Primary Adrenal Insufficiency (Addison Disease)

How to Cite This Chapter: Mohamed M, Prebtani APH, 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 July 18, 2024.
Last Updated: July 20, 2022
Last Reviewed: July 20, 2022
Chapter Information

Definition, Etiology, PathogenesisTop

Primary adrenal insufficiency (AI), also termed Addison disease, is a clinical syndrome caused by a long-term deficit of hormones of the adrenal cortex, primarily cortisol and often aldosterone, due to a direct injury to the adrenal gland. Symptoms of Addison disease develop when ~90% of the adrenal cortex is destroyed (this is preceded by subclinical Addison disease). Causes (also Table 1):

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. 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. PMID: 1775423; 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). Tuberculous and fungal granulomas may calcify (lesions are visible on chest radiographs and computed tomography [CT]). This is a less common cause in high-income countries.

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

4) Metabolic/infiltrative 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). AI may persist longer after discontinuation of mitotane. Patients on immunotherapy due to cancer may also develop primary AI.

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

8) Bilateral adrenal gland hemorrhage (Waterhouse-Friderichsen syndrome [Neisseria meningitidis] or anticoagulant agents), or heparin-induced thrombocytopenia (HIT).

9) Certain forms of congenital adrenal hyperplasia (CAH) that present in pediatric patients, including neonates.

10) Bilateral adrenalectomy.

Clinical Features and Natural HistoryTop

1. Symptoms: Weakness, presyncope (due to orthostatic hypotension), poor exercise tolerance, abdominal pain, weight loss, appetite loss, sometimes nausea (less frequently vomiting), craving for salty foods, 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 can be transient and caused by stress.

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/or oral mucosa, and scars that are caused by excess ACTH and melanotropin (melanocyte-stimulating hormone [MSH]), whose secretion is inadequately inhibited by cortisol feedback. Hypotension 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. For example, cutaneous depigmentation may also occur in patients with diffuse vitiligo.


Diagnostic Tests

1. Basic blood tests:

1) 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/dehydration). Mild normocytic anemia may be present.

Other hormone and biochemical tests may be indicated if autoimmune polyglandular syndrome is suspected (eg, thyroid-stimulating hormone [TSH], glucose, calcium, follicle-stimulating hormone [FSH], vitamin B12, antinuclear antibodies [ANAs], celiac screen).

2. Confirmatory hormone testing (testing of the hypothalamic-pituitary-adrenal axis; if these are performed to confirm the diagnosis, withhold hydrocortisone/prednisone ≥24 hours before the test):

1) Basal cortisol value (early morning/8:00 am):

a) ≤3 mg/dL (83 nmol/L): Repeat the test. Consistent results make a strong evidence of AI (of any cause).

b) 3 to 15 mg/dL (83 to ~400 nmol/L): This is an indication for dynamic testing (see below).

c) ≥15 mg/dL (>400 nmol/L): AI is unlikely in most patients.

Critically ill patients may have different cortisol cutoffs for normality (some experts suggest >700 nmol/L to exclude and <414 nmol/L to include AI) than non–critically ill patients, so dynamic testing may be clinically needed in these patients in conjunction with baseline cortisol levels.

In primary AI renin level is high and aldosterone levels are low.

2) Basal ACTH value: An elevated basal ACTH measurement with a low basal cortisol value is suggestive of primary AI. A low or normal basal ACTH measurement with low basal cortisol value is suggestive of central AI.

3) Dynamic testing of the hypothalamic-pituitary-adrenal axis (abnormal results do not differentiate between primary and secondary AI; this needs basal ACTH testing):

a) The gold standard is the insulin-induced hypoglycemia test (0.1 IU/kg of body weight) with expected hypoglycemia (<3 mmol/L) and increase in the cortisol level >18 mg/dL (~500 nmol/L) at 30 or 60 minutes; careful monitoring and physician attendance is required.

b) The other test is the metyrapone stimulation test: 750 mg of metyrapone every 4 hours for 24 hours; the expected normal result is an increase in the concentration of 11-deoxycortisol and decrease in the secretion of cortisol.

c) ACTH stimulation test: Basal cortisol and ACTH levels are measured prior to ACTH administration (0 min): A standard dose of 250 microg of ACTH is given IV or IM. Cortisol levels are measured 30 and 60 minutes after administration of ACTH. A cortisol peak of <18 mg/dL (500 nmol/L) at 30 or 60 minutes is suggestive of AI; thresholds may differ slightly depending on the assays used in specific laboratories. Of note, in some settings a dose <250 microg (eg, 1 microg) is used, but the thresholds remain similar. High 0 min/baseline ACTH levels in the context of AI suggest primary AI. Low or normal 0 min/baseline ACTH levels suggest central AI. ACTH stimulation testing may be falsely negative or normal if acute or mild central AI is present without enough opportunity to develop significant adrenal atrophy; in this case the test may need to be repeated in 6 to 8 weeks.

Note that both insulin-induced hypoglycemia and metyrapone stimulation tests are rarely used in clinical practice these days.

3. Immunologic studies: Most frequently specific adrenal antibodies are measured (antibodies to 21-hydroxylase) to support the diagnosis of autoimmune primary AI. Antibody levels decrease over time with the disappearance of autoantigens. In autoimmune polyglandular syndromes antibodies to the thyroid gland or other organs may be present.

4. Serum very long–chain fatty acids (VLCFAs) may be ordered in young men if adrenoleukodystrophy is suspected.

5. Electrocardiography (ECG) may reveal features of hyperkalemia.

6. 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) may reveal adrenal atrophy. Bilateral adrenal tumors most frequently indicate metastatic lesions or lymphoma. Imaging is usually not necessary unless the etiology is unclear.

Diagnostic Criteria

Criteria of overt AI: A high serum ACTH level and low serum cortisol level at baseline; impaired cortisol response to the short stimulation test with synthetic ACTH, insulin tolerance test (ITT), or metyrapone stimulation test. Clinical manifestations: see Clinical Features and Natural History, above.


Hormone Replacement Therapy

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 (with the highest dose administered in the morning). Assess the effects of hormone replacement doses based on the clinical status as well as serum sodium levels and avoid overreplacement to prevent Cushing syndrome. Consider the duration of action of each dose (4-8 hours), body weight, height, and increased requirement in cases of stress. Use hydrocortisone 15 to 20 mg/d orally, most frequently in 2 or 3 divided doses with the highest dose in the morning and next dose in the afternoon ± evening.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. PMID: 26760044; PMCID: PMC4880116. Prednisone 5 to 7.5 mg/d in 1 or 2 divided doses is also an option. 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.

Guidance on glucocorticoid dosage and sick day management: During times of physical stress (fever, infection, trauma, minor procedures such as tooth extraction), the patient should be advised to double or triple their glucocorticoid doses for 2 to 3 days. If they are unable to keep their glucocorticoids in due to vomiting, they should be advised to seek medical attention for consideration of IV glucocorticoid therapy. Check the patient’s knowledge of the “sick day rules” and reinforce emergency guidelines involving their partner or family members. Consider prescription of a hydrocortisone/dexamethasone emergency self-injection kit, in particular if delayed access to acute medical care is likely (rural areas, travel). Check if other medications include drugs known to induce (eg, rifampicin, mitotane, anticonvulsants such as phenytoin, carbamazepine, oxcarbazepine, phenobarbital, topiramate) or inhibit (eg, antiretroviral agents) hepatic cortisol inactivation by CYP3A4, which may require glucocorticoid dose adjustment.

Comparison of relative potency, dose equivalence, and biological half-times of selected glucocorticoids: Table 2.

2. Mineralocorticoid replacement: Fludrocortisone 0.025 to 0.2 mg/d in the morning (starting dose, 0.025-0.1 mg). 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 at physiologic doses. When using a well-adjusted mineralocorticoid dose, orthostatic hypotension should not occur. In patients with essential hypertension, add an appropriately selected antihypertensive agent without affecting the hormone replacement treatment (eg, dihydropyridine calcium channel blockers). The use of diuretics in general, and aldosterone antagonists specifically, should be avoided, as these may cause a sudden blood pressure decrease associated with hypovolemia.

3. Adrenal androgen replacement: Dehydroepiandrosterone (DHEA): Replacement of DHEA is usually not necessary. In most countries it is produced in an unregulated manner. DHEA can be considered in women with depressive symptoms, low libido, or low energy levels in very specific situations.


The key goals of treatment are reduction of symptoms, normalization of blood pressure/orthostasis and electrolyte levels, and general improvement of the patient’s condition while avoiding excessive doses of glucocorticoids to prevent Cushing syndrome. Use the lowest effective doses of hydrocortisone/prednisone and fludrocortisone. Serum ACTH measurements are of little use. Renin levels can be helpful in assessing fludrocortisone replacement and the goal is to keep the renin levels high normal. At every visit, review the patient’s sick day management.

Special ConsiderationsTop


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

Pregnant women may require higher doses of glucocorticoids around the time of delivery, especially in the case of a surgical mode of delivery.


Hydrocortisone during major or moderate surgeryEvidence 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. PMID: 8161268; PMCID: PMC1243159.: While precise evidence is lacking, our pattern of practice is to administer hydrocortisone 50 to 100 mg as an IV infusion en route to surgery, followed by 25 to 50 mg IM or IV every 6 to 8 hours or a continuous infusion of 200 mg over 24 hours. On day 1 after surgery, administer 25 to 50 mg IM or IV every 8 to 12 hours. On day 2 after surgery, administer 25 to 50 mg IM or IV in the morning. Starting from day 3 after surgery (or earlier if the patient tolerates fluids well and is clinically stable), switch to an oral physiologic replacement dose of hydrocortisone (less commonly prednisone). In case of surgical complications such as infection/sepsis, maintain a higher hydrocortisone dose (eg, 50 mg IV tid to qid) while reassessing the dose daily to avoid prolonged high-dose glucocorticoid exposure, and taper to the physiologic dose when the patient is clinically improved and stable. During high-dose hydrocortisone (>40 mg/d) treatment, fludrocortisone can be withheld since at this dose there is adequate mineralocorticoid therapy.

In minor surgeries the glucocorticoid dose can simply be doubled or tripled preoperatively and then tapered down quickly within 1 to 2 days.


In patients who receive appropriate hormone replacement treatment, primary AI does not significantly affect life expectancy. However, their quality of life may not be normal due to the currently used method of administering replacement therapy, which is not fully physiologic. Untreated disease can be fatal, and both undertreated and overtreated primary AI can cause significant morbidity.


Table 6.1-1. Causes of primary adrenal insufficiency


Adrenal hemorrhage, thrombosis, necrosis or infarction (due to coagulation disorder or sepsis)


– Autoimmune disorders: Autoimmune adrenalitis (most common)

– Infectious diseases: Tuberculosis, fungal infections, AIDS-related infections

– Medications: Cancer-related immunotherapies, ketoconazole, etomidate, tyrosine kinase inhibitors, antiepileptics

– Malignancy: Lymphoma, metastatic adrenal infiltrates (lung, breast, kidney)

– Genetic: Congenital adrenal hyperplasia, adrenoleukodystrophy (men), isolated

– Infiltrative: Amyloid, sarcoid, hemochromatosis

Table 6.1-2. Glucocorticoid potency equivalence


Relative potency

Dose equivalence

Biological half-time (h)



20 mg




5 mg




0.5 mg


Cortisone acetate


25 mg




4 mg


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