DisordersAdrenal and Paraganglionic Tumors

Late-night salivary cortisol and cortisone should be the initial screening test for cushing's syndrome

Open access
Mohamed, Ramjan Sanas, Abuelgasim, Biyaser, Barker, Sally, Prabhudev, Hemanth, Martin, Niamh M, Meeran, Karim, Williams, Emma L, Darch, Sarah +3 more·2022·Endocrine Connections
DOI 10.1530/ec-22-0050PMC PMC9254321
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Abstract

Endogenous Cushing’s syndrome (CS) poses considerable diagnostic challenges. Although late-night salivary cortisol (LNSC) is recommended as a first-line screening investigation, it remains the least widely used test in many countries. The combined measurement of LNSC and late-night salivary cortisone (LNS cortisone) has shown to further improve diagnostic accuracy. We present a retrospective study in a tertiary referral centre comparing LNSC, LNS cortisone, overnight dexamethasone suppression test, low-dose dexamethasone suppression test and 24-h urinary free cortisol results of patients investigated for CS. Patients were categorised into those who had CS (21 patients) and those who did not (33 patients). LNSC had a sensitivity of 95% and a specificity of 91%. LNS cortisone had a specificity of 100% and a sensitivity of 86%. With an optimal cut-off for LNS cortisone of >14.5 nmol/L the sensitivity was 95.2%, and the specificity was 100% with an area under the curve of 0.997, for diagnosing CS. Saliva collection is non-invasive and can be carried out at home. We therefore advocate simultaneous measurement of LNSC and LNS cortisone as the first-line screening test to evaluate patients with suspected CS.

AI snapshot

Written from the paper’s full text.

TL;DR

In a retrospective tertiary-centre study of 54 patients investigated for Cushing’s syndrome (CS), late-night salivary cortisol (LNSC) and late-night salivary cortisone (LNS cortisone) showed high diagnostic accuracy, with LNS cortisone at an optimal cut-off of >14.5 nmol/L achieving 95.2% sensitivity and 100% specificity. The authors advocate simultaneous LNSC and LNS cortisone measurement as the first-line screening test for suspected CS.

Key findings

  • Among 54 eligible patients (21 with CS, 33 without), LNSC had sensitivity 95%, specificity 91%, PPV 87%, NPV 97%, and AUC 0.931.
  • LNS cortisone had sensitivity 86%, specificity 100%, PPV 100%, NPV 92%, and AUC 0.929; at an optimal ROC-derived cut-off of >14.5 nmol/L, sensitivity was 95.2%, specificity 100%, and AUC 0.997.
  • ODST had sensitivity 100% and NPV 100% but specificity 77% and PPV 74%; LDDST had sensitivity 100% and NPV 100% with specificity 83% and PPV 87%.
  • UFC had specificity 100% and PPV 100% but the lowest sensitivity (60%) and NPV (56%) of the investigations.

Methods

  • Retrospective study at Imperial College Healthcare NHS Trust, a tertiary referral centre, using data from patients who underwent LNSC testing between 2017 and March 2021; patients with high pre-test probability for CS were included, while cyclical CS, subclinical CS, pseudo-CS, and known non-compliance were excluded.
  • Saliva was collected between 23:00 and midnight using Salivette tubes, with instructions to avoid brushing teeth, eating/drinking for 30 min, smoking/alcohol/coffee for 2 h, and steroid creams; salivary cortisol and cortisone were measured by LC-MS/MS.
  • Diagnostic accuracy measures included sensitivity, specificity, AUC, positive/negative likelihood ratios, PPV, and NPV, with ROC analysis used to derive optimal cut-offs.

Limitations

  • The authors state the study was retrospective, had a small number of patients with CS, and that selection of screening tests other than LNSC was based on clinicians’ preferences.
  • Evident from the text: the single tertiary referral centre and high pre-test probability population may limit generalisability to primary care or lower-prevalence settings.
  • Evident from the text: not all patients underwent every test (e.g., 36 underwent ODST and 15 underwent UFC), so comparative accuracy estimates are based on different subsets.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1530/ec-22-0050

Cites

25 of 25 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 38 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In this study, late-night salivary cortisol (LNSC) had a sensitivity of 95% and a specificity of 91% for diagnosing Cushing's syndrome.

    “LNSC had a sensitivity of 95% and a specificity of 91%.”
    • Also stated in: § Results · plain
      “LNSC had a sensitivity of 95%, a specificity of 91%, a PPV of 87% and a NPV of 97%.”
    Quote in the paperSubstantial claim
  • Findingown data

    With optimal cut-offs by ROC analysis, AUCs for LNSC, LNS cortisone, ODST, LDDST and UFC were 0.990, 0.997, 0.948, 0.881 and 0.900, respectively.

    “AUC for LNSC, LNS cortisone, ODST, LDDST and UFC levels with optimal cut-offs by ROC analysis showed 0.990, 0.997, 0.948, 0.881 and 0.900, respectively.”
    Quote in the paperSubstantial claim
  • Findingown data

    In this study, the majority of patients who had a positive LNSC had Cushing's syndrome.

    “In our study, the majority of the patients who had a positive LNSC had CS.”
    Quote in the paperSubstantial claim
  • Findingown data

    In this cohort, patients with proven recurrent Cushing's disease all had elevated LNSC.

    “In contrast with those findings, in our cohort, patients with proven recurrent CD all had elevated LNSC.”
    Quote in the paperSubstantial claim
  • Findingown data

    LNSC with an optimal cut-off of >3.3 nmol/L provided a sensitivity of 95.2% and a specificity of 97% for diagnosing Cushing's syndrome.

    “LNSC value of >3.3 nmol/L provided a sensitivity of 95.2% and a specificity of 97%”
    Quote in the paperSubstantial claim
  • May combine two claims. 21
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data

    ODST had a sensitivity of 100%, a specificity of 77%, a PPV of 74% and a NPV of 100% for diagnosing Cushing's syndrome.

    “Although the sensitivity and the NPV of ODST were 100%, the specificity and the PPV were 77 and 74% respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In sub-analysis, LNSC for Cushing's disease first presentation and recurrent Cushing's disease had the same sensitivity (100%), specificity (91%), NPV (100%), positive LR (10), negative LR (0) and AUC (0.960), except PPV was 77% and 67%, respectively.

    “Sub-analysis of LNSC for CD with first presentation (n = 10 patients) and recurrent CD (n = 6) had same sensitivity (100%), specificity (91%), NPV (100%), positive LR (10), negative LR (0) and AUC (0.960) except PPV with 77 and 67%, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LNS cortisone for Cushing's disease had a sensitivity of 90%, NPV of 97%, negative LR of 0.1 and AUC of 0.950.

    “LNS cortisone for CD had sensitivity of 90%, NPV 97%, negative LR 0.1 and AUC of 0.950.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    LDDST had a sensitivity of 100%, a specificity of 83%, a PPV of 87% and a NPV of 100% for diagnosing Cushing's syndrome.

    “Like ODST, LDDST had a sensitivity and a NPV of 100% but specificity (83%) and PPV (87%) were higher than with ODST.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Patients with recurrent Cushing's disease had LNS cortisone sensitivity of 83%, NPV of 97%, negative LR of 0.17 and AUC of 0.920, without affecting specificity (100%) or PPV.

    “Patients with recurrent CD had sensitivity of 83%, NPV 97%, negative LR 0.17 and AUC of 0.920 without affecting specificity (100%) or PPV”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    UFC had a sensitivity of 60%, a specificity of 100%, a PPV of 100% and a NPV of 56% for diagnosing Cushing's syndrome.

    “UFC was 100% specific with a PPV of 100% but had showed the lowest sensitivity (60%) and NPV (56%) of all investigations”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In this study, Cushing's syndrome was diagnosed in 21 patients and excluded in 33 patients.

    “CS was diagnosed in 21 patients and CS was excluded in 33 patients (Table 1).”
    • Also stated in: § Abstract · plain
      “Patients were categorised into those who had CS (21 patients) and those who did not (33 patients).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Only 0.3% interference from prednisolone was observed for the salivary cortisol assay and 1% interference from prednisone for salivary cortisone.

    “Only 0.3% interference from prednisolone was observed for salivary cortisol assay and 1% interference from prednisone for salivary cortisone.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Monaghan PJKeevil BGStewart PMTrainer PJ. Case for the wider adoption of mass spectrometry-based adrenal steroid testing, and beyond. Journal of Clinical Endocrinology and Metabolism2014994434–4437. (https://doi.org/10.1210/jc.2014-2258)10.1210/jc.2014-2258 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Contamination with topical hydrocortisone would be suggested by a normal salivary cortisone concentration and a high cortisol to cortisone ratio.

    “In this instance, contamination with topical hydrocortisone would be suggested by a normal salivary cortisone concentration and high cortisol to cortisone ratio (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Sandouk ZJohnston PBunch DWang SBena JHamrahian AKennedy L. Variability of late-night salivary cortisol in Cushing disease: a prospective study. Journal of Clinical Endocrinology and Metabolism2018103983–990. (https://doi.org/10.1210/jc.2017-02020)10.1210/jc.2017-02020 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Basu et al. reported higher LNSC levels in PCOS patients compared to controls.

    “However, Basu et al. reported higher LNSC levels in PCOS patients compared to controls (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Ozkaya HMKeskin FETuten AKorkmaz EOktay HZKadioglu P. Late-night salivary cortisol is unaltered in patients with polycystic ovarian syndrome (PCOS), irrespective of disease phenotype, and in obese women, irrespective of the presence of PCOS. Endocrine Practice2017231045–1052. (https://doi.org/10.4158/EP171887.OR)10.4158/EP171887.OR source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Normal LNSC:cortisone ratio is 0.2 with LC-MS/MS.

    “Normal LNSC: cortisone ratio is 0.2 with LC-MS/MS (6).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Raff HCushing syndrome update on testing . Endocrinology and Metabolism Clinics of North America20154443–50. (https://doi.org/10.1016/j.ecl.2014.10.005)10.1016/j.ecl.2014.10.005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ERCUSYN data suggest that LNSC is not frequently used in the diagnostic workup for suspected Cushing's syndrome despite having been shown to have excellent sensitivity and specificity.

    “ERCUSYN data suggest that LNSC is not frequently used in the diagnostic workup for suspected CS despite having been shown to have excellent sensitivity and specificity (6).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Raff HCushing syndrome update on testing . Endocrinology and Metabolism Clinics of North America20154443–50. (https://doi.org/10.1016/j.ecl.2014.10.005)10.1016/j.ecl.2014.10.005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A guideline update recommends only using LNSC if cortisone concentrations can also be reported if an adrenal tumour is suspected.

    “The previously mentioned guideline update on CS diagnosis and management recommends only using LNSC if cortisone concentrations can also be reported if an adrenal tumour is suspected (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Guignat LBertherat J. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline: commentary from a European perspective. European Journal of Endocrinology20101639–13. (https://doi.org/10.1530/EJE-09-0627)10.1530/EJE-09-06279709931 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several studies found an age-related increase in LNSC.

    “Several studies found that there appears to be an age-related increase in LNSC (14, 15).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Basu BRChowdhury OSaha SK. Possible link between stress-related factors and altered body composition in women with polycystic ovarian syndrome. Journal of Human Reproductive Sciences20181110–18. (https://doi.org/10.4103/jhrs.JHRS_78_17)10.4103/jhrs.JHRS_78_17 source

      Not checked in the free run.

    • cites [15] Coelli SFarias CBSoares AACrescente GMHirakata VNSouza LBCzepielewski MACamargo JLSilveiro SP. Influence of age, gender and body mass index on late-night salivary cortisol in healthy adults. Clinical Chemistry and Laboratory Medicine2017551954–1961. (https://doi.org/10.1515/cclm-2016-1100)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent guideline update suggests LNSC has 97% sensitivity and 97.5% specificity in diagnosing Cushing's syndrome and 75-90% sensitivity and 93-95% specificity in diagnosing recurrent Cushing's disease.

    “A recent guideline update on CS diagnosis and management suggests LNSC has 97% sensitivity and 97.5% specificity in diagnosing CS and 75–90% sensitivity and 93–95% specificity in diagnosing recurrent CD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Guignat LBertherat J. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline: commentary from a European perspective. European Journal of Endocrinology20101639–13. (https://doi.org/10.1530/EJE-09-0627)10.1530/EJE-09-06279709931 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LNSC collection is non-invasive and can be carried out at home.

    “Saliva collection is non-invasive and can be carried out at home.”
    • Also stated in: § Introduction · plain
      “Collection of LNSC is convenient for patients, it is non-invasive and avoids the need to obtain unstressed late-night blood samples, which is impractical in most circumstances (4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Fleseriu MAuchus RBancos IBen-Shlomo ABertherat JBiermasz NRBoguszewski CLBronstein MDBuchfelder MCarmichael JD, Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet: Diabetes and Endocrinology20219847–875. (https://doi.org/10.1016/S2213-8587(2100235-7)22178191

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ozkaya et al. found cortisol not to be affected by a PCOS phenotype.

    “Ozkaya et al. found cortisol not to be affected by a PCOS phenotype (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Jones RLOwen LJAdaway JEKeevil BG. Simultaneous analysis of cortisol and cortisone in saliva using XLC-MS/MS for fully automated online solid phase extraction. Journal of Chromatography: B, Analytical Technologies in the Biomedical and Life Sciences2012881–88242–48. (https://doi.org/10.1016/j.jchromb.2011.11.036)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Garrahy et al. showed that a combination of LNSC and LNS cortisone had a sensitivity of 94% compared to LNSC and LNS cortisone alone which had a sensitivity of 92% and 87%, respectively.

    “Garrahy et al. showed that a combination of LNSC and LNS cortisone had a sensitivity of 94% compared to LNSC and LNS cortisone alone which had a sensitivity of 92 and 87%, respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Garrahy et al.

      Not checked in the free run.

    • Rests on an assumption: LNSC and LNS cortisone can conveniently be analysed together with LC-MS/MS from a single saliva sample.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Salivary cortisol assay was linear up to 2293 nmol/L and salivary cortisone was linear up to 3676 nmol/L.

    “Salivary cortisol assay was linear up to a concentration of 2293 nmol/L and salivary cortisone was linear up to 3676 nmol/L.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Monaghan PJKeevil BGStewart PMTrainer PJ. Case for the wider adoption of mass spectrometry-based adrenal steroid testing, and beyond. Journal of Clinical Endocrinology and Metabolism2014994434–4437. (https://doi.org/10.1210/jc.2014-2258)10.1210/jc.2014-2258 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recently published study examining 1453 LNSC samples from 705 patients showed that a majority of patients who had at least one positive LNSC sample did not have Cushing's syndrome.

    “A recently published study examining 1453 LNSC samples from 705 patients received by a diagnostic laboratory requested by both primary care physicians and specialists as part of clinical care showed that a majority of patients who had at least one positive LNSC sample did not have CS (22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Raff HSingh RJ. Measurement of late-night salivary cortisol and cortisone by LC-MS/MS to assess preanalytical sample contamination with topical hydrocortisone. Clinical Chemistry201258947–948. (https://doi.org/10.1373/clinchem.2012.182717)10.1373/clinchem.2012.182717 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In newly diagnosed Cushing's disease, fluctuations rarely impair the diagnostic ability of LNSC, whereas in patients with recurrent or persistent disease after pituitary surgery, LNSC was frequently within the reference range, with the potential to cause false-negative results.

    “In newly diagnosed CD this seems to only rarely impair the diagnostic ability of LNSC, whereas in patients with recurrent or persistent disease after pituitary surgery, LNSC was frequently within the reference range, with the potential to cause false-negative results (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Harrison RFDebono MWhitaker MJKeevil BGNewell-Price JRoss RJ. Salivary cortisone to estimate cortisol exposure and sampling frequency required based on serum cortisol measurements. Journal of Clinical Endocrinology and Metabolism2019104765–772. (https://doi.org/10.1210/jc.2018-01172)10.1210/jc.2018-01172 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The lower limit of quantification was 0.75 nmol/L for cortisol and 0.5 nmol/L for cortisone.

    “The lower limit of quantification was found to be 0.75 nmol/L for cortisol and 0.5 nmol/L for cortisone (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Monaghan PJKeevil BGStewart PMTrainer PJ. Case for the wider adoption of mass spectrometry-based adrenal steroid testing, and beyond. Journal of Clinical Endocrinology and Metabolism2014994434–4437. (https://doi.org/10.1210/jc.2014-2258)10.1210/jc.2014-2258 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recently published data show that with upper reference limits of salivary cortisol 3.6 nmol/L and cortisone 13.5 nmol/L, the sensitivities and specificities of LNSC were 90% and 96%, and for LNS cortisone 100% and 95%, respectively.

    “Recently published data show that when an 23 h upper reference limit of salivary cortisol and cortisone of 3.6 nmol/L and 13.5 nmol/L were used, the sensitivities and specificities of LNSC were 90 and 96%, and for LNS cortisone 100 and 95%, respectively (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Harrison RFDebono MWhitaker MJKeevil BGNewell-Price JRoss RJ. Salivary cortisone to estimate cortisol exposure and sampling frequency required based on serum cortisol measurements. Journal of Clinical Endocrinology and Metabolism2019104765–772. (https://doi.org/10.1210/jc.2018-01172)10.1210/jc.2018-01172 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    LNSC has high sensitivity and high NPV when used in a tertiary referral setting.

    “Our data confirm that LNSC has high sensitivity and high NPV when used in a tertiary referral setting.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Multiple sequential LNSC measurements are very useful to investigate diagnostically challenging patients with cyclic Cushing's disease.

    “Multiple sequential LNSC measurements are very useful to investigate diagnostically challenging patients with cyclic Cushing’s disease.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Kannankeril JCarroll TFindling JWJavorsky BGunsolus ILPhillips JRaff H. Prospective evaluation of late-night salivary cortisol and cortisone by EIA and LC-MS/MS in suspected Cushing syndrome. Journal of the Endocrine Society20204bvaa107. (https://doi.org/10.1210/jendso/bvaa107)10.1210/jendso/bvaa107 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis by Carroll et al. concluded that LNSC is a robust and convenient test to screen and diagnose Cushing's syndrome, with a diagnostic sensitivity of 92% and a specificity of 96%.

    “A meta-analysis by Carroll et al. concluded that LNSC is a robust and convenient test to screen and diagnose CS. Similar to our own analysis, the authors found that LNSC had a diagnostic sensitivity of 92% and a specificity of 96% (18).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Elias PCLMartinez EZBarone BFCMermejo LMCastro MMoreira AC. Late-night salivary cortisol has a better performance than urinary free cortisol in the diagnosis of Cushing’s syndrome. Journal of Clinical Endocrinology and Metabolism2014992045–2051. (https://doi.org/10.1210/jc.2013-4262)10.1210/jc.2013-4262 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UFC has 91% sensitivity and 81.5% specificity in diagnosing Cushing's syndrome and 68% sensitivity and 100% specificity in diagnosing recurrent Cushing's disease.

    “Moreover, UFC has 91% sensitivity and 81.5% specificity in diagnosing CS and 68% sensitivity and 100% specificity in diagnosing recurrent CD (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Guignat LBertherat J. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline: commentary from a European perspective. European Journal of Endocrinology20101639–13. (https://doi.org/10.1530/EJE-09-0627)10.1530/EJE-09-06279709931 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    There is an option of measuring LNSC by immunoassay which is much easier and cheaper with similarly excellent results.

    “There is also the option of measuring LNSC by immunoassay which is much easier and cheaper with similarly excellent results (22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Raff HSingh RJ. Measurement of late-night salivary cortisol and cortisone by LC-MS/MS to assess preanalytical sample contamination with topical hydrocortisone. Clinical Chemistry201258947–948. (https://doi.org/10.1373/clinchem.2012.182717)10.1373/clinchem.2012.182717 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    More than 90% of the variability in salivary cortisone can be accounted for by changes in serum cortisol.

    “More than 90% of the variability in salivary cortisone can be accounted for by changes in serum cortisol (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Carroll TRaff HFindling JW. Late-night salivary cortisol for the diagnosis of Cushing syndrome: a meta-analysis. Endocrine Practice200915335–342. (https://doi.org/10.4158/EP09023OR)10.4158/EP09023OR source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LNSC has been shown to have high diagnostic sensitivity and specificity and to be cost-effective.

    “Despite the fact that LNSC has been shown to have high diagnostic sensitivity and specificity and that it has been shown to be cost-effective, it still remains the least widely used biochemical screening tool for CS (5, 6).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Raff HRaff JLFindling JW. Late-night salivary cortisol as a screening test for Cushing’s syndrome. Journal of Clinical Endocrinology and Metabolism1998832681–2686. (https://doi.org/10.1210/jcem.83.8.4936)28593924

      Not checked in the free run.

    • cites [6] Raff HCushing syndrome update on testing . Endocrinology and Metabolism Clinics of North America20154443–50. (https://doi.org/10.1016/j.ecl.2014.10.005)10.1016/j.ecl.2014.10.005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study was retrospective.

    “Limitations to our study were its retrospective nature, the small number of patients with CS and the fact that the selection of screening tests other than LNSC was based on the clinicians’ preferences.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The diagnosis of adrenal Cushing's syndrome was established by suppressed ACTH levels in the context of hypercortisolaemia and histology in keeping with a cortisol-producing adenoma or adrenocortical carcinoma.

    “The diagnosis of adrenal CS was established by suppressed adrenocorticotrophic hormone (ACTH) levels in the context of hypercortisolaemia and histology in keeping with a cortisol-producing adenoma/adrenocortical carcinoma.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The diagnosis of pituitary Cushing's disease was confirmed by positive histology.

    “The diagnosis of pituitary Cushing’s disease (CD) was confirmed by positive histology.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The selection of screening tests other than LNSC was based on the clinicians' preferences.

    “Limitations to our study were its retrospective nature, the small number of patients with CS and the fact that the selection of screening tests other than LNSC was based on the clinicians’ preferences.”
    Quote in the paperNot a substantial claim
34 of 34

  • The paper relies on this without support.

    Salivary glands express 11-β-hydroxysteroid dehydrogenase (11B-HSD2), which converts salivary cortisol to cortisone.

    “Salivary glands express 11-β-hydroxysteroid dehydrogenase (11B-HSD2) which converts salivary cortisol to cortisone.”

  • The paper relies on this without support.

    The amount of salivary cortisone is significantly greater than salivary cortisol, and an increased cortisol/cortisone ratio reflects exposure to both endogenous and exogenous cortisol.

    “The amount of salivary cortisone is significantly greater than salivary cortisol and an increased cortisol/cortisone ratio reflects exposure to both endogenous and exogenous cortisol.”

  • The paper relies on this without support.

    There is no evidence of 11B-HSD2 activity in collected saliva.

    “There is no evidence of 11B-HSD2 activity in collected saliva.”

  • The paper relies on this without support.

    LNSC is not affected by BMI or cortisol binding globulin and therefore accurately reflects serum cortisol concentrations.

    “LNSC is not affected by BMI or cortisol binding globulin and therefore accurately reflects serum cortisol concentrations.”

  • The paper relies on this without support.

    LNSC and LNS cortisone can conveniently be analysed together with LC-MS/MS from a single saliva sample.

    “LNSC and LNS cortisone can conveniently be analysed together with LC-MS/MS from a single saliva sample which appears to be one of the advantages compared to the immunoassay.”

  • The paper relies on this without support.

    UFC remains the first-line screening test in many countries.

    “Despite that, UFC remains the first-line screening test in many countries which can be explained by its historic use and therefore wider availability.”
6 of 6

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Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • LNSC specificity is reported as both 91% and 100%

    Minor

    The results paragraph first gives LNSC a specificity of 91%, then gives LNSC a specificity of 100%. The surrounding discussion of the latter figure appears to concern salivary cortisone, but the text names LNSC.

1 of 1

Cites

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Authors
Mohamed, R. S., Abuelgasim, B., Barker, S., Prabhudev, H., Martin, N. M., Meeran, K., Williams, E. L., Darch, S., Matthew, W., Tan, T., & Wernig, F.
Affiliations
  • National Health Service (GB)
  • Imperial College Healthcare NHS Trust (GB)
Corresponding author
Wernig, Florian
ORCID
Venue
Endocrine Connections
Publisher
Bioscientifica
Published
2022-07-01
Volume
11
Issue
7
ISSN
2049-3614 (ISSN-L)
DOI
10.1530/ec-22-0050
PMC
PMC9254321
OpenAlex
W4281678499
Semantic Scholar
cfc4f980ad017e2ea6d75e594712a77a69b4a8c7
Cited by
18
References
25
Citations by year
2026: 5 · 2025: 5 · 2024: 5 · 2023: 2 · 2022: 1
FWCI
2.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Endocrine Connections (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
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, late-night salivary cortisol, diagnostic screening, dexamethasone suppression test, 24-hour urinary free cortisol, diagnostic accuracy, endogenous Cushing's syndrome

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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