Review Autoimmune Polyendocrine Syndrome

Introduction Synonym - Autoimmune polyendocrine syndrome Polyglandular autoimmune syndrome [ PAS, PGA, PGAS ] Polyglandular autoimmune disease Polyglandular failure syndrome Definition - coexistence of at least two endocrine gland insufficiency based on autoimmune mechanisms - association with nonendocrime autoimmune disease - two subtypes

Classification Type I autoimmune polyendocrine syndrome - APDCED : autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy Clinical manifestation - persistent fungal infection (chronic mucocutaneous candidiasis) - aquired hypoparathyroidism - adrenal failure - first clinical manifestation early in life, in infant - preceding of skin candidiasis due to severe immunodeficiency - monogenic disorder : single gene mutation “AIRE gene” - autosomal recessive inheritance

Type II autoimmune polyendocrine syndrome Clinical manifestation - adrenal failure (Addison’s disease) + autoimmune thyroid disease with or without Type 1 DM - adrenal failure : preceding other endocrinopathy - pernicious anemia due to autoantibody to intrinsic factor Epidemiology - prevalence 1:20,000, - female dominant (3 times more than male) - family member often affected - more common than type 1 PAS - autosomal dominant inheritance - more complex polygenic disorder : associated with various HLA class I antigen - occur in adulthood, mainly 3rd~4th decade

Type III autoimmune polyendocrine syndrome - thyroid autoimmunity + other autoimmune endocrinopathy excluding Addison’s disease or type 1 DM Type IV autoimmune polyendocrine syndrome - two or more other organ-specific autoimmune disease  consideration of variable combination of PAS type II X-linked polyendocrinopathy, immune dysfuction and diarrhea [XPID] - fulminant widespread autoimmunity and type 1 DM - developed in neonates, often fatal - FOXP3 gene mutation

Characteristics of PAS

First disease manifestation in patients with PAS II J Clin Endocrinol Metab, July 2003, 88(7):2983–2992

Most frequent disease combinations in patients with PAS II J Clin Endocrinol Metab, July 2003, 88(7):2983–2992

Time interval between manifestation of first and second endocrine component diseases in 151 patients with PAS II J Clin Endocrinol Metab, July 2003, 88(7):2983–2992

Immunopathogenesis Environmental activation PAE cell : Peripheral Ag-expressing cell Environmental activation Administration of IFN-α Pregnancy T-cell-depleting monoclonal Ab AIRE protein : stimulation of expression of peripheral Ag to PAE cell

Stages in Development of Addison’s Disease Genetic susceptibility APC type I : AIRE gene APC type II : HLA-DR, DQ Precipitating event Administration of IFN-α Pregnancy T-cell-depleting monoclonal Ab

Assays for Autoimmune Marker Autoantibody assay - disease marker in T-cell-mediated immune disorder Autoantibody to the enzyme 21-hydroxylase - present in more than 90% of pts with Addison’s disease - almost preceding the onset of the disease - in case of no autoantibody with Addison’s disease  evaluation of alternative causes : esp. Tuberculous adrenalitis Autoantibody to TPO, Tg, TSH receptor - autoimmune thyroid disease : Hashimoto thyroiditis or Graves disease Autoantibody to islet cell, GAD, IA2, insulin - type 1 DM

Autoantigens in patients with PAS Autoantibodies agents Autoimmune disease TPO, Tg Hashimoto thyroiditis TSH receptor, TPO Graves’ disease Calcium sensing receptor Hypoparathyroidism P450 cytochrome : 21-OH, 17-OH, SCC Addison’s disease 17-OH Hypogonadism Islet cell, GAD, IA2, insulin Type 1 DM H+-K+-ATPase of the gastric parietal cells Autoimmune gastritis Intrinsic factor (gastric chief cell) Pernicious anemia Transglutaminase, gliadin Celiac disease Cytochrome enzyme : P450D6, 2C9, P450 1A2 Autoimmune hepatitis Tyrosine hydroxylase Alopecia areata Tyrosinase Vitiligo

Management Treatment - according to individual endocrine disorder In case of Addison’s disease with hypothyroidsim - preceding glucocorticoid replacement - followed thyroid hormone supplement - enhanced steroid metabolism by thyroid hormone - precipitated hypotension and adrenal crisis by thyroid hormone

Screening Recommendation Requirement of high index of suspicion for additional autoimmune endocrinopathy Patients with PAS type II and their first relatives with isolated Addison disease or type 1 DM - periodically screening for the development of hypothyroidism - screening for autoantibodies against to thyroid Absence of autoantibody - not exclude the disease - positive serology in not all patients Requirement of long-term follow-up and observation - long term interval between fisrt manifestation and further autoimmune endocrinopathy

Diagnostic Screening for Presence of PAS Functional Screening Baseline TSH, FSH, LH, free T4, testosterone, estradiol, fasting morning cortisol and glucose Serum Na, K, Ca, blood cell count Optional : ACTH stimulation test Serological screening : autoantibodies to Islet cells ,GAS, IA2 TPO, TSH receptor Cytochrome P450 enzymes H+-K+-ATPase of the parietal cells, instrinsic factor Transglutaminase, gliadin Optional : Genetic screening Molecular analysis of AIRE gene, especially for PAS type I HLA typing and sub typing

Summary Monoglandular autoimmune disease Functional screening for PAS Once every 3 years When Positive Serological screeing for organ-specific antibodies Optional : Functional screeing of first-degree relatives for PAS