Cushing’s syndrome

• Due to excess cortisol
• Prevalence of endogenous Cushing’s is around 50/million (80% of cases are ACTH dependent)

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Causes

• Steroids (exogenous Cushing’s, the most common cause). Can occur with any route of administration (IA, PO, nasal, dermal, inhaled, especially if routes combined)
• Adrenal adenoma, hyperplasia or carcinoma
• Pituitary adenoma (‘Cushing’s disease’)
• Therapeutic ACTH
• Ectopic ACTH (usually small cell lung cancer or pulmonary carcinoid but many others)

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Clinical features

• Moon-like face, obesity (85%)
• Facial plethora (80%)
• Supraclavicular fat pad (buffalo hump, 50%)
• Acne (25%), thin skin and bruising (50%), striae (45%), hirsutism/alopecia (75%)
• Hypertension
• Diabetes
• Proximal myopathy/muscle atrophy (70%)
• Osteoporosis (55%)
• Depression, insomnia, psychosis, cognitive dysfunction (80%)
• Hypokalaemia (especially if ectopic ACTH)
• Infections
• VTE (can be the presenting symptom)
• Infertility (menstrual irregularity in 75% of women), decreased libido
• Most discriminating features are the facial plethora, proximal myopathy, bruising and striae

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Investigation

• First – consider whether patient has been taking steroids (including over the counter preparations), the oral contraceptive pill or is pregnant
  • • All will give random cortisol levels as high
    • Oestrogen increases liver production of cortisol binding globulin
    • It takes 6 weeks for cortisol to fall after oral contraceptive use (only true for oral oestrogen use, IV oestrogen doesn’t effect it)
• Consider testing for Cushing’s if:
  • • There’s an adrenal incidentaloma
    • Difficult to treat hypertension or diabetes, or unexplained VTE
    • Cushingoid features (especially if uncommon for age – early HTN, osteoporosis, or if multiple progressive symptoms especially they’re if highly discriminating for Cushing’s)
• Check cortisol one off (normal < 500) and ACTH (takes longer to get back).
  • • Note that most patients with Cushing’s disease do not have a high random cortisol
    • However a cortisol of > 140 at midnight is suggestive (but often not convenient)
    • ACTH will be inappropriately normal or elevated in ACTH-dependent causes (ie >20pg/mL, source is pituitary or ectopic, occurs in 85%)
    • ACTH will be low (<10pg/mL, source is adrenal, occurs in 15%) in ACTH-independent causes of Cushing’s
• Do 24-hour urinary free cortisol (will be elevated in Cushing’s). Repeat again if positive.
• Overnight dexamethasone suppression
  • • Especially useful if difficult to admit the patient and low suspicion
    • Give 1mg dexamethasone at 11pm and measure cortisol at 9am
• Next: consider low dose dexamethasone suppression test – post dexamethasone cortisol should be supressed to < 50 in normal people
  • • However – lots of false positives (eg ASM medication, malabsorption)
    • Need to stop oral oestrogen 6 weeks prior
    • Sensitivity is high (95%), specificity lower (70%)
    • Involves checking 9am cortisol and ACTH and repeating in 48 hours (6 hours after last dose). Patient takes 0.5mg of dexamethasone every 6 hours
    • A high dose dexamethasone suppression test is not done anymore
• An alternative is a late-night salivary cortisol test (do at least twice)
• Consider MRI of pituitary (if ACTH not suppressed), however can be negative in 50% of cases of Cushing’s disease
• If ACTH suppressed – do CT or MRI adrenals
• Consider PET if adrenal nodule has worrisome features (eg >4cm, calcifications, irregular margins, HU >20)
• Bilateral simultaneous inferior petrosal sinus sampling
  • • For those with high ACTH levels but no clinically definite pituitary source (differentiates pituitary from non-pituitary source of ACTH)
    • Not required if pituitary adenoma >6mm
    • The procedure has multiple risks attached.
• Occasionally check DHEAS and CRH if ACTH low/normal and unilateral or bilateral adrenal enlargement (can differentiate between adrenal and pituitary cause)

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Pseudo-Cushing’s

• Some similar symptoms/signs. Investigations generally normal (if borderline, always discuss with endocrinology)
• Can occur in
  • • ETOH dependence
    • Severe obesity
    • PMOS
    • Neuropsychiatric disorders
    • T2DM
    • CKD

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Complications

• CV morbidity
• Around 4 x mortality of general population
• Hypertension, hyperlipidaemia, diabetes, obesity
• Fragility fractures
• Neuropsychiatric symptoms
• Infections
• VTE
• Nephrolithiasis
• Hypogonadotrophic hypogonadism
• If adrenals removed, pituitary tumour can enlarge – Nelson’s syndrome
• An adrenal crisis
  • • If you have adrenal cushing’s and suppressed ACTH, then the other adrenal gland will atrophy
    • If you operate, they will go into adrenal crisis unless you replace the cortisol
    • 3mg prednisolone OD is enough to allow other adrenal gland to recover

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Management

• Depends on the cause. Consider:
  • • Metyrapone 250mg TDS
    • Antihypertensives
    • Glycaemic control
    • Replace potassium
    • Give LMWH for VTE prophylaxis
    • Check visual fields
    • May need surgery
• Even after surgery, risk of complications and comorbidities can persist