In a patient with hemoglobin 118 g/L, low serum iron and normal ferritin, what is the likely cause and how should it be managed?

Ferritin is Normal - Likely Diagnosis and Management

In a patient with hemoglobin 118 g/L (mild anemia), low serum iron, and normal ferritin, the most likely diagnosis is functional iron deficiency (also called iron-restricted erythropoiesis), and you must measure transferrin saturation (TSAT) immediately to confirm the diagnosis and guide management.

Understanding the Clinical Picture

This presentation represents a critical diagnostic scenario where ferritin levels are misleading. The combination of:

• Mild anemia (Hb 118 g/L, below WHO threshold of 120 g/L for women, 130 g/L for men)
• Low serum iron
• Normal ferritin

This pattern strongly suggests functional iron deficiency rather than absolute iron deficiency. Ferritin is an acute-phase reactant that becomes elevated during inflammation, masking true iron deficiency 1. In inflammatory conditions, proinflammatory cytokines trigger increased hepcidin expression, which restricts iron availability for erythropoiesis despite adequate or elevated ferritin stores 1.

Diagnostic Algorithm

Step 1: Measure Transferrin Saturation Immediately

TSAT < 20% confirms iron deficiency even with normal ferritin 2, 3, 4. This is the critical diagnostic test you need.

Step 2: Interpret Ferritin in Context

• If ferritin is 45-100 μg/L with TSAT < 20%: Iron deficiency is present 2, 3
• If ferritin is 100-300 μg/L with TSAT < 20%: Functional iron deficiency in the setting of inflammation 1
• Ferritin > 150 μg/L makes absolute iron deficiency unlikely even with inflammation 3

The 2024 AGA guideline recommends a ferritin cut-off of 45 μg/L for optimal sensitivity and specificity in anemic patients 2. However, the 2021 British Society of Gastroenterology guidelines note that ferritin < 45 μg/L provides 92% specificity for iron deficiency 3.

Step 3: Identify Underlying Causes

Screen for inflammatory conditions that cause functional iron deficiency:

• Chronic kidney disease (24-85% prevalence of iron deficiency) 4
• Heart failure (37-61% prevalence) 4
• Inflammatory bowel disease (13-90% prevalence) 4
• Celiac disease
• Chronic infections
• Malignancy (18-82% prevalence) 4

Screen for blood loss sources:

• Gastrointestinal bleeding (consider H. pylori testing, bidirectional endoscopy if indicated) 2, 5
• Menstrual blood loss in premenopausal women
• Occult bleeding from NSAIDs

Screen for malabsorption:

• Celiac disease (noninvasive testing recommended) 5
• Atrophic gastritis
• Post-bariatric surgery 4

Management Strategy

Iron Replacement Approach

For patients WITHOUT chronic inflammatory conditions:

• Start oral iron: ferrous sulfate 325 mg daily or every other day 4, 5
• Every-other-day dosing improves absorption and reduces side effects 5
• Take on empty stomach when possible; if not tolerated, take with meals and vitamin C 500 mg 2
• Reassess response in 2-4 weeks 5

For patients WITH chronic inflammatory conditions (CKD, heart failure, IBD):

• Consider intravenous iron as first-line therapy 4, 5
• Oral iron is poorly absorbed in these conditions due to elevated hepcidin 1
• IV iron is specifically recommended for heart failure patients to increase exercise capacity 5

Treatment Targets

• Continue iron therapy until ferritin > 100 μg/L and TSAT > 20% in inflammatory conditions 1
• In non-inflammatory conditions, target ferritin > 30-45 μg/L 2, 4

Critical Pitfalls to Avoid

1. Do not dismiss iron deficiency based on normal ferritin alone - This is the most common diagnostic error. Always check TSAT 3, 1.

2. Do not over-treat with IV iron in dialysis patients - Functional iron deficiency with very high ferritin (>650 μg/L) and low TSAT can impair neutrophil function and increase infection risk 6. Balance is essential.

3. Do not assume oral iron will work in inflammatory conditions - Hepcidin elevation blocks intestinal iron absorption 1. These patients need IV iron.

4. Do not forget to investigate the underlying cause - Iron replacement treats the symptom, not the disease. In men and postmenopausal women with unexplained iron deficiency, bidirectional endoscopy is warranted 5.

5. Recognize that approximately 50% of patients discontinue oral iron due to side effects 5 - Have a low threshold to switch to IV iron if adherence is poor.

When to Use IV Iron

Absolute indications:

• Oral iron intolerance or non-adherence
• Malabsorption (celiac disease, post-bariatric surgery)
• Chronic inflammatory conditions (CKD, heart failure, IBD, cancer) 4, 5
• Ongoing blood loss
• Second and third trimesters of pregnancy 4
• Failure to respond to oral iron after 2-4 weeks 5

Modern IV iron formulations have hypersensitivity rates < 1% 5, making them safe and effective alternatives to oral therapy.