What is the best course of action for a patient with macrocytic anemia, indicated by elevated Mean Corpuscular Volume (MCV) and Mean Corpuscular Hemoglobin (MCH), low total iron (Hypoferritinemia) and high iron binding capacity (Hypertransferrinemia), with lab results showing total iron at 35 and iron binding capacity at 217?

Macrocytic Anemia with Low Iron and High TIBC: Diagnostic Approach

This patient presents with a paradoxical picture—elevated MCV and MCH suggest macrocytosis, but low serum iron (35) with high iron binding capacity (217) indicates iron deficiency, which typically causes microcytic anemia. This discordant pattern requires investigation for coexisting deficiencies, particularly vitamin B12 or folate deficiency masking underlying iron deficiency. 1

Understanding the Paradox

The key issue is that macrocytosis and iron deficiency do not typically coexist unless there are multiple concurrent deficiencies. 1

• Macrocytosis (elevated MCV/MCH) suggests: vitamin B12 deficiency, folate deficiency, medications (azathioprine, 6-mercaptopurine), alcohol abuse, hypothyroidism, or reticulocytosis 1
• Low iron (35) with high TIBC (217) definitively indicates iron deficiency, as raised total iron-binding capacity is a classic marker of depleted iron stores 1
• When both occur together: microcytosis from iron deficiency and macrocytosis from B12/folate deficiency can neutralize each other, resulting in a normal or even elevated MCV 1

Immediate Diagnostic Workup Required

Before initiating treatment, you must obtain the following tests to identify all deficiencies: 1

• Serum ferritin (most specific test for iron deficiency; <30 μg/L confirms iron deficiency without inflammation; <45 μg/L suggests deficiency even with mild inflammation) 1
• Vitamin B12 level (essential to rule out pernicious anemia or B12 deficiency) 1
• Folate level (must check before treating, as folate can mask B12 deficiency) 1
• Reticulocyte count (elevated suggests hemolysis or blood regeneration; low/normal suggests deficiency states) 1
• Complete blood count with RDW (red cell distribution width helps identify mixed deficiencies) 1
• Transferrin saturation (iron/TIBC × 100; <20% confirms iron deficiency) 2
• CRP or inflammatory markers (to assess if inflammation is affecting ferritin interpretation) 1

Critical Treatment Sequence

NEVER give folate before excluding and treating vitamin B12 deficiency, as folate supplementation can precipitate subacute combined degeneration of the spinal cord in undiagnosed B12 deficiency. 1

If B12 Deficiency is Confirmed:

Treat B12 deficiency FIRST and IMMEDIATELY: 1, 3

• With neurological symptoms: Hydroxocobalamin 1 mg IM on alternate days until no further improvement, then 1 mg IM every 2 months for life 1
• Without neurological symptoms: Hydroxocobalamin 1 mg IM three times weekly for 2 weeks, then 1 mg IM every 2-3 months for life 1
• Parenteral B12 is required for life in pernicious anemia; oral forms are not dependable 3

Then Address Iron Deficiency:

After initiating B12 treatment (if needed), start iron replacement: 1, 2

• Oral iron (ferrous sulfate 325 mg daily or on alternate days) is first-line for most patients 2
• Expect hemoglobin rise ≥10 g/L within 2 weeks if iron deficiency is the cause 1
• If no response to oral iron within 2-4 weeks, consider: malabsorption, continued bleeding, incorrect diagnosis, or need for parenteral iron 1, 2

Intravenous Iron Indications:

Consider IV iron if: 2

• Oral iron intolerance
• Malabsorption (celiac disease, post-bariatric surgery, atrophic gastritis)
• Ongoing blood loss
• Chronic inflammatory conditions
• Pregnancy (second/third trimester)

Investigate Underlying Causes

Investigation for the source of iron deficiency should be considered at any level of anemia, with stronger indication for more severe degrees. 1

Key Sources to Evaluate:

• Gastrointestinal bleeding (especially in men and non-menstruating women; colonoscopy if >50 years old) 1, 4
• Menstrual blood loss (in premenopausal women) 2, 4
• Malabsorption disorders (celiac disease, atrophic gastritis, H. pylori, IBD) 2
• Dietary inadequacy 2
• Medications (NSAIDs, anticoagulants) 2

For B12 deficiency, investigate: 1

• Pernicious anemia (most common cause)
• Malabsorption (ileal disease, post-gastrectomy, bariatric surgery)
• Dietary deficiency (strict vegans)

Common Pitfalls to Avoid

• Do NOT assume microcytosis must be present with iron deficiency—coexisting macrocytic causes can mask the typical microcytic picture 1
• Do NOT treat with folate before excluding B12 deficiency—this can cause irreversible neurological damage 1
• Do NOT rely on MCV alone—check RDW, as a high RDW indicates mixed cell sizes suggesting combined deficiencies 1
• Do NOT assume normal ferritin excludes iron deficiency in inflammatory states—ferritin up to 45-100 μg/L may still represent iron deficiency with inflammation 1
• Do NOT stop investigating after finding one deficiency—this patient likely has multiple concurrent problems 1