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Addison Disease

(Addison's Disease; Primary or Chronic Adrenocortical Insufficiency)


Ashley B. Grossman

, MD, University of Oxford; Fellow, Green-Templeton College

Reviewed/Revised Feb 2024
Topic Resources

Addison disease is an insidious, usually progressive hypofunctioning of the adrenal cortex. It causes various symptoms, including hypotension and hyperpigmentation, and can lead to adrenal crisis with cardiovascular collapse. Diagnosis is clinical and by finding elevated plasma adrenocorticotropic hormone (ACTH) with low plasma cortisol. Treatment depends on the cause but generally includes hydrocortisone and usually other hormones.

Addison disease develops in approximately 4/100,000 people annually (1 General reference Addison disease is an insidious, usually progressive hypofunctioning of the adrenal cortex. It causes various symptoms, including hypotension and hyperpigmentation, and can lead to adrenal crisis... read more General reference ). It occurs in all age groups, about equally in each sex, and tends to become clinically apparent during metabolic stress, infection, or trauma.

Adrenal crisis (onset of severe symptoms) may be precipitated by acute infection. Infection is a common cause, especially when there is septicemia. Other causes include trauma, surgery, and sodium loss due to excessive sweating. Even with treatment, Addison disease may cause a slight increase in mortality. It is not clear whether this increase is due to mistreated adrenal crises or long-term complications of inadvertent over-replacement.

General reference

  • 1. Alexandraki KI, Sanpawithayakul K, Grossman A. Adrenal Insufficiency. [Updated 2022 Nov 7]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000-. Available from:

Etiology of Addison Disease

Etiology reference

  • 1. Kemp WL, Koponen MA, Meyers SE. Addison Disease: The First Presentation of the Condition May be at Autopsy. Acad Forensic Pathol 2016;6(2):249-257. doi:10.23907/2016.026

Pathophysiology of Addison Disease

Both mineralocorticoids and glucocorticoids are deficient.

Mineralocorticoid deficiency

Because mineralocorticoids stimulate sodium reabsorption and potassium excretion, deficiency results in increased excretion of sodium and decreased excretion of potassium, chiefly in urine but also in sweat, saliva, and the gastrointestinal tract. A low serum concentration of sodium (hyponatremia Hyponatremia Hyponatremia is decrease in serum sodium concentration < 136 mEq/L (< 136 mmol/L) caused by an excess of water relative to solute. Common causes include diuretic use, diarrhea, heart failure... read more ) and a high concentration of potassium (hyperkalemia Hyperkalemia Hyperkalemia is a serum potassium concentration > 5.5 mEq/L (> 5.5 mmol/L), usually resulting from decreased renal potassium excretion or abnormal movement of potassium out of cells. There... read more ) result.

Urinary salt and water loss cause severe dehydration, plasma hypertonicity, acidosis, decreased circulatory volume, hypotension, and, eventually, circulatory collapse. However, when adrenal insufficiency is caused by inadequate adrenocorticotropic hormone (ACTH) production (secondary adrenal insufficiency Secondary Adrenal Insufficiency Secondary adrenal insufficiency is adrenal hypofunction due to a lack of adrenocorticotropic hormone (ACTH). Symptoms are the same as for Addison disease and include fatigue, weakness, weight... read more ), electrolyte levels are often normal or only mildly deranged, and the circulatory problems are less severe.

Glucocorticoid deficiency

Glucocorticoid deficiency contributes to hypotension and causes severe insulin sensitivity and disturbances in carbohydrate, fat, and protein metabolism. In the absence of cortisol, insufficient carbohydrate is formed from protein; hypoglycemia Hypoglycemia Hypoglycemia, or low plasma glucose level can result in sympathetic nervous system stimulation and central nervous system dysfunction. In patients with diabetes who take insulin or antihyperglycemic... read more and decreased liver glycogen result. Weakness follows, due in part to deficient neuromuscular function. Resistance to infection, trauma, and other stress is decreased. Myocardial weakness and dehydration reduce cardiac output, and circulatory failure can occur.

A decreased blood cortisol level results in increased pituitary ACTH production and increased blood beta-lipotropin level. Beta-lipotropin has melanocyte-stimulating activity and, together with ACTH, causes the hyperpigmentation of skin and mucous membranes characteristic of Addison disease. Thus, adrenal insufficiency secondary to pituitary failure Secondary Adrenal Insufficiency Secondary adrenal insufficiency is adrenal hypofunction due to a lack of adrenocorticotropic hormone (ACTH). Symptoms are the same as for Addison disease and include fatigue, weakness, weight... read more does not cause hyperpigmentation.

Symptoms and Signs of Addison Disease

Weakness, fatigue, and orthostatic hypotension are early symptoms and signs of Addison disease.

Hyperpigmentation is characterized by diffuse darkening of exposed and, to a lesser extent, unexposed portions of the body, especially on pressure points (bony prominences), skin folds, scars, and extensor surfaces. Black freckles are common on the forehead, face, neck, and shoulders. Bluish black discolorations of the areolae and mucous membranes of the lips, mouth, rectum, and vagina occur.

Anorexia, nausea, vomiting, and diarrhea often occur. Decreased tolerance to cold, with hypometabolism, may be noted. Dizziness and syncope may occur.

The gradual onset and nonspecific nature of early symptoms often lead to an incorrect initial diagnosis of neurosis.

Weight loss, dehydration, and hypotension are characteristic of the later stages of Addison disease.

Adrenal crisis

Adrenal crisis is characterized by

  • Profound asthenia (weakness)

  • Severe pain in the abdomen, lower back, or legs

  • Peripheral vascular collapse

  • Renal shutdown with azotemia

Body temperature may be low, although severe fever often occurs, particularly when crisis is precipitated by acute infection.

A significant number of patients with partial loss of adrenal function (limited adrenocortical reserve) appear well but experience adrenal crises when under physiologic stress (eg, surgery, infection, burns, critical illness). Shock and fever may be the only signs.

Diagnosis of Addison Disease

  • Electrolyte levels

  • Serum cortisol

  • Plasma adrenocorticotropic hormone (ACTH)

  • Sometimes ACTH stimulation testing

Clinical symptoms and signs suggest adrenal insufficiency. Sometimes the diagnosis is considered only on discovery of characteristic abnormalities of serum electrolytes, including low sodium, high potassium , low bicarbonate, and high BUN (blood urea nitrogen—see table ).


Test Results That Suggest Addison Disease



Blood chemistry

Serum sodium

< 135 mEq/L (< 135 mmol/L)

Serum potassium

> 5 mEq/L (> 5 mmol/L)

Ratio of serum sodium:potassium

< 30:1

Plasma glucose, fasting

< 50 mg/dL (< 2.8 mmol/L)

Plasma bicarbonate

< 15–20 mEq/L (< 15–20 mmol/L)

BUN (blood urea nitrogen)

> 20 mg/dL (> 7.1 mmol/L)




White blood cell count



Relative lymphocytosis




X-ray or CT of adrenals

Evidence of

  • Calcification in adrenal area

  • Hemorrhage

  • Atrophy

Differential diagnosis

The varied manifestations of Addison disease can also be caused by numerous other disorders.

Hyperpigmentation can result from

Weakness resulting from Addison disease subsides with rest, unlike neuropsychiatric weakness, which is often worse in the morning than after activity. Most myopathies that cause weakness can be differentiated by their distribution, lack of abnormal pigmentation, and characteristic laboratory findings (see also Weakness Weakness Weakness is one of the most common reasons patients present to primary care clinicians. Weakness is loss of muscle strength, although many patients also use the term when they feel generally... read more ).

Patients with adrenal insufficiency develop hypoglycemia Hypoglycemia Hypoglycemia, or low plasma glucose level can result in sympathetic nervous system stimulation and central nervous system dysfunction. In patients with diabetes who take insulin or antihyperglycemic... read more after fasting because of decreased gluconeogenesis and often show weight loss, which is not fully understood, but due at least in part to extracellular volume deficiency. In contrast, patients with hypoglycemia due to oversecretion of insulin usually have increased appetite with weight gain, and have normal adrenal function.


Laboratory tests, beginning with morning serum cortisol and plasma ACTH levels, confirm adrenal insufficiency (see table ). Elevated ACTH ( 50 pg/mL [ 11 pmol/L]) with low cortisol (< 5 mcg/dL [< 138 nmol/L]) is diagnostic, particularly in patients who are severely stressed or in shock. Low ACTH (< 5 pg/mL [< 1.1 pmol/L] ) and low cortisol suggest secondary adrenal insufficiency Secondary Adrenal Insufficiency Secondary adrenal insufficiency is adrenal hypofunction due to a lack of adrenocorticotropic hormone (ACTH). Symptoms are the same as for Addison disease and include fatigue, weakness, weight... read more . It is important to note that ACTH levels within the normal range are inappropriate when cortisol levels are very low.

If ACTH and cortisol levels are borderline and adrenal insufficiency is clinically suspected—particularly in a patient who is about to undergo major surgery—provocative testing must be done. If time is too short (eg, emergency surgery), the patient should be given hydrocortisone empirically (eg, 100 mg IV or IM). Provocative testing is done subsequently.

Provocative testing

Addison disease is diagnosed by showing failure of exogenous ACTH to increase serum cortisol. Secondary adrenal insufficiency is diagnosed by a prolonged ACTH stimulation test, glucagon stimulation test, or insulin tolerance test.

ACTH stimulation testing is done by injecting cosyntropin (synthetic ACTH) 250 mcg IV or IM followed by measurement of serum cortisol levels. Some authorities believe that in patients with suspected secondary adrenal insufficiency Secondary Adrenal Insufficiency Secondary adrenal insufficiency is adrenal hypofunction due to a lack of adrenocorticotropic hormone (ACTH). Symptoms are the same as for Addison disease and include fatigue, weakness, weight... read more , a low-dose ACTH stimulation test using 1 mcg IV instead of the standard 250 mcg-dose should be done because such patients may react normally to the higher dose. Patients taking glucocorticoid supplements or spironolactone should not take them on the day of the test.

Normal preinjection serum cortisol levels vary somewhat depending on the laboratory assay in use but typically range from 5 to 25 mcg/dL (138 to 690 nmol/L) and double in 30 to 90 minutes, reaching at least 20 mcg/dL (552 nmol/L). Patients with Addison disease have low or low-normal preinjection values that do not rise above a peak value of 15 to 18 mcg/dL (414 to 497 nmol/L) at 30 minutes. However, the precise normal values depend on the specific cortisol assay used, and the normal range should be verified for each laboratory.

In the glucagon stimulation test, plasma ACTH and cortisol levels fail to rise in response to glucagon in patients with secondary adrenal insufficiency.

In the insulin tolerance test, ACTH and cortisol fail to rise in response to enough intravenous regular insulin to cause a reduction in blood glucose to a critical level. The tolerance test carries a risk for hypoglycemic seizure and is not recommended in patients suspected of having severe adrenal insufficiency.


Confirmatory Serum Testing for Addison Disease



Plasma ACTH

High ( 50 pg/mL [ 11 pmol/L])

Serum cortisol

Low (< 5 mcg/dL [< 138 nmol/L])

ACTH stimulation test

Subnormal (ie, 30-minute cortisol should be < 15–18 mcg/dL [< 414–497 nmol/L], according to the assay)

Prolonged (24-hour) ACTH stimulation test

Cortisol should be subnormal at 1 hour and should not rise further at 24 hours

ACTH = adrenocorticotropic hormone.

A subnormal response to cosyntropin may occur in secondary adrenal insufficiency. However, because pituitary failure may cause adrenal atrophy (and hence failure to respond to ACTH), if pituitary disease is suspected, the patient may need to be primed with long-acting ACTH 1 mg IM once a day for 3 days before the ACTH stimulation test. After such priming, there should be a normal response to the test with a rise in serum cortisol to > 20 mcg/dL (> 552 nmol/L), although this threshold is assay dependent.

A prolonged ACTH stimulation test (sampling for 24 hours) may be used to diagnose secondary (or tertiary, ie, hypothalamic) adrenal insufficiency. Cosyntropin 1 mg IM is given, and cortisol is measured at intervals for 24 hours, typically at 1, 6, 12, and 24 hours. Results for the first hour are similar for both the short (sampling stopped after 1 hour) and prolonged tests, but in Addison disease there is no further rise beyond 60 minutes. In secondary and tertiary adrenal insufficiency, cortisol levels continue to rise for 24 hours. Only in cases of prolonged adrenal atrophy is adrenal priming (with long-acting ACTH) necessary. The simple short test is usually done initially, because a normal response obviates the need for further investigation.

If adrenal crisis is suspected, confirmation of Addison disease by ACTH stimulation testing is deferred until the patient has recovered. If ACTH stimulation testing is done, elevated ACTH levels together with low cortisol levels confirm the diagnosis.

Testing for etiology

In areas where granulomatous causes are less likely, the cause is usually assumed to be autoimmune, unless there is evidence otherwise. Adrenal autoantibodies can be assessed. In autoimmune Addison disease, adrenal antibodies are often positive, at least initially.

Where granulomatous causes are more likely, tuberculosis is a common cause, so a chest x-ray should be done; if doubt exists, CT of the adrenals is helpful. In patients with autoimmune disease, the adrenals are atrophied, whereas in patients with tuberculosis or other granulomas, the adrenals are enlarged (initially) with frequent calcification. Bilateral adrenal hyperplasia, particularly in children and young adults, suggests a genetic enzyme defect. Adrenal hemorrhage is usually obvious on CT scanning.

Treatment of Addison Disease

  • Hydrocortisone or prednisolone

  • Fludrocortisone

  • Dose increase during intercurrent illness

Normally, cortisol is secreted maximally in the early morning and minimally at night. Thus, hydrocortisone (identical to cortisol) is given in 2 or 3 divided doses with a typical total daily dose of 15 to 20 mg. One regimen gives half the total in the morning, and the remaining half split between lunchtime and early evening (eg, 10 mg, 5 mg, 5 mg). Others give two thirds in the morning and one third in the evening. Doses immediately before bed should generally be avoided because they may cause insomnia. Alternatively, prednisolone 4 to 5 mg orally in the morning and possibly an additional 2.5 mg orally in the evening may be used.

Additionally, fludrocortisone 0.1 to 0.2 mg orally once a day is recommended to replace aldosterone. The easiest way to adjust the fludrocortisone dosage is to titrate it to normalize blood pressure and serum potassium levels. Normal hydration and absence of orthostatic hypotension are evidence of adequate replacement therapy. In some patients, fludrocortisone causes hypertension, which is treated by reducing the dosage or starting a nondiuretic antihypertensive. Adequate doses of fludrocortisone should be given even if use requires the addition of antihypertensives.

Intercurrent illnesses (eg, infections) are potentially serious and should be vigorously treated; the patient’s hydrocortisone dose should be doubled during the illness. If nausea and vomiting preclude oral therapy, parenteral therapy is necessary. Patients should be instructed when to take supplemental prednisolone or hydrocortisone and taught to self-administer parenteral hydrocortisone for urgent situations. A preloaded syringe with 100 mg hydrocortisone should be available to the patient for intramuscular or subcutaneous administration. A bracelet or wallet card giving the diagnosis and corticosteroid dose may help in case of adrenal crisis that renders the patient unable to communicate.

When salt loss is severe, as in very hot climates, the dose of fludrocortisone may need to be increased.

In coexisting diabetes mellitus and Addison disease, the hydrocortisone dose usually should not be > 30 mg/day. Higher doses of hydrocortisone increase insulin requirements.

Treatment of adrenal crisis

Therapy should be instituted immediately upon suspicion of adrenal crisis. (CAUTION: In adrenal crisis, a delay in instituting corticosteroid therapy, particularly if there is hypoglycemia and hypotension, may be fatal.) If the patient is acutely ill, confirmation by an ACTH stimulation test should be postponed until the patient has recovered.

Hydrocortisone 100 mg is injected IV over 30 seconds and repeated every 6 to 8 hours for the first 24 hours. Immediate intravascular volume expansion is done by giving 1 L of a 5% dextrose in 0.9% saline solution over 1 to 2 hours. Additional 0.9% saline is given IV until hypotension, dehydration, and hyponatremia have been corrected. Serum potassium may fall during rehydration, requiring replacement. Mineralocorticoids are not required when high-dose hydrocortisone is given. Subsequently, hydrocortisone 50 or 100 mg IM every 6 hours can be given.

As an alternative, some centers use a hydrocortisone infusion, giving 1 to 2 mg hydrocortisone per hour with measurement of serum cortisol. Restoration of blood pressure and general improvement should occur within 1 hour after the initial dose of hydrocortisone. Inotropic agents may be needed until the effects of hydrocortisone are achieved.

A total dose of 150 mg hydrocortisone is usually given over the second 24-hour period if the patient has improved markedly, and 75 mg is given on the third day. Maintenance oral doses of hydrocortisone (15 to 20 mg) and fludrocortisone (0.1 mg) are given daily thereafter, as described above.

Recovery depends on treatment of the underlying cause (eg, infection, trauma, metabolic stress) and adequate hydrocortisone therapy.

For patients with some residual adrenal function who develop adrenal crisis when under stress, hydrocortisone treatment is the same, but fluid requirements may be much lower.

Pearls & Pitfalls

  • When adrenal crisis is suspected, give hydrocortisone treatment immediately; any delay, including for testing, may be fatal.

Treatment of complications

Fever > 40.6° C occasionally accompanies the rehydration process. An oral antipyretic may be given.

Complications of corticosteroid therapy may include psychotic reactions. If psychotic reactions occur, then the hydrocortisone dose can be reduced to the lowest level consistent with maintaining blood pressure and good cardiovascular function. Antipsychotics may be temporarily required, but use should not be prolonged.

Key Points

  • Addison disease is primary adrenal insufficiency.

  • Weakness, fatigue, and hyperpigmentation (generalized darkening or focal black spots involving skin and mucous membranes) are typical.

  • Low serum sodium, high serum potassium, and high BUN (blood urea nitrogen) occur.

  • Usually, plasma adrenocorticotropic hormone (ACTH) is high and serum cortisol levels are low.

  • Replacement doses of hydrocortisone and fludrocortisone are given; doses should be increased during intercurrent illness.

Drugs Mentioned In This Article

Drug Name Select Trade
A-Hydrocort, Ala-Cort, Ala-Scalp, Alkindi, Anucort-HC, Anumed-HC, Anusol HC, Aquaphor Children's Itch Relief, Aquaphor Itch Relief, Balneol for Her, Caldecort , Cetacort, Colocort , Cortaid, Cortaid Advanced, Cortaid Intensive Therapy, Cortaid Sensitive Skin, CortAlo, Cortef, Cortenema, Corticaine, Corticool, Cortifoam, Cortizone-10, Cortizone-10 Cooling Relief, Cortizone-10 External Itch Relief, Cortizone-10 Intensive Healing, Cortizone-10 Plus, Cortizone-10 Quick Shot, Cortizone-5 , Dermarest Dricort, Dermarest Eczema, Dermarest Itch Relief, Encort, First - Hydrocortisone, Gly-Cort , GRx HiCort, Hemmorex-HC, Hemorrhoidal-HC, Hemril , Hycort, Hydro Skin, Hydrocortisone in Absorbase, Hydrocortone, Hydroskin , Hydroxym, Hytone, Instacort, Lacticare HC, Locoid, Locoid Lipocream, MiCort-HC , Monistat Complete Care Instant Itch Relief Cream, Neosporin Eczema, NuCort , Nutracort, NuZon, Pandel, Penecort, Preparation H Hydrocortisone, Proctocort, Proctocream-HC, Procto-Kit, Procto-Med HC , Procto-Pak, Proctosert HC , Proctosol-HC, Proctozone-HC, Rectacort HC, Rectasol-HC, Rederm, Sarnol-HC, Scalacort, Scalpicin Anti-Itch, Solu-Cortef, Texacort, Tucks HC, Vagisil Anti-Itch, Walgreens Intensive Healing, Westcort
Extina, Ketodan, Kuric, Nizoral, Nizoral A-D, Xolegel
Aldactone, CAROSPIR
AK-Pred, AsmalPred, Econopred, Econopred Plus, Flo-Pred, Hydeltrasol, Inflamase Forte, Inflamase Mild, Millipred , Millipred DP, Millipred DP 12-Day, Millipred DP 6 Day, Ocu-Pred , Ocu-Pred A, Ocu-Pred Forte, Omnipred, Orapred, Orapred ODT, Pediapred, Pred Mild, Predalone, Pred-Forte, Prednoral, Pred-Phosphate , Prelone, Veripred-20
Advocate Glucose SOS, BD Glucose, Dex4 Glucose, Glutol , Glutose 15 , Glutose 45 , Glutose 5
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