Transcript APS1APS2. ppt - Trak.mcmaster.ca

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
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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
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Metabolic
Circulatory and renal
Growth
Immunologic
Skin, Bone, and Calcium effects
CNS
GCs: Metabolic Effect
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↑ 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
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Muscle weakness
Malaise
Anorexia
Vomiting
Weight loss
Physical Exam
- Orthostatic hypotension
- Hyperpigmentation
Adrenal insufficiency
(AI) labs
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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
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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
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Alopecia
Vitiligo
Spooning nails
Pernicious anemia
Jimmy’s story – 24 yo
• Photophobia
• Decreased visual
acuity
• Dx: Keratopathy
Summary of Jimmy’s clinical
diseases
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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
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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
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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
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↑ 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
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Pernicious anemia
Hepatitis
Myasthenia gravis
Celiac disease
Ectodermal dystrophies
Ovarian failure
APS II: Non endocrine
diseases
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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