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Cited by 269Adrenal and Paraganglionic TumorsPituitary Gland Disorders and TreatmentsAdrenal Hormones and Disorders

Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas

Open access
Debono, Miguel, Bradburn, Mike, Bull, Matthew, Harrison, Barney, Ross, Richard J., Newell-Price, John·2014·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2014-3007PMC PMC4255126
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Abstract

CONTEXT: Incidental benign adrenocortical adenomas, adrenal incidentalomas are found in 4.5% of abdominal computed tomography scans, with the incidence increasing to 10% in patients older than 70 years of age. These incidentalomas frequently show evidence of excess cortisol secretion but without overt Cushing's syndrome. The mortality rate is increased in Cushing's syndrome. OBJECTIVE: This study sought to investigate whether patients with adrenal incidentalomas have an increased mortality. DESIGN: This was a retrospective, longitudinal cohort study. SETTING: The study was carried out in an Endocrine Investigation Unit in a University Teaching Hospital. PATIENTS: Two hundred seventy-two consecutive patients with an incidental adrenal mass underwent a dedicated diagnostic protocol, which included dexamethasone testing for hypercortisolism between 2005 and 2013. Overall survival was assessed in 206 patients with a benign, adrenocortical adenoma. MAIN OUTCOME MEASURES: Survival analysis was carried out by using Kaplan-Meier curves and the effect of dexamethasone cortisol estimated by Cox-regression analysis. Cause-specific mortality was ascertained from death certificates and compared with local and national data. RESULTS: Eighteen of 206 patients died and the mean time (SD) from diagnosis to death was 3.2 (1.7) years. Seventeen of 18 patients who died had a post dexamethasone cortisol >1.8 μg/dL and there was a significant decrease in survival rate with increasing dexamethasone cortisol levels (P = .001). Compared with the <1.8 μg/dL group, the hazard ratio (95% confidence interval) for the 1.8-5 μg/dL group was 12.0 (1.6-92.6) whereas that of the >5 μg/dL group was 22.0 (2.6-188.3). Fifty percent and 33% of deaths were secondary to circulatory or respiratory/infective causes, respectively. CONCLUSIONS: PATIENTS with adrenal incidentalomas and a post-dexamethasone serum cortisol >1.8 μg/dL have increased mortality, mainly related to cardiovascular disease and infection.

AI snapshot

Written from the paper’s full text.

TL;DR

In a retrospective cohort of 206 patients with benign adrenocortical incidentalomas, higher post-dexamethasone serum cortisol was associated with increased mortality. Patients with cortisol >1.8 g/dL had markedly worse survival, mainly from circulatory and respiratory/infective causes.

Key findings

  • Eighteen of 206 patients died; mean (SD) time from diagnosis to death was 3.2 (1.7) years.
  • Seventeen of 18 patients who died had a post-dexamethasone cortisol >1.8 g/dL, and survival decreased with increasing cortisol levels (log-rank trend test, P = .001).
  • Compared with the <1.8 g/dL group, hazard ratios (95% CI) were 12.0 (1.6–92.6) for the 1.8–5 g/dL group and 22.0 (2.6–188.3) for the >5 g/dL group.
  • Causes of death were 50% circulatory and 33% respiratory/infective; malignancy accounted for 6%, lower than the local/national incidence of 29%.

Methods

  • Retrospective, longitudinal cohort study of 272 consecutive patients with incidental adrenal masses referred to an Endocrine Investigation Unit between January 2005 and July 2013; final survival analysis included 206 patients with benign adrenocortical adenoma.
  • Patients underwent a dedicated diagnostic protocol including a 1-mg overnight dexamethasone suppression test; cortisol groups were <1.8 g/dL, 1.8–5 g/dL, and >5 g/dL.
  • Survival was assessed with Kaplan-Meier curves and log-rank trend tests; hazard ratios were estimated by Cox regression. Cause-specific mortality came from death certificates and was compared with local Sheffield and UK national data; a subanalysis excluded patients with extra-adrenal malignancy (n = 190).

Limitations

  • Stated: small number of deaths and retrospective design preclude causative extrapolation; only an initial dexamethasone suppression test was available; dexamethasone levels were not measured; vaccination records were unavailable; hypercortisolism could be secondary to conditions such as alcoholism, depression, or psychotic disease, though no deaths from suicide or alcohol-related issues occurred.
  • Stated: multivariable modeling was limited by the small number of events, yielding unstable models and imprecise coefficients.
  • Evident from the text: single-center design, no prospective randomized intervention, and inability to determine whether patients died because of or with hypercortisolism.

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

Integrity signals

Registry

Crossref · 10.1210/jc.2014-3007

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 44 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The neutrophil-to-lymphocyte ratio was higher in patients with post-dexamethasone cortisol above 1.8 μg/dL (P = .014).

    “The neutrophil to lymphocyte ratio was significantly higher in patients with a serum cortisol Ͼ1.8 g/dL post dexamethasone (P ϭ .014).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Patients with bilateral adrenal disease had higher post-dexamethasone serum cortisol than those with unilateral disease (median 2.25 vs 1.8 μg/dL; P = .019).

    “Patients with bilateral disease also had a higher post-dexamethasone serum cortisol level, although this relationship was less pronounced (median, 2.25 g/dL [62 nmol/L] bilateral vs 1.8 g/dL [51 nmol/L] unilateral; P ϭ .019).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The hazard ratio for death in the 1.8-5 μg/dL cortisol group versus the <1.8 μg/dL group was 12.0, with a 95% confidence interval of 1.6-92.6.

    “the hazard ratio (95% confidence interval) for the 1.8 -5g/dL group was 12.0 (1.6 -92.6)”
    • Also stated in: § Results · plain
      “The hazard ratio (95% confidence interval) for the 1.8 -5-g/dL group was 12.0 (1.6 -92.6) whereas that of the Ͼ5 g/dL group was 22.0 (2.6 -188.3) using the Ͻ1.8-g/dL group as reference.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A single baseline overnight dexamethasone suppression test adequately classifies long-term cortisol exposure for mortality risk.
  • Findingown data

    Seventeen of the 18 patients who died had a post-dexamethasone cortisol above 1.8 μg/dL.

    “Seventeen of 18 patients who died had a post dexamethasone cortisol Ͼ1.8 g/dL”
    Quote in the paperSubstantial claim
    • Rests on an assumption: A single baseline overnight dexamethasone suppression test adequately classifies long-term cortisol exposure for mortality risk.
  • Findingown data

    Death risk rises as post-dexamethasone serum cortisol category increases.

    “there was a significant decrease in survival rate with increasing dexamethasone cortisol levels (P ϭ .001).”
    • Also stated in: § Results · boosted
      “These show a significant decrease in survival rate that worsens with increasing post-dexamethasone cortisol cutoffs (log-rank trend test, P ϭ .001).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Patients lost to follow-up do not differ systematically in mortality risk from those included in the final analysis.
    • Rests on an assumption: A single baseline overnight dexamethasone suppression test adequately classifies long-term cortisol exposure for mortality risk.
    • Rests on an assumption: The cohort of patients referred to a single UK endocrine unit is representative of patients with adrenal incidentalomas generally.
  • May combine two claims. 26
  • Classified as probably not a substantial claim. 26
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    The cohort's proportions of circulatory and respiratory/infective deaths exceeded the local and national figures of 31% and 14%, respectively.

    “which were higher than the 31% circulatory and the 14% respiratory/infective causes recorded locally in Sheffield, and nationally in the United Kingdom.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Death certificates accurately identify the underlying cause of death.
    • Rests on an assumption: Local and national mortality data are comparable to the study cohort.

  • May combine two claims.

    Findingown data

    In the cohort, half of deaths were attributed to circulatory causes and one third to respiratory or infective causes.

    “Fifty percent and 33% of deaths were secondary to circulatory or respiratory/infective causes, respectively.”
    • Also stated in: § Results · plain
      “In our cohort there were 50% circulatory and 33% respiratory/ infective causes of death”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Death certificates accurately identify the underlying cause of death.

  • May combine two claims.

    Findingown data

    Six percent of cohort deaths were attributed to malignancy, which was lower than the local and national rate of 29%.

    “Conversely, 6% of our patients died directly resulting from malignancy, a percentage much lower than the local and national incidence of 29% (Figure 3).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Death certificates accurately identify the underlying cause of death.
    • Rests on an assumption: Local and national mortality data are comparable to the study cohort.

  • May combine two claims.

    Findingown data

    Hypertension, dyslipidemia, and diabetes were not associated with mortality in this cohort.

    “There was no relationship between the presence of hypertension (P ϭ .8),dyslipidemia (P ϭ .5),nor diabetes (P ϭ .6)and mortality.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Post-dexamethasone serum cortisol did not differ significantly between women and men (median 1.88 vs 1.92 μg/dL; P = .72).

    “There was no significant difference in post-dexamethasone serum cortisol between sexes (median 1.88 g/dL [52 nmol/L] women vs 1.92 g/dL [53 nmol/L] men; P ϭ .72).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Post-dexamethasone serum cortisol showed a positive correlation with age (Spearman rho 0.32, P < .001).

    “Post-dexamethasone serum cortisol was correlated with size of adenoma (Spearman's ϭ 0.35, P Ͻ .001) and age (Spearman's ϭ 0.32; P Ͻ .001).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Fasting glucose levels were similar between patients who survived and those who died.

    “Fasting glucose levels were similar in patients who survived or died.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean survival was 8.4 years for cortisol <1.8 μg/dL, 7.3 years for 1.8-5 μg/dL, and 6.9 years for >5 μg/dL.

    “The mean (95% confidence interval) survival for the post-dexamethasone groups were as follows: cortisol Ͻ1.8, 1.8 -5, and Ͼ5 g/dL was 8.4 (8.2-8.6), 7.3 (6.8 -7.8), and 6.9 (5.6 -8.3) years, respectively.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In this cohort, the average interval from diagnosis to death was 3.2 years.

    “In our study, however, the mean time to death was 3.2 years.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In that subanalysis, no deaths occurred among patients with cortisol below 1.8 μg/dL, 10 of 85 (12%) died in the 1.8-5 μg/dL group, and 5 of 16 (31%) died in the >5 μg/dL group.

    “There were 15 deaths in total: none with serum cortisol 1.8 g/dL; 10 with serum cortisol 1.8 -5 g/dL (10/85[12%]); and five with a serum cortisol Ͼ5 g/dL (5/16[31%]).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Patients lost to follow-up do not differ systematically in mortality risk from those included in the final analysis.

  • May combine two claims.

    Findingown data

    In the subanalysis excluding extra-adrenal malignancy, deaths were 53% circulatory, 27% respiratory/infection, and 7% malignant.

    “Similar results were observed in the cohort of patients excluding those with extra-adrenal malignancy in whom there were 53, 27, and 7% deaths from circulatory, respiratory/infection, and malignant causes, respectively.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Death certificates accurately identify the underlying cause of death.

  • May combine two claims.

    Findingown data

    The authors' data show increased mortality from both cardiovascular disease and infections in patients with adrenal incidentaloma and low-grade excess cortisol.

    “Our data show an increased mortality both from cardiovascular disease and infections in patients with adrenal incidentaloma and low-grade excess cortisol.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The association between post-dexamethasone cortisol category and mortality is not due to unmeasured confounding.
    • Rests on an assumption: The recorded causes of death accurately reflect the underlying causes.

  • May combine two claims.

    Premisecitation

    Adrenal incidentalomas that secrete excess cortisol are associated with multiple complications, including diabetes, hypertension, visceral obesity, low bone mineral density, vertebral fractures, a tendency to thrombosis, and cardiovascular disease.

    “Adrenal incidentalomas secreting excess cortisol are associated with multiple complications including diabetes, hypertension, visceral obesity, low bone mineral density, vertebral fractures, a predisposition to thrombosis (2,15,25,26), and cardiovascular disease (8,15).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [2]

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    • cites [15]

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    • cites [25]

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    • cites [26]

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    • cites [8]

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

    Premisecitation

    In elderly people, greater total cortisol exposure measured in saliva is associated with atherosclerosis, independent of other cardiovascular risk factors.

    “Cross-sectional data show that increased total cortisol exposure, measured in salivary cortisol samples, a marker of free cortisol, is associated with the development of atherosclerosis in the elderly, independent of the presence of other cardiovascular risk factors (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34]

      Not checked in the free run.

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

    Study design and conductnone given

    All patients diagnosed with adrenal incidentalomas after radiological investigation were referred to the endocrinology unit regardless of diagnosis and health status.

    “Locally, all patients diagnosed with adrenal incidentalomas, after radiological investigation, were referred for investigation to the endocrinology unit irrespective of underlying diagnosis and health status.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Glucocorticoids reduce Th-1 responses needed against bacterial infection and lower the Th-1:Th-2 ratio.

    “An important effect of glucocorticoids is to reduce Th-1 responses needed to counter bacterial infection, and reduce the Th-1:Th-2 cell ratio (41), and lower cellular immunity (42).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overt endogenous Cushing's syndrome and excess exogenous glucocorticoid use are associated with more cardiovascular events and higher mortality from cardiovascular disease or infection.

    “Overt endogenous Cushing's syndrome and use of excess exogenous glucocorticoids are associated with increases in cardiovascular events and mortality from cardiovascular disease or infection (11)(12)(13)(14).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11]

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    • cites [12]

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    • cites [13]

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  • May combine two claims.

    Interpretationreasoning

    Altered cortisol exposure may disrupt lymphocyte rhythms and impair immune function.

    “Changes in cortisol exposure may distort lymphocyte rhythms resulting in impaired immune function.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationown data

    The authors' consecutive patient data extend the prior observations.

    “Our data, on a consecutive series of patients, extend these observations.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Most highly selected surgical studies found that adrenal incidentaloma patients with excess cortisol secretion had better cardiovascular risk profiles than those managed conservatively.

    “In most highly selected surgical studies patients with adrenal incidentalomas secreting excess cortisol have experienced improvement in their cardiovascular risk pro-file when compared with patients treated conservatively (30,31), but this finding is not universal (32).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30]

      Not checked in the free run.

    • cites [31]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    A post-dexamethasone cortisol above 1.8 μg/dL is consistent with cortisol excess according to Endocrine Society guidelines.

    “A post-dexamethasone cortisol Ͼ1.8 g/dL is in keeping with a diagnosis of cortisol excess as recommended by Endocrine Society guidelines (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20]

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Prior studies have found increased cardiovascular disease risk in patients with adrenal incidentalomas, and one recent study suggested higher cardiovascular mortality.

    “Nevertheless, a number of studies have shown an increased risk of cardiovascular disease in patients with adrenal incidentalomas (8,9), and a recent study has suggested increased mortality from cardiovascular causes (10).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8]

      Not checked in the free run.

    • cites [9]

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    • cites [10]

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The small number of events restricts the modeling that can be done and the precision of the estimates.

    “The small number of events hampers the extent of modeling, which can be undertaken and the precision of the estimates, but nonetheless the data strongly suggest that hypercortisolemia in the context of an adrenal incidentaloma is detrimental.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The authors carefully ascertained subjects to define benign adrenocortical adenoma and to assess the significance of the adenoma and excess cortisol by dexamethasone testing.

    “We did, however, carefully ascertain our subjects to define the benign adrenocortical adenoma and assess the significance of the presence of this and excess cortisol as evidenced by dexamethasone testing.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Excluding patients taking CYP3A4 inducers or inhibitors did not materially alter the results.

    “When excluding patients on drugs that induce CYP3A4 (n ϭ 5) and inhibit CYP3A4 (n ϭ 8) results were similar.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Glucocorticoids promote eosinophil apoptosis.

    “Glucocorticoids also stimulate apoptosis of eosinophils (43) and impair neutrophil apoptosis (44).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43]

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

    Study design and conductown data

    Twenty-one patients were lost to follow-up.

    “In addition, 21 patients were lost to follow-up.The final survival analysis was carried out on 206 patients (primary analysis).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Local and national mortality data recorded 31% circulatory, 14% respiratory/infective, and 29% malignancy deaths.

    “which were higher than the 31% circulatory and the 14% respiratory/infective causes recorded locally in Sheffield, and nationally in the United Kingdom.”
    • Also stated in: § Results · plain
      “a percentage much lower than the local and national incidence of 29% (Figure 3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18]

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    • cites [19]

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

    Study design and conductcitation

    Dexamethasone levels were not measured.

    “Dexamethasone levels were not measured, but recent data suggest that measuring dexamethasone levels does not improve the diagnostic performance of the 1-mg overnight dexamethasone-suppression test (45).”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    A higher neutrophil-to-lymphocyte ratio in patients who did not suppress cortisol after dexamethasone might indicate a cortisol-immune relationship.

    “A higher neutrophil/lymphocyte ratio in our patients who failed to suppress serum cortisol after dexamethasone might be an indicator of such a relationship.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In healthy young people, lymphocyte counts and some subsets show circadian variation, with higher levels at night when cortisol is lowest, while CD8 and CD16 cells peak at 1200 h.

    “Under normal circumstances in the young there is a circadian change to the total number of lymphocytes and some lymphocyte subpopulations such as CD3 (total T cells), CD4 (T-helper), and CD20 (total B-cells) with higher levels at night when cortisol levels are lowest, whereas CD8 (T-suppressor and cytotoxic) and CD16 (natural killer) cells are higher at 1200 h (40).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cortisol's cardiovascular effects may involve glucocorticoid binding to glucocorticoid and mineralocorticoid receptors in cardiovascular tissues, increasing vascular smooth muscle contractility via noradrenaline sensitivity and reducing endothelium-dependent vasodilatation.

    “This effect may also be explained by the binding of glucocorticoids to glucocorticoid and mineralocorticoid receptors in cardiovascular tissues such as the heart and vascular walls, enhancing contractility of vascular smooth muscle by increasing sensitivity to noradrenaline and decreasing endothelium-dependent vasodilatation (37).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37]

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  • May combine two claims.

    Premisecitation

    Overt Cushing's syndrome is associated with higher mortality, predominantly from cardiovascular disease and infection.

    “Patients with overt Cushing's syndrome have increased mortality due mainly to cardiovascular disease and infection (27).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low-grade excess cortisol secretion in adrenal incidentalomas is associated with higher prevalence of insulin resistance, hypertension, and visceral obesity.

    “Low-grade excess cortisol secretion in adrenal incidentalomas has also been associated with an increased prevalence of insulin resistance, hypertension, and visceral obesity (15)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15]

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

    Premisecitation

    In mood disorder patients, dexamethasone nonsuppression and higher baseline serum cortisol are associated with cardiovascular death.

    “For example, nonsuppression on dexamethasone testing and higher baseline serum cortisol levels has been associated with cardiovascular disease death in patients with mood disorders (33).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33]

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

    Premisecitation

    In patients with glucocorticoid receptor polymorphisms, hypercortisolism and increased glucocorticoid sensitivity are associated with severe atherosclerosis and coronary artery disease.

    “Hypercortisolism and increased sensitivity to glucocorticoids in patients with glucocorticoid receptor polymorphisms have also been associated with severe atherosclerosis and coronary artery disease (36).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36]

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

    Study design and conductown data

    The proportional hazards assumption was not contradicted by residual assessment, though formal tests were limited by the low death rate.

    “The model assumption (proportional hazards) was not contradicted by the assessment of residuals, although again the formal tests are limited by the low death rate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Multivariable modeling was limited by the small number of events (24), which would produce unstable models and imprecise coefficients.

    “Furthermore, multivariable modeling was limited by the small number of events (24), which would yield unstable models and imprecise coefficients.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Average life expectancy in the local and national population during the study period was about 78 years for men and 82 years for women.

    “The average overall life expectancy for the local and national population during this time period was approximately 78 years for men and 82 years for women (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18]

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

    Study design and conductown data

    The study was approved and registered as an institutional case-notes review.

    “The study was approved and registered as an institutional case-notes review at Sheffield Teaching Hospitals National Health Service Foundation Trust (Registration No. 5133).”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The study was reported according to STROBE guidelines.

    “The study is reported as recommended by the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines, that recommend parameters to be included in a complete and accurate report of an observational study (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17]

      Not checked in the free run.

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

    Study design and conductnone given

    Subjects had only an initial dexamethasone suppression test, which is a study limitation.

    “It is important to note that our subjects only had an initial dexamethasone suppression test, and this is a limitation of the study.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The authors lacked records of flu and pneumococcal vaccination and cannot say whether vaccination influenced infection-related mortality.

    “In the United Kingdom it is recommended for all patients age 65 years and over to receive the flu and pneumococcal vaccines but we did not have any records of this and cannot comment on whether this may have influenced infection-related mortality.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Hazard ratios could not be calculated because no patient in the <1.8-g/dL group died.

    “Hazard ratios could not be calculated because no patients from the Ͻ1.8-g/dL group died (subanalysis).”
    Quote in the paperNot a substantial claim
44 of 44

  • The paper relies on this without support.

    Death certificates accurately identify the underlying cause of death.

    “The primary cause of death was ascertained from death certificates obtained from the General Register Office in the United Kingdom so that all-cause and cause-specific mortality could be determined.”
    “Death certificates were coded using the 10th revision of the International Classification of Disease (ICD-10).”

  • The paper relies on this without support.

    Patients lost to follow-up do not differ systematically in mortality risk from those included in the final analysis.

    “In addition, 21 patients were lost to follow-up.The final survival analysis was carried out on 206 patients (primary analysis).”

  • The paper relies on this without support.

    Local and national mortality data are comparable to the study cohort.

    “The cause-specific mortality in the adrenal incidentaloma patients was compared with local incidence figures in 2010 obtained from the Sheffield Director of Public Health Report, 2011 (18).”

  • The paper relies on this without support.

    A single baseline overnight dexamethasone suppression test adequately classifies long-term cortisol exposure for mortality risk.

    “Only a baseline overnight dexamethasone suppression test is carried out in our unit (although we do acknowledge that in some cases post-dexamethasone cortisol levels may worsen (10) or normalize (22) on followup).”

  • The paper relies on this without support.

    The cohort of patients referred to a single UK endocrine unit is representative of patients with adrenal incidentalomas generally.

    “A retrospective, longitudinal, cohort study was performed on a consecutive series of 272 patients diagnosed with adrenal incidentalomas between January 2005 and July 2013, and referred to the Endocrine Investigation Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals National Health Service Foun-dation Trust, Sheffield, United Kingdom, a University Hospital.”

  • The paper relies on this without support.

    The association between post-dexamethasone cortisol category and mortality is not due to unmeasured confounding.

    “When adjusting for age the relationship between postdexamethasone cortisol category and mortality remained identical.”

  • The paper relies on this without support.

    The life expectancy at birth of the general population is a valid comparator for the age at death of patients with adrenal incidentalomas.

    “In addition, the age of death for patients with adrenal incidentalomas was lower than the life expectancy at birth of the general population (men/women, 74/72 vs 78/82 y) (18).”

  • The paper relies on this without support.

    The recorded causes of death accurately reflect the underlying causes.

    “Graphs show a higher rate of mortality from circulatory and infective/respiratory (resp) causes in the adrenal incidentaloma group of patients between January 2005 and July 2013.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Cortisol levels between 1.9 and 5.0 μg/dL may indicate possible autonomous cortisol secretion, and cortisol levels above 5.0 μg/dL are suggested to confirm autonomous cortisol secretion.

    “Levels between 1.9 and 5.0 μg/dL (50-140 nmol/L) may indicate “possible autonomous cortisol secretion,” and cortisol levels above 5.0 μg/dL (140 nmol/L) are suggested to confirm ACS (79,220).”

    From Adrenal incidentaloma (2020) · cites this paper as [220]

  • A study with up to 15 years of follow-up in patients with autonomous cortisol secretion documented increased cardiovascular morbidity (43% vs 8.8%, P < .005) and mortality (22.6% vs 2.5%, P < .02) compared with nonfunctioning adrenal incidentaloma.

    “A study with up to 15 years of follow-up in patients with ACS has documented increased cardiovascular morbidity (43% vs 8.8%, P < .005) and mortality (22.6% vs 2.5%, P < .02) in ACS patients compared with nonfunctioning AI.”

    From Adrenal incidentaloma (2020) · cites this paper as [220]

Self-check

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.

  • Endocrine Society guideline cites the wrong reference

    Minor

    The text attributes the cortisol cutoff to Endocrine Society guidelines numbered (20), but reference 20 is a patient follow-up study. The reference list identifies the Endocrine Society guideline as reference 18.

  • Local mortality data cite an unrelated reference

    Minor

    The cited reference 18 is an Endocrine Society guideline, not the Sheffield Director of Public Health Report named in the text.

2 of 2

Cites

Flagged first, then by citations

5 of the 53 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Debono, M., Bradburn, M., Bull, M., Harrison, B., Ross, R. J., & Newell-Price, J.
Affiliations
  • National Health Service (GB)
  • University of Sheffield (GB)
Corresponding author
Newell-Price, John
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2014-12
Volume
99
Issue
12
Pages
4462-4470
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2014-3007
PMC
PMC4255126
OpenAlex
W1968633315
Semantic Scholar
137d1f8a2ad1b183c0a736363bfdd73ae4786040
Cited by
269
References
53
Citations by year
2026: 21 · 2025: 15 · 2024: 18 · 2023: 23 · 2022: 30 · 2021: 35 · 2020: 26 · 2019: 22 · 2018: 24 · 2017: 22 · 2016: 18 · 2015: 15
FWCI
18.05
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute for Health and Care Research (CL-2013-04-001, BRF-2011-005)
Topics
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
adrenal incidentaloma, adrenal adenoma, cortisol, mortality, dexamethasone suppression test, hypercortisolism, Cushing's syndrome, survival, cardiovascular disease, infection
MeSH terms
Adrenal Cortex Neoplasms, Adrenal Gland Neoplasms, Aged, Aged, 80 and over, Dexamethasone, Female, Humans, Hydrocortisone, Longitudinal Studies, Male, Middle Aged, Retrospective Studies, Cohort Studies, Biomarkers, Survival Analysis

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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