Should a patient with normal ferritin but low serum iron be treated for iron deficiency?

Should Normal Ferritin with Low Serum Iron Be Treated?

Yes, a patient with normal ferritin but low serum iron should be treated if transferrin saturation is <16–20%, because this pattern indicates functional iron deficiency—insufficient iron is available for erythropoiesis despite seemingly adequate storage iron. 1

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Understanding the Laboratory Pattern

• Low serum iron combined with low transferrin saturation (TSAT <16–20%) confirms iron deficiency, regardless of ferritin level, because TSAT reflects iron readily available for red blood cell production rather than total body stores. 1

• Ferritin alone provides an incomplete picture of iron status; it must be interpreted alongside TSAT and clinical context. 1

• "Normal" ferritin does not exclude iron deficiency in three critical scenarios:

  • Inflammation or chronic disease: Ferritin rises as an acute-phase reactant, masking depleted iron stores. A ferritin of 30–100 μg/L with elevated CRP/ESR may represent true iron deficiency. 1, 2
  • Functional iron deficiency: Iron is sequestered in storage sites (normal or elevated ferritin) but unavailable for erythropoiesis (low TSAT). This occurs in chronic kidney disease, heart failure, inflammatory bowel disease, and cancer. 1, 2
  • Early iron deficiency: Ferritin 15–50 μg/L may appear "normal" but represents depleted stores before anemia develops. 1, 3

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Diagnostic Algorithm

Step 1: Calculate Transferrin Saturation

• TSAT = (serum iron × 100) ÷ TIBC. 1

• If TSAT <16–20%, iron deficiency is confirmed and treatment should be initiated immediately. 1

Step 2: Assess for Inflammation

• Order CRP and ESR to detect occult inflammation. 1

• If CRP/ESR are elevated:

  • Ferritin <30 μg/L → absolute iron deficiency. 1
  • Ferritin 30–100 μg/L → mixed iron deficiency (absolute + functional). 1
  • Ferritin >100 μg/L with TSAT <20% → anemia of chronic disease (inflammatory iron block). 1

• If CRP/ESR are normal:

  • Ferritin <15 μg/L → absolute iron deficiency (99% specificity). 1
  • Ferritin 15–50 μg/L → early iron deficiency with low stores. 1, 3

Step 3: Consider Soluble Transferrin Receptor (sTfR) if Discordant Results

• Elevated sTfR confirms true iron deficiency, even in the presence of inflammation, because sTfR is not affected by acute-phase reactions. 1

• sTfR/log ferritin ratio >1.5–2.0 indicates iron-deficient erythropoiesis despite "normal" ferritin. 1, 4

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Treatment Protocol

Initiate Oral Iron Supplementation Immediately

• Start ferrous sulfate 65 mg elemental iron daily (or ferrous bisglycinate 30–60 mg daily). 1

• Alternate-day dosing (60–65 mg every other day) improves absorption by 30–50% and reduces gastrointestinal side effects (constipation, nausea, diarrhea). 1

• Take on an empty stomach for optimal absorption, or with meals if GI symptoms occur. 1

• Expected response: hemoglobin should rise by ≥10 g/L within 2 weeks. 1

Investigate the Underlying Cause

• Screen for celiac disease with tissue transglutaminase (tTG) antibodies; celiac disease accounts for 3–5% of iron deficiency cases and causes treatment failure if missed. 1

• Test for Helicobacter pylori infection (stool antigen or urea breath test), as it impairs iron absorption. 1

• Assess menstrual blood loss history in premenopausal women, as heavy menses are the most common cause of iron deficiency in this population. 1

• Reserve bidirectional endoscopy for:

  • Age ≥50 years (higher malignancy risk). 1
  • GI symptoms (abdominal pain, altered bowel habits, visible blood). 1
  • Positive celiac or H. pylori testing requiring confirmation. 1
  • Failure to respond to adequate oral iron after 8–10 weeks. 1
  • Strong family history of colorectal cancer. 1

Switch to Intravenous Iron if Indicated

• Use IV ferric carboxymaltose (15 mg/kg, max 1000 mg per dose) when:

  • Oral iron intolerance (severe nausea, constipation, diarrhea). 1
  • Malabsorption (celiac disease, inflammatory bowel disease, post-bariatric surgery). 1
  • Ongoing blood loss exceeding oral replacement capacity. 1
  • Chronic inflammatory conditions (CKD, heart failure, cancer). 1
  • Pregnancy in the second/third trimester. 1

• IV iron produces reticulocytosis within 3–5 days and yields a mean hemoglobin increase of ≈8 g/L over 8 days. 1

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Follow-Up and Monitoring

• Repeat CBC and ferritin at 8–10 weeks to assess response to treatment. 1

• Target ferritin >100 ng/mL to fully replenish iron stores and prevent recurrence. 1

• Continue oral iron for 3 months after hemoglobin normalizes, as absorbed iron is preferentially used for red-cell production before refilling storage compartments. 1

• For high-risk groups (menstruating females, vegetarians, athletes, blood donors), schedule ferritin screening every 6–12 months. 1

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Critical Pitfalls to Avoid

• Do not assume "normal" ferritin excludes iron deficiency; TSAT is the key parameter for assessing iron availability for erythropoiesis. 1

• Do not overlook celiac disease screening; its 3–5% prevalence in iron deficiency cases leads to treatment failure if missed. 1

• Do not discontinue iron therapy once hemoglobin normalizes; an additional 3 months of supplementation is required for ferritin to reach >100 ng/mL. 1

• Do not delay endoscopic evaluation in high-risk patients (age ≥50, alarm symptoms, treatment failure), as GI malignancy can present solely with iron deficiency. 1

• Do not supplement iron when TSAT <20% with ferritin >300 ng/mL; this represents anemia of chronic inflammation where iron is sequestered and supplementation will not improve anemia. 1