Primary adrenal insufficiency (Addison disease) is caused by dysfunction or absence of the adrenal cortices. Secondary adrenal insufficiency is caused by deficient secretion of ACTH.

Addison disease refers to a chronic deficiency of cortisol caused by adrenocortical insufficiency (plasma ACTH and alpha-MSH levels are consequently elevated) causing pigmentation that ranges from none to strikingly dark.

Patients with destruction of the adrenal cortices or with classic 21-hydroxylase deficiency also have mineralocorticoid deficiency, typically with hyponatremia, volume depletion, and hyperkalemia. In contrast, mineralocorticoid deficiency is not present in patients with familial corticosteroid deficiency, Allgrove syndrome, or secondary adrenal insufficiency.

Acute adrenal (Addisonian) crisis is an emergency caused by insufficient cortisol. Crisis may occur in the course of treatment of chronic adrenal insufficiency, or it may be the presenting manifestation of adrenal insufficiency. Acute adrenal crisis is more commonly seen in primary adrenal insufficiency than in secondary adrenal insufficiency. It is usually precipitated by one of the following:

  1. Severe stress (eg, infection, trauma, surgery, hyperthyroidism, or prolonged fasting), or minor stress (vaccinations) in patients with latent or treated adrenal insufficiency;
  2. Hyperthyroidism or prescription of thyroid hormone to patients with untreated adrenal insufficiency;
  3. Nonadherence to glucocorticoid replacement or sudden withdrawal of adrenocortical hormone in patients with chronic primary or secondary adrenal insufficiency 
  4. Bilateral adrenalectomy or removal of a functioning adrenal tumor that had suppressed the other adrenal gland;
  5. Sudden destruction of the pituitary gland (pituitary necrosis) or damage to both adrenals (by trauma, hemorrhage, anticoagulant therapy, thrombosis, infection or, rarely, metastatic carcinoma);
  6. Administration of intravenous etomidate (used for rapid anesthesia induction or intubation).


Autoimmunity is the most common cause of Addison disease in industrialized countries, accounting for about 90% of spontaneous cases; adrenal function decreases over several years as it progresses to overt adrenal insufficiency. Over half the cases of autoimmune Addison disease occur as part of an autoimmune polyendocrine syndrome (APS-1, APS-2). Addison disease can also occur following treatment for malignancies with PD-1 immune checkpoint inhibitors.

APS-1 is caused by a defect in T cell‚Äďmediated immunity that is caused by mutations in the autoimmune regulator gene (AIRE). It is inherited as an autosomal recessive trait with a prevalence of 1:100,000 in most countries. APS-1, also known as autoimmune-polyendocrine-candidiasis-ectodermal dystrophy syndrome (APECED), usually presents in early childhood with mucocutaneous candidiasis, followed by hypoparathyroidism and dystrophy of the teeth and nails; Addison disease occurs in over 94% of affected patients, usually appearing by age 15 years. Partial or late expression of the syndrome is common. A varied spectrum of associated diseases may be seen in adulthood, including hypogonadism, hypothyroidism, pernicious anemia, alopecia, vitiligo, hepatitis, malabsorption, and Sj√∂gren syndrome.

APS-2 is more common than APS-1 with a prevalence of 1:1000. It is characterized by two of the following: Addison disease, type 1 diabetes mellitus, autoimmune thyroid disease. APS-2 has a polygenetic inheritance pattern and typically presents in young adulthood and more commonly affects women. Other autoimmune conditions occur frequently, particularly in patients with Addison disease, including celiac disease, vitiligo, alopecia, pernicious anemia, and premature autoimmune ovarian failure.

Treating malignancy with immune checkpoint inhibitors can cause acquired autoimmune endocrine syndromes. Addison disease and type 1 diabetes have occurred following treatment with PD-1 blockers such as pembrolizumab or nivolumab.

Bilateral adrenal infiltrative diseases cause primary adrenal insufficiency. Causative neoplasms include lymphomas, breast cancer, and lung cancer. Causative infections include tuberculosis, coccidiomycosis, histoplasmosis, cytomegalovirus, cryptococcus, and syphilis.

Infections of the adrenal glands, particularly with cytomegalovirus, are found in nearly half of patients with untreated HIV at autopsy. However, a much lower percentage have clinical Addison disease. The diagnosis of adrenal insufficiency in HIV patients is often problematic. A cortisol resistance syndrome has been described in patients with HIV, and a revision of normal range for the cosyntropin test for these patients has been advocated (normal peak cortisol over 22 mcg/dL). Also, isolated hyperkalemia occurs commonly in HIV patients, particularly during therapy with pentamidine; this is usually due to isolated hypoaldosteronism and responds to mineralocorticoid (fludrocortisone) therapy alone.

Bilateral adrenal hemorrhage may occur with sepsis, heparin-associated thrombocytopenia, anticoagulation, or the antiphospholipid antibody syndrome. It may occur in association with major surgery or trauma, presenting about 1 week later with pain, fever, and shock. It may also occur spontaneously and present with flank pain. Meningococcemia may be associated with purpura and adrenal insufficiency secondary to adrenal infarction (Waterhouse-Friderichsen syndrome).

Adrenoleukodystrophy is an X-linked peroxisomal disorder causing accumulation of very long-chain fatty acids in the adrenal cortex, testes, brain, and spinal cord. Adrenal insufficiency ultimately occurs in 80% of affected patients and accounts for one-third of cases of Addison disease in boys. It presents most commonly in childhood or adolescence but can manifest at any age. Aldosterone deficiency occurs in 9%. Hypogonadism is common. Psychiatric symptoms often include mania, psychosis, or cognitive impairment. Neurologic deterioration may be severe or mild (particularly in heterozygote women), mimics symptoms of multiple sclerosis, and can occur years after the onset of adrenal insufficiency.

Congenital adrenal insufficiency occurs in several conditions. Familial corticosteroid deficiency is an autosomal recessive disease that is caused by mutations in the adrenal ACTH receptor (melanocortin 2 receptor, MC2R). It is characterized by isolated cortisol deficiency and ACTH resistance and may present with neonatal hypoglycemia, frequent infections, and dark skin pigmentation. Triple A (Allgrove) syndrome is caused by a mutation in the AAAS gene that encodes a protein known as ALADIN (alachrima, achalasia, adrenal insufficiency, neurologic disorder). It is characterized by variable expression of the following: adrenal ACTH resistance with cortisol deficiency, achalasia, alacrima, nasal voice, autonomic dysfunction, and neuromuscular disease of varying severity (hyperreflexia to spastic paraplegia). Cortisol deficiency usually presents in infancy but may not occur until the third decade of life.

Congenital adrenal hyperplasia is caused by various genetic defects in the enzymes responsible for steroid synthesis. Due to defective cortisol synthesis, patients have variable degrees of adrenal insufficiency and increased levels of ACTH that causes hyperplasia of the adrenal cortex. The most common enzyme defect is P450c21 (21-hydroxylase deficiency). Patients with severely defective P450c21 (classic congenital adrenal hyperplasia) manifest a deficiency of mineralocorticoids (salt wasting) in addition to deficient cortisol and excessive androgens. Hypertension commonly develops in older adult patients. Testicular adrenal rests can be found in 44% of men with the condition. Women with milder enzyme defects have adequate cortisol, but develop hirsutism in adolescence or adulthood and are said to have “late-onset” congenital adrenal hyperplasia. (See Hirsutism.) Congenital adrenal hypoplasia causes adrenal insufficiency due to absence of the adrenal cortex; patients may also have hypogonadotropic hypogonadism, myopathy, and high-frequency hearing loss.

Patients with deficient P450c17 (17-hydroxylase deficiency) have varying degrees of cortisol deficiency with associated hypertension, hypokalemia, and primary hypogonadism. Severely affected genetic 46 XY males may present with female genitalia at birth (pseudohermaphroditism). The diagnosis is confirmed with high serum levels of 11-deoxycorticosterone and corticosterone. The absence of sex hormones results in primary amenorrhea.

Patients with deficient P450c11 (11-hydroxylase deficiency) present at birth with partial virilization and ambiguous genitalia in genetically female infants, childhood virilization in both sexes, and virilization and reduced fertility in adult women. Most patients have hypertension and variable degrees of cortisol deficiency. The diagnosis is established with elevated serum levels of 11-deoxycorticosterone and 11-deoxycortisol.

Drugs that cause primary adrenal insufficiency include mitotane, abiraterone acetate, and the tyrosine kinase inhibitors lenvatinib and vandetanib. Rare causes of adrenal insufficiency include lymphoma, metastatic carcinoma, scleroderma, amyloidosis, and hemochromatosis.

Clinical Findings

A. Symptoms and Signs

The onset of symptoms can occur suddenly but usually develops gradually over months or years. The diagnosis is often delayed, since many early symptoms are nonspecific. Over 90% of patients complain of fatigue, reduced stamina, weakness, anorexia, and weight loss. Over 80% of affected patients present with symptoms of orthostatic hypotension (aggravated by dehydration caused by nausea or vomiting), lightheadedness with standing, salt craving, and eventually hyperpigmentation of skin and gums. Abdominal pain, nausea, and vomiting eventually develop in most patients; diarrhea can occur, aggravating dehydration and hypotension. Fevers and lymphoid tissue hyperplasia may also occur. Patients often have significant pain: arthralgias, myalgias, chest pain, abdominal pain, back pain, leg pain, or headache. Psychiatric symptoms include anxiety, irritability and depression; by the time of diagnosis, over 40% of patients have been told that their symptoms were psychological. Cerebral edema can cause headache, vomiting, gait disturbance, and intellectual dysfunction that may progress to coma. Hypoglycemia can occur and worsen the patient’s weakness and mental functioning. Patients treated long-term for adrenal insufficiency appear to be more prone to pneumonia and gastrointestinal and urinary tract infections.

Hyperpigmentation of the skin and gums eventually occurs in most patients with Addison disease and is caused by increased pituitary secretion of alpha-MSH (melanocyte-stimulating hormone). Skin hyperpigmentation varies among affected patients (eg, from none to increased freckling to diffuse darkening that resembles a suntan or a bronze appearance). Sun-exposed areas darken the most, but nonexposed areas darken as well. Hyperpigmentation is often especially prominent over the knuckles, elbows, knees, posterior neck, palmar creases, gingival mucosa, and vermilion border of the lips. Nail beds may develop longitudinal pigmented bands. Nipples and areolas tend to darken. The skin also darkens in pressure areas, such as the belt or brassiere lines and the buttocks. Skin folds and new scars may also become pigmented. Conversely, patches of autoimmune vitiligo can be found in about 10% of patients. Scant axillary and pubic hair typically develops in women.

In pregnancy, undiagnosed adrenal insufficiency is rare, since the condition tends to cause anovulation and reduced fertility. In the first trimester, symptoms such as fatigue, nausea, vomiting, abdominal pain, and orthostasis are typically attributed to the pregnancy, thus delaying the diagnosis. Worse, the increased skin pigmentation of adrenal insufficiency may be mistaken for chloasma (melasma). Undiagnosed adrenal insufficiency can cause intrauterine growth retardation and fetal loss. Pregnant women with undiagnosed adrenal insufficiency can experience shock from adrenal crisis, particularly during the first trimester, concurrent illness, labor, or postpartum.

Patients with preexistent type 1 diabetes experience more frequent hypoglycemia with the onset of adrenal insufficiency, such that their insulin dosage must be reduced.

Acute adrenal crisis is an immediate threat to life. Affected patients have magnified symptoms of chronic adrenal insufficiency and experience an acute deterioration in their health, typically with acute gastrointestinal symptoms and fever that can mimic an abdominal emergency. Infections (lower respiratory, urinary, or gastrointestinal) are common triggers for acute adrenal crisis. Patients also frequently experience back pain, arthralgias, and profound fatigue. They may have delirium or coma, sometimes aggravated by hypoglycemia. Adrenal crisis is marked by orthostatic dizziness and hypotension (blood pressure below 100 mm Hg systolic or 20 mm Hg lower than their basline). Reversible cardiomyopathy and heart failure can also occur, causing hypotension that can progress to life-threatening shock that does not respond to intravenous fluids and vasopressors.

B. Laboratory Findings

Typically, there is mild anemia, moderate neutropenia, lymphocytosis, and eosinophilia (total eosinophil count over 300/mcL). Among patients with chronic adrenal insufficiency, the serum sodium is usually low (88%) and the potassium usually elevated (64%). However, patients with vomiting or diarrhea may not be hyperkalemic. Fasting hypoglycemia is common. Hypercalcemia may be present.

A plasma cortisol less than 3 mcg/dL (83 nmol/L) at 8 AM is diagnostic, especially if accompanied by simultaneous elevation of the plasma ACTH level greater than 200 pg/mL (44 pmol/L).

The diagnosis is confirmed by a simplified cosyntropin stimulation test:

  1. Synthetic ACTH1‚Äď24¬†(cosyntropin), 0.25 mg, is given intramuscularly.
  2. Serum cortisol is obtained 45 minutes after cosyntropin is administered.

Normally, serum cortisol rises to at least 20 mcg/dL (550 pmol/L), whereas patients with adrenal insufficiency have stimulated serum cortisol levels less than 20 mcg/dL (550 pmol/L). For patients receiving corticosteroid treatment, hydrocortisone must not be given for at least 8 hours before the test. Other corticosteroids (eg, prednisone, dexamethasone) do not interfere with specific assays for cortisol. Cosyntropin is usually well tolerated, but infrequent (less than 5%) side effects have included hypersensitivity reactions with nausea, headache, dizziness, dyspnea, palpitations, flushing, edema, and local injection site reactions. Cosyntropin may be administered during pregnancy; however, the test may lack sensitivity, since adrenal ACTH-responsiveness increases during pregnancy.

Serum DHEA levels are less than 1000 ng/mL (350 nmol/L) in 100% of patients with adrenal insufficiency but also in about 15% of the population, so the test is very sensitive but not specific.

One or more serum anti-adrenal antibodies are found in about 50% of cases of autoimmune Addison disease. The sensitivity of four serum anti-adrenal antibodies is as follows: cytoplasmic antibodies (26%), 21-hydroxylase antibodies (21%), 17-hydroxylase antibodies (21%), and side-chain cleavage antibodies (16%). Antibodies to thyroid (45%) and other tissues may also be present.

Elevated plasma renin activity (PRA) indicates the presence of depleted intravascular volume and the need for fludrocortisone administration. Serum epinephrine levels are low in untreated patients with adrenal insufficiency. These patients do not have the high local concentrations of cortisol that are required to induce the adrenal medullary enzyme PNMT that converts norepinephrine to epinephrine.

Salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency is usually diagnosed at birth in females due to ambiguous genitalia. Males and patients with milder enzyme defects may present later. The diagnosis of adrenal insufficiency is made as above. The specific diagnosis requires elevated serum levels of 17-OH progesterone.

Young men with idiopathic Addison disease are screened for X-linked adrenoleukodystrophy by determining plasma very long-chain fatty acid levels; affected patients have high levels.

In acute adrenal crisis, blood, sputum, or urine cultures may be positive if bacterial infection is the precipitating cause.

C. Imaging

When adrenal insufficiency is not clearly autoimmune, a CT scan of the adrenal glands should be obtained. Small, noncalcified adrenals are seen in autoimmune Addison disease. The adrenals are enlarged in about 85% of cases related to metastatic or granulomatous disease. Adrenal calcifications occur in about 50% of cases of tuberculous Addison disease but are also seen with hemorrhage, fungal infection, pheochromocytoma, and melanoma.


A. General Measures

Patients and family members must be thoroughly educated about adrenal insufficiency.¬†Patients are advised to wear a medical alert bracelet or medal reading, ‚ÄúAdrenal insufficiency‚ÄĒtakes¬†hydrocortisone.‚Ä̬†They need to be provided with a dose escalation schedule for increased corticosteroids for illness, accidents, or prior to minor surgical procedures and for increased¬†fludrocortisone¬†for hot weather or prolonged strenuous exercise. Corticosteroids and¬†fludrocortisone¬†must be prescribed in liberal amounts with automatic refills to avoid the patient‚Äôs running out of medication. It is also advisable to prescribe a routine antiemetic such as¬†ondansetron¬†ODT 8-mg tablets to be taken every 8 hours for nausea. Parenteral¬†hydrocortisone¬†(Solu-Cortef) 100 mg is also prescribed for patient self-injection in the event of vomiting. Patients must receive advance instructions to seek medical attention at an emergency facility immediately in the event of vomiting or severe illness. All infections should be treated immediately and vigorously, with¬†hydrocortisone¬†administered at appropriately increased doses.

B. Specific Therapy

Replacement therapy should include corticosteroids with mineralocorticoids for primary adrenal insufficiency. In mild cases, corticosteroids alone may be adequate.

1. Corticosteroid replacement therapy

Maintenance therapy for most patients with Addison disease is 15‚Äď30 mg of¬†hydrocortisone¬†orally daily in two or three divided doses (eg, 10 mg at 7¬†AM, 10 mg at 1¬†PM, and 5 mg at 7¬†PM). Some patients respond better to¬†prednisone¬†or¬†methylprednisolone¬†in doses of about 3‚Äď6 mg daily in divided doses. Adjustments in dosage are made according to the clinical response. The corticosteroid dose should be kept at the lowest level at which the patient feels clinically well.

Patients with partial ACTH deficiency (basal morning serum cortisol above 8 mg/dL [220 mmol/L]) require¬†hydrocortisone¬†replacement in lower doses of about 5 mg orally twice daily or even 10 mg every morning. Some patients feel better with the substitution of¬†prednisone¬†(2‚Äď7.5 mg/day orally) or¬†methylprednisolone¬†(2‚Äď6 mg/day orally), given in divided doses.¬†Fludrocortisone¬†is not required. Additional corticosteroid must be given during stress, (eg, infection, trauma, or surgical procedures). For mild illness or mild-moderate surgical stress, corticosteroid doses are doubled or tripled. For severe illness, trauma, or major surgical stress,¬†hydrocortisone¬†100 mg is given intravenously, followed by 200 mg daily, given as either a continuous intravenous infusion or as 50 mg boluses given every 6 hours intravenously or intramuscularly and then reduced to usual doses as the stress subsides.

Patients with secondary adrenal insufficiency due to treatment with corticosteroids require their usual daily dose of corticosteroid during minor surgery and mild illness; supplemental hydrocortisone is required for major surgeries or illness.

Plenadren MR (5- or 20-mg modified-release tablets) is a once-daily dual-release oral preparation of¬†hydrocortisone¬†that may be administered in the morning (usual dose range is 20‚Äď30 mg daily). Preliminary studies indicate that plenadren may improve quality of life in some patients with adrenal insufficiency. It is not available in the United States but is available in Canada and elsewhere.

To determine the optimal corticosteroid replacement dosage, it is necessary to monitor patients carefully for clinical signs of over- or under-replacement. A proper corticosteroid dose usually results in clinical improvement. A white blood cell (WBC) count with a differential can be useful, since a relative neutrophilia and lymphopenia can indicate corticosteroid over replacement, and vice versa. Serum ACTH levels vary substantially and should not be used to determine dosing.

Caution:¬†Increased corticosteroid dosing is required in circumstances of infection, trauma, surgery, stressful diagnostic procedures, or other forms of stress.¬†Rifampin¬†use increases the clearance of¬†hydrocortisone¬†and necessitates increased dosing of¬†hydrocortisone¬†by up to 50%. During the third trimester of pregnancy, corticosteroid requirements are higher, so usual corticosteroid doses are increased by 50%. For severe stress of major illness, surgery, or delivery, a maximum stress dose of¬†hydrocortisone¬†is given as 50‚Äď100 mg intravenously or intramuscularly, followed by 50 mg every 6 hours (continuous intravenous infusion or boluses), then reduced over several days. However, following major trauma, increased doses of replacement¬†hydrocortisone¬†may be required for up to several weeks. Lower doses, oral or parenteral, are used for less severe stress. For immunizations that are given with an adjuvant, such as varicella zoster (Shingrix), there is sufficient local inflammation that increased doses of¬†hydrocortisone¬†are recommended for 5 days following the immunization. The dose is reduced back to normal as the stress subsides. Decreased corticosteroid dosing is required when medications are prescribed that inhibit corticosteroid metabolism by blocking the isoenzyme CYP34A, particularly the antifungals¬†ketoconazole¬†or¬†itraconazole, the antidepressant¬†nefazodone, anti-HIV protease inhibitors, and¬†cobicistat.

2. Mineralocorticoid replacement therapy

Fludrocortisone¬†acetate¬†has a potent sodium-retaining effect. The dosage is 0.05‚Äď0.3 mg orally daily or every other day. In the presence of postural hypotension, hyponatremia, or hyperkalemia, the dosage is increased. Similarly, in patients with fatigue, an elevated PRA indicates the need for a higher replacement dose of¬†fludrocortisone. If edema, hypokalemia, or hypertension ensues, the dose is decreased. During treatment with¬†hydrocortisone¬†with maximum doses appropriate for stress,¬†fludrocortisone¬†replacement is not required. Some patients cannot tolerate¬†fludrocortisone¬†and must substitute NaCl tablets to replace renal sodium loss.

3. DHEA replacement therapy

DHEA is given to some women with adrenal insufficiency. In a double-blind clinical trial, women taking DHEA 50 mg orally each morning experienced an improved sense of well-being, increased muscle mass, and a reversal in bone loss at the femoral neck. DHEA replacement did not improve fatigue, cognitive problems, or sexual dysfunction; however, its placebo effect may be significant in that regard. Older women who receive DHEA should be monitored for androgenic effects. Because over-the-counter preparations of DHEA have variable potencies, it is best to have the pharmacy formulate this with pharmaceutical-grade micronized DHEA.

4. Treatment of acute adrenal crisis

If acute adrenal crisis is suspected but the diagnosis of adrenal insufficiency is not yet established, intravenous access must be established. Blood is drawn for cultures, plasma ACTH, serum cortisol, serum glucose, BUN, creatinine, and electrolyte levels. A urinalysis is obtained to screen for a urinary tract infection. Without waiting for the results, treatment is initiated immediately with hydrocortisone, 100 mg by intravenous bolus followed by 50 mg intravenously every 6 hours as either intravenous boluses or a continuous intravenous infusion. The hydrocortisone dosage may then be reduced according to the clinical picture and laboratory test results.

Intravenous fluids are administered as either 0.9% normal saline or 0.9% normal saline/5%¬†dextrose¬†solutions. A volume of 2‚Äď3 L is given quickly and then the intravenous rate is reduced according to clinical parameters and frequent serum electrolytes and glucose determinations. When intravenous saline is stopped, mineralocorticoid replacement is commenced with¬†fludrocortisone, starting with 0.1 mg orally daily and adjusted according to serum electrolyte determinations.

Since bacterial infection frequently precipitates acute adrenal crisis, broad-spectrum antibiotics should be administered empirically while waiting for the results of initial cultures. The patient must also be treated for electrolyte abnormalities, hypoglycemia, and dehydration, as indicated.

When the patient is able to take food by mouth,¬†hydrocortisone¬†is administered orally in doses of 10‚Äď20 mg every 6 hours, and the dosage is reduced to maintenance levels as needed. Most patients ultimately require¬†hydrocortisone¬†twice daily (10‚Äď20 mg in the morning; 5‚Äď10 mg in the evening). Mineralocorticoid replacement is not needed when large amounts of¬†hydrocortisone¬†are given, but as its dose is reduced, it is usually necessary to add¬†fludrocortisone¬†acetate, 0.05‚Äď0.2 mg orally daily. Some patients never require¬†fludrocortisone¬†or become edematous at doses of more than 0.05 mg once or twice weekly. Once the crisis has passed, the patient must be evaluated to assess the degree of permanent adrenal insufficiency and to establish the cause, if possible.

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