1. Review Autoimmune Polyendocrine Syndrome

2. 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

3. 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

4. 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

5. 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

6. Characteristics of PAS

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

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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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