Background Information

Definition

Adrenal insufficiency (hypoadrenalism) is defined as the inadequate production of adrenal cortex hormones.

Aetiology

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

Complication

Main complication is the risk of acute adrenal crisis, which is potentially life-threatening. See below for management.

Diagnosis

Risk Factors

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

Clinical Features

Common features include:

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

Paediatric Populations

Some features are more common in children:

• Prolonged neonatal jaundice
• Hypotensive crisis
• Faltering growth
• Early puberty (mostly seen in congenital adrenal hyperplasia)

Investigation and Diagnosis

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.

Non-Diagnostic Tests

Key biochemical changes:

• Hyponatraemia
• Hyperkalaemia
• Normal anion gap metabolic acidosis
• Hypoglycaemia

Some other tests:

• 21-hydroxylase antibodies +ve (suggest Addison’s disease)
• ↑ Renin and ↓ aldosterone

Endocrine Studies

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

Further testing:

• Morning ACTH test
• ACTH stimulation test (short synacthen test)

Test Interpretation

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

Long-Term Management

Conservative / General Management

Patient should be offered all the following:

• Emergency steroid card 
• Medical alerts, medical IDs
• Emergency management kit (contains hydrocortisone IM injection – to be given when adrenal crisis is suspected)
• Education and information on 1) importance of glucocorticoid treatment 2) sick day rules 3) features of under- or over-hormone replacement 4) when to seek medical help

Pharmacological Management

Definitive management is lifelong oral hormone replacement:

Primary adrenal insufficiency (e.g. Addison’s disease)	Hydrocortisone (immediate release in divided doses), and Fludrocortisone
Secondary adrenal insufficiency	Hydrocortisone only
Tertiary adrenal insufficiency

Alternative to hydrocortisone: prednisolone or modified-release hydrocortisone (which allows single daily dosing, instead of multiple daily doses)

Management During Specific Situations

Management During Physiological Stress

Changes to hormone replacement

• Increase the hydrocortisone dose during the event
  • At least 40 mg daily in 2-4 divided doses
  • Usually the normal daily dose is doubled (sick-day dose)
• NO changes is necessary to the fludrocortisone dose (if the patient is taking it)

If the patient is unable to take oral tablets (usually due to vomiting):

• Immediate action: give IM hydrocortisone + attend the emergency department
• In-hospital management:
  • Give hydrocortisone 100 mg IM / IV
  • Ongoing therapy: hydrocortisone 50 mg IM / IV QDS or 200mg over 24 hours

Management Before Surgery or Invasive Medical Procedures

There are 3 main phases:

Pre-operative phase	Continue the usual oral hydrocortisone (and fludrocortisone if taking it) regimen up to the time of surgery If NBM is necessary, change to IV hydrocortisone
Intra-operative phase	Give hydrocortisone 100mg IV on induction, followed by continuous infusion of hydrocortisone 200mg / 24 hours
Post-operative phase	Once able to tolerate oral intake → sick-day (~double) hydrocortisone doses for 48 hours or for up to a week following major surgery

Management During Pregnancy

Consider increasing glucocorticoid (and mineralocorticoid doses in primary adrenal insufficiency) in:

• 3rd trimester of pregnancy, and
• Until 48 hours postpartum

After delivery, use sick-day dosing of oral glucocorticoids for 48 hours and then resume the usual dose.

Adrenal Crisis Management

Acute Management

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, sick-day doses (~doubled doses) should be maintained until the underlying cause has resolved

 

• Fluid resuscitation: IV 0.9% NaCl (1L over 30 min)
  • Subsequent fluid therapy should be determined by haemodynamic and electrolyte status

References