What are the causes and treatment options for low ferritin levels with normal iron saturation?

Low Ferritin with Normal Iron Saturation: Causes and Clinical Approach

Low ferritin with normal iron saturation indicates early-stage absolute iron deficiency (Stage 1 iron deficiency) where iron stores are depleted but iron availability for erythropoiesis remains adequate—this pattern warrants investigation and treatment even before anemia develops. 1

Understanding the Pathophysiology

This specific pattern represents the earliest detectable stage of iron deficiency:

• Ferritin reflects storage iron in the liver, spleen, and bone marrow reticuloendothelial cells, serving as the most sensitive early indicator of depleted iron stores 1
• Transferrin saturation (TSAT) reflects circulating iron that is immediately available for red blood cell production 1
• In Stage 1 iron deficiency, storage iron becomes depleted first (low ferritin) while the body maintains adequate circulating iron for erythropoiesis (normal TSAT) by mobilizing remaining stores 1
• Hemoglobin remains normal at this stage because iron delivery to the bone marrow is still sufficient 1

Diagnostic Thresholds

Without Inflammation Present

• Ferritin <15 μg/L has 99% specificity for absolute iron deficiency and confirms the diagnosis definitively 2, 1
• Ferritin 15-30 μg/L indicates low body iron stores and generally warrants treatment 1
• Ferritin <35 μg/L defines iron deficiency in athletes and general populations 1
• Ferritin <45 μg/L provides optimal sensitivity-specificity balance (specificity 0.92) for clinical decision-making 1

Critical Caveat: Rule Out Inflammation

Ferritin is an acute-phase reactant that becomes falsely elevated during inflammation, infection, malignancy, or hepatic disease, potentially masking true iron deficiency. 2, 3

• Check C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) to exclude inflammatory conditions 1, 4
• In inflammatory conditions (IBD, CKD, heart failure, cancer), ferritin thresholds shift upward to <100 μg/L 1, 3
• If CRP/ESR are elevated and ferritin is 30-100 μg/L, this may represent mixed iron deficiency with inflammation 1

Common Causes of Low Ferritin with Normal Iron Saturation

Blood Loss (Most Common)

• Menstrual bleeding: 38% of nonpregnant reproductive-age women have iron deficiency without anemia 5
• Gastrointestinal blood loss: NSAID use, occult bleeding from colonic cancer/polyps, angiodysplasia, peptic ulcer disease 2, 5
• Regular blood donation 1

Inadequate Dietary Intake

• Vegetarian or vegan diets lacking heme iron 4, 5
• Eating disorders or underweight status 4
• Low socioeconomic status with limited access to iron-rich foods 6

Impaired Iron Absorption

• Celiac disease: 2-3% of patients presenting with iron deficiency have celiac disease 2, 5
• Atrophic gastritis or gastrectomy (partial or total) 2, 5
• Post-bariatric surgical procedures 5
• Helicobacter pylori infection 6

Increased Iron Requirements

• Pregnancy: up to 84% of pregnant women in the third trimester have iron deficiency 5
• Adolescence and rapid growth phases 4
• High-performance athletes 1, 4

Chronic Inflammatory Conditions (with functional component)

• Inflammatory bowel disease (IBD): 13-90% prevalence 5, 3
• Chronic kidney disease (CKD): 24-85% prevalence 5, 3
• Chronic heart failure: 37-61% prevalence 5, 3
• Cancer: 18-82% prevalence 5

Clinical Significance and Symptoms

Depleted iron stores cause significant symptoms even without anemia, including:

• Fatigue and lethargy 1, 5
• Reduced aerobic performance and exercise intolerance 1, 5
• Difficulty concentrating and irritability 5
• Restless legs syndrome (32-40% of iron-deficient patients) 5
• Pica (40-50% of iron-deficient patients) 5

Diagnostic Algorithm

Step 1: Confirm Iron Deficiency

• Measure ferritin and calculate TSAT (serum iron × 100 ÷ total iron-binding capacity) 1, 6
• Check CRP or ESR to assess for inflammation 1, 4

Step 2: Interpret Results

If ferritin <15 μg/L:

• Absolute iron deficiency is confirmed 1
• Proceed to investigate the source of iron loss 1

If ferritin 15-35 μg/L:

• Iron deficiency with low stores is likely 1
• Consider iron supplementation and dietary counseling 1

If ferritin 30-100 μg/L with elevated CRP/ESR:

• Mixed picture of true iron deficiency and inflammation 1
• Address underlying inflammatory condition while treating iron deficiency 1

If ferritin >100 μg/L with elevated CRP/ESR:

• Anemia of chronic disease (inflammatory iron block) is more likely 1
• Treat underlying inflammatory condition as primary intervention 1

Step 3: Investigate Underlying Cause

For all patients with confirmed iron deficiency:

• Detailed dietary history: identify iron-deficient diets, vegetarian/vegan status 2, 4
• Medication review: document aspirin, NSAIDs, anticoagulants 2, 5
• Menstrual history in women: assess for heavy or prolonged menstruation 4, 5
• Urine analysis: exclude hematuria 7
• Serological testing for celiac disease: small bowel biopsies should be taken during upper endoscopy as 2-3% of patients with iron deficiency have celiac disease 2, 6
• Testing for H. pylori infection: noninvasive testing recommended 6

For men and postmenopausal women:

• Bidirectional endoscopy (gastroscopy and colonoscopy) should be performed to exclude gastrointestinal malignancy 2, 7, 6
• Upper GI endoscopy reveals a cause in 30-50% of patients 2

For younger patients with plausible cause (e.g., heavy menstrual bleeding):

• Reasonable to treat the bleeding source and provide iron supplementation initially 6
• If no response or recurrence, proceed with full gastrointestinal evaluation 6

Treatment Approach

First-Line: Oral Iron Supplementation

Oral iron (ferrous sulfate 325 mg daily or on alternate days) is first-line therapy for most patients. 5, 6

• Every-other-day dosing improves absorption and reduces gastrointestinal side effects 6
• Use preparations with 28-50 mg elemental iron to prevent reduced compliance from gastrointestinal side effects 4
• Dietary counseling: integrate heme iron, identify enhancers (vitamin C), avoid inhibitors (tea, coffee, calcium) 4
• Evaluate response in 2-4 weeks by repeating hemoglobin and iron studies 6
• Repeat basic blood tests after 8-10 weeks to measure treatment success 4

Indications for Intravenous Iron

Intravenous iron is indicated for:

• Oral iron intolerance (approximately 50% of patients have decreased adherence due to adverse effects) 5, 6
• Impaired absorption: celiac disease, post-bariatric surgery, atrophic gastritis 5
• Chronic inflammatory conditions: CKD, heart failure (to increase exercise capacity), IBD, cancer 5, 6
• Ongoing blood loss 5
• Second and third trimesters of pregnancy 5
• Inadequate response to oral iron 6

Long-Term Management

For patients with recurrent low ferritin:

• Intermittent oral iron supplementation to preserve iron stores 4
• Screen every 6-12 months depending on risk factors 1, 4
• Menstruating females require twice yearly screening; males require annual screening 1

Common Pitfalls to Avoid

• Do not assume dietary deficiency is the sole cause even with a positive dietary history—full gastrointestinal investigation is still required 2
• Do not delay investigation in patients taking NSAIDs or anticoagulants—these should not deter investigation 2
• Do not use ferritin alone in inflammatory conditions—always assess TSAT and inflammatory markers 1, 3
• Do not provide long-term daily oral or intravenous iron with normal or high ferritin values—this is potentially harmful 4
• Do not miss celiac disease—small bowel biopsies should be routine during upper endoscopy for iron deficiency 2