Primary Causes:
- Pituitary Adenoma (Cushing Disease) - Most common endogenous cause
- Adrenal Adenoma/Carcinoma - Autonomous cortisol secretion
- Ectopic ACTH Production - Commonly from small cell lung cancer or other neuroendocrine tumours
Secondary Causes:
- Iatrogenic Cushing Syndrome - Most common cause overall, due to chronic corticosteroid use

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History and Examination Features

Psych: Mood changes, depression, psychosis
Neuro: Headaches, fatigue
Derma/Haema:
- Thin skin, easy bruising, purple striae
- Skin atrophy (subcutaneous fat loss), poor wound healing
- Immunosuppression (e.g., recurrent infections)
Ophtha: Blurred vision, glaucoma (via increased intraocular pressure)
Endo:
- Hypertension, peripheral oedema
- Hypokalaemia (mineralocorticoid effects), hyperglycaemia
GI:
- Central obesity, "moon face," "buffalo hump"
- Gastritis or peptic ulcers
MSK:
- Proximal myopathy, osteoporosis, fractures

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Pertinent Long-term Steroid Side Effects

Osteoporosis, fractures
Hyperglycaemia, insulin resistance
Hypertension
Immunosuppression
Cataracts
Muscle weakness

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Notes:

Testing for Cushing Syndrome:
- Initial: 1 mg overnight dexamethasone suppression test, 24-hour urinary cortisol, or late-night salivary cortisol
- Beware of false positives (e.g., estrogen-containing drugs, rifampicin)
Treatment:
- Surgical resection of the pituitary or adrenal tumour
- Pharmacological cortisol blockade preoperatively or if surgery fails
Technically, corticosteroid = glucocorticoid + mineralocorticoid but is often used as synonym for glucocorticoid
Cortisol is most important type of glucocorticoid

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Investigations:

If low suspicion of Cushing’s, select any 1 test; if high suspicion, use 2 tests
- Late-night salivary cortisol
- 24h urinary free cortisol excretion (requires ≥2x normal levels for diagnosis)
- Overnight 1 mg dexamethasone suppression test (first choice if performing a single test)

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Overnight 1 mg Dexamethasone Suppression Test:

Measures morning cortisol following dexamethasone administration the night before
Spare blood tube for ACTH levels if elevated cortisol is detected
Normal or low cortisol: Excludes Cushing’s
High cortisol: Inappropriate suppression → Indicates Cushing’s syndrome

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8 mg Dexamethasone Suppression Test (to find cause):

Differentiates pituitary, adrenal, or ectopic sources:
- Pituitary (Cushing’s disease): Low ACTH and cortisol suppressed with 8 mg (but not 1 mg)
- Adrenal: Low ACTH but high cortisol (autonomous adrenal cortisol secretion)
- Ectopic ACTH production: High ACTH and high cortisol (failure to suppress)

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Additional Notes:

If ACTH-independent Cushing’s syndrome is suspected (e.g., adrenal adenoma), perform an adrenal CT or MRI
Use a high-dose dexamethasone suppression test to distinguish between pituitary and ectopic ACTH sources

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Key Considerations:

Pseudo-Cushing’s syndrome (e.g., obesity, alcoholism, depression) may mimic biochemical findings; repeat tests in equivocal cases
Consider measuring midnight plasma cortisol if salivary cortisol is unavailable

Cushing's syndrome

Aetiology:

Primary Causes:

Pituitary Adenoma (Cushing's Disease): ACTH-secreting pituitary adenoma, the most common endogenous cause, is approximately five times more frequent than adrenal causes.
Adrenal Adenoma: Produces cortisol independently.
Ectopic ACTH Production: Tumours, such as small cell lung cancer, secrete ACTH, leading to cortisol overproduction.
Bilateral Adrenal Hyperplasia (BAH): Rare, can also contribute to cortisol overproduction.

Secondary Cause:

Iatrogenic Cushing's Syndrome: Due to long-term oral corticosteroid use, which is the most common cause overall.

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Symptoms:

General Appearance:

Moon Face, Buffalo Hump, Central Obesity: Classic appearance includes a rounded face (moon face), fat pad between shoulders (buffalo hump), and truncal obesity with thin extremities (resembling "lemon with matchsticks" sign).
Skin Changes: Purple abdominal striae, hirsutism (androgen excess in females), acne, spontaneous bruising, and delayed wound healing due to skin thinning.
Musculoskeletal: Proximal myopathy, osteoporosis, and pathological fractures.
Psychiatric: Mood disturbances, depression, and insomnia.
Metabolic and Endocrine: Hypertension, hyperglycaemia (diabetes mellitus), polyuria, and polydipsia.

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Long-term Side Effects of Steroid Use:

Osteoporosis, hyperglycaemia, hypertension, immunosuppression, cataracts, and muscle weakness.

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Differential Diagnosis:

Metabolic syndrome (due to overlapping obesity and hypertension).
Polycystic ovary syndrome (PCOS) with similar features of obesity and androgen excess in females.

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Investigations:

Screening Tests:

Late-night Salivary Cortisol: Detects abnormal diurnal cortisol rhythm.
24-hour Urinary Free Cortisol (UFC): Assesses overall cortisol production.
Overnight 1 mg Dexamethasone Suppression Test (DST): Preferred for initial screening; lack of suppression indicates Cushing’s syndrome.

Dexamethasone Suppression Test (DST) Interpretation:

Low-dose DST: Measures cortisol level the morning after 1 mg dexamethasone at night. Non-suppressed cortisol levels suggest Cushing’s.
High-dose DST: Differentiates causes:
- Pituitary (Cushing's Disease): Suppressed cortisol and low ACTH.
- Adrenal: Low ACTH, high cortisol (non-suppressible).
- Ectopic ACTH Production: Both ACTH and cortisol remain elevated and non-suppressible.

Imaging Studies:

Pituitary MRI: For suspected pituitary adenoma.
Abdominal CT/MRI: For adrenal adenomas or carcinomas.
Chest CT: If ectopic ACTH production is suspected.

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Management:

Pituitary Tumour: Transsphenoidal surgery for pituitary adenoma, followed by radiotherapy if needed.
Adrenal Tumour: Surgical resection for adrenal adenomas.
Ectopic ACTH-producing Tumour: Tumour resection if possible; otherwise, medical therapy to control cortisol.
Iatrogenic Cushing's (from Steroid Use): Gradual tapering of corticosteroid dosage under medical supervision to prevent adrenal crisis.

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Complications:

Cardiovascular issues i.e., hypertension and increased risk of myocardial infarction.
Metabolic issues such as diabetes and hypokalaemia.
Osteoporosis with increased fracture risk due to prolonged cortisol exposure.

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Prognosis:

Prognosis depends on cause and treatment success. Surgical intervention for pituitary or adrenal causes can lead to remission. Chronic corticosteroid use requires careful management and monitoring to mitigate complications.

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Notes:

Terminology Note: Corticosteroid refers to glucocorticoid plus mineralocorticoid, but it is often used synonymously with glucocorticoid.
Feedback Mechanism: Cortisol exerts a negative feedback loop on the hypothalamic-pituitary axis, reducing ACTH secretion under normal conditions.
Depression Link: Cortisol levels in Cushing’s resemble stress-induced profiles, often resulting in psychiatric symptoms like depression and mood disturbances

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