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Cited by 281Adrenal and Paraganglionic TumorsAdrenal Hormones and DisordersHormonal Regulation and Hypertension

Diagnosis and Treatment of Subclinical Hypercortisolism

Open access
Chiodini, Iacopo·2011·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2010-2722
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Abstract

Context: Subclinical hypercortisolism (SH) is a condition of biochemical cortisol excess without the classical signs or symptoms of overt hypercortisolism. It is thought to be present in the 5–30% of patients with incidentally discovered adrenal mass (adrenal incidentalomas), which in turn are found in 4–7% of the adult population. Therefore, SH has been suggested to be present in 0.2–2.0% of the adult population. Some studies suggested that this condition is present in 1–10% of patients with diabetes or established osteoporosis. The present manuscript reviews the literature on diagnostic procedures and the metabolic effect of the recovery from SH. Evidence Acquisition: A PubMed search was used to identify the available studies. The most relevant studies from 1992 to November 2010 have been included in the review. Evidence Synthesis: The available data suggest that SH may be associated with chronic complications, such as hypertension, diabetes mellitus, overweight/obesity, and osteoporosis. The available intervention studies suggest that the recovery from SH may lead to the improvement of hypertension and diabetes mellitus. A retrospective study suggests that this beneficial effect could be predicted before surgery. Conclusions: SH is suggested to be associated with some chronic complications of overt cortisol excess. Recovery from this condition seems to improve these complications. However, a large, prospective, randomized study is needed to confirm this hypothesis and to establish the best diagnostic approach to identify patients with adrenal incidentalomas who can benefit from surgery.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes the diagnosis, prevalence, and management of subclinical hypercortisolism (SH), defined as biochemical cortisol excess without classical signs or symptoms of overt hypercortisolism. It concludes that no consensus or gold standard exists for diagnosis, that the DST-UFC-ACTH combination is the best available compromise, and that surgery may improve metabolic complications but evidence remains limited.

Key findings

  • SH is estimated to be present in 5–30% of patients with adrenal incidentalomas (AI); because AI are found in 4–7% of adults, SH may be present in 0.2–2.0% of the adult population, and in 1–10% of patients with diabetes or established osteoporosis.
  • No single HPA-axis parameter has adequate sensitivity and specificity. In one scintigraphy-validated study, the 1-mg DST cutoff of 3.0 μg/dl showed the best compromise (sensitivity 63%, specificity 75%); in 231 AI patients, the DST-UFC-ACTH combination criterion had sensitivity 61.9%, specificity 77.1%, and accuracy 75.8% for predicting a cluster of complications.
  • Prevalence in at-risk groups varied: 10.8% in 294 type 2 diabetic inpatients; 4.8% in osteoporosis and 10.8% in osteoporosis with vertebral fractures. SH appears more commonly of adrenal than pituitary origin.
  • In the only prospective randomized study cited (23 surgically treated, 22 conservatively treated), surgery improved hypertension, diabetes, obesity, and dyslipidemia in 66.7%, 62.5%, 50%, and 37.5% of cases, respectively; conservative management worsened hypertension, diabetes, and dyslipidemia in 80%, 33.3%, and 20%.

Methods

  • Narrative clinical review of the literature on diagnostic procedures and the metabolic effects of recovery from SH.
  • Synthesizes studies of patients with adrenal incidentalomas and at-risk populations (diabetes, osteoporosis), including diagnostic accuracy studies and surgical versus conservative treatment/follow-up studies; tables summarize HPA-axis alterations, diagnostic accuracy, prevalence, and outcomes.
  • Main analysis is qualitative synthesis; no new primary data or meta-analysis are presented.

Limitations

  • The paper states there is no consensus on clinical or biochemical criteria for SH, no clinical gold standard, and that cortisol secretion is a continuum and highly variable; ACTH and 24-h UFC reliability is low, comorbidities and medications affect the DST, and salivary cortisol methods are not standardized.
  • The paper states that no large prospective randomized trial has compared surgical versus conservative treatment, available studies are small and often retrospective or nonrandomized, and data on hard endpoints and cost-effectiveness are lacking.
  • Evident from the text: as a single-author narrative review, it draws on heterogeneous studies with differing cutoffs, assays, and outcome definitions, which limits comparability across findings.

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

Integrity signals

Registry

Crossref · 10.1210/jc.2010-2722

Cites

111 of 111 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 207 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    In patients with 1-mg dexamethasone suppression test values between those limits, midnight serum cortisol greater than 4.0 mg/dl or ACTH less than 10.0 pg/ml combined with at least two metabolic complications before surgery had 76% accuracy in predicting improvement.

    “In patients with 1-mg DST between these values, the presence of MSeC greater than 4.0 mg/dl (110 nmol/liter) or ACTH less than 10.0 pg/ml (2.2 pmol/ liter) combined with the presence of at least two metabolic complications before surgery had a 76% accuracy in predicting improvement.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Eller-Vainicher, 2010, Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma., Eur J Endocrinol source

      Not checked in the free run.

  • Findingcitation

    In retrospective data on 55 surgically treated adrenal incidentaloma patients, 1-mg dexamethasone suppression test values greater than 5 g/dl and less than 2 g/dl had the best specificity and sensitivity (96.9% and 91.3%) for identifying patients who may improve after surgery.

    “Looking to the above-mentioned retrospective data on 55 surgically treated patients with AI (60), 1-mg DST greater than 5 g/dl (138 nmol/liter) and less than 2 g/dl (55 nmol/liter) had the best specificity and sensitivity (96.9 and 91.3%, respectively) for identifying patients that may improve after surgery.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Eller-Vainicher, 2010, Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma., Eur J Endocrinol source

      Not checked in the free run.

  • Findingcitation

    Using the protocol, improvement after surgery was correctly predicted before surgery in more than 80% of cases.

    “Using the protocol illustrated in the study, in more than 80% of cases the improvement after surgery was correctly predicted before surgery (60).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Eller-Vainicher, 2010, Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma., Eur J Endocrinol source

      Not checked in the free run.

  • Premisecitation

    Progression from subclinical hypercortisolism to overt clinical hypercortisolism is very rare.

    “the progression toward overt clinical hypercortisolism is very rare (11)(12)(13).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (11)(12)(13)

      Not checked in the free run.

  • Premisecitation

    Glucocorticoid sensitivity may differ among individuals and among tissues within the same individual, partly because of polymorphisms in the glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 1 genes.

    “the glucocorticoid sensitivity may be different among the different individuals and among the different tissues in the same individual, due also to polymorphisms of both glucocorticoid receptor (25)(26)(27)(28) and 11␤-hydroxysteroid-dehydrogenase type 1 genes (29,30).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites (25)(26)(27)(28)

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    • cites [29] Tomlinson, 2004, 11β-Hydroxysteroid dehydrogenase type 1: a tissue specific regulator of glucocorticoid response., Endocr Rev source

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    • cites [30] Hwang, 2009, HSD11B1 polymorphisms predicted bone mineral density and fracture risk in postmenopausal women without clinically apparent hypercortisolemia., Bone source

      Not checked in the free run.

  • May combine two claims. 43
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingcitation

    After excluding midnight serum cortisol, all combinations of the remaining HPA axis parameters lacked sufficient reliability for predicting postsurgical hypocortisolism, and normal preoperative HPA axis parameters could not rule out postsurgical adrenal insufficiency with 100% probability.

    “Moreover, after excluding MSeC, all combinations of the remaining parameters did not show enough reliability for predicting hypocortisolism after surgery, and conversely, the normality of all parameters of HPA axis activity before surgery could not rule out with 100% probability the appearance of postsurgical adrenal insufficiency.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Eller-Vainicher, 2010, Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the same study, lowering the 1-mg dexamethasone suppression test cutoff reduced specificity from 85.7% to 23.8% and increased sensitivity from 33.3% to 79.5%.

    “Also in this study, lowering the cutoff of 1-mg DST was demonstrated to lead to a reduction in specificity (from 85.7 to 23.8%) and an increase in sensitivity (from 33.3 to 79.5%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Eller-Vainicher, 2010, Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In a study of 60 patients with adrenal incidentalomas, simultaneous elevated urinary free cortisol and midnight serum cortisol above 5.4 g/dl before surgery had 100% specificity for predicting postsurgical hypocortisolism but only 30.8% sensitivity.

    “We found that the simultaneous presence of elevated UFC and MSeC levels [Ͼ5.4 g/dl (149 nmol/liter)] before surgery had a 100% specificity for predicting postsurgical hypocortisolism, but at the expense of a 30.8% sensitivity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Eller-Vainicher, 2010, Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In a recent retrospective study of 55 surgically treated and 33 conservatively treated adrenal incidentaloma patients, the DST-UFC-ACTH combination criterion showed the best accuracy in predicting improvement (sensitivity 65.2%, specificity 68.8%) in surgical patients and worsening (sensitivity 55.6%, specificity 82.9%) in conservative patients.

    “The DST-UFC-ACTH combination criterion was confirmed to be useful because it showed the best accuracy in predicting improvement (sensitivity, 65.2%; specificity, 68.8%) in surgically treated patients and worsening of the endpoints (sensitivity, 55.6%; specificity, 82.9%), in the conservatively treated subjects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Eller-Vainicher, 2010, Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma., Eur J Endocrinol source

      Not checked in the free run.

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

    Premisenone given

    Some studies have suggested that subclinical hypercortisolism occurs in 1-10% of patients with diabetes or established osteoporosis.

    “Some studies suggested that this condition is present in 1-10% of patients with diabetes or established osteoporosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In patients with adrenal incidentalomas, cortisol secretion forms a continuum from normal to clearly increased and varies greatly within the same person.

    “particularly in AI patients, cortisol secretion is a continuum from completely normal to clearly increased levels, and it is highly variable in the same individual (3,22).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Grumbach, 2003, Management of the clinically inapparent adrenal masses (“incidentaloma”)., Ann Intern Med source

      Not checked in the free run.

    • cites [22] Terzolo, 2005, Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma., Eur J Endocrinol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    The National Institutes of Health State-of-the-Science Conference and the American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons guidelines recommend a 5 g/dl cutoff as normal cortisol suppression in patients with suspected subclinical hypercortisolism.

    “The National Institutes of Health State-of-the-Science Conference (64) and the American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons Medical Guidelines for the Management of AI (65) recommend the cutoff of 5 g/dl (138 nmol/liter) as the normal level of cortisol suppression in patients with suspected SH.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] 2002, NIH State-of-the-science statement on management of the clinically inapparent adrenal mass (“incidentaloma”)., 2002 NIH Consensus and State-of-the-Science Statements

      Not checked in the free run.

    • cites [65] Zeiger, 2009, American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas., Endocr Pract source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Midnight serum cortisol is a promising tool for diagnosing subclinical hypercortisolism, but its use is limited by the need for hospital admission.

    “Even if midnight serum cortisol (MSeC) has been shown to be a promising tool for diagnosing SH (22), its use is limited by the need of the hospital admission for the cumbersome procedure, and it could be used as a confirmative test in selected patients (60).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Terzolo, 2005, Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma., Eur J Endocrinol source

      Not checked in the free run.

    • cites [60] Eller-Vainicher, 2010, Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma., Eur J Endocrinol source

      Not checked in the free run.

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

    Premisecitation

    Several studies and the French Society for Endocrinology have proposed a lower 1-mg dexamethasone suppression test cutoff to increase sensitivity.

    “Several studies (19,21,32,34,38,39,44,46,49,53,60,61,67) and recently the French Society for Endocrinology (68), however, have proposed a lower cutoff to increase sensitivity.”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [19] Chiodini, 2004, Spinal volumetric bone mineral density and vertebral fractures in female patients with adrenal incidentalomas: the effect of subclinical hypercortisolism and gonadal status., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [21] Chiodini, 2009, Bone mineral density, prevalence of vertebral fractures and bone quality in patients with adrenal incidentalomas with and without subclinical hypercortisolism: an Italian Multicenter Study., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [32] Masserini, 2009, The limited role of midnight salivary cortisol in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentalomas., Eur J Endocrinol source

      Not checked in the free run.

    • cites [34] Reincke, 1992, Preclinical Cushing's syndrome in adrenal incidentalomas: comparison with adrenal Cushing's syndrome., J Clin Endocrinol Metab

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    • cites [38] Bardet, 1996, 131I-6-b-Iodomethylnorcholesterol scintigraphy: an assessment of its role in the investigation of adrenocortical incidentalomas., Clin Endocrinol (Oxf) source

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    • cites [39] Bondanelli, 1997, Evaluation of hormonal function in a series of incidentally discovered adrenal masses., Metabolism source

      Not checked in the free run.

    • cites [44] Tanabe, 2001, Autonomy of cortisol secretion in clinically silent adrenal incidentaloma., Horm Metab Res source

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    • cites [46] Midorikawa, 2001, The improvement of insulin resistance in patients with adrenal incidentalomas by surgical resection., Clin Endocrinol (Oxf) source

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    • cites [49] Chiodini, 2001, Bone loss rate in adrenal incidentalomas: a longitudinal study., J Clin Endocrinol Metab source

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    • cites [53] Chiodini, 2002, Bone involvement in eugonadal male patients with adrenal incidentaloma and subclinical hypercortisolism., J Clin Endocrinol Metab source

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  • May combine two claims.

    Interpretationreasoning

    Urinary free cortisol is not an adequate screening test for subclinical hypercortisolism and should be used with other tests or in specific populations.

    “Therefore, UFC should not be considered an adequate screening test for SH and should be used in combination with other tests or in specific populations (1,14).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Terzolo, 2005, Subclinical Cushing's syndrome in adrenal incidentalomas., Endocrinol Metab Clin North Am source

      Not checked in the free run.

    • cites [14] Nieman, 2008, The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline., J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Lowering the 1-mg dexamethasone suppression test cutoff decreases specificity and increases false diagnoses of subclinical hypercortisolism.

    “Thus, reducing the cutoff of 1-mg DST leads to a decrease in specificity and, therefore, to more false diagnosis of SH (65).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Zeiger, 2009, American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas., Endocr Pract source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In patients without signs or symptoms of hypercortisolism, the prior probability of subclinical hypercortisolism is lower than the probability of a false-positive result, which justifies using a higher screening cutoff.

    “The reason to screen for SH with a higher cutoff than that recommended for overt cortisol excess [1.8 g/dl (50 nmol/liter)] (66) is that in patients without signs or symptoms suggestive of hypercortisolism, the a priori possibility of having SH is estimated to be lower than that of a false-positive result (1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Terzolo, 2005, Subclinical Cushing's syndrome in adrenal incidentalomas., Endocrinol Metab Clin North Am source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Midnight salivary cortisol should not be used for diagnosing subclinical hypercortisolism until further studies and standardization of laboratory methods are available.

    “Thus, this test should not be used for diagnosing SH until further studies and a standardization of the laboratory methods are available.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Some authors found low sensitivity of midnight salivary cortisol for identifying subclinical hypercortisolism, whereas others found that consistent or frequent elevations may indicate the condition.

    “Some authors found a low sensitivity of MSaC in identifying SH (31,32), whereas others showed that subjects with either consistent or frequent elevations of this parameter may actually have SH (69).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [31] Nunes, 2009, Late-night salivary cortisol for diagnosis of overt and subclinical Cushing's syndrome in hospitalized and ambulatory patients., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [32] Masserini, 2009, The limited role of midnight salivary cortisol in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentalomas., Eur J Endocrinol source

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    • cites [69] Kidambi, 2007, Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing's syndrome., Eur J Endocrinol source

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  • May combine two claims.

    Premisecitation

    Low-dose dexamethasone suppression testing has been used to diagnose subclinical hypercortisolism without advantages, except possibly in patients with alcoholism, psychiatric disorders, or diabetes.

    “Similarly, LDDST has been used to diagnose SH (18,40,41,55) without advantages, with the exception of patients affected with alcoholism, psychiatric disorders, and diabetes in whom this test may be more accurate (1,14,66).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [18] Rossi, 2000, Subclinical Cushing's syndrome in patients with adrenal incidentaloma: clinical and biochemical features., J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [40] Kasperlik-Zeluska, 1997, Incidentally discovered adrenal mass (incidentaloma): investigation and management of 208 patients., Clin Endocrinol (Oxf) source

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    • cites [41] Tsagarakis, 1998, Elevated post-dexamethasone suppression cortisol concentrations correlate with hormonal alterations of the hypothalamo-pituitary adrenal axis in patients with adrenal incidentalomas., Clin Endocrinol (Oxf) source

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    • cites [55] Hadjidakis, 2003, Does subclinical hypercortisolism adversely affect the bone mineral density of patients with adrenal incidentalomas?, Clin Endocrinol (Oxf) source

      Not checked in the free run.

    • cites [1] Terzolo, 2005, Subclinical Cushing's syndrome in adrenal incidentalomas., Endocrinol Metab Clin North Am source

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    • cites [14] Nieman, 2008, The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline., J Clin Endocrinol Metab source

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    • cites [66] Arnaldi, 2003, Diagnosis and complications of Cushing's syndrome: a consensus statement., J Clin Endocrinol Metab source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisereasoning

    Combining different HPA axis parameters has been proposed to increase specificity without affecting sensitivity.

    “Because the increase in sensitivity is accompanied by the decrease in specificity with the lowering of the 1-mg DST cutoff and vice versa, the combination of different parameters of HPA axis activity has been proposed to increase specificity without affecting sensitivity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Postsurgical hypocortisolism reflects only pituitary sensitivity to cortisol excess and not peripheral tissue sensitivity.

    “The main criticism to this approach for diagnosing SH is that postsurgical hypocortisolism reflects only the pituitary sensi- tivity to cortisol excess and not that at the peripheral tissues (25)(26)(27)(28)(29)(30).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (25)(26)(27)(28)(29)(30)

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  • May combine two claims.

    Premisecitation

    ACTH levels above 20 pg/ml or below 10 pg/ml suggest an ACTH-dependent or ACTH-independent cause of subclinical hypercortisolism, respectively.

    “In particular, ACTH levels above 20 pg/ml (4.4 pmol/liter) or below 10 pg/ml (2.2 pmol/liter) suggest an ACTH-dependent or -independent cause of SH, respectively (66).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Arnaldi, 2003, Diagnosis and complications of Cushing's syndrome: a consensus statement., J Clin Endocrinol Metab source

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  • May combine two claims.

    Premisecitation

    With lower 1-mg dexamethasone suppression test cutoffs of 1.8 and 2.2 g/dl, specificity decreased to 67-72% and sensitivity increased to 75-100%.

    “However, if the lowest cutoffs were used [1.8 and 2.2 g/dl (50 and 60.6 nmol/liter), respectively], specificity decreased to 67-72%, whereas sensitivity increased to 75-100% (48 -62, 64 -67).”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [48] Valli, 2001, Biochemical screening for subclinical cortisol-secreting adenomas amongst adrenal incidentalomas., Eur J Endocrinol source

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    • cites [49] Chiodini, 2001, Bone loss rate in adrenal incidentalomas: a longitudinal study., J Clin Endocrinol Metab source

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    • cites [50] Barzon, 2002, Development of overt Cushing's syndrome in patients with adrenal incidentalomas., Eur J Endocrinol source

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    • cites [51] Bülow, 2002, Adrenal incidentaloma—experience of a standardized diagnostic programme in the Swedish prospective study., J Intern Med source

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    • cites [52] Libè, 2002, Long-term follow-up study of patients with adrenal incidentalomas., Eur J Endocrinol source

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    • cites [53] Chiodini, 2002, Bone involvement in eugonadal male patients with adrenal incidentaloma and subclinical hypercortisolism., J Clin Endocrinol Metab source

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    • cites [54] Emral, 2003, Prevalence of subclinical Cushing's syndrome in 70 patients with adrenal incidentalomas: clinical, biochemical and surgical outcomes., Endocr J source

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    • cites [55] Hadjidakis, 2003, Does subclinical hypercortisolism adversely affect the bone mineral density of patients with adrenal incidentalomas?, Clin Endocrinol (Oxf) source

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    • cites [56] Katabami, 2005, Discrepancies in results of low- and high-dose dexamethasone suppression tests for diagnosing preclinical Cushing's syndrome., Endocr J source

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    • cites [57] Toniato, 2009, Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study., Ann Surg source

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  • May combine two claims.

    Interpretationnone given

    The DST-UFC-ACTH combination criterion is limited to diagnosing subclinical hypercortisolism of adrenal origin because ACTH levels are useless in suspected ACTH-dependent disease.

    “Moreover, the use of the DST-UFC-ACTH combination criterion is limited to the diagnosis of SH of adrenal origin because ACTH levels are useless in patients with suspected ACTH-dependent SH.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Postsurgical hypocortisolism after removal of an adrenal adenoma has been proposed as a gold standard for diagnosing subclinical hypercortisolism.

    “The occurrence of hypocortisolism after the removal of an adrenal adenoma has been proposed as the gold standard for diagnosing SH (58).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Eller-Vainicher, 2010, Post-surgical hypocortisolism after removal of an adrenal incidentaloma: is it predictable by an accurate endocrinological work-up before surgery?, Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Using iodocholesterol scintigraphy as the gold standard, 1-mg dexamethasone suppression testing at the highest cutoff of 5 g/dl had good specificity (83-100%) but low sensitivity (44-58%).

    “Using the highest cutoff [5 g/dl (138 nmol/liter)], 1-mg DST was confirmed to have good specificity (83-100%) but low sensitivity (44 -58%).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Valli, 2001, Biochemical screening for subclinical cortisol-secreting adenomas amongst adrenal incidentalomas., Eur J Endocrinol source

      Not checked in the free run.

    • cites [67] Barzon, 2001, Overnight dexamethasone suppression of cortisol is associated with radiocholesterol uptake patterns in adrenal incidentalomas., Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    The complications used as endpoints-osteoporosis, diabetes mellitus, and hypertension-are not specific for cortisol excess and are highly prevalent in the general population.

    “The limit of this approach is that these complications (i.e.osteoporosis, diabetes mellitus, and hypertension) are not specific for cortisol excess, being highly prevalent in the general population.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Terzolo et al. proposed combinations of several HPA axis parameters and the terms definitive, probable, and possible subclinical hypercortisolism.

    “In a seminal paper, Terzolo et al. (42) proposed the use of different combinations of several different parameters (i.e.high UFC levels, cortisol levels after 1-mg DST, high average daily serum cortisol, altered circadian cortisol rhythm, low basal ACTH levels, or blunted ACTH response to CRH) to screen for SH and the terms “definitive SH,” “probable SH,” and “possible SH”.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Terzolo, 1998, Subclinical Cushing's syndrome in adrenal incidentaloma., Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In studies using arbitrarily defined biochemical criteria as the gold standard, HPA axis parameters showed good specificity (90-98% using 1-mg DST) but generally poor sensitivity (41-86% using ACTH).

    “Overall, in these studies, the different parameters showed a good specificity (90 -98%, using 1-mg DST) but, generally, a poor sensitivity (41-86% using ACTH levels).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [9] Mantero, 2000, A survey on adrenal incidentaloma in Italy., J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [31] Nunes, 2009, Late-night salivary cortisol for diagnosis of overt and subclinical Cushing's syndrome in hospitalized and ambulatory patients., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [32] Masserini, 2009, The limited role of midnight salivary cortisol in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentalomas., Eur J Endocrinol source

      Not checked in the free run.

    • cites [52] Libè, 2002, Long-term follow-up study of patients with adrenal incidentalomas., Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Few studies have evaluated the sensitivity and specificity of HPA axis parameters for diagnosing subclinical hypercortisolism, and such studies are difficult because no gold standard exists.

    “A few studies (summarized in Table 2) evaluated the sensitivity and specificity of the different HPA axis parameters or combination of parameters for diagnosing SH.The difficulty in performing such studies is due to the lack of a clinical, biochemical, or functional parameter that can be used as the gold standard.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Diabetes mellitus and osteoporosis are frequently found in patients with cortisol excess.

    “It is known that diabetes mellitus and osteoporosis are frequently found in patients with cortisol excess.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Altered circadian rhythm and urinary free cortisol levels were not sensitive enough for diagnosing subclinical hypercortisolism.

    “The altered circadian rhythm, evaluated by either MSaC or MSeC, and UFC levels were not found to be sensitive enough for diagnosing SH (31,32).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] Nunes, 2009, Late-night salivary cortisol for diagnosis of overt and subclinical Cushing's syndrome in hospitalized and ambulatory patients., J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [32] Masserini, 2009, The limited role of midnight salivary cortisol in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentalomas., Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Morelli study confirmed the low sensitivity and specificity of 1-mg dexamethasone suppression testing at high or low cutoffs and the low accuracy of reduced ACTH and increased urinary free cortisol as single criteria.

    “This study confirmed the low sensitivity and specificity of 1-mg DST when the high or low cutoff, respectively, is used and the low accuracy of the reduced ACTH and increased UFC level, when used as single criterion (59).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Morelli, 2010, Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects., Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The DST-UFC-ACTH combination criterion seems the best compromise for diagnosing subclinical hypercortisolism because it has been validated on a clinical basis.

    “However, to date, the DST-UFC-ACTH combination criterion seems the best compromise to diagnose SH because it has been validated on a clinical basis (32,59,60).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [32] Masserini, 2009, The limited role of midnight salivary cortisol in the diagnosis of subclinical hypercortisolism in patients with adrenal incidentalomas., Eur J Endocrinol source

      Not checked in the free run.

    • cites [59] Morelli, 2010, Subclinical hypercortisolism: correlation between biochemical diagnostic criteria and clinical aspects., Clin Endocrinol (Oxf) source

      Not checked in the free run.

    • cites [60] Eller-Vainicher, 2010, Accuracy of several parameters of hypothalamic-pituitary-adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma., Eur J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subclinical hypercortisolism may be associated with a high risk of osteoporotic fractures and metabolic consequences.

    “Because in past years several studies have shown that SH may also be associated with a high risk of osteoporotic fractures and metabolic consequences (15)(16)(17)(18)(19)(20)(21)(22)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (15)(16)(17)(18)(19)(20)(21)(22)

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Criteria for defining improvement of possible complications of subclinical hypercortisolism differed among studies and were not always reported.

    “Importantly, the criteria for defining an improvement of the possible complications of SH have been different among the different studies and were not always reported.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The only available prospective randomized study found improvement of hypertension, diabetes, obesity, and dyslipidemia in 66.7%, 62.5%, 50%, and 37.5% of 23 surgically treated subjects, respectively.

    “The only available prospective randomized study found in 23 surgically treated subjects improvement of hypertension, diabetes, obesity, and dyslipidemia in 66.7, 62.5, 50, and 37.5% of cases, respectively (57).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Toniato, 2009, Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study., Ann Surg source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rossi et al. found blood pressure and diabetes improved in 100% and 60% of five surgically treated subclinical hypercortisolism patients, with no changes in seven conservatively treated subjects.

    “Rossi et al. (18) found that blood pressure and diabetes improved in 100 and 60% of five surgically treated SH patients, respectively, whereas no changes were seen in seven conservatively treated SH subjects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Rossi, 2000, Subclinical Cushing's syndrome in patients with adrenal incidentaloma: clinical and biochemical features., J Clin Endocrinol Metab

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a larger study of 200 diabetic patients using a lower 1-mg dexamethasone suppression test cutoff, subclinical hypercortisolism was found in four patients (2.0% prevalence), with three pituitary and one adrenal origin.

    “In a larger study of a similar population using 1-mg DST as a screening test with a lower and, therefore, more sensitive cutoff, SH was ascertained in four (three of pituitary and one of adrenal origin) of 200 diabetic patients studied (2.0% prevalence) (82).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Catargi, 2003, Occult Cushing's syndrome in type-2 diabetes., J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 22 conservatively treated patients in that study, hypertension, diabetes, and dyslipidemia worsened in 80%, 33.3%, and 20% of cases.

    “On the contrary, in 22 conservatively treated patients, hypertension, diabetes, and dyslipidemia worsened in 80, 33.3, and 20% of cases (57).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Toniato, 2009, Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study., Ann Surg source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study of more than 200 osteoporosis patients, subclinical hypercortisolism was present in 4.8% of patients with osteoporosis and 10.8% of patients with osteoporosis and vertebral fractures; adrenal and pituitary origins were 4.1% and 0.7%.

    “A subsequent study from our group on more than 200 patients using the same screening test showed that SH was present in 4.8% of patients with osteoporosis and 10.8% of patients with osteoporosis and vertebral fractures.In this study, SH was of adrenal and pituitary origin in 4.1 and 0.7% of patients, respectively (91).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Chiodini, 2007, Subclinical hypercortisolism among outpatients referred for “osteoporosis.”, Ann Intern Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These studies suggest that subclinical hypercortisolism may be more frequent in patients with diabetes and osteoporosis, thus explaining the increased fracture risk.

    “These studies suggest that SH may be more frequent in patients with diabetes and osteoporosis, thus explaining the increased fracture risk.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A subsequent study of 10 subjects found after recovery from subclinical hypercortisolism improvement of blood pressure, metabolic control of diabetes, and dyslipidemia in 83%, 22%, and 67% of cases; in 12 conservatively treated subjects, hypertension, diabetes, and obesity worsened in 17%, 25%, and 17%.

    “A subsequent study of 10 subjects found after recovery from SH an improvement of blood pressure, metabolic control of diabetes, and dyslipidemia in 83, 22, and 67% of cases, respectively, whereas in 12 conservatively treated subjects, hypertension, diabetes, and obesity worsened in 17, 25, and 17% of cases, respectively (96).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Tsuiki, 2008, Cardiovascular risks and their long-term clinical outcome in patients with subclinical Cushing's syndrome., Endocr J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a controlled study of 294 diabetic inpatients, the prevalence of subclinical hypercortisolism was 10.8%, with pituitary, adrenal, and undefined/ectopic origins accounting for 1.4%, 7.2%, and 2.2%, respectively.

    “These data were confirmed in a similar controlled study on 294 diabetic inpatients in whom a 10.8% prevalence of SH was found, with pituitary, adrenal, and undefined/ectopic origin accounting for 1.4, 7.2, and 2.2%, respectively (83).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Chiodini, 2005, Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients., Eur J Endocrinol source

      Not checked in the free run.

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

    Interpretationreasoning

    It is possible that some patients classified as not having subclinical hypercortisolism had a mild degree of cortisol hypersecretion, suggesting that the diagnosis of SH was not sensitive enough.

    “It is possible to hypothesize that some patients classified as not having SH had, in fact, a mild degree of cortisol hypersecretion, suggesting that the diagnosis of SH had not been sensitive enough.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The study suffers from the limits of a small sample and a retrospective, nonrandomized design.

    “This study clearly suffers from the limits of the small sample and of its retrospective and nonrandomized design.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Reducing the screening test cutoff and increasing sensitivity made the adrenal cause of subclinical hypercortisolism more frequent than the pituitary cause.

    “Moreover, in reducing the cutoff of the screening test and therefore increasing its sensitivity, the adrenal cause of SH became more frequent than the pituitary cause.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In 90 obese diabetic patients with poor metabolic control, Leibowitz et al. found a 3.3% prevalence of subclinical hypercortisolism, with one adrenal adenoma and two pituitary adenomas, using a 1-mg dexamethasone suppression test cutoff above 5.1 g/dl.

    “In a cross-sectional study on 90 obese diabetic patients with poor metabolic control, Leibowitz et al. (63) found a 3.3% prevalence of SH due to an adrenal adenoma in one patient and a pituitary adenoma in two patients using 1-mg DST above 5.1 g/dl (140 nmol/liter) as a screening test.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Leibowitz, 1996, Pre-clinical Cushing's syndrome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients., Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that study, overall prevalence of subclinical hypercortisolism could be estimated at almost 5.5%, with pituitary and adrenal origin at 1.5% and 4.0%, respectively.

    “Overall in this study, the prevalence of SH could be estimated to be almost 5.5%, with a pituitary and adrenal origin of 1.5 and 4.0%, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Catargi, 2003, Occult Cushing's syndrome in type-2 diabetes., J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Somatostatin analogs have been used to control food-dependent cortisol hypersecretion due to aberrant glucose-dependent insulinotropic peptide receptors; propranolol has been proposed in adrenal hypercortisolism and leuprolide acetate in LH-dependent Cushing's syndrome.

    “Indeed, somatostatin analogs have been used to control food-dependent cortisol hypersecretion due to the presence of aberrant glucose-dependent insulinotropic peptide receptors (100, 101); propranolol has been proposed in patients with adrenal hypercortisolism (102) and leuprolide acetate in LH-dependent Cushing's syndrome (103).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [100] Libé, 2010, Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing's syndrome., Eur J Endocrinol source

      Not checked in the free run.

    • cites [101] de Herder, 1996, Food-dependent Cushing's syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells., J Clin Endocrinol Metab

      Not checked in the free run.

    • cites [102] Lacroix, 1997, Propranolol therapy for ectopic β-adrenergic receptors in adrenal Cushing's syndrome., N Engl J Med source

      Not checked in the free run.

    • cites [103] Lacroix, 1999, Leuprolide acetate therapy in luteinizing hormone-dependent Cushing's syndrome., N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The small sample size of available studies and the lack of a large prospective randomized trial prevent firm conclusions about the advantage of surgery.

    “However, to date, the small sample size of the available studies and the lack of a large prospective randomized trial could not allow us to draw any firm conclusion about this point.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Difficulties in defining a follow-up protocol relate to the variability of cortisol secretion, because even a 2-year follow-up may be too short to ascertain subclinical hypercortisolism.

    “The difficulties in defining a protocol are related to the variability of cortisol secretion in these patients (3,22) because even a 2-yr follow-up may be too short to ascertain the presence of SH (79).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Grumbach, 2003, Management of the clinically inapparent adrenal masses (“incidentaloma”)., Ann Intern Med source

      Not checked in the free run.

    • cites [22] Terzolo, 2005, Midnight serum cortisol as a marker of increased cardiovascular risk in patients with a clinically inapparent adrenal adenoma., Eur J Endocrinol source

      Not checked in the free run.

    • cites [79] Donadio, 2009, Role of adrenal gland scintigraphy in patients with incidentally discovered adrenal mass and subclinical hypercortisolism., J Endocrinol Invest source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Uncertainties about diagnosis and surgery bring into question the real clinical importance of subclinical hypercortisolism and the need for surgical treatment instead of optimized medical therapy.

    “These uncertainties, in turn, bring into question the real clinical importance of SH itself and the need of a surgical treatment in these patients instead of the optimization of medical therapy (61).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Chiodini, 2010, Beneficial metabolic effects of prompt surgical treatment in patients with an adrenal incidentaloma causing biochemical hypercortisolism., J Clin Endocrinol Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Optimization of medical therapy is not completely free of adverse events, and adrenal surgery is becoming increasingly safer by endoscopic procedures.

    “Moreover, it must be considered that the optimization of the medical therapy is not completely free of adverse events and that adrenal surgery is becoming increasingly safer by endoscopic procedures.”
    Quote in the paperNot a substantial claim
50 of 50

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?

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.

  • The osteoporosis studies are said to use the same DST dose, but Table 3 lists different doses

    Minor

    The text says the subsequent study used the same screening test as the 3-mg DST study. Table 3 lists a 1-mg DST for the subsequent Chiodini study.

  • Study 97 is cited as showing both a positive surgical effect and no difference

    Minor

    The paper includes study 97 among studies showing a clear positive effect of surgery, but elsewhere says that study found no difference between surgical and conservative treatment.

2 of 2

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11 of the 122 references couldn’t be matched to a known paper.

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Related

Authors
Chiodini, I.
Affiliations
University of Milan (IT)
Corresponding author
Chiodini, Iacopo
ORCID
Chiodini, Iacopo
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2011-05-01
Volume
96
Issue
5
Pages
1223-1236
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2010-2722
OpenAlex
W2068496880
Semantic Scholar
b3e38e55547be819a98f080fc5eb59dd9144701d
Cited by
279
References
122
Citations by year
2026: 6 · 2025: 5 · 2024: 5 · 2023: 11 · 2022: 10 · 2021: 23 · 2020: 22 · 2019: 21 · 2018: 27 · 2017: 21 · 2016: 19 · 2015: 28 · 2014: 19 · 2013: 24 · 2012: 27
FWCI
4.63
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
Keywords
subclinical hypercortisolism, adrenal incidentaloma, cortisol excess, hypertension, diabetes mellitus, osteoporosis, obesity, adrenal surgery, metabolic recovery
MeSH terms
Adrenal Gland Neoplasms, Adult, Child, Cushing Syndrome, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Treatment Outcome

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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.

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