Cushing's Syndrome and Disease

Question 1

What is Cushing’s syndrome? Cushing’s disease?

Answer 1

Used to describe a state of excess free circulating glucocorticoid - of any aetiolgoy

Iatrogenic i.e. due to excess exogenous ACTH or glucocorticoids
= syndrome = most common

Disease i.e. problem in the pituitary gland itself = rare (5/1,000,000/yr) - most common in adults 20-50yrs, and in women

Question 2

What is the pathology of Cushing’s (syndrome/disease)

Answer 2

ACTH dependent vs independent:

• Dependent = body makes too much ACTH is made which in turn increases cortisol production (few ways)
• Independent = adrenal glands are making too much cortisol (cortisol secreting adenoma in cortex of adrenal gland), therefore ACTH levels are low = primary hypercortisolism

Causes of ACTH-dependent disease:

• Increased secretion from anterior pituitary due to a an adenoma = secondary hypercortisolism
• Increased secretion of CRH from the hypothalamus leading to increased ACTH = teritary hypercortisolism
• Secretion from ectopic sites outside these glands i.e. from a cancer as part of a paraneoplastic syndrome (small-cell carcinoma of the lung and bronchial carcinoid tumours or any other NET)

Question 3

How does Cushing’s present?

Answer 3

Weight gain:

• General
• ‘Moon face’
• Fat pad on back of neck
• Straie/stretchmarks
• Oedema

Diabetes/impaired glucose tolerance

• Thirst
• Poluria

Thin skin, bruising, hirsuitism, acne, pigmentation (if ACTH-dependent)

Osteoporosis, fractures, kyphosis
Back pain
Skin infections, slower sound healing

Polyria, glycosuria

A/oligomenorrhoea

Depression, insomnia

Question 4

How do you investigate Cushing’s?

Answer 4

General:

• FBC = raised WCC common
• U+E = hypokalaemia common with ectopic form; metabolic acidosis

These tests will identify the presence of Cushing’s syndrome, not tell you what the cause is:

Drug Hx:
- To rule out an iatrogenic cause

24hr urinary free cortisol measurements:

• Will need repeating for reliability - 3x collections
• Measure creatinine at the same time
• Diagnosible if 2+ collections measure cortisol at >3x upper limit of normal
• False positives are common (e.g. alcoholism, psychoses, anorexia, pregnancy, exercise, intercurrent illness)

Midnight cortisol levels:

• Between 11pm and 1am
• Blood taken from indwelling cannula with relaxed patient
• Demonstrates a loss of normal diurnal variation of reduced cortisol produced in the PM compared to the AM
• Can also do late night salivary cortisol measurement (as a screening test)

Overnight and low dose dexamethasone test +/- low dose dex/CRH suppression test

Question 5

How does dexamethasone testing work?
How is low dose testing delivered?
How is the high dose suppression test delivered? How is the low dose dex/CRH suppression test delivered?

Answer 5

Dexamethasone is a synthetic glucocorticoid medication

Administration should reduce ACTH (and thus cortisol) in normally functioning individuals
- If ATCH dependent cause then will have an abnormal response to this test

Overnight low dose dex:

• 1mg ingested at 11pm and serum cortisol measured at 8-9am the next morning
• In Cushing’s disease - cortisol levels will be high in the morning (as not suppressed); if normal - will be low (as suppressed by the dex)

Low dose dex:

• May be used if overnight is inconclusive
• 8 doses of 0.5mg dex given in 48hrs (9am, 3pm, 9pm, 3am)
• Again, normal = cortisol levels suppressed, Cushing’s = not suppressed

Low dose dex and CRH:

• Same protocol for Low dose dex but
• 2hrs after 48hr blood sample, give IV CRH
• Measure serum cortisol 15 mins after CRH admission
• Again, will not be suppressed in Cushing’s

Question 6

How do you investigate the cause of the Cushing’s syndrome?

Answer 6

Once the preliminary tests have identified the presents of Cushing’s syndrome, we need to know which type it is:

Plasma ACTH:

• Secretion is pulsatile with diurnal variation (peaking @ 8am, lowest at 12am)
• Undetectable plasma ATCH + elevated cortisol = diagnostic for ATCH-independent Cushing’s = adrenal adenoma/carcinoma (or exogenous steroids, but should have excluded)
• Elevated ATCH = dependent Cushing’s, follow with:

High dose dex suppression test:

• 8mg overnight dex suppression + 48hr high dose dex may be useful when ATCH baseline levels are equivocal and may be helpful to diagnose pituitary or ectopic origins
• > 90% reduction in basal urinary free cortisol following these tests supports pituitary adenoma as a Dx as ectopic causes result in less of a suppression

MRI/CT:
To diagnose adrenal + pituitary adenomas

CXR/Chest CT:
To check for carcinoma of the bronchus/lung

Question 7

How do you manage Cushing’s?

Answer 7

Drugs:

• Metyrapone, ketoconazole, and mitotane - Can all be used to lower cortisol by directly inhibiting synthesis and secretion in the adrenal gland
• Metyrapone (11beta hydroxylase inhibitor) + ketoconazole (antifungal -> cytochrome P450 14α-demethylase) = enzyme inhibitors - not effective for long term treatment, mainly used before surgery or as an adjunct after surgery/radiotherapy to the pituitary
• Mitotane = adrenolytic drug, for longer term control
• Etomidate can be used for acute control of severe hypercortisolaemia

Surgery:

• Pituitary tumours - trans-sphenoidal microsurgery; radiotherapy
• Adrenal surgery/adrenelectomy

Question 8

What are the complications of Cushing’s?

Answer 8

Metabolic syndrome 
HTN 
Diabetes/impaired glucose tolerance 
Hyperlipidaemia 
Obesity 
Coagulopathy 
Osteoporosis 
Impaired immunity 
Cardiovascular disease