Cushing’s Syndrome
NICE CKS Cushing’s syndrome. Last revised: Dec 2024.
NICE BNF Treatment summaries Cushing’s syndrome.
Background Information
Definition
Cushing’s syndrome is a multi-system condition that occurs as a result of chronic glucocorticoid excess (exogenous or endogenous).
Note that Cushing’s syndrome is NOT the same as Cushing’s disease:
- Cushing’s syndrome: the clinical state caused by chronic exposure to excess glucocorticoids, from any cause
- Cushing’s disease: a specific cause of Cushing’s syndrome — due to an ACTH-secreting pituitary adenoma
Aetiology
Exogenous cause (most common overall): secondary to systemic glucocorticoid therapy
Endogenous causes:
- ACTH-dependent causes
- Cushing’s disease (ACTH-secreting pituitary adenoma) – most common overall endogenous cause
- Ectopic ACTH-secreting tumours – mostly lung cancer (small cell), or other neuroendocrine tumours
- ACTH-independent causes
- Adrenal adenoma – most common ACTH-independent cause
- Adrenal carcinoma
- Rare causes
- Primary bilateral macronodular adrenal hyperplasia (usually in adults).
- Primary pigmented nodular adrenal disease (isolated or as part of Carney complex, often in young adults).
- McCune-Albright syndrome
The 3 bolded causes above (Cushing’s disease, ectopic tumour, and adrenal adenoma) are the most frequently examined causes. Students are often expected to interpret test results to reach the most likely diagnosis. It is important to appreciate which is ACTH-dependent and which is ACTH-independent in order to answer these questions correctly.
Note that Cushing’s syndrome is NOT the same as Cushing’s disease:
- Cushing’s syndrome: the clinical state caused by chronic exposure to excess glucocorticoids, from any cause
- Cushing’s disease: a specific cause of Cushing’s syndrome — due to an ACTH-secreting pituitary adenoma
Clinical Features
No single sign or symptom is pathognomonic for Cushing’s syndrome, as the presentation is very non-specific and overlaps with other conditions.
Typical clinical features by the affected body system:
| Body system | Specific features |
|---|---|
| Skin |
|
| MSK |
|
| Endocrine |
|
| Cardiovascular |
|
| Reproductive | Male
Female
|
| Neuropsychiatric |
|
| Eyes |
|
Diagnosis
Non-Diagnostic Tests
Key biochemical changes:
- Hypernatraemia
- Hypokalaemia
- Metabolic alkalosis
- Metabolic panel
- Hyperglycaemia
- Hyperlipidaemia
Endocrinology is one of the few topics where physiology is truly useful… Instead of memorising the above-mentioned biochemical changes, one can reason them out.
- Cortisol usually raises blood glucose and lipid levels → cortisol excess would result in hyperglycaemia and hyperlipidaemia
- In Cushing’s disease, the excess cortisol can bind and activate mineralocorticoid receptors (this is normally regulated by 11β-HSD, which converts cortisol into cortisone to prevent cortisol from activating mineralocorticoid receptors) (however, in Cushing’s disease, 11β-HSD becomes saturated)
- This results in excess mineralocorticoid receptor activity (aldosterone usually retains sodium, excretes potassium, and excretes hydrogen) → hypernatraemia + hypokalaemia + metabolic alkalosis
Endocrine Studies
As mentioned above, the 3 main causes of endogenous Cushing’s syndrome that students are expected to be able to diagnose based on endocrine studies are:
- Cushing’s disease (ACTH-secreting pituitary adenoma)
- Ectopic ACTH causes (most common small cell lung cancer)
- Adrenal cause (most common adrenal adenoma)
Note that exogenous Cushing’s syndrome (i.e. secondary to systemic glucocorticoid) is diagnosed primarily clinically, based on characteristic clinical features + history of steroid use. [Ref]
The following endocrine testing is NOT indicated. [Ref]
Step 1 – Screening Test (Confirming Cushing’s Syndrome)
NICE CKS states that if exogenous Cushing’s syndrome is suspected, investigations are not routinely required.
NICE CKS recommends any of the following as 1st line tests to confirm hypercortisolism:
| Test | Interpretation |
|---|---|
| Overnight (low-dose) dexamethasone suppression test | Cortisol NOT suppressed (higher than reference range)
*In those without Cushing’s syndrome, the dexamethasone would suppress cortisol secretion, and its level would be undetectable |
| 24-hour urinary free cortisol | ↑ |
| Late-night salivary cortisol | ↑ |
For exam purposes, overnight dexamethasone suppression test is often considered the ‘gold standard’ screening test for diagnosing Cushing’s syndrome. However, it is more important to know how to interpret its results.
Step 2 – Localisation Tests (Identifying Cause of Cushing’s syndrome)
To localise the cause of Cushing’s syndrome, measure the morning ACTH level
- ↑ ACTH → ACTH-dependent (i.e. pituitary or ectopic cause likely)
- ↓ ACTH → ACTH-independent (i.e. adrenal cause likely)
Depending on the ACTH levels, there are 2 work-up pathways.
↑ ACTH Pathway (Pituitary or Ectopic Cause Likely)
First, perform dynamic endocrine tests to differentiate pituitary cause (i.e. Cushing’s disease) from ectopic causes:
| Test | Method | Key Interpretation |
|---|---|---|
| High-dose dexamethasone suppression test | Give 8mg dexamethasone overnight or 2mg 6-hourly for 48 hr, then measure cortisol level | Cortisol level suppressed (and ACTH decreases) → suggests Cushing’s disease
No suppression of cortisol (and ACTH) → suggests ectopic ACTH source |
| CRH stimulation test | Give IV CRH, then measure ACTH & cortisol levels | ↑ Cortisol and/or ACTH → suggests Cushing’s disease
No / minimal rise → ectopic ACTH cause |
Second, perform imaging studies (depending on what is suspected based on dynamic endocrine tests):
- Likely Cushing’s disease → pituitary MRI
- Likely ectopic cause →
- 1st line: neck to pelvis CT or CT TAP
- 2nd line: PET scan
Gold standard test: bilateral inferior petrosal sinus sampling
- Confirm pituitary vs ectopic ACTH source when imaging is equivocal
- ↑ ACTH suggests Cushing’s disease
- Normal / ↓ ACTH suggests other causes (ectopic or adrenal cause)
↓ ACTH Pathway (Adrenal Cause Likely)
Perform CT / MRI of the adrenal glands to assess for adrenal adenoma or carcinoma
Adrenal venous sampling can be used to differentiate between unilateral from bilateral cortisol production (e.g. bilateral adrenal hyperplasia vs unilateral adrenal adenoma), which is important for guiding management.
Management
Exogenous Cushing’s Syndrome
If it’s due to corticosteroid use:
- Gradual reduction and withdrawal of corticosteroid treatment
- Consider steroid-sparing agents
Endogenous Cushing’s Syndrome
Management depends on the underlying cause:
| Cause | Treatment |
|---|---|
| Cushing’s disease (ACTH-secreting pituitary tumour) |
|
| Adrenal adenoma carcinoma |
|
| Ectopic ACTH-secreting tumours |
|
Medical therapy for Cushing’s syndrome (not for Cushing’s disease):
- Metyrapone (inhibits 11β-hydroxylase → reduce cortisol synthesis)
- Ketoconazole (inhibits multiple enzymes involved in steroid synthesis at high doses)
Summary Table
Endocrine Testing Summary Table
This table provides an overview of how frequently examined tests and various differential diagnoses of Cushing’s syndrome correlate. Please use this table in conjunction with the information above.
| Parameter / Test | No Cushing’s syndrome | Cushing’s disease (ACTH-secreting pituitary adenoma) | Ectopic ACTH source (e.g. small cell lung cancer) | Adrenal adenoma / carcinoma |
|---|---|---|---|---|
| Cortisol level | – | ↑ | ↑ | ↑ |
| ACTH level | – | ↑ | ↑ | ↓ |
| Low-dose dexamethasone suppression test | ↓ Cortisol | No cortisol suppression | No cortisol suppression | No cortisol suppression |
| High-dose dexamethasone suppression test | ↓ Cortisol | ↓ Cortisol (↓ ACTH) | No cortisol (and ACTH) suppression | No cortisol suppression (ACTH remains low) |
| CRH stimulation test | ↑ ACTH ↑ Cortisol |
↑ ACTH ↑ Cortisol |
No changes to ACTH and cortisol | No changes to ACTH and cortisol |