Autoimmune polyglandular syndromes


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Autoimmune polyglandular syndromes

  1. 1. APSDr.Yassin M Al-saleh Dr.Mohammad Algufiliy
  2. 2. ‫الرحيم‬ ‫الرحمن‬ ‫هللا‬ ‫بسم‬ (‫إال‬ ‫العلم‬ ‫من‬ ‫أوتيتم‬ ‫وما‬ ‫قليال‬)
  3. 3. OBJIECTIVES • Case. • Introduction. • Classification. • APS-1 • Pathogenesis. • Presentation. • Management. • APS-2. • Other APS.
  4. 4. Case • rafal is 3 year old girl referred from MCH- Qasseem with hypoparathyrodisim. • Where she presented with generalized convulsion . • found to have low ca 1.1 ,high phosporus 3.7 ,low PTH 0.27 • Also patient having malabsorption in regular follow up with GIT clinic . • Family history: consangious marriage. • father have DM and hemihypertorphy. • One cousin with APS-1.
  5. 5. case • On exam: • Wt:5th. Ht: 5th. Poor dentation,Hemihypertrophy. • Screeing done for her: • LFT:WNL . • U/E:WNL. • HbA1c:WNL. • ACTH,cortisol:WNL • TFT:WNL • Islet cell, throid,adrenal antibodies :negative. • AIRE gene mutation :positive.
  6. 6. synonyms • autoimmune polyendorine syndromes (APS). • autoimmune polyglandular syndromes (APS). • polyglandular autoimmune syndromes (PAS)/ (PGAS). • autoimmune polyendocrinopathy. • polyglandular failure syndromes.
  7. 7. introduction • Definition: • are a heterogeneous group of uncommon diseases characterized by autoimmune activity against more than one organ (endocrine OR non-endocrine). • The autoimmune polyglandular syndromes result from a loss of tolerance to self-antigens. Maurizio Cutolo. Autoimmune polyendocrine syndromes. Autoimmunity Reviews 13 (2014) 85–89
  8. 8. classification
  9. 9. Autoimmune polyendocrine syndrome type 1 (APS-1) • This condition is also termed as APECED autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. • Also called Whitaker's syndrome • Due to a monogenetic mutation • Males and females are equally affected Dtsch Med Wochenschr. 2013 Feb;138(7):319-26; quiz 327-8. doi: 10.1055/s- 0032-1327355. Epub 2013 Feb 7.[Autoimmune polyglandular syndromes]. introduction
  10. 10. epidemiology • the disease is not common • an incidence of 1:100 000 . • The highest prevalence have been found in certain populations with high degree of consanguinity . • in Iranian Jews (1:9,000) • in Finland (1:14,000) • in Sardinia (1:25,000) • In Norway (1:80,000) George J Kahaly. Polyglandular autoimmune syndromes. European Journal of Endocrinology (2009) 161 11–20 Autoimmune polyendocrine syndrome type 1 (APS-1)
  11. 11. pathogenesis • an autosomal recessive disease. • linked to mutation of the AIRE gene (Autoimmune Regulator gene) on chromosome 21q22.3. Autoimmune polyendocrine syndrome type 1 (APS-1) MichelsAW: Autoimmune polyglandular syndromes.nat rev endocrinology. 2010 May;6(5):270-7. doi: 10.1038/nrendo.2010.40. Epub 2010 Mar 23.
  12. 12. pathogenesis • AIRE gene is expressed mainly in the thymus. • Expressed in medullary thymic epithelial cells (mTECS) . • But also in lymph nodes, liver, pancreas, adrenal cortex, and testes. Autoimmune polyendocrine syndrome type 1 (APS-1)
  13. 13. pathogenesis • More than 70 different mutations in the AIRE gene have now been reported. • mutations can be confirmed in more than 95% of patients with clinical diagnoses of APS I Autoimmune polyendocrine syndrome type 1 (APS-1)
  14. 14. Pathogenesis North American, British, and Norwegian Iranian Jews Sardinian Finland Autoimmune polyendocrine syndrome type 1 (APS-1)
  15. 15. pathogenesis • several hypotheses have been put forward to explain how an individual can lose its tolerance against self antigens. • the release of sequestered antigens. • environment-induced alterations of host membrane proteins. • crossreactivity between environmental agents and host antigens. • A defect in the cells regulating the immune response Corrado Betterle, Renato Zanchetta: Update on autoimmune polyendocrine syndromes (APS) .ACTA BIO MEDICA 2003; 74; 9-33 Autoimmune polyendocrine syndrome type 1 (APS-1)
  16. 16. pathogenesis • Also hypothesis is that organs deriving from a same germ layer can express common germ-layer specific antigens that could serve as targets for the autoimmune responses in APS • it has been suggested that an APS may be due to external agents sharing one or more epitopes with a common antigen in several endocrine tissues Autoimmune polyendocrine syndrome type 1 (APS-1)
  17. 17. pathogenesis • It has been hypothesized that mutations of the AIRE gene cause loss of peripheral antigen expression in the thymus and probably decreased deletion of autoreactive T lymphocytes that target such peripheral antigens. Autoimmune polyendocrine syndrome type 1 (APS-1) De martinilo :APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors. Front immunology. 2013 Oct 23;4:331. eCollection 2013.
  18. 18. pathogenesis • AIRE gene function : expression of tissue specific antigen (self-antigin) to thymocytes • which lead to self tolerance by elimination of the autoreactive T cells. Autoimmune polyendocrine syndrome type 1 (APS-1)
  19. 19. T T-cell precursor or developing T-cell A Auto reactive, self-reactive, pathological T-cell (CD4+ or CD8+) Rn Ri Natural regulatory T-cell or suppressor induced regulatory T-cell or suppressor mTEC Medullary thymic epithelial cell APC Antigen presenting cell Antigen CD 4 H CD4+ helper cell (CD4+,CD25+, FOXP3)R
  20. 20. THYMUS CENTRAL TOLERANCE T T-cell precursor negative Selection (apoptosis) T mTEC + AIRE A A APC + AIREA anergy Ignorance Ri Ri A A A A A A PERIPHERY Rn Rn Rn positive selection A Rn Rn Rn Rn Rn Rn CD 4 H CD4+ and CD8+ TCD4+ or CD8+ TEC
  21. 21. Diagnosis of APS-1 • Clinical diagnosis requires the presence of two from three major criteria (Whitaker’s triad) : • 1-mucocutaneous candidiasis. • 2-Hypoparathyroidism. • 3- Adrenocortical insufficiency (or autoantibodies against 21 hydroxylase) • or If a sibling has the syndrome only one major is required • diagnosis could be made by molecular genetics in presence of minors. Proust- lemoine E. Polyglandular autoimmune syndrome type I. Presse Med .2012 Dec;41(12 P 2):e651-62. doi: 10.1016/j.lpm.2012.10.005. Epub 2012 Nov 23. Autoimmune polyendocrine syndrome type 1 (APS-1)
  22. 22. • Different genotype lead to different phenotypes. • Different genotype can lead to same phenotype. (overlaping) • One genotype can lead to different phenotypes presentation Autoimmune polyendocrine syndrome type 1 (APS-1)
  23. 23. presentation • Patients begin with CMC, followed by hypoparathyrodism and finally by addison. • It has been observed that the earlier was the first clinical presentation, greater will be the number of diseases that will develop during the life of a patient with APS-1 Sarinda Millar, Dennis Carson. Clinical phenotypes of autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy seen in the Northern Ireland paediatric population over the last 30 years. Ulster Med J 2012;81(3):118-122 Autoimmune polyendocrine syndrome type 1 (APS-1)
  24. 24. Chronic mucocutaneous candidiasis CMC • is often the first condition detected . • The onset is usually before 5 years of age . • the first sign of APS I in 60% patients. • by 40 years of age 100% of patient with APS will developed candidiasis . Autoimmune polyendocrine syndrome type 1 (APS-1)
  25. 25. CMC • the etiology :due to a selective immunological deficiency of T cells towards Candida albicans. • Humoral immunity B-cell function normal. • Anticytokines autoantibodies against the Th17- related cytokines (IL-22,IL-17A and IL-17F) were implicated . Sarinda Millar, Dennis Carson. Clinical phenotypes of autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy seen in the Northern Ireland paediatric population over the last 30 years. Ulster Med J 2012;81(3):118-122 Autoimmune polyendocrine syndrome type 1 (APS-1)
  26. 26. • Presentation: • Oral candidiasis (thrush) • Diaper rash. • vulvovaginal candidiasis at puberty in females. • Nail infection :leading to a darkened discoloration, thickening, or erosion. • intestinal mucosal candidiasis :lead to intermittent abdominal pain and diarrhea. Chronic mucocutaneous candidiasis CMC Autoimmune polyendocrine syndrome type 1 (APS-1)
  27. 27. Chronic mucocutaneous candidiasis CMC • Retrosternal pain occurring in patients with confirmed oral candidiasis suggests esophageal candidiasis which may lead to stricture and dysphagia. • epithelial carcinoma of the oral mucosa, tongue or esophagus with its high mortality is well described in APS I patients with chronic mucosal candidiasis. Autoimmune polyendocrine syndrome type 1 (APS-1)
  28. 28. Chronic hypoparathyroidism • usually presents before puberty. • Pathology: • an atrophy and infiltration of the parathyroid glands with mononuclear cells. • clinically patient may present with paresthesias, hypereccitability, hypotension, carbopedal spasim , laryngospasm and generalized seizures. • These symptoms may, however, be masked in the presence of adrenal insufficiency. • Papilledema and calcification of the basal ganglia are other signs of chronic hypocalcaemia. Autoimmune polyendocrine syndrome type 1 (APS-1)
  29. 29. Chronic hypoparathyroidism • hypocalcemia ,Hyperphosphatemia with a low parathyroid hormone(PTH) level is diagnostic. • Recently, in patients with APS-1 and hypoparathyrodisim, autoantibodies against calcium- sensing receptors and other autoantibodies have been reported • Antibodies aginest NALP5 have been found in 49% of patient with APS-1. Autoimmune polyendocrine syndrome type 1 (APS-1)
  30. 30. Addison disease • is found in more than 85% of APS I • adrenocortical failure usually has its peak onset before adolescence. • Pathology: • showed atrophy of the glands and lymphocyte infiltration • Deficiencies of cortisol, aldosterone, and adrenal andogens may present simultaneously or may evolve over months to several years. Autoimmune polyendocrine syndrome type 1 (APS-1)
  31. 31. Addison disease • Clinical Presentation • The initial clinical features are often non specific • These include fatigue, weight loss, myalgias, arthralgias, behavioral changes, nausea and vomiting, abdominal pain, weight loss and diarrhea. • Hyperpigmentation and postural hypotension • Adrenal crises with hyponatremia, hyperkalemia, and hypoglycemia . Autoimmune polyendocrine syndrome type 1 (APS-1)
  32. 32. Other associated diseases (Minor) Mohammed Al-Owain :Renal Failure Associated with APECED and Terminal 4q Deletion:Evidence of Autoimmune Nephropathy Case Report. Clinical and Developmental Immunology Volume 2010, Article ID 586342, 7 pages watanbe M .Myopathy in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Uscle nerve. 2012 Jun;45(6):904-8. hyposplenism or asplenia.Gonadal failure. policlonal hypergammaglobulinemiaautoimmune thyroiditis. IgA deficiency.autoimmune hepatitis. Vasculitis.type 1 diabetes. sublenticular cataract.Cholelithiasis. calcification of basal ganglia.Atrophic gastritis. tympanic membranes calcification.Malabsorption. rheumatoid arthritisDental enamel hypoplasia. pure red cell aplasia.Vitiligo. Cerebellar Degeneration.Alopecia. KeratoconjunctivitisPericarditis. Sjögren’s syndrome.Pernicious anemia. Polyneuropathy.pulmonary disease. Myopathy*IDA Autoimmune Nephropathy*Encephalopathy. (APS-1)
  33. 33. gonadal failure (Hypergonadotropic hypogonadism) • more common in females. • 50% of women with APS I develop ovarian failure by 20 years of age. • In most cases presents usually as secondary amenorrhoea although in some cases as primary Amenorrhoea • Also menstrual irregularities, polycystic ovaries, or infertility • Less than 30% of men with APS I develop testicular failure. • In 60-80% of patients with APS-1, steroid-producing cell antibodies (StCA) have been detected . Autoimmune polyendocrine syndrome type 1 (APS-1)
  34. 34. Autoimmune thyroid diseases • Autoimmune thyroid diseases (ATD) occur in 4- 36% of cases . • between 9-32 years of age and usually as chronic thyroiditis • Anti-microsomial (anti-peroxidase) and/or anti- thyroglobulin antibodies are detected in most patients with autoimmune thyroid diseases Autoimmune polyendocrine syndrome type 1 (APS-1)
  35. 35. Autoimmune hepatitis • Autoimmune Hepatitis occurs in 10% to 31% of APS I. • Subclinical to fulminant hepatic failure. • the leading cause of death in these patients. • all patients suspected of having APS I should have their liver function regularly monitored. • Autoimmune hepatitis in APS-1 correlates with positive antibodies against liver and kidney microsomes (anti- LKM) • Anti-LKM antibodies are present even in 25% without alterations in their liver function tests. Autoimmune polyendocrine syndrome type 1 (APS-1) Bialkosowska J: Hepatitis and the polyglandular autoimmune syndrome, type 1. Aech med sci . 2011 Jun;7(3):536-9. doi: 10.5114/aoms.2011.23427. Epub 2011 Jul 11.
  36. 36. malapsorption • Many ossotiated condition implicated including: • Coeliac disease ,cystic fibrosis, pancreatic insufficiency ,intestinal infections from Candida Albicans, intestinal lymphangectasia , idiopathic cholecystokinin deficiency • In some patients cause unknown “idiopathic malabsorption” • in 48% of patients with APS-1 the tryptophan hydroxylase autoantibodies were detected. • TPH-Abs are absent in patients with gastrointestinaldisorders but unaffected by APS-1 Autoimmune polyendocrine syndrome type 1 (APS-1)
  37. 37. Management Autoimmune polyendocrine syndrome type 1 (APS-1) Specific organ autoantibody screening assessment of endocrine function Genetic study + general antibodies
  38. 38. screening • In hypothyroid patients with confirmed APS, evidence for adrenal autoimmunity must also be sought before starting thyroid hormone replacement therapy • Usually, sudden hypercalcemia in hypoparathyroid individuals may signal the beginning of adrenal insufficiency Autoimmune polyendocrine syndrome type 1 (APS-1)
  39. 39. screening • Any patients with APS-1 should be seen and screen for autoantibodies at 6-month intervals. Autoimmune polyendocrine syndrome type 1 (APS-1)
  40. 40. Meloni A, Furcas Met al. Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 2008;93:4389–97 • Studies showed that upto 100% of patients with APS-1 have been found to express autoantibodies reacting with interferon-omega . • also the great majority express autoantibodies reacting with interferon alpha. • their role in pathogenesis still controversy. PathogenesisAutoimmune polyendocrine syndrome type 1 (APS-1) (Anti-IFN-ω and Anti-IFN-α)
  41. 41. jaaskelainen j ,Perheentupa Autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED)--a diagnostic and therapeutic challenge. endocrinology review 2009 Dec;7(2):15-28. • search for autoantibodies against interferon-omega, enables proof or exclusion of APECED with more certainty than gene analysis. • It is highly specific and sensitive for APECED if thymoma and myasthenia gravis are excluded • Its present early in course of the disease and persist for years Autoimmune polyendocrine syndrome type 1 (APS-1)
  42. 42. screening • Any patient with suspected APS should be screened with a panel of autoantibodies : • type I interferons autoantibodies (α and ω) • adrenal cortex cytoplasmic autoantibodies. • 21 hydroxylase autoantibodies. • GADA, IA-2A, IAA,ZnT8 andICA • thyroid microsomal/thyroperoxidase autoantibodies. • thyroglobulin autoantibodies. • steroidal cell autoantibodies. • P450 1A2 and AADC autoantibodies • Anti-LKM antibodies. • endomysial or transglutaminase autoantibodies. • Internisic factor. • H+ K+ ATPase autoantibodies. • Parital cell autoantibodies. • Autoantibodies against tyrosine hydroxylase • Complement-fixing melanocyte antibodies
  43. 43. Assessment of end-organ function • Assessment of end-organ function in any patient with autoantibodies is recommended annually. Investigation early morning cortisol levels electrolyte :sodium, potassium renins Fasting blood glucose testing calcium, phosphate, and PTH TSH level,FT4 Investigation FSH and LH levels Testesteron , estradiol hemoglobin and hematocrit mean corpuscular volume vitamin B12 level Liver function tests Autoimmune polyendocrine syndrome type 1 (APS-1)
  44. 44. Treatment of APS-1 • will depend upon the autoimmune disorder identified . • Candidiasis: antifungal. • aggressive therapy of oral is indicated in order to prevent the late complication of epithelial carcinoma. • Fluconazole is preferred over ketconazole. • Hypoparathyrodisim: calcium and one alph. • Addision : hydrocortison or prednisolone + fludrocortisone. • Type 1 DM: insulin. Autoimmune polyendocrine syndrome type 1 (APS-1)
  45. 45. • Hypothyrodisim: levothyroxine. • Hypergonadotropic hypogonadism: testosterone in male, estrogen and progestrone in female. • asplenia :vaccinations and prophylactic antibiotic. • Autoimmune hepatitis : immunosuppresent. • Keratoconjunctivitis : immunosuppresent. • Malabsorption : immunosuppresent. • pure red cell aplasia : immunosuppresent. Treatment of APS-1 Autoimmune polyendocrine syndrome type 1 (APS-1)
  46. 46. • APS-2 is the most common autoimmune polyendocrine syndrome. • incidence of 1:20 000 • more common in females than in males. • onset in adulthood. • particularly during the third or fourth decades. Dtsch Med Wochenschr. 2013 Feb;138(7):319-26; quiz 327-8. doi: 10.1055/s-0032-1327355. Epub 2013 Feb 7.[Autoimmune polyglandular syndromes]. Autoimmune polyendocrine syndrome type 2 (APS-2)
  47. 47. pathogenesis of APS II • the precise aetiology is unknown. • cases occur sporadically or within families. • inheritance of PAS II is complex. • Within some families, it appears to be inherited as an autosomal dominant. • genes on chromosome 6 playing a predominant role. this chromosome contains the major histocompatibility loci. George J Kahaly. Polyglandular autoimmune syndromes. European Journal of Endocrinology (2009) 161 11–20 Autoimmune polyendocrine syndrome type 2 (APS-2)
  48. 48. pathogenesis • patients with APS II have HLA associations similar to those of patients with type 1 diabetes.. • The primary association of APS-2, appears to be with class II HLA alleles with DR3/DQ2 and DR4/DQ8 • Primary adrenal insufficiency in type 2, but not in type 1 APS, is strongly associated with both HLADR3 and HLA-DR4 Autoimmune polyendocrine syndrome type 2 (APS-2)
  49. 49. Diagnosis of APS II • is defined by the coexistence of : • Autoimmune adrenocortical insufficiency or serologic evidence of adrenalitis with one or more of the following : • 1- autoimmune thyroiditis or serologic evidence of thyroid autoimmunity. • 2- type 1 diabetes mellitus or islet autoimmunity. • (Schmidt syndrome) : adrenocortical insufficiency + autoimmune thyroiditis • (Carpenter syndrome) Schmidt syndrome + type 1 diabetes Autoimmune polyendocrine syndrome type 2 (APS-2)
  50. 50. Presentation • Adrenocortical failure is the intial presentation in approximately 50% of APS II cases. • autoimmune thyroid disease (AITD) coexists in 80– 90% of females with Addison disease. • Type 1 diabetes coexists in nearly 50% of patients with Addison disease. Autoimmune polyendocrine syndrome type 2 (APS-2) Ali Y: Polyglandular autoimmune syndrome type 2: diagnosed in the intensive care unit. Ther Adv Endocrinol Metab. 2013 Dec;4(6):170-2. doi: 10.1177/2042018813515698.
  51. 51. • Vitiligo. • autoimmune lymphocytic gastritis. • Alopecia. • Gonadal failure. • Hypophysitis. • empty sella syndrome. • ulcerative colitis. • primary biliary cirrhosis. • Sarcoidosis. • Achalasia. • neuropathy. • Thrombocytopenic purpura • IgA deficiency. • juvenile dermatomyositis • dermatitis herpetiformis, • scleroderma, Other associated diseases Autoimmune polyendocrine syndrome type 2 (APS-2)
  52. 52. Other APS • IPEX. • Thymic tumor disease. • POEMS syndrome. • Hirata syndrome. • Adult combined pitutary hormone deficincy(CPHD). • Kearn-sayre syndrome. • DIDMOAD syndrome.
  53. 53. IPEX • IPEX (immune dysfunction, polyendocrinopathy, and enteropathy, X-linked). • also called XLAAD (X-linked autoimmunity and allergic dysregulation) • fatal autoimmune lymphoproliferative disease. • rare X-linked recessive. • Due to the absence of normal FoxP3 expression • Neonatal onset type 1 diabetes,dermatitis, enteropathy, thyroiditis, hemolytic anemia, and thrombocytopenia. • long-term immunosuppression or bone marrow transplantation appears to be the only effective therapy for IPEX.
  54. 54. ‫رب‬ ‫يا‬ ‫األطفال‬ ‫ضحكة‬ ‫وصن‬‫انها‬ ‫إذا‬‫غردت‬ ‫ما‬‫الرمل‬ ‫موحش‬ ‫في‬‫اعشبا‬