Autoimmune polyglandular syndromes

1. Autoimmune polyglandular syndromes Irene Fung PGY2 Endocrinology rounds January 30, 2009

2. Objectives • Overview of autoimmune endocrine disease • To recognize the clinical presentation of APS-1 and APS-2 • To understand work-up and management of primary adrenal insufficiency and hypothyroidism • To learn the underlying patho-physiology of APS-1 and APS-2

3. Autoimmune disease and endocrinology • Hashimoto’s thyroiditis • Grave’s disease • Addison’s disease • Oophoritis • Hypoparathyroidism • Lymphocytic hypophysitis

4. Autoimmune endocrine disease • Genetics component • Type I DM risk • Monogenic twins: ~50% • Siblings: 3-4% • General population: 0.3% • Polymorphisms in HLA DR and DQ

5. Monogenic diseases • APS1 • Autoimmune polyglandular syndrome type 1 • IPEX • Immune dysregulation, polyendocrinopathy, enteropathy, X-linked

6. Jimmy’s Story

7. Jimmy: 18 months • 18 months, previously well child • Seizures, progressive frequency • Low calcium • Low PTH http://jimneydandme.wordpress.com/james-story/

8. DDx: neonatal hypocalcemia w/ low PTH • Impaired synthesis or secretion • Genetic • DiGeorge Syndrome • HDR Syndrome (Hypoparathyroidism, deafness, renal anomaly) • Sanjad-Sakati syndrome • Mitochondrial disorders (eg. MELAS Syndrome) • Defect of the calcium sensing receptor • Infiltration of parathyroid gland (eg. iron overload) • Infection (eg. gram-negative sepsis, HIV) • Autoimmune polyglandular syndrome type 1 (APS1)

9. Jimmy’s story – 6 yo • Recurrent infections • Otherwise healthy

10. Jimmy’s story – 14 yo • Vomiting • Weight loss • Decreased appetite

11. Review of Glucocorticoid Function • Metabolic • Circulatory and renal • Growth • Immunologic • Skin, Bone, and Calcium effects • CNS

12. GCs: Metabolic Effect • ↑ hepatic GNG • ↑ hepatic glycogen production • ↑ cellular resistance to insulin • ↑ lipolysis • ↑ proteolysis (except in heart and diaphragm)

13. GCs: Circulation & Renal • Positive ionotrope effect on heart • Permissive effect on Epi and Norepi

14. GCs: Growth • Inhibit linear growth and skeletal maturation • Decrease GH and IGF-1 • Accelerate tissue development and differentiation

15. GCs: Skin, Bone, Calcium • Inhibit fibroblasts • ↓GI absorption of Ca2+, • ↓renal absorption of Ca2+ and phosphorus • 2º↑ in PTH) • Risk of osteoporosis

16. GCs: Immunologic • Block histamine and pro-inflammatory cytokines • Decrease chemotaxis and phagocytosis of PMNs • Decrease cellular immune response

17. GCs: CNS effects • Stimulate appetite • Reduce REM sleep • ↑ sensitivity to serotonin receptors

18. Review of Mineralocorticoid: Function • Maintain intravascular volume • Conserve Na+ • Eliminate K+ and H+

19. Adrenal Insufficiency Clinical Presentation • Muscle weakness • Malaise • Anorexia • Vomiting • Weight loss Physical Exam • Orthostatic hypotension • Hyperpigmentation

20. Adrenal insufficiency (AI) labs • Low BS • Ketosis • Anemia • High eosinophils, lymphocytes • High K+ , Low Na+

21. Adrenal insufficiency (AI) labs • Stage 1: high renin, nr/low aldosterone • Stage 2: impaired cortisol response to cosyntropin • Stage 3: ↑ morning ACTH • Stage 4: Inappropriately low cortisol • ↑ urinary excretion of Na and Cl

22. Autoimmune AI: antibodies • +adrenal Abs (92% PPV for AI devpt) • Stronger predictor of eventual AI in children vs adults • Other markers • Anti-CYP21A2 Ab • Anti-interferon Abs (esp. interferon –omega)

23. Autoimmune AI: antibodies • Check for Abs against other endocrine glands • Anti TPO Ab • Gastric parietal cell Ab • Intrinsic factor (IF) Ab • Gonadal Ab • Anti-parathyroid gland Ab • Anti IA-2 tyrosine phosphatase-like protein, insulin

24. AI presentation based on age Infants: • Can get ill very quickly • Decrease activity, anorexia, vomiting • High K, Low Na, Low BS • May not have ketosis

25. AI presentation based on age Older Children • Muscle weakness • Malaise • Anorexia • Vomiting • Weight loss • May have salt craving • May have hyper-pigmentation • Orthostatic hypotension • Can be mistaken for gastroenteritis, acute infection

26. Definitive testing for AI ACTH stimulation test • Baseline cortisol level • 0.25 mg cosyntropin (ACTH) • Cortisol at 30 min or 60 min after • In 1o AI: resting level is low and does not increase • In 2o AI: may show low resting level and significant response

27. Acute Tx of AI • Low volume, Low Na+, Low BS: • D5NS • Hydrocortisone q6h x 4 doses • 25 mg for toddlers, 50 mg for child, 100 mg for adolescent • High K+: IV Ca gluconate, Kayexalate, IV glucose/insulin

28. A word of caution: AI and hypothyroidism Providing thyroxine can increase cortisol clearance Adrenal crisis can be precipitated if hypothyroidism treated without first providing GC replacement!

29. Chronic Tx of AI Hydrocortisone 10 mg/m2/daypo divided TID • ACTH used to monitor adequacy of GC replacement • Stress dose: increase dose by 2- or 3-fold

30. Chronic Tx of AI Fludrocortisone (Florinef) 0.05-0.3 mg po OD • Renin to monitor adequate replacement

31. Jimmy’s story – 16 yo • Polyuria • Polydipsia • Dx: Type I DM • Rx: Insulin

32. Jimmy’s story – 18 yo • Alopecia • Vitiligo • Spooning nails • Pernicious anemia

33. Jimmy’s story – 24 yo • Photophobia • Decreased visual acuity • Dx: Keratopathy

34. Summary of Jimmy’s clinical diseases • Candidiasis • Hypoparathyroidism • Adrenal insufficency • Alopecia • Vitiligo • Pernicious anemia • Type I DM • Keratopathy

35. Autoimmune Polyglandular Syndromes • Constellations of ≥ 2 endocrine gland insufficiencies as well as disorders of non-endocrine organs • Caused by an immune-mediated dysregulation of endocrine glands

36. APS-1 • Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) • Rare, pockets of higher frequency in Finland, Iran, Sardania • Autosomal recessive

37. APS-1 • 2 of 3 of: • Candidiasis • Hypoparathyroidism • Adrenal insufficiency • All 3 usually seen by 2nd decade

38. J Clin Endo Metab 1998:83(4):1049-1055

39. APS-1 • Other closely associated autoimmune disorders: • Gonadal failure (~60 %) • Intestinal malabsorption, chronic active hepatitis (~25%) • Hypothyroidism and type I diabetes mellitus occur in (~10%) • Alopecia, vitiligo, keratopathy, enamel hypoplasia, nail dystrophy

40. APS-1 • Organ specific immunity (versus systemic)

41. AIRE1 gene • several domains reminiscent of transcriptional regulators • 60 different mutations in the AIRE1 gene described

42. AIRE gene • Encodes a 545 amino acid protein • Missense mutations clustered in 3 regions: • HSR region: dimerization • SAND domain: DNA binding • PHD domains: ?E3 ubiquitin ligase

43. APS-1 genetics • AIRE expression in lymphoid organs, in particular the thymus • Expressed in medullary thymic epithelial cells (mTECS) as well as in dendritic cells

44. AIRE • Aire knockout mouse: multi-organ autoimmunity (serum autoAbs, inflammatory infiltrates) • Transfer of thymic epithelial cell of Aire knockout into recipient led to autoimmunity

45. AIRE regulates transcription of peripheral tissue antigens (PTAs)

46. Nature Reviews Immunology 2007 7:645-650

47. Nature Reviews Immunology 2007 7:645-650

48. Molecular mechanisms How does AIRE control expression of a range of genes encoding proteins with divergent transcriptional regulation in their usual cellular locations? How is expression of AIRE controlled? Other proteins does AIRE partner with?

49. Development • Does AIRE affect the differentiation of thymic medullary epithelial cells? If so, how? • Does AIRE influence the survival of MECs? If so, how? • During what age-window is AIRE important?

50. Immunological issues • Additional role(s) of AIRE in clonal deletion of thymocytes? • Why are some peripheral organs attacked in the absence of AIRE and others not? • Why do patients with APS-1 almost universally develop candidiasis infections?