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

Alwani, R A; Jongbloed, L W Schmit; Jong, Frank H. de; Lely, Aart-Jan van der; Herder, Wouter W. de; Feelders, Richard A

doi:10.1530/eje-13-0702

Cited by 76 publications

(71 citation statements)

References 48 publications

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“…Alwani et al (83) recently found that a higher cut-off for the serum cortisol response to CRH after dexamethasone suppression was necessary to improve the specificity (100%) albeit with a slightly lower sensitivity (94%) compared to prior studies (Table 2). It was also found that increased late-night salivary cortisol and the evening-to-morning cortisol ratio aided in the diagnostic approach.…”

Section: Dexamethasone-crh Testmentioning

confidence: 85%

“…As a result, desmopressin acetate administration can stimulate ACTH secretion in patients with Cushing's disease (83,84,85,86). On the other hand, the response to DDAVP is typically small or absent in healthy subjects and those with physiological hypercortisolism (83,84,85,86). The test is usually performed in the morning with plasma ACTH and serum cortisol levels measured before and 15-, 30-and 60-min after DDAVP (10 µg intravenously) administration.…”

Section: Ddavp Stimulationmentioning

confidence: 99%

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DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome)

Findling

Raff

2017

European Journal of Endocrinology

107

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Endogenous hypercortisolism (Cushing's syndrome) usually implies the presence of a pathologic condition caused by either an ACTH-secreting neoplasm or autonomous cortisol secretion from a benign or malignant adrenal neoplasm. However, sustained or intermittent hypercortisolism may also accompany many medical disorders that stimulate physiologic/nonneoplastic activation of the HPA axis (formerly known as pseudo-Cushing's syndrome); these two entities may share indistinguishable clinical and biochemical features. A thorough history and physical examination is often the best (and sometimes only) way to exclude pathologic/neoplastic hypercortisolism. The presence of alcoholism, renal failure, poorly controlled diabetes and severe neuropsychiatric disorders should always raise suspicion that the presence of hypercortisolism may be related to physiologic/non-neoplastic Cushing's syndrome. As late-night salivary cortisol and low-dose dexamethasone suppression have good sensitivity and negative predictive value, normal studies exclude Cushing's syndrome of any form. However, these tests have imperfect specificity and additional testing over time with clinical follow-up is often needed. When there is persistent diagnostic uncertainty, secondary tests such as the DDAVP stimulation test and the dexamethasone-CRH test may provide evidence for the presence or absence of an ACTH-secreting tumor. This review will define and characterize the numerous causes of physiologic/non-neoplastic hypercortisolism and provide a rational clinical and biochemical approach to distinguish it from pathologic/neoplastic hypercortisolism (true Cushing's syndrome).

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Section: Dexamethasone-crh Testmentioning

confidence: 85%

Section: Ddavp Stimulationmentioning

confidence: 99%

DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome)

Findling

Raff

2017

European Journal of Endocrinology

107

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“…Phenotypic features of CS may occur from overactivity (physiological) of the hypothalamic–pituitary–adrenal (HPA) axis in conditions such as chronic alcoholism, psychiatric disorders, severe obesity, poorly controlled diabetes and states of extreme physical stress. This condition is referred to as pseudo-Cushing's syndrome (PCS) 8. Subclinical Cushing's syndrome (SCS), seen in some cases of adrenal incidentalomas, is a result of alteration in the HPA axis without overt signs or symptoms of hypercortisolism.…”

Section: Clinical Suspicion Of Csmentioning

confidence: 99%

“…A variety of drugs and clinical conditions can affect the bioavailability of dexamethasone, potentially interfering with ODST results 3 8 13 14 21. Several drugs (eg, anticonvulsants and alcohol) induce hepatic CYP 3A4 enzyme and accelerate dexamethasone metabolism causing a false positive result.…”

Section: Initial Screening Tests: Evidences Sensitivity Specificitymentioning

confidence: 99%

“…This test may be more specific in excluding conditions that may be associated with PCS 8 13. Dexamethasone is given in doses of 0.5 mg at six-hourly intervals for 48 hours starting at 09:00 on day 1, and serum cortisol measurement is performed at 09:00 on day 3, 6 hours after the last dexamethasone dose.…”

Section: Initial Screening Tests: Evidences Sensitivity Specificitymentioning

confidence: 99%

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Cushing's syndrome: a practical approach to diagnosis and differential diagnoses

et al. 2017

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Diagnosis of Cushing's syndrome (CS) and identification of the aetiology of hypercortisolism can be challenging. The Endocrine Society clinical practice guidelines recommends one of the four tests for initial screening of CS, namely, urinary-free cortisol, late night salivary cortisol, overnight dexamethasone suppression test or a longer low-dose dexamethasone suppression test, for 48 hours. Confirmation and localisation of CS requires additional biochemical and radiological tests. Radiological evaluation involves different imaging modalities including MRI with or without different radio-nuclear imaging techniques. Invasive testing such as bilateral inferior petrosal sinus sampling may be necessary in some patients for accurate localisation of the cause for hypercortisolism. This best practice review discusses a practical approach for the diagnostic evaluation of CS with a brief discussion on differential diagnoses, and cyclical CS, to enhance the skills of clinicians and laboratory personnel.

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Glycogen storage disease presenting as Cushing syndrome

et al. 2019

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Impaired growth is common in patients with glycogen storage disease (GSD), who also may have “cherubic” facies similar to the “moon” facies of Cushing syndrome (CS). An infant presented with moon facies, growth failure, and obesity. Laboratory evaluation of the hypothalamic‐pituitary‐adrenal (HPA) axis was consistent with CS. He was subsequently found to have liver disease, hypoglycemia, and a pathogenic variant in PHKA2 , leading to the diagnosis of GSD type IXa. The cushingoid appearance, poor linear growth and hypercortisolemia improved after treatment to prevent recurrent hypoglycemia. We suspect this child's HPA axis activation was “appropriate” and caused by chronic hypoglycemic stress, leading to increased glucocorticoid secretion that may have contributed to his poor growth and excessive weight gain. This is in contrast to typical CS, which is due to excessive adrenocorticotropic hormone (ACTH) or cortisol secretion from neoplastic pituitary or adrenal glands, ectopic secretion of ACTH or corticotropin‐releasing hormone (CRH), or exogenous administration of corticosteroid or ACTH. Pseudo‐CS is a third cause of excessive glucocorticoid secretion, has no HPA axis pathology, is most often associated with underlying psychiatric disorders or obesity in children and, by itself, is thought to be benign. We speculate that some diseases, including chronic hypoglycemic disorders such as the GSDs, may have biochemical features and pathologic consequences of CS. We propose that excessive glucocorticoid secretion due to chronic stress be termed “stress‐induced Cushing (SIC) syndrome” to distinguish it from the other causes of CS and pseudo‐CS, and that evaluation of children with chronic hypoglycemia and poor statural growth include evaluation for CS.

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

Cited by 76 publications

References 48 publications

DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome)

DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome)

Cushing's syndrome: a practical approach to diagnosis and differential diagnoses

Glycogen storage disease presenting as Cushing syndrome

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