What is the appropriate workup and management for low serum ferritin?

Workup and Management of Low Serum Ferritin

Begin oral iron supplementation immediately with ferrous sulfate 65 mg elemental iron daily (or alternate-day dosing) while simultaneously investigating the underlying cause—do not delay treatment pending diagnostic workup. 1

Diagnostic Interpretation

Ferritin Thresholds for Iron Deficiency

• Ferritin <15 μg/L has 99% specificity for absolute iron deficiency, providing definitive confirmation without need for additional testing 1
• Ferritin 15-30 μg/L indicates depleted iron stores and warrants treatment 1
• Ferritin <45 μg/L provides optimal sensitivity-specificity balance (92% specificity) for clinical decision-making 1

Critical Caveat: Rule Out Inflammation

Ferritin is an acute-phase reactant that rises during inflammation, infection, or tissue damage, potentially masking true iron deficiency. 1 In patients with chronic inflammatory conditions (inflammatory bowel disease, chronic kidney disease, heart failure, cancer), the diagnostic threshold shifts upward to ferritin <100 μg/L. 1

Always calculate transferrin saturation (TSAT): Values <16-20% confirm iron deficiency even when ferritin appears normal or elevated due to inflammation. 1 The formula is: (serum iron × 100) ÷ total iron-binding capacity. 1

Mandatory Workup to Identify the Source

For All Adults

• Screen for celiac disease with tissue transglutaminase IgA antibodies—celiac disease accounts for 3-5% of iron deficiency cases and causes treatment failure if missed 1
• Test for Helicobacter pylori non-invasively (stool antigen or urea breath test) as it impairs iron absorption 1

For Adult Men and Postmenopausal Women

Urgent bidirectional endoscopy (upper GI gastroscopy + colonoscopy) is mandatory because iron deficiency may be the sole manifestation of gastrointestinal malignancy. 1

For Premenopausal Women

GI investigation is conditional rather than mandatory unless specific red flags are present. 1 First assess menstrual blood loss history, as heavy menses are the most common cause 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

Treatment Protocol

First-Line: Oral Iron Supplementation

Start ferrous sulfate 65 mg elemental iron daily (equivalent to 325 mg ferrous sulfate tablet). 1 Alternatively, 60-65 mg every other day improves absorption by 30-50% and reduces GI side effects. 1

• Take on empty stomach for optimal absorption, or with meals if GI symptoms occur 1
• Expected side effects: constipation, nausea, diarrhea—can be minimized by taking with food or switching to alternate-day dosing 1
• Expected response: hemoglobin should rise ≥10 g/L within 2 weeks 1

Continue oral iron for 3 months after hemoglobin normalizes to achieve target ferritin >100 ng/mL and prevent rapid recurrence. 1 Standard-dose oral iron does not cause ferritin to rise until hemoglobin levels normalize. 2

When to Switch to Intravenous Iron

Use IV ferric carboxymaltose (15 mg/kg, maximum 1000 mg per dose) when any of the following apply: 1

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

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

Follow-Up and Monitoring

• Repeat CBC and ferritin at 8-10 weeks to assess response to treatment 1
• Target ferritin >100 ng/mL to restore iron stores and prevent recurrence 1
• If no improvement occurs, consider malabsorption, non-compliance, ongoing blood loss, or need for IV iron 1

For high-risk groups (menstruating females, vegetarians, athletes, regular blood donors), screen ferritin every 6-12 months to detect early depletion before anemia develops. 1

Common Pitfalls to Avoid

• Do not assume normal ferritin excludes iron deficiency—transferrin saturation is the key parameter for assessing iron availability when inflammation is present 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
• In patients with normocytic anemia and ferritin >50 μg/L, do not automatically assume adequate iron stores—consider checking soluble transferrin receptor or sTfR-ferritin index to exclude functional iron deficiency 3