Diagnosis of Cushing's Syndrome
- 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.
Who Should Be Treated
- Patients with unusual features for age (e.g., osteoporosis, hypertension) (Table 1)
- Patients with multiple and progressive features, particularly those who are more predictive of Cushing's syndrome (Table 1).
- Children with decreasing height percentile and increasing weight.
- Patients with adrenal incidentaloma compatible with adenoma.
- 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)
- 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).
Cyclic Cushing's syndrome:
Table 1. Overlapping Conditions and Clinical Features of Cushing’s Syndromea
|Cushing's syndrome features in the general population that are common and/or less discriminatory|
|Features that best discriminate Cushing's syndrome; most do not have a high sensitivity|
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
|Some clinical features of Cushing's syndrome may be present|
|Unlikely to have any clinical features of Cushing's syndrome|
Table 3. Selected Drugs That May Interfere with the Evaluation of Tests for the Diagnosis of Cushing's Syndromea
|Drugs that accelerate dexamethasone metabolism by induction of CYP 3A4|
|Drugs that impair dexamethasone metabolism by inhibition of CYP 3A4|
|Drugs that increase CBG and may falsely elevate cortisol results|
|Drugs that increase UFC results|
Data regarding CYP3A4 obtained from http://medicine.iupui.edu/flockhart/table.htm.
Figure 1. Algorithm for Testing Patients Suspected of Having Cushing's Syndrome (CS)
- 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
- GC: Glucocorticoid(s)
- GH: Growth Hormone
- GI: Gastrointestinal
- 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
- fT4: Free Thyroxine
- h: Hour(s)
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