Addison's disease and other conditions inducing hypocortisolism


  • The symptoms of insufficient levels of cortisol include weight loss, fatigue and hypotension. Skin pigmentation 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.
  • Note! The reference range and clinical decision-making thresholds of 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. In some laboratories the cortisol concentrations may be e.g. 20–30% lower than the ones indicated in this article.

Aetiology of hypocortisolism

  • Adrenocortical disease (Addison's disease)
  • Pituitary or hypothalamic disease
    • Tumour, trauma, infection, or circulatory disorder (in the elderly)
    • No skin pigmentation, and as there is no mineralcorticoid deficiency hyperkalaemia will not be present.
  • Long-term glucocorticoid treatment causes glucocorticoid depression (Pharmacological glucocorticoid treatment)


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 pigmentation in 80%
    • Note that in hypopituitarism-induced hypocortisolism the skin is pale.
  • More rarely
    • Abdominal pain, diarrhoea, constipation
    • Craving for salt, fainting, vitiligo

Laboratory findings

  • Electrolyte disturbances
    • Hyponatraemia is the earliest electrolyte disturbance in Addison's disease.
    • In advanced Addison's disease, hyperkalaemia, and sometimes hypercalcaemia, may occur 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

  • Plasma cortisol Dynamed
    • Hypocortisolism is a possible diagnosis if the morning cortisol concentration is under 350 nmol/l and probable if the concentration is under 180 nmol/l. An occasional reading under 400 nmol/l in a seriously ill patient denotes adrenal insufficiency, and only a reading > 900 nmol/l is a certain sign of normal adrenal function.
  • A short ACTH test Dynamed should be performed, as required, to confirm hypocortisolism. This can be carried out within primary health care if such service is available.
  • If the results of these tests are suggestive of Addison's disease, the patient must be sent to specialist health 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 male patients, the possibility of adrenoleukodystrophy should be kept in mind (serum VLCFA test).
  • Glucocorticoid therapy induced suppression of the pituitary-adrenal axis (suppressed ACTH secretion) can be evaluated towards the end of the tapering off period by measuring the plasma cortisol concentration from a blood sample collected in the morning. For glucocorticoid treatment to be safely withdrawn, the cortisol level should be > 200 nmol/l. 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. The patient may still need glucocorticoid therapy during stressful situations (fever, intense physical strain).

Addisonian crisis

  • Addisonian crisis is a medical emergency and presents as a constellation of symptoms that indicate severe 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 test should be carried out: haematocrit, plasma potassium, plasma sodium, blood glucose, plasma creatinine, plasma cortisol (save a sample for later determination) and ECG. Laboratory tests to confirm infection and a chest x-ray are also often indicated. Without waiting for the results, replacement therapy is started: hydrocortisone 100–200 mg i.v. Dynamed. 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 possible hyponatraemia and hypoglycaemia. See table T1.
  • Antimicrobials should be started if there are signs of a bacterial infection.
  • During the acute phase, haematocrit, plasma potassium, sodium and blood glucose must be closely monitored.

Table 1. Treatment of acute Addisonian crisis
1. Correction of hypotension and electrolyte imbalances.
  • NaCl 0.9% 1,000 ml/ first hour and thereafter 500 ml/hour.
2. Hydrocortisone replacement therapy as soon as blood samples have been collected for diagnosis
  • Initial dose hydrocortisone 100(–200) mg i.v.
  • Subsequent doses. First day: hydrocortisone 50–100 mg every 6 hours i.v./i.m. or hydrocortisone 50–100 mg as an infusion over 8 hours repeated three times.
  • Second day: hydrocortisone 50 mg every 6 hours i.m./i.v.
  • Third day: hydrocortisone 25 mg every 8 hours p.o. (if possible, oral medication is started)
  • To be followed by hydrocortisone 40 mg + 20 mg p.o., and after the acute situation has stabilised a maintenance dose is introduced.
  • Fludrocortisone 0.1 mg/day is introduced when the hydrocortisone dose is smaller than 50 mg/day
3. Treatment of the underlying problem that precipitated the crisis

Replacement therapy

  • In adults, hydrocortisone Dynamed10–25 mg/day (15 mg/day in a patient weighing 70 kg) divided into 2 or 3 doses (between 8 a.m. and 6 p.m.). In special circumstances, prednisone 2.5 mg–5 mg at bedtime, and (if necessary) hydrocortisone 5–10 mg in the afternoon. The smallest effective doses should be used in the basic treatment; additional doses are taken in special situations (see below). New modes of administration where the release of hydrocortisone is slow and modified are being introduced.
  • The mineralcorticoid Dynamed 0.05–0.2 mg is administered once daily.
  • DHEA replacement therapy (25–50 mg/day) Dynamed 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.
  • Products releasing glucocorticoid in such a manner that the cortisol levels better resemble the physiological circadian profile are under development.

Treatment in special situations

  • The patient must be given written advice, and he/she should carry a medical alert card (necklace, wristband).
  • The dose of hydrocortisone must be doubled during a febrile infection.
    • The patient may also need a supplemental dose of hydrocortisone (5–10 mg) to cover less strenuous physical or mental stress (e.g. intense exercise of a long duration or an examination at school/university).
  • The patient is advised to increase the fludrocortisone dose and salt intake if unusually great sodium loss (perspiration, diarrhoea) is expected.
  • The hydrocortisone dose is usually increased Dynamed by about 50% during the last trimester of pregnancy mainly because of the anticipated additional requirement during delivery. The requirement for mineralocorticoids is also often increased during the last trimester of pregnancy.

Treatment during surgery

  • See table T2

Table 2. The dosing of glucocorticoids during infections and surgery
Procedure or clinical condition Dosing of glucocorticoids
Minor surgical procedure or illness
  • Inguinal hernia repair
  • Colonoscopy
  • Mild febrile illness
  • Mild gastroenteritis
  • Before the procedure, hydrocortisone 25 mg orally or intravenously in addition to the normal dose.
  • On the days of illness (see the left column), double the normal dose.
Moderate surgical procedure or illness
  • Cholecystectomy
  • Hemicolectomy
  • Pneumonia
  • Severe gastroenteritis
  • Before the procedure, hydrocortisone 50–75 mg (or alternatively methylprednisolone 10–15 mg) intravenously in addition to the normal dose. The dose is tapered over 1–2 days to the usual dose.
  • On the days of illness, hydrocortisone 50–75 mg orally, intramuscularly or intravenously divided into 2–3 doses in addition to the normal dose. The dose is tapered to the usual dose according to recovery from the illness.
Major procedure or illness
  • By-pass surgery
  • Liver resection
  • Pancreatectomy
  • Pancreatitis
  • On the day of the procedure, hydrocortisone 100 mg (or alternatively methylprednisolone 20 mg) intravenously divided into 2-3 doses in addition to the normal dose. The dose is tapered over 1–2 days to the usual dose.
  • On the days of illness, hydrocortisone 100 mg intravenously divided into 2–3 doses in addition to the normal dose. The dose is tapered to the usual dose according to recovery from the illness.
Critical illness
  • Sepsis
  • Shock
  • Hydrocortisone 100 mg intravenously, followed by 50 mg intravenously every 6–8 hours. Gradual tapering off (table T1)


  • Annual appointment
    • Clinical examination and the patient's condition (general coping, ability to concentrate, sexual health, sleep)
    • Weight
    • Blood pressure
    • Plasma sodium and potassium
    • Oedema is suggestive of too high a mineralcorticoid dose
    • The patient should be asked about salt craving (signifies a need for a mineralcorticoid), and plasma ACTH and renin should be determined, if necessary.
    • Plasma cortisol measurement is not indicated in routine follow-up.
  • The probability of contracting other autoimmune diseases (type 1 diabetes, hypothyroidism, pernicious anaemia, hypogonadism) is clearly increased in patients with autoimmune adrenalitis.


1. Bancos I, Hahner S, Tomlinson J et al. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol 2015;3(3):216-26.  [PMID:25098712]

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