Addison's Disease


Overview Addison's disease is a disease characterised by adrenal insufficiency. Adrenal insufficiency results in a decrease of the adrenal gland hormones: mineralocorticoids, glucocorticoids and to an extent androgens. There are many causes of addison's disease. The most common cause in the developed world is autoimmune (approximately 70% cases). Signs and symptoms of adrenal sufficiency don't really occur until 90% of adrenal function is lost.

Adrenal insufficiency: Adrenal insufficiency results from inadequate adrenocortical function and may be due to destruction of the adrenal cortex (primary or Addison’s disease) or to disordered pituitary and hypothalamic function (secondary).
Addison's Disease: Primary adrenal sufficiency independent of hypothalamic, pituitary dysfunction
Cushing's Disease: Hypercortisolemia from an ACTH-secreting pituitary tumor (ACTH Dependent)

Adrenal Glands


  • The normal adrenal glands weigh 4–5 g.
  • The cortex represents 90% of the normal gland and surrounds the medulla.
  • The arterial blood supply arises from the renal arteries, aorta, and inferior phrenic artery.
  • Venous drainage occurs via the central vein into the inferior vena cava on the right, and into the left renal vein on the left.
  • Three layers of the adrenal glands
    • Zona fasiculata
    • Zona glomerulosa
    • Zona Reticularis


  • Glucocorticoids (zona fasciculata)
  • Mineralcorticoids (zona glomerulosa)
  • Androgens (zona reticularis and zona fasciculata)
Endocrinology - Adrenal Hormones

Adrenal Gland physiology

Signs and Symptoms


  • Adrenal Crisis (Life-threatening)
Think Acute Adrenal insufficiency (Adrenal Crisis) is commonly caused when patients who are on long term glucocorticoids suddenly stop or do not increase dosage during febrile illness.

General presentation (Chronic)

  • Anorexia and weight loss (>90%)
  • Tiredness
  • Weakness—generalized, no particular muscle groups
  • Pigmentation—generalized, but most common in light-exposed areas and areas exposed to pressure (elbows and knees, and under bras and belts); mucosa and scars acquired after onset of adrenal insufficiency. Look at palmar creases in Caucasians.
  • Dizziness
  • GI symptoms—nausea and vomiting, abdominal pain, diarrhea
  • Arthralgia and myalgia
  • ↓ Axillary and pubic hair and reduced libido in women


Clinical Examination 

  • Skin pigmentation (sun exposed areas, mucosal surfaces)
  • Cachexia
  • Loss of body hair
  • Low grade fever (rare)
  • Postural hypotension
  • Signs of dehydration


Differential Diagnosis

  • Hyperthyroidism such as Graves Disease
  • Anorexia Nervosa
  • Adrenal suppression due to long-term corticosteroids (for example patients with some rheumatological conditions will be on long-term corticosteroids)
  • Haemochromotosis
Schmidt syndrome Addison's Disease and Autoimmune hypothyroidism
Carpenter Syndrome Addison's Disease, Autoimmune hypothyroidism and/or Type 1 diabetes mellitus


  • EUC - hyponaturemia (90%), hyperkalaemia (65%), urea elevated
  • Serum Cortisol - undetectable is diagnostic of adrenal insufficiency
  • Serum ACTH - Elevated in Primary adrenal insufficiency
Think In Secondary Adrenal Insufficiency there is ↓Serum Cortisol and ↓ACTH
  • Response to ACTH
  • Plasma renin
  • Thyroid function test
  • Adrenal autoantibodies - antibodies to 21-hydroxylase and 17-hydroxylase.
  • CT scan - tumours



There are many causes of Addison's Disease

  • Autoimmune (70%)
  • Malignancy (metastatic, lymphoma)
  • Infiltration (amyloid, haemochromatosis)
  • Infection
  • Vascular haemorrhage
  • Infarction
  • Adrenoleucodystrophy
  • Congenital adrenal hyperplasia
  • Iatrogenic (Adrenalectomy, Drugs)


Adrenal gland destruction or dysfunction occurs from a disease process that usually involves all three zones of the adrenal cortex, resulting in inadequate glucocorticoid, mineralocorticoid, and androgen secretion. Autoimmunity is the main etiologic factor.

The manifestations of insufficiency do not usually appear until at least 90% of the gland has been destroyed and are usually gradual in onset, with partial adrenal insufficiency leading to an impaired cortisol response to stress, and the features of complete insufficiency occurring later.

Acute adrenal insufficiency may occur in the context of acute septicemia (e.g., meningococcal or hemorrhage).


Mineralocorticoid deficiency leads to reduced sodium retention and hypotension with ↓ intravascular volume, in addition to hyperkalemia due to ↓ renal potassium and hydrogen ion excretion.

Androgen deficiency presents in women with reduced axillary and pubic hair and reduced libido. (Testicular production of androgens is more important in men.)

Lack of cortisol negative feedback increases CRH and ACTH secretion. An increase in other POMC-related peptides leads to skin pigmentation and other mucous membranes.


  • Patient Education
  • Glucocorticoid replacement (Hydrocortisone)
  • Mineralocorticoid replacement - Fludrocortisone (9-flurohydrocortisone)
  • Dihydroepiandrosterone replacement
  • Monitor and review


Side note Dehydroepiandrosterone (DHEA) is an abundant circulating adrenal androgen with a production rate of 25–50 mg/day. Its levels undergo a progressive decline with ↑ age, and there has been interest in its physiological role.
Side note Patient education is the key to successful management. Must be taught never to miss a dose, encouraged to wear a Medic Alert bracelet and every patient should know how to double the dose of glucocorticoid during febrile illness and to get medical attention if unable to take the tablets because of vomiting.

Complications and Prognosis

  • Treatment related Hypertension
  • Cushing's Syndrome
  • Osteopenia → Osteoporosis
  • Adrenal crisis


Adrenal Crisis


Best Practice
Oxford Handbook of Endocrinology and Diabetes