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53-473: Addison's disease , also known as primary adrenal insufficiency , is a rare long-term endocrine disorder characterized by inadequate production of the steroid hormones cortisol and aldosterone by the two outer layers of the cells of the adrenal glands ( adrenal cortex ), causing adrenal insufficiency . Symptoms generally come on slowly and insidiously and may include abdominal pain and gastrointestinal abnormalities, weakness, and weight loss. Darkening of

106-421: A MedicAlert bracelet or information card) for the attention of emergency medical services personnel who might need to attend to their needs. A needle, syringe, and injectable form of cortisol are also recommended to be carried for emergencies. People with Addison's disease are advised to increase their medication during periods of illness or when undergoing surgery or dental treatment. Immediate medical attention

159-405: A classic example of careful medical observation. Tuberculosis used to be a major cause of Addison's disease and acute adrenal failure worldwide. It remains a leading cause in developing countries today. 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

212-479: A delayed but normal response is seen. Other tests may be performed to distinguish between various causes of hypoadrenalism, including renin and adrenocorticotropic hormone levels, as well as medical imaging – usually in the form of ultrasound , computed tomography or magnetic resonance imaging . Adrenoleukodystrophy , and the milder form, adrenomyeloneuropathy , cause adrenal insufficiency combined with neurological symptoms. These diseases are estimated to be

265-410: 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. People with Addison's are often advised to carry information on them (e.g., in the form of

318-926: A far higher prevalence in Finland ; these are known collectively as Finnish heritage disease . Similarly, there are rare genetic diseases among the Amish religious communities in the US and among ethnically Jewish people . A rare disease is defined as one that affects fewer than 200,000 people across a broad range of possible disorders. Chronic genetic diseases are commonly classified as rare. Among numerous possibilities, rare diseases may result from bacterial or viral infections, allergies , chromosome disorders, degenerative and proliferative causes, affecting any body organ . Rare diseases may be chronic or incurable , although many short-term medical conditions are also rare diseases. The NIH 's Office of Rare Diseases Research (ORDR)

371-421: A given year), is used to describe the impact of rare diseases. The Global Genes Project estimates some 300 million people worldwide are affected by a rare disease. The European Organization for Rare Diseases (EURORDIS) estimates that between 3.5 and 5.9% of the world's population is affected by one of approx. 6,000 distinct rare diseases identified to-date. European Union has suggested that between 6 and 8% of

424-470: A glucocorticoid, such as prednisone . 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. In anticipation of stressful situations, such as staying in a boarding kennel, dogs require an increased dose of prednisone. Lifelong treatment

477-531: A lack of resources, and severity of the disease, the term orphan disease is frequently used as a synonym for rare disease . But in the United States and the European Union , "orphan diseases" have a distinct legal meaning. The United States' Orphan Drug Act includes both rare diseases and any non-rare diseases "for which there is no reasonable expectation that the cost of developing and making available in

530-525: A multi-step nationwide reporting process or case reports. Therefore, the data is often incomplete and complex to amalgamate, compare, and update continually. The Genetic and Rare Diseases Information Center at the National Center for Advancing Translational Sciences curates and compiles rare disease prevalence and incidence from PubMed articles and abstracts using a combination of deep learning algorithms and rare disease experts. About 40 rare diseases have

583-697: A number of other symptoms when DAX-1 is deleted together with a number of other genes. To form cortisol, the adrenal gland requires cholesterol , which is then converted biochemically into steroid hormones. Interruptions in the delivery of cholesterol include Smith–Lemli–Opitz syndrome and abetalipoproteinemia . Of the synthesis problems, congenital adrenal hyperplasia is the most common (in various forms: 21-hydroxylase , 17α-hydroxylase , 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase ), lipoid CAH due to deficiency of StAR and mitochondrial DNA mutations. Some medications interfere with steroid synthesis enzymes (e.g., ketoconazole ), while others accelerate

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636-545: A plan and the all-party parliamentary group on Rare, Genetic and Undiagnosed Conditions produced a report Leaving No One Behind: Why England needs an implementation plan for the UK Strategy for Rare Diseases in February 2017. In March 2017 it was announced that NHS England would develop an implementation plan. In January 2018 NHS England published its Implementation Plan for the UK Strategy for Rare Diseases . In January 2021

689-604: Is cystic fibrosis , a genetic disease: it is rare in most parts of Asia but relatively common in Europe and in populations of European descent. In smaller communities, the founder effect can result in a disease that is very rare worldwide being prevalent within the smaller community. Many infectious diseases are prevalent in a given geographic area but rare everywhere else. Other diseases, such as many rare forms of cancer , have no apparent pattern of distribution but are simply rare. The classification of other conditions depends in part on

742-681: Is 2.19 and 2.86, respectively. Death for individuals with Addison's disease often occurs due to cardiovascular disease, infectious disease, and malignant tumors, among other possibilities. The frequency rate of Addison's disease in the human population is sometimes estimated at one in 100,000. Some put the number closer to 40–144 cases per million population (1/25,000–1/7,000). Addison's can affect persons of any age, sex, or ethnicity, but it typically presents in adults between 30 and 50 years of age. Research has shown no significant predispositions based on ethnicity. About 70% of Addison's disease diagnoses occur due to autoimmune reactions, which cause damage to

795-554: Is a medical emergency and potentially life-threatening situation requiring immediate emergency treatment. Characteristic symptoms are: 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

848-584: Is called autoimmune polyendocrine syndrome type 1 . The presence of Addison's in addition to autoimmune thyroid disease, type 1 diabetes, or both, is called autoimmune polyendocrine syndrome type 2 . 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

901-408: Is considered the rarest known disease, affecting three known individuals, two of whom are identical twins. With four diagnosed patients in 27 years, ribose-5-phosphate isomerase deficiency is considered the second rarest. While no single number has been agreed upon for which a disease is considered rare, several efforts have been undertaken to estimate the number of unique rare diseases. In 2019,

954-465: Is excluded. If the short test is abnormal, the long test is used to differentiate between primary adrenal insufficiency and secondary adrenocortical insufficiency. 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,

1007-539: Is generally diagnosed by blood tests , urine tests , and medical imaging . Treatment involves replacing the absent or low hormones. This involves taking a synthetic corticosteroid , such as hydrocortisone or fludrocortisone . These medications are typically taken orally . Lifelong, continuous steroid replacement therapy is required, with regular follow-up treatment and monitoring for other health problems which may occur. A high-salt diet may also be useful in some people. If symptoms worsen, an injection of corticosteroid

1060-455: Is later defined as generally meaning fewer than 1 in 2,000 people. Diseases that are statistically rare, but not also life-threatening, chronically debilitating, or inadequately treated, are excluded from their definition. The definitions used in the medical literature and by national health plans are similarly divided, with definitions ranging from 1/1,000 to 1/200,000. Because of definitions that include reference to treatment availability,

1113-630: 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. 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. Sources of calcium include dairy products, leafy greens, and fortified flours among many others. Vitamin D can be obtained through

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1166-567: Is no single, widely accepted definition for rare diseases. Some definitions rely solely on the number of people living with a disease, and other definitions include other factors, such as the existence of adequate treatments or the severity of the disease. In the United States , the Rare Diseases Act of 2002 defines rare disease strictly according to prevalence, specifically "any disease or condition that affects fewer than 200,000 people in

1219-448: Is present but is biochemically unable to produce cortisol), or adrenal destruction (disease processes leading to glandular damage). 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 because melanocyte-stimulating hormone (MSH) and ACTH share

1272-412: Is recommended (people need to carry a dose with them at all times). Often, large amounts of intravenous fluids with the sugar dextrose are also required. With appropriate treatment, the overall outcome is generally favorable, and most people are able to lead a reasonably normal life. Without treatment, an adrenal crisis can result in death. Addison's disease affects about 9 to 14 per 100,000 people in

1325-608: Is required, but the prognosis for dogs with hypoadrenocorticism is very good. 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. Rare disease Most rare diseases are genetic in origin and thus are present throughout the person's entire life, even if symptoms do not immediately appear. Many rare diseases appear early in life, and about 30% of children with rare diseases will die before reaching their fifth birthdays. Fields condition

1378-423: Is the most common cause of Addison's disease in the industrialized world as it represents between 68% and 94% of cases. Autoimmune destruction of the adrenal cortex is caused by an immune reaction against the enzyme 21-hydroxylase (a phenomenon first described in 1992). 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

1431-531: The Department of Health and Social Care published the UK Rare Diseases Framework , a policy paper which included a commitment that the four nations would develop action plans, working with the rare disease community, and that "where possible, each nation will aim to publish the action plans in 2021". NHS England published England Rare Diseases Action Plan 2022 in February 2022. Organisations around

1484-658: The Monarch Initiative released a rare disease subset of the Mondo ontology that reconciles a wide variety of rare disease knowledge sources, such as OMIM and Orphanet . This was the first count since 1983, demonstrating that there were >10,500 rare diseases where prior estimates had been ~7,000 in the Orphan Drug Act . Global Genes has also estimated that currently approximately 10,000 rare diseases exist globally, with 80% of these having identified genetic origins. There

1537-491: The thyroid and pancreas , may also be affected. Adrenal destruction is also a feature of adrenoleukodystrophy , and when the adrenal glands are involved in metastasis (seeding of cancer cells from elsewhere in the body, especially lung ), hemorrhage (e.g., in Waterhouse–Friderichsen syndrome or antiphospholipid syndrome ), particular infections ( tuberculosis , histoplasmosis , coccidioidomycosis ), or

1590-479: The European population could be affected by a rare disease sometime in their lives. About 80% of rare diseases have a genetic component and only about 400 have therapies, according to Rare Genomics Institute. Rare diseases can vary in prevalence between populations, so a disease that is rare in some populations may be common in others. This is especially true of genetic diseases and infectious diseases . An example

1643-623: The United Kingdom government published The UK Strategy for Rare Diseases which "aims to ensure no one gets left behind just because they have a rare disease", with 51 recommendations for care and treatment across the UK to be implemented by 2020. Health services in the four constituent countries agreed to adopt implementation plans by 2014, but by October 2016, the Health Service in England had not produced

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1696-433: The United States a drug for such disease or condition will [be] recovered from sales in the United States of such drug" as orphan diseases . The European Organization for Rare Diseases (EURORDIS) also includes both rare diseases and neglected diseases into a larger category of "orphan diseases". Prevalence (number of people living with a disease at a given moment), rather than incidence (number of new diagnoses in

1749-652: The United States", or about 1 in 1,500 people. This definition is essentially the same as that of the Orphan Drug Act of 1983 , a federal law that was written to encourage research into rare diseases and possible cures. In Japan, the legal definition of a rare disease is one that affects fewer than 50,000 patients in Japan, or about 1 in 2,500 people. The European Commission on Public Health defines rare diseases as "life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them". The term low prevalence

1802-664: The adrenal cortex. Addison's disease is named after Thomas Addison , the British physician who first described the condition in On the Constitutional and Local Effects of Disease of the Suprarenal Capsules (1855). He originally described it as "melasma suprarenale", but later physicians gave it the medical eponym "Addison's disease" in recognition of Addison's discovery. While the six under Addison in 1855 all had adrenal tuberculosis,

1855-509: The adrenal gland does not produce sufficient amounts of the steroid hormones cortisol and (sometimes) aldosterone . 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 glands. In many adult cases it is unclear what has triggered the onset of this disease, though it sometimes follows tuberculosis . Causes can include certain medications, sepsis , and bleeding into both adrenal glands. Addison's disease

1908-778: The adrenal glands. Low blood cortisol can cause a variety of symptoms, including fatigue , malaise , muscle and joint pain, reduced appetite , weight loss , and increased sensitivity to cold. Gastrointestinal symptoms such as nausea, abdominal pain, and vomiting are particularly common. Low aldosterone can cause affected people to crave salty foods, as well as develop low blood pressure that leads to dizziness upon standing. In women, low dehydroepiandrosterone (DHEA) can result in dry and itchy skin, loss of armpit and pubic hair, and reduced sexual drive. Young children with Addison's disease may have insufficient weight gain and recurrent infections. Low cortisol also interferes with adrenocorticotropic hormone (ACTH) regulation, sometimes resulting in

1961-453: The body is strained, as in rigorous exercise or being sick, the latter often needing emergency treatment with intravenous injections to treat the crisis. Individuals with Addison's disease have more than a doubled mortality rate . Furthermore, individuals with Addison's disease and diabetes mellitus have an almost four-fold increase in mortality compared to individuals with only diabetes. The risk ratio for cause mortality in males and females

2014-423: 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 . Treatment for Addison's disease involves replacing the missing cortisol, sometimes in the form of hydrocortisone tablets, or prednisone tablets in

2067-737: The darkening of the skin and mucous membranes, particularly in areas exposed to sun or regular friction. 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). Most people with Addison's disease develop or have a preexisting autoimmune disease. Particularly common comorbid conditions are autoimmune thyroid disease (40% of people with Addison's), premature ovarian failure (up to 16% of people with Addison's), type 1 diabetes (11%), pernicious anemia (10%), vitiligo (6%) and celiac disease (2%). The combination of Addison's disease in addition to mucocutaneous candidiasis , hypoparathyroidism , or both,

2120-580: The deposition of abnormal protein in amyloidosis . 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

2173-470: The developed world. It occurs most frequently in middle-aged females. The disease is named after Thomas Addison , a graduate of the University of Edinburgh Medical School , who first described the condition in 1855. The symptoms of Addison's disease can develop over several months and resemble other medical conditions. Most common symptoms are caused by low levels of hormones that would normally be produced by

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2226-425: The face. He is possibly the most famous known case. Hypoadrenocorticism is uncommon in dogs, and rare in cats, with less than 40 known feline cases worldwide, since first documented in 1983. Individual cases have been reported in a grey seal , a red panda , a flying fox, and a sloth. In dogs, hypoadrenocorticism has been diagnosed in many breeds. Vague symptoms, which wax and wane, can cause delay in recognition of

2279-414: The normal breakdown of hormones by the liver (e.g., rifampicin , phenytoin ). Routine laboratory investigations may show: In suspected cases of Addison's disease, demonstration of low adrenal hormone levels even after appropriate stimulation (called the ACTH stimulation test or synacthen test ) with synthetic pituitary ACTH hormone tetracosactide is needed for the diagnosis. Two tests are performed,

2332-438: 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. 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

2385-495: The population being studied: All forms of cancer in children are generally considered rare, because so few children develop cancer, but the same cancer in adults may be more common. Estimating the incidence and prevalence of rare diseases is a complex process due to their wide range of prevalence rates. Rare diseases with higher prevalences can be estimated through a screening panel or patient registries, while diseases which are exceedingly rare may only be able to be estimated through

2438-535: The presence of the disease. Female dogs appear more affected than male dogs, though this may not be the case in all breeds. 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. Treatment of hypoadrenocorticism must replace the hormones (cortisol and aldosterone) which the dog cannot produce itself. This is achieved either by daily treatment with fludrocortisone , or monthly injections with desoxycorticosterone pivalate (DOCP) and daily treatment with

2491-429: The same precursor molecule, pro-opiomelanocortin (POMC). After production in the anterior pituitary gland, POMC gets cleaved into gamma-MSH, ACTH, and 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. Autoimmune adrenalitis

2544-404: The short and the long test. Dexamethasone does not cross-react with the assay and can be administered concomitantly during testing. 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

2597-432: The skin in certain areas may also occur. Under certain circumstances, an adrenal crisis may occur with low blood pressure , vomiting , lower back pain , and loss of consciousness . Mood changes may also occur. Rapid onset of symptoms indicates acute adrenal failure, which is a clinical emergency. An adrenal crisis can be triggered by stress, such as from an injury, surgery, or infection. Addison's disease arises when

2650-466: 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. 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

2703-459: The term "Addison's disease" does not imply an underlying disease process. The condition was initially considered a form of anemia 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

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2756-462: The world are exploring ways of involving people affected by rare diseases in helping shape future research, including using online methods to explore the perspectives of multiple stakeholders. Rare Disease Day is held in Europe , Canada , the United States, and India on the last day of February (thus, in leap years , on February 29, the rarest day) to raise awareness for rare diseases. There are

2809-485: Was established by H.R. 4013/Public Law 107–280 in 2002. H.R. 4014, signed the same day, refers to the "Rare Diseases Orphan Product Development Act". Similar initiatives have been proposed in Europe. The ORDR also runs the Rare Diseases Clinical Research Network (RDCRN). The RDCRN provides support for clinical studies and facilitating collaboration, study enrollment and data sharing. In 2013,

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