What is Schmidt syndrome (autoimmune polyendocrine syndrome type 2) and what are the recommended diagnostic work‑up and treatment plan?

Schmidt Syndrome (Autoimmune Polyendocrine Syndrome Type 2)

Schmidt syndrome is a life-threatening autoimmune disorder defined by the presence of Addison's disease (primary adrenal insufficiency) combined with autoimmune thyroid disease and/or type 1 diabetes mellitus, requiring immediate recognition and lifelong hormone replacement therapy to prevent fatal adrenal crisis. 1, 2

Definition and Clinical Components

Schmidt syndrome, also known as autoimmune polyendocrine syndrome type 2 (APS-2), consists of the following mandatory and associated features:

Mandatory component:

• Primary adrenal insufficiency (Addison's disease) - must be present 2, 3

Plus at least one of:

• Autoimmune thyroid disease (Hashimoto's thyroiditis or Graves' disease) 1, 4
• Type 1 diabetes mellitus 2, 3

Additional associated autoimmune conditions (occur in ~50% of patients):

• Hypergonadotropic hypogonadism 5
• Vitiligo 5
• Pernicious anemia 1
• Celiac disease 6
• Autoimmune hepatitis 5

Epidemiology and Genetics

• Predominantly affects women (3:1 female-to-male ratio) in their third to fourth decade of life 5
• Autosomal dominant inheritance with incomplete penetrance 2
• Associated genetic markers include HLA-DR3, HLA-DR4, CTLA-4, PTPN22, and CD25-IL-2 2
• Can occur in young males without family history, though less common 3

Diagnostic Work-Up

Clinical Recognition

Cardinal symptoms of adrenal insufficiency (Addison's disease):

• Hyperpigmentation (especially sun-exposed areas, gums, palmar creases) - highly specific for primary adrenal insufficiency 1, 3
• Profound fatigue and weakness developing over months 1
• Orthostatic hypotension 1
• Salt craving - highly specific for mineralocorticoid deficiency 1
• Unintentional weight loss 1
• Nausea, vomiting, and morning anorexia 1
• Muscle pain or cramps 1

Thyroid disease manifestations:

• Hypothyroidism symptoms (fatigue, cold intolerance, weight gain) 4
• Hyperthyroid phase can occur initially in Hashimoto's thyroiditis (Hashitoxicosis) 4

Diabetes manifestations:

• Polyuria, polydipsia, weight loss 3
• Hypoglycemia may be the presenting feature due to cortisol deficiency 2, 3

Laboratory Diagnostic Algorithm

Step 1: Confirm primary adrenal insufficiency

• Paired measurement of serum cortisol and plasma ACTH (first-line diagnostic test) 6
  • Serum cortisol <250 nmol/L with elevated ACTH is diagnostic 6
  • Serum cortisol <400 nmol/L with elevated ACTH raises strong suspicion 6
• If equivocal: ACTH stimulation test (cosyntropin 0.25 mg IM or IV) 6
  • Peak cortisol <500 nmol/L is diagnostic of adrenal insufficiency 6, 7

Step 2: Identify electrolyte abnormalities

• Hyponatremia (present in 90% of cases) 1, 7
• Hyperkalemia (present in ~50% of cases) 6, 3
• Elevated plasma renin activity 6, 1
• Low aldosterone 6

Step 3: Determine autoimmune etiology

• Measure 21-hydroxylase (anti-adrenal) autoantibodies 6
• If antibodies negative, obtain CT imaging of adrenals 6
• In males, measure very long-chain fatty acids to exclude adrenoleukodystrophy 6

Step 4: Screen for associated autoimmune conditions

• Thyroid function tests (TSH, free T4) 3, 4
• Anti-thyroid peroxidase (anti-TPO) antibodies 5
• Fasting glucose and HbA1c 3
• Anti-islet cell antibodies if diabetes suspected 2

Step 5: Screen for other autoimmune diseases

• Complete blood count (for pernicious anemia) 5
• Vitamin B12 level 1
• Anti-parietal cell antibodies 5
• Tissue transglutaminase antibodies (for celiac disease) 6
• FSH and estradiol (for hypogonadism) 5
• ANA if clinically indicated 5

Step 6: Exclude APS-1 in children and young adults

• Consider APS-1 if patient presents with hypoparathyroidism and/or chronic mucocutaneous candidiasis 6
• Test for anti-interferon omega antibodies or AIRE gene mutations 6

Critical Diagnostic Pitfalls

Do not delay treatment for diagnostic confirmation:

• If acute adrenal crisis suspected (hypotension, collapse, severe vomiting), immediately administer IV hydrocortisone 100 mg and 0.9% saline without waiting for cortisol results 7
• Treatment should never be delayed by diagnostic procedures 6

Do not rely solely on electrolyte abnormalities:

• Sodium may be only marginally reduced 6
• Potassium is elevated in only ~50% of cases at diagnosis 6, 1
• Severe vomiting can cause hypokalaemia and alkalosis, masking the diagnosis 6

Recognize that initiating thyroid hormone replacement before treating adrenal insufficiency can precipitate fatal adrenal crisis:

• Thyroxine increases cortisol clearance and metabolic rate 5
• Always treat adrenal insufficiency first, then thyroid disease 5

Be aware of atypical presentations:

• Hypoglycemia as presenting feature (cortisol is counter-regulatory hormone) 2, 3
• Psychiatric symptoms mimicking anxiety or depression 8
• Acute abdomen requiring surgical evaluation 4
• Thyroid storm precipitating adrenal crisis 4

Treatment Plan

Acute Adrenal Crisis Management (Life-Threatening Emergency)

Immediate interventions:

• IV hydrocortisone 100 mg bolus, then 100 mg every 6-8 hours 6
• Isotonic (0.9%) sodium chloride solution at 1 L/hour initially until hemodynamic improvement 6
• Identify and treat precipitating cause (infection, trauma, surgery) 6
• Monitor electrolytes, glucose, and vital signs closely 6

Chronic Maintenance Therapy

Glucocorticoid replacement (treat adrenal insufficiency FIRST):

• Hydrocortisone 15-25 mg daily in split doses 6
  • First dose immediately upon waking 6
  • Last dose at least 6 hours before bedtime 6
• Alternative: Cortisone acetate 18.75-31.25 mg daily 6
• Children: 6-10 mg/m² body surface area 6
• Use lowest dose compatible with health and well-being 6

Mineralocorticoid replacement:

• Fludrocortisone 50-200 μg once daily 6
• Children and younger adults may require higher doses 6
• If hypertension develops, reduce dose but do not stop 6
• Advise liberal salt intake 6
• Avoid liquorice and grapefruit juice (interfere with mineralocorticoid action) 6

Thyroid hormone replacement (initiate AFTER adrenal insufficiency is treated):

• Levothyroxine for hypothyroidism 4, 5
• Antithyroid drugs (methimazole or propylthiouracil) if hyperthyroid phase present 4
• Monitor TSH and adjust dose accordingly 4

Diabetes management (if present):

• Insulin therapy for type 1 diabetes 3
• Monitor for hypoglycemia risk due to cortisol deficiency 2

Stress Dosing and Sick Day Rules

Minor illness (fever, cold, gastroenteritis):

• Double or triple usual hydrocortisone dose 6
• Continue until recovered 6

Major surgery or invasive procedures:

• IV or IM hydrocortisone 100 mg perioperatively 6
• Continue increased oral doses postoperatively 6

Pregnancy considerations:

• Small dose adjustments may be needed, especially in third trimester 6
• Parenteral hydrocortisone during delivery 6

Patient Education and Safety Measures

Mandatory safety precautions:

• Wear medical alert identification jewelry 6
• Carry steroid emergency card at all times 6
• Provide emergency hydrocortisone injection kit for self-administration 6
• Educate patient and family on recognizing adrenal crisis 6
• Teach stress dosing protocols 6

Long-Term Monitoring

Regular surveillance required:

• Monitor for development of additional autoimmune diseases (occurs in ~50% of patients) 1
• Annual screening for thyroid dysfunction, diabetes, pernicious anemia, and celiac disease 1
• Assess adequacy of hormone replacement (symptoms, blood pressure, electrolytes) 6
• Monitor for signs of over-replacement (hypertension, weight gain, osteoporosis) 6

Prognosis

With appropriate lifelong hormone replacement therapy, patients can have normal life expectancy and quality of life. However, delayed diagnosis or inadequate treatment can result in life-threatening adrenal crisis with high mortality. The insidious nature of symptom development often leads to delayed diagnosis, emphasizing the importance of clinical vigilance for this syndrome. 1, 8