Home |  Specialties |  Resource Centers |  Learning Centers |  CME  |  Contributor Recruitment
Privacy Policy Changes
  Articles Images CME Advanced Search Edit My Profile    Consumer Health Link to this site
eMedicine - Addison Disease : Article by CME available

Author: Sylvester Odeke, MD, FACE, Assistant Professor of Medicine, Division of Endocrinology and Metabolism, Department of Internal Medicine, Brody School of Medicine, East Carolina University

Sylvester Odeke is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, and North Carolina Medical Society

Coauthor(s): Steven B Nagelberg, MD, Department of Medicine, Division of Endocrinology and Metabolism, Clinical Professor, Drexel University College of Medicine

Editors: Daniel Einhorn, MD, Medical Director, Scripps/Whittier Diabetes Institute, Department of Medicine, Associate Clinical Professor of Medicine, University of California at San Diego School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Affiliate Research Professor, School of Computational Sciences; Principal, Bioinformatics and Computational Biology Program, C/A Informatics, LLC; Mark Cooper, MD, Head, Vascular Division, Baker Medical Research Institute; Professor of Medicine, Monash University; George T Griffing, MD, Professor of Medicine, Director of General Internal Medicine, St Louis University

Author and Editor Disclosure

Synonyms and related keywords: primary adrenocortical insufficiency, Addison disease, Addison's disease, addisonian crisis, adrenal cortex, glucocorticoid function, mineralocorticoid function


Thomas Addison first described the clinical presentation of primary adrenocortical insufficiency (Addison disease) in 1855 in his classic paper, On the Constitutional and Local Effects of Disease of the Supra-Renal Capsules.


Addison disease is adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal cortex. It affects both glucocorticoid and mineralocorticoid function. The onset of disease usually occurs when 90% or more of both adrenal cortices are dysfunctional or destroyed.


United States

Prevalence is 40-60 cases per 1 million population.


The condition is rare. The reported prevalence in countries where data are available is 39 cases per 1 million population in Great Britain and 60 cases per 1 million population in Denmark.


  • Morbidity and mortality usually are due to failure or delay in making the diagnosis or a failure to institute adequate glucocorticoid and mineralocorticoid replacement.
  • If not treated promptly, acute addisonian crisis may result in death. This may be provoked either de novo, such as by adrenal hemorrhage, or in the setting of an acute event superimposed on chronic or inadequately treated adrenocortical insufficiency.
  • With slow-onset chronic Addison disease, significant low-level nonspecific, but debilitating, symptomatology may occur.


  • Addison disease is not associated with a racial predilection.


  • Idiopathic autoimmune Addison disease tends to be more common in females and children.


  • The most common age at presentation in adults is 30-50 years, but the disease could present earlier in patients with any of the polyglandular autoimmune syndromes, congenital adrenal hyperplasia (CAH), or if onset is due to a disorder of long-chain fatty acid metabolism.


Patients usually present with features of both glucocorticoid and mineralocorticoid deficiency. The predominant symptoms vary depending on the duration of disease.

Patients may present with clinical features of chronic Addison disease or in acute addisonian crisis precipitated by stress factors such as infection, trauma, surgery, vomiting, diarrhea, or noncompliance with replacement steroids.

  • Presentation of chronic Addison disease
    • The onset of symptoms most often is insidious and nonspecific.

    • Hyperpigmentation of the skin and mucous membranes often precedes all other symptoms by months to years.

      • It is caused by the stimulant effect of excess adrenocorticotrophic hormone (ACTH) on the melanocytes to produce melanin.

      • Hyperpigmentation usually is generalized but most often prominent on the sun-exposed areas of the skin, extensor surfaces, knuckles, elbows, knees, and scars formed after the onset of disease. Scars formed before the onset of disease (before the ACTH is elevated) usually are not affected. Palmar creases, nail beds, mucous membranes of the oral cavity (especially the dentogingival margins and buccal areas), and the vaginal and perianal mucosa may be similarly affected.

      • Hyperpigmentation, however, need not be present in every long-standing case and may not be present in cases of short duration.

    • Other skin findings include vitiligo, which most often is seen in association with hyperpigmentation in idiopathic autoimmune Addison disease. It is due to the autoimmune destruction of melanocytes.

    • Almost all patients complain of progressive weakness, fatigue, poor appetite, and weight loss.

    • Prominent gastrointestinal symptoms may include nausea, vomiting, and occasional diarrhea. Glucocorticoid-responsive steatorrhea has been reported.

    • Dizziness with orthostasis due to hypotension occasionally may lead to syncope. This is due to the combined effects of volume depletion, loss of the mineralocorticoid effect of aldosterone, and loss of the permissive effect of cortisol in enhancing the vasopressor effect of the catecholamines.

    • Myalgias and flaccid muscle paralysis may occur due to hyperkalemia.

    • Patients may have a history of using medications known to affect adrenocortical function or to increase cortisol metabolism.

    • Other reported symptoms include muscle and joint pains; a heightened sense of smell, taste, and hearing; and salt craving.

    • Patients with diabetes that previously was well-controlled may suddenly develop a marked decrease in insulin requirements and hypoglycemic episodes due to an increase in insulin sensitivity.

    • Impotence and decreased libido may occur in male patients, especially in those with compromised or borderline testicular function.

    • Female patients may have a history of amenorrhea due to the combined effect of weight loss and chronic ill health or secondary to premature autoimmune ovarian failure. Steroid-responsive hyperprolactinemia may contribute to the impairment of gonadal function and to the amenorrhea.

  • Presentation of acute Addison disease
    • Patients in acute adrenal crisis most often have prominent nausea, vomiting, and vascular collapse. They may be in shock and appear cyanotic and confused.

    • Abdominal symptoms may take on features of an acute abdomen.

    • Patients may have hyperpyrexia, with temperatures reaching 105°F or higher, and may be comatose.

    • In acute adrenal hemorrhage, the patient, usually in an acute care setting, deteriorates with sudden collapse, abdominal or flank pain, and nausea with or without hyperpyrexia.


  • Physical examination in long-standing cases most often reveals increased pigmentation of the skin and mucous membranes, with or without areas of vitiligo.
  • Patients show evidence of dehydration, hypotension, and orthostasis.
  • Female patients may show an absence of axillary and pubic hair and decreased body hair. This is due to loss of the adrenal androgens, a major source of androgens in women.
  • Addison disease caused by another specific disease may be accompanied by clinical features of that disease.
  • Calcification of the ear and costochondral junctions is described but is a rare physical finding.


The most common cause of Addison disease is idiopathic autoimmune adrenocortical insufficiency resulting from autoimmune atrophy, fibrosis, and lymphocytic infiltration of the adrenal cortex, usually with sparing of the adrenal medulla. This accounts for more than 80% of reported cases. Idiopathic autoimmune adrenocortical atrophy and tuberculosis (TB) account for nearly 90% of cases of Addison disease.

  • Antibodies against the adrenal tissue are present in a significant number of these patients, and evidence of cell-mediated immunity against the adrenal gland also may be present.

  • Patients may have a hereditary predisposition to autoimmune Addison disease.

  • Idiopathic autoimmune Addison disease may occur in isolation or in association with other autoimmune phenomena (eg, Schmidt syndrome, polyglandular autoimmune disease types 1 and 2).
    • Idiopathic hypoparathyroidism

    • Mucocutaneous candidiasis

    • Type 1 diabetes mellitus

    • Hashimoto thyroiditis

    • Graves disease

    • Vitiligo

    • Alopecia areata, totalis and universalis

    • Premature ovarian or testicular failure

    • Pernicious anemia

    • Myasthenia gravis

    • Idiopathic hypophysitis

    • Chronic active hepatitis

    • Primary biliary cirrhosis

    • The association of Addison disease and Hashimoto thyroiditis is known as Schmidt syndrome.

    • The association of Addison disease with hypoparathyroidism and mucocutaneous candidiasis is described as polyglandular autoimmune syndrome type 1. It may have an autosomal recessive mode of inheritance. It has no human leukocyte antigen (HLA) associations.

    • The association of Addison disease with type 1 diabetes mellitus and Hashimoto thyroiditis or Graves disease is described as polyglandular autoimmune syndrome type 2 and may be associated with HLA-B8 and DR-3.

    • Other autoimmune phenomena, as outlined above, can occur in either of the 2 polyglandular syndromes.
  • Additional causes of chronic Addison disease
    • Chronic granulomatous diseases

      • TB, sarcoidosis, histoplasmosis, blastomycosis, and cryptococcosis could involve the adrenal glands.

      • In the preantibiotic era, TB was the most common cause and still may be a major consideration in areas where TB is common. It tends to involve both the adrenal cortex and the medulla; however, medullary involvement may not have any major consequences.

      • TB of the adrenal glands usually is a tertiary disease due to the hematogenous spread of infection to the adrenal glands, but clinical evidence of the primary infection is not always present.
    • Hematologic malignancies

      • Malignant infiltration of the adrenal cortices, as with Hodgkin and non-Hodgkin lymphoma and leukemia, may cause Addison disease.

      • Hodgkin and non-Hodgkin lymphoma initially could present with adrenal gland involvement and features of adrenocortical insufficiency.
    • Metastatic malignant disease: Bilateral involvement of the adrenal glands could occur in the setting of metastatic cancer of the lung, breast, or colon or renal cell carcinoma.

    • Infiltrative metabolic disorders: Amyloidosis and hemochromatosis could involve the adrenal glands and lead to primary adrenocortical insufficiency.

    • Acquired immunodeficiency syndrome

      • The adrenocortical insufficiency in patients with AIDS tends to occur late and usually in the setting of a low CD4 cell count.

      • It is caused by opportunistic infections such as cytomegalovirus, Mycobacterium avium intracellulare, cryptococci, or Kaposi sarcoma.

      • Adrenocortical hypofunction in patients with HIV may be due to glucocorticoid resistance syndrome. These patients tend to present with features of adrenocortical insufficiency and mucocutaneous hyperpigmentation but also with increased plasma and urinary cortisol levels and a slight elevation in ACTH levels. Hyperpigmentation in patients with HIV is thought to be due to elevated alpha interferon levels.

      • Another possible cause of adrenocortical insufficiency in patients with AIDS is the use of megestrol acetate (Megace) as an appetite stimulant to stem HIV wasting disease. However, this causes secondary adrenocortical insufficiency and not Addison disease. The glucocorticoid effect of megestrol acetate suppresses pituitary ACTH production and leads to secondary adrenocortical insufficiency.
    • Allgrove syndrome

      • Although patients with congenital adrenocortical unresponsiveness to ACTH (Allgrove syndrome) may present with features of glucocorticoid deficiency and skin hyperpigmentation, the aldosterone production and function in these patients is normal and responds appropriately to low sodium intake.

      • This typically presents in childhood with failure to thrive, features of adrenocortical insufficiency, and hypoglycemia.

      • Some patients may have components of alacrima and achalasia.
    • Abnormalities of beta-oxidation of very-long-chain fatty acids

      • These patients (usually men) present with adrenocortical insufficiency and features of progressive demyelination of the CNS.

      • This is caused by the accumulation of very-long-chain fatty acids (VLCFA) in various organs, including the adrenal cortex, brain, testis, and liver.

      • These disorders are X-linked recessive, with poor penetrance.

      • Other symptoms include cognitive dysfunction, behavioral problems, disturbance of gait, and emotional lability.

      • Two subtypes are described. The first subtype is adrenoleukodystrophy (ALD). This usually presents in childhood. Thirty percent of cases may present with adrenal insufficiency before the onset of neurologic symptoms. Other features include severe hypotonia, seizure disorder, retinitis pigmentosa, and optic atrophy. The second subtype is adrenomyeloneuropathy (AMN). This usually is mild. It tends to present in the 20- to 40-year age group with features of adrenal insufficiency and progressive CNS demyelination.
    • Congenital adrenal hyperplasia

      • Primary adrenocortical insufficiency may occur in patients with the stAR or 20,22-desmolase enzyme deficiency, 3-beta hydroxysteroid dehydrogenase enzyme deficiency, and the severe form of the 21-hydroxylase enzyme deficiency (virilizing and salt wasting).

      • Infants usually present in shock, with hypoglycemia and adrenal insufficiency.

      • In 3-beta hydroxysteroid dehydrogenase enzyme deficiency, female infants appear virilized whereas male infants may have pseudohermaphroditism from insufficient androgen activity.

      • The 20,22-desmolase-enzyme deficiency, also known as congenital lipoid hyperplasia, most often is incompatible with life. It usually presents in the neonatal period with severe adrenocortical insufficiency. Male infants usually have features of pseudohermaphroditism due to an associated deficiency of gonadal steroids.

      • The rapid ACTH test usually helps establish the diagnosis. Patients with CAH respond with a marked increase in 17-OH progesterone levels, an increase in other precursors preceding the enzyme block, and a subnormal cortisol response.
    • Drug-related causes

      • Ketoconazole inhibits the adrenal cytochrome P450 steroidogenic enzymes.

      • Aminoglutethimide blocks the early conversion of cholesterol to pregnenolone by inhibiting the 20,22-desmolase enzyme.

      • Mitotane (O,P'-DDD) blocks adrenal mitochondrial steroid biosynthesis.

      • Busulphan, etomidate, and trilostane inhibit or interfere with adrenal steroid biosynthesis.

      • Methadone, perhaps by depleting pituitary ACTH, may cause secondary adrenocortical insufficiency in some patients.
    • Abdominal irradiation

      • Addison disease could result from situations where a radiation field involves the adrenal glands.

      • The lag time to onset of disease usually is 2-7 years, but the disease could occur earlier depending on the dose of the radiation.

  • Causes of acute Addison disease

    • Stress: Acute adrenal crisis precipitated by infection, trauma, surgery, emotional turmoil, or other stress factors may be the initial presentation of Addison disease in as many as 25% of cases.

    • Failure to increase steroids

      • Failure to appropriately increase daily replacement steroid doses in patients with adrenocortical insufficiency in times of stress could precipitate an adrenal crisis.

      • Failure to adjust the replacement steroid dose in patients on cytochrome P450 enzyme-inducing medications such as rifampin and Dilantin also could precipitate an adrenal crisis.
    • Bilateral adrenal hemorrhage

      • This may be the cause of an acute adrenal crisis, and it may occur as a complication of bacterial infection with Meningococcus or Pseudomonas species, as in Waterhouse-Friderichsen syndrome.

      • It also may occur as a complication of pregnancy, anticoagulant therapy with heparin or warfarin, and as a complication of coagulopathies such as antiphospholipid syndrome (APS) in patients with systemic lupus erythematosus (SLE).

      • The mechanism of action of adrenal hemorrhage is not fully understood. Diagnosis usually is made in the setting of a critically ill patient on anticoagulants (or with any of the causes mentioned above) who becomes acutely hypotensive with tachycardia, nausea, vomiting, fever, and confusion or disorientation. Abdominal or flank pain with associated tenderness may develop.

      • A rapid ACTH test usually should be performed in this setting, and the patient should be started on hydrocortisone without waiting for the results. When time is critical, a random cortisol should be drawn and the patient started on hydrocortisone in stress doses. An abdominal CT scan often reveals bilateral adrenal gland enlargement.
    • Bilateral adrenal artery emboli and bilateral vein thrombosis

      • This is a very rare cause of Addison disease but may occur in critically ill patients on heparin as a complication of heparin-induced thrombosis (HIT) or as a complication of other states that predispose to thrombosis.

      • It also may occur as a complication of radiographic contrast studies involving the adrenal glands.
    • Bilateral adrenalectomy for any reason

      • The surgical removal of a unilateral cortisol-producing adrenal adenoma in a patient with Cushing syndrome can cause an acute adrenal crisis from secondary adrenocortical insufficiency.

      • This is due to the atrophy of the normal adrenal cortex from lack of the stimulant effect of pituitary ACTH.

Adrenal Crisis
Adrenal Hemorrhage
C-17 Hydroxylase Deficiency

Other Problems to be Considered

Bacterial sepsis and other shock states
Pellagra and other skin pigmenting conditions
Secondary adrenocortical insufficiency

Lab Studies

  • A quick review of the clinical presentation, physical examination findings, and laboratory findings (when available) quickly heightens the index of suspicion and possibly leads to more appropriate tests and diagnosis. A high index of suspicion is necessary for diagnosis.

  • The diagnosis of adrenocortical insufficiency rests on the assessment of the functional capacity of the adrenal cortex to synthesize cortisol. This is accomplished primarily by use of the rapid ACTH stimulation test (Cortrosyn, cosyntropin, or Synacthen).

    • ACTH, through complex mechanisms, activates cholesterol esterase enzymes and leads to the release of free cholesterol from cholesterol esters. It also activates the 20,22-desmolase enzyme, which catalyzes the rate-limiting step in adrenal steroidogenesis and increases the NADPH (nicotinamide adenine dinucleotide phosphate) levels necessary for the various hydroxylation steps in steroidogenesis.

    • Within 15-30 minutes of ACTH infusion, the normal adrenal cortex releases 2-5 times its basal plasma cortisol output.

    • Although ACTH stimulation is not normally the major stimulus for aldosterone production, it increases aldosterone production to peak levels within 30 minutes. This response, however, is affected by dietary sodium intake.

    • An increase in the plasma cortisol and aldosterone levels above basal levels after ACTH injection reflects the functional integrity of the adrenal cortex.
  • Performing the rapid adrenocorticotrophic hormone test

    • Blood is drawn in 2 separate tubes for baseline cortisol and aldosterone values.

    • Synthetic ACTH (1-24 amino acid sequence) in a dose of 250 mcg (0.25 mg) is given IM or IV. Smaller doses of synthetic ACTH, as low as 1 mcg, have been used with accuracy approaching the standard test. Proponents of this modified test argue that a dose of 1 mcg or lower is more physiologic, whereas the 250-mcg dose is pharmacologic. However, the modified test is more sensitive only for the 30-minute samples, not the 60-minute samples.

    • Thirty or 60 minutes after the ACTH injection, 2 more blood samples are drawn; one for cortisol and one for aldosterone. No significant reason exists to draw both the 30-minute and 60-minute samples because the sensitivity of the 30-minute value for accurate diagnosis is well documented. The baseline and 30-minute samples usually are adequate to establish the diagnosis.
  • Interpreting the rapid adrenocorticotrophic hormone test

    • Two criteria are necessary for diagnosis: (1) an increase in the baseline cortisol value of 7 mcg/dL or more and (2) the value must rise to 20 mcg/dL or more in 30 or 60 minutes, establishing normal adrenal glucocorticoid function.

    • A low aldosterone value of less than 5 ng/100 mL that fails to double or increase by at least 4 ng/100 mL 30 minutes after ACTH administration denotes abnormal mineralocorticoid function of the adrenal cortex.

    • The 30-minute aldosterone value is more sensitive than the 60-minute value because aldosterone levels actually have been shown to decrease in the 60-minute sample.

    • The absolute 30- or 60-minute cortisol value carries more significance than the incremental value, especially in patients who may be in great stress and at their maximal adrenal output. These patients may not show a significant increase in cortisol output with ACTH stimulation.

    • A normal 30- or 60-minute rapid ACTH test excludes Addison disease but may not adequately exclude mild impairment of the hypothalamic pituitary adrenal axis in secondary adrenal insufficiency.

    • In patients with Addison disease, both cortisol and aldosterone show minimal or no change in response to ACTH, even with prolonged ACTH stimulation tests lasting 24-48 hours.

    • When the results of the rapid ACTH test are equivocal and do not meet the 2 criteria mentioned above, further testing might be required to distinguish Addison disease from secondary adrenocortical insufficiency. Plasma ACTH values and prolonged ACTH stimulation tests may be useful in making this distinction.

    • ACTH levels often are elevated to higher than 250 pg/mL in patients with Addison disease. However, ACTH is unstable in plasma, and specimen collection and storage may require special attention. The specimen should be collected in iced anticoagulated plastic containers and frozen immediately.

    • Importantly, note that ACTH levels also may be high in patients recovering from steroid-induced secondary adrenocortical insufficiency and in patients with ACTH-refractory syndromes.

    • ACTH-inducing tests such as metyrapone stimulation and insulin-induced hypoglycemia, which may be useful in the evaluation of some cases of secondary adrenocortical insufficiency, have no role in the diagnosis of Addison disease and may in fact be lethal to the patient with Addison disease.
  • In acute adrenal crisis, where treatment should not be delayed in order to do the tests, a blood sample for a random plasma cortisol level should be drawn prior to starting hydrocortisone replacement.

    • A random plasma cortisol value of 25 mcg/dL or greater effectively excludes adrenal insufficiency of any kind. However, a random cortisol value in patients who are acutely ill should be interpreted with caution and in correlation with the circumstances of each individual patient. Random cortisol levels should also be interpreted cautiously in critically ill patients with hypoproteinemia (serum albumin <2.5 g/dL). Approximately 40% of these patients will have baseline and cosyntropin-stimulated cortisol levels below the reference range even though the patients have normal adrenal function (as evidenced by the measurement of free cortisol levels). This phenomenon is because more than 90% of circulating cortisol in human serum is protein-bound.

    • Cortisol is known to be elevated by stress, but exactly how high it should rise to constitute a normal response in times of severe stress is not known.

    • An abnormal test result should prompt a proper evaluation of the hypothalamic pituitary adrenal axis after the patient's condition improves before committing a patient to lifelong steroid replacement.

    • In order to perform the ACTH stimulation test in this situation, the patient should be switched to dexamethasone and then tested 24-36 hours later. Dexamethasone does not interfere with the cortisol assay, as does hydrocortisone or prednisone. However, dexamethasone may interfere with interpretation of the random cortisol value drawn after dexamethasone already has been initiated. Dexamethasone also does not have any mineralocorticoid activity, which may be needed in patients with Addison disease.
  • Other laboratory tests

    • Comprehensive metabolic panel

      • The most prominent findings are hyponatremia, hyperkalemia, and a mild non–anion-gap metabolic acidosis due to the loss of the sodium-retaining and potassium and hydrogen ion-secreting action of aldosterone.

      • Urinary and sweat sodium also may be elevated.

      • The most consistent finding is elevated blood urea nitrogen (BUN) and creatinine due to the hypovolemia, a decreased glomerular filtration rate, and a decreased renal plasma flow.

      • Hypercalcemia, the cause of which is not well understood, may be present in a small percentage of patients. However, hypocalcemia could occur in patients with Addison disease accompanied by idiopathic hypoparathyroidism.

      • Hypoglycemia may be present in fasted patients, or it may occur spontaneously. It is caused by the increased peripheral utilization of glucose and increased insulin sensitivity. It is more prominent in children and in patients with secondary adrenocortical insufficiency.

      • Liver function tests may reveal a glucocorticoid-responsive liver dysfunction.
    • CBC count

      • CBC count may reveal a normocytic normochromic anemia, which, upon initial presentation, may be masked by dehydration and hemoconcentration. Relative lymphocytosis and eosinophilia may be present.

      • All of these findings are responsive to glucocorticoid replacement.  
    • Thyroid-stimulating hormone

      • Increased thyroid-stimulating hormone (TSH), with or without low thyroxine, with or without associated thyroid autoantibodies, and with or without symptoms of hypothyroidism, may occur in patients with Addison disease and in patients with secondary adrenocortical insufficiency due to isolated ACTH deficiency. These findings may be slowly reversible with cortisol replacement.

      • In the setting of both adrenocortical insufficiency and hypothyroidism that requires treatment, corticosteroids should be given before thyroid hormone replacement to avoid precipitating an acute adrenal crisis.
  • Autoantibody testing: Thyroid autoantibodies, specifically antithyroglobulin (anti-Tg) and antimicrosomal or antithyroid peroxidase (anti-TPO) antibodies, and/or adrenal autoantibodies may be present.

  • Prolactin testing

    • Modest hyperprolactinemia has been reported in cases of Addison disease and also in secondary adrenocortical insufficiency. It is responsive to glucocorticoid replacement.

    • The cause of the hyperprolactinemia is thought to be the hyperresponsiveness of the lactotroph to thyrotropin-releasing hormone (TRH) in the absence of the steroid-induced or steroid-enhanced hypothalamic dopaminergic tone.

Imaging Studies

  • Chest radiograph
    • The chest x-ray may be normal but often reveals a small heart.

    • Stigmata of earlier infection or current evidence of TB or fungal infection may be present when this is the cause of Addison disease.

  • CT scan
    • Abdominal CT scan may be normal but may show bilateral enlargement of the adrenal glands in patients with Addison disease because of TB, fungal infections, adrenal hemorrhage, or infiltrating diseases involving the adrenal glands.

    • In Addison disease due to TB or histoplasmosis, evidence of calcification involving both adrenal glands may be present.

    • In idiopathic autoimmune Addison disease, the adrenal glands usually are atrophic.

Other Tests

  • ECG may show low-voltage QRS tracing with nonspecific ST-T wave changes and/or changes due to hyperkalemia. These changes are reversible with glucocorticoid replacement.
  • Sputum examination, examination of gastric washings for acid-fast and alcohol-fast bacilli, and a Mantoux or purified protein derivative (PPD) skin test may be needed if TB is thought to be the cause.

Histologic Findings

In cases due to idiopathic autoimmune adrenocortical atrophy, the adrenal glands usually are atrophic, with marked lymphocytic infiltration and fibrosis of the adrenal capsule. The adrenal medulla is spared.

In cases due to TB, the adrenal glands may be enlarged and contain caseating granulomas. Diffuse calcification may be evident, and the adrenal medulla usually is involved.

In patients with AIDS, the adrenal glands may show necrotizing inflammation, hemorrhage, and infarction.

Medical Care

In patients in acute adrenal crisis, IV access should be established urgently, and an infusion of isotonic sodium chloride solution should be begun to restore volume deficit and correct hypotension. Some patients may require glucose supplementation. The precipitating cause should be sought and corrected where possible.

  • In stress situations, the normal adrenal gland output of cortisol is approximately 250-300 mg in 24 hours. This amount of hydrocortisone in soluble form (hydrocortisone sodium succinate or phosphate) should be given, preferably by continuous infusion.
    • Administer 100 mg of hydrocortisone in 100 cc of isotonic sodium chloride solution by continuous IV infusion at a rate of 10-12 cc/h. Infusion may be initiated with 100 mg of hydrocortisone as an IV bolus.

    • An alternative method of hydrocortisone administration is 100 mg as an IV bolus every 6-8 hours.

    • The infusion method maintains plasma cortisol levels more adequately at steady stress levels, especially in the small percentage of patients who are rapid metabolizers and who may have low plasma cortisol levels between the IV boluses.

  • Clinical improvement, especially blood pressure response, should be evident within 4-6 hours of hydrocortisone infusion. Otherwise, the diagnosis of adrenal insufficiency would be questionable.

  • After 2-3 days, the stress hydrocortisone dose should be reduced to 100-150 mg, infused over a 24-hour period, irrespective of the patient's clinical status. This is to avoid stress gastrointestinal bleeding.
  • As the patient improves and as the clinical situation allows, the hydrocortisone infusion can be gradually tapered over the next 4-5 days to daily replacement doses of approximately 3 mg/h (72-75 mg over 24 h) and eventually to daily oral replacement doses, when oral intake is possible.
  • As long as the patient is receiving 100 mg or more of hydrocortisone in 24 hours, no mineralocorticoid replacement is necessary. The mineralocorticoid activity of hydrocortisone in this dosage is sufficient.
  • Thereafter, as the hydrocortisone dose is weaned further, mineralocorticoid replacement should be instituted in doses equivalent to the daily adrenal gland aldosterone output of 0.05-0.20 mg every 24 hours. The usual mineralocorticoid used for this purpose is 9-alpha-fludrocortisone, usually in doses of 0.05-0.10 mg per day or every other day.

  • Patients may need to be advised to increase salt intake in hot weather.

Surgical Care

  • Parenteral steroid coverage should be used in times of major stress, trauma, or surgery and during any major procedure.
  • During surgical procedures, 100 mg of hydrocortisone should be given, preferably by the IM route, prior to the start of a continuous IV infusion. The IM dose of hydrocortisone assures steroid coverage in case of problems with the IV access.
    • When continuous IV infusion is not practical, an intermittent IV bolus injection every 6-8 hours may be used.

    • After the procedure, the hydrocortisone may be rapidly tapered within 24-36 hours to the usual replacement doses, or as gradually as the clinical situation dictates.

    • Mineralocorticoid replacement usually can be withheld until the patient resumes daily replacement steroids.


Whenever possible, an endocrinologist should be involved in both the acute care and on-going treatment of these patients.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Corticosteroid

These drugs are used for replacement therapy in Addison disease and secondary adrenocortical insufficiency.

Drug NamePrednisone (Deltasone, Sterapred, Orasone)
DescriptionUsed for glucocorticoid hormone replacement. Longer acting than hydrocortisone, with a biologic half-life of 18-36 h.
Adult Dose5-7.5 mg PO qd in am or 5 mg PO qd in am and 2.5 mg PO qd at 4-5 pm
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease
InteractionsCoadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsAbrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug NameFludrocortisone (Florinef)
DescriptionSynthetic adrenocortical steroid with very potent mineralocorticoid activity. For use in Addison disease and states of aldosterone deficiency.
Adult Dose0.05-0.1 mg PO qd; some patients may only require alternate-day dosing
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; systemic fungal infections
InteractionsAntagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects; decreases salicylate levels; may increase toxicity of anticoagulants; could lead to digitalis toxicity in patients on digoxin, due to hypokalemia
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsTaper dose gradually when therapy is discontinued; caution in potassium loss and sodium retention

Drug NameHydrocortisone sodium succinate or phosphate (Cortef, Hydrocortone)
DescriptionDOC for steroid replacement in acute adrenal crisis and for daily maintenance in patients with Addison disease or secondary adrenocortical insufficiency. Has both glucocorticoid and mineralocorticoid properties. Biologic half-life is 8-12 h. Easiest way to set up infusion is to have pharmacy mix 100 mg of hydrocortisone in 100 mL of 0.9 saline.
Adult DoseAcute adrenal crisis: 200-300 mg, preferably by continuous IV infusion, q24h; may be preceded by 100 mg IV bolus
Infuse at 10-12 mL/h over 24 h (alternatively, can be given at 100 mg IV/IM q6-8h)
Taper dose after 2-3 d, irrespective of patient's condition, to 150 mg IV infused at a continuous rate of 6 mL/h q24h
Patients who are unable to take oral medication or who continue to be ill should be maintained at 75 mg q24h equivalent to a continuous infusion rate of 3 mL/h q24h
Oral maintenance dose of hydrocortisone: 20-30 mg PO qd; 15-20 mg PO in am and 5-10 mg PO at 4-5 pm; alternatively, 10 mg PO in am, 5 mg PO in pm, and 5 mg PO hs)
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; viral, fungal, or tubercular skin infections
InteractionsIncreased clearance with concurrent use of phenytoin, barbiturates, ephedrine, and rifampin
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsCaution in hyperthyroidism, osteoporosis, peptic ulcer, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis

Further Inpatient Care

  • With the exception of treatable causes such as TB, where adequate and timely treatment may allow recovery of normal adrenal function, patients need glucocorticoid and mineralocorticoid replacement for life.
  • Fludrocortisone replacement therapy
    • Some patients may not need fludrocortisone replacement, or they may need it only in hot weather.

    • The fludrocortisone daily replacement dose should be titrated to maintain normal blood pressure and normal sodium and potassium levels. No dose adjustment is needed in stressful situations.

    • Periodic monitoring is needed to assess general well being, weight, blood pressure, electrolytes, the presence or absence of pedal edema, and the presence of cushingoid features.

  • Hydrocortisone replacement therapy
    • The usual daily replacement dose of hydrocortisone should be given in a way that mimics the circadian rhythm and keeps with the daily basal cortisol production rate of 8-12 mg/m2/d.

    • Patients who are thin may require smaller doses, whereas patients who are obese may require larger doses.

    • Patients on medications that induce the action of the cytochrome P450 enzyme require higher replacement doses. Patients with decreased cortisol clearance, as in liver disease, may require lower replacement doses.

    • The individual daily hydrocortisone or prednisone replacement dose should be titrated to the patient's general well being and the presence or absence of symptoms of adrenal insufficiency.

    • The intermediate-acting steroids, such as prednisone or prednisolone, may be used for daily replacement therapy in place of hydrocortisone. The equivalent daily replacement dose is 5-7.5 mg.

Further Outpatient Care

  • Patients on steroid replacement therapy need to be closely monitored by their primary care physician and by an endocrinologist.
  • Close monitoring for any signs of inadequate replacement (eg, morning headaches, weakness, and dizziness) and any signs of over-replacement (eg, cushingoid features) should prompt appropriate dosage adjustment. A periodic bone dual-energy x-ray absorptiometry (DEXA) scan may be useful in detecting early osteoporosis in patients who are inadvertently over-replaced with maintenance steroids.

Patient Education

  • Patients should wear an emergency medical alert bracelet.
  • Patients should be instructed to double or triple their steroid replacement doses in stressful situations such as a common cold or tooth extraction.
  • Patients should be instructed to contact their regular physician or to go to the emergency department in case of illness.
  • Patients should be instructed on how to give themselves IM injections. They should be given a prescription for parenteral hydrocortisone for use in times when oral intake may not be possible or in situations of marked vomiting or diarrhea. No adjustment needs to be made on the mineralocorticoid replacement dose in stressful situations.

Medical/Legal Pitfalls

  • Patients should be advised to have identification indicating their addisonian status. Most often this is a medical alert bracelet or pendant.
  • Education regarding effects of stress and requirement for additional steroids should be documented.

Special Concerns

  • Hypothyroidism
    • Hypothyroidism occurring in association with Addison disease may be steroid-responsive and may not require thyroxine replacement. Some patients who have symptoms of hypothyroidism may need only temporary levothyroxine replacement during the symptomatic phase. Therefore, holding off or delaying levothyroxine replacement may be prudent in asymptomatic patients until a variable period on steroid replacement has passed before committing them to unnecessary lifelong thyroxine replacement.

    • Patients who require thyroxine replacement need periodic monitoring to assess the recovery of thyroid function. Levothyroxine should be withheld for 6-8 weeks or longer until further clinical evaluation and repeat TSH testing is performed. Additionally, if it has not already been done, steroid replacement should be given before thyroid replacement is instituted. If a question about adrenal insufficiency remains and thyroid replacement must be instituted urgently (ie, profound hypothyroidism), corticosteroids should be given and the adrenal status should be sorted out later.

  • Pregnancy
    • In pregnancy, the usual steroid replacement doses should be maintained. Occasionally, dose adjustments may need to be made depending on the patient's well being and the presence or absence of symptoms of adrenal insufficiency.

    • Pregnancy increases the production of cortisol-binding globulins (CBGs) and, therefore, cortisol binding. Free cortisol is proportionately increased so no dose adjustments should be needed.

    • In labor and delivery, vaginal or caesarean, parenteral stress-dose steroid coverage should be used as at other times of major stress. Stress-dose steroids also may be needed during the stress related to hyperemesis gravidarum.

    • The preferred mode of steroid administration is by continuous IV infusion and then rapid dose-tapering to the usual maintenance doses when the clinical situation allows.

  • Addison T. On the constitutional and local effects of disease of the supra-renal capsules. London, UK: Samuel Highley; 1855.
  • Barnett AH, Donald RA, Espiner EA. High concentrations of thyroid-stimulating hormone in untreated glucocorticoid deficiency: indication of primary hypothyroidism?. Br Med J (Clin Res Ed). Jul 17 1982;285(6336):172-3. [Medline].
  • Barnett AH, Espiner EA, Donald RA. Patients presenting with Addison's disease need not be pigmented. Postgrad Med J. Nov 1982;58(685):690-2. [Medline].
  • Bethune JE. The Adrenal cortex: a scope monograph. Kalamazoo, Mich: Upjohn Co; 1974.
  • Bethune JE. The diagnosis and treatment of adrenal insufficiency. In: De Groot LJ, ed. Endocrinology. Vol 2. 2nd ed. Philadelphia, PA: WB Saunders; 1989:1647-59.
  • Burke CW. Adrenocortical insufficiency. Clin Endocrinol Metab. Nov 1985;14(4):947-76. [Medline].
  • Dackis CA, Gurpegui M, Pottash AL, Gold MS. Methadone induced hypoadrenalism. Lancet. Nov 20 1982;2(8308):1167. [Medline].
  • Demers LM, Whitley RJ. Function of the adrenal cortex: protocol for the rapid ACTH test. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. Vol 43. 3rd ed. Philadelphia, PA: Vol 43. 3rd ed. WB Saunders; 1999:1530-60.
  • Dickstein G, Shechner C, Nicholson WE, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab. Apr 1991;72(4):773-8. [Medline].
  • Dluhy RG, Himathongkam T, Greenfield M. Rapid ACTH test with plasma aldosterone levels. Improved diagnostic discrimination. Ann Intern Med. Jun 1974;80(6):693-6. [Medline].
  • Eisenbarth GS, Wilson PW, Ward F, Buckley C, Lebovita H. The polyglandular failure syndrome: disease inheritance, HLA type, and immune function. Ann Intern Med. Oct 1979;91(4):528-33. [Medline].
  • Elansary EH, Earis JE. Rifampicin and adrenal crisis. Br Med J (Clin Res Ed). Jun 11 1983;286(6381):1861-2. [Medline].
  • Gharib H, Hodgson SF, Gastineau CF, Scholz DA, Smith LA. Reversible hypothyroidism in Addison's disease. Lancet. Oct 7 1972;2(7780):734-6. [Medline].
  • Glasgow BJ, Steinsapir KD, Anders K, Layfield LJ. Adrenal pathology in the acquired immune deficiency syndrome. Am J Clin Pathol. Nov 1985;84(5):594-7. [Medline].
  • Gordon WH, Dluhy RG. Diseases of the adrenal cortex. In: Fauci A, Brunwald E, Martin JB et al, eds. Harrison's Principles of Internal Medicine. Vol 332. 14th ed. New York, NY: McGraw-Hill; 1998:2035-54.
  • Greene LW, Cole W, Greene JB, et al. Adrenal insufficiency as a complication of the acquired immunodeficiency syndrome. Ann Intern Med. Oct 1984;101(4):497-8. [Medline].
  • Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med. Apr 15 2004;350(16):1629-38. [Medline].
  • Kaplan NM. The adrenal glands. In: Griffin JE, Ojeda S, eds. Textbook of Endocrine Physiology. 3rd ed. Oxford, UK: Oxford University Press; 1996:284-313.
  • 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. Nov 1991;67(793):984-7. [Medline].
  • Kyriazopoulou V, Parparousi O, Vagenakis AG. Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab. Dec 1984;59(6):1204-6. [Medline].
  • Lever EG, McKerron CG. Auto-immune Addison's disease associated with hyperprolactinaemia. Clin Endocrinol (Oxf). Oct 1984;21(4):451-7. [Medline].
  • Lindholm J, Kehlet H. Re-evaluation of the clinical value of the 30 min ACTH test in assessing the hypothalamic-pituitary-adrenocortical function. Clin Endocrinol (Oxf). Jan 1987;26(1):53-9. [Medline].
  • Mason AS, Meade TW, Lee JA, Morris JN. Epidemiological and clinical picture of Addison's disease. Lancet. Oct 5 1968;2(7571):744-7. [Medline].
  • May ME, Carey RM. Rapid adrenocorticotropic hormone test in practice. Retrospective review. Am J Med. Dec 1985;79(6):679-84. [Medline].
  • McBrien DJ. Steatorrhea in Addison's disease. Lancet. 1963;i:25-6.
  • Meakin JW, Nelson DH, Thorn GW. Addison's disease in two brothers. J Clin Endocrinol Metab. Jun 1959;19(6):726-31. [Medline].
  • Membreno L, Irony I, Dere W, Klein R, Biglieri EG, Cobb E. Adrenocortical function in acquired immunodeficiency syndrome. J Clin Endocrinol Metab. Sep 1987;65(3):482-7. [Medline].
  • Migeon CJ, Kenny EM, Kowarski A, et al. The syndrome of congenital adrenocortical unresponsiveness to ACTH. Report of six cases. Pediatr Res. Nov 1968;2(6):501-13. [Medline].
  • Norbiato G, Galli M, Righini V, Moroni M. The syndrome of acquired glucocorticoid resistance in HIV infection. Baillieres Clin Endocrinol Metab. Oct 1994;8(4):777-87. [Medline].
  • Oelkers W, Diederich S, Bahr V. Diagnosis and therapy surveillance in Addison's disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone. J Clin Endocrinol Metab. Jul 1992;75(1):259-64. [Medline].
  • Pombo M, Devesa J, Taborda A, et al. Glucocorticoid deficiency with achalasia of the cardia and lack of lacrimation. Clin Endocrinol (Oxf). Sep 1985;23(3):237-43. [Medline].
  • Rose LI, Williams GH, Jagger PI, Lauler DP. The 48-hour adrenocorticotrophin infusion test for adrenocortical insufficiency. Ann Intern Med. Jul 1970;73(1):49-54. [Medline].
  • Sloper JC. The pathology of the adrenals, thymus and certain other endocrine glands in Addisons disease: an analysis of 37 necropsies. Royal Soc Med. 1955;48:628-35.
  • Symington T, ed. Functional pathology of the adrenal gland. Edinburgh, Scotland: Churchill Livingstone; 1969.
  • Van Dellen RG, Purnell DC. Hyperkalemic paralysis in Addison's disease. Mayo Clin Proc. Dec 1969;44(12):904-14. [Medline].
  • Waterhouse R. A case of suprarenal apoplexy. Lancet. 1911;3:577-8.
  • Wood JB, Frankland AW, James VH, Landon J. A rapid test of adrenocortical function. Lancet. Jan 30 1965;191:243-5. [Medline].

Addison Disease excerpt

Article Last Updated: Jul 11, 2006

About Us | Privacy | Code of Ethics | Terms of Use | Contact Us | Advertising | Institutional Subscribers
Labelled with ICRA © 1996-2006 by WebMD.
All Rights Reserved.

Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER

Privacy Policy Changes
Important Announcement:

WebMD, Inc. ("WebMD Health"), a leader in online health information services to the medical professional community has acquired eMedicine. This acquisition was completed January 18, 2006.  As we become more fully integrated, eMedicine users are now eligible to utilize the services available to physicians through WebMD Health's professional portals, including Medscape.com, theheart.org and Medsite.com.  Your eMedicine account information will now be accessible to WebMD Health where it will be maintained in accordance with the WebMD Professional Services Privacy Policy.   Click here to view the WebMD Professional Services Privacy Policy.

If you desire to remove your account information from WebMD Health, please send an email to PrivacyPolicyNotice@emedicine.com.