Background Information
Definition
Adrenal insufficiency (hypoadrenalism) is defined as the inadequate production of adrenal cortex hormones.
Aetiology
| Category | Important causes |
|---|---|
| Primary adrenal insufficiency |
|
| Secondary adrenal insufficiency |
|
| Tertiary adrenal insufficiency |
|
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
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.
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
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.
Endocrine Studies
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 interpretation:
| Test | Primary adrenal insufficiency | Secondary adrenal insufficiency |
|---|---|---|
| Morning serum cortisol | ↓ | ↓ |
| Morning ACTH | ↑ | – / ↓ |
| ACTH stimulation (short synacthen) | No / ↓ Cortisol increase after ACTH | ↓ Cortisol increase after ACTH In secondary adrenal insufficiency, a short synACTHen test is expected to give a blunted / subnormal cortisol increase in response to exogenous ACTH. Specifically, the peak serum cortisol at 30 or 60 minutes after administration of synACTHen will typically be below the assay-specific threshold for normal adrenal function. Rationale: Chronic deficiency of endogenous ACTH will reduce the capacity of the adrenal glands to snythesis and secrete cortisol. |
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) |
|
| Secondary adrenal insufficiency |
|
| Tertiary adrenal insufficiency |
Alternative to hydrocortisone: prednisolone or modified-release hydrocortisone (which allows single daily dosing, instead of multiple daily doses)
High-yield prescription information (BNF):
- Hydrocortisone PO – typically 20-30 mg daily, in 2 divided doses
- The larger / majority (~60%) dose is given as the first morning dose, and the remaining to be given in the afternoon
- A typical regimen: 15mg in the morning and 10mg in the afternoon
- The purpose of this splitting is to mimic the natural circadian rhythm of cortisol secretion
- Fludrocortisone PO – 0.05 – 0.2mg daily, single dose in the morning
In children, dosing of glucocorticoid depends on body surface area.
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.
Hydrocortisone is a replacement of endogenous glucocorticoid (cortisol), and fludrocortisone is a replacement of endogenous mineralocorticoid (aldosterone)
Management During Specific Situations
Management During Physiological Stress
In adrenal insufficiency, stress means any situation where the body would normally increase cortisol output, such as:
- Sepsis
- Major trauma (e.g. road traffic accident)
- Febrile illness
- Pneumonia
- Vomiting / diarrhoea
- Psychological stress (e.g. psychotic episode)
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
In children, a total daily hydrocortisone dose of ~30 mg/m2/day given as 4 evenly spaced doses is recommended.
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 200 mg / 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
Refer to the hospital immediately (via an ambulance without a referral).
Hospital management:
- 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
NICE guideline Adrenal insufficiency: identification and management