What is the best treatment approach for a patient with iron deficiency (hypoferritinemia not applicable due to normal ferritin levels) and normal ferritin levels?

Low Iron with Normal Ferritin: Diagnostic Approach and Management

Primary Recommendation

When serum iron is low but ferritin is normal, you must immediately check transferrin saturation and inflammatory markers (CRP/ESR) to distinguish between early absolute iron deficiency, functional iron deficiency, or inflammation-masked iron deficiency—all of which require iron supplementation if transferrin saturation is <20%. 1

Diagnostic Algorithm

Step 1: Measure Transferrin Saturation and Inflammatory Markers

• Transferrin saturation <16-20% with ferritin 15-45 μg/L indicates early absolute iron deficiency with depleting iron stores, even though ferritin appears "normal" 1, 2
• Check CRP and/or ESR immediately, as ferritin is an acute phase reactant that rises falsely with inflammation, masking true iron deficiency 3, 1
• In inflammatory conditions, ferritin up to 100 μg/L can still represent iron deficiency if transferrin saturation is <20% 1, 4

Step 2: Interpret Based on Clinical Context

Without inflammation (normal CRP/ESR):

• Ferritin 15-30 μg/L + transferrin saturation <20% = absolute iron deficiency requiring treatment 3, 1
• Ferritin 30-45 μg/L + transferrin saturation <20% = early iron deficiency, treat if symptomatic 3, 2
• Ferritin >45 μg/L + transferrin saturation <20% = consider functional iron deficiency or recheck in inflammatory state 1

With inflammation (elevated CRP/ESR):

• Ferritin <100 μg/L + transferrin saturation <20% = combined absolute and functional iron deficiency 1, 4
• Ferritin 30-100 μg/L + transferrin saturation <20% = functional iron deficiency from inflammation sequestering iron 1
• Do not dismiss iron deficiency based on ferritin 30-100 μg/L in inflammatory states—this is a critical pitfall 1

Step 3: Identify Underlying Cause

• In premenopausal women with heavy menstrual bleeding and no GI symptoms, treat empirically without endoscopy if age <45 years 3
• In men, postmenopausal women, or anyone >45 years: perform bidirectional endoscopy (gastroscopy and colonoscopy) to exclude GI malignancy 3, 2
• Test for celiac disease serologically in all patients (found in 3-5% of iron deficiency cases) 3, 2
• Check urinalysis to exclude urinary tract bleeding 3
• Consider H. pylori testing as both infection and treatment-related atrophic gastritis impair iron absorption 2, 4

Treatment Approach

First-Line: Oral Iron

• Ferrous sulfate 325 mg daily or every other day (alternate-day dosing improves absorption and reduces side effects by 50%) 5, 2
• Continue for 3 months after hemoglobin normalizes to replenish iron stores 3
• Expect hemoglobin rise of 1-2 g/dL within 2-4 weeks—if this doesn't occur, consider malabsorption, ongoing bleeding, or misdiagnosis 3, 2
• Co-administer with vitamin C to enhance absorption; avoid tea/coffee around dosing 3

Indications for Intravenous Iron

Use IV iron (1 g ferric carboxymaltose as single dose over 15 minutes) when: 3, 5

• Oral iron intolerance (occurs in ~50% of patients) 5, 2
• Malabsorption (celiac disease, atrophic gastritis, post-bariatric surgery) 5, 4
• Chronic inflammatory conditions (CKD, heart failure, IBD, cancer) 3, 5
• Ongoing blood loss that cannot be immediately controlled 5
• Second or third trimester pregnancy 5
• In heart failure with iron deficiency: IV iron increases exercise capacity regardless of anemia presence 5, 2

Special Population Thresholds

Chronic kidney disease: 3

• Predialysis/peritoneal dialysis: treat if transferrin saturation ≤20% AND ferritin ≤100 ng/mL
• Hemodialysis: treat if transferrin saturation ≤20% AND ferritin ≤200 ng/mL

Athletes (particularly females): 3

• Screen twice yearly in females, annually in males
• Ferritin <35 μg/L = iron deficiency requiring supplementation
• Even without anemia, low iron impairs aerobic performance 3

Critical Pitfalls to Avoid

• Never dismiss iron deficiency based on ferritin 30-100 μg/L alone—always check transferrin saturation and inflammatory markers 1, 2
• Ferritin >150 μg/L makes absolute iron deficiency unlikely even with inflammation, but functional deficiency may still exist 3
• Do not use fecal occult blood testing—it is insensitive and non-specific for evaluating iron deficiency 3
• Do not confuse functional iron deficiency with iron overload—low transferrin saturation with elevated ferritin in inflammation indicates sequestered, not excessive, iron 1
• Recheck iron studies 8-10 weeks after IV iron, not earlier, as ferritin remains falsely elevated immediately post-infusion 3

Follow-Up Monitoring

• Recheck hemoglobin at 2-4 weeks for oral iron, expecting 1-2 g/dL rise 3, 2
• After normalization, monitor every 3 months for 1 year, then annually 3
• If hemoglobin/MCV cannot be maintained with oral iron, further investigation is mandatory 3