Addison’s Disease and Adrenal Insufficiency

Primary adrenal insufficiency is when the adrenal glands are unable to produce enough gluco- +/- mineralo-corticoid hormones due to the presence of adrenal disease.

Secondary adrenal insufficiency is when the adrenal glands are essentially normal but there is glucocorticoid insufficiency due to a lack of stimulation from ACTH.

Background

  • Primary insufficiency is relatively rare (incidence of around 1/10000/year; prevalence of around the same in the UK).  Primary adrenal insufficiency is known as Addison’s disease.
  • Secondary insufficiency is really quite common (may be present in up to 25-30% of patients admitted to critical care)

Aetiology/Pathophysiology

Primary Hypoadrenalism (Addison’s disease)

  • Autoimmune destruction (most common in the developed world- accounting for 70-90% of cases)
    • Around 40% have isolated adrenal disease and 60% have multi-organ disease
      • Most commonly parathyroid (type 1 polyglandular autoimmune syndrome; rarer; presents in childhood); and thyroid, pancreas (insulin-dependent diabetes) and hypogonadism (type 2 polyglandular autoimmune syndrome- more common; presents between 30-50 years old)
    • Antibodies against the 21-hydroxylase enzyme are usually present (type 2) and occasionally those against 17α-hydroxylase also (type 1)
    • Cause a predominantly T-cell mediated inflammation of the adrenal cortex.  This can lead to necrosis and shrinking of the adrenal glands.
  • Infective causes e.g tuberculosis (TB), histoplasmosis, cytomegalovirus and HIV- are the most common causes worldwide.
  • Other rarer causes include haemorrhage (e.g. anticoagulants, severe sepsis (Waterhouse-Friderichsen syndrome- usually meningococcal disease); infarction (e.g. in antiphospholipid syndrome); invasion (e.g. neoplasms- adrenal primary or secondary metastases); rare genetic causes (e.g. adrenoleukodystrophy)
    • Note that surgical removal of the adrenal gland(s) effectively results in Addison’s disease.  Other ‘secondary’ causes of primary hypoadrenalism are drugs e.g. ketoconazole/metapyrone, cytotoxic agents

Congenital Adrenal Hyperplasia

  • Rare (1:18000 for classic; 1:3000 nonclassic), congenital, usually autosomal recessive, disorder characterised by a deficiency of steroid enzymes e.g. 21-hydroxylase, 3β-hydroxysteroid dehydrogenase.
  • There are several forms of the disease
    • ‘Classical’- usually more severe and is picked up within the first few weeks of life.  There is a salt-losing form and a non-salt-losing form.
      • Females are usually picked up early due to ambiguous genitalia (enlarged clitoris and a common urogenital tract)
      • Males can either present within the first few weeks of life with an acute adrenal crisis (salt-losing form) or at 2-4 years with virilisation.
    • ‘Nonclassic’ or ‘cryptogenic’- usually milder and presents later in childhood/early adulthood
      • May present with early-onset puberty; females occasionally with infertility, hirsutism, oligo- or amenorrhoea with PCOS.  Otherwise, symptoms may be absent and the diagnosis may be incidental.
  • Can be diagnosed by serum 17-hydroxyprogesterone (raised if 21-hydroxylase deficient) but gold standard is a Synacthen test (give dose of ACTH and test adrenal response)
  • Management is with replacement steroids (usually only classic type; nonclassic is not usually severe enough to warrant treatment):
    • Hydrocortisone in children; prednisolone usually in adults
    • Fludrocortisone
    • Salt losing form may also require sodium chloride supplementation

Secondary Hypoadrenalism

  • Most commonly secondary to exogenous steroid use (most common cause of hypoadrenalism).  This suppresses the hypothalamic-pituitary-adrenal axis.  When steroids are stopped, the adrenal glands are no longer producing endogenous steroids.
  • Other rarer causes include pituitary tumours (suppressing ACTH production); CRH deficiency; cranial radiotherapy; surgery; panhypopituitarism of other cause

Presentation

  • Acute adrenal insufficiency (rare but life-threatening) (Around half of patients with Addison’s are diagnosed only after an Addisonian crisis)
    • Often occurs in patients who are acutely unwell for other reasons e.g. sepsis, gastroenteritis, major surgery, major haemorrhage
    • Patients can present with
      • Hypotension/tachycardia
      • Hypovolaemic shock
      • Acute abdominal pain
      • Low grade fever
      • Vomiting and dehydration
      • Confusion/delirium
      • Weakness
  • Chronic adrenal insufficiency often presents with the gradual onset of rather non-specific symptoms:
    • Fatigue
    • Hyperpigmentation (increased ACTH)- particularly in sun-exposed areas, recent scars, pressure points, areas of friction, palmar creases and mucous membranes
      • Note that this won’t be present in secondary addison’s
    • Muscle weakness (cramps and joint pain may also occur)
    • GI symptoms: weight loss, loss of appetite; premature satiety; nausea/vomiting; change in bowel habit; abdominal pain; salt craving
    • Postural dizziness or syncope/presyncope
    • Headache
    • Low grade fever
    • Polydipsia and polyuria
    • Confusion or personality change/irritability
    • Oligo- or amenorrhoea
    • Loss of pubic hair in women

Investigations

  • Blood tests
    • FBC – there may be a normocytic anaemia; lymphocytosis; eosinophilia
    • U&Es- hyponatraemia, hyperkalaemia, raised urea
    • Abnormal LFTs
    • ABGs– Other electrolytes may also be disturbed e.g. low chloride; low bicarbonate, resulting in a raised anion gap
    • Hypercalcaemia
    • Hypoglycaemia
    • TFTs- Raised TSH may be seen
  • Definitive test
    • A short synacthen test
      • Injection of synthetic ACTH (corticotropin) (250μg of tetracosactide)
      • Serum cortisol measured immediately, at 30 and at 60 mins.
        • Raise to >500nmol/l is considered normal.
    • Urinary 17-hydroxysteroid following IV infusion of 250mg ACTH for 3-5 days can distinguish between primary and secondary hypoadrenalism
      • In primary insufficiency, levels do not change.  In secondary insufficiency, levels rise 3-5 fold
      • Alternatively, serum ACTH can also be measured
  • Other tests to determine the cause
    • CXR for lung neoplasm
    • MRI adrenals (looking for small or large adrenals- Addison’s or CAH, respectively)
    • Adrenal autoantibodies
  • Other tests
    • ECG- prolonged PR and QT interval, peaked T waves (all due to hyperkalaemia)
    • Pituitary function tests

Management

  • Replacement of steroid hormones
    • Cortisol- usually hydrocortisone 15-25mg/day, divided into 2 or 3 divided doses (usually 2/3 morning dose and 1/3 later dose to mimic normal)
      • During illness/injury/prolonged physical stress, patients should double/triple dose
        • IMPORTANT: Patients should be educated about the seriousness of getting ill and seeking medical attention early.
    • Fludrocortisone (50-200μg per day)
  • Management of an acute crisis
    • IV fluids, dextrose and hydrocortisone (200mg IV stat then 100mg IV every 6 hours for 24 hours; thereafter, half the dose again)
    • Treat the underlying cause
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