Materiały źródłowe

• #1 Addison Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK441994/

  Addison disease, also known as autoimmune adrenalitis, is an acquired primary adrenal insufficiency. Primary adrenal insufficiency is termed Addison disease when an autoimmune process causes the condition and is a rare but potentially life-threatening emergency condition. Addison disease results from the destruction of the bilateral adrenal cortex, leading to decreased adrenocortical hormones, including cortisol, aldosterone, and androgens. Addison disease’s insidious course of action usually presents with glucocorticoid deficiency followed by mineralocorticoid. However, the condition can also present acutely, often triggered by intercurrent illness. The presentation of adrenal insufficiency depends on the rate and extent of adrenal function involvement. The most common cause of primary adrenal insufficiency is Addison disease, associated with increased levels of 21-hydroxylase antibodies.[1][2]

• #2 Addison Disease | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/17183

  Addison disease, also known as autoimmune adrenalitis, is an acquired primary adrenal insufficiency. Addison disease results from the destruction of the bilateral adrenal cortex, leading to decreased adrenocortical hormones, including cortisol, aldosterone, and androgens. […] 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. […] 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. […] Adrenal failure in Addison disease results in decreased cortisol production initially followed by that of aldosterone, both of which will eventually result in an elevation of adrenocorticotropic (ACTH) and melanocyte-stimulating hormone (MSH) hormones due to the loss of negative feedback inhibition.

• #3 Addison’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Addison%27s_disease

  Addison’s disease arises when 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. […] Autoimmune adrenalitis 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. […] 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. […] Causes of adrenal insufficiency can be categorized by the mechanism through which they cause the adrenal glands to produce insufficient cortisol.

• #4

  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.

• #5 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).

• #6 Addison’s Disease: Symptoms, Causes, & Treatment

  https://www.webmd.com/a-to-z-guides/understanding-addisons-disease-basics

  Addison’s disease happens when the adrenal glands don’t make enough of a hormone called cortisol, or less often, a related hormone called aldosterone. […] Primary adrenal insufficiency, or Addison’s disease, happens when the adrenal gland stops working as it should, making it unable to make enough aldosterone and cortisol. It mostly happens when the immune system mistakenly attacks and damages the adrenal cortex, the largest part of the adrenal gland. […] Autoimmune disease accounts for 70% of cases of Addison’s disease. This occurs when the body’s immune system mistakenly attacks the adrenal glands. This autoimmune assault destroys the outer layer of the glands. […] Addison’s disease may happen as a complication of treating adrenal glands that have cancer cells in them with radiation.

• #7 Autoimmune Addison disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/autoimmune-addison-disease/

  In autoimmune Addison disease, however, an immune response is triggered by a normal adrenal gland protein, typically a protein called 21-hydroxylase. This protein plays a key role in producing certain hormones in the adrenal glands. The prolonged immune attack triggered by 21-hydroxylase damages the adrenal glands (specifically the outer layers of the glands known, collectively, as the adrenal cortex), preventing hormone production. A shortage of adrenal hormones (adrenal insufficiency) disrupts several normal functions in the body, leading to hypoglycemia, hyponatremia, hypotension, muscle cramps, skin hyperpigmentation and other features of autoimmune Addison disease.

• #8 Addison’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Addison%27s_disease

  Addison’s disease arises when 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. […] Autoimmune adrenalitis 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. […] 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. […] Causes of adrenal insufficiency can be categorized by the mechanism through which they cause the adrenal glands to produce insufficient cortisol.

• #9 Addison Disease: Early Detection and Treatment Principles | AAFP

  https://www.aafp.org/pubs/afp/issues/2014/0401/p563.html

  Autoimmune adrenalitis can be divided into stages of progression. As the disease develops, individuals lose adrenocortical function over a period of years. In the first three stages, the human leukocyte antigen genes confer genetic risk; an unknown precipitating event initiates antiadrenal autoimmunity; and 21-hydroxylase antibodies are produced, which predict future disease. 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. In the fourth stage, overt adrenal insufficiency develops. One of the first metabolic abnormalities to occur is an increase in plasma renin level, followed by the sequential development of other abnormalities, including a decreased response to adrenocorticotropic hormone (ACTH) stimulation in the fifth stage. If symptoms of adrenal insufficiency are present but go undiagnosed, an addisonian crisis can occur.

• #10 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  The first sign of an ongoing autoimmune process is the presence of autoantibodies against 21-hydroxylase, which can be found in about 90% of cases, and detection of these antibodies is diagnostic of PAI. […] The HPA axis, with endogenous cortisol exerting strong negative feedback at the hypothalamic and pituitary levels, describes the close interaction between these three endocrine organs. […] Cortisol deficiency in PAI results in elevated levels of plasma ACTH and CRH due to loss of negative feedback. […] In PAI, the loss of adrenal cortex is gradual, and symptoms and signs of AI do not appear until at least 90% of adrenal cortex is lost. […] Several other organ-specific autoimmune diseases (eg, thyroid disorders, type 1 diabetes mellitus (DM), vitiligo, hypoparathyroidism, vitamin B12 deficiency and premature ovarian insufficiency) frequently occur in combination with PAI, or as part of APS-1 and APS-2.

• #11 Mechanism of autoimmun adrenal destruction | Endocrine Medicine | UiB

  https://www.uib.no/en/rg/endocrine/125745/mechanism-autoimmun-adrenal-destruction

  Autoimmune Addisons disease, or primary adrenal insufficiency, was among the first diseases recognized as autoimmune during the 1950s, approximately 100 years after initially described by the British physician Thomas Addison. […] We know that the immune system of patients with Addison’s disease attacks the hormone-producing cells of the adrenal cortex and that the adrenal cortex is invaded by T and B lymphocytes. […] Still, we lack knowledge about why this attack is occurring. What initiates it? How are the adrenocortical cells destroyed? […] As for most autoimmune disease, Addisons disease is presumed to be caused by a combination of genetic and environmental factors. […] We know that almost all patients with autoimmune Addisons disease have antibodies directed against an enzyme almost exclusively expressed in the adrenal cortex. This enzyme is called 21-hydroxylase and plays a key role in the synthesis of vital steroid hormones like cortisol and aldosterone.

• #12 Addison Disease Clinical Presentation: History, Physical, Causes

  https://emedicine.medscape.com/article/116467-clinical

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

• #13 Mechanism of autoimmun adrenal destruction | Endocrine Medicine | UiB

  https://www.uib.no/en/rg/endocrine/125745/mechanism-autoimmun-adrenal-destruction

  It is suspected that a subgroup of T lymphocytes, the so-called cytotoxic T lymphocytes, that actually kills and destroys the hormone producing cells of the adrenal cortex in a highly selective manner. […] If successful in establishing such model systems we will not only gain increased insight to the mechanisms leading to autoimmune Addisons disease, but also be granted the opportunity to test out new treatments and drugs that are targeted to halt or possibly even reverse the disease.

• #14

  https://link.springer.com/article/10.1007/s40618-019-01079-6

  Addisons disease (AD) is a rare disorder and among adult population in developed countries is most commonly caused by autoimmunity. […] This review describes epidemiology, pathogenesis, genetics, natural history, clinical manifestations, immunological markers and diagnostic strategies in patients with AD. […] Progress in optimizing replacement therapy for patients with AD has allowed the patients to lead a normal life. […] However, continuous education of patients and health care professionals of ever-present danger of adrenal crisis is essential to save lives of patients with AD. […] Mechanism of inhibition of cytochrome P450 C21 enzyme activity by autoantibodies from patients with Addisons disease. […] The substrate-binding domain of 21-hydroxylase, the main autoantigen in autoimmune Addisons disease, is an immunodominant T cell epitope. […] High frequency of cytolytic 21-hydroxylase-specific CD8+T cells in autoimmune Addisons disease patients. […] From genetic predisposition to molecular mechanisms of autoimmune primary adrenal insufficiency.

• #15 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).

• #16 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  The first sign of an ongoing autoimmune process is the presence of autoantibodies against 21-hydroxylase, which can be found in about 90% of cases, and detection of these antibodies is diagnostic of PAI. […] The HPA axis, with endogenous cortisol exerting strong negative feedback at the hypothalamic and pituitary levels, describes the close interaction between these three endocrine organs. […] Cortisol deficiency in PAI results in elevated levels of plasma ACTH and CRH due to loss of negative feedback. […] In PAI, the loss of adrenal cortex is gradual, and symptoms and signs of AI do not appear until at least 90% of adrenal cortex is lost. […] Several other organ-specific autoimmune diseases (eg, thyroid disorders, type 1 diabetes mellitus (DM), vitiligo, hypoparathyroidism, vitamin B12 deficiency and premature ovarian insufficiency) frequently occur in combination with PAI, or as part of APS-1 and APS-2.

• #17 Causes of primary adrenal insufficiency (Addison disease) – UpToDate

  https://www.uptodate.com/contents/causes-of-primary-adrenal-insufficiency-addison-disease

  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.

• #18 Pathogenesis of Autoimmune Addisons disease | Endocrine Medicine | UiB

  https://www.uib.no/en/rg/endocrine/66945/pathogenesis-autoimmune-addisons-disease

  Autoimmune Addison’s disease (AAD) is caused by multiple genetic and environmental factors. Variants of genes encoding immunologically important proteins such as the HLA molecules are strongly associated with AAD, but any environmental risk factors have yet to be defined. […] AAD is a disorder caused by an immunological attack on the adrenal cortex. The interferon (IFN)-inducible chemokine CXCL10 is elevated in serum of AAD patients, suggesting a peripheral IFN signature. However, CXCL10 can also be induced in adrenocortical cells stimulated with IFNs, cytokines, or microbial components. […] One of our hypotheses is that our adrenocortical cells in large part affect the way Addisons disease occurs and how inflammation of the adrenal gland is maintained. Traditionally it has been assumed that autoimmune diseases such as Addisons disease primarily is caused by cells of the immune system for some reason attacking the bodys own organs, and killing the cells there. We believe that the cells in the adrenal glands themselves play an important part in this process during the development of Addisons disease, by recruiting and activating cells from the immune system, Eirik Bratland says.

• #19 Autoimmune Addison disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/autoimmune-addison-disease/

  Autoimmune Addison disease affects the function of the adrenal glands, which are small hormone-producing glands located on top of each kidney. It is classified as an autoimmune disorder because it results from a malfunctioning immune system that attacks the adrenal glands. As a result, the production of several hormones is disrupted, which affects many body systems. […] The cause of autoimmune Addison disease is complex and not completely understood. A combination of environmental and genetic factors plays a role in the disorder, and changes in multiple genes are thought to affect the risk of developing the condition. […] The most well-known risk factor for autoimmune Addison disease is a variant of the HLA-DRB1 gene called HLA-DRB1*04:04. This and other disease-associated HLA gene variants likely contribute to an inappropriate immune response that leads to autoimmune Addison disease, although the mechanism is unknown.

• #20 Pathogenesis of primary adrenal insufficiency – PubMed

  https://pubmed.ncbi.nlm.nih.gov/19500759/

  Autoimmune Addison’s disease is caused by autoreactivity towards the adrenal cortex involving 21-hydroxylase autoantibodies and autoreactive T cells. […] Autoimmune destruction of the adrenal cortex is triggered by hitherto unknown environmental factors in individuals with genetic susceptibility. […] Several genes have been identified, of which the major histocompatibility complex haplotypes DR3-DQ2 and DR4-DQ8 are most strongly associated. […] In addition, other genes also implicated in other autoimmune diseases are linked to Addison’s disease, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), protein tyrosine phosphatase non-receptor type 22 (PTPN22), major histocompatibility complex class II transactivator (CIITA), and most recently the C-lectin type gene (CLEC16A). […] Studies employing T cells in humans and animal models, and the collection of large patient cohorts facilitating genome-wide screening projects, will hopefully improve the understanding of the pathogenesis of the disease in the near future.

• #21 Autoimmune Addison disease: pathophysiology and genetic complexity | Nature Reviews Endocrinology

  https://www.nature.com/articles/nrendo.2011.245

  AAD has a strong genetic component, but owing to its rarity the recurrence rate in family members is of the order of 2%. […] Several disease-susceptibility alleles have been identified, including three loci associated with organ-specific autoimmunity (MHC, CTLA4 and PTPN22), and others that encode proteins involved in innate immune responses.

• #22 Pathogenesis of primary adrenal insufficiency – PubMed

  https://pubmed.ncbi.nlm.nih.gov/19500759/

  Autoimmune Addison’s disease is caused by autoreactivity towards the adrenal cortex involving 21-hydroxylase autoantibodies and autoreactive T cells. […] Autoimmune destruction of the adrenal cortex is triggered by hitherto unknown environmental factors in individuals with genetic susceptibility. […] Several genes have been identified, of which the major histocompatibility complex haplotypes DR3-DQ2 and DR4-DQ8 are most strongly associated. […] In addition, other genes also implicated in other autoimmune diseases are linked to Addison’s disease, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), protein tyrosine phosphatase non-receptor type 22 (PTPN22), major histocompatibility complex class II transactivator (CIITA), and most recently the C-lectin type gene (CLEC16A). […] Studies employing T cells in humans and animal models, and the collection of large patient cohorts facilitating genome-wide screening projects, will hopefully improve the understanding of the pathogenesis of the disease in the near future.

• #23 Pathogenesis of primary adrenal insufficiency – PubMed

  https://pubmed.ncbi.nlm.nih.gov/19500759/

  Autoimmune Addison’s disease is caused by autoreactivity towards the adrenal cortex involving 21-hydroxylase autoantibodies and autoreactive T cells. […] Autoimmune destruction of the adrenal cortex is triggered by hitherto unknown environmental factors in individuals with genetic susceptibility. […] Several genes have been identified, of which the major histocompatibility complex haplotypes DR3-DQ2 and DR4-DQ8 are most strongly associated. […] In addition, other genes also implicated in other autoimmune diseases are linked to Addison’s disease, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), protein tyrosine phosphatase non-receptor type 22 (PTPN22), major histocompatibility complex class II transactivator (CIITA), and most recently the C-lectin type gene (CLEC16A). […] Studies employing T cells in humans and animal models, and the collection of large patient cohorts facilitating genome-wide screening projects, will hopefully improve the understanding of the pathogenesis of the disease in the near future.

• #24 Pathogenesis of primary adrenal insufficiency – PubMed

  https://pubmed.ncbi.nlm.nih.gov/19500759/

  Autoimmune Addison’s disease is caused by autoreactivity towards the adrenal cortex involving 21-hydroxylase autoantibodies and autoreactive T cells. […] Autoimmune destruction of the adrenal cortex is triggered by hitherto unknown environmental factors in individuals with genetic susceptibility. […] Several genes have been identified, of which the major histocompatibility complex haplotypes DR3-DQ2 and DR4-DQ8 are most strongly associated. […] In addition, other genes also implicated in other autoimmune diseases are linked to Addison’s disease, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), protein tyrosine phosphatase non-receptor type 22 (PTPN22), major histocompatibility complex class II transactivator (CIITA), and most recently the C-lectin type gene (CLEC16A). […] Studies employing T cells in humans and animal models, and the collection of large patient cohorts facilitating genome-wide screening projects, will hopefully improve the understanding of the pathogenesis of the disease in the near future.

• #25 Pathogenesis of primary adrenal insufficiency – PubMed

  https://pubmed.ncbi.nlm.nih.gov/19500759/

  Autoimmune Addison’s disease is caused by autoreactivity towards the adrenal cortex involving 21-hydroxylase autoantibodies and autoreactive T cells. […] Autoimmune destruction of the adrenal cortex is triggered by hitherto unknown environmental factors in individuals with genetic susceptibility. […] Several genes have been identified, of which the major histocompatibility complex haplotypes DR3-DQ2 and DR4-DQ8 are most strongly associated. […] In addition, other genes also implicated in other autoimmune diseases are linked to Addison’s disease, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), protein tyrosine phosphatase non-receptor type 22 (PTPN22), major histocompatibility complex class II transactivator (CIITA), and most recently the C-lectin type gene (CLEC16A). […] Studies employing T cells in humans and animal models, and the collection of large patient cohorts facilitating genome-wide screening projects, will hopefully improve the understanding of the pathogenesis of the disease in the near future.

• #26 GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility | Nature Communications

  https://www.nature.com/articles/s41467-021-21015-8

  Autoimmune Addisons disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. […] We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P5108). […] In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. […] The strongest, p.R471C (rs74203920, OR=3.4 (2.74.3), P=9.01025) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. […] This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 3541% of heritability (h2).

• #27 GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility | Nature Communications

  https://www.nature.com/articles/s41467-021-21015-8

  Here we utilize the two largest Addisons disease biobanks in the world, enabling us to uncover both known and novel associations. […] Most intriguingly, we link AAD to protein-coding risk variants in AIRE, a gene crucial for antigen presentation in the thymus and for central immunological tolerance. […] Given that mutations in AIRE cause the monogenic disease APS-1 (OMIM #240300), of which AAD is a major component, this association peak was investigated in particular detail. […] The strong association with the lead SNP in AIRE was a striking finding (rs74203920, OR=3.4 (2.74.3), P=9.01025). […] The risk effects of both SNPs were best described by an additive model. […] The two independent associations with AIRE point to alterations in central immunological tolerance as an underlying mechanism in AAD development. […] Dysregulation of antigen presentation in the setting of negative selection in the thymus may be one of the factors that makes AAD exceptional among organ-specific autoimmune diseases, and the pathways identified should be explored in the development of preventive treatment strategies.

• #28 GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility | Nature Communications

  https://www.nature.com/articles/s41467-021-21015-8

  Autoimmune Addisons disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. […] We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P5108). […] In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. […] The strongest, p.R471C (rs74203920, OR=3.4 (2.74.3), P=9.01025) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. […] This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 3541% of heritability (h2).

• #29 GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility | Nature Communications

  https://www.nature.com/articles/s41467-021-21015-8

  Here we utilize the two largest Addisons disease biobanks in the world, enabling us to uncover both known and novel associations. […] Most intriguingly, we link AAD to protein-coding risk variants in AIRE, a gene crucial for antigen presentation in the thymus and for central immunological tolerance. […] Given that mutations in AIRE cause the monogenic disease APS-1 (OMIM #240300), of which AAD is a major component, this association peak was investigated in particular detail. […] The strong association with the lead SNP in AIRE was a striking finding (rs74203920, OR=3.4 (2.74.3), P=9.01025). […] The risk effects of both SNPs were best described by an additive model. […] The two independent associations with AIRE point to alterations in central immunological tolerance as an underlying mechanism in AAD development. […] Dysregulation of antigen presentation in the setting of negative selection in the thymus may be one of the factors that makes AAD exceptional among organ-specific autoimmune diseases, and the pathways identified should be explored in the development of preventive treatment strategies.

• #30 GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility | Nature Communications

  https://www.nature.com/articles/s41467-021-21015-8

  Autoimmune Addisons disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. […] We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P5108). […] In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. […] The strongest, p.R471C (rs74203920, OR=3.4 (2.74.3), P=9.01025) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. […] This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 3541% of heritability (h2).

• #31 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  Adrenal insufficiency (AI), first described by Thomas Addison in 1855, is characterised by inadequate hormonal production by the adrenal gland, which could either be primary, due to destruction of the adrenal cortex, or secondary/tertiary, due to lack of adrenocorticotropic hormone or its stimulation by corticotropin-releasing hormone. […] Acquired PAI is caused primarily by autoimmune adrenalitis (immune system targeting 21-hydroxylase), which constitutes 70%80% of all cases in the Western world and can occur in isolation (40%) or as a component of autoimmune polyendocrinopathy syndrome (APS) (60%). […] It is thought that a viral infection or an exaggerated body response to an inflammatory signal, in a genetically susceptible individual, starts an autoimmune cascade, which eventually leads to AI.

• #32 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  Adrenal insufficiency (AI), first described by Thomas Addison in 1855, is characterised by inadequate hormonal production by the adrenal gland, which could either be primary, due to destruction of the adrenal cortex, or secondary/tertiary, due to lack of adrenocorticotropic hormone or its stimulation by corticotropin-releasing hormone. […] Acquired PAI is caused primarily by autoimmune adrenalitis (immune system targeting 21-hydroxylase), which constitutes 70%80% of all cases in the Western world and can occur in isolation (40%) or as a component of autoimmune polyendocrinopathy syndrome (APS) (60%). […] It is thought that a viral infection or an exaggerated body response to an inflammatory signal, in a genetically susceptible individual, starts an autoimmune cascade, which eventually leads to AI.

• #33 Autoimmune Addison disease: pathophysiology and genetic complexity | Nature Reviews Endocrinology

  https://www.nature.com/articles/nrendo.2011.245

  Autoimmune Addison disease is a rare autoimmune disorder with symptoms that typically develop over months or years. Following the development of serum autoantibodies to the key steroidogenic enzyme, 21-hydroxylase, patients have a period of compensated or preclinical disease, characterized by elevations in adrenocortocotropic hormone and renin, before overt, symptomatic adrenal failure develops. […] We propose that local failure of steroidogenesis, causing breakdown of tolerance to adrenal antigens, might be a key factor in disease progression. The etiology of autoimmune Addison disease has a strong genetic component in man, and several dog breeds are also susceptible. […] An aberrant immune response directed, at least in part, at the steroidogenic enzymes of the adrenal cortex (in particular 21-hydroxylase) underlies most cases of AAD.

• #34 Addison’s disease: diagnosis and management strategies | IJGM

  https://www.dovepress.com/addisons-disease-diagnosis-and-management-strategies-peer-reviewed-fulltext-article-IJGM

  COVID-19 infection is a strong player amid this third year of pandemic although we still not do have large cohorts in this particular matter as seen, for instance, in thyroid anomalies. In our opinion, the most important topic for research is immune checkpoint inhibitors, which cause a large panel of endocrine side effects, AD being one of them. […] A study on newly detected cases of ICP-associated AD included 1134 suspected cases and 46 confirmed AD (US FDA Adverse Event Reporting System); males and elderly had a higher risk of AD (p 0.001 and p =0.009, respectively); lower body weight was associated with a poor outcome in AD (OR = 0.984, 95% CI: 0.9690.998, p = 0.029); anti-CTLA-4 plus anti-PD-1 had a higher risk than anti-PD-1-only regarding AD (p 0.001). […] One case report also introduced a 74-year-old male with pulmonary malignancy who developed AD under nivolumab, while large trials focused on a large panel of ICP-induced side effects.

• #35 Addison Disease: Early Detection and Treatment Principles | AAFP

  https://www.aafp.org/pubs/afp/issues/2014/0401/p563.html

  Autoimmune adrenalitis can be divided into stages of progression. As the disease develops, individuals lose adrenocortical function over a period of years. In the first three stages, the human leukocyte antigen genes confer genetic risk; an unknown precipitating event initiates antiadrenal autoimmunity; and 21-hydroxylase antibodies are produced, which predict future disease. 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. In the fourth stage, overt adrenal insufficiency develops. One of the first metabolic abnormalities to occur is an increase in plasma renin level, followed by the sequential development of other abnormalities, including a decreased response to adrenocorticotropic hormone (ACTH) stimulation in the fifth stage. If symptoms of adrenal insufficiency are present but go undiagnosed, an addisonian crisis can occur.

• #36 Addison Disease: Early Detection and Treatment Principles | AAFP

  https://www.aafp.org/pubs/afp/issues/2014/0401/p563.html

  Autoimmune adrenalitis can be divided into stages of progression. As the disease develops, individuals lose adrenocortical function over a period of years. In the first three stages, the human leukocyte antigen genes confer genetic risk; an unknown precipitating event initiates antiadrenal autoimmunity; and 21-hydroxylase antibodies are produced, which predict future disease. 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. In the fourth stage, overt adrenal insufficiency develops. One of the first metabolic abnormalities to occur is an increase in plasma renin level, followed by the sequential development of other abnormalities, including a decreased response to adrenocorticotropic hormone (ACTH) stimulation in the fifth stage. If symptoms of adrenal insufficiency are present but go undiagnosed, an addisonian crisis can occur.

• #37 Addison Disease: Early Detection and Treatment Principles | AAFP

  https://www.aafp.org/pubs/afp/issues/2014/0401/p563.html

  Autoimmune adrenalitis can be divided into stages of progression. As the disease develops, individuals lose adrenocortical function over a period of years. In the first three stages, the human leukocyte antigen genes confer genetic risk; an unknown precipitating event initiates antiadrenal autoimmunity; and 21-hydroxylase antibodies are produced, which predict future disease. 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. In the fourth stage, overt adrenal insufficiency develops. One of the first metabolic abnormalities to occur is an increase in plasma renin level, followed by the sequential development of other abnormalities, including a decreased response to adrenocorticotropic hormone (ACTH) stimulation in the fifth stage. If symptoms of adrenal insufficiency are present but go undiagnosed, an addisonian crisis can occur.

• #38 Addison Disease: Early Detection and Treatment Principles | AAFP

  https://www.aafp.org/pubs/afp/issues/2014/0401/p563.html

  Autoimmune adrenalitis can be divided into stages of progression. As the disease develops, individuals lose adrenocortical function over a period of years. In the first three stages, the human leukocyte antigen genes confer genetic risk; an unknown precipitating event initiates antiadrenal autoimmunity; and 21-hydroxylase antibodies are produced, which predict future disease. 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. In the fourth stage, overt adrenal insufficiency develops. One of the first metabolic abnormalities to occur is an increase in plasma renin level, followed by the sequential development of other abnormalities, including a decreased response to adrenocorticotropic hormone (ACTH) stimulation in the fifth stage. If symptoms of adrenal insufficiency are present but go undiagnosed, an addisonian crisis can occur.

• #39 Autoimmune Addison disease: pathophysiology and genetic complexity | Nature Reviews Endocrinology

  https://www.nature.com/articles/nrendo.2011.245

  Autoimmune Addison disease is a rare autoimmune disorder with symptoms that typically develop over months or years. Following the development of serum autoantibodies to the key steroidogenic enzyme, 21-hydroxylase, patients have a period of compensated or preclinical disease, characterized by elevations in adrenocortocotropic hormone and renin, before overt, symptomatic adrenal failure develops. […] We propose that local failure of steroidogenesis, causing breakdown of tolerance to adrenal antigens, might be a key factor in disease progression. The etiology of autoimmune Addison disease has a strong genetic component in man, and several dog breeds are also susceptible. […] An aberrant immune response directed, at least in part, at the steroidogenic enzymes of the adrenal cortex (in particular 21-hydroxylase) underlies most cases of AAD.

• #40 Addison Disease: Early Detection and Treatment Principles | AAFP

  https://www.aafp.org/pubs/afp/issues/2014/0401/p563.html

  Autoimmune adrenalitis can be divided into stages of progression. As the disease develops, individuals lose adrenocortical function over a period of years. In the first three stages, the human leukocyte antigen genes confer genetic risk; an unknown precipitating event initiates antiadrenal autoimmunity; and 21-hydroxylase antibodies are produced, which predict future disease. 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. In the fourth stage, overt adrenal insufficiency develops. One of the first metabolic abnormalities to occur is an increase in plasma renin level, followed by the sequential development of other abnormalities, including a decreased response to adrenocorticotropic hormone (ACTH) stimulation in the fifth stage. If symptoms of adrenal insufficiency are present but go undiagnosed, an addisonian crisis can occur.

• #41 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.[4] […] Autoimmune destruction of the adrenal glands is the most common cause of Addison’s disease.[5] This destruction occurs as antibodies develop against the adrenal cortex.[6] Autoimmune destruction can be an isolated finding or type 1 and 2 autoimmune polyglandular endocrinopathies. Patients with autoimmune adrenal disease are more likely to have polyglandular autoimmune syndromes.[7][8][9] […] Adrenal failure in Addison disease results in decreased cortisol production initially followed by that of aldosterone, both of which will eventually result in an elevation of adrenocorticotropic (ACTH) and melanocyte-stimulating hormone (MSH) hormones due to the loss of negative feedback inhibition.[22]

• #42 Addison Disease | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/17183

  Addison disease, also known as autoimmune adrenalitis, is an acquired primary adrenal insufficiency. Addison disease results from the destruction of the bilateral adrenal cortex, leading to decreased adrenocortical hormones, including cortisol, aldosterone, and androgens. […] 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. […] 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. […] Adrenal failure in Addison disease results in decreased cortisol production initially followed by that of aldosterone, both of which will eventually result in an elevation of adrenocorticotropic (ACTH) and melanocyte-stimulating hormone (MSH) hormones due to the loss of negative feedback inhibition.

• #43 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 is an insidious, usually progressive hypofunctioning of the adrenal cortex. […] 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. […] Both mineralocorticoids and glucocorticoids are deficient. […] Because mineralocorticoids stimulate sodium reabsorption and potassium excretion, deficiency results in increased excretion of sodium and decreased excretion of potassium, chiefly in urine but also in sweat, saliva, and the gastrointestinal tract. […] Glucocorticoid deficiency contributes to hypotension and causes severe insulin sensitivity and disturbances in carbohydrate, fat, and protein metabolism. […] A decreased blood cortisol level results in increased pituitary ACTH production and increased blood beta-lipotropin level.

• #44 Addison’s Disease – Endocrinology Advisor

  https://www.endocrinologyadvisor.com/ddi/addisons-disease/

  The loss of cortisol in Addison’s disease produces hypoglycemia, anorexia, nausea and vomiting, weight loss, and weakness. The loss of aldosterone produces hyperkalemia, metabolic acidosis, and hypotension. […] Adrenocorticotropic hormone (ACTH) regulates cortisol production. Therefore, increased levels of ACTH results in hyperpigmentation in patients with Addison’s disease. […] A diagnosis of Addison’s disease should be suspected of all patients who present with general fatigue or severe weakness, unexplained dehydration, hypotension, weight loss, fever, abdominal pain, and hyperpigmentation. […] Addison’s disease is likely if cortisol is 5g/dL (138nmol/L) with a concomitant ACTH that is more than 2-fold above the upper limit of the normal range. […] Addison’s disease is not typically thought to be life threatening. But there is evidence that traumatic brain injury can lead to deficiency in the secretion of corticotropin, resulting in adrenal insufficiency (Addison’s disease) and life-threatening hyponatremia and hypotension. […] The treatment of Addison’s disease includes glucocorticoid (hydrocortisone or prednisone) and mineralocorticoid (fludrocortisone) hormone replacement therapy.

• #45 Addison’s Disease – Endocrinology Advisor

  https://www.endocrinologyadvisor.com/ddi/addisons-disease/

  The loss of cortisol in Addison’s disease produces hypoglycemia, anorexia, nausea and vomiting, weight loss, and weakness. The loss of aldosterone produces hyperkalemia, metabolic acidosis, and hypotension. […] Adrenocorticotropic hormone (ACTH) regulates cortisol production. Therefore, increased levels of ACTH results in hyperpigmentation in patients with Addison’s disease. […] A diagnosis of Addison’s disease should be suspected of all patients who present with general fatigue or severe weakness, unexplained dehydration, hypotension, weight loss, fever, abdominal pain, and hyperpigmentation. […] Addison’s disease is likely if cortisol is 5g/dL (138nmol/L) with a concomitant ACTH that is more than 2-fold above the upper limit of the normal range. […] Addison’s disease is not typically thought to be life threatening. But there is evidence that traumatic brain injury can lead to deficiency in the secretion of corticotropin, resulting in adrenal insufficiency (Addison’s disease) and life-threatening hyponatremia and hypotension. […] The treatment of Addison’s disease includes glucocorticoid (hydrocortisone or prednisone) and mineralocorticoid (fludrocortisone) hormone replacement therapy.

• #46 Addison’s Disease – Endocrinology Advisor

  https://www.endocrinologyadvisor.com/ddi/addisons-disease/

  The loss of cortisol in Addison’s disease produces hypoglycemia, anorexia, nausea and vomiting, weight loss, and weakness. The loss of aldosterone produces hyperkalemia, metabolic acidosis, and hypotension. […] Adrenocorticotropic hormone (ACTH) regulates cortisol production. Therefore, increased levels of ACTH results in hyperpigmentation in patients with Addison’s disease. […] A diagnosis of Addison’s disease should be suspected of all patients who present with general fatigue or severe weakness, unexplained dehydration, hypotension, weight loss, fever, abdominal pain, and hyperpigmentation. […] Addison’s disease is likely if cortisol is 5g/dL (138nmol/L) with a concomitant ACTH that is more than 2-fold above the upper limit of the normal range. […] Addison’s disease is not typically thought to be life threatening. But there is evidence that traumatic brain injury can lead to deficiency in the secretion of corticotropin, resulting in adrenal insufficiency (Addison’s disease) and life-threatening hyponatremia and hypotension. […] The treatment of Addison’s disease includes glucocorticoid (hydrocortisone or prednisone) and mineralocorticoid (fludrocortisone) hormone replacement therapy.

• #47 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 is an insidious, usually progressive hypofunctioning of the adrenal cortex. […] 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. […] Both mineralocorticoids and glucocorticoids are deficient. […] Because mineralocorticoids stimulate sodium reabsorption and potassium excretion, deficiency results in increased excretion of sodium and decreased excretion of potassium, chiefly in urine but also in sweat, saliva, and the gastrointestinal tract. […] Glucocorticoid deficiency contributes to hypotension and causes severe insulin sensitivity and disturbances in carbohydrate, fat, and protein metabolism. […] A decreased blood cortisol level results in increased pituitary ACTH production and increased blood beta-lipotropin level.

• #48 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 is an insidious, usually progressive hypofunctioning of the adrenal cortex. […] 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. […] Both mineralocorticoids and glucocorticoids are deficient. […] Because mineralocorticoids stimulate sodium reabsorption and potassium excretion, deficiency results in increased excretion of sodium and decreased excretion of potassium, chiefly in urine but also in sweat, saliva, and the gastrointestinal tract. […] Glucocorticoid deficiency contributes to hypotension and causes severe insulin sensitivity and disturbances in carbohydrate, fat, and protein metabolism. […] A decreased blood cortisol level results in increased pituitary ACTH production and increased blood beta-lipotropin level.

• #49 Addison’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/addisons-disease/symptoms-causes/syc-20350293

  Stress on the body such as injury, infection or illness can trigger adrenal crisis. Typically, the adrenal glands make two or three times the usual amount of cortisol in response to physical stress. But with adrenal insufficiency, the adrenal glands don’t make enough cortisol to meet this need. And that can lead to adrenal crisis. […] 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.

• #50 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 is an insidious, usually progressive hypofunctioning of the adrenal cortex. […] 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. […] Both mineralocorticoids and glucocorticoids are deficient. […] Because mineralocorticoids stimulate sodium reabsorption and potassium excretion, deficiency results in increased excretion of sodium and decreased excretion of potassium, chiefly in urine but also in sweat, saliva, and the gastrointestinal tract. […] Glucocorticoid deficiency contributes to hypotension and causes severe insulin sensitivity and disturbances in carbohydrate, fat, and protein metabolism. […] A decreased blood cortisol level results in increased pituitary ACTH production and increased blood beta-lipotropin level.

• #51 Addison’s Disease – Endocrinology Advisor

  https://www.endocrinologyadvisor.com/ddi/addisons-disease/

  The loss of cortisol in Addison’s disease produces hypoglycemia, anorexia, nausea and vomiting, weight loss, and weakness. The loss of aldosterone produces hyperkalemia, metabolic acidosis, and hypotension. […] Adrenocorticotropic hormone (ACTH) regulates cortisol production. Therefore, increased levels of ACTH results in hyperpigmentation in patients with Addison’s disease. […] A diagnosis of Addison’s disease should be suspected of all patients who present with general fatigue or severe weakness, unexplained dehydration, hypotension, weight loss, fever, abdominal pain, and hyperpigmentation. […] Addison’s disease is likely if cortisol is 5g/dL (138nmol/L) with a concomitant ACTH that is more than 2-fold above the upper limit of the normal range. […] Addison’s disease is not typically thought to be life threatening. But there is evidence that traumatic brain injury can lead to deficiency in the secretion of corticotropin, resulting in adrenal insufficiency (Addison’s disease) and life-threatening hyponatremia and hypotension. […] The treatment of Addison’s disease includes glucocorticoid (hydrocortisone or prednisone) and mineralocorticoid (fludrocortisone) hormone replacement therapy.

• #52 Addison’s Disease – Endocrinology Advisor

  https://www.endocrinologyadvisor.com/ddi/addisons-disease/

  The loss of cortisol in Addison’s disease produces hypoglycemia, anorexia, nausea and vomiting, weight loss, and weakness. The loss of aldosterone produces hyperkalemia, metabolic acidosis, and hypotension. […] Adrenocorticotropic hormone (ACTH) regulates cortisol production. Therefore, increased levels of ACTH results in hyperpigmentation in patients with Addison’s disease. […] A diagnosis of Addison’s disease should be suspected of all patients who present with general fatigue or severe weakness, unexplained dehydration, hypotension, weight loss, fever, abdominal pain, and hyperpigmentation. […] Addison’s disease is likely if cortisol is 5g/dL (138nmol/L) with a concomitant ACTH that is more than 2-fold above the upper limit of the normal range. […] Addison’s disease is not typically thought to be life threatening. But there is evidence that traumatic brain injury can lead to deficiency in the secretion of corticotropin, resulting in adrenal insufficiency (Addison’s disease) and life-threatening hyponatremia and hypotension. […] The treatment of Addison’s disease includes glucocorticoid (hydrocortisone or prednisone) and mineralocorticoid (fludrocortisone) hormone replacement therapy.

• #53 Addison’s Disease – Endocrinology Advisor

  https://www.endocrinologyadvisor.com/ddi/addisons-disease/

  The loss of cortisol in Addison’s disease produces hypoglycemia, anorexia, nausea and vomiting, weight loss, and weakness. The loss of aldosterone produces hyperkalemia, metabolic acidosis, and hypotension. […] Adrenocorticotropic hormone (ACTH) regulates cortisol production. Therefore, increased levels of ACTH results in hyperpigmentation in patients with Addison’s disease. […] A diagnosis of Addison’s disease should be suspected of all patients who present with general fatigue or severe weakness, unexplained dehydration, hypotension, weight loss, fever, abdominal pain, and hyperpigmentation. […] Addison’s disease is likely if cortisol is 5g/dL (138nmol/L) with a concomitant ACTH that is more than 2-fold above the upper limit of the normal range. […] Addison’s disease is not typically thought to be life threatening. But there is evidence that traumatic brain injury can lead to deficiency in the secretion of corticotropin, resulting in adrenal insufficiency (Addison’s disease) and life-threatening hyponatremia and hypotension. […] The treatment of Addison’s disease includes glucocorticoid (hydrocortisone or prednisone) and mineralocorticoid (fludrocortisone) hormone replacement therapy.

• #54 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 is an insidious, usually progressive hypofunctioning of the adrenal cortex. […] 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. […] Both mineralocorticoids and glucocorticoids are deficient. […] Because mineralocorticoids stimulate sodium reabsorption and potassium excretion, deficiency results in increased excretion of sodium and decreased excretion of potassium, chiefly in urine but also in sweat, saliva, and the gastrointestinal tract. […] Glucocorticoid deficiency contributes to hypotension and causes severe insulin sensitivity and disturbances in carbohydrate, fat, and protein metabolism. […] A decreased blood cortisol level results in increased pituitary ACTH production and increased blood beta-lipotropin level.

• #55 Addison’s Disease – Endocrinology Advisor

  https://www.endocrinologyadvisor.com/ddi/addisons-disease/

  The loss of cortisol in Addison’s disease produces hypoglycemia, anorexia, nausea and vomiting, weight loss, and weakness. The loss of aldosterone produces hyperkalemia, metabolic acidosis, and hypotension. […] Adrenocorticotropic hormone (ACTH) regulates cortisol production. Therefore, increased levels of ACTH results in hyperpigmentation in patients with Addison’s disease. […] A diagnosis of Addison’s disease should be suspected of all patients who present with general fatigue or severe weakness, unexplained dehydration, hypotension, weight loss, fever, abdominal pain, and hyperpigmentation. […] Addison’s disease is likely if cortisol is 5g/dL (138nmol/L) with a concomitant ACTH that is more than 2-fold above the upper limit of the normal range. […] Addison’s disease is not typically thought to be life threatening. But there is evidence that traumatic brain injury can lead to deficiency in the secretion of corticotropin, resulting in adrenal insufficiency (Addison’s disease) and life-threatening hyponatremia and hypotension. […] The treatment of Addison’s disease includes glucocorticoid (hydrocortisone or prednisone) and mineralocorticoid (fludrocortisone) hormone replacement therapy.

• #56 Primary Adrenal Insufficiency (Addison Disease) – Adrenal Insufficiency – Adrenal Gland Diseases – Endocrinology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.11.1.1.

  Primary adrenal insufficiency (AI), also termed Addison disease, is a clinical syndrome caused by a long-term deficit of hormones of the adrenal cortex, primarily cortisol and often aldosterone, due to a direct injury to the adrenal gland. […] The autoantigens are enzymes of the steroid pathway most frequently 21-hydroxylase, 17-hydroxylase, and 20-22-lyase. Other autoimmune diseases may coexist, most often thyroid disease (autoimmune polyglandular syndromes). […] In the early stages adrenal glands may be enlarged (due to lymphocytic infiltrates), while in later stages they become small (due to atrophy). […] In primary AI renin level is high and aldosterone levels are low. […] A high serum ACTH level and low serum cortisol level at baseline; impaired cortisol response to the short stimulation test with synthetic ACTH, insulin tolerance test (ITT), or metyrapone stimulation test.

• #57 Orphanet: Addison disease

  https://www.orpha.net/en/disease/detail/85138

  A chronic and rare endocrine disorder due to autoimmune destruction of the adrenal cortex and resulting in a glucocorticoid and mineralocorticoid deficiency. […] AD results from autoimmune destruction of the adrenal cortex and can be isolated or seen as part of an autoimmune disorder (autoimmune polyendocrine syndrome type 1, 2 or 4). […] Biochemical tests are needed to diagnose AD. Early morning serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels are measured. Plasma ACTH is much higher in individuals with AD (22 pmol/L) and morning serum cortisol levels are usually low (500 nmol/L) after exogenous ACTH administration but no increase is seen in AD patients. Raised plasma ACTH levels confirm AD diagnosis. […] Management is life-long and requires a multidisciplinary team. Glucocorticoid replacement with oral hydrocortisone (10-25 mg daily taken in 2-3 doses) is given to mimic physiological cortisol secretion patterns. Oral fludrocortisone is given to replace mineralocorticoid hormones. Dehydroepiandrosterone replacement is optional. Glucocorticoid levels can be adjusted during times of stress to prevent AAI. […] There is no cure for AD but with proper treatment and care taken to prevent AAI there is no decrease in life expectancy. AD is only life threatening when ignored.

• #58 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  The first sign of an ongoing autoimmune process is the presence of autoantibodies against 21-hydroxylase, which can be found in about 90% of cases, and detection of these antibodies is diagnostic of PAI. […] The HPA axis, with endogenous cortisol exerting strong negative feedback at the hypothalamic and pituitary levels, describes the close interaction between these three endocrine organs. […] Cortisol deficiency in PAI results in elevated levels of plasma ACTH and CRH due to loss of negative feedback. […] In PAI, the loss of adrenal cortex is gradual, and symptoms and signs of AI do not appear until at least 90% of adrenal cortex is lost. […] Several other organ-specific autoimmune diseases (eg, thyroid disorders, type 1 diabetes mellitus (DM), vitiligo, hypoparathyroidism, vitamin B12 deficiency and premature ovarian insufficiency) frequently occur in combination with PAI, or as part of APS-1 and APS-2.

• #59 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.[4] […] Autoimmune destruction of the adrenal glands is the most common cause of Addison’s disease.[5] This destruction occurs as antibodies develop against the adrenal cortex.[6] Autoimmune destruction can be an isolated finding or type 1 and 2 autoimmune polyglandular endocrinopathies. Patients with autoimmune adrenal disease are more likely to have polyglandular autoimmune syndromes.[7][8][9] […] Adrenal failure in Addison disease results in decreased cortisol production initially followed by that of aldosterone, both of which will eventually result in an elevation of adrenocorticotropic (ACTH) and melanocyte-stimulating hormone (MSH) hormones due to the loss of negative feedback inhibition.[22]

• #60 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  Patients with APS-1, which is a rare autosomal recessive disease caused by a mutation in the autoimmune regulator (AIRE) gene, will have at least two of three main components: PAI, hypoparathyroidism and chronic mucocutaneous candidiasis, and those with APS-2, a far more common condition than APS one and with polygenic inheritance, have at least two of the three endocrinopathies, namely, PAI, type 1 diabetes and autoimmune thyroiditis. […] In the early stages in SAI and TAI, basal ACTH secretion is maintained, while stress-induced ACTH secretion is affected. […] With time, basal ACTH secretion is also affected causing gradual atrophy of zonae fasciculata and reticularis of the adrenal cortex but aldosterone secretion by the zona glomerulosa remains intact.

• #61 Orphanet: Addison disease

  https://www.orpha.net/en/disease/detail/85138

  A chronic and rare endocrine disorder due to autoimmune destruction of the adrenal cortex and resulting in a glucocorticoid and mineralocorticoid deficiency. […] AD results from autoimmune destruction of the adrenal cortex and can be isolated or seen as part of an autoimmune disorder (autoimmune polyendocrine syndrome type 1, 2 or 4). […] Biochemical tests are needed to diagnose AD. Early morning serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels are measured. Plasma ACTH is much higher in individuals with AD (22 pmol/L) and morning serum cortisol levels are usually low (500 nmol/L) after exogenous ACTH administration but no increase is seen in AD patients. Raised plasma ACTH levels confirm AD diagnosis. […] Management is life-long and requires a multidisciplinary team. Glucocorticoid replacement with oral hydrocortisone (10-25 mg daily taken in 2-3 doses) is given to mimic physiological cortisol secretion patterns. Oral fludrocortisone is given to replace mineralocorticoid hormones. Dehydroepiandrosterone replacement is optional. Glucocorticoid levels can be adjusted during times of stress to prevent AAI. […] There is no cure for AD but with proper treatment and care taken to prevent AAI there is no decrease in life expectancy. AD is only life threatening when ignored.

• #62 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  Patients with APS-1, which is a rare autosomal recessive disease caused by a mutation in the autoimmune regulator (AIRE) gene, will have at least two of three main components: PAI, hypoparathyroidism and chronic mucocutaneous candidiasis, and those with APS-2, a far more common condition than APS one and with polygenic inheritance, have at least two of the three endocrinopathies, namely, PAI, type 1 diabetes and autoimmune thyroiditis. […] In the early stages in SAI and TAI, basal ACTH secretion is maintained, while stress-induced ACTH secretion is affected. […] With time, basal ACTH secretion is also affected causing gradual atrophy of zonae fasciculata and reticularis of the adrenal cortex but aldosterone secretion by the zona glomerulosa remains intact.

• #63 Orphanet: Addison disease

  https://www.orpha.net/en/disease/detail/85138

  A chronic and rare endocrine disorder due to autoimmune destruction of the adrenal cortex and resulting in a glucocorticoid and mineralocorticoid deficiency. […] AD results from autoimmune destruction of the adrenal cortex and can be isolated or seen as part of an autoimmune disorder (autoimmune polyendocrine syndrome type 1, 2 or 4). […] Biochemical tests are needed to diagnose AD. Early morning serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels are measured. Plasma ACTH is much higher in individuals with AD (22 pmol/L) and morning serum cortisol levels are usually low (500 nmol/L) after exogenous ACTH administration but no increase is seen in AD patients. Raised plasma ACTH levels confirm AD diagnosis. […] Management is life-long and requires a multidisciplinary team. Glucocorticoid replacement with oral hydrocortisone (10-25 mg daily taken in 2-3 doses) is given to mimic physiological cortisol secretion patterns. Oral fludrocortisone is given to replace mineralocorticoid hormones. Dehydroepiandrosterone replacement is optional. Glucocorticoid levels can be adjusted during times of stress to prevent AAI. […] There is no cure for AD but with proper treatment and care taken to prevent AAI there is no decrease in life expectancy. AD is only life threatening when ignored.

• #64 Addison Disease Clinical Presentation: History, Physical, Causes

  https://emedicine.medscape.com/article/116467-clinical

  Patients may have a hereditary predisposition to autoimmune Addison disease. […] 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. […] The mechanism of action of adrenal hemorrhage is not fully understood.

• #65 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  The first sign of an ongoing autoimmune process is the presence of autoantibodies against 21-hydroxylase, which can be found in about 90% of cases, and detection of these antibodies is diagnostic of PAI. […] The HPA axis, with endogenous cortisol exerting strong negative feedback at the hypothalamic and pituitary levels, describes the close interaction between these three endocrine organs. […] Cortisol deficiency in PAI results in elevated levels of plasma ACTH and CRH due to loss of negative feedback. […] In PAI, the loss of adrenal cortex is gradual, and symptoms and signs of AI do not appear until at least 90% of adrenal cortex is lost. […] Several other organ-specific autoimmune diseases (eg, thyroid disorders, type 1 diabetes mellitus (DM), vitiligo, hypoparathyroidism, vitamin B12 deficiency and premature ovarian insufficiency) frequently occur in combination with PAI, or as part of APS-1 and APS-2.

• #66 Etiology, clinical characteristics and mortality among Indian patients with Addison’s disease in: Endocrine Connections Volume 12 Issue 3 (2023)

  https://ec.bioscientifica.com/view/journals/ec/12/3/EC-22-0439.xml

  The etiology, presentation and mortality of patients with primary adrenal insufficiency (PAI) in developing countries may differ from economically developed nations. […] The most frequent etiologies of PAI were adrenal histoplasmosis (AH, 45%), adrenal tuberculosis (AT, 15%), autoimmunity (AI, 25%) and primary lymphoma (6%). […] Patients with an autoimmune etiology had a higher frequency of 21-hydroxylase antibodies (41% vs 3%) and autoimmune thyroid disease (46% vs 5%) vs those with infectious etiologies. […] Mortality was significantly higher in AH (45%) compared with AT (8%) or AI (5%) (P = 0.001). […] In conclusion, infections, especially AH, were the most frequent cause of PAI in north India. […] Despite appropriate therapy, AH had very high mortality as compared with AT and AI.

• #67 Adrenal insufficiency: pathophysiology, diagnosis and management – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/adrenal-insufficiency-pathophysiology-diagnosis-and-management

  Autoimmune primary adrenal insufficiency, commonly known as Addison’s disease, can occur at any age, but most often presents in patients between the ages of 20 years and 50 years. […] Primary adrenal insufficiency is caused by a defect in the adrenal cortex itself, most commonly resulting from either autoimmune destruction, adrenoleukodystrophy or congenital adrenal hyperplasia. […] Autoimmune primary adrenal insufficiency has a significant genetic component and a high degree of heritability, as well as being associated with other autoimmune endocrinopathies, such as thyroid disorders and type 1 diabetes mellitus. […] Infections associated with primary adrenal insufficiency include tuberculosis, HIV and cytomegalovirus. […] As a consequence of the gland itself being affected, patients with primary adrenal insufficiency become deficient in all of the hormones usually secreted from the cortex.

• #68 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  The first sign of an ongoing autoimmune process is the presence of autoantibodies against 21-hydroxylase, which can be found in about 90% of cases, and detection of these antibodies is diagnostic of PAI. […] The HPA axis, with endogenous cortisol exerting strong negative feedback at the hypothalamic and pituitary levels, describes the close interaction between these three endocrine organs. […] Cortisol deficiency in PAI results in elevated levels of plasma ACTH and CRH due to loss of negative feedback. […] In PAI, the loss of adrenal cortex is gradual, and symptoms and signs of AI do not appear until at least 90% of adrenal cortex is lost. […] Several other organ-specific autoimmune diseases (eg, thyroid disorders, type 1 diabetes mellitus (DM), vitiligo, hypoparathyroidism, vitamin B12 deficiency and premature ovarian insufficiency) frequently occur in combination with PAI, or as part of APS-1 and APS-2.

• #69 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  The first sign of an ongoing autoimmune process is the presence of autoantibodies against 21-hydroxylase, which can be found in about 90% of cases, and detection of these antibodies is diagnostic of PAI. […] The HPA axis, with endogenous cortisol exerting strong negative feedback at the hypothalamic and pituitary levels, describes the close interaction between these three endocrine organs. […] Cortisol deficiency in PAI results in elevated levels of plasma ACTH and CRH due to loss of negative feedback. […] In PAI, the loss of adrenal cortex is gradual, and symptoms and signs of AI do not appear until at least 90% of adrenal cortex is lost. […] Several other organ-specific autoimmune diseases (eg, thyroid disorders, type 1 diabetes mellitus (DM), vitiligo, hypoparathyroidism, vitamin B12 deficiency and premature ovarian insufficiency) frequently occur in combination with PAI, or as part of APS-1 and APS-2.

• #70 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  The first sign of an ongoing autoimmune process is the presence of autoantibodies against 21-hydroxylase, which can be found in about 90% of cases, and detection of these antibodies is diagnostic of PAI. […] The HPA axis, with endogenous cortisol exerting strong negative feedback at the hypothalamic and pituitary levels, describes the close interaction between these three endocrine organs. […] Cortisol deficiency in PAI results in elevated levels of plasma ACTH and CRH due to loss of negative feedback. […] In PAI, the loss of adrenal cortex is gradual, and symptoms and signs of AI do not appear until at least 90% of adrenal cortex is lost. […] Several other organ-specific autoimmune diseases (eg, thyroid disorders, type 1 diabetes mellitus (DM), vitiligo, hypoparathyroidism, vitamin B12 deficiency and premature ovarian insufficiency) frequently occur in combination with PAI, or as part of APS-1 and APS-2.

• #71 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  The first sign of an ongoing autoimmune process is the presence of autoantibodies against 21-hydroxylase, which can be found in about 90% of cases, and detection of these antibodies is diagnostic of PAI. […] The HPA axis, with endogenous cortisol exerting strong negative feedback at the hypothalamic and pituitary levels, describes the close interaction between these three endocrine organs. […] Cortisol deficiency in PAI results in elevated levels of plasma ACTH and CRH due to loss of negative feedback. […] In PAI, the loss of adrenal cortex is gradual, and symptoms and signs of AI do not appear until at least 90% of adrenal cortex is lost. […] Several other organ-specific autoimmune diseases (eg, thyroid disorders, type 1 diabetes mellitus (DM), vitiligo, hypoparathyroidism, vitamin B12 deficiency and premature ovarian insufficiency) frequently occur in combination with PAI, or as part of APS-1 and APS-2.

• #72 Causes of primary adrenal insufficiency (Addison disease) – UpToDate

  https://www.uptodate.com/contents/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). 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.

• #73 Causes of primary adrenal insufficiency (Addison disease) – UpToDate

  https://www.uptodate.com/contents/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). 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.

• #74 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. […] 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.

• #75 Addison’s Disease – Endocrinology Advisor

  https://www.endocrinologyadvisor.com/ddi/addisons-disease/

  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. […] Another potential cause of Addison’s disease is infections such as HIV, fungal adrenalitis, meningococcal sepsis, and African trypanosomiasis. […] The availability of corticosteroid replacement therapy and advances in diagnostic testing have improved the prognosis of patients with Addison’s disease. […] The prognosis depends on the etiology, the time frame in which Addison’s disease is diagnosed and treated, and any challenges that arise from comorbid conditions.

• #76 Adrenal insufficiency: pathophysiology, diagnosis and management – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/adrenal-insufficiency-pathophysiology-diagnosis-and-management

  Autoimmune primary adrenal insufficiency, commonly known as Addison’s disease, can occur at any age, but most often presents in patients between the ages of 20 years and 50 years. […] Primary adrenal insufficiency is caused by a defect in the adrenal cortex itself, most commonly resulting from either autoimmune destruction, adrenoleukodystrophy or congenital adrenal hyperplasia. […] Autoimmune primary adrenal insufficiency has a significant genetic component and a high degree of heritability, as well as being associated with other autoimmune endocrinopathies, such as thyroid disorders and type 1 diabetes mellitus. […] Infections associated with primary adrenal insufficiency include tuberculosis, HIV and cytomegalovirus. […] As a consequence of the gland itself being affected, patients with primary adrenal insufficiency become deficient in all of the hormones usually secreted from the cortex.

• #77 Etiology, clinical characteristics and mortality among Indian patients with Addison’s disease in: Endocrine Connections Volume 12 Issue 3 (2023)

  https://ec.bioscientifica.com/view/journals/ec/12/3/EC-22-0439.xml

  The etiology, presentation and mortality of patients with primary adrenal insufficiency (PAI) in developing countries may differ from economically developed nations. […] The most frequent etiologies of PAI were adrenal histoplasmosis (AH, 45%), adrenal tuberculosis (AT, 15%), autoimmunity (AI, 25%) and primary lymphoma (6%). […] Patients with an autoimmune etiology had a higher frequency of 21-hydroxylase antibodies (41% vs 3%) and autoimmune thyroid disease (46% vs 5%) vs those with infectious etiologies. […] Mortality was significantly higher in AH (45%) compared with AT (8%) or AI (5%) (P = 0.001). […] In conclusion, infections, especially AH, were the most frequent cause of PAI in north India. […] Despite appropriate therapy, AH had very high mortality as compared with AT and AI.

• #78 Causes of primary adrenal insufficiency (Addison disease) – UpToDate

  https://www.uptodate.com/contents/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). 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.

• #79

  https://step1.medbullets.com/endocrine/109017/addison-disease

  any process that damages the adrenal cortices and leads to a deficiency of aldosterone, catecholamines, and cortisol […] autoimmune adrenalitis (Addison disease) […] both humoral and cell-mediated immune mechanisms against the adrenal cortex […] a small percentage of patients may have polyglandular autoimmune syndrome […] infectious adrenalitis […] tuberculosis (most common cause in the developing world) […] disseminated fungal infections (e.g., histoplasmosis) […] HIV infection […] hemorrhagic infarction […] Waterhouse-Friderichsen syndrome associated with meningococcemia (Neisseria meningitidis) […] anticoagulant drug or heparin therapy (e.g., heparin-induced thrombocytopenia) […] metastatic disease […] commonly associated with lung, breast, and melanoma cancers.

• #80 Addison Disease (Hypoadrenocorticism) in Animals – Endocrine System – Merck Veterinary Manual

  https://www.merckvetmanual.com/endocrine-system/the-adrenal-glands/addison-disease-hypoadrenocorticism-in-animals

  Addison disease (hypoadrenocorticism) results from a lack of glucocorticoids, mineralocorticoids, or both. […] Most cases of canine Addison disease are due to primary adrenocortical failure, the cause of which is unknown but is suspected to be immune mediated. […] Other causes of adrenocortical failure include cytotoxic drugs (mitotane), adrenocortical enzyme inhibitors (trilostane), infiltration of the adrenal glands by metastatic neoplasia or granulomatous disease, and adrenal gland hemorrhage. […] Although rare, secondary Addison disease, resulting from deficient ACTH secretion from the pituitary gland, can occur and is clinically indistinguishable from isolated glucocorticoid deficiency resulting from primary adrenocortical failure. […] Mineralocorticoid and glucocorticoid deficiency result in a constellation of characteristic abnormalities that are evident on routine laboratory evaluation.

• #81 Addison’s disease: diagnosis and management strategies | IJGM

  https://www.dovepress.com/addisons-disease-diagnosis-and-management-strategies-peer-reviewed-fulltext-article-IJGM

  COVID-19 infection is a strong player amid this third year of pandemic although we still not do have large cohorts in this particular matter as seen, for instance, in thyroid anomalies. In our opinion, the most important topic for research is immune checkpoint inhibitors, which cause a large panel of endocrine side effects, AD being one of them. […] A study on newly detected cases of ICP-associated AD included 1134 suspected cases and 46 confirmed AD (US FDA Adverse Event Reporting System); males and elderly had a higher risk of AD (p 0.001 and p =0.009, respectively); lower body weight was associated with a poor outcome in AD (OR = 0.984, 95% CI: 0.9690.998, p = 0.029); anti-CTLA-4 plus anti-PD-1 had a higher risk than anti-PD-1-only regarding AD (p 0.001). […] One case report also introduced a 74-year-old male with pulmonary malignancy who developed AD under nivolumab, while large trials focused on a large panel of ICP-induced side effects.

• #82 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Addisons-Disease-Causes.aspx

  The exact mechanism by which this defective gene causes Addisons disease is not yet known. […] Disease like amyloidosis that leads to the accumulation of amyloid protein in the adrenal glands may lead to Addisons disease. […] There may be secondary adrenal insufficiency as well caused by a lack of ACTH. ACTH stimulates the adrenal to secrete its hormones. Without ACTH to stimulate the adrenal glands the cortisol production level falls. Aldosterone production is not usually affected.

• #83 Addison disease: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/000378.htm

  Addison disease is a disorder that causes the adrenal glands to not produce enough hormones. […] Addison disease results from damage to the adrenal cortex. The damage causes the cortex to produce hormone levels that are too low. […] This damage may be caused by the following: The immune system mistakenly attacking the adrenal glands (autoimmune disease). […] Certain rare genetic defects may also cause adrenal insufficiency.

• #84 Addison’s disease | Endocrine Conditions

  https://www.yourhormones.info/endocrine-conditions/addisons-disease/

  Addison’s disease is caused by the destruction of the cortex of each adrenal gland. This means that the adrenal gland cannot produce the hormones glucocorticoids (especially cortisol), mineralocorticoids (especially aldosterone) and sex steroids. People with Addison’s disease develop symptoms as a result of this loss of adrenal hormones. […] Primary adrenal insufficiency or primary Addison’s disease; autoimmunity is the most common cause of Addisons disease. This occurs when bodys immune system making a mistake and attacking and destroying the cells of the adrenal glands in error. This type of Addisons is called autoimmune Addisons. […] Rare causes of Addisons disease include removal of the adrenal glands by surgery, bleeding into the adrenal glands (for instance after abdominal injuries), and genetic defects such as adrenoleukodystrophy. The pituitary gland produces hormones that cause the adrenal gland to produce its hormones. If the pituitary gland stops working properly, this can cause 'secondary’ adrenal insufficiency – in other words, the adrenal glands stop working, not because they are diseased, but because the pituitary gland has stopped telling them to produce their hormones. In patients with secondary adrenal insufficiency, patients have a low cortisol, but a normal aldosterone.

• #85 Addison’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/addisons-disease/symptoms-causes/syc-20350293

  Addison’s disease is a rare condition that happens when the body doesn’t make enough of some hormones. Another name for Addison’s disease is primary adrenal insufficiency. With Addison’s disease, the adrenal glands make too little of the hormone cortisol. Often, they also make too little of another hormone called aldosterone. […] 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. […] This condition happens when the outer layer of the adrenal glands becomes damaged and can’t make enough hormones. 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.

• #86

  https://www.addisonsdisease.org.uk/what-is-addisons-disease

  Addison’s disease (also called primary adrenal insufficiency). This is where the adrenal glands themselves stop working – no cortisol is produced. There is also the loss of the mineralocorticoid aldosterone and this is why people with primary adrenal insufficiency (Addisons) also take the medication fludrocortisone. […] Often Addison’s is caused by the bodys immune system making a mistake and attacking and destroying the cells of the adrenal glands in error. This type of Addisons is called autoimmune Addisons. Addison’s can also be caused by an infection (such as tuberculosis or HIV) damaging the adrenal glands. Occasionally, a person may need to have their adrenal glands removed. This is called a bilateral adrenalectomy and is another cause of primary adrenal insufficiency. […] While the different types of adrenal insufficiency listed above have different causes, people who live with them day-to-day experience similar challenges regarding their steroid dependency, resulting from the inability of their adrenal glands to produce cortisol. They need to take steroid medication every day to stay healthy.

• #87 Adrenal Insufficiency and Addison Disease | Concise Medical Knowledge

  https://www.lecturio.com/concepts/adrenal-insufficiency-and-addisons-disease/

  Primary AI, also called Addisons disease, is caused by adrenal gland disorder (autoimmune disease, infections, and malignancy, among others). […] Primary adrenal insufficiency: The adrenals are damaged, regardless of the etiology. Consequently, there is a decline in the production of cortisol and mineralocorticoids. […] The zona glomerulosa is primarily regulated by the renin-angiotensin system and potassium levels. […] Hypocortisolism, hypoaldosteronism, and hypoandrogenism occur when 90% of the adrenal cortex is destroyed. […] Compensatory ACTH leads to hyperpigmentation. […] In primary AI, mineralocorticoid is given to prevent volume depletion, salt loss, and hyperkalemia. […] Adrenal crisis is the acute decompensation of adrenal function that can be triggered by another disease, surgery, stress, or increased glucocorticoid inactivation. […] Cortisol levels are low in primary AI, while aldosterone production is preserved.

• #88 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  The first sign of an ongoing autoimmune process is the presence of autoantibodies against 21-hydroxylase, which can be found in about 90% of cases, and detection of these antibodies is diagnostic of PAI. […] The HPA axis, with endogenous cortisol exerting strong negative feedback at the hypothalamic and pituitary levels, describes the close interaction between these three endocrine organs. […] Cortisol deficiency in PAI results in elevated levels of plasma ACTH and CRH due to loss of negative feedback. […] In PAI, the loss of adrenal cortex is gradual, and symptoms and signs of AI do not appear until at least 90% of adrenal cortex is lost. […] Several other organ-specific autoimmune diseases (eg, thyroid disorders, type 1 diabetes mellitus (DM), vitiligo, hypoparathyroidism, vitamin B12 deficiency and premature ovarian insufficiency) frequently occur in combination with PAI, or as part of APS-1 and APS-2.

• #89 Addison’s Disease – Armando Hasudungandownloadbookprintpencilchevron-leftchevron-righttwitterfacebookhand-o-rightfilterchainlist-ulenvelopelinkedinangle-rightangle-upyoutubexinginstagramlong-arrow-uppaper-planepinterest-pwhatsappcommentingaddress-book-ox-

  https://armandoh.org/disease/addisons-disease/?srsltid=AfmBOopssFnEvG6Zt1ANs_tYp7zU-UxjRRmg-sVoG8EEZHWQOdHIoCFI

  Androgen deficiency presents in women with reduced axillary and pubic hair and reduced libido. (Testicular production of androgens is more important in men.) […] Lack of cortisol negative feedback increases CRH and ACTH secretion. An increase in other POMC-related peptides leads to skin pigmentation and other mucous membranes.

• #90

  https://www.nhs.uk/conditions/addisons-disease/causes/

  The production of hormones from the adrenal gland can also be affected by damage to the pituitary gland a pea-sized gland located below the brain that produces a hormone that stimulates the adrenal gland. This is called secondary adrenal insufficiency and is a separate condition to Addison’s disease.

• #91 Addison’s Disease: Causes, Risks & Treatment

  https://www.healthline.com/health/addisons-disease

  Addisons disease occurs when the adrenal cortex is damaged, and the adrenal glands dont produce enough of the steroid hormones cortisol and aldosterone. […] Primary adrenal insufficiency occurs when your adrenal glands are damaged so severely that they can no longer produce hormones. This type of Addisons disease is most often caused when your immune system attacks your adrenal glands. This is called an autoimmune disease. […] Tertiary adrenal insufficiency originates in the hypothalamus, a region of the brain near the pituitary gland. The hypothalamus normally sends corticotropin-releasing hormone (CRH) to the pituitary, stimulating it to produce ACTH. […] When the hypothalamus fails to produce sufficient CRH, the pituitary fails in turn to produce enough hormones to stimulate the adrenal glands. […] Addisonian crisis causes low blood pressure, high potassium in the blood, and low blood sugar levels.

• #92 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Addisons-Disease-Causes.aspx

  The exact mechanism by which this defective gene causes Addisons disease is not yet known. […] Disease like amyloidosis that leads to the accumulation of amyloid protein in the adrenal glands may lead to Addisons disease. […] There may be secondary adrenal insufficiency as well caused by a lack of ACTH. ACTH stimulates the adrenal to secrete its hormones. Without ACTH to stimulate the adrenal glands the cortisol production level falls. Aldosterone production is not usually affected.

• #93 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  Patients with APS-1, which is a rare autosomal recessive disease caused by a mutation in the autoimmune regulator (AIRE) gene, will have at least two of three main components: PAI, hypoparathyroidism and chronic mucocutaneous candidiasis, and those with APS-2, a far more common condition than APS one and with polygenic inheritance, have at least two of the three endocrinopathies, namely, PAI, type 1 diabetes and autoimmune thyroiditis. […] In the early stages in SAI and TAI, basal ACTH secretion is maintained, while stress-induced ACTH secretion is affected. […] With time, basal ACTH secretion is also affected causing gradual atrophy of zonae fasciculata and reticularis of the adrenal cortex but aldosterone secretion by the zona glomerulosa remains intact.

• #94 Addison’s disease | Endocrine Conditions

  https://www.yourhormones.info/endocrine-conditions/addisons-disease/

  Addison’s disease is caused by the destruction of the cortex of each adrenal gland. This means that the adrenal gland cannot produce the hormones glucocorticoids (especially cortisol), mineralocorticoids (especially aldosterone) and sex steroids. People with Addison’s disease develop symptoms as a result of this loss of adrenal hormones. […] Primary adrenal insufficiency or primary Addison’s disease; autoimmunity is the most common cause of Addisons disease. This occurs when bodys immune system making a mistake and attacking and destroying the cells of the adrenal glands in error. This type of Addisons is called autoimmune Addisons. […] Rare causes of Addisons disease include removal of the adrenal glands by surgery, bleeding into the adrenal glands (for instance after abdominal injuries), and genetic defects such as adrenoleukodystrophy. The pituitary gland produces hormones that cause the adrenal gland to produce its hormones. If the pituitary gland stops working properly, this can cause 'secondary’ adrenal insufficiency – in other words, the adrenal glands stop working, not because they are diseased, but because the pituitary gland has stopped telling them to produce their hormones. In patients with secondary adrenal insufficiency, patients have a low cortisol, but a normal aldosterone.

• #95 Adrenal insufficiency | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/7/435

  Patients with APS-1, which is a rare autosomal recessive disease caused by a mutation in the autoimmune regulator (AIRE) gene, will have at least two of three main components: PAI, hypoparathyroidism and chronic mucocutaneous candidiasis, and those with APS-2, a far more common condition than APS one and with polygenic inheritance, have at least two of the three endocrinopathies, namely, PAI, type 1 diabetes and autoimmune thyroiditis. […] In the early stages in SAI and TAI, basal ACTH secretion is maintained, while stress-induced ACTH secretion is affected. […] With time, basal ACTH secretion is also affected causing gradual atrophy of zonae fasciculata and reticularis of the adrenal cortex but aldosterone secretion by the zona glomerulosa remains intact.

• #96 Addison Disease: Early Detection and Treatment Principles | AAFP

  https://www.aafp.org/pubs/afp/issues/2014/0401/p563.html

  Autoimmune adrenalitis can be divided into stages of progression. As the disease develops, individuals lose adrenocortical function over a period of years. In the first three stages, the human leukocyte antigen genes confer genetic risk; an unknown precipitating event initiates antiadrenal autoimmunity; and 21-hydroxylase antibodies are produced, which predict future disease. 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. In the fourth stage, overt adrenal insufficiency develops. One of the first metabolic abnormalities to occur is an increase in plasma renin level, followed by the sequential development of other abnormalities, including a decreased response to adrenocorticotropic hormone (ACTH) stimulation in the fifth stage. If symptoms of adrenal insufficiency are present but go undiagnosed, an addisonian crisis can occur.

• #97 Addison’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/addisons-disease/symptoms-causes/syc-20350293

  Stress on the body such as injury, infection or illness can trigger adrenal crisis. Typically, the adrenal glands make two or three times the usual amount of cortisol in response to physical stress. But with adrenal insufficiency, the adrenal glands don’t make enough cortisol to meet this need. And that can lead to adrenal crisis. […] 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.

• #98 Addison’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/addisons-disease/symptoms-causes/syc-20350293

  Stress on the body such as injury, infection or illness can trigger adrenal crisis. Typically, the adrenal glands make two or three times the usual amount of cortisol in response to physical stress. But with adrenal insufficiency, the adrenal glands don’t make enough cortisol to meet this need. And that can lead to adrenal crisis. […] 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.

• #99 Addison’s Disease: Causes, Risks & Treatment

  https://www.healthline.com/health/addisons-disease

  Addisons disease occurs when the adrenal cortex is damaged, and the adrenal glands dont produce enough of the steroid hormones cortisol and aldosterone. […] Primary adrenal insufficiency occurs when your adrenal glands are damaged so severely that they can no longer produce hormones. This type of Addisons disease is most often caused when your immune system attacks your adrenal glands. This is called an autoimmune disease. […] Tertiary adrenal insufficiency originates in the hypothalamus, a region of the brain near the pituitary gland. The hypothalamus normally sends corticotropin-releasing hormone (CRH) to the pituitary, stimulating it to produce ACTH. […] When the hypothalamus fails to produce sufficient CRH, the pituitary fails in turn to produce enough hormones to stimulate the adrenal glands. […] Addisonian crisis causes low blood pressure, high potassium in the blood, and low blood sugar levels.

• #100 Addison’s Disease: Causes, Risks & Treatment

  https://www.healthline.com/health/addisons-disease

  Addisons disease occurs when the adrenal cortex is damaged, and the adrenal glands dont produce enough of the steroid hormones cortisol and aldosterone. […] Primary adrenal insufficiency occurs when your adrenal glands are damaged so severely that they can no longer produce hormones. This type of Addisons disease is most often caused when your immune system attacks your adrenal glands. This is called an autoimmune disease. […] Tertiary adrenal insufficiency originates in the hypothalamus, a region of the brain near the pituitary gland. The hypothalamus normally sends corticotropin-releasing hormone (CRH) to the pituitary, stimulating it to produce ACTH. […] When the hypothalamus fails to produce sufficient CRH, the pituitary fails in turn to produce enough hormones to stimulate the adrenal glands. […] Addisonian crisis causes low blood pressure, high potassium in the blood, and low blood sugar levels.

• #101 Addison’s Disease: Causes, Risks & Treatment

  https://www.healthline.com/health/addisons-disease

  Addisons disease occurs when the adrenal cortex is damaged, and the adrenal glands dont produce enough of the steroid hormones cortisol and aldosterone. […] Primary adrenal insufficiency occurs when your adrenal glands are damaged so severely that they can no longer produce hormones. This type of Addisons disease is most often caused when your immune system attacks your adrenal glands. This is called an autoimmune disease. […] Tertiary adrenal insufficiency originates in the hypothalamus, a region of the brain near the pituitary gland. The hypothalamus normally sends corticotropin-releasing hormone (CRH) to the pituitary, stimulating it to produce ACTH. […] When the hypothalamus fails to produce sufficient CRH, the pituitary fails in turn to produce enough hormones to stimulate the adrenal glands. […] Addisonian crisis causes low blood pressure, high potassium in the blood, and low blood sugar levels.

• #102 Addison’s Disease: Causes, Risks & Treatment

  https://www.healthline.com/health/addisons-disease

  Addisons disease occurs when the adrenal cortex is damaged, and the adrenal glands dont produce enough of the steroid hormones cortisol and aldosterone. […] Primary adrenal insufficiency occurs when your adrenal glands are damaged so severely that they can no longer produce hormones. This type of Addisons disease is most often caused when your immune system attacks your adrenal glands. This is called an autoimmune disease. […] Tertiary adrenal insufficiency originates in the hypothalamus, a region of the brain near the pituitary gland. The hypothalamus normally sends corticotropin-releasing hormone (CRH) to the pituitary, stimulating it to produce ACTH. […] When the hypothalamus fails to produce sufficient CRH, the pituitary fails in turn to produce enough hormones to stimulate the adrenal glands. […] Addisonian crisis causes low blood pressure, high potassium in the blood, and low blood sugar levels.

• #103 Addison Disease: Practice Essentials, Epidemiology

  https://emedicine.medscape.com/article/1096911-overview

  Addison disease (or Addison’s disease) is adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal cortex. It affects glucocorticoid and mineralocorticoid function. The onset of disease usually occurs when 90% or more of both adrenal cortices are dysfunctional or destroyed. […] The diagnosis of adrenocortical insufficiency rests on the assessment of the functional capacity of the adrenal cortex to synthesize cortisol. This is accomplished primarily by use of the rapid adrenocorticotrophic hormone (ACTH) stimulation test (Cortrosyn, cosyntropin, or Synacthen). […] Corticosteroid drugs are used for replacement therapy in Addison disease and secondary adrenocortical insufficiency. […] In patients in acute adrenal crisis, intravenous (IV) access should be established urgently, and an infusion of isotonic sodium chloride solution should be begun to restore volume deficit and correct hypotension. Some patients may require glucose supplementation. The precipitating cause should be sought and corrected where possible. […] Husebye E, Lovas K. Pathogenesis of primary adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. 2009 Apr. 23(2):147-57.

• #104 Addison Disease: Practice Essentials, Epidemiology

  https://emedicine.medscape.com/article/1096911-overview

  Addison disease (or Addison’s disease) is adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal cortex. It affects glucocorticoid and mineralocorticoid function. The onset of disease usually occurs when 90% or more of both adrenal cortices are dysfunctional or destroyed. […] The diagnosis of adrenocortical insufficiency rests on the assessment of the functional capacity of the adrenal cortex to synthesize cortisol. This is accomplished primarily by use of the rapid adrenocorticotrophic hormone (ACTH) stimulation test (Cortrosyn, cosyntropin, or Synacthen). […] Corticosteroid drugs are used for replacement therapy in Addison disease and secondary adrenocortical insufficiency. […] In patients in acute adrenal crisis, intravenous (IV) access should be established urgently, and an infusion of isotonic sodium chloride solution should be begun to restore volume deficit and correct hypotension. Some patients may require glucose supplementation. The precipitating cause should be sought and corrected where possible. […] Husebye E, Lovas K. Pathogenesis of primary adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. 2009 Apr. 23(2):147-57.

• #105 Addison Disease: Practice Essentials, Epidemiology

  https://emedicine.medscape.com/article/1096911-overview

  Addison disease (or Addison’s disease) is adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal cortex. It affects glucocorticoid and mineralocorticoid function. The onset of disease usually occurs when 90% or more of both adrenal cortices are dysfunctional or destroyed. […] The diagnosis of adrenocortical insufficiency rests on the assessment of the functional capacity of the adrenal cortex to synthesize cortisol. This is accomplished primarily by use of the rapid adrenocorticotrophic hormone (ACTH) stimulation test (Cortrosyn, cosyntropin, or Synacthen). […] Corticosteroid drugs are used for replacement therapy in Addison disease and secondary adrenocortical insufficiency. […] In patients in acute adrenal crisis, intravenous (IV) access should be established urgently, and an infusion of isotonic sodium chloride solution should be begun to restore volume deficit and correct hypotension. Some patients may require glucose supplementation. The precipitating cause should be sought and corrected where possible. […] Husebye E, Lovas K. Pathogenesis of primary adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. 2009 Apr. 23(2):147-57.

• #106 Autoimmune Addison disease: pathophysiology and genetic complexity | Nature Reviews Endocrinology

  https://www.nature.com/articles/nrendo.2011.245

  Autoimmune Addison disease is a rare autoimmune disorder with symptoms that typically develop over months or years. Following the development of serum autoantibodies to the key steroidogenic enzyme, 21-hydroxylase, patients have a period of compensated or preclinical disease, characterized by elevations in adrenocortocotropic hormone and renin, before overt, symptomatic adrenal failure develops. […] We propose that local failure of steroidogenesis, causing breakdown of tolerance to adrenal antigens, might be a key factor in disease progression. The etiology of autoimmune Addison disease has a strong genetic component in man, and several dog breeds are also susceptible. […] An aberrant immune response directed, at least in part, at the steroidogenic enzymes of the adrenal cortex (in particular 21-hydroxylase) underlies most cases of AAD.

• #107

  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. […] Addison’s 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 will not be able to produce enough of the steroid hormones cortisol and aldosterone. Once levels of these start decreasing, you’ll experience symptoms of Addison’s disease. […] It’s not clear how these genes lead to Addison’s disease and similar conditions, but it does mean your risk of developing Addison’s disease is increased if you or a close family member have another autoimmune condition. […] TB is a bacterial infection that mostly affects the lungs but can also spread to other parts of your body. It can cause Addison’s disease if it damages your adrenal glands.

• #108 Pathogenesis of autoimmune Addison’s disease and polyendocrine syndromes – identifying pathologies and pathways for future treatment – Prosjektbanken

  https://prosjektbanken.forskningsradet.no/en/project/FORISS/335093?Kilde=FORISS&distribution=Ar&chart=bar&calcType=funding&Sprak=no&sortBy=date&sortOrder=desc&resultCount=30&offset=30&Geografi.1=Vestland&source=FORISS&projectId=167737

  To fill these knowledge gaps, we will elucidate the functional impacts of genetic variants associated with AAD (in particular AIRE-variants), and develop novel mouse models. […] The results will provide new insights beyond the state of the art into the fundamental questions on how AAD and organ-specific autoimmune diseases arise, deliver improved and personalized diagnostic and prognostic tests, and lay the foundations for targeted treatment and prevention of AAD and APS in the future.

• #109 Pathogenesis of autoimmune Addison’s disease and polyendocrine syndromes – identifying pathologies and pathways for future treatment – Prosjektbanken

  https://prosjektbanken.forskningsradet.no/en/project/FORISS/335093?Kilde=FORISS&distribution=Ar&chart=bar&calcType=funding&Sprak=no&sortBy=date&sortOrder=desc&resultCount=30&offset=30&Geografi.1=Vestland&source=FORISS&projectId=167737

  To fill these knowledge gaps, we will elucidate the functional impacts of genetic variants associated with AAD (in particular AIRE-variants), and develop novel mouse models. […] The results will provide new insights beyond the state of the art into the fundamental questions on how AAD and organ-specific autoimmune diseases arise, deliver improved and personalized diagnostic and prognostic tests, and lay the foundations for targeted treatment and prevention of AAD and APS in the future.

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