4/30/15 Autoimmune Polyglandular Failure Mark S. Anderson, MD, PhD Professor UCSF Diabetes Center Goals • Review clinical Autoimmune Polyglandular Failure syndromes • Disease spectrum • Broad treatment, diagnostic recommendations • Highlight newly discovered mechanism of disease for APS type I • May have applications to more common autoimmune diseases 1
4/30/15 Definitions Autoimmune Polyglandular Failure broadly divided into two major categories: • APS type I (Whitaker’s Syndrome, APECED) • APS type II (Schmidt’s Syndrome) APS I (%) APS II (%) Comparative Frequency Less Common More Common Onset Infancy/early childhood Late childhood/adulthood Heredity Autosomal Recessive Polygenic Gender Male = Females Female Predominance Genetics AIRE gene; no HLA association HLA association; DR/DQ Hypoparathyroidism 77-89 None Mucocutaneous candiditis 73-100 None Ectodermal dysplasia 77 None Addison’s Disease 60-86 70-100 Type 1 Diabetes 4-18 41-52 Autoimmune thyroid disease 8-10 70 Pernicious anemia 12-15 2-25 Gonandal failure Females 30-60 3.5-10 Males 7-17 5 Vitiligo 4-13 4-5 Alopecia 27 2 Autoimmune hepatitis 10-15 Rare Malabsorption 10-18 Rare 2
4/30/15 APS I: Epidemiology • First description in 1929 • Synonyms: Whitaker’s, Polyglandular Autoimmune Disease Type 1, APECED • Prevalence variable - rare outside clusters • Phenotype typically emerges in childhood • Males and females equally affected APS I: Clinical Features • Major components: (1) Chronic mucocutaneous candidiasis (2) Chronic hypoparathyroidism (3) Autoimmune adrenal insufficiency • 2 of the 3 required for diagnosis • Multiple minor clinical features 3
4/30/15 APS I: Clinical Presentation # Cases (n=41) Betterle, JCEM 1998; 83(4):1050 Mucocutaneous Candidiasis • Most frequent major clinical feature (93%) • Presents: 1 month to 21 years of age • Affects nails, dermis, oral, vaginal, and esophageal mucosa • Chronic infection associated with carcinoma • Treated PRN. Fluconazole and/or Nystatin S&S 4
4/30/15 Why Candida? Hypoparathyroidism • Second major clinical manifestation • Occurs in 73-90% of APS 1 patients • Presents: 3 months to 44 years of age • Diagnosis: Ionized Ca/PTH • Nalp5 autoantibodies as a marker 5
4/30/15 The new engl and jour nal of medicine original article Autoimmune Polyendocrine Syndrome Type 1 and NALP5, a Parathyroid Autoantigen Mohammad Alimohammadi, M.D., Peyman Björklund, Ph.D., Åsa Hallgren, B.Sc., Nora Pöntynen, M.Sc., Gabor Szinnai, M.D., Noriko Shikama, Ph.D., Marcel P. Keller, Ph.D., Olov Ekwall, M.D., Ph.D., Sarah A. Kinkel, B.Sc., Eystein S. Husebye, M.D., Ph.D., Jan Gustafsson, M.D., Ph.D., Fredrik Rorsman, M.D., Ph.D., Leena Peltonen, M.D., Ph.D., Corrado Betterle, M.D., Ph.D., Jaakko Perheentupa, M.D., Ph.D., Göran Åkerström, M.D., Ph.D., Gunnar Westin, Ph.D., Hamish S. Scott, Ph.D., Georg A. Holländer, M.D., and Olle Kämpe, M.D., Ph.D. Addison’s Disease • Third major manifestation to appear • Presents: 6 months to 41 years of age • Adrenal cortex Ab (anti-21 Hydroxylase) near 100% at Dx. • Anti-adrenal Ab’s positive predicitive value • Traditional management with corticosteroid replacement 6
4/30/15 APS I: Minor Clinical Features • Hypergonadotropic • Chronic active hepatitis hypogonadism • Vitiligo • Autoimmune • Alopecia hypothyroidism • Ectodermal dystrophy • Type I diabetes • Keratoconjunctivitis • Hypophysitis • Cellular/humoral defects • Pernicious anemia • Asplenia • Atrophic gastritis • Cholelithiasis • Malabsorption Betterle et al. JCEM 83:1049-1055, 1998 7
4/30/15 Hypergonadotripic Hypogonadism • Present in 17-50% of APS 1 patients • Anti-Cyp450side chain or 17-OH autoantibodies have predictive value • Onset: pre-pubertal to age 40 • Fertility counseling Diabetes Mellitus Type 1 • DM type 1 in 10% patients with APS 1 • Most with DM: anti-GAD+ • Many patients anti-GAD+ that do not progress to DM • Fasting glucose and A1C also recommended 8
4/30/15 Autoimmune Thyroid Disease • Hashimoto’s thyroiditis or atrophic thyroiditis in 10% of patients with APS 1 • Again presence of antibodies common • Grave’s also seen in some patients but more rare • Monitor TSH and antibodies Autoimmune Gastrointestinal Disease • Pernicious anemia in 11-13% patients • Mean age of onset 20 years • Parietal cell & intrinsic factor autoantibodies • Malabsorption in 18-22% patients • celiac disease, pancreatic insufficiency, infections, intestinal lymphangectasia 9
4/30/15 Chronic Active Hepatitis • Prevalence of 10 -25% of APS 1 patients • Presentation: 5-21 years of age • Variable clinical course • Autoantibodies: LKM, smooth muscle, mitochondrial, P450IA2 • Responsive to corticosteroids and azathioprine Autoimmune Skin Disease • Vitiligo in 8-13% of patients • Presents: 1 month to 15 years of age • Complement-fixing melanocyte autoantibodies • Alopecia in 29-32% of patients • Presents: 3-30 years of age • Total hair loss commonly seen, psychological impact important 10
4/30/15 Prognosis • Prior to 1970 mortality was 70% by age 30 • Mortality now 10-15% over 50 years 100 90 Cumulative Survival (%) 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Years follow-up Betterle, JCEM 1998; 83(4):1054 APS 1 Clinical Recommendations • Affected patients have lifetime susceptibility to multiple organ-specific autoimmune diseases. Vigilant follow-up by an endocrinologist at least quarterly with replacement Rx carefully monitored. • Particular attention to hypocalcemia and a low threshold for working up at risk syndromes is essential • Immunosuppression only used in non-endocrine autoimmune diseases (i.e. autoimmune hepatitis) • ?Role of genetic testing and counseling now that the causative gene has been identified On Web: http://www.geneclinics.org/servlet/access? prg=j&db=genetests&site=gt&id=8888890&fcn=c&qry=3 7600&res=&key=hJaU-ilZlicSw&show_flag=c 11
4/30/15 APS II • 1926 Schmidt described lymphocytic infiltrate of thyroid and adrenal in two patients • Definition varies from author to author APS II Definition • Co-existence of two or more of any of these three autoimmune diseases: • Type 1 diabetes • Autoimmune thyroid disease • Addison’s disease 12
4/30/15 APS II Clinical Syndromes • Major components • Type 1 diabetes • Autoimmune thyroid disease • Addison’s disease • Minor components -Gonadal failure -Vitiligo -Pernicious anemia and/or autoimmune Gastritis -Celiac disease -Alopecia APS II Epidemiology • Onset late childhood to adulthood, peak is in third decade • Females more commonly affected; at least 3:1 ratio • Genetics complex; HLA DR/DQ 13
4/30/15 APS I (%) APS II (%) Comparative Frequency Less Common More Common Onset Infancy/early childhood Late childhood/adulthood Heredity Autosomal Recessive Polygenic Gender Male = Females Female Predominance Genetics AIRE gene; no HLA association HLA association; DR/DQ Hypoparathyroidism 77-89 None Mucocutaneous candiditis 73-100 None Ectodermal dysplasia 77 None Addison’s Disease 60-86 70-100 Type 1 Diabetes 4-18 41-52 Autoimmune thyroid disease 8-10 70 Pernicious anemia 12-15 2-25 Gonandal failure Females 30-60 3.5-10 Males 7-17 5 Vitiligo 4-13 4-5 Alopecia 27 2 Autoimmune hepatitis 10-15 Rare Malabsorption 10-18 Rare Addison’s Disease • 50% of APS II cases present with Addison’s • Adrenal cortex Ab (anti-21 Hydroxylase) near 100% at Dx • Anti-adrenal Ab’s positive predicitive value • Diagnosis based on Cortrosyn Stimulation Test, elevated ACTH, and clinical picture (hyponatremia, hyperkalemia). • Traditional management with corticosteroid replacement (including mineralocorticoid rx) • ** Should be ruled out in suspected APS patients starting thyroid replacement 14
4/30/15 Diabetes Mellitus Type 1 • Screening with fasting glucose and anti- GAD, I-A2, insulin Antibodies • **Patients with co-existing Addison’s are excellent candidates for treatment with Glargine Insulin for prevention of hypoglycemia. Celiac Disease • Relatively common in APS II patients • Disease risk very strong correlation with HLA-DQA1*0501 DQB1*0201 • Seen in >90% of cases • Also a risk allele for other APS II syndromes • Antibody screening with anti-transglutaminase and anti- endomysial antibodies as a screen. If positive small bowel biopsy if diagnosis still uncertain. • Antibody tests are excellent screen with anti-endomysial sensitivity and specificity 90 and 98% 15
4/30/15 Gonadal Autoimmunity • Occurs before age 40 in 10-20% of female patients • Anti-Cyp450side chain or 17-OH autoantibodies have predictive value for disease • Fertility counseling Autoantibody Screening Disease Autoantibody Sens/Spec Type 1 DM GAD, I-A2,Insulin Addison ’ s 21-OH Thyroid TPO, Tg, TSI All generally>90% Sens BUT **Spec <90% Ovarian Cyp450side chain Pernicious Anemia Parietal Cell Celiac Endomysial, Gliadin **>90%/98% 16
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