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  3. Adrenal Insufficiency (Hypoadrenalism)

Adrenal Insufficiency (Hypoadrenalism)

NICE guideline [NG243] Adrenal insufficiency: identification and management. Published: Aug 2024.

Background Information

Category Important causes
Primary adrenal insufficiency 
  • Addison's disease (autoimmune adrenalitis) (most common cause)
  • Infections (e.g. Tuberculosis - most common worldwide but rare in the UK, CMV, histoplasmosis)
  • Congenital adrenal hyperplasia
  • Vascular causes (e.g adrenal haemorrhage, adrenal vein thrombosis, antiphospholipid syndrome)
  • Infiltrative diseases (e.g. tumours, amyloidosis, haemochromatosis, sarcoidosis)
  • Adrenalectomy
Secondary adrenal insufficiency
  • Any causes of hypopituitarism
    • Pituitary tumour / surgery
    • Pituitary infarction (Sheehan's syndrome)
    • Infiltrative disease affecting the pituitary
  • Sudden withdrawal of long-term steroid therapy 
  • Presence of stress (e.g. infection, trauma, surgery) in those who take long-term steroid therapy
Tertiary adrenal insufficiency
  • Any causes of hypothalamic dysfunction
  • Sudden withdrawal of long-term steroid therapy 
 

Diagnosis Guidelines

Autoimmune association (having co-existing conditions), such as:
  • Autoimmune thyroid disease (including Hashimoto’s thyroiditis and Graves’ disease)
  • Type 1 diabetes mellitus
  • Primary ovarian insufficiency
  • Pernicious anaemia
  • Vitiligo
  • Coeliac disease
  • Autoimmune hepatitis

Common features include:
  • Unexplained hyperpigmentation
  • GI features
    • Salt craving
    • Nausea or vomiting
    • Diarrhoea
    • Lack of appetite
  • Non-specific features
    • Weight loss
    • Lethargy
    • Postural hypotension

 

Note that hyperpigmentation may not be seen on black or brown skin. One should assess the buccal mucosa or any surgical scars to assess for hyperpigmentation in these patients.

Note that hyperpigmentation is a hallmark of primary adrenal insufficiency, caused by elevated ACTH and MSH stimulating melanin production. Therefore, hyperpigmentation is ABSENT in secondary or tertiary adrenal insufficiency where ACTH is low or normal.

Some features are more common in children:
  • Prolonged neonatal jaundice
  • Hypotensive crisis
  • Faltering growth
  • Early puberty (mostly seen in congenital adrenal hyperplasia)

Note that while primary adrenal insufficiency affects both cortisol and aldosterone synthesis primarily, secondary adrenal insufficiency affects mainly cortisol synthesis, leaving aldosterone synthesis relatively spared.

Therefore, some changes due to aldosterone deficiency may not be seen or may be less obvious in a secondary adrenal insufficiency case.
 

Key biochemical changes:
  • Hyponatraemia
  • Hyperkalaemia
  • Normal anion gap metabolic acidosis
  • Hypoglycaemia

 

Endocrinology is one of the few topics where physiology is truly useful... Instead of memorising the above-mentioned biochemical changes, one can reason them out.

  • Cortisol usually raises blood glucose → cortisol deficiency would result in hypoglycaemia
  • Aldosterone usually retains sodium, excretes potassium, and excretes hydrogen → aldosterone deficiency would result in the opposite - hyponatraemia + hyperkalaemia + metabolic acidosis
Some other tests:
  • 21-hydroxylase antibodies +ve (suggest Addison's disease)
  • ↑ Renin and ↓ aldosterone

 

Note that these findings are NOT diagnostic of adrenal insufficiency. However, exam questions frequently expect students to work out the diagnosis based on clinical features and biochemical changes.

1st line test: morning (8-9 am) serum cortisol test 

Further testing:
  • Morning ACTH test
  • ACTH stimulation test (short synacthen test)

 

Cortisol secretion follows a predictable pattern where its level peak in the morning and then gradually decline throughout the day, reaching the lowest point at night. Therefore, when one suspects adrenal insufficiency (low cortisol), it would be sensible to measure when it is supposed to be at its peak level.

Test Primary adrenal insufficiency Secondary adrenal insufficiency
Morning serum cortisol ↓ ↓
Morning ACTH ↑ - / ↓
ACTH stimulation (short synacthen) No / ↓ cortisol increase after ACTH No / ↓ cortisol increase after ACTH
 

Management Guidelines

Patient should be offered:
  • Emergency steroid card 
  • Medical alerts, medical IDs
  • Emergency management kit (contains hydrocortisone IM injection - to be given when adrenal crisis is suspected)

Definitive management is life-long hormone replacement:
  • Primary adrenal insufficiency → glucocorticoid (hydrocortisone) + mineralocorticoid (fludrocortisone) replacement
  • Secondary and tertiary insufficiency → glucocorticoid (hydrocortisone) replacement alone

 

Note that while primary adrenal insufficiency affects both cortisol and aldosterone synthesis primarily, secondary adrenal insufficiency affects mainly cortisol synthesis, leaving aldosterone synthesis relatively spared.

Increase the hydrocortisone dose during the event
  • Usually double the dose

If the patient is unable to take oral tablets → admit to the hospital to give IM or IV hydrocortisone

Consider increasing glucocorticoid and mineralocorticoid doses in:
  • 3rd trimester of pregnancy, and
  • Until 48 hours postpartum

Attend hospital immediately (NICE says via ambulance without needing a referral):
  • IV / IM hydrocortisone 100mg to be given immediately (FIRST PRIORITY)
    • IM dose can be given by anyone (e.g. from an emergency management kit)
    • IV / IM hydrocortisone should be continued over 24 hours, until haemodynamically stable and able to take oral medications
    • Once on oral hydrocortisone, doubled doses should be maintained until the underlying cause has resolved
 
  • 0.9% NaCl IV infusion (1L over 30 min)
    • Subsequent fluid therapy should be determined by haemodynamic and electrolyte status

References

Author: Adams Lau
Reviewer:
Last edited: 14/08/25