Autoimmune Polyglandular Syndrome (APS)
Summary
Autoimmune Polyglandular Syndromes (APS) are a group of rare disorders characterised by the coexistence of multiple autoimmune endocrine gland failures, often accompanied by non-endocrine autoimmune manifestations. The syndromes result from immune-mediated destruction of endocrine organs, leading to hormone deficiencies requiring lifelong replacement therapy. APS is categorised into distinct types based on clinical presentation, genetic background, and age of onset. Early recognition and systematic screening are essential to prevent life-threatening complications such as Addisonian crisis, severe hypoglycaemia, or hypocalcaemic seizures.
Key Facts
- Prevalence: APS-1: 1:100,000; APS-2: 1:20,000 (more common)
- Genetics: APS-1: Autosomal recessive (AIRE gene); APS-2: Polygenic (HLA-DR3/DR4)
- Peak onset: APS-1: Childhood (before age 10); APS-2: Adulthood (30-40 years)
- Sex ratio: APS-1: Equal; APS-2: Female predominance (3:1)
- Core components: Addison's disease is central to APS-2
- Screening principle: If one autoimmune endocrinopathy exists, screen for others annually
- Life-threatening risk: Undiagnosed adrenal insufficiency in patients with T1DM
- Classic triad (APS-1): Chronic mucocutaneous candidiasis, hypoparathyroidism, Addison's disease
- Classic triad (APS-2): Addison's disease, autoimmune thyroid disease, Type 1 diabetes
- Treatment: Hormone replacement for each deficiency
Clinical Pearls
"The Rule of Three": APS-1 presents with the triad of Candidiasis, Hypoparathyroidism, and Addison's — usually appearing in that order during childhood. If you see one, look for the others.
"Schmidt's Syndrome Warning": APS-2 (Schmidt syndrome) classically presents as Addison's + T1DM + Thyroid disease. A patient with T1DM and vitiligo should be screened for adrenal insufficiency and thyroid dysfunction.
"The Dangerous Duo": Undiagnosed adrenal insufficiency in a patient with T1DM can be life-threatening. Cortisol deficiency impairs gluconeogenesis, causing refractory hypoglycaemia, while reducing catecholamine response.
"Annual Screen": Any patient with one autoimmune endocrine condition should have annual TFTs, glucose, and clinical assessment for adrenal insufficiency.
"AIRE Gene = APS-1": Mutations in the AIRE (Autoimmune Regulator) gene cause failure of central tolerance in the thymus, leading to multi-organ autoimmunity in childhood.
Why This Matters Clinically
Autoimmune polyglandular syndromes represent a significant diagnostic challenge due to their variable presentation and potential for life-threatening complications. Missing the diagnosis of adrenal insufficiency in a patient presenting with another endocrinopathy can be fatal. Systematic screening and a high index of suspicion in patients with any autoimmune endocrine disorder can prevent morbidity and mortality.[1,2]
Incidence & Prevalence
| Syndrome | Prevalence | Incidence |
|---|---|---|
| APS-1 (APECED) | 1:100,000 (general population) | Higher in Finland (1:25,000), Iran, Sardinia |
| APS-2 (Schmidt) | 1-2:100,000 | 1.4-2.0 per 100,000/year |
| APS-3 | More common than APS-2 | Variable, linked to thyroid autoimmunity |
Demographics
| Factor | APS-1 | APS-2 |
|---|---|---|
| Age of onset | Childhood (median 5-7 years) | Adulthood (20-60 years, peak 30-40) |
| Sex ratio | 1:1 | Female predominance 3:1 |
| Genetic inheritance | Autosomal recessive | Polygenic, HLA-associated |
| Ethnic clusters | Finnish, Iranian Jews, Sardinians | No specific ethnic predominance |
Risk Factors
| Factor | Relative Risk | Notes |
|---|---|---|
| Family history of autoimmune disease | 5-10x | First-degree relatives |
| HLA-DR3 haplotype | 3-5x | APS-2 |
| HLA-DR4 haplotype | 2-3x | APS-2, especially with T1DM |
| Female sex | 3x | For APS-2 |
| AIRE gene mutations | >5% | Diagnostic for APS-1 |
| Existing autoimmune endocrinopathy | Variable | Triggers screening protocol |
| Other autoimmune diseases | 2-3x | Vitiligo, pernicious anaemia, coeliac disease |
Mechanism
Step 1: Genetic Predisposition
- APS-1: Mutations in AIRE gene (chromosome 21) cause defective negative selection in thymus
- APS-2: HLA class II associations (DR3-DQ2, DR4-DQ8) predispose to autoimmunity
- Polymorphisms in CTLA-4, PTPN22, and other immune regulatory genes contribute
- Environmental triggers (infections, molecular mimicry) may initiate disease
Step 2: Loss of Immune Tolerance
- AIRE gene normally promotes expression of tissue-specific antigens in thymic medullary epithelial cells
- Defective AIRE leads to failure of central tolerance — autoreactive T cells escape thymic deletion
- In APS-2, peripheral tolerance mechanisms fail with HLA-restricted antigen presentation
- Regulatory T cell dysfunction contributes to loss of self-tolerance
Step 3: Organ-Specific Autoimmunity
- Autoreactive T lymphocytes infiltrate target endocrine organs
- B cells produce organ-specific autoantibodies
- Cytotoxic CD8+ T cells and cytokines mediate tissue destruction
- Gradual loss of functional endocrine tissue over months to years
Step 4: Endocrine Gland Failure
- Progressive destruction leads to hormone deficiency
- Adrenal cortex: Cortisol and aldosterone deficiency (Addison's disease)
- Thyroid: Hypo- or hyperthyroidism (Hashimoto's or Graves')
- Pancreatic beta cells: Insulin deficiency (Type 1 diabetes)
- Parathyroids: PTH deficiency (hypoparathyroidism)
- Gonads: Premature ovarian failure or testicular failure
Step 5: Multi-System Manifestations
- Non-endocrine autoimmune features develop (vitiligo, alopecia, pernicious anaemia)
- APS-1: Ectodermal dystrophy, hepatitis, keratitis
- Disease expression varies even within families with same mutations
- Sequential development of conditions over years to decades
Classification
| Type | Alternative Names | Core Features | Genetics |
|---|---|---|---|
| APS-1 | APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) | Chronic mucocutaneous candidiasis + Hypoparathyroidism + Addison's (2 of 3 required) | AIRE gene mutation (autosomal recessive) |
| APS-2 | Schmidt syndrome (if Addison's + thyroid) | Addison's disease + Autoimmune thyroiditis and/or Type 1 diabetes | Polygenic (HLA-DR3, DR4) |
| APS-3 | — | Autoimmune thyroid disease + Other autoimmune disease (excluding Addison's/hypoparathyroidism) | Polygenic |
| APS-4 | — | Combinations not fitting Types 1-3 | Variable |
Autoantibody Targets
| Target Organ | Autoantibody | Clinical Significance |
|---|---|---|
| Adrenal cortex | 21-hydroxylase (CYP21A2) antibodies | Marker for adrenal autoimmunity (>0% of autoimmune Addison's) |
| Thyroid | TPO antibodies, Thyroglobulin antibodies, TSH receptor antibodies | Hashimoto's or Graves' disease |
| Pancreatic islets | GAD65, IA-2, ZnT8, insulin antibodies | Type 1 diabetes |
| Parathyroid | NALP5, CaSR antibodies | Hypoparathyroidism |
| Gastric parietal cells | Intrinsic factor antibodies | Pernicious anaemia |
| Gonads | Steroidogenic enzyme antibodies | Premature ovarian failure |
Symptoms by System
| System | Symptoms |
|---|---|
| Adrenal (Addison's) | Fatigue (100%), weakness, weight loss, salt craving, postural dizziness, nausea, abdominal pain |
| Thyroid (Hypothyroidism) | Fatigue, cold intolerance, weight gain, constipation, dry skin, depression |
| Thyroid (Hyperthyroidism) | Weight loss, heat intolerance, tremor, palpitations, anxiety, diarrhoea |
| Pancreas (T1DM) | Polyuria, polydipsia, weight loss, fatigue |
| Parathyroid | Muscle cramps, paraesthesias, tetany, seizures |
| Mucocutaneous (APS-1) | Oral thrush, nail dystrophy, skin candidiasis |
Signs
| System | Physical Signs |
|---|---|
| Adrenal insufficiency | Hyperpigmentation (buccal mucosa, palmar creases, scars), hypotension, cachexia |
| Hypothyroidism | Bradycardia, dry skin, delayed relaxation of reflexes, periorbital oedema |
| Hyperthyroidism | Tachycardia, tremor, lid lag, warm moist skin, goitre, exophthalmos (Graves') |
| Hypoparathyroidism | Chvostek's sign, Trousseau's sign, tetany |
| T1DM | Weight loss, may have lipodystrophy at injection sites |
| Vitiligo | Depigmented patches |
| Alopecia | Patchy or total hair loss |
APS-1 Specific Features
| Feature | Frequency | Notes |
|---|---|---|
| Chronic mucocutaneous candidiasis | 75-100% | Usually first manifestation (often before age 5) |
| Hypoparathyroidism | 80-85% | Second component to appear |
| Addison's disease | 70-75% | Usually develops by age 15 |
| Alopecia | 30-40% | May be areata or totalis |
| Primary gonadal failure | 45-60% (females) | Premature ovarian insufficiency |
| Vitiligo | 10-25% | Patchy depigmentation |
| Autoimmune hepatitis | 10-15% | Can be severe |
| Enamel hypoplasia | 70% | Ectodermal dystrophy feature |
| Nail dystrophy | 50% | Ectodermal dystrophy |
| Keratitis | 15-25% | Can cause visual impairment |
APS-2 Specific Features
| Feature | Frequency | Notes |
|---|---|---|
| Addison's disease | 100% | Defining feature |
| Autoimmune thyroid disease | 70% | Hashimoto's or Graves' |
| Type 1 diabetes | 50% | May precede or follow Addison's |
| Pernicious anaemia | 5-10% | B12 deficiency |
| Vitiligo | 5-10% | Depigmentation |
| Primary gonadal failure | 5-10% | Less common than APS-1 |
| Coeliac disease | 2-5% | Associated autoimmunity |
Red Flags
[!CAUTION] Red Flags — Seek Urgent Assessment:
- Hypotension, hyponatraemia, hyperkalaemia — suspect Addisonian crisis
- Recurrent unexplained hypoglycaemia in T1DM — screen for adrenal insufficiency
- Seizures or tetany with hypocalcaemia — urgent IV calcium needed
- Altered consciousness with hypothermia — myxoedema coma
- High fever, tachycardia, agitation in known thyroid disease — thyroid storm
- Treatment-refractory oral or systemic candidiasis in a child — consider APS-1
Structured Approach
General Inspection:
- Skin pigmentation (hyperpigmentation of Addison's vs vitiligo patches)
- Body habitus (wasting suggests adrenal or metabolic disease)
- Alopecia (areata or totalis)
- Oral examination (candidiasis, hyperpigmented buccal mucosa)
Cardiovascular:
- Blood pressure (postural hypotension in Addison's)
- Heart rate (bradycardia in hypothyroidism, tachycardia in hyperthyroidism)
- Signs of heart failure
Neck:
- Thyroid examination (goitre, nodularity)
- Thyroidectomy scar
- Lymphadenopathy
Hands:
- Tremor (hyperthyroidism)
- Palmar crease pigmentation (Addison's)
- Nail dystrophy (APS-1)
- Vitiligo
Neurological:
- Chvostek's sign (tap facial nerve → facial twitch = hypocalcaemia)
- Trousseau's sign (blood pressure cuff → carpal spasm = hypocalcaemia)
- Peripheral neuropathy (B12 deficiency, diabetes)
- Deep tendon reflexes (delayed in hypothyroidism)
Skin:
- Vitiligo patches
- Hyperpigmentation pattern
- Fungal infections (candidiasis)
- Injection sites (lipodystrophy in T1DM)
Special Tests
| Test | Technique | Significance |
|---|---|---|
| Chvostek's sign | Tap facial nerve below zygoma | Positive = hypocalcaemia |
| Trousseau's sign | Inflate BP cuff above systolic for 3 min | Carpopedal spasm = hypocalcaemia |
| Postural BP | Lying to standing BP | Drop >0 mmHg systolic = autonomic dysfunction/adrenal insufficiency |
| Thyroid palpation | Assess size, nodules, tenderness | Goitre, nodule detection |
| Visual acuity | Snellen chart | Keratitis screening in APS-1 |
First-Line Investigations
| Investigation | Rationale | Expected Findings |
|---|---|---|
| 9 AM serum cortisol | Adrenal function screening | Low (<00 nmol/L) suggests insufficiency; high-normal (>00 nmol/L) excludes |
| TFTs (TSH, free T4) | Thyroid function | High TSH + low T4 = hypothyroidism; Low TSH + high T4 = hyperthyroidism |
| Fasting glucose / HbA1c | Diabetes screening | Elevated in T1DM |
| Calcium (corrected) | Parathyroid function | Low in hypoparathyroidism |
| PTH | Parathyroid function | Low/inappropriately normal with low calcium = hypoparathyroidism |
| FBC | Anaemia screening | Macrocytic anaemia (B12 deficiency), normocytic anaemia (chronic disease) |
| U&E | Electrolyte disturbance | Hyponatraemia, hyperkalaemia in Addison's |
| Vitamin B12, folate | Pernicious anaemia | Low B12 with macrocytic anaemia |
Confirmatory Investigations
| Investigation | Indication | Interpretation |
|---|---|---|
| Short Synacthen Test | Suspected adrenal insufficiency | Cortisol fails to rise to >50 nmol/L at 30 min = Addison's |
| Adrenal autoantibodies (21-hydroxylase) | Confirm autoimmune aetiology | Positive in >0% autoimmune Addison's |
| TPO antibodies | Autoimmune thyroiditis | Positive in Hashimoto's |
| GAD65, IA-2 antibodies | T1DM autoimmune markers | Positive supports autoimmune T1DM |
| Intrinsic factor antibodies | Pernicious anaemia | Positive = autoimmune gastritis |
| AIRE gene testing | Suspected APS-1 | Confirms diagnosis if mutations found |
Imaging
| Modality | Indication | Findings |
|---|---|---|
| Adrenal CT | Distinguish autoimmune from other causes | Small, atrophic adrenals (autoimmune); enlarged (infiltrative/haemorrhage/TB) |
| Thyroid ultrasound | Goitre, nodule evaluation | Heterogeneous, hypoechoic in Hashimoto's |
| DEXA scan | Osteoporosis screening | Reduced BMD (corticosteroid excess, hypogonadism) |
Genetic Testing
| Test | Indication |
|---|---|
| AIRE gene sequencing | Suspected APS-1, childhood onset, mucocutaneous candidiasis |
| HLA typing | Research/risk stratification for APS-2 |
Management Algorithm
AUTOIMMUNE POLYGLANDULAR SYNDROME
↓
┌─────────────────────────────────────────────────────────────┐
│ INITIAL ASSESSMENT │
│ - Full endocrine panel (cortisol, TFTs, glucose, Ca, PTH) │
│ - Autoantibody screen (21-OH, TPO, GAD, IF) │
│ - AIRE gene testing if childhood onset/APS-1 suspected │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ TREAT EACH COMPONENT │
├─────────────────────────────────────────────────────────────┤
│ ADDISON'S DISEASE: │
│ ➤ Hydrocortisone 15-25 mg/day (divided doses) │
│ ➤ Fludrocortisone 50-200 mcg/day │
│ ➤ SICK DAY RULES: Double/triple dose when unwell │
│ ➤ Emergency injection kit + MedicAlert bracelet │
├─────────────────────────────────────────────────────────────┤
│ HYPOTHYROIDISM: │
│ ➤ Levothyroxine (start low 25-50 mcg if adrenal insuffi- │
│ ciency; ALWAYS replace steroids FIRST) │
├─────────────────────────────────────────────────────────────┤
│ TYPE 1 DIABETES: │
│ ➤ Insulin therapy (basal-bolus or pump) │
│ ➤ Beware: Adrenal insufficiency → recurrent hypoglycaemia │
├─────────────────────────────────────────────────────────────┤
│ HYPOPARATHYROIDISM: │
│ ➤ Calcium supplements (1-3 g/day in divided doses) │
│ ➤ Active vitamin D (alfacalcidol/calcitriol) │
│ ➤ Target: Low-normal calcium to avoid hypercalciuria │
├─────────────────────────────────────────────────────────────┤
│ MUCOCUTANEOUS CANDIDIASIS (APS-1): │
│ ➤ Topical/oral antifungals (fluconazole, nystatin) │
│ ➤ Prophylactic if recurrent │
└─────────────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────────────┐
│ ANNUAL SCREENING PROTOCOL │
│ - TFTs (TSH, fT4) │
│ - Fasting glucose / HbA1c │
│ - 9 AM cortisol (if symptoms or new fatigue) │
│ - Calcium, PTH │
│ - FBC, B12 (pernicious anaemia) │
│ - Coeliac serology if GI symptoms │
│ - Gonadal function assessment if fertility concerns │
└─────────────────────────────────────────────────────────────┘
Hormone Replacement Protocols
| Condition | First-Line Treatment | Monitoring |
|---|---|---|
| Addison's disease | Hydrocortisone 15-25 mg/day (divided: 10 mg AM, 5 mg lunch, 5 mg PM) + Fludrocortisone 50-200 mcg daily | Clinical (BP, weight, pigmentation), electrolytes, renin |
| Hypothyroidism | Levothyroxine 1.6 mcg/kg/day (start low if cardio risk) | TSH every 6-8 weeks until stable, then annually |
| Type 1 diabetes | Insulin (basal-bolus MDI or pump) | HbA1c every 3-6 months, CGM encouraged |
| Hypoparathyroidism | Calcium 1-3 g/day + Calcitriol 0.25-1 mcg/day | Serum calcium, phosphate, urinary calcium, renal function |
| Premature ovarian failure | HRT (oestrogen + progesterone if uterus intact) | Bone health, cardiovascular risk, fertility counselling |
Critical Treatment Considerations
| Scenario | Action | Rationale |
|---|---|---|
| Starting levothyroxine in adrenal insufficiency | Replace steroids FIRST, then levothyroxine | Thyroxine increases cortisol metabolism → precipitates Addisonian crisis |
| Sick day rules (Addison's) | Double hydrocortisone if febrile/unwell; triple if vomiting | Physiological stress requires increased cortisol |
| Surgery preparation | IV hydrocortisone 100 mg preop + 50-100 mg q8h | Prevent perioperative adrenal crisis |
| Hypoglycaemia in T1DM + Addison's | Screen for adrenal insufficiency; reduce insulin | Cortisol needed for gluconeogenesis |
Patient Education
- MedicAlert bracelet: Essential for all patients with adrenal insufficiency
- Emergency injection kit: IM hydrocortisone for emergencies when oral intake impossible
- Sick day card: Instructions for dose adjustment during illness
- Annual screening adherence: Even if well, new autoimmune conditions can develop
Immediate (Hours)
| Complication | Incidence | Clinical Features | Management |
|---|---|---|---|
| Addisonian crisis | Variable in undiagnosed | Hypotension, shock, hyponatraemia, hyperkalaemia, hypoglycaemia | IV hydrocortisone 100 mg bolus then 50-100 mg q6h, IV fluids |
| Hypoglycaemic coma | T1DM patients | Confusion, seizures, unconsciousness | IV glucose, glucagon, assess for adrenal insufficiency |
| Hypocalcaemic tetany/seizures | Hypoparathyroidism | Carpopedal spasm, laryngospasm, generalised seizures | IV calcium gluconate 10%, monitor ECG |
| Thyroid storm | Undiagnosed Graves' | High fever, tachycardia, delirium | PTU, beta-blockers, steroids, supportive care |
Early (Days-Weeks)
| Complication | Clinical Features | Management |
|---|---|---|
| Electrolyte disturbance | Hyponatraemia, hyperkalaemia | Steroid replacement, IV fluids |
| Metabolic derangement | Ketoacidosis (T1DM) | Insulin, fluids, potassium |
| Infection (candidiasis) | Oral/oesophageal thrush | Antifungals |
Late (Months-Years)
| Complication | Incidence | Notes |
|---|---|---|
| Osteoporosis | 20-30% | Due to glucocorticoid replacement, hypogonadism |
| Cardiovascular disease | Increased | Associated with thyroid disease, diabetes |
| New autoimmune conditions | Ongoing risk | Requires annual screening |
| Infertility | Variable | Premature ovarian failure, testicular failure |
| Adrenal crisis during intercurrent illness | Preventable | Patient education on sick day rules |
| Visual impairment (APS-1) | 15-25% | Keratitis, cataracts |
| Hepatitis (APS-1) | 10-15% | Monitor LFTs |
Natural History
| Syndrome | Prognosis | Life Expectancy |
|---|---|---|
| APS-1 | Chronic, lifelong; accumulation of components over time | Reduced if complications (hepatitis, adrenal crisis, malignancy) |
| APS-2 | Variable; depends on adequacy of hormone replacement | Near-normal with good management |
Prognostic Factors
| Good Prognosis | Poor Prognosis |
|---|---|
| Early diagnosis and treatment | Delayed diagnosis with crisis presentation |
| Good treatment adherence | Poor compliance with replacement therapy |
| Regular screening and follow-up | Missed appointments / lost to follow-up |
| Access to specialist care | Limited healthcare access |
| Education on sick day rules | Lack of patient education |
Treatment Outcomes
| Condition | Outcome with Treatment |
|---|---|
| Addison's disease | Excellent QoL with adequate replacement; persistent fatigue in some |
| Hypothyroidism | Normal life with levothyroxine |
| T1DM | Good glycaemic control reduces microvascular complications |
| Hypoparathyroidism | Symptomatic improvement; monitoring for renal calcification needed |
Key Guidelines
| Guideline | Organisation | Year | Key Points |
|---|---|---|---|
| Primary Adrenal Insufficiency Guidelines | Endocrine Society | 2016 | Hydrocortisone preferred; stress dosing protocols; fludrocortisone for all PAI |
| Hypothyroidism Management | ATA/AACE | 2012 | Levothyroxine monotherapy; TSH targets |
| Type 1 Diabetes Standards | ADA | 2024 | Individualised HbA1c targets; CGM recommended |
| Hypoparathyroidism Guidelines | Endocrine Society | 2022 | Calcium + active vitamin D; avoid hypercalciuria |
Landmark Trials and Evidence
AIRE Gene Discovery (1997)
- Finnish-German Consortium identified AIRE mutations in APS-1
- Established genetic basis for disease
- Enabled diagnostic testing
- PMID: 9425231
Betterle et al. Natural History Study (2002)
- n=195 patients with autoimmune Addison's
- 50% developed additional autoimmune diseases over follow-up
- Established need for systematic screening
- PMID: 12456856
Husebye et al. Clinical Registry (2009)
- Norwegian registry of APS patients
- Documented spectrum of complications
- Informed screening protocols
- PMID: 19246518
Bornstein et al. (2016) — Endocrine Society PAI Guidelines
- Comprehensive management recommendations
- Stress dosing protocols
- Quality of life considerations
- PMID: 26760044
Evidence Strength
| Intervention | Level | Evidence Source |
|---|---|---|
| Hydrocortisone replacement | 1a | Multiple RCTs, meta-analyses |
| Fludrocortisone for mineralocorticoid replacement | 1b | RCTs |
| Annual screening for new components | 2a | Cohort studies, expert consensus |
| Sick day rules education | 2b | Observational studies, case series |
| AIRE gene testing for APS-1 | 1a | Diagnostic accuracy studies |
What is Autoimmune Polyglandular Syndrome?
Autoimmune Polyglandular Syndrome (APS) is a condition where your immune system, which normally protects you from infections, mistakenly attacks the glands that make important hormones. This leads to several hormone-producing glands not working properly at the same time.
Why does it happen?
In APS, the immune system becomes confused and produces antibodies that attack your own glands. This can run in families and is related to your genes. In children, a specific gene called AIRE is often involved. In adults, a combination of genes makes some people more likely to develop these problems.
What are the symptoms?
Symptoms depend on which glands are affected:
- Adrenal glands: Tiredness, weakness, weight loss, low blood pressure, salt cravings, darkening of the skin
- Thyroid gland: Tiredness, weight changes, feeling too hot or cold
- Pancreas: Increased thirst and urination, weight loss (diabetes)
- Parathyroid glands: Muscle cramps, tingling in fingers and toes
How is it treated?
Each hormone deficiency is treated by replacing the missing hormone:
- Steroid tablets (hydrocortisone) for adrenal problems
- Thyroid hormone tablets for thyroid problems
- Insulin injections for diabetes
- Calcium and vitamin D for parathyroid problems
With proper treatment, most people can live normal, active lives.
What to expect?
This is a lifelong condition, but with regular medication and check-ups, you can manage your symptoms well. You will need to take medications every day and see your doctor regularly for blood tests.
When to seek help urgently
Seek immediate medical attention if you experience:
- Severe weakness, dizziness, or fainting (especially if unwell)
- Vomiting and unable to keep medications down
- Muscle cramps or twitching that doesn't stop
- Very fast heartbeat with high temperature
- Confusion or reduced consciousness
Always carry a steroid emergency card and wear a medical alert bracelet.
Primary Guidelines
-
Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389. PMID: 26760044
-
Brandi ML, Bilezikian JP, Shoback D, et al. Management of Hypoparathyroidism: Summary Statement and Guidelines. J Clin Endocrinol Metab. 2016;101(6):2273-2283. PMID: 26943718
Key Studies
-
Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 1997;17(4):399-403. PMID: 9425231
-
Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev. 2002;23(3):327-364. PMID: 12050123
-
Husebye ES, Perheentupa J, Rautemaa R, Kämpe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265(5):514-529. PMID: 19382991
-
Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol. 2009;161(1):11-20. PMID: 19411300
-
Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat Rev Endocrinol. 2010;6(5):270-277. PMID: 20309000
Reviews & Resources
-
Husebye ES, Anderson MS, Kämpe O. Autoimmune Polyendocrine Syndromes. N Engl J Med. 2018;378(12):1132-1141. PMID: 29562162
-
Magitta NF, Bøe Wolff AS, Johansson S, et al. A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes. Genes Immun. 2009;10(2):120-124. PMID: 18946481
-
Society for Endocrinology. Emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. 2020. sofe.org/adrenal-crisis
-
Addison's Disease Self-Help Group. Patient resources. addisonsdisease.org.uk
-
British Thyroid Foundation. Patient information. btf-thyroid.org
High-Yield Exam Topics
| Topic | Key Points |
|---|---|
| APS classification | Type 1 = AIRE gene, childhood, candidiasis/hypopara/Addison's; Type 2 = HLA-associated, adult, Addison's + thyroid + T1DM |
| AIRE gene | Autoimmune Regulator; mutations cause failure of central tolerance in thymus |
| 21-hydroxylase antibodies | Marker for autoimmune adrenal insufficiency (>0% positive) |
| Treatment priorities | ALWAYS replace steroids before starting levothyroxine |
| Sick day rules | Double hydrocortisone if febrile; triple if vomiting; IM injection if unable to take oral |
| Addisonian crisis management | IV hydrocortisone 100 mg stat, IV 0.9% saline, treat underlying cause |
Sample Viva Questions
Q1: A 35-year-old woman with Type 1 diabetes presents with recurrent hypoglycaemia despite reducing insulin doses. What should you consider?
Model Answer: Consider concurrent adrenal insufficiency (APS-2). Cortisol is essential for gluconeogenesis and counter-regulatory response to hypoglycaemia. Check 9 AM cortisol and perform Short Synacthen Test. Screen for 21-hydroxylase antibodies. If confirmed, start hydrocortisone replacement which may allow normalisation of insulin doses.
Q2: Why must steroids be replaced before starting levothyroxine in a patient with both adrenal insufficiency and hypothyroidism?
Model Answer: Levothyroxine increases metabolic rate and cortisol clearance. In a patient with undiagnosed or undertreated adrenal insufficiency, starting levothyroxine precipitates Addisonian crisis by depleting already low cortisol reserves. Always confirm adequate steroid replacement before initiating thyroid hormone therapy.
Q3: A 7-year-old presents with recurrent oral thrush and hypocalcaemia. What is the likely diagnosis and what investigation would you perform?
Model Answer: This presentation is highly suggestive of APS-1 (APECED). The triad includes chronic mucocutaneous candidiasis (usually first), hypoparathyroidism, and Addison's disease. Perform AIRE gene sequencing for confirmation. Screen for adrenal insufficiency with 9 AM cortisol and Short Synacthen Test. Annual screening for new components is essential.
Common Exam Errors
| Error | Correct Approach |
|---|---|
| Starting levothyroxine before steroids | Always replace steroids first |
| Missing adrenal insufficiency in T1DM with hypoglycaemia | Screen for Addison's if unexplained hypoglycaemia |
| Forgetting screening in patients with single autoimmune endocrinopathy | Annual TFTs, glucose, symptoms review |
| Not educating about sick day rules | All patients with Addison's need written sick day guidance |
| Misclassifying APS types | APS-1 = AIRE/childhood/candidiasis; APS-2 = adult/HLA/no candidiasis |
Last Reviewed: 2025-12-24 | MedVellum Editorial Team
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.