Addison's disease arises when the adrenal gland does not produce sufficient amounts of the steroid hormonescortisol and (sometimes)aldosterone.[1] It is anautoimmune disease which affects some genetically predisposed people in whom the body's own immune system has started to target the adrenal glands.[7] In many adult cases it is unclear what has triggered the onset of this disease, though it sometimes followstuberculosis.[7] Causes can include certain medications,sepsis, and bleeding into both adrenal glands.[1][8] Addison's disease is generally diagnosed byblood tests,urine tests, andmedical imaging.[1]
Treatment involves replacing the absent or low hormones.[1] This involves taking a syntheticcorticosteroid, such ashydrocortisone orfludrocortisone.[1][2] These medications are typically takenorally.[1] Lifelong, continuous steroid replacement therapy is required, with regular follow-up treatment and monitoring for other health problems which may occur.[9] A high-salt diet may also be useful in some people.[1] If symptoms worsen, an injection of corticosteroid is recommended (people need to carry a dose with them at all times).[1] Often, large amounts ofintravenous fluids with the sugardextrose are also required.[1] With appropriate treatment, the overall outcome is generally favorable,[10] and most people are able to lead a reasonably normal life.[11] Without treatment, an adrenal crisis can result in death.[1]
Addison's disease affects about 9 to 14 per 100,000 people in the developed world.[1][3] It occurs most frequently in middle-aged females.[1] The disease is named afterThomas Addison, a graduate of theUniversity of Edinburgh Medical School, who first described the condition in 1855.[12][13]
The symptoms of Addison's disease can develop over several months and resemble other medical conditions.[14] Most common symptoms are caused by low levels of hormones that would normally be produced by the adrenal glands. Low blood cortisol can cause a variety of symptoms, includingfatigue,malaise, muscle and joint pain,reduced appetite,weight loss, and increased sensitivity to cold.[15][14] Gastrointestinal symptoms such as nausea, abdominal pain, and vomiting are particularly common.[16][14] Low aldosterone can cause affected people to crave salty foods, as well as developlow blood pressure that leads to dizziness upon standing.[16] In women, lowdehydroepiandrosterone (DHEA) can result in dry and itchy skin, loss of armpit and pubic hair, and reduced sexual drive.[15] Young children with Addison's disease may haveinsufficient weight gain and recurrent infections.[15] Low cortisol also interferes withadrenocorticotropic hormone (ACTH) regulation, sometimes resulting in the darkening of the skin and mucous membranes, particularly in areas exposed to sun or regular friction.[14]
An "adrenal crisis" or "Addisonian crisis" is a constellation of symptoms that indicates severe adrenal insufficiency. This may be the result of either previously undiagnosed Addison's disease, a disease process suddenly affecting adrenal function (such asadrenal hemorrhage), or an intercurrent problem (e.g., infection, trauma) in someone known to have Addison's disease. It is a medical emergency and potentially life-threatening situation requiring immediate emergency treatment.[19]
Causes of adrenal insufficiency can be categorized by the mechanism through which they cause the adrenal glands to produce insufficient cortisol. This can be due to damage or destruction of the adrenal cortex. These deficiencies include glucocorticoid and mineralocorticoid hormones as well. These are adrenal dysgenesis (the gland has not formed adequately during development), impaired steroidogenesis (the gland is present but is biochemically unable to produce cortisol), or adrenal destruction (disease processes leading to glandular damage).[12]
Darkening (hyperpigmentation) of the skin, including areas not exposed to the sun – characteristic sites of darkening are skin creases (e.g., of the hands), nipple, and the inside of the cheek (buccal mucosa); also, old scars may darken. This occurs becausemelanocyte-stimulating hormone (MSH) and ACTH share the same precursor molecule,pro-opiomelanocortin (POMC). After production in theanterior pituitary gland, POMC gets cleaved into gamma-MSH, ACTH, andbeta-lipotropin. The subunit ACTH undergoes further cleavage to produce alpha-MSH, the most important MSH for skin pigmentation. In secondary and tertiary forms of adrenal insufficiency, skin darkening does not occur, as ACTH is not overproduced.
Autoimmune adrenalitis is the most common cause of Addison's disease in the industrialized world as it represents between 68% and 94% of cases.[6][21][22]Autoimmune destruction of theadrenal cortex is caused by an immune reaction against the enzyme21-hydroxylase (a phenomenon first described in 1992).[23] This may be isolated or in the context ofautoimmune polyendocrine syndrome (APS type 1 or 2), in which other hormone-producing organs, such as thethyroid andpancreas, may also be affected.[24]
All causes in this category are genetic, and generally very rare. These includemutations to theSF1transcription factor,congenital adrenal hypoplasia due toDAX-1 gene mutations and mutations to theACTH receptor gene (or related genes, such as in theTriple-A or Allgrove syndrome).DAX-1 mutations may cluster in a syndrome withglycerol kinase deficiency with a number of other symptoms whenDAX-1 is deleted together with a number of other genes.[12]
Metabolic acidosis (increased blood acidity), also is due to loss of the hormonealdosterone because sodium reabsorption in thedistal tubule is linked with acid/hydrogen ion (H+) secretion. Absent or insufficient levels of aldosterone stimulation of the renal distal tubule lead to sodium wasting in the urine and H+ retention in the serum.
In suspected cases of Addison's disease, demonstration of low adrenal hormone levels even after appropriate stimulation (called theACTH stimulation test or synacthen test) with synthetic pituitary ACTH hormonetetracosactide is needed for the diagnosis. Two tests are performed, the short and the long test.Dexamethasone does not cross-react with the assay and can be administered concomitantly during testing.[26][27]
The short test compares blood cortisol levels before and after 250 micrograms of tetracosactide (intramuscular or intravenous) is given. If one hour later,plasma cortisol exceeds 170 nmol/L and has risen by at least 330 nmol/L to at least 690 nmol/L, adrenal failure is excluded. If the short test is abnormal, the long test is used to differentiate between primary adrenal insufficiency and secondary adrenocortical insufficiency.[28]
The long test uses 1 mg tetracosactide (intramuscular). Blood is taken 1, 4, 8, and 24 hours later. Normal plasma cortisol level should reach 1,000 nmol/L by 4 hours. In primary Addison's disease, the cortisol level is reduced at all stages, whereas in secondary corticoadrenal insufficiency, a delayed but normal response is seen. Other tests may be performed to distinguish between various causes of hypoadrenalism, includingrenin andadrenocorticotropic hormone levels, as well asmedical imaging – usually in the form ofultrasound,computed tomography ormagnetic resonance imaging.[28]
Adrenoleukodystrophy, and the milder form,adrenomyeloneuropathy, cause adrenal insufficiency combined with neurological symptoms. These diseases are estimated to be the cause of adrenal insufficiency in about 35% of diagnosed males with idiopathic Addison's disease and should be considered in the differential diagnosis of any male with adrenal insufficiency. Diagnosis is made by a blood test to detectvery long-chain fatty acids.[29]
Treatment for Addison's disease involves replacing the missing cortisol, sometimes in the form ofhydrocortisone tablets, orprednisone tablets in a dosing regimen that mimics the physiological concentrations of cortisol. Alternatively, one-quarter as muchprednisolone may be used forequal glucocorticoid effect as hydrocortisone. Treatment is usually lifelong. In addition, many people requirefludrocortisone as a replacement for the missing aldosterone.[19]
People with Addison's are often advised to carry information on them (e.g., in the form of aMedicAlert bracelet or information card) for the attention ofemergency medical services personnel who might need to attend to their needs.[30][31] A needle, syringe, and injectable form of cortisol are also recommended to be carried for emergencies.[31] People with Addison's disease are advised to increase their medication during periods of illness or when undergoing surgery or dental treatment.[31] Immediate medical attention is needed when severe infections, vomiting, or diarrhea occur, as these conditions can precipitate an Addisonian crisis. A person who is vomiting may require injections of hydrocortisone, instead.[32]
Those with low aldosterone levels may also benefit from a high-sodium diet. It may also be beneficial for the people with Addison's disease to increase their dietary intake of calcium and vitamin D. High dosages of corticosteroids are linked to osteoporosis so these may be necessary for bone health.[33] Sources of calcium include dairy products, leafy greens, and fortified flours among many others.[34] Vitamin D can be obtained through the sun, oily fish, red meat, and egg yolks among many others. Though there are many sources to obtain vitamin D through diet, supplements are also an option.[35]
Standard therapy involves intravenous injections of glucocorticoids and large volumes of intravenous saline solution with dextrose (glucose). This treatment usually brings rapid improvement. If intravenous access is not immediately available, intramuscular injection of glucocorticoids can be used. When the person is capable of swallowing fluids and medications by mouth, the amount of glucocorticoids is decreased until a maintenance dose is reached. If aldosterone is deficient, maintenance therapy also includes oral doses of fludrocortisone acetate.[36]
Outcomes are typically good when treated. Most people can expect to live relatively normal lives. Someone with the disease should be observant of symptoms of an "Addison's crisis" while the body is strained, as in rigorous exercise or being sick, the latter often needing emergency treatment with intravenous injections to treat the crisis.[11]
Individuals with Addison's disease have more than a doubledmortality rate.[37] Furthermore, individuals with Addison's disease anddiabetes mellitus have an almost four-fold increase in mortality compared to individuals with only diabetes.[38] The risk ratio for cause mortality in males and females is 2.19 and 2.86, respectively.[37]
Death for individuals with Addison's disease often occurs due to cardiovascular disease, infectious disease, and malignant tumors, among other possibilities.[37]
Recent studies indicate that individuals with Addison's disease may have an increased risk of osteoporotic fractures and higher rates of work loss, including sick leave and disability pension.[39][40]
The frequency rate of Addison's disease in the human population is sometimes estimated at one in 100,000.[41] Some put the number closer to 40–144 cases per million population (1/25,000–1/7,000).[1][42][43] Addison's can affect persons of any age, sex, or ethnicity, but it typically presents in adults between 30 and 50 years of age.[43][44] Research has shown no significant predispositions based on ethnicity.[42] About 70% of Addison's disease diagnoses occur due to autoimmune reactions, which cause damage to the adrenal cortex.[5]
Addison's disease is named afterThomas Addison, the Britishphysician who first described the condition inOn the Constitutional and Local Effects of Disease of the Suprarenal Capsules (1855).[45][46] He originally described it as "melasma suprarenale", but later physicians gave it themedical eponym "Addison's disease" in recognition of Addison's discovery.[47]
While the six patients examined by Addison in 1855 all had adrenal tuberculosis,[48] the term "Addison's disease" does not imply an underlying disease process.
The condition was initially considered a form ofanemia associated with the adrenal glands. Because little was known at the time about the adrenal glands (then called "Supra-Renal Capsules"), Addison's monograph describing the condition was an isolated insight. As the adrenal function became better known, Addison's monograph became known as an important medical contribution and a classic example of careful medical observation.[49]Tuberculosis used to be a major cause of Addison's disease and acute adrenal failure worldwide. It remains a leading cause indeveloping countries today.[5]
US presidentJohn F. Kennedy (1917–1963) suffered from complications of Addison's disease throughout his life, including during his presidency,[50] resulting infatigue and hyperpigmentation of the face. He is possibly the most famous known case.Helen Reddy also had Addison's disease.
Hypoadrenocorticism is uncommon in dogs,[51] and rare in cats, with less than 40 known feline cases worldwide, since first documented in 1983.[52][53] Individual cases have been reported in agrey seal,[54] ared panda,[55] a flying fox,[56] and a sloth.[57]
In dogs, hypoadrenocorticism has been diagnosed in many breeds.[51] Vague symptoms, which wax and wane, can cause delay in recognition of the presence of the disease.[58] Female dogs appear more affected than male dogs, though this may not be the case in all breeds.[58][59] The disease is most often diagnosed in dogs that are young to middle-aged, but it can occur at any age from 4 months to 14 years.[58] Treatment of hypoadrenocorticism must replace the hormones (cortisol and aldosterone) which the dog cannot produce itself.[60] This is achieved either by daily treatment withfludrocortisone, or monthly injections withdesoxycorticosterone pivalate (DOCP) and daily treatment with a glucocorticoid, such asprednisone.[60] Several follow-up blood tests are required so the dose can be adjusted until the dog is receiving the correct amount of treatment, because the medications used in the therapy of hypoadrenocorticism can cause excessive thirst and urination if not prescribed at the lowest effective dose.[60] In anticipation of stressful situations, such as staying in a boarding kennel, dogs require an increased dose of prednisone.[60] Lifelong treatment is required, but the prognosis for dogs with hypoadrenocorticism is very good.[58] Michigan State University has conducted a study that explores the process of getting to the lowest effective dose safely. This must be done slowly over time, so that crisis does not occur. Medications should never be suddenly stopped, as this will cause severe medical issues quickly.
Hypoadrenocorticism can also occur in cats but is extremely rare. It is usually caused by an immune reaction, resulting in adrenal insufficiency. An ACTH stimulation test is used to diagnosis the condition.[61]
^"Addison's Disease". National Endocrine and Metabolic Diseases Information Service. Archived fromthe original on 28 October 2007. Retrieved26 October 2007.
^Quinkler M, Dahlqvist P, Husebye ES, Kämpe O (January 2015). "A European Emergency Card for adrenal insufficiency can save lives".European Journal of Internal Medicine.26 (1):75–76.doi:10.1016/j.ejim.2014.11.006.PMID25498511.
^Chantzichristos D, Persson A, Eliasson B, Miftaraj M, Franzén S, Bergthorsdottir R, et al. (1 April 2016). "Patients with Diabetes Mellitus Diagnosed with Addison´s Disease Have a Markedly Increased Additional Risk of Death".Cushing Syndrome and Primary Adrenal Disorders. Meeting Abstracts. Endocrine Society. Archived fromthe original on 9 June 2021. Retrieved9 June 2021.
^Tapper J, Thompson A (May 20, 2025).Original Sin: President Biden's Decline, Its Cover-Up, and His Disastrous Choice to Run Again (1st ed.). New York: Penguin Press. p. 51.ISBN979-8-217-06067-2.
^Brock AP, Hall NH, Cooke KL, Reese DJ, Emerson JA, Wellehan JF (June 2013). "Diagnosis and management of atypical hypoadrenocorticism in a variable flying fox (Pteropus hypomelanus)".Journal of Zoo and Wildlife Medicine.44 (2):517–519.doi:10.1638/2012-0276R2.1.PMID23805580.S2CID38918707.
^Kline S, Rooker L, Nobrega-Lee M, Guthrie A (March 2015). "Hypoadrenocorticism (Addison's disease) in a Hoffmann's two-toed sloth (Choloepus hoffmanni)".Journal of Zoo and Wildlife Medicine.46 (1):171–174.doi:10.1638/2014-0003R2.1.PMID25831596.S2CID20775341.
^abcdScott-Moncrieff JC (2015). "Chapter 12: Hypoadrenocorticism". In Feldman EC, Nelson RW, Reusch CE, Scott-Moncrieff JC (eds.).Canine and Feline Endocrinology (4th ed.). Saunders Elsevier. pp. 485–520.ISBN978-1-4557-4456-5.
