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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

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autoimmune polyglandular syndromes

Autoimmune polyglandular syndromes

Irene Fung PGY2

Endocrinology rounds

January 30, 2009

objectives
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
Autoimmune disease and endocrinology
  • Hashimoto’s thyroiditis
  • Grave’s disease
  • Addison’s disease
  • Oophoritis
  • Hypoparathyroidism
  • Lymphocytic hypophysitis
autoimmune endocrine disease
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
Monogenic diseases
  • APS1
    • Autoimmune polyglandular syndrome type 1
  • IPEX
    • Immune dysregulation, polyendocrinopathy, enteropathy, X-linked
jimmy 18 months
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
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
Jimmy’s story – 6 yo
  • Recurrent infections
  • Otherwise healthy
jimmy s story 14 yo
Jimmy’s story – 14 yo
  • Vomiting
  • Weight loss
  • Decreased appetite
review of glucocorticoid function
Review of Glucocorticoid Function
  • Metabolic
  • Circulatory and renal
  • Growth
  • Immunologic
  • Skin, Bone, and Calcium effects
  • CNS
gcs metabolic effect
GCs: Metabolic Effect
  • ↑ hepatic GNG
  • ↑ hepatic glycogen production
  • ↑ cellular resistance to insulin
  • ↑ lipolysis
  • ↑ proteolysis (except in heart and diaphragm)
gcs circulation renal
GCs: Circulation & Renal
  • Positive ionotrope effect on heart
  • Permissive effect on Epi and Norepi
gcs growth
GCs: Growth
  • Inhibit linear growth and skeletal maturation
  • Decrease GH and IGF-1
  • Accelerate tissue development and differentiation
gcs skin bone calcium
GCs: Skin, Bone, Calcium
  • Inhibit fibroblasts
  • ↓GI absorption of Ca2+,
  • ↓renal absorption of Ca2+ and phosphorus
  • 2º↑ in PTH)
  • Risk of osteoporosis
gcs immunologic
GCs: Immunologic
  • Block histamine and pro-inflammatory cytokines
  • Decrease chemotaxis and phagocytosis of PMNs
  • Decrease cellular immune response
gcs cns effects
GCs: CNS effects
  • Stimulate appetite
  • Reduce REM sleep
  • ↑ sensitivity to serotonin receptors
review of mineralocorticoid function
Review of Mineralocorticoid: Function
  • Maintain intravascular volume
  • Conserve Na+
  • Eliminate K+ and H+
adrenal insufficiency
Adrenal Insufficiency

Clinical Presentation

  • Muscle weakness
  • Malaise
  • Anorexia
  • Vomiting
  • Weight loss

Physical Exam

  • Orthostatic hypotension
  • Hyperpigmentation
adrenal insufficiency ai labs
Adrenal insufficiency (AI) labs
  • Low BS
  • Ketosis
  • Anemia
  • High eosinophils, lymphocytes
  • High K+ , Low Na+
adrenal insufficiency ai labs21
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
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 antibodies23
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
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 age25
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
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
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
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
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
chronic tx of ai30
Chronic Tx of AI

Fludrocortisone (Florinef) 0.05-0.3 mg po OD

  • Renin to monitor adequate replacement
jimmy s story 16 yo
Jimmy’s story – 16 yo
  • Polyuria
  • Polydipsia
  • Dx: Type I DM
  • Rx: Insulin
jimmy s story 18 yo
Jimmy’s story – 18 yo
  • Alopecia
  • Vitiligo
  • Spooning nails
  • Pernicious anemia
jimmy s story 24 yo
Jimmy’s story – 24 yo
  • Photophobia
  • Decreased visual acuity
  • Dx: Keratopathy
summary of jimmy s clinical diseases
Summary of Jimmy’s clinical diseases
  • Candidiasis
  • Hypoparathyroidism
  • Adrenal insufficency
  • Alopecia
  • Vitiligo
  • Pernicious anemia
  • Type I DM
  • Keratopathy
autoimmune polyglandular syndromes35
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
APS-1
  • Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
  • Rare, pockets of higher frequency in Finland, Iran, Sardania
  • Autosomal recessive
aps 137
APS-1
  • 2 of 3 of:
    • Candidiasis
    • Hypoparathyroidism
    • Adrenal insufficiency
  • All 3 usually seen by 2nd decade
aps 139
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 140
APS-1
  • Organ specific immunity (versus systemic)
aire1 gene
AIRE1 gene
  • several domains reminiscent of transcriptional regulators
  • 60 different mutations in the AIRE1 gene described
aire gene
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
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
slide44
AIRE
  • Aire knockout mouse: multi-organ autoimmunity (serum autoAbs, inflammatory infiltrates)
  • Transfer of thymic epithelial cell of Aire knockout into recipient led to autoimmunity
molecular mechanisms
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
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
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
Treatments?
  • How could we re-establish tolerance in individuals who lack AIRE?
hannah s story

Hannah’s Story

Pediatrics in Review. 2005;26:68-74.

hannah
Hannah

17 yo girl w/ pedal edema and fatigue x 2 mths

  • ROS:
    • Frequent headaches
    • Decreased appetite
    • Amenorrhea
hannah physical exam
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
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 labs57
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.
slide58
Dx?
  • Additional labs?
hypothyroidism effects
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
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
Hannah’s Physical Exam (continued)
  • Small patch of vitiligo on trunk
  • Other autoimmune diseases present?
workup for ai
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
ACTH stimulation test
  • Baseline and stimulated serum cortisol level of 5.5 nmol/L
slide64
Consistent with Addison’s Disease
  • Rx: Hydrocortisone, Fludrocortisone
further investigations
Further investigations
  • FSH, LH: normal
  • Estrogen: normal
  • Fasting blood sugar: normal
aps ii
APS-II
  • Autoimmune adrenal insufficency; and
  • Autoimmune thyroid disease; and/or
  • Type I DM
aps ii other autoimmune diseases
APS-II: Other autoimmune diseases
  • Pernicious anemia
  • Hepatitis
  • Myasthenia gravis
  • Celiac disease
  • Ectodermal dystrophies
  • Ovarian failure
aps ii non endocrine diseases
APS II: Non endocrine diseases
  • Ulcerative colitis
  • Primary biliary cirrhosis
  • Sarcoidosis
  • Achalasia
  • Myositis
  • Neuropathy
aps ii69
APS-II
  • More common than type 1
  • Polygenic, AD, and AR all reported
  • Presents in late childhood or early adulthood
aps ii presentation
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
slide71
AITD occurs in 80–90% of females with APS II
    • The single most common component of APS II that occurs in isolation
take home points
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 points74
Take home points
  • ACTH stimulation test helps confirm adrenal insufficiency
  • TSH and thyroxine to confirm hypothyroidism
  • Check for auto-antibodies!
take home points75
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 points76
Take home points

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