Autoimmunity and genetics as they relate to hormone disease
Autoimmune polyglandular syndromes
| APS-1 (APECED) | APS-2 (Schmidt) | |
|---|---|---|
| Genetics | Monogenic - AIRE, autosomal recessive | Polygenic, HLA-associated |
| Onset | Infancy / early childhood | Late childhood to adulthood (peak 20-40y) |
| Sex | M = F | F > M (~3:1) |
| Triad | Chronic mucocutaneous candidiasis + hypoparathyroidism + Addison's (HAM) | Addison's + autoimmune thyroid disease + type 1 diabetes |
| Hypoparathyroidism | Yes - characteristic | No |
| Candidiasis | Yes - usually the first feature | No |
- APS-1 diagnosis: any 2 of the triad (or 1 plus an affected sibling)
- APS-2 is far commoner than APS-1
- If you see hypoparathyroidism with adrenal insufficiency, it is APS-1. If you see thyroid disease with adrenal insufficiency, it is APS-2
APS-3 / APS-4
- APS-3 - autoimmune thyroid disease + another autoimmune disease without adrenal insufficiency
- APS-4 - combinations not fitting the above
Epidemiology
- APS-1 ~1 in 90,000-200,000; founder populations enriched: Finnish, Sardinian, Iranian Jewish
- APS-2 ~1 in 20,000
- Hypoparathyroidism is the commonest autoimmune association of autoimmune Addison's disease (via APS-1)
- ~40-50% of people with autoimmune Addison's have at least one other autoimmune disease
- Type 1 diabetes: ~20% develop autoimmune thyroid disease; ~5-10% coeliac disease
AIRE - the central tolerance gene
- AIRE (21q22.3) in medullary thymic epithelial cells
- Drives promiscuous expression of peripheral tissue-restricted antigens in the thymus
- -> negative selection of autoreactive thymocytes + generation of Tregs
- Loss of function -> autoreactive T cells escape into the periphery -> multi-organ autoimmunity
- Neutralising anti-type-1-interferon (IFN-omega, IFN-alpha) autoantibodies are present in >95% - a near-pathognomonic screening test, present before disease onset
- Also explains the susceptibility to chronic mucocutaneous candidiasis: anti-IL-17/IL-22 autoantibodies
HLA and polygenic risk
HLA and polygenic risk in APS-2 and isolated endocrine autoimmunity
| Disease | Association |
|---|---|
| Type 1 diabetes | HLA-DR3-DQ2 and DR4-DQ8 (highest risk in heterozygotes); protective DQB1*0602 |
| Addison's | HLA-DR3-DQ2, DR4; MICA 5.1 |
| Graves' | HLA-DR3; CTLA-4, PTPN22, TSHR |
| Hashimoto's | HLA-DR3/DR5 |
| Coeliac | HLA-DQ2 / DQ8 (negative testing effectively excludes it) |
- Shared non-HLA loci: PTPN22 (R620W), CTLA-4, IL2RA, AIRE variants
- PTPN22 and CTLA-4 recur across T1DM, Graves', Addison's, RA and SLE - they set the threshold for T-cell activation
Other monogenic immune-endocrine syndromes
- IPEX - FOXP3, X-linked; Treg failure -> neonatal T1DM + enteropathy + eczema
- Thymoma - acquired AIRE-like failure; myasthenia, pure red cell aplasia, autoimmune endocrinopathy
- DiGeorge 22q11 - thymic aplasia, hypoparathyroidism (developmental, not autoimmune)
Antibodies by gland
| Gland | Antibody | Comment |
|---|---|---|
| Adrenal | 21-hydroxylase | Positive in ~85-90% of autoimmune Addison's; predicts progression |
| Thyroid | TPO, thyroglobulin, TRAb | TPO most sensitive for Hashimoto's; TRAb for Graves' |
| Pancreas | GAD65, IA-2, ZnT8, insulin (IAA) | Number of antibodies predicts progression to T1DM |
| Parathyroid | NALP5 / CaSR | Research use |
| Stomach | Parietal cell, intrinsic factor | Pernicious anaemia |
| Gut | tTG-IgA, deamidated gliadin | Coeliac; always with total IgA |
| Ovary | Steroidogenic cell (SCC, 17-OH) | Premature ovarian insufficiency |
| APS-1 screen | Anti-interferon-omega | >95% sensitive, precedes disease |
Screening a patient with one autoimmune endocrinopathy
- New Addison's -> TFT + TPO, HbA1c/fasting glucose, B12, coeliac serology; AIRE testing if young or hypoparathyroid
- New T1DM -> TSH + TPO at diagnosis then annually, coeliac serology at diagnosis and periodically
- New autoimmune thyroid disease -> screen further only if symptomatic or high risk
- Do not screen indiscriminately - screen where a positive result changes management or prevents a crisis
The trap
- *Unexplained recurrent hypoglycaemia or falling insulin requirement in a person with type 1 diabetes = Addison's disease until excluded*
- Hypocalcaemia with high phosphate = hypoparathyroidism (contrast vitamin D deficiency: low Ca, low phosphate, high PTH)
Replace, in the right order
- *Glucocorticoid before levothyroxine, always* - correcting hypothyroidism first accelerates cortisol clearance and precipitates adrenal crisis
- Addison's: hydrocortisone (divided, weighted to the morning) + fludrocortisone; sick day rules, emergency injection kit, medical alert
- Hypoparathyroidism: calcitriol + calcium (plain colecalciferol is inadequate - 1-alpha-hydroxylation is PTH-dependent)
- T1DM: insulin; insulin requirements fall when adrenal insufficiency develops
- Hypothyroidism: levothyroxine
Surveillance
- APS-1: lifelong annual review - new components appear over decades
- Also: ectodermal dystrophy (nail, enamel), keratoconjunctivitis, autoimmune hepatitis, asplenia, malabsorption, oral squamous cell carcinoma from chronic candidiasis
- Vaccinate as functionally asplenic
- APS-2: annual TSH, HbA1c, and clinical review; 21-hydroxylase antibodies if adrenal symptoms
- Family screening: siblings of APS-1 probands; first-degree relatives of Addison's/T1DM probands only in a research or symptom-driven setting
Disease-modifying therapy
- Teplizumab (anti-CD3) delays progression from stage 2 to stage 3 type 1 diabetes by ~2 years - available in the US; not PBS-listed in Australia
Syndrome components
- APS-1 (AIRE): mucocutaneous candidiasis, hypoparathyroidism, Addison's, hypothyroidism, gonadal failure, pernicious anaemia, alopecia, vitiligo, autoimmune hepatitis, asplenia, ectodermal dystrophy
- APS-2: Addison's, autoimmune thyroid disease, type 1 diabetes, coeliac, vitiligo, alopecia, pernicious anaemia, premature ovarian insufficiency, myasthenia gravis
- IPEX (FOXP3): neonatal diabetes, enteropathy, dermatitis
- Thymoma: myasthenia gravis, red cell aplasia, Good syndrome
- Checkpoint inhibitors: iatrogenic thyroiditis, hypophysitis, adrenalitis, fulminant type 1 diabetes
- Interferon-alpha therapy: thyroiditis
Natural history
- Autoantibodies precede clinical disease by years - a preclinical window exists in T1DM, Addison's and thyroid disease
- APS-1 components accumulate over a lifetime - candidiasis in infancy, hypoparathyroidism by ~10y, Addison's by ~15y, then others into adulthood
- A child with isolated mucocutaneous candidiasis needs long-term follow-up, not discharge
- APS-2 components typically appear over 10-20 years; Addison's is often the last
- Adrenal crisis remains the main cause of preventable death in both
- Mortality in APS-1 also from oral/oesophageal SCC and invasive infection (asplenia)
- Anticipate the next gland rather than diagnosing it at presentation in crisis
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