Choroba addisona – Etiologia i przyczyny

Choroba addisona
Etiologia i przyczyny

Choroba Addisona, czyli pierwotna niedoczynność nadnerczy, to schorzenie endokrynologiczne wynikające z destrukcji około 90% kory nadnerczy, prowadzącej do niedoboru kortyzolu i aldosteronu. W krajach rozwiniętych dominującą etiologią (70-90%) jest autoimmunologiczne zapalenie nadnerczy, w którym obecne są przeciwciała przeciwko 21-hydroksylazie u 85-90% pacjentów. Początkowo obserwuje się wzrost aktywności reninowej osocza przy prawidłowym lub niskim stężeniu aldosteronu, a następnie zmniejszoną odpowiedź kortyzolu na ACTH i podwyższone stężenie ACTH w surowicy. Choroba może występować izolowanie lub w ramach zespołów wielogruczołowych, takich jak APS-1 i APS-2, często współistniejąc z innymi schorzeniami autoimmunologicznymi (np. choroby tarczycy, cukrzyca typu 1). Predyspozycje genetyczne oraz rodzinne występowanie przeciwciał przeciwnadnerczowych zwiększają ryzyko rozwoju choroby.

Etiologia choroby Addisona

Choroba Addisona (pierwotna niedoczynność nadnerczy) to rzadkie schorzenie endokrynologiczne charakteryzujące się niedostatecznym wytwarzaniem hormonów kory nadnerczy – głównie kortyzolu i aldosteronu. Do wystąpienia objawów klinicznych dochodzi zazwyczaj dopiero po zniszczeniu około 90% tkanki kory nadnerczy, co może trwać od kilku miesięcy do kilku lat.¹²

Przyczyny autoimmunologiczne

Najczęstszą przyczyną choroby Addisona w krajach rozwiniętych jest reakcja autoimmunologiczna, która odpowiada za 70-90% wszystkich przypadków.¹² W tym mechanizmie układ immunologiczny pacjenta błędnie rozpoznaje komórki kory nadnerczy jako obce i atakuje je, prowadząc do stopniowego niszczenia tkanki gruczołowej.¹ Proces autoimmunologicznego niszczenia nadnerczy może trwać latami, zanim pojawią się objawy kliniczne.¹

W autoimmunologicznym zapaleniu nadnerczy występują zarówno mechanizmy odpowiedzi humoralnej, jak i komórkowej. U około 85-90% pacjentów z autoimmunologiczną postacią choroby Addisona można wykryć w surowicy przeciwciała skierowane przeciwko enzymom steroidogennym, najczęściej przeciwko 21-hydroksylazie.¹² Obserwacje kliniczne wskazują, że pierwszą oznaką autoimmunologicznej niewydolności nadnerczy jest zwykle wzrost aktywności reninowej osocza przy jednoczesnym prawidłowym lub niskim stężeniu aldosteronu, co sugeruje początkowe zajęcie warstwy kłębkowatej kory nadnerczy. Dopiero po kilku miesiącach lub latach dochodzi do dysfunkcji warstwy pasmowatej, co objawia się zmniejszoną odpowiedzią kortyzolu na stymulację ACTH, a następnie podwyższonym stężeniem ACTH w surowicy.¹

Badania naukowe wykazały, że niektóre osoby z określonymi genami są bardziej predysponowane do rozwoju zaburzeń autoimmunologicznych, w tym choroby Addisona.¹ Istnieją dowody na rodzinne występowanie predyspozycji do autoimmunologicznej niedoczynności nadnerczy – do 10% krewnych pierwszego stopnia pacjentów z autoimmunologiczną postacią choroby Addisona wykazuje obecność przeciwciał przeciwnadnerczowych i ma zwiększone ryzyko rozwoju tego schorzenia.¹

Zespoły wielogruczołowe autoimmunologiczne

Autoimmunologiczna choroba Addisona może występować jako izolowane schorzenie (u około 40% pacjentów) lub jako część zespołów wielogruczołowych (u pozostałych 60%).¹ U około 50% osób z chorobą Addisona spowodowaną autoimmunologicznym zapaleniem nadnerczy rozwija się w ciągu życia inne schorzenie autoimmunologiczne.¹ Wyróżniamy dwa główne zespoły:

Autoimmunologiczny zespół wielogruczołowy typu 1 (APS-1) – rzadki, dziedziczony autosomalnie recesywnie zespół charakteryzujący się współwystępowaniem choroby Addisona z niedoczynnością przytarczyc i kandydozą śluzówkowo-skórną.¹ Nie ma związku z układem HLA.²
Autoimmunologiczny zespół wielogruczołowy typu 2 (zespół Schmidta) – skojarzenie choroby Addisona z chorobami autoimmunologicznymi tarczycy (zapaleniem tarczycy Hashimoto lub chorobą Gravesa-Basedowa) i/lub cukrzycą typu 1. Ten zespół może być związany z antygenami HLA-B8 i DR-3.¹

Inne schorzenia autoimmunologiczne, które mogą współwystępować z chorobą Addisona to: celiakia, bielactwo, łysienie plackowate, przedwczesna niewydolność jajników lub jąder, niedokrwistość złośliwa, miastenia, idiopatyczne zapalenie przysadki, przewlekłe aktywne zapalenie wątroby i pierwotna marskość żółciowa.¹

Przyczyny infekcyjne

W przeszłości gruźlica była główną przyczyną choroby Addisona, a obecnie nadal pozostaje istotną przyczyną w krajach rozwijających się.¹² Gruźlica może rozprzestrzeniać się do nadnerczy i prowadzić do ich zniszczenia.¹

Inne zakażenia mogące prowadzić do niewydolności nadnerczy to:

Zakażenie HIV/AIDS i powiązane infekcje oportunistyczne¹²
Zakażenia grzybicze (histoplazmoza, blastomykoza, kryptokokoza)¹²
Zakażenie wirusem cytomegalii (CMV)¹
Posocznica, zwłaszcza meningokokowa¹
Kiła¹
Afrykańska trypanosomoza¹

HIV stał się obecnie istotną przyczyną niewydolności nadnerczy związaną z martwicą nadnerczy. Niewydolność nadnercza u pacjentów z AIDS ma tendencję do występowania w późnych stadiach choroby, zazwyczaj przy niskim poziomie limfocytów CD4.¹²

Krwawienie do nadnerczy

Obustronne krwotoki do nadnerczy mogą być przyczyną ostrej niewydolności nadnerczy i mogą wystąpić w następujących okolicznościach:

Rozsiane wykrzepianie wewnątrznaczyniowe (DIC)¹
Urazy¹
Posocznica meningokokowa (zespół Waterhouse’a-Friderichsena)¹
Procesy nowotworowe¹
Powikłania stosowania leków przeciwkrzepliwych¹²

Przyczyny nowotworowe

Choroba Addisona może rozwinąć się w wyniku zajęcia nadnerczy przez procesy nowotworowe:

Przerzuty nowotworowe z innych narządów, głównie z nowotworów płuc, piersi, żołądka, jelita grubego i nerki¹²
Nowotwory układu krwiotwórczego – chłoniaki Hodgkina i nie-Hodgkina, białaczki¹
Pierwotne nowotwory nadnerczy¹

Do niewydolności nadnerczy dochodzi zazwyczaj przy obustronnym zajęciu nadnerczy przez proces nowotworowy.¹

Przyczyny jatrogenne

Jatrogenne przyczyny choroby Addisona obejmują:

Chirurgiczne usunięcie obu nadnerczy (adrenalektomia obustronna), np. w celu usunięcia guza¹
Leki blokujące syntezę kortyzolu, takie jak ketokonazol (lek przeciwgrzybiczy) i etomidat (lek stosowany w anestezji ogólnej)¹²
Radioterapia okolicy nadnerczy¹
Niektóre leki stosowane w leczeniu zespołu Cushinga¹
Inhibitory punktów kontrolnych układu immunologicznego używane w leczeniu nowotworów, które mogą wywoływać autoimmunologiczne zapalenie nadnerczy¹

Choroby naciekowe i metaboliczne

Infiltracja nadnerczy może występować w przebiegu następujących schorzeń:

Amyloidoza – choroba, w której białko amyloidowe wytwarzane przez komórki szpiku kostnego gromadzi się w nadnerczach i uszkadza je¹²
Hemochromatoza – choroba charakteryzująca się nadmiernym gromadzeniem żelaza w organizmie¹²
Choroby ziarniniakowe – sarkoidoza¹²

Przyczyny genetyczne

Rzadkie przyczyny genetyczne choroby Addisona obejmują:

Adrenoleukodystrofia (ALD) – rzadka, dziedziczna choroba związana z chromosomem X, wpływająca na nadnercza i komórki nerwowe w mózgu, występująca głównie u chłopców¹²
Wrodzona hiperplazja nadnerczy – grupa zaburzeń genetycznych wpływających na enzymy uczestniczące w produkcji hormonów nadnerczy¹²
Mutacje czynnika transkrypcyjnego SF1¹
Wrodzona hipoplazja nadnerczy związana z mutacjami genu DAX-1¹
Mutacje genu receptora ACTH¹
Zespół Smitha-Lemliego-Opitza i abetalipoproteinemia – zaburzenia dostarczania cholesterolu¹

Stres i czynniki wyzwalające przełom nadnerczowy

Ostre przełomy nadnerczowe mogą być pierwszym objawem choroby Addisona u nawet 25% pacjentów. Takie przełomy mogą być wyzwalane przez:

Zakażenia¹
Urazy¹
Zabiegi chirurgiczne¹
Stres emocjonalny¹
Nagłe odstawienie leczenia glikokortykosteroidami u pacjentów z rozpoznaną niewydolnością nadnerczy¹

W takich sytuacjach niepowodzenie w odpowiednim zwiększeniu dawki steroidów u pacjentów z niewydolnością kory nadnerczy może spowodować przełom nadnerczowy.¹

Wtórna i trzeciorzędowa niewydolność nadnerczy

Warto podkreślić, że choroba Addisona (pierwotna niedoczynność nadnerczy) różni się od wtórnej i trzeciorzędowej niewydolności nadnerczy, które mają inne przyczyny, ale mogą dawać podobne objawy kliniczne.¹

Wtórna niewydolność nadnerczy występuje, gdy przysadka mózgowa nie produkuje wystarczającej ilości hormonu adrenokortykotropowego (ACTH), który stymuluje nadnercza do produkcji kortyzolu. Przyczyny wtórnej niewydolności nadnerczy obejmują:

Guzy przysadki mózgowej¹
Zapalenie przysadki¹
Uraz głowy¹
Operacje przysadki¹
Napromienianie obszaru przysadki¹

Trzeciorzędowa niewydolność nadnerczy ma swoje źródło w podwzgórzu i najczęściej jest spowodowana nagłym odstawieniem długotrwale stosowanych kortykosteroidów.¹ Długotrwałe stosowanie egzogennych steroidów prowadzi do zahamowania osi podwzgórze-przysadka-nadnercza i zmniejszenia produkcji ACTH, co skutkuje zanikaniem nadnerczy wskutek braku stymulacji.¹²

Podsumowanie etiologii choroby Addisona

Choroba Addisona rozwija się wskutek uszkodzenia kory nadnerczy, co prowadzi do niedoboru hormonów kortyzolu i aldosteronu. Główne przyczyny tego schorzenia można podsumować następująco:

Autoimmunologiczne (70-90% przypadków w krajach rozwiniętych) – układ odpornościowy atakuje i niszczy komórki kory nadnerczy
Infekcyjne – gruźlica (główna przyczyna w krajach rozwijających się), HIV/AIDS, zakażenia grzybicze
Nacieki nowotworowe – przerzuty nowotworowe, chłoniaki, białaczki
Krwotoki do nadnerczy – w przebiegu DIC, posocznicy, urazów, stosowania leków przeciwkrzepliwych
Jatrogenne – adrenalektomia obustronna, leki, radioterapia
Choroby naciekowe – amyloidoza, hemochromatoza, sarkoidoza
Genetyczne – adrenoleukodystrofia, wrodzona hiperplazja nadnerczy

Niezależnie od pierwotnej przyczyny, do wystąpienia objawów klinicznych choroby Addisona dochodzi dopiero po zniszczeniu około 90% tkanki kory nadnerczy.¹² Proces ten może trwać miesiące lub lata, co tłumaczy często opóźnioną diagnozę tego schorzenia. Dlatego tak ważna jest świadomość różnorodnych przyczyn choroby Addisona i uwzględnianie jej w diagnostyce różnicowej u pacjentów z niespecyficznymi objawami, takimi jak przewlekłe zmęczenie, osłabienie, hipotonia czy hiperpigmentacja skóry.

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Materiały źródłowe

#1 Addison’s Disease: What It Is, Causes, Symptoms & Treatment
https://my.clevelandclinic.org/health/diseases/15095-addisons-disease
Addisons disease is a rare chronic condition in which your adrenal glands dont produce enough of the hormones cortisol and aldosterone. It’s most often caused by an autoimmune attack. […] The most common cause of Addisons disease is an autoimmune response, which occurs when your immune system attacks healthy tissues for an unknown reason. With Addisons disease, your immune system attacks the outer portion of your adrenal glands (the adrenal cortex), where they make cortisol and aldosterone. Symptoms dont usually develop until 90% of the adrenal cortex has been damaged, which can take several months to years. […] Approximately 75% of cases of Addisons disease are due to an autoimmune attack. Autoimmune Addisons disease may happen by itself or as part of a rare, inherited syndrome, specifically autoimmune polyendocrine syndromes I (APS type-1) and II (Schmidt syndrome).
#1
https://www.nhs.uk/conditions/addisons-disease/
Addison’s disease is usually the result of a problem with the immune system, which causes it to attack the outer layer of the adrenal gland (the adrenal cortex), disrupting the production of the steroid hormones aldosterone and cortisol. […] It’s not clear why this happens, but it’s responsible for 70% to 90% of cases in the UK. […] Other potential causes include conditions that can damage the adrenal glands, such as tuberculosis (TB), although this is uncommon in the UK.
#1 Addison’s disease – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/addisons-disease/symptoms-causes/syc-20350293
Damage to the adrenal glands causes Addison’s disease. […] Addison’s disease also is known as primary adrenal insufficiency. A related condition is called secondary adrenal insufficiency. These conditions have different causes. […] Most often, the damage is due to a disease in which the immune system attacks healthy tissues and organs by mistake. This is called an autoimmune disease. People with Addison’s disease are more likely than are other people to have another autoimmune disease as well. […] Other causes of Addison’s disease can include: a serious infection called tuberculosis that mainly affects the lungs and also can destroy the adrenal glands; other infections of the adrenal glands; spread of cancer to the adrenal glands; bleeding into the adrenal glands; a group of genetic conditions present at birth that affect the adrenal glands; medicines that block the body’s ability to make glucocorticoid; treatment for cancer with medicines called checkpoint inhibitors. […] Addison’s disease can lead to other health conditions called complications. These include adrenal crisis, also called addisonian crisis. If you have Addison’s disease and haven’t started treatment, you may develop this life-threatening complication.
#1 Causes of primary adrenal insufficiency (Addison disease) – UpToDate
https://www.uptodate.com/contents/causes-of-primary-adrenal-insufficiency-addison-disease
Antibodies that react with several steroidogenic enzymes (most often 21-hydroxylase) and all three zones of the adrenal cortex are present in the serum of up to 86 percent of patients with autoimmune primary adrenal insufficiency, but only rarely in patients with other causes of adrenal insufficiency, or in normal subjects. […] However, up to 10 percent of first-degree relatives of patients with autoimmune primary adrenal insufficiency express these antibodies and have an increased risk of developing adrenal insufficiency. […] The first evidence of autoimmune adrenal insufficiency is usually an increase in plasma renin activity in association with a normal or low serum aldosterone concentration, suggesting that the zona glomerulosa is involved initially. Several months to years later, zona fasciculata dysfunction becomes evident, first by a decreasing serum cortisol response to corticotropin (ACTH) stimulation, later by increased basal serum ACTH concentrations, and finally by decreasing basal serum cortisol concentrations and symptoms.
#1 Addison’s disease | NHS inform
https://www.nhsinform.scot/illnesses-and-conditions/glands/addisons-disease/
In the UK, a problem with the immune system is the most common cause of Addisons disease, accounting for 70% to 90% of cases. […] Addisons disease develops when the outer layer of your adrenal glands (your adrenal cortex) is damaged, reducing the levels of hormones it produces. […] Addisons disease can develop if your immune system attacks your adrenal glands and severely damages your adrenal cortex. When 90% of the adrenal cortex is destroyed, your adrenal glands won’t be able to produce enough of the steroid hormones cortisol and aldosterone. […] Research has shown that some people with certain genes are more likely to develop autoimmune disorders. […] Tuberculosis (TB) is the most common cause of Addisons disease worldwide, but is rare in the UK. TB is a bacterial infection that mostly affects the lungs, but can also spread to other parts of your body. It can cause Addisons disease if it damages your adrenal glands.
#1 Adrenal Insufficiency and Addison’s Disease | Doctor
https://patient.info/doctor/adrenal-insufficiency-and-addisons-disease
Primary insufficiency (Addison’s disease) – there is an inability of the adrenal glands to produce enough steroid hormones. The most common cause for this in the developed world is autoimmune disease but is most commonly caused by TB worldwide. […] Addison’s disease is the term used to describe primary adrenal insufficiency but it can have many causes. In Western Europe, 85% of cases of Addison’s disease now have an autoimmune basis. […] Tuberculosis (TB) was the most common cause in the first half of the 20th century and remains a common cause elsewhere in the world. […] Autoimmune adrenal destruction is isolated in 40% of cases, and part of an autoimmune polyendocrinopathy syndrome in 60%. There is progressive destruction of the adrenal glands via immune mechanisms. Antibodies against steroid 21-hydroxylase can be found in about 85% of patients. Clinical and biochemical insufficiency only occurs once 90% of the gland is destroyed. […] Secondary adrenal insufficiency is most commonly caused by a pituitary adenoma. […] Administration of exogenous steroids is the most common cause of tertiary adrenal insufficiency.
#1 Addison Disease: Early Detection and Treatment Principles | AAFP
https://www.aafp.org/pubs/afp/issues/2014/0401/p563.html
Primary adrenal insufficiency, or Addison disease, has many causes, the most common of which is autoimmune adrenalitis. […] Autoimmune adrenalitis is the most common cause of primary adrenal insufficiency, or Addison disease, in the United States. […] Less common causes include infection, hemorrhage, metastatic cancer, medication use, and adrenoleukodystrophy. […] Autoimmune adrenalitis is a disorder in which the adrenal cortex is destroyed, resulting in the loss of mineralocorticoid, glucocorticoid, and adrenal androgen hormone production. […] The production of these antibodies can precede symptom onset by years to decades, and they are present in more than 90% of recent-onset cases. […] Approximately 50% of persons with Addison disease caused by autoimmune adrenalitis develop another autoimmune disorder during their lifetime, necessitating lifelong vigilance for associated autoimmune conditions.
#1 Addison Disease Clinical Presentation: History, Physical, Causes
https://emedicine.medscape.com/article/116467-clinical
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). Other autoimmune conditions linked to Addison disease include the following: Celiac disease, 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.
#1 Addison Disease Clinical Presentation: History, Physical, Causes
https://emedicine.medscape.com/article/116467-clinical
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. […] Additional causes of chronic Addison disease: Chronic granulomatous diseases, TB, sarcoidosis, histoplasmosis, blastomycosis, and cryptococcosis could involve the adrenal glands. […] Hematologic malignancies, Malignant infiltration of the adrenal cortices, as with Hodgkin and non-Hodgkin lymphoma and leukemia, may cause Addison disease. […] 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.
#1 Addison’s Disease: What It Is, Causes, Symptoms & Treatment
https://my.clevelandclinic.org/health/diseases/15095-addisons-disease
In the past, tuberculosis was a major cause of Addisons disease. It remains a prominent cause of the condition in developing countries. […] Other less common causes of Addisons disease include: Repeated infections, including HIV/AIDS-related infections and fungal infections. When cancer cells from another part of your body invade your adrenal glands. Bleeding (hemorrhaging) into your adrenal glands. Surgical removal of your adrenal glands. Amyloidosis (a condition in which amyloid proteins build up in vital organs, causing damage).
#1
https://www.nhs.uk/conditions/addisons-disease/causes/
Addison’s disease develops when the outer layer of your adrenal glands (adrenal cortex) is damaged, reducing the levels of hormones it produces. […] A problem with the immune system is the most common cause of Addison’s disease in the UK. […] Addison’s disease can develop if your immune system attacks your adrenal glands and severely damages your adrenal cortex. […] It’s not clear why some people develop this problem with their immune system, although it can run in families. […] Tuberculosis (TB) is the most common cause of Addison’s disease worldwide, but it’s rare in the UK. […] It can cause Addison’s disease if it damages your adrenal glands. […] Other possible causes of Addison’s disease include: infections such as those linked to AIDS, or fungal infections; a haemorrhage very heavy bleeding into the adrenal glands, sometimes associated with meningitis or other types of severe sepsis; cancer if cancer cells from elsewhere in your body spread to your adrenal glands; amyloidosis a disease where amyloid, a protein produced by your bone marrow cells, builds up in your adrenal glands and damages them; surgical removal of both adrenal glands (adrenalectomy) for example, to remove a tumour; adrenoleukodystrophy (ALD) a rare, life-limiting inherited condition that affects the adrenal glands and nerve cells in the brain, and is mostly seen in young boys; certain treatments needed for Cushing’s syndrome a collection of symptoms caused by very high levels of cortisol in the body.
#1 Addison Disease – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK441994/
Addison disease is caused by an inability of the adrenal cortices to produce adequate adrenocortical hormones. The condition is classified as primary or secondary adrenal insufficiency. […] Any disease process that causes direct injury to the adrenal cortex can result in primary adrenal insufficiency (ie, Addison disease), including autoimmune, infectious, hemorrhagic, pharmacologic, and infiltrative etiologies. […] Autoimmune destruction of the adrenal glands is the most common cause of Addison’s disease. This destruction occurs as antibodies develop against the adrenal cortex. […] Infectious etiologies include sepsis, tuberculosis, cytomegalovirus, and HIV. The prevalence of tuberculosis has declined, but HIV has emerged as the most important cause of adrenal insufficiency associated with adrenal necrosis.
#1 Addison Disease Clinical Presentation: History, Physical, Causes
https://emedicine.medscape.com/article/116467-clinical
Acquired immunodeficiency syndrome (AIDS) – The adrenocortical insufficiency in patients with AIDS tends to occur late and usually in the setting of a low CD4 cell count. […] 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. […] Bilateral adrenal hemorrhage 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.
#1 Causes of Addison’s disease: Adrenal gland disruption and others
https://www.medicalnewstoday.com/articles/186235
Infections that can increase the risk of Addisons disease include: TB, HIV, syphilis, histoplasmosis and other fungal infections, sepsis, cytomegalovirus. […] The main cause of Addisons disease is a faulty autoimmune response. Other causes include injury, steroid use, and conditions such as cancer, HIV, and TB.
#1 Addison’s Disease – Endocrinology Advisor
https://www.endocrinologyadvisor.com/ddi/addisons-disease/
Another potential cause of Addison’s disease is infections such as HIV, fungal adrenalitis, meningococcal sepsis, and African trypanosomiasis. […] Cancers of the lung, stomach, breast, and colon also might cause Addison’s disease. […] Addison’s disease, otherwise known as primary adrenal insufficiency, is caused by autoimmune destruction of the adrenal cortex. This results in decreased synthesis of adrenocortical hormones leading to reduced levels of circulating cortisol, aldosterone, and adrenal androgens.
#1 Addison Disease – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK441994/
DIC, trauma, meningococcemia, and neoplastic processes can precipitate bilateral adrenal hemorrhages. […] Adrenal infiltration frequently occurs with hemochromatosis, amyloidosis, and metastases. […] Certain pharmacologic etiologies can lead to adrenal insufficiency by blocking cortisol synthesis. […] Secondary insufficiency occurs most commonly due to exogenous steroid administration, resulting in the suppression of ACTH synthesis.
#1
https://www2.hse.ie/conditions/addisons-disease/causes/
If cancer cells from elsewhere in your body spread to your adrenal glands. […] Amyloidosis is a disease where amyloid, a protein produced by your bone marrow cells, builds up in your adrenal glands and damages them. […] Adrenalectomy is the surgical removal of both adrenal glands. […] Adrenoleukodystrophy (ALD) is a rare, life-limiting, inherited condition. […] Certain treatments needed for Cushing’s syndrome are a possible cause of Addison’s disease. […] The production of hormones from the adrenal gland can also be affected by damage to the pituitary gland. […] Secondary adrenal insufficiency can occur if your pituitary gland becomes damaged.
#1 Addison’s Disease: Symptoms, Causes, & Treatment
https://www.webmd.com/a-to-z-guides/understanding-addisons-disease-basics
Less commonly, internal bleeding in the adrenal glands can cause Addisons disease. […] You may be more likely to have Addisons disease if you had surgery that involved your pituitary or adrenal glands, such as an adrenalectomy, which is a surgery to remove your adrenal glands. […] Addisons disease may happen as a complication of treating adrenal glands that have cancer cells in them with radiation.
#1 Addison’s Disease – Endocrinology Advisor
https://www.endocrinologyadvisor.com/ddi/addisons-disease/
Addison disease also referred to as primary adrenal insufficiency occurs when the adrenal glands do not produce enough cortisol and/or aldosterone. […] In the past, Addison’s disease was predominantly caused by adrenal damage from tuberculosis, but as the treatment of tuberculous has improved, this has become less common. Today most cases of Addison’s disease in developed countries are the result of autoimmune disorders. […] The most common cause of Addison’s disease is autoimmune adrenalitis, which appears to result from a complex intertwining of genetic, immunologic, and environmental factors. […] Some evidence suggests that immune checkpoint inhibitors, which block checkpoint proteins from binding with their partner proteins and thereby enable T cells to kill cancer cells, can trigger autoimmune adrenalitis.
#1 Addison Disease – Endocrine and Metabolic Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/adrenal-disorders/addison-disease
Addison disease develops in approximately 4/100,000 people annually. It occurs in all age groups, about equally in each sex, and tends to become clinically apparent during metabolic stress, infection, or trauma. […] Approximately 70% of cases in the United States are due to idiopathic atrophy of the adrenal cortex, probably caused by autoimmune processes. The remainder result from destruction of the adrenal gland by granuloma (eg, tuberculosis, histoplasmosis), tumor, amyloidosis, hemorrhage, or inflammatory necrosis. […] Addison disease may coexist with diabetes mellitus or hypothyroidism in polyglandular deficiency syndrome. In children, the most common cause of primary adrenal insufficiency is congenital adrenal hyperplasia.
#1 Addison’s disease – Wikipedia
https://en.wikipedia.org/wiki/Addison%27s_disease
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. […] Interruptions in the delivery of cholesterol include Smith-Lemli-Opitz syndrome and abetalipoproteinemia. […] Some medications interfere with steroid synthesis enzymes, while others accelerate the normal breakdown of hormones by the liver.
#1 Addisonâs Disease: Causes, Risks & Treatment
https://www.healthline.com/health/addisons-disease
There are also many other causes of secondary adrenal insufficiency, including: tumors, medications, genetics, traumatic brain injury. […] Tertiary adrenal insufficiency originates in the hypothalamus, a region of the brain near the pituitary gland. […] Tertiary adrenal insufficiency is most often caused by suddenly stopping corticosteroids after long time use.
#1 Addisonâs Disease – Symptoms, Causes, Diagnosis, and Treatment
https://www.icliniq.com/articles/endocrine-diseases/addisons-disease
Secondary adrenal insufficiency results when the pituitary gland does not produce the adrenocorticotropic hormone (ACTH). ACTH is produced by the pituitary gland, and this hormone stimulates the adrenal cortex to release its hormones. In the absence of ACTH, the adrenal cortex does not produce cortisol, aldosterone, and androgens, which results in Addisons disease. The conditions that can cause this are: Benign pituitary tumors. Inflammation of the pituitary gland. Medications. Prior pituitary surgery. Traumatic brain injury. Genetics. […] Adrenal insufficiency can also result when people who are under treatment with corticosteroids for conditions like asthma and arthritis stop taking medicine abruptly. […] The factors that increase the risk of a person getting Addisons disease are: Cancer. Treatment with blood thinners. Chronic infections like tuberculosis. Autoimmune conditions like arthritis (joint inflammation) and Graves disease (overactive thyroid). Partial adrenalectomy (part of the adrenal gland is surgically removed). […] Addison’s disease is a condition that is caused by the reduced production of cortisol and aldosterone hormones. This condition affects the adrenal gland, which produces cortisol and aldosterone hormones.
#1 Adrenal Insufficiency (Addison’s Disease) | Pituitary Network Association – International non-profit organization for patients with pituitary tumors and disorders
https://pituitary.org/disorders/adrenal-insuffieciency-addison-s-disease/
This form of Addisons disease can be traced to a lack of ACTH, which causes a drop in the adrenal glands production of cortisol but not aldosterone. […] Another cause of secondary adrenal insufficiency is the surgical removal of benign, or noncancerous, ACTH-producing tumors of the pituitary gland (Cushings disease). […] Less commonly, adrenal insufficiency occurs when the pituitary gland either decreases in size or stops producing ACTH.
#1 Addison’s disease | Beacon Health System
https://www.beaconhealthsystem.org/library/diseases-and-conditions/addisons-disease?content_id=CON-20154557
Addison’s disease is a rare condition that happens when the body doesn’t make enough of some hormones. […] Damage to the adrenal glands causes Addison’s disease. […] Addison’s disease also is known as primary adrenal insufficiency. A related condition is called secondary adrenal insufficiency. These conditions have different causes. […] Most often, the damage is due to a disease in which the immune system attacks healthy tissues and organs by mistake. This is called an autoimmune disease. People with Addison’s disease are more likely than are other people to have another autoimmune disease as well. […] Other causes of Addison’s disease can include: A serious infection called tuberculosis that mainly affects the lungs and also can destroy the adrenal glands. […] Addison’s disease can lead to other health conditions called complications. These include adrenal crisis, also called addisonian crisis. If you have Addison’s disease and haven’t started treatment, you may develop this life-threatening complication. […] Factors that can cause the pituitary gland to make too little ACTH include: Pituitary tumors that aren’t cancer. […] A short-term cause of secondary adrenal insufficiency can happen in people who suddenly stop taking medicines called corticosteroids.
#2 Causes of primary adrenal insufficiency (Addison disease) – UpToDate
https://www.uptodate.com/contents/causes-of-primary-adrenal-insufficiency-addison-disease
Antibodies that react with several steroidogenic enzymes (most often 21-hydroxylase) and all three zones of the adrenal cortex are present in the serum of up to 86 percent of patients with autoimmune primary adrenal insufficiency, but only rarely in patients with other causes of adrenal insufficiency, or in normal subjects. […] However, up to 10 percent of first-degree relatives of patients with autoimmune primary adrenal insufficiency express these antibodies and have an increased risk of developing adrenal insufficiency. […] The first evidence of autoimmune adrenal insufficiency is usually an increase in plasma renin activity in association with a normal or low serum aldosterone concentration, suggesting that the zona glomerulosa is involved initially. Several months to years later, zona fasciculata dysfunction becomes evident, first by a decreasing serum cortisol response to corticotropin (ACTH) stimulation, later by increased basal serum ACTH concentrations, and finally by decreasing basal serum cortisol concentrations and symptoms.
#2 Symptoms & Causes of Adrenal Insufficiency & Addison’s Disease – NIDDK
https://www.niddk.nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisons-disease/symptoms-causes
Different types of adrenal insufficiency have different causes. The most common cause of adrenal insufficiency overall is suddenly stopping corticosteroids after taking them for a long time. […] Damage to the adrenal glands in Addisons disease is usually caused by autoimmune disease when your immune system attacks your bodys own cells and organs. In developed countries, autoimmune disease causes 8 or 9 of every 10 cases of Addisons disease. […] Certain infections can also cause Addisons disease. Tuberculosis (TB) can damage the adrenal glands and used to be the most common cause of Addisons disease. […] Less common causes of Addisons disease are cancer cells in the adrenal glands, surgical removal of the adrenal glands to treat other conditions, bleeding into the adrenal glands, genetic disorders that affect the way the adrenal glands develop or function, certain medicines, such as antifungal medicines or etomidate, a type of general anesthesia.
#2 Addison Disease Clinical Presentation: History, Physical, Causes
https://emedicine.medscape.com/article/116467-clinical
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. The steroidogenic enzyme 21-hydroxylase (21OH) is the main autoantigen, but antibodies against this enzyme are not directly involved in the tissue destruction. […] Patients may have a hereditary predisposition to autoimmune Addison disease.
#2 Addison Disease Clinical Presentation: History, Physical, Causes
https://emedicine.medscape.com/article/116467-clinical
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). Other autoimmune conditions linked to Addison disease include the following: Celiac disease, 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.
#2 Causes of primary adrenal insufficiency (Addison disease) – UpToDate
https://www.uptodate.com/contents/causes-of-primary-adrenal-insufficiency-addison-disease
Causes of primary adrenal insufficiency (Addison disease) […] When Thomas Addison described the disease that now bears his name, bilateral adrenal destruction by tuberculosis was its most common cause. Now tuberculosis accounts for only 7 to 20 percent of cases; autoimmune disease is responsible for 70 to 90 percent, with the remainder being caused by other infectious diseases, replacement by metastatic cancer or lymphoma, adrenal hemorrhage or infarction, or drugs. […] What long was termed „idiopathic” primary adrenal insufficiency is the result of an autoimmune process that destroys the adrenal cortex. There is evidence of both humoral and cell-mediated immune mechanisms directed at the adrenal cortex, often associated with autoimmune destruction of other endocrine glands (referred to as polyglandular autoimmune syndromes).
#2 Addison Disease – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK441994/
Addison disease is caused by an inability of the adrenal cortices to produce adequate adrenocortical hormones. The condition is classified as primary or secondary adrenal insufficiency. […] Any disease process that causes direct injury to the adrenal cortex can result in primary adrenal insufficiency (ie, Addison disease), including autoimmune, infectious, hemorrhagic, pharmacologic, and infiltrative etiologies. […] Autoimmune destruction of the adrenal glands is the most common cause of Addison’s disease. This destruction occurs as antibodies develop against the adrenal cortex. […] Infectious etiologies include sepsis, tuberculosis, cytomegalovirus, and HIV. The prevalence of tuberculosis has declined, but HIV has emerged as the most important cause of adrenal insufficiency associated with adrenal necrosis.
#2 Addison Disease Clinical Presentation: History, Physical, Causes
https://emedicine.medscape.com/article/116467-clinical
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. […] Additional causes of chronic Addison disease: Chronic granulomatous diseases, TB, sarcoidosis, histoplasmosis, blastomycosis, and cryptococcosis could involve the adrenal glands. […] Hematologic malignancies, Malignant infiltration of the adrenal cortices, as with Hodgkin and non-Hodgkin lymphoma and leukemia, may cause Addison disease. […] 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.
#2 Addison Disease Clinical Presentation: History, Physical, Causes
https://emedicine.medscape.com/article/116467-clinical
Acquired immunodeficiency syndrome (AIDS) – The adrenocortical insufficiency in patients with AIDS tends to occur late and usually in the setting of a low CD4 cell count. […] 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. […] Bilateral adrenal hemorrhage 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.
#2
https://www2.hse.ie/conditions/addisons-disease/causes/
Addison’s disease develops when the outer layer of your adrenal glands (adrenal cortex) is damaged, reducing the levels of hormones it produces. […] Addisons disease can develop if your immune system attacks your adrenal glands and severely damages your adrenal cortex. When 90% of the adrenal cortex is destroyed, your adrenal glands won’t be able to produce enough cortisol and aldosterone. […] Your risk of developing Addison’s disease is increased if you or a close family member have another autoimmune condition. […] Tuberculosis (TB) is the most common cause of Addison’s disease worldwide, but it is rare in Ireland. […] It can cause Addisons disease if it damages your adrenal glands. […] Infections such as those linked to AIDS, or fungal infections. […] Very heavy bleeding (haemorrhage) into the adrenal glands.
#2 Addison Disease | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/17183
DIC, trauma, meningococcemia, and neoplastic processes can precipitate bilateral adrenal hemorrhages. […] Adrenal infiltration frequently occurs with hemochromatosis, amyloidosis, and metastases. Other causes include sarcoidosis, lymphoma, and genetic disorders such as congenital adrenal hyperplasia and adrenal leukodystrophy. […] Certain pharmacologic etiologies can lead to adrenal insufficiency by blocking cortisol synthesis. For instance, ketoconazole directly inhibits adrenal enzymes, and etomidate can have a dose-dependent effect by selectively inhibiting 11-hydroxylase, decreasing deoxycortisol conversion to cortisol. […] Secondary insufficiency occurs most commonly due to exogenous steroid administration, resulting in the suppression of ACTH synthesis.
#2 Addison Disease – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK441994/
DIC, trauma, meningococcemia, and neoplastic processes can precipitate bilateral adrenal hemorrhages. […] Adrenal infiltration frequently occurs with hemochromatosis, amyloidosis, and metastases. […] Certain pharmacologic etiologies can lead to adrenal insufficiency by blocking cortisol synthesis. […] Secondary insufficiency occurs most commonly due to exogenous steroid administration, resulting in the suppression of ACTH synthesis.
#2
https://www2.hse.ie/conditions/addisons-disease/causes/
If cancer cells from elsewhere in your body spread to your adrenal glands. […] Amyloidosis is a disease where amyloid, a protein produced by your bone marrow cells, builds up in your adrenal glands and damages them. […] Adrenalectomy is the surgical removal of both adrenal glands. […] Adrenoleukodystrophy (ALD) is a rare, life-limiting, inherited condition. […] Certain treatments needed for Cushing’s syndrome are a possible cause of Addison’s disease. […] The production of hormones from the adrenal gland can also be affected by damage to the pituitary gland. […] Secondary adrenal insufficiency can occur if your pituitary gland becomes damaged.
#2 Addison’s disease – Wikipedia
https://en.wikipedia.org/wiki/Addison%27s_disease
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. […] Interruptions in the delivery of cholesterol include Smith-Lemli-Opitz syndrome and abetalipoproteinemia. […] Some medications interfere with steroid synthesis enzymes, while others accelerate the normal breakdown of hormones by the liver.
#2 Addison’s disease | NHS inform
https://www.nhsinform.scot/illnesses-and-conditions/glands/addisons-disease/
In the UK, a problem with the immune system is the most common cause of Addisons disease, accounting for 70% to 90% of cases. […] Addisons disease develops when the outer layer of your adrenal glands (your adrenal cortex) is damaged, reducing the levels of hormones it produces. […] Addisons disease can develop if your immune system attacks your adrenal glands and severely damages your adrenal cortex. When 90% of the adrenal cortex is destroyed, your adrenal glands won’t be able to produce enough of the steroid hormones cortisol and aldosterone. […] Research has shown that some people with certain genes are more likely to develop autoimmune disorders. […] Tuberculosis (TB) is the most common cause of Addisons disease worldwide, but is rare in the UK. TB is a bacterial infection that mostly affects the lungs, but can also spread to other parts of your body. It can cause Addisons disease if it damages your adrenal glands.