Primary Adrenal Insufficiency (Addison Disease)

How to Cite This Chapter: Rodríguez-Gutiérrez R, Mancillas-Adame LG, Gonzalez-Nava V, Dorsey-Treviño EG, Bednarczuk T, Płaczkiewicz-Jankowska E, Kasperlik-Załuska AA. Primary Adrenal Insufficiency (Addison Disease). McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed August 15, 2022.
Last Updated: January 26, 2018
Last Reviewed: August 7, 2019
Chapter Information

Definition, Etiology, PathogenesisTop

Primary adrenal insufficiency (Addison disease) is a clinical syndrome caused by a long-term deficit of hormones of the adrenal cortex, primarily cortisol, due to a direct injury to the adrenal gland. Symptoms of adrenal insufficiency develop only in the case of major bilateral involvement of the adrenal glands. Causes:

1) Autoimmune disorders (most common).Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Zelissen PM, Bast EJ, Croughs RJ. Associated autoimmunity in Addison's disease. J Autoimmun. 1995 Feb;8(1):121-30. PubMed PMID: 7734032.Kasperlik-Zaluska AA, Migdalska B, Czarnocka B, Drac-Kaniewska J, Niegowska E, Czech W. Association of Addison's disease with autoimmune disorders--a long-term observation of 180 patients. Postgrad Med J. 1991 Nov;67(793):984-7. PubMed PMID: 1775423; PubMed Central PMCID: PMC2399126. The autoantigens are enzymes of the steroid pathway—most frequently 21-hydroxylase, 17-hydroxylase, and 20-22-lyase. Other autoimmune diseases may coexist, most often thyroid disease (autoimmune polyglandular syndromes). In the early stages adrenal glands may be enlarged (due to lymphocytic infiltrates), while in later stages they become small (due to atrophy).

2) Tuberculosis and other infectious diseases (histoplasmosis, cryptococcosis, blastomycosis, coccidioidomycosis; AIDS-related infections, most commonly cytomegalovirus). Symptoms of Addison disease develop when ~90% of the adrenal cortex is destroyed (this is preceded by subclinical Addison disease). Tuberculous and fungal granulomas may calcify (lesions are visible on chest radiographs and computed tomography [CT]).

3) Malignancy (lymphoma; metastatic lesions, eg, renal or lung carcinoma, and rarely bilateral adrenocortical carcinoma).

4) Metabolic disorders, including amyloidosis, adrenoleukodystrophy, and hemochromatosis.

5) Hereditary disorders, including hereditary adrenal hypertrophy or adrenocorticotropic hormone (ACTH) insensitivity.

6) A drug-induced reduction in the secretion of adrenal hormones. The reduction is usually transient and resolves after discontinuation of the offending drug (eg, mitotane, aminoglutethimide, ketoconazole, metyrapone, etomidate). Adrenal insufficiency may persist longer after discontinuation of mitotane. Of note, secondary adrenal insufficiency from prolonged administration of pharmacologic doses of synthetic glucocorticoids rarely presents with adrenal crisis.

7) An increase in cortisol metabolism by enzyme inducers such as rifampin (INN rifampicin).

8) Bilateral adrenal gland hemorrhage (Waterhouse-Friderichsen syndrome [Neisseria meningitidis] or anticoagulant agents).

Clinical Features and Natural HistoryTop

1. Symptoms: Weakness, syncope (due to orthostatic hypotension or hypoglycemia), poor exercise tolerance, weight loss, appetite loss, sometimes nausea (less frequently vomiting), craving for salty foods, oligomenorrhea, loose stools, muscle and joint pain, abdominal pain. Symptoms are often associated with stress, such as infection or major trauma. In subclinical Addison disease episodes of weakness, loss of appetite, and muscle pain are only transient and caused by stress, particularly related to strenuous exercise.

2. Signs: Skin hyperpigmentation, which is particularly evident in areas exposed to sunlight or pressure, with brown discoloration of elbows, palmar and dorsal hand creases, nipple areolae, and scars; some patients also have brown spots on the oral mucosa that are caused by excess ACTH and melanotropin (melanocyte-stimulating hormone [MSH]), whose secretion is due to increased production of proopiomelanocortin (POMC), a prohormone of both ACTH and MSH. Low blood pressure and orthostatic hypotension may also be present.

3. Coexisting autoimmune disorders affecting organs other than adrenal glands may change the clinical features and course of Addison disease. Concomitant secondary adrenal deficiency leads to resolution of skin hyperpigmentation. Cutaneous depigmentation may also occur in patients with diffuse vitiligo.


Diagnostic Tests

1. Basic blood tests:

1) Complete blood count (CBC) may reveal neutropenia, lymphocytosis, monocytosis, and eosinophilia.

2) Serum biochemical tests may reveal hyperkalemia, hyponatremia, sometimes hypoglycemia (especially during longer periods between meals and after strenuous exercise), rarely hypercalcemia, sometimes elevated serum urea and creatinine levels (due to decreased glomerular filtration rate).

2. Hormone tests: If these are performed to confirm diagnosis, discontinue hydrocortisone 24 hours before a test.

1) Low levels of serum cortisol (<138 nmol/L [5 microg/dL]) and high levels of serum ACTH (2 × upper limit of normal) in morning blood samples collected at the same time are the key feature of Addison disease. Serum ACTH levels become elevated first (if serum cortisol is normal, subclinical Addison disease is diagnosed).

2) The short stimulation test with 250 microg synthetic ACTH can be performed in an outpatient setting to exclude primary adrenal insufficiency. The test involves the administration of synthetic human ACTH (cosyntropin [INN tetracosactide] 0.25 mg IV or IM) with measurements of serum cortisol levels at baseline, 30 minutes, and 60 minutes. An increase in the cortisol level >497 nmol/L (18 microg/dL) in any of the measurements excludes primary adrenal insufficiency; results close to this value may suggest a reduced adrenal reserve. A trend to use lower-dose ACTH stimuli in the recent years may suggest that 1 microg could also be used as a provocative dose with reported higher sensitivity in detecting secondary adrenal dysfunction.

3) The insulin-induced hypoglycemia test (performed rarely, only in specialized centers): Rapid IV insulin (0.05-0.15 IU/kg) is given to achieve adequate hypoglycemia (<40 mg/dL [2.2 mmol/L)]; measurements of glucose and cortisol are obtained at −30, 0, 30, 60, and 120 minutes. Cortisol levels <500 to 550 nmol/L (18-20 microg/dL) are considered diagnostic for adrenal insufficiency. The test is contraindicated in patients with seizures or cardiac disease. It is rarely performed, with the exception of recent suspected ACTH deficiency or concomitant growth hormone deficiency (eg, suspected secondary adrenal insufficiency).

4) The adrenal reserve test (performed rarely, only in specialized centers): Performed to differentiate between primary and secondary adrenal insufficiency. The test involves the administration of long-acting IM cosyntropin (synthetic ACTH) 0.5 mg every 12 hours for 2 days and daily measurements of urinary excretion of free cortisol or 17-hydroxycorticosteroids (17-OHCS) on both test days. Currently this test has become less important, as the results of ACTH and cortisol level measurements and the short ACTH stimulation test are considered sufficient for diagnosis.

5) Other results include low dehydroepiandrosterone sulfate (DHEAS), androstenedione, and aldosterone levels and a high plasma renin activity (PRA) or renin level (an early manifestation).

3. Immunologic studies and other blood tests: Most frequently specific adrenal antibodies are measured (antibodies to 21-hydroxylase, less often to desmolase or to 17-hydroxylase). Antibody levels decrease over time with the disappearance of autoantigens. In autoimmune polyglandular syndromes antibodies to the thyroid gland or other organs are present.

Rarely, serum levels of very–long chain fatty acids (VLCFAs) in boys and young men with primary adrenal insufficiency are measured—if the abovementioned adrenal antibodies are not found and imaging excludes the presence of adrenal metastases or infiltrates destroying adrenal glands—for the diagnosis of adrenoleukodystrophy or adrenomyeloneuropathy, respectively.

4. Electrocardiography (ECG) may reveal features of hyperkalemia or rarely hypercalcemia.

5. Imaging studies: Abdominal radiography, CT, and ultrasonography may reveal adrenal calcifications caused by prior adrenal tuberculosis or fungal infection. In the late stages of autoimmune Addison disease, abdominal CT or magnetic resonance imaging (MRI) reveals adrenal atrophy. Bilateral adrenal tumors most frequently indicate metastatic lesions or lymphoma.

Diagnostic Criteria

Criteria of overt adrenal insufficiency: A high serum ACTH level and low serum cortisol level at baseline. Clinical manifestations: see Clinical Features and Natural History, above.


Hormone Replacement Therapy

Ongoing replacement therapy should be augmented in periods of increased hormone requirements. Advise the patient how to modify hydrocortisone dosage to adjust to stress (eg, infection, trauma, minor procedures such as tooth extraction; see below). The patient should receive and always carry a drug dosage handout. Schedule follow-up studies. In patients with adrenocortical insufficiency, replacement of glucocorticoids, mineralocorticoids, and androgens may be necessary.

1. Glucocorticoid replacement aims to reproduce the diurnal rhythm of cortisol secretion, which equals 8 to 12 mg/m2 (with the highest dose administered in the morning). Assess the effects of hormone replacement doses on the basis of symptoms, physical performance, and serum sodium and potassium levels. Consider the duration of action of each dose (4-8 hours), body weight, height, and increased requirement in case of stress. In patients with diabetes mellitus, an additional dose of 5 mg administered in the evening may prevent nocturnal hypoglycemia. Use hydrocortisone 15 to 30 mg/d in 2 divided doses, for instance, in the morning and at approximately 15:00 (15 mg + 5 mg or 20 mg + 10 mg); alternatively, you may use a 3-dose regimen: in the morning, at approximately 13:00, and at approximately 18:00 (15 mg + 10 mg + 5 mg).Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and indirectness of some studies.Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89. doi: 10.1210/jc.2015-1710. Epub 2016 Jan 13. Review. PubMed PMID: 26760044; PubMed Central PMCID: PMC4880116. Sustained-release hydrocortisone in the forms of 5-mg and 20-mg tablets provides more stable blood levels of hydrocortisone and may be administered once daily. The patient should receive a dosage handout and should be advised to carry it at all times. Although prednisone, dexamethasone, and other long-acting synthetic analogues of cortisol are usually not recommended as the first option (they do not mimic the normal diurnal rhythm), they represent a valid alternative and may be unavoidable when hydrocortisone is not available.

Guidance on hydrocortisone dosage:

1) In case of moderate stress, the patient should increase the dose by 10 to 30 mg/d.

2) Before major physical exercise, the patient should take an additional dose of 5 to 10 mg.

3) In case of infection with fever (>39 degrees Celsius), for instance, of the upper respiratory tract, the dose should be increased 2- to 3-fold. If after 3 days symptoms of infection worsen or the patient is unable to return to the previous doses, medical attention should be sought.

4) In case of vomiting or diarrhea, the patient should seek medical attention. In such situations, administer IM or IV hydrocortisone 50 mg every 8 to 12 hours. In special cases (eg, in patients with hypertension or edema), hydrocortisone may be replaced with prednisolone at equivalent doses (20 mg hydrocortisone equals 5 mg prednisolone).

2. Mineralocorticoid replacement: Fludrocortisone 0.025 to 0.2 mg/d in the morning (starting dose, 0.025-0.1 mg/d; in hot weather use the upper range of the dose). Individual dose adjustment is necessary. Reduce the dose or consider discontinuation in case of hypertension or edema, especially in the elderly. Note that hydrocortisone has a weak mineralocorticoid effect. When using a well-adjusted mineralocorticoid dose, orthostatic hypotension should not occur. In patients with essential hypertension, add an appropriately selected antihypertensive agent without changing the replacement treatment; however, do not use diuretics, as these may cause a sudden blood pressure decrease associated with hypovolemia.

3. Adrenal androgen replacement: Dehydroepiandrosterone (DHEA): In women, use 5 to 50 mg after breakfast, most frequently 10 mg/d; consider using 25 mg/d, particularly in women with depressive symptoms, low libido, or low energy levels. In men, use 10 to 25 mg/d. Using higher doses in women may cause symptoms of androgen excess; determining serum DHEAS levels is useful if such excess is suspected. In patients after surgery with impaired wound healing, DHEA 50 mg/d may be beneficial.


The key goals of treatment are reduction of symptoms, normalization of blood pressure and electrolyte levels, and general improvement of the patient’s condition. Use the lowest effective doses of hydrocortisone and fludrocortisone. Serum ACTH measurements are of little use as they can be above the upper limit of normal; morning values within or below the lower limit of normal indicate excess hydrocortisone, in which case the dose should be reduced.

Special ConsiderationsTop


A common approach is to increase hydrocortisone dose by 20% to 40% during the third trimester, especially in case of worsening of symptoms (particularly weakness). In patients with hypertension reduce the dose of fludrocortisone.

Administration of hydrocortisone during and after delivery in women with adrenal insufficiency: At the beginning of delivery, our approach is to administer hydrocortisone 100 mg IV followed by 50 mg IV or IM every 6 to 8 hours or by a continuous infusion of 200 mg over 24 hours; in case of a blood pressure decrease, add 100 mg as an IV infusion in 500 mL of 0.9% saline. On days 1 and 2 after delivery, administer 50 mg IM or IV every 6 to 8 hours. On days 3 and 4 after delivery, administer 60 mg/d orally in 3 divided doses (eg, in the morning, at approximately 13:00, and at approximately 18:00; 30 mg + 20 mg + 10 mg). On days 5 and 6 after delivery, administer 40 mg/d orally in 2 to 3 divided doses (eg, in the morning, at approximately 13:00, and at approximately 18:00; 25 mg + 10 mg + 5 mg). On day 7 after delivery, administer 30 mg/d orally (eg, in the morning and approximately at 15:00; 20 mg + 10 mg).


Administration of hydrocortisone during major surgery in patients with adrenal insufficiencyEvidence 3Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias (observational studies) and indirectness of outcomes measured.Salem M, Tainsh RE Jr, Bromberg J, Loriaux DL, Chernow B. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg. 1994 Apr;219(4):416-25. Review. PubMed PMID: 8161268; PubMed Central PMCID: PMC1243159.: On the day before surgery, our approach is to administer 40 mg/d orally. On the day of surgery, administer 100 mg as an IV infusion during surgery followed by 100 mg IV every 8 hours or by an IV infusion of 200 mg over 24 hours. On day 1 after surgery, administer 100 mg IV every 8 hours. On day 2 after surgery, administer 50 mg IM or IV every 6 hours, and in case of a blood pressure decrease, add 100 mg as an IV infusion. This management should be continued until the patient is able to tolerate food and drink, and then it should be followed by oral hydrocortisone. Administer oral hydrocortisone for 2 days at a dose twice as high as before surgery and taper it down, so that at the end of the first week the dose is the same as the baseline dose administered before surgery. This dosage is based on our pattern of practice; slightly lower or slightly higher doses may be equally reasonable.

Administration of hydrocortisone during minor surgery in patients with adrenal insufficiency: Our approach is to administer 100 mg as an IV infusion before anesthesia, followed by oral hydrocortisone over the next 24 hours at a dose twice as high as the previous oral dose. Before tooth extraction, use additional 20 mg of oral hydrocortisone 1 hour prior to surgery. The subsequent dose administered on that day should be doubled.

Administration of hydrocortisone during colonoscopy in patients with adrenal insufficiency: The patient may need to be hospitalized. In the evening, administer IM or IV hydrocortisone 100 mg and IV fluids to ensure adequate volume status. Immediately before colonoscopy, administer another dose of IM hydrocortisone 100 mg.


In patients who receive appropriate hormone replacement treatment, Addison disease does not affect life expectancy; however, untreated disease is always fatal. In patients with adrenal insufficiency caused by tuberculosis, the prognosis depends on the extent of infection. In patients with bilateral adrenal metastases or lymphoma, the prognosis is poor.

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