Addison's disease

Source: Wikipedia, the free encyclopedia.
This article is about medically-recognized primary adrenal insufficiency. For a term used in alternative medicine, see Adrenal fatigue.
Addison's disease
Other namesAddison disease, primary adrenal insufficiency,[1] primary adrenocortical insufficiency, chronic adrenal insufficiency, chronic adrenocortical insufficiency, primary hypocorticalism, primary hypocortisolism, primary hypoadrenocorticism, primary hypocorticism, primary hypoadrenalism
Darkening of the skin seen on the legs of an otherwise fair-skinned patient.
SpecialtyEndocrinology
SymptomsAbdominal pain, weakness, weight loss, darkening of the skin[1]
ComplicationsAdrenal crisis[1]
Usual onsetMiddle-aged females[1]
CausesProblems with the adrenal gland[1]
Diagnostic methodBlood tests, urine tests, medical imaging[1]
TreatmentSynthetic corticosteroid such as hydrocortisone and fludrocortisone[1][2]
Frequency0.9–1.4 per 10,000 people (developed world)[1][3]
DeathsDoubles risk of death
Named afterThomas Addison

Addison's disease, also known as primary adrenal insufficiency,

Mood changes may also occur. Rapid onset of symptoms indicates acute adrenal failure, which is a clinical emergency.[5] An adrenal crisis can be triggered by stress, such as from an injury, surgery, or infection.[1]

Addison's disease arises from problems with the adrenal gland such that not enough of the steroid hormone cortisol and possibly aldosterone are produced.[1] It is an autoimmune disease which affects some genetically predisposed people in whom the body's own immune system has started to target the adrenal gland.[7] While it can follow tuberculosis, in many adult cases it is unclear what has triggered onset of the disease.[7] Causes can include certain medications, sepsis, and bleeding into both adrenal glands.[1][8] Addison's disease is generally diagnosed by blood tests, urine tests, and medical imaging.[1]

Treatment involves replacing the absent hormones.

dextrose are also required.[1] With appropriate treatment, long-term outcomes are typically 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] Secondary adrenal insufficiency is more prevalent.[3] The disease is named after Thomas Addison, a graduate of the University of Edinburgh Medical School, who first described the condition in 1855.[12][13]

Signs and symptoms

Hyperpigmentation as seen in a woman with Addison's disease

The symptoms of Addison's disease can develop over several months and resemble other medical conditions.

fatigue, 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 develop low blood pressure that leads to dizziness upon standing.[16] In women, low dehydroepiandrosterone (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 have insufficient weight gain and recurrent infections.[15] Low cortisol also interferes with adrenocorticotropic hormone (ACTH) regulation, sometimes resulting in the darkening of the skin and mucus membranes, particularly in areas exposed to sun or regular friction.[14]

Blood tests in people with Addison's disease often reveal

low blood sodium. Many also have high blood potassium and/or high thyroid-stimulating hormone (TSH).[14]

Most people with Addison's disease develop or have a preexisting autoimmune disease.

celiac disease (2%).[15] The combination of Addison's disease in addition to mucocutaneous candidiasis, hypoparathyroidism, or both, is called autoimmune polyendocrine syndrome type 1.[17] The presence of Addison's in addition to autoimmune thyroid disease, type 1 diabetes, or both, is called autoimmune polyendocrine syndrome type 2.[18]

Adrenal crisis

Main article: Adrenal crisis

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 as

adrenal 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]

Characteristic symptoms are:[20]

Causes

The negative feedback loop for glucocorticoids

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 (

beta-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.

Adrenal destruction

Autoimmune adrenalitis is the most common cause of Addison's disease in the industrialized world as it represents between 68% and 94% of cases.

21-hydroxylase (a phenomenon first described in 1992).[23] This may be isolated or in the context of autoimmune polyendocrine syndrome (APS type 1 or 2), in which other hormone-producing organs, such as the thyroid and pancreas, may also be affected.[24]

Adrenal destruction is also a feature of

hemorrhage (e.g., in Waterhouse–Friderichsen syndrome or antiphospholipid syndrome), particular infections (tuberculosis, histoplasmosis, coccidioidomycosis), or the deposition of abnormal protein in amyloidosis.[25]

Adrenal dysgenesis

All causes in this category are genetic, and generally very rare. These include

mutations to the SF1 transcription factor, congenital adrenal hypoplasia due to DAX-1 gene mutations and mutations to the ACTH receptor gene (or related genes, such as in the Triple-A or Allgrove syndrome). DAX-1 mutations may cluster in a syndrome with glycerol kinase deficiency with a number of other symptoms when DAX-1 is deleted together with a number of other genes.[12]

Impaired steroidogenesis

To form cortisol, the adrenal gland requires

3β-hydroxysteroid dehydrogenase), lipoid CAH due to deficiency of StAR and mitochondrial DNA mutations.[12] Some medications interfere with steroid synthesis enzymes (e.g., ketoconazole), while others accelerate the normal breakdown of hormones by the liver (e.g., rifampicin, phenytoin).[12]

Diagnosis

Suggestive features

Routine laboratory investigations may show:[12]

Testing

Cortisol
Aldosterone

In suspected cases of Addison's disease, demonstration of low adrenal hormone levels even after appropriate stimulation (called the

tetracosactide 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, including

computed tomography or magnetic resonance imaging.[28]

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 detect very long-chain fatty acids.[29]

Treatment

Maintenance

Treatment for Addison's disease involves replacing the missing cortisol, sometimes in the form of hydrocortisone tablets, or prednisone tablets in a dosing regimen that mimics the physiological concentrations of cortisol. Alternatively, one-quarter as much prednisolone may be used for equal glucocorticoid effect as hydrocortisone. Treatment is usually lifelong. In addition, many people require fludrocortisone 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 a MedicAlert bracelet or information card) for the attention of emergency 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. 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.[citation needed]

Crisis

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.[34]

Prognosis

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 doubled

diabetes mellitus have an almost four-fold increase in mortality compared to individuals with only diabetes.[36] The risk ratio for cause mortality in males and females is 2.19 and 2.86, respectively.[citation needed
]

Death from individuals with Addison's disease often occurs due to cardiovascular disease, infectious disease, and malignant tumors, among other possibilities.[35]

Epidemiology

The frequency rate of Addison's disease in the human population is sometimes estimated at one in 100,000.[37] Some put the number closer to 40–144 cases per million population (1/25,000–1/7,000).[1][38][39] Addison's can affect persons of any age, sex, or ethnicity, but it typically presents in adults between 30 and 50 years of age.[39][40] Research has shown no significant predispositions based on ethnicity.[38] About 70% of Addison's disease diagnoses occur due to autoimmune reactions, which cause damage to the adrenal cortex.[5]

History

Addison's disease is named after

medical eponym "Addison's disease" in recognition of Addison's discovery.[43]

While the six under Addison in 1855 all had adrenal tuberculosis,[44] the term "Addison's disease" does not imply an underlying disease process.

The condition was initially considered a form of

developing countries today.[5]

US president John F. Kennedy (1917-1963) suffered from complications of Addison's Disease throughout his life, including during his presidency, resulting in fatigue
and hyperpigmentation of the face.

Other animals

Main article: Hypoadrenocorticism in dogs

Hypoadrenocorticism is uncommon in dogs,[46] and rare in cats, with less than 40 known feline cases worldwide, since first documented in 1983.[47][48] Individual cases have been reported in a grey seal,[49] a red panda,[50] a flying fox,[51] and a sloth.[52]

In dogs, hypoadrenocorticism has been diagnosed in many breeds.[46] Vague symptoms, which wax and wane, can cause delay in recognition of the presence of the disease.[53] Female dogs appear more affected than male dogs, though this may not be the case in all breeds.[53][54] 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.[53] Treatment of hypoadrenocorticism must replace the hormones (cortisol and aldosterone) which the dog cannot produce itself.[55] This is achieved either by daily treatment with fludrocortisone, or monthly injections with desoxycorticosterone pivalate (DOCP) and daily treatment with a glucocorticoid, such as prednisone.[55] 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.[55] In anticipation of stressful situations, such as staying in a boarding kennel, dogs require an increased dose of prednisone.[55] Lifelong treatment is required, but the prognosis for dogs with hypoadrenocorticism is very good.[53]

References

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