Addison's disease and other conditions inducing hypocortisolism


  • The most common symptoms of insufficient levels of cortisol include weight loss, fatigue, nausea and hypotension. Skin hyperpigmentation may also be present. The disease may also present as an acute Addisonian crisis.
  • Patients receiving replacement therapy should increase the drug dose prophylactically in stressful situations.
  • The reference range and clinical decision-making thresholds of the cortisol concentration depend on the method used by the laboratory.
    • Check the relevant method comparison table in the laboratory’s handbook to find comparable cortisol concentrations.

Aetiology of hypocortisolism

  • Adrenocortical disease (Addison's disease)
    • The most common cause (75–95%) is autoimmune adrenalitis.
    • Other causes include infections (such as tuberculosis, HIV), haemorrhage, infiltrative disease, metastases, trauma, adrenalectomy, medication, hereditary diseases (such as congenital adrenocortical hyperplasia).
    • May appear as a manifestation of the autoimmune polyendocrine syndrome type 1 (APS-1) (APECED (autoimmune polyendocrinopathy -candidiasis -ectodermal dystrophy)).
  • Pituitary or hypothalamic disease
    • Tumour, trauma, infection, or circulatory disorder (in the elderly)
    • No skin hyperpigmentation. As there is no mineralcorticoid deficiency, hyperkalaemia will also not be present.
  • Long-term glucocorticoid treatment (Pharmacological glucocorticoid treatment) (including long-term treatment with opioids) of several weeks may cause pituitary adrenocortical insufficiency and depression of endogenous cortisol production.


Slowly developing symptoms

  • Fatigue and asthenia in almost 100% of patients
  • Loss of appetite, nausea in 90%, weight loss in 80%
  • Hypotension (< 110/70 mmHg) in 90%, initially only postural
  • Skin or mucosal hyperpigmentation in 80%
    • Note that in hypopituitarism-induced hypocortisolism the skin is pale.
  • Less frequently
    • Abdominal pain, vomiting
    • Craving for salt
    • In women, menstrual disturbances, in men decreased libido
    • Mood disorders, depression

Laboratory findings

  • Electrolyte imbalances
    • Hyponatraemia is the earliest electrolyte disturbance in Addison's disease.
    • As Addison's disease advances, findings include hyperkalaemia, and sometimes hypercalcaemia, in addition to hyponatraemia.
    • In secondary hypocortisolism (ACTH deficiency) the electrolyte levels are often normal; hyponatraemia may occur.
  • Hypoglycaemia, even neuroglycopenia
  • Normocytic anaemia and eosinophilia

Diagnostic tests

  • Serum cortisol and plasma ACTH
    • A diagnosis of hypocortisolism is possible if the morning cortisol concentration is under 250(–300) nmol/l and probable if the concentration is under 150 nmol/l. Morning cortisol concentrations exceeding 250(–300) nmol/l normally exclude hypocortisolism.
  • A short ACTH stimulation test can sometimes be performed to confirm hypocortisolism.
  • If the results of these tests are suggestive of Addison's disease, the patient should be referred to specialized care for further investigations and planning of treatment.
    • If antiadrenal antibodies are negative in a patient with primary adrenal insufficiency, imaging of the adrenals should be considered.
    • In secondary hypocortisolism, other pituitary hormones should be tested and the pituitary imaged unless the condition is clearly glucocorticoid therapy-induced suppression of the pituitary-adrenal axis (suppressed ACTH secretion).
  • Glucocorticoid therapy-induced suppression of the pituitary-adrenal axis can be evaluated towards the end of the tapering off period by measuring the serum cortisol concentration from a blood sample collected in the morning.
    • For glucocorticoid treatment to be withdrawn, the cortisol level should be > 250 nmol/l.
    • In case of crisis (fever, severe physical strain), the patient may still need glucocorticoid treatment.
    • The sample should be collected so that there is an interval of at least 48 hours since the latest prednisone dose and at least 24 hours since the latest hydrocortisone dose.

Addisonian crisis

  • Addisonian crisis is an acute situation with the clinical picture predominated by severe symptoms of hypocortisolism.
  • The possibility of Addisonian crisis must be borne in mind in patients with extreme fatigue and asthenia, hypotension, nausea and vomiting, and an impaired level of consciousness.
  • Addisonian crisis may be the result of an infection or severe stress in a patient with untreated hypocortisolism.


  • Hydrocortisone replacement therapy
    • As soon as the diagnosis is suspected the following tests should be carried out: basic blood count with platelet count, potassium, sodium, plasma glucose, creatinine, serum cortisol, plasma ACTH and ECG. Laboratory tests to confirm infection and a chest x-ray may also be indicated.
    • Without waiting for the results, replacement therapy is started: 100 mg hydrocortisone i.v. Follow-up treatment is presented in table T1.
  • Management of fluid balance and correction of electrolyte imbalances
    • The aim is to correct hypovolaemia and dehydration, as well as any hyponatraemia and hypoglycaemia. See table T1.
  • Antimicrobial therapy should be started if there are signs of a bacterial infection.
  • During the acute phase, basic blood count with platelet count, potassium, sodium and plasma glucose should be monitored.
Table 1. Treatment of acute Addisonian crisis
1. Correction of hypotension and electrolyte imbalances.
  • NaCl 0.9% or NaCl 0.9%/G5 solution, 1,000 ml/ during the first hour; adults need 3,000–4,000 ml during the first 24 hours.
2. Hydrocortisone replacement therapy as soon as blood samples have been collected for diagnosis
  • Initial dose 100 mghydrocortisone i.v.
  • Subsequent doses. First day: 50 mg hydrocortisone every 6 hours i.v./i.m. or 200 mg hydrocortisone as a 24-hour infusion.
  • Second day: 50 mg hydrocortisone every 12 hours i.m./i.v.
  • Third day: 25 mg hydrocortisone 3 times daily p.o. (if oral medication can be started)
  • To be followed first by hydrocortisone 40 mg in the morning and 20 mg in the afternoon p.o., and as the acute situation subsides, the former maintenance dose used at home is introduced.
  • Fludrocortisone (Florinef®) 0.1 mg/day should be introduced when the crisis is over or the hydrocortisone dose is lower than 40 mg/day
3. Treatment of the underlying problem that precipitated the crisis

Replacement therapy

  • For adults, 15–25 mg/day of hydrocortisone (for patients weighing 70 kg, 15 mg/day) divided into 2 or 3 doses (between 8 a.m. and 6 p.m.). The highest dose should be taken in the morning after waking up. The last dose should be taken 4–6 hours before going to bed.
  • 2.5–5 mg prednisolone can be considered in rare cases; dexamethasone is not recommended.
  • New modes of administration where the release of hydrocortisone is slow and modified are used in some countries but not yet available everywhere.
  • The mineralcorticoid (Florinef®) should be given in doses of 0.05–0.2 mg administered once daily.
  • DHEA replacement therapy (25–50 mg/day) may be considered in women.
  • Long-term studies indicate that patients with treated Addison’s disease still have reduced quality of life. Also the mortality is increased.

Treatment in special situations

  • The patient should be given written advice, and he/she should carry a medical alert card provided by the treating unit.
  • The dose of hydrocortisone must be doubled during a febrile infection.
    • The patient may need a supplemental dose of hydrocortisone (5–10 mg) to cover significant physical (lengthy exercise session, hot weather) or mental stress.
  • The need for fludrocortisone may be increased by exposure to hot weather, abundant sweating.
  • The hydrocortisone dose is usually increased individually by about 2.5–10 mg/day during the last trimester of pregnancy. Mineralocorticoid need is also often increased during the last trimester of pregnancy.

Treatment in association with surgery

  • See table T2
Table 2. Recommended glucocorticoid dosage in stress situations in patients with adrenal insufficiency
Procedure or clinical condition Dosing of glucocorticoids
Minor surgical procedure or illness
  • Inguinal hernia repair
  • Colonoscopy
  • Mild febrile illness
  • Mild gastroenteritis
  1. Before the procedure, 25 mg hydrocortisone orally or intravenously in addition to the normal replacement dose.
  2. On the days of illness, double the normal replacement dose.
Moderate surgical procedure or illness
  • Cholecystectomy
  • Hemicolectomy
  • Pneumonia
  • Severe gastroenteritis
  1. Before the procedure, 50 mg hydrocortisone or 10 mg methylprednisolone intravenously in addition to the normal replacement dose. The dose should be tapered over 1–2 days to the usual dose.
  2. On the days of illness, 50 mg hydrocortisone orally, intramuscularly or intravenously divided into 2 doses in addition to the normal replacement dose. The dose should be tapered to the usual dose according to recovery from the illness.
Major procedure or illness
  • Bypass surgery
  • Liver resection
  • Pancreatectomy
  • Pancreatitis
  1. On the day of the procedure, 150 mg hydrocortisone or 30 mg methylprednisolone intravenously divided into 2-3 doses in addition to the normal replacement dose. The dose should be tapered over 2 days to the usual dose depending on recovery.
  2. On the days of illness, 100 mg hydrocortisone intravenously divided into 2 doses in addition to the normal replacement dose. The dose should be tapered to the usual dose according to recovery from the illness.
Critical illness
  • Sepsis
  • Shock
  1. 100 mg Hydrocortisone intravenously, followed by 50 mg intravenously every 6 hours.
  2. Gradual tapering off


  • Annual appointment
    • Clinical examination and the patient's condition (general coping, ability to concentrate, sexual health, sleep)
    • Any clinical signs of excessive glucocorticoid dosage
    • Weight
    • Blood pressure
    • Plasma sodium and potassium, basic blood count with platelet count
    • Oedema may be suggestive of too high a mineralcorticoid dose
    • The patient should be asked about salt craving (signifies a need for a mineralcorticoid), and, as necessary, plasma renin should be determined.
    • Serum cortisol or plasma ACTH measurements are not beneficial in routine follow-up.
  • As the probability of developing other autoimmune diseases (type 1 diabetes, hypothyroidism, pernicious anaemia, coeliac disease, hypogonadism) is clearly increased in patients with autoimmune adrenalitis, follow-up should also include HbA1c, TSH, transcobalamin II-bound vitamin B12, and IgA class tissue transglutaminase antibodies.


1. Øksnes M, Husebye ES. Approach to the Patient: Diagnosis of Primary Adrenal Insufficiency in Adults. J Clin Endocrinol Metab 2023;109(1):269-278  [PMID:37450570]
2. Husebye ES, Pearce SH, Krone NP, et al. Adrenal insufficiency. Lancet 2021;397(10274):613-629  [PMID:33484633]
3. Betterle C, Presotto F, Furmaniak J. Epidemiology, pathogenesis, and diagnosis of Addison's disease in adults. J Endocrinol Invest 2019;42(12):1407-1433  [PMID:31321757]
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