Cushing's Syndrome Flashcards
Where is cortisol produced?
State some of actions of cortisol
- Zona fasciculata of adrenal cortex
- Cortisol actions:
- Increase glycogen synthesis
- Increase gluconeogenesis
- Increase protein catabolism
- Increase inuslin resistance
- Increase fat deposition
- Increase BP
- Immunosupression
- Increase osteoclast activity
For cortisol state:
- What levels it lowers when it exerts negative feedback on hypothalamus and anterior pituitary
- What cortisol is bound to in blood
- What cortisol immunoassays measure
- Example conditions/situations in which measured cortisol levels may be increased but actual biolofically active free levels are not increased
- State it’s circadian rhythm
- Cortisol acts on hypothalamus to decrease CRH and vasopressin. Acts on ant pituitary to decrease ACTH.
- Most is bound to cortisol binding globulin (80-90%) and some bound to albumin (5-10%). Only small amount free
- Immunoassays measure bound & free cortisol
- Conditions which elevate cortisol binding globulin e.g. oestrogen therapy can increase measured cortisol levels without actually increasing biologically free active levels. (increase amont bound, only free can exert negative feedback, increase total cortisol)
- High early morning, low ~0:00 (if you are asleep)
Discuss for adrenal androgens:
- Which sex they are more importantn in
- Example androgens produced by zona reticularis
- What parts of body androgens effect
- Important in both sexes pre-puberty. After puberty more important role in women as men rely mainly on testicular production of androgens
- Androgens produced: DHEA, DHEA-s, androstenedione (weak steoids whcih are converted to more potent testosterone & dihydrotestosterone in peripheral tissues)
- Effects on: sebaceous glands, hair follicles, prostrate, external genitalia
For mineralocorticoids:
- State name of major mineralocorticoid
- Discuss role of mineralocorticoids in RAAS
- Aldosterone
- Aldosterone secretion regulated by renin-angiotension aldosterone system.
- Low circulating blood volume, hyponatraemia or hyperkalaemia causes renin is released
- Renin catalyses conversion of angiotensinogen to angiotensin I
- ACE converts angiotensin I to angiotensin II
- Angiotension II binds to angiotensin receptor and stimuates aldosterone release
- Aldosterone increases ENaC channels in DCT to cause Na+ retention, water retention and K+ loss
What is Cushing’s syndrome?
Signs & symptoms due to prolonged elevation of cortisol
What is Cushin’g disease?
Pituitary adenoma that secretes excessive ACTH. Cushing’s disease is a cause of Cushing’s syndrome.
What is pseudo-cushings?
Pseudo- Cushings syndrome (PCS) is a group of conditions associated with clinical and biochemical features of Cushing syndrome, but the hypercortisolemia is usually secondary to other factors. Example conditions include:
- Depression
- PCOS
- Chronic alcoholism
- Alcohol withdrawal
- Obesity
- Malnutrition
.
… thought that conditions lead to chronic activation of HPA axis
What is glucocorticoid resistance syndrome?
Explain how it can lead to Cushing’s syndrome
- Mutation in gene that codes for glucorticoid receptor hence get mutated receptor
- Mutated receptor results in reduced effects of cortisol, including reduced negative feedback, hence hyperactivity of HPA axis occurs
Describe the typical presentation of a pt with Cushing’ syndrome
“Round in middle with thin limbs”
- Round ‘moon’ face
- Central obestiy
- Abdominal striae
- Buffalo hump
- Proximal limb muscle wasting
“High levels of stress hormone”
- Hypertension
- Cardiac hypertrophy
- Hyperglycaemia (T2DM)
- Depression
- Insomnia
“Extra effects”
- Osteoporosis
- Easy bruisng
- Poor skin healing
- Irregular periods
- Hirtuism & acne
- Hyperpigmentation
Explain why pts can get hyperpigmentation, hirtuism & acne in Cushing’s disease ONLY
- Hyperpigmentation: increased ACTH synthesis. ACTH synthesised from POMC. One of breakdown products of ACTH is alpha-MSH which is involved in melanin synthesis
- Hirtuism & acne: increased ACTH from pituitary adenoma can lead to increased production of all hormones from adrenals; zona reticularis produces androgens
Explain why someone with Cushing’s syndrome may have hypertension and hypokalaemia
- At high circulating levels, glucocorticoids can act on mineralocorticoid receptors
- Cortisol can act on mineralocorticoid receptors (e.g. aldosterone receptors) resulting in increased expression of ENaC channels- increases Na+ and hence water reabsorption (hypertension) and increases K+ excretion (hypokalaemia)
What investigations would you do if you suspect a pt has Cushing’s syndrome, include:
- Bedside
- Bloods
- Imaging
*Include all possible investigations you could do… we will narrow it down on another flashcard
Bedside
- Pregnancy test (if woman of child-bearing age)
- Plasma glucose
- 24hr urinary cortisol
- Late night (23:00-00:00) salivary cortisol
Bloods
- FBCs: may show raised WCC
- U&Es: potassium may be low if aldosterone also secreted by adrenal adenoma. Also, at high concentrations glucocorticoids can act on mineralocorticoid receptors
- LFTs
- Cortisol: check if raised
- ACTH: check if ACTH dependent or independent
- Inferior petrosal sinus sampling
Imaging
- MRI brain: for pituitary adenoma
- Chest CT: for small cell lung cancer
- Abdominal CT: for adrenal tumours
What time should you measure cortisol if you suspect it to be high (as in Cushing’s)?
~ 0:00 (test it when you expect it to be low)
You find that a pt has a high plasma cortisol. Discuss what your first line investigatons would be
-
Low dose dexamethasone supression test (1mg)
- Or 24hr urinary excretion of free cortisol is an alternative
- If low dose test gives an abnormal result, a high dose test is performed
Describe the low dose dexamethasone test, include:
- How it is done
- What normal result should be and why
- What result indicates Cushing’s syndrome
- Pt takes 1mg dexamethasone (synthetic glucocorticoid) at night e.g. 22:00-0:00. Their cortisol and ACTH is then measured in morning at 8/9am.
- Low ACTH and cortisol; dexamethasone should supress ACTH release and cortisol release as it exerts negative feedback on hypothalamus and pituitary
- If ACTH and cortisol is not supressed, this indicates Cushing’s syndrome
Describe the high dose dexamethasone test, include:
- How it is done
- What result indicates Cushing’s disease
- What result indicates adrenal adenoma
- What result indicates ectopic ACTH production e.g. small cell lung cancer
- Pt takes 8mg dexamethasone (synthetic glucocorticoid) at night e.g. 22:00-0:00. Their cortisol and ACTH is then measured in morning at 8/9am
- Cushing’s disease: pituitary still shows some reponse ot negative feedback and the 8mg is enough to supress cortisol & ACTH
- Adrenal adenoma: cortisol production is independent from pituitary therefore not supressed. However, ACTH is supressed due to negative feedback.
- Ectopic ACTH production: neither ACTH or cortisol will be supressed becasue ACTH, and hence cortisol production, is independent of HPA axis
Describe how drugs such as mmetyrapone, ketoconazole and mitotane can help in Cushing’s syndrome
They inhibit enzymes involved in synthesis of adrenal hormones
*Metyrapone inhibits 11-B-hydroxylation reaction in adrenal cortex. ADRS: arrhythmias, hypotension, anxiety, confusion, dehyhddration, nausea & vomitting, diarrhoea, epigastric pain
