* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download APS1APS2. ppt - Trak.mcmaster.ca
Survey
Document related concepts
Anti-nuclear antibody wikipedia , lookup
Rheumatic fever wikipedia , lookup
Transmission (medicine) wikipedia , lookup
Kawasaki disease wikipedia , lookup
Behçet's disease wikipedia , lookup
African trypanosomiasis wikipedia , lookup
Rheumatoid arthritis wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Multiple sclerosis research wikipedia , lookup
Globalization and disease wikipedia , lookup
Neuromyelitis optica wikipedia , lookup
Germ theory of disease wikipedia , lookup
Hypothyroidism wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Graves' disease wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Molecular mimicry wikipedia , lookup
Transcript
Autoimmune polyglandular syndromes Irene Fung PGY2 Endocrinology rounds January 30, 2009 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 Autoimmune disease and endocrinology • • • • • • Hashimoto’s thyroiditis Grave’s disease Addison’s disease Oophoritis Hypoparathyroidism Lymphocytic hypophysitis 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 Monogenic diseases • APS1 – Autoimmune polyglandular syndrome type 1 • IPEX – Immune dysregulation, polyendocrinopathy, enteropathy, Xlinked Jimmy’s Story Jimmy: 18 months • 18 months, previously well child • Seizures, progressive frequency • Low calcium • Low PTH http://jimneydandme.wordpress.com/james-story/ 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) Jimmy’s story – 6 yo • Recurrent infections • Otherwise healthy Jimmy’s story – 14 yo • Vomiting • Weight loss • Decreased appetite Review of Glucocorticoid Function • • • • • • Metabolic Circulatory and renal Growth Immunologic Skin, Bone, and Calcium effects CNS GCs: Metabolic Effect • • • • • ↑ hepatic GNG ↑ hepatic glycogen production ↑ cellular resistance to insulin ↑ lipolysis ↑ proteolysis (except in heart and diaphragm) GCs: Circulation & Renal • Positive ionotrope effect on heart • Permissive effect on Epi and Norepi GCs: Growth • Inhibit linear growth and skeletal maturation • Decrease GH and IGF-1 • Accelerate tissue development and differentiation GCs: Skin, Bone, Calcium • Inhibit fibroblasts • ↓GI absorption of Ca2+, • ↓renal absorption of Ca2+ and phosphorus • 2º ↑ in PTH) • Risk of osteoporosis GCs: Immunologic • Block histamine and pro-inflammatory cytokines • Decrease chemotaxis and phagocytosis of PMNs • Decrease cellular immune response GCs: CNS effects • Stimulate appetite • Reduce REM sleep • ↑ sensitivity to serotonin receptors Review of Mineralocorticoid: Function • Maintain intravascular volume • Conserve Na+ • Eliminate K+ and H+ Adrenal Insufficiency Clinical Presentation – – – – – Muscle weakness Malaise Anorexia Vomiting Weight loss Physical Exam - Orthostatic hypotension - Hyperpigmentation 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 1o AI: resting level is low and does not increase • In 2o 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/m2/day po divided TID – ACTH used to monitor adequacy of GC replacement – Stress dose: increase dose by 2- or 3fold Chronic Tx of AI Fludrocortisone (Florinef) 0.05-0.3 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 polyendocrinopathycandidiasis-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 2nd decade J Clin Endo Metab 1998:83(4):1049-1055 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 2007 7:645-650 Nature Reviews Immunology 2007 7:645-650 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):1049-1055 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 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 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 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. • Dx? • Additional labs? 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 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 Hannah’s Physical Exam (continued) • Small patch of vitiligo on trunk • Other autoimmune diseases present? 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 ACTH stimulation test • Baseline and stimulated serum cortisol level of 5.5 nmol/L • Consistent with Addison’s Disease • Rx: Hydrocortisone, Fludrocortisone Further investigations • FSH, LH: normal • Estrogen: normal • Fasting blood sugar: normal APS-II • Autoimmune adrenal insufficency; and • Autoimmune thyroid disease; and/or • Type I DM APS-II: Other autoimmune diseases • • • • • • Pernicious anemia Hepatitis Myasthenia gravis Celiac disease Ectodermal dystrophies Ovarian failure APS II: Non endocrine diseases • • • • • • Ulcerative colitis Primary biliary cirrhosis Sarcoidosis Achalasia Myositis Neuropathy 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 selftolerance during thymic T-cell selection