Adrenal Insufficiency

Hypoadrenalism

The most common cause of hypoadrenalism is Addisons, which describes the autoimmune destruction of the adrenal glands.

Causes may be divided into primary and secondary.

Primary

The problem is with the adrenal glands.

Autoimmune

• Addisons disease. Associated with polyglandular syndromes.

Infections

• Tuberculosis: most common cause worldwide, but rare in the UK
  ‍
• CMV disease in immunosuppressed states (especially AIDS)
  ‍
• Histoplasmosis

Adrenal haemorrhage/Thrombosis

• Meningococcal septicaemia: Waterhouse‑Friderichsen syndrome
  ‍
• In APLS, venous thrombosis and/or adrenal haemorrhage is the leading cause.

Infiltration of the adrenal glands

• Metastatic disease, e.g., bronchial carcinoma
  ‍
• Amyloidosis
  ‍
• Haemochromatosis
  ‍
• TB

Adrenalectomy:

• Removal of the adrenal glands.

Defective enzymes (impaired cortisol production)

• Cortisol synthesis inhibitors
  ‍
• 21β-hydroxylase deficiency (see congenital adrenal hyperplasia)

Vitamin B5 deficiency

• Causes atrophy of the adrenal cortex, with associated lipid depletion.

Secondary

The adrenals are fine, but there is a problem upstream in the hypothalamic-pituitary-end-organ axis.

• Hypopituitarism for any reason (e.g. tumours, irradiation, infiltration)
  

• Exogenous glucocorticoid therapy. Prolonged iatrogenic suppression of the hypothalamic-pituitary-adrenal axis. Can lead to an addisonian crisis (see below after Addisons disease).

Addison's Disease

Addison's disease describes the autoimmune destruction of the adrenal glands

Features

• Abdominal pain nausea & vomiting, weight loss, 'salt-craving'
  

• Hyperpigmentation (especially palmar creases)

1. ~~Low levels of cortisol, means there is an elevated amount of ACTH.
   ‍
2. ~~ACTH is derived from precursor molecule pro-opiomelanocortin (POMC)
   ‍
3. ~~POMC is also a precursor for melanocyte-stimulating hormone (MSH)
   ‍
4. ~~ ↑ Production of POMC to make ACTH = ↑ melanocyte-stimulating hormone (MSH).
   ‍
5. ~~MSH= Proliferation of melanocytes, leading to hyperpigmentation.
   

• Vitiligo may be seen, as it is often associated with addisons.
  

• Loss of pubic hair in women.

1. ~~The adrenal glands also produce androgens.
   ‍
2. ~~Deficiency of androgen can cause loss of body hair and diminished sex drive in women.
   

• Hypotension

1. ~~Cortisol increases heart rate and blood pressure, in it’s absence there may be hypotension.
   

• Hypoglycaemia (why? See causes of hypoglycemia)
  

• Hyponatraemia and hyperkalaemia and metabolic acidosis,

1. ~~Due to diminished secretion of cortisol and aldosterone.
   ‍
2. ~~ ↑ADH  results in water retention and a reduction in the plasma sodium concentration.
   ‍
3. ~~Decreased potassium and H+ secretion leads to hyperkalaemia and metabolic acidosis.
   

• Crisis: collapse, shock, pyrexia

Investigations

Screening: 9 am serum cortisol

• > 500 nmol/l makes Addison's very unlikely
  
  
• < 100 nmol/l is definitely abnormal
  
  
• 100-500 nmol/l should prompt a ACTH stimulation test to be performed
  

Definitive diagnosis:  ACTH stimulation test (short Synacthen).

• Plasma cortisol is measured before and 30 minutes after giving Synacthen 250ug IM
  

Antibody testing can also be done, e.g, anti-21-hydroxylase.

The endocrine society recommends measuring renin and aldosterone levels as part of the work up.

Metabolic abnormalities:

• Hyperkalaemia
• Hyponatraemia
• Hypoglycaemia
• Metabolic acidosis

Management

Patients will require glucocorticoid and mineralocorticoid replacement therapy.

• Hydrocortisone: usually given in 2 or 3 divided doses. Patients typically require 20-30 mg per day, with the majority given in the morning dose to mimic the natural production.
  
  
• Fludrocortisone
  
  
• MedicAlert bracelets and steroid cards may be needed.

Important to tell the patient not to miss a dose, and explain sick day rules:

• In most cases double the glucocorticoid dose.
  
  
• If the person has vomited, they should use their emergency hydrocortisone injection and seek immediate medical advice, emphasizing that it is an Addison's disease emergency.
  
  
• After a major injury, the person should take 20 mg hydrocortisone orally.
  
  
• If the person is undertaking strenuous exercise (such as a marathon), they will need to increase their medication. Up to double the normal dose of glucocorticoid and mineralocorticoid and increasing fluid intake is suggested.
  
  
• If a less strenuous activity (such as hiking) is being undertaken, the person should add 5 mg to 10 mg hydrocortisone to their normal regimen shortly before the activity

The endocrine society recommends that patients should be monitored by testing blood electrolyte levels and checking for symptoms like salt craving, light-headedness, blood pressure changes and swelling of the legs and feet.

Addisonian crisis

This is where the demand of cortisol suddenly is increased for one reason or the other and there is not adequate supply.

Causes:

• ↑ Stress, e.g., surgery, sepsis, infection. Increases the requirement for cortisol, and can precipitate a crisis in chronic insufficiency.
  
  
• Adrenal haemorrhage, complication of fulminant meningococcemia known as Waterhouse-Friderichsen syndrome.

Features:

• Hypotension, shock, abdominal pain [typical exam presentation]
  

• Impaired consciousness
  
  
• Fever
  
  
• Vomiting, diarrhea
  
  
• Hypoglycemia, hyponatremia, hyperkalemia, and metabolic acidosis

Management:

• Hydrocortisone: 100 mg IV.
  ‍
• ~Continue hydrocortisone 6 hourly until the patient is stable.
  
• ~No fludrocortisone, as high cortisol levels have a weak mineralocorticoid action
  

• Aggressive fluid resuscitation; hypotension; hyponatremia
  
  
• 1 litre normal saline infused over 30-60 mins or with dextrose if hypoglycaemic
  
  
• Intensive care monitoring
  
  
• Oral replacement may begin after 24 hours and be reduced to maintenance over 3-4 days

Guidelines

Endocrine society

NICE