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Buccal: 30 mg twice daily (every 12 hours) applied to the gum region above
the incisor tooth.
IM (testosterone enanthate or testosterone cypionate):
Initial: 75 to 100 mg/week or 150 to 200 mg every 2 weeks; dosage range: 50
to 100 mg/week or 100 to 200 mg every 2 weeks (AUA [Mulhall 2018];
Endocrine Society [Bhasin 2018]).
IM (testosterone undecanoate): Initial: 750 mg, followed by 750 mg
administered 4 weeks later, then 750 mg administered every 10 weeks
thereafter.
Management cont’d
Source: UpToDate](https://image.slidesharecdn.com/autoimmunepolyendocrinesyndromes-210310063800/75/Autoimmune-polyendocrine-syndromes-39-2048.jpg)
Uploaded byTarun Prudvi Betha
Autoimmune polyendocrine syndromes
This document discusses autoimmune polyglandular syndromes (APS), including three main types: APS1, APS2, and IPEX. APS1 is caused by mutations in the AIRE gene and involves candidiasis, hypoparathyroidism, and Addison's disease. APS2 has a polygenic basis and commonly involves type 1 diabetes, hypothyroidism, and Addison's disease. IPEX is X-linked and involves early onset type 1 diabetes, dermatitis, and life-threatening diarrhea. Management involves hormone replacement, immunosuppression, vaccination, and patient education on screening and managing adrenal insufficiency.
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Autoimmune polyendocrine syndromes
- 1. Autoimmune polyglandular syndromes. Types, pathogenesis,diagnosis, management Dr. Tarun P Betha 2nd year internal medicine resident Poona hospital and research centre 1
- 2. Outline • Introduction • Types •APS1 • APS2 • IPEX 2
- 3. Introduction Autoimmune polyendocrine syndromesare insidious and are characterised by circulating autoantibodies and lymphocytic infiltration of the endocrine tissues and organs, eventually leading to organ failure. 3 Source: Cecil textbook of medicine
- 4. Types • Autoimmune polyglandularsyndrome type 1 • Autoimmune polyglandular syndrome type 2 • IPEX* 4 *immunedysregulation, polyendocrinopathy, enteropathy, x linked
- 5. Autoimmune polyglandular syndrome type1 • Also called polyendocrinopathy-candidiasis- Ectodermal dystrophy. (APECED) • Autosomal recessive. • Mutation in AIRE gene. • Highest prevalence in Finnish countries. 5
- 6. APS1 cont’d Cardinal components Hypoparathyroidism Addisson’sdisease Chronic mucocutaneous candidasis 6
- 7. • Enamel hypoplasia •Premature ovarian failure (60% in females) • Testicular failure (rare) • Bilateral keratitis • Autoimmune hepatitis • Nephritis, pancreatitis, asplenia. 7 APS1 cont’d Other features
- 8. • Chronic mucocutaneouscandidiasis- squamous cell Ca (common cause of death) • Other causes of death include- Hypocalcemic crisis, adrenal crisis. 8 APS1 cont’d
- 9. 9 APS1 cont’d Genetics andmechanisms ‘AIRE’ gene mTEC medullary thymic epithelial cells Source: NEJM
- 10. • Mutations inAIRE gene. • Absence of regulatory T cells. • Auto reactive T cells escape removal • These cells then act on the auto antigens which leads to disease in various organs. 10 APS1 cont’d
- 11. 11 APS1 cont’d Mutations • Finnishmajor mutation (p.R257X). • 13 base pair deletion in histone proteins. Autoantibodies NALP5 GAD65 21 hydroxylase Type 1 Interferon Source: NEJM
- 12. 12 Autoimmune polyglandular syndrome type2 • More common • Women predominate. • Onset - young adult hood. • Diagnosis - clinical features and autoantibodies identification.
- 13. • Celiac disease •Alopecia • Vitiligo • Primary ovarian insufficiency • Pernicious anemia. 13 APS2 cont’d Cardinal components Type 1 diabetes Mellitus Hypothyroidism Addison’s disease Other features
- 14. • Polygenic- MHCetc • DR3-DQ2, DR4-DQ8 • Antibodies against TPO, GAD65, 21 hydroxylase are seen. 14 APS2 cont’d Genetics and mechanisms
- 15.
- 16. IPEX • X linked •Polyendocrinopathy • Enteropathy • Early onset type 1 diabetes Mellitus. • Classically presents in infancy. 16
- 17.
- 18. 18 Cardinal components Life threateningchronic diarrhoea Autoimmune endocrinopathy (type 1 DM or thyroiditis) Dermatitis IPEX cont’d Other features Immune related cytopenia. Nephritis Hyper reactivation of immune system to infections Allergic airway disease. Source: NEJM
- 19. 19 Mutations FOXP3 gene mutations IPEXcont’d Other manifestations Gastrointestinal Endocrinopathies (diabetes m/c, thyroiditis, hypoadrenalism, growth hormone deficiency) Haematological disorders (haemolytic anemia’s, thrombocytopenia, neutropenia) Sepsis (enterococcal, staphylococcal, cytomegalovirus, Candida)
- 20.
- 21.
- 22. Management Outline • General management •Hormone replacement • Patient education 24
- 23. Mucocutaneous candidiasis 25 General management Antifungals Topicalantifungals (clotrimazole oral paste) Oral antifungals (fluconazole, ketoconazole) Fluconazole: Oral: Loading dose of 200 mg on day 1, then 100 to 200 mg once daily for 7 to 14 days; recommended for patients unresponsive to topical therapy or those with moderate to severe infection Source: medscape
- 24.
- 25. 27 Type 1 DiabetesMellitus HbA1c targets in most adults is 7% and 7.5% in children and adolescents (ADA). Target glucose range is 70- 180mg/dL Insulin replacement goal- intensive regimen. Meal time bonuses of rapid acting insulin. Management cont’d
- 26.
- 27. • Modified intensiveregimen: offers benefit of fewer injections during school hours and flexibility around meals while at home. • This includes NPH + rapid acting insulin at breakfast. Insulin glargine or detemir with dose of rapid acting insulin at dinner. • This regimen avoids need of lunch time dose of insulin. 29 Management cont’d
- 28. • Intensive insulinregimen: closely approaches physiologic insulin secretion. • Basal insulin + with premeal and presnack boluses of rapid acting insulin. • Intensive insulin regimen showed better results in adults.* *In adults DCCT (diabetes control and complication trial) demonstrated intensive insulin therapy achieved better glycemic control and reduced long term sequelae. 30 Management cont’d Source: UpToDate
- 29. Investigational therapies fortype 1 diabetes Mellitus in children. Diabetes prevention- trials of vaccine against GAD, Rituximab, teplizumab. Artificial pancreas. Adjunctive therapies- pramlintide- most promising. Transplantation- limited to adults. 31 Management cont’d
- 30. Thyroiditis Hyperthyroid phase- symptomatictreatment. propranolol 40-120 mg daily atenolol 25 to 50 daily Thyroid function should be monitored every 4 to 8 weeks. Glucocorticoids can be used in severe cases. 32 Management cont’d
- 31. Hypothyroid phase- Treat whenTSH exceeds 10mU/L, even in absence of symptoms. Usual dose of T4 is 50 to 100 mcg daily. Thyroid levels are monitored every 4 to 6 weeks. 33 Management cont’d
- 32. Autoimmune enteropathy (IPEX) 34 Managementcont’d Acute management Correcting electrolyte derangement and hydration Treating infections Isolation to prevent nosocomial infections Immunesuppression Source: UpToDate
- 33. 35 Management cont’d Long termmanagement Intensive immune suppression (high dose prednisolone) Steroid sparing agents- tacrolimus, cyclosporine, sirolimus. Nutrition- extensively formalised feeds to reduce exposure to allergens. Replacing vitamins and minerals. Avoidance of vaccination- these can trigger fatal flares (IPEX) Hematopoetic stem cell transplantation Source: UpToDate
- 34. Pernicious anemia Replacement withcyanocobalamin is the goal of therapy. 1 mg IM once a day for 7 days, and then weekly for 1-2 months or until the hemoglobin is normalized. Long- term therapy is 1 mg/mo. Correction of hypokalemia. 36 Management cont’d Source: medscape
- 35. • Thyroid hormonereplacement. • premature ovarian failure OCP till the age of 50 to 51 years to all women with POI to manage estrogen deficiency symptoms, prevent long term risks. 37 Management cont’d Hormone replacement
- 36. • Estrogen-progesterone hormonetherapy- transdermal estradiol (100mcg daily) or estradiol vaginal ring (100 mcg daily). • Young women - low doses. 38 Management cont’d Source: UpToDate
- 37. • Progestin- firstline progestin is micronised progesterone 200 mg per day for first 12 days of month. • MPA (10 mg daily for 12 days per calendar month). • Exogenous gonadotropin is ineffective. • IVF with donor oocytes. 39 Management cont’d Source: UpToDate
- 38. 40 Oral capsule: Testosteroneundecanoate: Initial: 237 mg twice daily. Dosage range: 158 to 396 mg twice daily. Pellet (for subcutaneous implantation): 150 to 450 mg every 3 to 6 months. SubQ (testosterone enanthate): Initial: 75 mg once weekly. Dosage range: 50 to 100 mg once weekly. Testosterone replacement Source: UpToDate
- 39. 41 Buccal: 30 mgtwice daily (every 12 hours) applied to the gum region above the incisor tooth. IM (testosterone enanthate or testosterone cypionate): Initial: 75 to 100 mg/week or 150 to 200 mg every 2 weeks; dosage range: 50 to 100 mg/week or 100 to 200 mg every 2 weeks (AUA [Mulhall 2018]; Endocrine Society [Bhasin 2018]). IM (testosterone undecanoate): Initial: 750 mg, followed by 750 mg administered 4 weeks later, then 750 mg administered every 10 weeks thereafter. Management cont’d Source: UpToDate
- 40. Replace steroids: ~15–25mghydrocortisone daily, 2 –3 doses, eg: 10mg on waking, 5mg lunchtime. Avoid giving late (may cause insomnia). Mineralocorticoids to correct postural hypotension, Na+, K+: fludrocortisone PO from 50–200mcg daily. 42 Adrenal insufficiency Management cont’d
- 41.
- 42. Asplenia vaccination andantibiotic prophylaxis Recommended vaccines • 13-valent pneumococcal conjugate vaccine (PCV13) • 23-valent pneumococcal polysaccharide vaccine (PPSV23) • H. influenzae type b vaccine (Hib) • Quadrivalent meningococcal conjugate ACWY vaccine series (MenACWY) • Monovalent meningococcal serogroup B vaccine series (MenB-4C or MenB-FHbp) 44 Management cont’d
- 43.
- 44. Immunocompromising conditions (eg,hematologic malignancy, hypogammaglobulinemia, solid organ transplantation, advanced liver disease, or HIV infection) 46 antibiotic prophylaxis Management cont’d Daily antibiotic prophylaxis until age 5 and for at least one year. Immunocompromised - at least 18 yrs or until immunocompromised status or lifelong. history of sepsis or other severe infections caused by encapsulated organisms (eg, S. pneumoniae), - lifelong prophylaxis. adults- daily antibiotic prophylaxis for at least one year. Source: UpToDate
- 45. 47 antibiotic prophylaxis -cont’d Management cont’d Source: UpToDate
- 46. Outpatient management shouldinclude patient education on the various components of polyglandular autoimmune (PGA) syndrome, and the need to screen close relatives as appropriate. An important aspect of patient education is the provision of information about adrenal deficiency; subtle deficiency that goes unnoticed in normal, daily-life situations may become life- threatening in stressful situations. 48 Patient education
- 47. Because multiple componentsof the syndrome can appear asynchronously, periodic evaluation for the early appearance of additional disease components is indicated. 49 Source: Oxford handbook of clinical medicine.
- 48.
Editor's Notes
- #2 clinical conditions characterized by functional impairment of multiple endocrine glands due to loss of immune tolerance. These syndromes also frequently include conditions such as alopecia, vitiligo, celiac disease, and autoimmune gastritis with vitaminB12 deficiency that affect nonendocrine organs. syndromes can occur in patients from early infancy to old age, and new components of a given syndrome can appear throughout life.
- #7 Primary adrenal insufficiency is a characteristic of both APS-1 and APS-2; type 1 diabetes is a characteristic of APS-1, APS-2, and IPEX; and enteropathy is a characteristic of APS-1 and IPEX.
- #10 Chr 21. normal central immune tolerance, the autoimmune regulator (Aire) that is expressed in medullary thymic epithelial cells (mTEC) promotes expression of tissue-specific antigens, which are displayed on the surface. Autoreactive T cells with affinity for self-proteins either die by apoptosis or be- come forkhead box P3 (FoxP3)–expressing regulatory T cells (Tregs). When Aire is lacking (Panel A, bottom), the tissue-specific antigens are not displayed on the mTEC surface and autoreactive T cells escape to the general circulation and peripheral lymphoid organs, where they can cause autoimmune reactions and APS-1.
- #12 NALP5 (NACHT, leucine-rich re- peat, pyrin domain–containing protein 5, an auto- antibody expressed in the parathyroid and to some extent in the ovaries, which is also known as NLRP5 [NOD-like receptor family, pyrin domain– containing protein 5) Autoantibodies to type 1 interferons, namely interferon-ω and interferon-α, are the most prevalent type of autoantibody in APS-1 and are present in almost all patients
- #16 Patients with a clinical diagnosis of APS-1 should have AIRE sequenced for mutations.
- #25 In general, management of autoimmune polyendocrine syndromes includes hormone-replacement therapy as needed and treatment of complications.
- #29 Glucose monitoring- at least 4 times a day with finger sticks (fasting, before meals, bedtime) Continuous glucose monitors- continuously measures interstitial fluid glucose levels and approved for use in children. Conventional dosing- intermediate acting insulin twice daily and rapid or short acting insulin twice or thrice daily.
- #31 Dose- 0.5 to 1 units/kg. Basal insulin requirement in children 40-50% of total daily. Roughly 1 unit of insulin required to cover 20 gram of carb in most young children, 10 grams of carb in adolescents.
- #37 Symptomatic hypokalemia may occur within 48 hours of initiating therapy, and supplemental potassium may be needed. With therapy, the reticulocytosis should rise and peak in 1 week, followed by a rising hemoglobin level in the next 6-8 weeks.
- #39 Girls or young women in whom secondary sexual characteristics have failed should be given low doses to mimic gradual puberty maturation.
- #43 Treatment is influenced by the question of whether or not the patient is in crisis with hypotension and consequently requires IV fluids and IV steroids. In chronic and stable patients oral steroids can be used with or without fludrocortisone. Advise wearing a bracelet declaring steroid use. Add 5–10mg hydrocortisone to daily intake before strenuous activity/exercise. Double steroids in febrile illness, injury, or stress. Give out syringes and in-date IM hydrocortis one, and show how to inject 100mg IM if vomiting prevents oral intake
- #44 Adrenal insufficiency can be masked by primary hypothyroidism by prolonging the half-life of cortisol. The caveat therefore is that replacement therapy with thyroid hormone can precipitate an adrenal crisis in an undiagnosed individual. Hence, all patients with hypothyroidism and the possibility of APS should be screened for adrenal insufficiency to allow treatment with glucocorticoids prior to the initiation of thyroid hormone replacement.
- #47 Since asplenia can develop insidiously in patients with APS-1, we recommend vaccination against pneumococcus (with both 13-valent and 23-valent pneumococcal polysaccharide vaccines), meningococcus, Haemophilus influenzae type b, and influenza