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
Adrenal insufficiency (AI) labs -Low BS -Ketosis -Anemia -High eosinophils, lymphocytes -High K +, Low Na +
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
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)
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
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
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
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
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
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!
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
Chronic Tx of AI Fludrocortisone (Florinef) mg po OD –Renin to monitor adequate replacement
Jimmy’s story – 16 yo Polyuria Polydipsia Dx: Type I DM Rx: Insulin
Jimmy’s story – 18 yo Alopecia Vitiligo Spooning nails Pernicious anemia
Jimmy’s story – 24 yo Photophobia Decreased visual acuity Dx: Keratopathy
Summary of Jimmy’s clinical diseases Candidiasis Hypoparathyroidism Adrenal insufficency Alopecia Vitiligo Pernicious anemia Type I DM Keratopathy
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
APS-1 Autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED) Rare, pockets of higher frequency in Finland, Iran, Sardania Autosomal recessive
APS-1 2 of 3 of: –Candidiasis –Hypoparathyroidism –Adrenal insufficiency All 3 usually seen by 2 nd decade
J Clin Endo Metab 1998:83(4):
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
APS-1 Organ specific immunity (versus systemic)
AIRE1 gene several domains reminiscent of transcriptional regulators 60 different mutations in the AIRE1 gene described
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
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
AIRE Aire knockout mouse: multi-organ autoimmunity (serum autoAbs, inflammatory infiltrates) Transfer of thymic epithelial cell of Aire knockout into recipient led to autoimmunity
AIRE regulates transcription of peripheral tissue antigens (PTAs)
Nature Reviews Immunology :
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?
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?
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?
Treatments? How could we re-establish tolerance in individuals who lack AIRE?
J Clin Endo Metab 1998:83(4):
Hannah’s Story Pediatrics in Review. 2005;26:68-74.
Hannah 17 yo girl w/ pedal edema and fatigue x 2 mths –ROS: Frequent headaches Decreased appetite Amenorrhea
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
APS-II More common than type 1 Polygenic, AD, and AR all reported Presents in late childhood or early adulthood
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
AITD occurs in 80–90% of females with APS II –The single most common component of APS II that occurs in isolation
Endocrinol Metab Clin North Am. 2002;31 :339 –352
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
Take home points ACTH stimulation test helps confirm adrenal insufficiency TSH and thyroxine to confirm hypothyroidism Check for auto-antibodies!
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
Take home points The study of AIRE mutations in APS-1 demonstrates mechanisms of self- tolerance during thymic T-cell selection