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Diagnosis of Cushing's Syndrome
Endocrine Society
Publication Date: November 14, 2018
Key Points
The most common cause of Cushing's syndrome is iatrogenic from medically prescribed corticosteroids.
Excess cortisol production may be caused by either excess adrenocorticotropic hormone (ACTH) secretion (from a pituitary or other ectopic tumor) or independent adrenal overproduction of cortisol.
The diagnosis can be challenging in mild cases.
Endocrine Society (ES) recommends initial use of one test with high diagnostic accuracy (urine free cortisol [UFC], late night salivary cortisol, 1-mg overnight or 2-mg 48-h dexamethasone suppression test).
Testing for Cushing's syndrome in certain high-risk populations has shown an unexpectedly high incidence of unrecognized Cushing's syndrome as compared with the general population. Although there are limited data on the prevalence of the syndrome in these disorders, the diagnosis should be considered.
Often patients have a number of features that are caused by cortisol excess but that are also common in the general population such as obesity, depression, diabetes, hypertension, or menstrual irregularity.
As a result, there is an overlap in the clinical presentation of individuals with and without the disorder. The distinction between these groups is difficult, and there is no one correct diagnostic strategy.
There is a wide spectrum of clinical manifestations at any given level of hypercortisolism. Because Cushing's syndrome tends to progress, accumulation of new features increases the probability that the syndrome is present.
Caregivers are encouraged to consider Cushing's syndrome as a secondary cause of these conditions, particularly if additional features of the disorder are present. If Cushing's syndrome is not considered, the diagnosis is all too often delayed.
Cushing's syndrome tends to progress and severe hypercortisolism is probably associated with a worse outcome, it is likely that early recognition and treatment of mild disease would reduce the risk of residual morbidity.
Diagnosis
Who Should Be Treated
ES recommends obtaining a thorough drug history to exclude excessive exogenous glucocorticoid exposure leading to iatrogenic Cushing's syndrome before conducting biochemical testing. ( 1-H )
ES recommends testing for Cushing's syndrome in the following groups:
Patients with unusual features for age (e.g., osteoporosis, hypertension) (Table 1)
( 1-L )
Patients with multiple and progressive features, particularly those who are more predictive of Cushing's syndrome (Table 1).
( 1-L )
Children with decreasing height percentile and increasing weight.
( 1-VL )
Patients with adrenal incidentaloma compatible with adenoma.
( 1-VL )
ES recommends against widespread testing for Cushing's syndrome in any other patient group. ( 1-VL )
Initial Testing
For the initial testing for Cushing's syndrome, ES recommends one of the following tests based on its suitability for a given patient (Fig. 1): ( 1-VL )
UFC (at least two measurements)
Late-night salivary cortisol (two measurements)
1-mg overnight dexamethasone suppression test (DST)
Longer low-dose DST (2 mg/d for 48 h)
ES recommends against the use of the following to test for Cushing's syndrome: ( 1-VL )
Random serum cortisol or plasma ACTH levels
Urinary 17-ketosteroids
Insulin tolerance test
Loperamide test
Tests designed to determine the cause of Cushing's syndrome (e.g., pituitary and adrenal imaging, 8 mg DST).
In individuals with normal test results in whom the pretest probability is high (patients with clinical features suggestive of Cushing's syndrome and adrenal incidentaloma or suspected cyclic hypercortisolism), ES recommends further evaluation by an endocrinologist to confirm or exclude the diagnosis. ( 1-VL )
In other individuals with normal test results (in whom Cushing's syndrome is very unlikely), ES suggests reevaluation in 6 months if signs or symptoms progress. ( 2-VL )
In individuals with at least one abnormal test result (for whom the results could be falsely positive or indicate Cushing's syndrome), ES recommends further evaluation by an endocrinologist to confirm or exclude the diagnosis. ( 1-VL )
Subsequent Evaluation
For the subsequent evaluation of abnormal initial test results, ES recommends performing another recommended test (Fig. 1). ( 1-VL )
ES suggests the additional use of the dexamethasone-suppressed corticotropin-releasing hormone (Dex-CRH) test or the midnight serum cortisol test in specific situations (Fig. 1). ( 1-VL )
ES suggests against the use of the desmopressin test, except in research studies, until additional data validate its utility. ( 2-VL )
ES recommends against any further testing for Cushing's syndrome in individuals with concordantly negative results on two different tests (except in patients suspected of having the very rare case of cyclical disease). ( 1-VL )
ES recommends tests to establish the cause of Cushing's syndrome in patients with concordantly positive results from two different tests, provided there is no concern regarding possible non-Cushing's hypercortisolism (Table 2). ( 1-L )
ES suggests further evaluation and follow-up for the few patients with concordantly negative results who are suspected of having cyclical disease and also for patients with discordant results, especially if the pretest probability of Cushing's syndrome is high. ( 2-VL )
Special Populations/Considerations
Pregnancy:
ES recommends the use of UFC and against the use of dexamethasone testing in the initial evaluation of pregnant women. ( 1-M )
Epilepsy:
ES recommends against the use of dexamethasone testing in patients receiving antiepileptic drugs known to enhance dexamethasone clearance and recommends instead measurements of nonsuppressed cortisol in blood, saliva, or urine. ( 1-M )
Renal failure:
ES suggests using the 1-mg overnight DST rather than UFC for initial testing for Cushing's syndrome in patients with severe renal failure. ( 2-VL )
Cyclic Cushing's syndrome:
ES suggests use of UFC or midnight salivary cortisol tests rather than DSTs in patients suspected of having cyclic Cushing's syndrome. ( 2-VL )
Adrenal incidentaloma:
ES suggests use of the 1-mg DST or late-night cortisol test, rather than UFC, in patients suspected of having mild Cushing's syndrome. ( 2-L )
Table 1. Overlapping Conditions and Clinical Features of Cushing’s Syndromea
Symptoms
Signs
Overlapping conditions
Cushing's syndrome features in the general population that are common and/or less discriminatory
Depression
Fatigue
Weight gain
Back pain
Changes in appetite
Decreased concentration
Decreased libido
Impaired memory (especially short term)
Insomnia
Irritability
Menstrual abnormalities
Dorsocervical fat pad ("buffalo hump")
Facial fullness
Obesity
Supraclavicular fullness
Thin skinb
Peripheral edema
Acne
Hirsutism or female balding
Poor skin healing
Hypertensionb
Incidental adrenal mass
Vertebral osteoporosisb
Polycystic ovary syndrome
Type 2 diabetesb
Hypokalemia
Kidney stones
Unusual infections
In children, slow growth
In children, abnormal genital virilization
In children, short stature
In children, pseudoprecocious puberty or delayed puberty
Features that best discriminate Cushing's syndrome; most do not have a high sensitivity
Easy bruising
Facial plethora
Proximal myopathy (or proximal muscle weakness)
Striae (especially if reddish purple and > 1 cm wide)
In children, weight gain with decreasing growth velocity
a Features are listed in random order.
b Cushing's syndrome is more likely if onset of the feature is at a younger age.
Table 2. Conditions Associated with Hypercortisolism in the Absence of Cushing's Syndromea
Conditions
Some clinical features of Cushing's syndrome may be present
Pregnancy
Depression and other psychiatric conditions
Alcohol dependence
Glucocorticoid resistance
Morbid obesity
Poorly controlled diabetes mellitus
Unlikely to have any clinical features of Cushing's syndrome
Physical stress (hospitalization, surgery, pain)
Malnutrition, anorexia nervosa
Intense chronic exercise
Hypothalamic amenorrhea
CBG excess (increased serum but not urine cortisol)
a Whereas Cushing's syndrome is unlikely in these conditions, it may rarely be present. If there is a high clinical index of suspicion, the patient should undergo testing, particularly those within the first group.
Cushing's Syndrome
Table 3. Selected Drugs That May Interfere with the Evaluation of Tests for the Diagnosis of Cushing's Syndromea
Drugs
Drugs that accelerate dexamethasone metabolism by induction of CYP 3A4
Figure 1. Algorithm for Testing Patients Suspected of Having Cushing's Syndrome (CS)
Grading System
Quality of Evidence
Description of Evidence
High Quality
Moderate Quality
Low Quality
Very Low Quality
Well-performed RCTs
Very strong evidence from unbiased observational studies
RCTs with some limitations
Strong evidence from unbiased observational studies
RCTs with serious flaws
Some evidence from observational studies
Unsystematic clinical observations
Very indirect evidence from observational studies
Strength of Recommendation
Strong (1): "ES recommends..."
Benefits clearly outweigh harms and burdens or vice versa
1-H
1-M
1-L
1-VL
Conditional (2): "ES suggests..."
Benefits closely balanced with harms and burdens
2-H
2-M
2-L
2-VL
Ungraded Good Practice Statement
UGPS
Abbreviations
ACC
adrenocortical carcinoma
ACTH
adrenocorticotropic hormone
ADX
adrenalectomy
BMAH
bilateral macronodular adrenal hyperplasia
BMD
bone mineral density
CBG
corticosteroid binding globulin
CD
Cushing's disease
CNS
central nervous system
CS
Cushing's syndrome
DDI
drug-drug interactions
EAS
ectopic ACTH secretion
ES
Endocrine Society
fT4
free thyroxine
GC
glucocorticoid(s)
GH
growth hormone
GI
gastrointestinal
h
hour(s)
HPA
hypothalamic-pituitary-adrenal
HRQOL
health-related quality of life
HT
hypertension
HU
Hounsfield units
ICU
intensive care unit
IPSS
inferior petrosal sinus sampling
LFTs
liver function tests
QOL
quality of life
QTc
corrected QT interval
RT
radiation therapy
SST
somatostatin receptor
T4
thyroid hormone
TSS
transsphenoidal selective adenomectomy
UFC
urine free cortisol
WBC
white blood cell count
Source Citation
Lynnette K. Nieman, Beverly M. K. Biller, James W. Findling, John Newell-Price, Martin O. Savage, Paul M. Stewart, Victor M. Montori, The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 93, Issue 5, 1 May 2008, Pages 1526–1540, https://doi.org/10.1210/jc.2008-0125
Disclaimer
This resource is for informational purposes only, intended as a quick-reference tool based on the cited source guideline(s), and should not be used as a substitute for the independent professional judgment of healthcare providers. Practice guidelines are unable to account for every individual variation among patients or take the place of clinician judgment, and the ultimate decision concerning the propriety of any course of conduct must be made by healthcare providers after consideration of each individual patient situation. Guideline Central does not endorse any specific guideline(s) or guideline recommendations and has not independently verified the accuracy hereof. Any use of this resource or any other Guideline Central resources is strictly voluntary.
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