What is the diagnostic plan and management of Autoimmune Polyendocrine Syndrome (APS)?

Diagnostic Plan and Management of Autoimmune Polyendocrine Syndrome

Initial Diagnostic Approach

When you suspect APS, immediately measure paired morning (8 AM) serum cortisol and plasma ACTH to screen for primary adrenal insufficiency, as this is the most life-threatening component and present in the majority of APS cases. 1

Step 1: Confirm Primary Adrenal Insufficiency (PAI)

• Basal cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of PAI 1, 2
• Basal cortisol <400 nmol/L with elevated ACTH generates strong suspicion and warrants further testing 1
• If cortisol is indeterminate (250-400 nmol/L), perform cosyntropin stimulation test: administer 0.25 mg intramuscularly or intravenously, measure cortisol at 30 and/or 60 minutes—peak cortisol >550 nmol/L is normal, <500 nmol/L confirms PAI 1, 2
• Critical pitfall: Hyponatremia occurs in 90% of PAI cases, but hyperkalemia is present in only ~50%—do not rely on electrolytes alone to exclude the diagnosis 1, 2
• Never delay treatment for diagnostic testing if adrenal crisis is suspected—give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion, but secure blood samples for cortisol and ACTH before treatment if possible 1, 2

Step 2: Establish Autoimmune Etiology

• Measure 21-hydroxylase autoantibodies (21OH-Ab) as the first etiologic test—positive in ~85% of autoimmune PAI cases in Western populations 1, 2
• If 21OH-Ab positive, no further etiologic workup is generally necessary 1
• If 21OH-Ab negative, obtain CT imaging of adrenals to evaluate for hemorrhage, tuberculosis, tumors, or other structural causes 1, 2

Step 3: Determine APS Subtype

APS-1 Diagnostic Criteria:

• Presence of two of three major components: chronic mucocutaneous candidiasis, hypoparathyroidism, or PAI 1, 3, 4
• Consider APS-1 in young patients (<20 years) presenting with any major component, especially if accompanied by enamel hypoplasia, keratitis, autoimmune hepatitis, or malabsorption 1, 5
• Measure interferon-omega (IFN-ω) autoantibodies—present in >95% of APS-1 cases and highly specific 1, 3, 5
• Perform AIRE gene mutational analysis—identifies mutations in >95% of APS-1 cases 1, 3, 4

APS-2 Diagnostic Criteria:

• Presence of PAI plus at least one of: autoimmune thyroid disease (hypothyroidism or Graves' disease), type 1 diabetes mellitus, premature ovarian insufficiency, vitiligo, or celiac disease 1, 6
• Typically manifests in early adulthood (20-40 years), though pediatric cases occur 6
• Complex polygenic inheritance pattern—no single gene test available 1

Step 4: Screen for Associated Autoimmune Conditions

Mandatory screening tests at diagnosis:

• Thyroid function (TSH, free T4) and thyroid peroxidase antibodies (TPO-Ab) 1
• Fasting glucose and HbA1c for type 1 diabetes 1
• Serum calcium and PTH for hypoparathyroidism (especially in APS-1) 3, 4, 5
• Complete blood count for pernicious anemia 1, 4
• Tissue transglutaminase antibodies for celiac disease 1
• Vitamin B12 level 1
• In women: FSH, LH, estradiol to screen for premature ovarian insufficiency 1

For APS-1 specifically, also screen for:

• Liver function tests (autoimmune hepatitis) 1, 4
• Dental examination (enamel hypoplasia) 1, 5
• Ophthalmologic examination (keratitis) 1
• Assess for chronic candidiasis of skin, nails, and mucous membranes 3, 4, 5

Management Strategy

Acute Management: Adrenal Crisis

If patient presents with hypotension, collapse, vomiting, or severe illness:

• Immediately administer hydrocortisone 100 mg IV bolus, followed by 100 mg IV every 6-8 hours 7
• Infuse 0.9% saline at 1 L/hour initially 1, 2
• Do not delay treatment to perform diagnostic tests 1, 2
• Monitor electrolytes, glucose, and blood pressure closely 7

Chronic Glucocorticoid Replacement

For primary adrenal insufficiency (both APS-1 and APS-2):

• Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg morning, 5 mg afternoon, 2.5-5 mg evening to mimic diurnal rhythm) 2, 7
• Alternative: cortisone acetate 25-37.5 mg daily in divided doses 2
• Alternative: prednisolone 4-5 mg daily 2
• In children: hydrocortisone 6-10 mg/m² body surface area daily 7

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)

• Fludrocortisone 50-200 µg once daily (typically start at 100 µg) 2, 7
• Monitor blood pressure, serum sodium, potassium, and plasma renin activity 7
• Secondary adrenal insufficiency does NOT require mineralocorticoid replacement 2

Stress Dosing Protocol

Educate all patients on stress dosing:

• Minor stress (mild illness, dental procedures): double usual daily dose for 1-2 days 2
• Moderate stress (fever >38°C, gastroenteritis, moderate surgery): hydrocortisone 50-75 mg daily or prednisone 20 mg daily 2
• Major stress (major surgery, severe illness): hydrocortisone 100-150 mg daily IV/IM in divided doses 2, 7
• Prescribe emergency hydrocortisone 100 mg IM injection kit with self-injection training 2

Management of Other APS Components

Hypoparathyroidism (common in APS-1):

• Calcium supplementation and active vitamin D (calcitriol) 3, 4
• Monitor serum calcium, phosphate, and 24-hour urinary calcium 4

Autoimmune thyroid disease:

• Hypothyroidism: levothyroxine replacement 1
• Critical: When treating concurrent hypothyroidism and adrenal insufficiency, start corticosteroids several days before initiating thyroid hormone to prevent precipitating adrenal crisis 2

Type 1 diabetes:

• Insulin therapy with standard diabetes management 1, 6

Chronic mucocutaneous candidiasis (APS-1):

• Oral fluconazole or other antifungal therapy 3, 4

Long-Term Monitoring and Follow-Up

Annual screening for all APS patients:

• Clinical assessment: weight, blood pressure, signs of over/under-replacement 7
• Serum electrolytes (sodium, potassium) 7
• Screen for new autoimmune manifestations: thyroid function, fasting glucose, complete blood count, vitamin B12 2, 8
• In APS-1: liver function tests, calcium, PTH 4, 5
• Assess quality of life and psychosocial status 8

Screen first-degree relatives:

• Family members of APS patients have high incidence of developing autoimmune endocrinopathies 8
• Measure organ-specific autoantibodies (21OH-Ab, TPO-Ab, islet cell antibodies) in asymptomatic relatives 8
• If autoantibodies positive, perform annual screening for subclinical disease 8

Patient Education and Safety Measures

Mandatory for all patients:

• Wear medical alert bracelet or necklace indicating adrenal insufficiency 2, 7
• Carry steroid emergency card at all times 7
• Educate on warning signs of adrenal crisis: severe weakness, confusion, abdominal pain, vomiting 2
• Instruct to triple dose during illness and seek emergency care if unable to take oral medications 2
• Provide written instructions for stress dosing 7

Special Populations

Pregnancy:

• Small adjustments in hydrocortisone and fludrocortisone may be needed, particularly in third trimester 7
• Stress-dose hydrocortisone during labor and delivery 7

Surgery:

• Mandatory endocrine consultation for pre-operative planning 2
• Administer stress-dose corticosteroids perioperatively based on surgical severity 2

Critical Pitfalls to Avoid

• Never attribute symptoms to chronic fatigue or functional disorders without definitively ruling out adrenal insufficiency 2
• Do not wait for hyperkalemia to diagnose PAI—it is absent in 50% of cases 1, 2
• Exogenous steroids (prednisolone, dexamethasone, inhaled fluticasone) suppress the HPA axis and confound diagnostic testing 2
• If treating suspected adrenal crisis but diagnosis uncertain, use dexamethasone 4 mg IV instead of hydrocortisone to allow subsequent cortisol testing 2
• APS-1 can present in adulthood with mild phenotypes—maintain high index of suspicion even in older patients with multiple autoimmune manifestations 5
• Mortality remains high in APS-1 despite treatment—structured follow-up in specialized centers is essential 5, 8