Adrenal Disease Flashcards
Which hormones does the adrenal gland produce?
-
CORTEX (out to in):
- Zona glomerulosa → mineralocorticoids (eg. aldosterone)
- Zona fasciculata → glucocorticoids (eg. cortisol)
- Zona reticularis → androgens
-
MEDULLA (catecholamines):
- Noradrenaline
- Adrenaline
- Dopamine
Cushing’s syndrome is caused by prolonged exposure to an excess of glucocorticoids.
For causes of Cushing’s sydrome, what is meant by exogenous versus endogenous, and which is more common?
- Exogenous → derived externally, occurs due to administration of glucocorticoids either as medication or misuse - this is by far most common cause
- Endogenous → derived internally, occurs due to excess production of glucocorticoids by body itself - very rare
What is Cushing’s disease?
- Endogenous type of Cushing’s syndrome
- Refers to cases caused by pituitary adenoma
- Responsible for majority of endogenous cases
Cushing’s syndrome is defined based upon its aetiology - whether the cortisol excess is ACTH dependent or independent.
What is meant by ACTH-dependent?
- This is when cortisol excess is driven by ACTH, either from pituitary or ectopic sources
- Cushing’s disease (80%) → bilateral adrenal hyperplasia from ACTH-secreting pituitary adenoma; peak age 30-55yrs
- Ectopic ACTH production (5-10%) → small cell lung cancer; carcinoid tumours
- Ectopic CRH production → rarely produced by malignant tissue
What is meant by ACTH-independent?
- Cortisol excess is independent of ACTH
- Includes exogenous causes (consumption of cortisol)
- Also adrenal lesions (adenomas, carcinomas)
- McCune-Albright syndrome (rarer cause)
What role does the HPA axis have in controlling cortisol secretion?
- Corticotropin-releasing hormone (CRH) → released by hypothalamus, transported via hypophyseal portal system to anterior pituitary, stimulating ACTH release
- Adrenocorticotropic hormone (ACTH) → released from corticotrophs of anterior pituitary, stimulates release of cortisol; XS is a feature of both Addison’s and ACTH-dependent Cushing’s syndrome
- Cortisol → released from adrenal cortisol in response to ACTH; exerts negative feedback on release of both ACTH and CRH; exhibits diurnal variation - highest around 8am
Pseudo-Cushing’s mimics cushing’s. What are causes for this?
- Alcohol excess or severe depression
- Causes false positive dexamethasone suppression test or 24hr urinary free cortisol
- Insulin stress test may be used to differentiate
The clinical features asssociated with Cushing’s syndrome are related to the effects of excess cortisol.
What are the symptoms (not signs) of Cushing’s syndrome?
- Tiredness
- Depression
- Weight gain
- Easy bruising
- Amenorrhoea
- Reduced libido
- Striae
What are the clinical signs of Cushing’s syndrome?
- Acne
- Moon facies
- Plethora (facial redness)
- Buffalo hump
- Hypertension
- Proximal muscle weakness
- Hyperpigmentation (in ACTH-dependent causes)
The work-up for Cushing’s syndrome follows two stages, establishing a diagnosis and establishing a cause.
For exogenous disease, there should be a clear history of prolonged glucocorticoid use.
Which tests are performed for endogenous cases?
- 24hr urinary cortisol → initial test; 3+ collections needed; levels 3-4x normal are highly suggestive of cushing’s syndrome; measure creatinine levels too as variation in levels between samples (>10%) indicates repeat for test
- Midnight cortisol → demonstrates loss of normal circadial pattern; can be salivary or blood based; if blood, take samples from indwelling cannula
- Low-dose dexamethasone suppression → demonstrates loss of normal negative feedback on pituitary and hypothalamus; 1mg of dex given at 11pm and serum cortisol measured at 8am; normally, dex should suppress morning rise in serum cortisol but in pts w/ cushing’s there’s a lack of suppression
- Dexamethasone-CRH test → less common; can help distinguish between Cushing’s and HPA axis dysregulation in severe depression
After diagnosing cortisol excess we must identify the underlying aetiology.
What tests can be done to identify causes?
- Plasma ACTH done first, points to whether ACTH independent or dependent
- ?ACTH independent → CT or MRI
- ?ACTH dependent → High dose dex test:
- pituitary adenoma (ACTH suppressed)
- ectopic (ACTH continued production)
What is the management of exogenous Cushing’s syndrome?
- Withdrawal of glucocorticoid
- Should not abruptly stop (risk of Addisonian crisis)
- Instead, gradual tapering regimen
- Close safety netting + monitoring
What is the gold standard management of Cushing’s disease?
Transsphenoidal surgery :
- Microadenomectomy → identifiable adenoma found + resected
- Subtotal resection of anterior pituitary → used where no identifiable adenoma + no desire for fertility after counselling - risk of hypopituitarism
What is the medical therapy for Cushing’s disease?
- Most commonly used as bridge to definitive surgical rx
- Or when surgery not possible / fails
- Metyrapone used (inhibitor of 11B-hydroxylase) → reduction in corticol synthesis
- Children + young people → pituitary irradiation
When is adrenalectomy performed, for Cushing’s?
- For those where all other therapies have failed
- Bilateral adrenalectomy
- Mandates lifelong glucocorticoid + mineralocorticoid replacement
How is unilateral adrenal adenoma treated?
- Unilateral adrenalectomy (curative)
- Laparoscopic > open surgery
- Follow-up tapering of exogenous steroids for period of time as endogenous CRH/ACTH suppressed
How is bilateral adrenal hyperplasia treated?
- Bilateral adrenalectomy
- In pts w/ overt Cushing’s
- Require replacement of glucocorticoids and mineralocorticoids
How is adrenal carcinoma treated?
- Appropriate staging
- Resection is mainstay of treatment
- Adjuvant chemo, radio or mitotane may be given
What is Addison’s disease?
- Primary adrenal insufficiency
- Caused by destruction or dysfunction of adrenal cortex
- Hence low glucocorticoids and mineralocorticoids (mainly)
- In women, loss of androgens → axilla/pubic hair loss and loss of libido
- Men have testes to make androgens so few problems there
- Lots of symptoms mediated by lack of normal glucocorticoids and mineralocorticoids
- Profound and acute losses → addisonian crisis
What is the function of aldosterone?
- Reduced in Addison’s
- A mineralocorticoid released from zona glomerulosa
- Released in response to Ang II, ACTH and K+
- Primary action = increase sodium and water reabsorption, potassium excretion
What are common causes of Addison’s?
- Western world → Autoimmune
- Worldwide → Tuberculosis
Addison’s disease is often diagnosed late due to its non-specific presentation.
What are clinical features of chronic Addison’s?
- Chronic, insidious onset
- Fatigue / Anorexia / Abdo pain
- Androgen deficiency in women
- Muscle wasting
- Postural hypotension
- Hyperpigmentation
Addisonian crisis is a potentially life-threatening presentation of Addison’s disease. It is most commonly seen in tertiary adrenal insufficiency (termed an ‘adrenal crisis’) as a result of the sudden withdrawal of exogenous steroids. Occurs following an acute decompensation where an additional stress (e.g. infection) results in an exacerbation of a pre-existing deficiency. Bilateral adrenal gland haemorrhage can also result in a crisis.
What are clinical features of an addisonian crisis?
- Dehydration
- Hypotension
- Confusion
- Hyponatraemia / Hyperkalaemia / Hypoglycaemia
The diagnosis of Addison’s may utilise both blood tests and stimulation tests.
What do blood tests show?
- U+Es → hyponatraemia and hyperkalaemia
- BM → hypoglycaemia
- FBC → anaemia and eosinophilia
- 21-hydroxylase adrenal autoantibodies → positive in autoimmune disease
What is the Synacthen test?
- IV administration of 250 mcg of tetracosactide (synthetic ACTH)
- Cortisol measured 3 times: 0 (immediately before), 30 mins + 60 mins following administration
- Serum cortisol > 500-550 nanomol/L either before or following the ACTH is considered normal
What is the management of Addison’s disease?
- Glucocorticoid replacement → hydrocortisone 15-30mg/day
- Mineralocorticoid replacement → fludrocortisone 50-300 mcg/day
- Patient education + sick day rules (double dose)
- Carry steroid card and MediAlert identification
How is an Addisonian crisis managed?
- Medical emergency → prompt recognition + treatment
- IV hydrocortisone 100mg
- IV fluid rehydration
- Cardiac, electrolyte + blood sugar monitoring
- Following initial resus → hydrocortisone/dextrose infusion, target of 400mg of hydrocortisone / 24 hours
- Specialist input should be sought
What is primary hyperaldosteronism?
- Excess production of aldosterone, independent of RAS
- Hypernatraemia + water retention
- Reduced renin release
- Hypokalaemia
What are clinical features of primary hyperaldosteronism?
- Often asymptomatic
- Hypokalaemia signs → weakness / cramps / paraesthesia / polyuria / polydipsia
- Hypertension sometimes
What are causes of primary hyperaldosteronism?
- Conn’s syndrome → solitary aldosterone-producing adenoma
- Bilateral adrenocortical hyperplasia
Rarer causes → adrenal carcinoma / glucocorticoid-remediable aldosteronism (GRA)
What investigations are done for hyperaldosteronism?
- 1st-line → aldosterone:renin ratio - in suspected primary hyperaldosteronism, shows high aldosterone levels alongside low renin levels
- CT Abdo + adrenal vein sampling → used to differentiate between unilateral and bilateral sources of aldosterone XS
What is the management for Conn’s syndrome?
- Laparoscopic adrenalectomy
- Spironolactone for 4wks pre-op controls BP + potassium
What is the mangement for bilateral adrenocortical hyperplasia?
- Medically treated w/ spironolactone or amiloride
What is secondary hyperaldosteronism?
- Due to high renin from decreased renal perfusion
- Causes:
- renal artery stenosis
- accelerated hypertension
- diuretics
- CCF
- hepatic fialure
What is Bartter’s syndrome?
- Inherited cause (autosomal recessive)
- Severe hypokalaemia
- Defective chloride absorption at NKCC2 in ascending loop of Henle
- Associated w/ normal BP
Loop diuretics work by inhibiting NKCC2 - think of Bartter’s syndrome as like taking large doses of furosemide
What are clinical features of Bartter’s syndrome?
- Usually presents in childhood (failure to thrive)
- Polyuria. polydipsia
- Hypokalaemia
- Normal BP
- Weakness
What is the management of Bartter’s syndrome?
- Potassium replacement
- NSAIDs to inhibit prostaglandins
- ACEi
What is phaeochromocytoma?
- Rare catecholamine secreting tumour
- Arise from sympathetic paraganglia cells
- Found in adrenal medulla
- Extra-adrenal tumours rarer + often found by aortic bifurcation
- 90% are sporadic and 10% part of hereditary cancer syndromes (Thyroid, MEN II, neurofibromatosis, Von-Hippel-Lindau)
What are the clinical features (typically episodic) of phaeochromocytoma?
- CVS → tachycardia / palps / dyspnoea / angina / MI / LVF / cardiomyopathy
- Psych → anxiety / hyperactivity / confusion / episodic psychosis
- Neuro → headache / visual disorder / dizziness / tremor / numbness
- Gut → D+V / abdo pain
- Other → sweats / heat intolerance / backache
What investigations are done for phaeochromocytoma?
- 24hr urinary collection of metanephrines
- Localisation by abdominal CT / MRI or meta-iodobenzylguanidine scan
What is the management for phaeochromocytoma?
- Pre-op → alpha-blockade (eg. phenoxybenzamine) before beta-blocker to avoid crisis from unopposed alpha adrenergic stimulation
- Post-op → 24hr urine metanephrine 2ks post-op + monitor BP
