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

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Presentation on theme: "Autoimmune polyglandular syndromes Irene Fung PGY2 Endocrinology rounds January 30, 2009."— Presentation transcript:

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

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 Ca 2+, ↓ renal absorption of Ca 2+ 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 1 o AI: resting level is low and does not increase In 2 o 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/m 2 /day po 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 2 nd 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


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?

51 Treatments? How could we re-establish tolerance in individuals who lack AIRE?

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

53 Hannah’s Story Pediatrics in Review. 2005;26:68-74.

54 Hannah 17 yo girl w/ pedal edema and fatigue x 2 mths –ROS: Frequent headaches Decreased appetite Amenorrhea

55 Hannah: Physical Exam Rough, waxy & dry skin, sallow complexion Proportional Ht and Wt BP 80/40 Non-pitting pedal edema Diffuse, firm non-tender, enlarged thyroid Tanner Stage 4 “Hung-up” knee jerk reflexes

56 Hannah: Labs CBC and electrolyte panel: Nr ESR: 55 mm/h Serum total protein: 74 g/L Albumin: 41 g/L ALT: 169 U/L AST: 145 U/L Alkaline phosphatase: 48 U/L Total bilirubin: 6.8 mcmol/L

57 Hannah: Labs ↑ Cholesterol: 8.6 mmol/L ↑ Triglycerides: 5.0 mmol/L HDL: 1.1 mmol/L Creatine kinase: 751 U/L Lactic acid dehydrogenase: 1,001 U/L.

58 Dx? Additional labs?

59 Hypothyroidism: Effects Secondary dyslipidemia: –Downregulation of LDL receptors  high LDL levels –Decreased activity of lipoprotein lipase  elevated VLDL High PRL - due to excessive TRH production and decreased PRL clearance Elevated liver enzymes, LDH, creatine kinase

60 Hypothyroidism: Investigations ↑ TSH: 1,250 mcIU/L ↓ Free thyroxine: 0.77 pmol/L Anti TPO Ab: 5,826 IU/mL Thyroid stimulatory Ab: 26 IU/mL Anti-thyroglobulin Ab: 2,521 IU/mL ↑ Serum PRL: 92 mcg/L

61 Hannah’s Physical Exam (continued) Small patch of vitiligo on trunk Other autoimmune diseases present?

62 Workup for AI ↓ Morning cortisol level: 13.8 nmol/L ↓ Aldosterone < 1.0 ng/dL (0.0277 nmol/L) ↑ ACTH: 374.2 pmol/L ↑ Renin level of 253.3 nmol/L/h + Anti-adrenal antibody screen

63 ACTH stimulation test Baseline and stimulated serum cortisol level of 5.5 nmol/L

64 Consistent with Addison’s Disease Rx: Hydrocortisone, Fludrocortisone

65 Further investigations FSH, LH: normal Estrogen: normal Fasting blood sugar: normal

66 APS-II Autoimmune adrenal insufficency; and Autoimmune thyroid disease; and/or Type I DM

67 APS-II: Other autoimmune diseases Pernicious anemia Hepatitis Myasthenia gravis Celiac disease Ectodermal dystrophies Ovarian failure

68 APS II: Non endocrine diseases Ulcerative colitis Primary biliary cirrhosis Sarcoidosis Achalasia Myositis Neuropathy

69 APS-II More common than type 1 Polygenic, AD, and AR all reported Presents in late childhood or early adulthood

70 APS II: Presentation 3:1 Female Male Adrenocortical failure is the initial endocrine abnormality in ~50% –Simultaneous T1DM in ~ 1/5 –Simultaneous Autoimmune Thyroid Disease (AITD) in ~2/3

71 AITD occurs in 80–90% of females with APS II –The single most common component of APS II that occurs in isolation

72 Endocrinol Metab Clin North Am. 2002;31 :339 –352

73 Take home points Be suspicious of endocrine disease in the unwell child Adrenal insufficiency can gradual (adolescent) or acute (infant) When one autoimmune endocrine disorder presents, be suspicious of others

74 Take home points ACTH stimulation test helps confirm adrenal insufficiency TSH and thyroxine to confirm hypothyroidism Check for auto-antibodies!

75 Take home points The APS-1 triad: –Chronic mucocutaneous candidiasis –Hypoparathyroidism –Adrenal insufficiency The APS-II –Autoimmune adrenal insufficency; and –Autoimmune thyroid disease; and/or –Type I DM

76 Take home points The study of AIRE mutations in APS-1 demonstrates mechanisms of self- tolerance during thymic T-cell selection

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