In a 23‑year‑old woman presenting with severe anemia, hypothyroidism, and hypotension, what is the most likely diagnosis and which investigations should be performed?

Most Likely Diagnosis: Primary Adrenal Insufficiency (Addison's Disease)

In a 23-year-old woman presenting with severe anemia, hypothyroidism, and hypotension, primary adrenal insufficiency is the most likely unifying diagnosis, representing an autoimmune polyglandular syndrome.

Clinical Reasoning

This triad strongly suggests autoimmune polyglandular syndrome (APS), where multiple endocrine glands are simultaneously affected by autoimmune destruction 1, 2. The combination of:

• Severe anemia (likely multifactorial)
• Hypothyroidism (autoimmune thyroid disease)
• Hypotension (suggesting adrenal insufficiency with mineralocorticoid deficiency)

...points toward primary adrenal insufficiency as the critical missing diagnosis that ties these findings together 3.

Why Adrenal Insufficiency is the Priority

Hypotension in the setting of hypothyroidism is paradoxical and demands immediate investigation for adrenal insufficiency 4. Hypothyroidism typically causes mild hypertension and narrowed pulse pressure, not hypotension 4. The presence of hypotension should immediately raise suspicion for concurrent adrenal insufficiency 3.

Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases and can be indistinguishable from other causes if adrenal function is not specifically assessed 3. The absence of hyperkalemia cannot rule out adrenal insufficiency, as it occurs in only approximately 50% of cases 3.

Immediate Investigations Required

Critical First-Line Tests (Morning, Before Treatment)

If the patient is hemodynamically unstable with suspected adrenal crisis, treatment must NEVER be delayed for diagnostic procedures 3. Immediately administer 100 mg IV hydrocortisone and 0.9% saline infusion at 1 L/hour, drawing blood for cortisol and ACTH before steroid administration if feasible 3.

If the patient is stable, obtain the following tests preferably at 8 AM:

• Morning serum cortisol and plasma ACTH (first-line diagnostic tests) 3

  • Basal cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH (>300 pg/mL) is diagnostic of primary adrenal insufficiency 3
  • Basal cortisol <400 nmol/L with elevated ACTH raises strong suspicion 3

• Basic metabolic panel (sodium, potassium, glucose) 3

  • Hyponatremia plus hyperkalemia suggests primary adrenal insufficiency 3
  • Hyponatremia without hyperkalemia may still represent adrenal insufficiency 3

• Complete blood count with reticulocyte count 5

• Thyroid function tests (TSH, free T4) 4

Confirmatory Testing

Cosyntropin (Synacthen) stimulation test if morning cortisol is indeterminate (5-18 μg/dL) 3:

• Administer 0.25 mg (250 mcg) cosyntropin IV or IM 3
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes 3
• Peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 3
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes adrenal insufficiency 3

Etiologic Workup for Primary Adrenal Insufficiency

Once adrenal insufficiency is confirmed:

• 21-hydroxylase (anti-adrenal) autoantibodies 3

  • Positive in ~85% of autoimmune Addison's disease 3
  • If positive, no further etiologic testing needed 3

• If autoantibodies negative: CT imaging of adrenals to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative disease 3

• In males with negative antibodies: Very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy 3

Anemia Workup

The anemia in this patient is likely multifactorial 6, 7, 5:

• Serum iron profile (iron, TIBC, ferritin) 4, 5

  • Microcytic anemia occurs in 43.3% of hypothyroid patients, usually from iron deficiency 5

• Vitamin B12 and folate levels 5

  • Macrocytic anemia from B12 deficiency occurs in 10% of hypothyroid patients 5
  • Pernicious anemia occurs 20 times more frequently in hypothyroidism 7

• Anti-parietal cell antibodies 2, 5

  • To screen for pernicious anemia, which commonly coexists with autoimmune endocrinopathies 2

• Anti-tissue transglutaminase antibodies (with total IgA) 3

  • To screen for celiac disease, which increases risk of anemia in autoimmune thyroid disease 6

• Peripheral blood smear 7

  • Normocytic normochromic anemia is most common (51.6%) in hypothyroidism 5
  • Acanthocytosis suggests hypothyroidism in ~90% of cases 7

• Reticulocyte count 5

  • Reticulopenia suggests bone marrow suppression from hypothyroidism 7

Additional Autoimmune Screening

Given the high likelihood of autoimmune polyglandular syndrome:

• Anti-thyroid peroxidase (anti-TPO) antibodies 5
• Fasting glucose and HbA1c 4
  • To screen for type 1 diabetes mellitus, which can coexist 1

Common Pitfalls to Avoid

Never attribute hypotension to hypothyroidism alone 4. Hypothyroidism causes mild hypertension, not hypotension 4. Hypotension in a hypothyroid patient mandates evaluation for adrenal insufficiency 3.

Do not rely on the presence of hyperkalemia to diagnose or exclude adrenal insufficiency 3. Hyperkalemia is present in only ~50% of cases 3.

Never delay treatment of suspected adrenal crisis for diagnostic testing 3. If the patient presents with unexplained collapse, severe hypotension, or altered mental status, immediately give 100 mg IV hydrocortisone and aggressive saline resuscitation 3.

Do not assume anemia is solely due to hypothyroidism 6, 7, 5. Anemia in hypothyroidism is often multifactorial, requiring comprehensive workup for iron deficiency, B12 deficiency, pernicious anemia, and celiac disease 6, 5.

Adrenal insufficiency must be excluded before diagnosing SIADH in patients with hyponatremia, as both conditions present with similar laboratory findings 3.