What are the causes and treatment options for low ferritin levels, indicative of iron deficiency?

Causes and Treatment of Low Ferritin

Low ferritin indicates depleted iron stores and warrants investigation and treatment even before anemia develops, with oral iron supplementation as first-line therapy for most patients, while intravenous iron is reserved for specific clinical scenarios including active inflammation, malabsorption, or intolerance to oral therapy. 1

Causes of Low Ferritin

Primary Mechanisms of Iron Depletion

Blood loss is responsible for 94% of iron deficiency cases and must be systematically investigated: 2, 3

• Gastrointestinal bleeding from any source (ulcers, polyps, malignancy, inflammatory bowel disease) 3
• Menstrual blood loss, particularly heavy or prolonged menstruation in premenopausal women 1, 3
• Occult bleeding that may not be clinically apparent 3

Inadequate dietary intake is a fundamental cause: 3

• Vegetarian/vegan diets with substantially lower iron bioavailability compared to meat-based diets 3
• Poor nutritional intake following bariatric surgery 3
• Eating disorders and underweight status 4

Malabsorption conditions that impair iron uptake: 1

• Celiac disease requiring adherence to gluten-free diet 1
• Post-bariatric surgical procedures (especially gastric bypass) creating anatomical changes that limit absorption 3
• Helicobacter pylori infection 1
• Atrophic gastritis 5

Chronic inflammatory conditions causing functional iron deficiency: 3

• Inflammatory bowel disease (affects 13-90% of patients) 3
• Chronic kidney disease 5
• Heart failure 5
• Cancer 5

High-Risk Populations Requiring Enhanced Vigilance

• Menstruating females (require twice-yearly screening) 6, 3
• Pregnant women (up to 84% affected in third trimester) 5
• Athletes and high-performance sport participants 3
• Regular blood donors 6
• Males (require annual screening) 3

Diagnostic Thresholds and Interpretation

Critical Ferritin Cut-offs

Without inflammation present: 6, 3

• Ferritin <15 μg/L has 99% specificity for absolute iron deficiency and confirms diagnosis definitively 6, 3
• Ferritin 15-30 μg/L indicates depleted iron stores requiring intervention 6, 3
• Ferritin <45 μg/L provides optimal sensitivity-specificity balance (92% specificity) for clinical decision-making 1, 6

With inflammation present (elevated CRP/ESR): 1

• Ferritin <100 μg/L is diagnostic of iron deficiency in inflammatory conditions 1, 3
• Transferrin saturation <20% serves as complementary marker when inflammation elevates ferritin 1, 3

Common Diagnostic Pitfall

Ferritin is an acute-phase reactant that rises during inflammation, infection, or tissue damage, potentially masking true iron deficiency. 6, 3 Always check CRP or ESR when ferritin is 30-100 μg/L to avoid missing iron deficiency in the setting of inflammation. 6

Treatment Algorithm

Step 1: Initiate Oral Iron Supplementation (First-Line for Most Patients)

Oral iron is recommended as first-line treatment in patients with: 1

• Clinically inactive disease 1
• Mild anemia 1
• No previous intolerance to oral iron 1
• Ferritin <30 μg/L without inflammation 3
• Ferritin 30-100 μg/L with transferrin saturation <20% 3

Specific oral iron formulations and dosing: 1, 7, 4

• Ferrous sulfate 325 mg daily (65 mg elemental iron) 7, 5
• Ferrous fumarate 325 mg daily 8
• Ferrous gluconate 324 mg daily 9
• Optimal dosing: 30-60 mg elemental iron daily 6, 4
• Alternate-day dosing (60 mg every other day) may improve absorption and reduce gastrointestinal side effects compared to daily dosing 1, 6

Administration instructions to optimize absorption: 1

• Take on empty stomach for optimal absorption 1, 6
• If gastrointestinal symptoms occur, take with meals (particularly with meat protein) 1
• Add 500 mg vitamin C to improve absorption even with calcium or fiber present 1

Expected side effects: 1, 6

• Constipation, nausea, or diarrhea (affects approximately 50% of patients) 1, 2
• Minimize by taking with food or switching to alternate-day dosing 1, 6

Step 2: Consider Intravenous Iron (First-Line in Specific Scenarios)

Intravenous iron should be considered as first-line treatment in patients with: 1

• Clinically active inflammatory bowel disease 1
• Active inflammation with compromised absorption 1
• Previous intolerance to oral iron 1
• Hemoglobin below 100 g/L 1
• Need for erythropoiesis-stimulating agents 1
• Heart failure (to increase exercise capacity) 2
• Celiac disease with inadequate response to oral iron despite gluten-free diet 1
• Second and third trimesters of pregnancy 5
• Ongoing blood loss unresponsive to oral therapy 1, 5

Intravenous iron is more effective, shows faster response, and is better tolerated than oral iron in these populations. 1

Step 3: Follow-Up and Monitoring

Assess response to treatment: 6, 4

• Repeat CBC and ferritin in 8-10 weeks (for oral iron) or 2-4 weeks (initial assessment) 6, 2
• Target ferritin >100 ng/mL to restore iron stores and prevent recurrence 6

If no improvement after 8-10 weeks, consider: 6

• Malabsorption 6
• Non-compliance 6
• Ongoing blood loss 6
• Need for intravenous iron 6

Long-term monitoring for recurrent low ferritin: 1, 6

• Screen every 6-12 months in high-risk populations (menstruating females, vegetarians, athletes) 1, 6
• Re-treat when ferritin drops below 100 μg/L after successful treatment 3

Critical Safety Warning

Do not continue daily iron supplementation once ferritin normalizes, as this is potentially harmful. 6, 4 Long-term daily oral or intravenous iron supplementation in the presence of normal or high ferritin values is not recommended. 4

Investigation of Underlying Causes

For Premenopausal Women

GI evaluation is conditional rather than mandatory: 6

• Perform non-invasive testing for H. pylori and celiac disease serologies 6
• If negative and patient is young with heavy menses, empiric iron supplementation alone is reasonable 6

Reserve bidirectional endoscopy for: 6

• Positive H. pylori or celiac testing 6
• GI symptoms present 6
• Persistent iron deficiency despite adequate supplementation 6
• Age >50 years (higher risk of GI malignancy) 6
• New or worsening GI symptoms (abdominal pain, change in bowel habits, blood in stool) 6

For Men and Postmenopausal Women

Bidirectional endoscopy should be performed to investigate gastrointestinal blood loss. 2 Always investigate gastrointestinal sources when iron deficiency is unexplained in these populations. 3