Circadian rhythms & Adrenal insufficiency

Question 1

When is cortisol level at it’s highest and lowest?

Answer 1

• Within 30 minutes of waking between 8-9am
• Slight peak during lunch and dinner times
• Lowest around midnight

Question 2

How is the sleep-wake cycle regulated? What effects does it have on the body to regulate sleep?

Answer 2

• Controlled by the suprachiasmatic nucleus (SCN) in the hypothalamus
• SCN receives information from specialised ganglia in the retina containing photopigments (melanopsin)
• These ganglion cells transmit impulses to the SCN via the retinohypothalmic tract
• SCN transmits light information to pineal gland
• Pineal gland secretes melatonin in response to low light to initiate sleep
• In the morning, optic nerve senses light SCN sends signals to increase body temp, increase HR, increase BP, delay release of hormone such as melatonin

Question 3

What are the 3 types of adrenal insufficiency and what is the underlying pathology and most common causes of each?

Answer 3

1. Primary (Addison’s disease)
   - Problem with the adrenal glands themselves
   - Deficiency in both cortisol and aldosterone production
   - Most common cause is autoimmune adrenalitis in developed countries (60% cases)
   - Autoimmune polyglandular syndrome type 1 (predisposition to endocrine autoimmune disorders T1DM, pernicious anaemia, addisons) (15% cases)
   - Congenital adrenal hyperplasia, mets, haemorrhage, infection (TB), infiltration (amyloid) are other rarer causes
2. Secondary (Hypopituitarism)
   - Results from insufficient pituitary ACTH production
   - Cortisol deficiency but aldosterone levels normal
   - Pituitary macroadenoma is most common cause
   - Apoplexy (infarction of pituitary), radiotherapy, congenital disorders, hypophysitis (inflammation of pituitary), infiltration, infection are other causes
3. Tertiary (suppression of HPA axis)
   - Reduced CRH from hypothalamus so deficient cortisol but normal aldosterone
   - Most common cause is sudden withdrawal of chronic glucocorticoid therapy (steroids) and resolution of cushing’s syndrome (removal of tumour)
   - When medication or tumour is removed, adrenal insufficiency ensues until CRH returns to normal (up to a year)

Question 4

Biochemistry indicative of adrenal insufficiency

Answer 4

• Low sodium and high potassium
• Eosinophilia
• Borderling elevated TSH

Question 5

What investigations do we do for adrenal insufficiency and classifying the type of AI?

Answer 5

Measure hormones we know are meant to be high at certain time
- 9am cortisol and ACTH measurement
>450nmol/L then AI unlikely
<100nmol/L then AI likely

ACTH >22pmol/L = primary cause
ACTH <5pmol/L = secondary cause

Renin/aldosterone - elevated renin in primary cause

Synacthen test - stimulatio test with synthetic ACTH and measure the cortisol response

Question 6

Symptoms of adrenal crisis

Answer 6

• Hypotension
• Vomiting
• Abdominal pain
• Fever
• Mental status changes. (confusion-coma)

Question 7

Managing adrenal crisis

Answer 7

• Take cortisol and ACTH bloods if possible
• Immediate hydrocortisone 100mg IV or IM
• Fluid resuscitation (1L saline over 1 hr)
• Hydrocortisone 50-100mg IV, IM 6 hourly
• Wean dose down when stable over 24-72 hours

Question 8

What is a ‘sick day rule’?

Answer 8

• Rules to follow to prevent adrenal insufficiency
• Always carry 10 x 10mg tablets hydrocortisone
• If unwell with flu etc. double steroid dose (double if in doubt)
• If vomiting = emergency injection of hydrocortisone 100mg IM
• Go to emergency room if can’t inject hydrocortisone
• Carry steroid card and medic alert

Question 9

When is glucocorticoid replacement used?

Answer 9

Once the patients are stable and if they need medication

- usually hydrocortisone 15-25mg divided into 3 doses per day

Question 10

When do we use mineralocorticoid treatment?

Answer 10

Patients who have adrenal failure

- fludrocortisone replaces aldosterone (50-300ug once or twice daily)

Question 11

What is the new glucocorticoid formulation which has been approved for adrenal insufficiency in children?

Answer 11

Alkindi - bead like medication with an inert core, covered in hydrocortisone.
- good for children as can be mixed in foods instead of capsule

Question 12

What is the problem with current hydrocortisone treatment for adults with AI? What are the newer options and why are they better?

Answer 12

Current treatment causes

• Increased mortality
• Impaired QOL
• People feel very tired
• They are taking medication 3x a day causing big peaks and troughs in cortisol levels

Chronocort

• small beads with inert core coated in hydrocortisone
• delayed release polymer through pH coating so it is only released at pH of 6.8 (not stomach)
• This means the drug will work overnight as digestion slows and the medication can be released slowly (does not cause peaks and emulates the normal rhythm of cortisol release in the body)
• Currently being trialed in clinical studies but emerging treatment