How should low ferritin be evaluated and managed?

Evaluation and Management of Low Ferritin

Begin oral iron supplementation immediately with ferrous sulfate 65 mg elemental iron daily (or alternate-day dosing) while simultaneously investigating the underlying cause, because low ferritin represents depleted iron stores that require treatment even before anemia develops. 1, 2

Diagnostic Thresholds and Interpretation

Ferritin < 15 µg/L has 99% specificity for absolute iron deficiency and definitively confirms the diagnosis. 1, 3 However, this threshold is too restrictive for clinical practice:

• Ferritin 15–30 µg/L indicates depleted body iron stores and warrants treatment 1, 3
• Ferritin < 45 µg/L provides optimal sensitivity-specificity balance (specificity 0.92) for clinical decision-making 1, 3
• In patients with chronic inflammation (IBD, CKD, heart failure), the diagnostic threshold shifts upward to < 100 µg/L 1, 2

Critical Caveat: Ferritin is an Acute-Phase Reactant

Ferritin rises during inflammation, infection, or tissue damage independently of iron status, potentially masking true iron deficiency. 1, 4 When ferritin is 30–100 µg/L:

• Check CRP and ESR to detect inflammation 1
• Calculate transferrin saturation (TSAT): (serum iron × 100) ÷ TIBC 1
• TSAT < 16–20% confirms iron deficiency even when ferritin is elevated by inflammation 1, 2, 3

Immediate Treatment Protocol

Start oral ferrous sulfate 65 mg elemental iron daily or 60–65 mg every other day; alternate-day dosing improves absorption by 30–50% and reduces gastrointestinal side effects. 1, 2, 3

• Take on empty stomach for optimal absorption, or with meals if gastrointestinal symptoms occur 1
• Expected response: hemoglobin should rise by ≥ 10 g/L within 2 weeks 1, 3
• Continue oral iron for 3 months after hemoglobin normalizes to achieve ferritin > 100 ng/mL and fully restore iron stores 1, 2

Alternative Oral Formulations

When ferrous sulfate is not tolerated, use ferrous bisglycinate 30–60 mg elemental iron daily or ferrous gluconate/fumarate at equivalent doses. 1

Mandatory Investigation of Underlying Causes

All Patients Require:

1. Screen for celiac disease with tissue transglutaminase IgA antibodies—celiac disease accounts for 3–5% of iron-deficiency cases and causes treatment failure when missed 1, 2, 3
2. Test for Helicobacter pylori infection (stool antigen or urea-breath test) because the organism impairs iron absorption 1, 2, 3

Indications for Bidirectional Endoscopy:

Reserve upper and lower GI endoscopy for: 1, 2

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

Special Consideration for Premenopausal Women:

In premenopausal women < 50 years with heavy menstrual bleeding and no GI symptoms, empiric oral iron supplementation without immediate endoscopy is appropriate. 1, 2 However, GI evaluation becomes mandatory if oral iron fails after 8–10 weeks. 1

Indications for Intravenous Iron

Switch to intravenous ferric carboxymaltose (15 mg/kg, maximum 1000 mg per dose) when any of the following are present: 1, 5, 2, 3

Clinical Indication	Rationale
Oral iron intolerance	Severe nausea, constipation, or diarrhea preventing adherence [1,2]
Malabsorption syndromes	Celiac disease, IBD, post-bariatric surgery [1,2,3]
Ongoing blood loss	Blood loss exceeding oral replacement capacity [1,2]
Chronic inflammatory conditions	CKD, heart failure, cancer, IBD [6,1,2,3]
Pregnancy	Second and third trimesters [1,2,3]
Treatment failure	No hemoglobin response after 8–10 weeks of adequate oral iron [1,2]

IV iron produces reticulocytosis within 3–5 days and yields a mean hemoglobin increase of ≈ 8 g/L over 8 days, demonstrating superior efficacy in these populations. 1, 5

Special Evidence for Heart Failure:

In patients with heart failure and iron deficiency (ferritin < 100 ng/mL or ferritin 100–300 ng/mL with TSAT < 20%), intravenous ferric carboxymaltose improves 6-minute walk distance by 25 meters compared to placebo and should be used regardless of anemia status. 6, 5

Follow-Up and Monitoring

• Repeat CBC and ferritin at 8–10 weeks to assess response 1, 2, 3
• Target ferritin > 100 ng/mL to restore iron stores and prevent recurrence 1, 2
• For high-risk groups (menstruating females, vegetarians, athletes), screen ferritin every 6–12 months 1, 2

Failure to Respond Indicates:

• Ongoing occult blood loss requiring urgent GI evaluation 1, 2
• Undiagnosed celiac disease or H. pylori infection 1, 2
• Malabsorption requiring switch to IV iron 1, 2
• Non-compliance with oral therapy 1

Critical Pitfalls to Avoid

1. Do not assume ferritin will normalize spontaneously—dietary iron alone is insufficient to replenish stores within a clinically acceptable timeframe 1
2. Do not discontinue iron therapy once hemoglobin normalizes—an additional 3 months of supplementation is required for ferritin to reach > 100 ng/mL 1, 2
3. Do not overlook celiac disease screening (3–5% prevalence)—missing this diagnosis leads to treatment failure 1, 2, 3
4. Do not delay endoscopic evaluation in high-risk patients (age ≥ 50, alarm symptoms, treatment failure)—GI malignancy can present solely with iron deficiency 1, 2
5. Do not interpret ferritin in isolation when inflammation is present—always calculate TSAT to confirm true iron deficiency 1, 4, 3