Why does hemoglobin (Hgb) continue to fall in patients with iron deficiency anemia despite iron supplementation?

Why Hemoglobin Continues to Fall Despite Iron Supplementation

When hemoglobin fails to rise by at least 1-2 g/dL after 3-4 weeks of iron therapy, you must immediately reassess for non-adherence, ongoing blood loss, malabsorption, inflammatory conditions blocking iron utilization, or alternative diagnoses masquerading as iron deficiency anemia. 1

Systematic Approach to Non-Response

Expected Response Timeline and Failure Definition

• Normal response: Hemoglobin should increase by approximately 1-2 g/dL within 3-4 weeks of adequate oral iron therapy 2, 1
• Treatment failure: Lack of this hemoglobin rise indicates immediate need for reassessment rather than continuing ineffective therapy 1
• Among patients who failed oral iron after 14 days, only 21% responded to an additional 4 weeks of oral therapy, demonstrating futility of prolonging ineffective treatment 1

Primary Causes of Continued Hemoglobin Decline

1. Ongoing Blood Loss Exceeding Iron Replacement

• The most common reason for persistent anemia is that gastrointestinal or other blood loss exceeds the intestinal capacity to absorb supplemented iron 3
• Patients with intestinal angiodysplasia, occult malignancy, or heavy menstrual bleeding may lose iron faster than oral supplementation can replace it 3, 4
• Action required: Complete upper endoscopy with small bowel biopsy and colonoscopy (or CT colonography) to identify bleeding sources 2, 1

2. Non-Adherence Due to Gastrointestinal Side Effects

• Nausea, constipation, and dyspepsia are common causes of non-compliance with oral iron 1
• Solution: Switch to alternate-day dosing (ferrous sulfate 200 mg once daily or every other day), which improves tolerance while maintaining effectiveness 1, 4
• Consider alternative formulations (ferrous gluconate, ferrous fumarate) if ferrous sulfate is not tolerated 2

3. Malabsorption Conditions

• Celiac disease, atrophic gastritis, Helicobacter pylori infection, and post-bariatric surgery states impair iron absorption 2, 4
• Testing required: Check celiac serology (tissue transglutaminase antibody) in all patients with refractory anemia 1
• H. pylori should be sought by non-invasive testing if IDA persists after normal endoscopy, and eradicated if present 2

4. Inflammatory Conditions and Anemia of Chronic Disease

• Inflammation upregulates hepcidin, which blocks intestinal iron absorption and traps iron in storage sites, preventing response to oral therapy 1
• Diagnostic criteria for anemia of chronic disease (ACD): Ferritin >100 μg/L with transferrin saturation <20% in the presence of inflammation 2
• If ferritin is 30-100 μg/L, a combination of true iron deficiency and ACD is likely 2
• Check C-reactive protein to identify inflammatory conditions blocking iron utilization 1
• Common culprits: inflammatory bowel disease (13-90% have iron deficiency), chronic kidney disease (24-85%), heart failure (37-61%), and cancer (18-82%) 4

5. Alternative or Coexisting Diagnoses

• Vitamin B12 or folate deficiency: Can coexist with iron deficiency, particularly in malabsorption syndromes 2
• Thalassemia minor or sickle cell trait: In patients of African, Mediterranean, or Southeast Asian ancestry, hemoglobin electrophoresis should be performed to exclude these causes of microcytic anemia unresponsive to iron 1
• Myelodysplastic syndrome, hypothyroidism, chronic kidney disease: Consider these if standard workup is unrevealing 2

Laboratory Reassessment Protocol

When oral iron fails, perform the following tests 1:

• Repeat complete blood count with red cell indices
• Serum ferritin and transferrin saturation
• C-reactive protein to assess for inflammation
• Celiac serology (tissue transglutaminase antibody)
• Hemoglobin electrophoresis if appropriate ancestry
• Renal function tests if not recently checked

Transition to Intravenous Iron

Switch to intravenous iron if: 2, 1

• No hemoglobin increase after 4 weeks of documented adherence to oral therapy
• Intolerance to at least two different oral iron preparations
• Malabsorption conditions (celiac disease, post-bariatric surgery)
• Chronic inflammatory conditions (IBD, CKD, heart failure, cancer)
• Hemoglobin <10 g/dL
• Ongoing blood loss that exceeds oral replacement capacity

IV iron is superior in non-responders: 65% of oral iron failures responded to IV iron versus only 21% who responded to continued oral therapy 1

Preferred IV formulations: 2, 1

• Ferric carboxymaltose 1000 mg over 15 minutes
• Iron dextran as total dose infusion (20 mg/kg over 6 hours)
• Iron sucrose 200 mg over 10 minutes (requires multiple doses)

Critical safety requirement: Resuscitation facilities must be available for all intravenous iron administration due to anaphylaxis risk (0.6-0.7% with iron dextran) 2, 1

Common Pitfalls to Avoid

• Do not continue ineffective oral iron beyond 4 weeks without reassessment—this delays appropriate diagnosis and treatment 1
• Do not assume compliance—directly ask about adherence and side effects 1
• Do not fail to investigate the underlying cause while supplementing iron 2, 1
• Do not overlook inflammatory conditions that render oral iron ineffective through hepcidin upregulation 1
• Do not assess response before 3-4 weeks, as earlier evaluation may miss the expected trajectory 1