Adrenal Insufficiency

Question 1

What are the classifications of adrenal insufficiency?

Answer 1

Primary:

• 80% due to Addison’s disease (autoimmune = most common cause in the west; TB also common elsewhere)
• Surgical removal, trauma; other anatomic destruction of the gland e.g. neoplastic, haemorrhage
• Congenital adrenal hyperplasia (SEE PAEDS DECK 21-hydroxylase deficiency)
• Drugs e.g. -konazole’s, metapyrone
• Idiopathic

Secondary:

• Pituitary cause - often pituitary adenoma suppressing production of ACTH; Sheehan’s syndrome
• Hypothalamic cause - leading to decrease in release of CRH; brain tumours, sudden withdrawal from long term exogenous steroid use (the most common cause over all), antipsychotics e.g. chlorpormazine

Also critical illness:

• Sepsis
• Severe pneumonia
• ARDS
• Trauma

Question 2

What is the epidemiology of adrenal insufficiency?

Answer 2

Primary:

• Rare, 8400 people in the UK
• Most common age of onset 30-50
• F>M

Secondary:

• More common - specifically caused by steroid induced HPA dysfunction
• 150-280 per million
• Peak onset 50-60yrs
• F>M

Question 3

What is the pathophysiology of adrenal insufficiency?

Answer 3

Adrenal glands produce insufficient steroid hormones:

• Especially cortisol (glucocorticoid)
• Also aldosterone (mineralocorticoid)

When the result of autoimmune adrenalitis/Addison’s:
- Autoimmune destruction of 21-hydroxylase enzymes

When the consequence of exogenous steroid use:

• High dose for >1wk starts to suppress adrenals by suppressing CRH and subsequent ACTH release
• Prolonged suppression leads to adrenal atrophy which can take months to recover after cessation (during this time, patient is vulnerable to hypoadrenalism during times of illness/stress)

Question 4

What is the pathophysiology of mineralocorticoid and glucocorticoid deficiencies? What are the key features of the clinical presentation?

Answer 4

Mineralocorticoid deficiency (aldosterone):
- Impairment of Na reabsorption and K excretion = hyponatraemia + hyperkalaemia 
= severe dehydration, acidosis, decreased circulating volume, hypotension, circulatory collapse (this is all more significant in primary adrenal insufficiency)

Glucocortoid deficiency (cortisol):

• Contributes to hypotension
• Causes severe insulin sensitivity + carbohydrate dysregulation - without cortisol, insufficiency carbs are formed from protein - hypoglycaemia and decreased liver glycogen result
• Then follows weakness, poor immunity, poor response to stress
• Myocardial weakness, dehydration - reduced cardiac output and circulatory failure
• Drop in cortisol stimulates ATCH -> hyperpigmentation of skin and mucous membranes

Question 5

How does adrenal insufficiency present acutely?

Answer 5

Maybe as a crisis precipitated by:

• Infection
• Trauma
• Surgery

Features:

• Hypotension
• Hypovolaemic shock
• Acute abdo pain
• Low grade fever
• Vomiting

Adrenal crisis also caused by abrupt cessation of steroids in people on long term steroid therapy (anything over 2wks) as they have suppressed HPA axes

Question 6

How does adrenal insufficiency present chronically?

Answer 6

Same as acute but symptoms may be insidious and mild:

• Fatigue + weakness (most common)
• Anorexia
• N+V
• Weight loss
• Diarrhoea, constipation
• Craving salty foods e.g. soy sauce or liquorice (primary insufficiency)
• Muscle cramps/joint pains
• Confusion, personality change, irritability
• Hyperpigmentation (buccal mucosa, lips, palmar creases; only in primary)
• (postural) Hypotension

Question 7

What other situations would prompt investigation of Addison’s?

Answer 7

People with hypothyroid who’s symptoms get worse when thyroxine treatment starts

Unexplained recurrent episodes of hypoglycaemia in people with T1DM

Presence of other autoimmune diseases (pernicious anaemia, vitiligo, premature ovarian failure etc. - polyglandualr autoimmune syndromes are common in those with Addison’s)

Low Na + high K

Question 8

How do you investigate adrenal insufficiency?

Answer 8

U+E:

• Na - low - in 90% of newly diagnosed cases of primary adrenal insufficiency
• K - raised - in 50%
• Ca - raised in 10-20%

Other bloods:

• FBC - ?mild anaemia/eosinophilia + lymphocytosis
• LFT - ?raised transaminases - Glucose - ?low

Cortisol:

• Blood level taken between 8-9am (should be highest)
• c. <100nmol/L urgent investigation/admission; 100-500nmol/L referral to endo
• Seek specialist advice in: shift work (diurnal variation altered), people taking oestrogen (can increase cortsiol-binding globulin in the liver), pregnant people and people on long term steroids

ACTH - to differentiate primary/secondary:

• Raised in primary
• Low/normal in secondary

Plasma renin and aldosterone levels:

• Will give an indication of mineralocorticoid activity
• Renin is often high and aldosterone low in Addison’s disease
• Usually unaffected in secondary insufficiency

Question 9

What is an ATCH stimulation test?

Answer 9

Can be used to confirm Dx

Patient given synthetic ACTH IV/IM (Synacthen) to stimulate cortisol production

Take blood cortisol levels at 0 and 30 mins → should rise sharply

Addison’s ruled out if cortisol rises to above 550nmol/L

Question 10

What other tests can be used to identify the cause of the adrenal insufficiency?

Answer 10

Will depend on whether it appears to be primary or secondary but tests might include:

• Adrenal autoantibodies
• TB testing e.g. tuberculin skin test/Mantoux; interferon gamma release assay
• CXR - to exclude lung neoplasm or TB
• AXR - adrenal calcification might be a sign of previous TB
• CT adrenals
• MRI hypothalamus + pituitary when central cases suspected
• HPA axis testing e.g. TSH, PRL, FSH/LH

Question 11

How do you manage adrenal insufficiency?

Answer 11

Glucocortioid replacement:

• Hydrocortisone
• 15-30mg in 3 divided doses with highest dose in AM (to mimic normal diurnal rhythm)
• During illness/surgery - doses need increasing (up to 3x normal in minor; 10x in major) to avoid an adrenal crisis
• If co-existent thyroid deficiency then thyroid hormones should be replaced AFTER glucocorticoids to avoid precipitating a crisis

Mineralocorticoid replacement:

• Fludrocortisone
• 50-300mcg/day depending on activity/weight/metabolism
• To assess adequacy - monitoring of BP looking for postural drop + Na/K looking for normalising

Signs of over-replacement = HTN, thin skin, striae, easy bruising, glucose intolerence, hyperglycaemia, electrolyte abnormalities

Question 12

What patient education is important?

Answer 12

Info about the condition

Med alert bracelet

Steroid card

Importance of not missing steroids and not stopping abruptly

Intercurrent illness rules - e.g. doubling of meds

Medication is free

Travel advice - extra meds, emergency self injection kit

Question 13

What ongoing monitoring is required?

Answer 13

Hx - Energy? Appetite?

Check patient understanding

Weight

Skin - pigmentation?

BP - sitting + standing

U+E’s

Annual screening for other autoimmune disease:

• TFT
• Glucose + HbA1c
• FBC
• B12
• Coeliac screen

Question 14

How do you manage adrenal crisis?

Answer 14

Emergency hospital admission

Start treatment STAT based on clinical features

IV/IM hydrocortisone:

• 100mg in adult
• Other lower doses for children of different ages
• At these doses hydrocortisone has mineralocorticoid functions as well so fludrocortisone not required as well
• Then infusion over 24hrs until stable then recommence on oral therapy

Rehydration with IV saline

Manage electrolyte imbalances:
- Na replacement (though not too quickly or can cause demyelination in those with chronic hyponatraemia = osmotic demyelination syndrome)

Continuous cardiac + electrolyte monitoring

Manage precipitating cause e.g. Abx needed