What is the differential diagnosis and treatment for a 26-year-old patient with normal serum iron and ferritin levels but low iron saturation?

Low Iron Saturation with Normal Serum Iron and Ferritin in a 26-Year-Old

This presentation most likely represents functional iron deficiency or early iron deficiency in the context of inflammation, and you should assess inflammatory markers (CRP, ESR) immediately to guide diagnosis and treatment. 1

Differential Diagnosis

The combination of normal serum iron and ferritin with low transferrin saturation (<16-20%) creates a diagnostic challenge that requires systematic evaluation:

Primary Considerations:

Functional Iron Deficiency

• Iron stores are adequate (normal ferritin), but iron cannot be mobilized rapidly enough to meet erythropoietic demands 1
• The percent transferrin saturation decreases despite normal or elevated serum ferritin 1
• This occurs when there is increased demand for iron that exceeds the rate of release from reticuloendothelial stores 1

Early Iron Deficiency with Inflammation

• Ferritin is an acute phase reactant and can appear falsely normal in the presence of inflammation 1
• A ferritin between 30-100 μg/L with transferrin saturation <16% suggests coexisting iron deficiency and anemia of chronic disease 1
• In inflammatory states, the lower limit of ferritin consistent with normal iron stores should be raised to 100 μg/L 1

Anemia of Chronic Disease (Inflammatory Block)

• Ferritin >100 μg/L with transferrin saturation <16% indicates anemia of chronic disease 1
• Distinguishing this from functional iron deficiency requires serial monitoring: inflammatory block shows abrupt ferritin increase with sudden transferrin saturation drop 1
• High ferritin (>500 ng/mL) with low transferrin saturation is strongly associated with inflammation rather than true iron stores 2

Less Common Causes in This Age Group:

Chronic Inflammatory Conditions

• Inflammatory bowel disease (13-90% prevalence of iron deficiency) 3
• Celiac disease with impaired iron absorption 3
• Chronic kidney disease (24-85% prevalence) 3

Genetic Disorders of Iron Metabolism

• Transferrin deficiency: presents with low transferrin saturation, high ferritin, and microcytic anemia 1
• DMT1 defects: microcytic anemia with increased transferrin saturation and variable ferritin 1

Diagnostic Algorithm

Step 1: Assess Inflammatory Status Immediately

• Measure CRP and ESR to determine if inflammation is confounding iron studies 1
• Check complete blood count with indices (MCV, MCH) 1
• Obtain hemoglobin level to determine if anemia is present 1

Step 2: Interpret Based on Inflammation

Without inflammation (normal CRP/ESR):

• Ferritin <30 μg/L or transferrin saturation <16% defines iron deficiency 1
• Normal ferritin with low transferrin saturation suggests functional iron deficiency 1

With inflammation (elevated CRP/ESR):

• Ferritin 30-100 μg/L with transferrin saturation <16%: mixed iron deficiency and anemia of chronic disease 1
• Ferritin >100 μg/L with transferrin saturation <16%: anemia of chronic disease 1

Step 3: Additional Testing if Diagnosis Unclear

• Soluble transferrin receptor (sTfR): high in iron deficiency, normal or low in anemia of chronic disease 1
• Reticulocyte hemoglobin concentration: more accurate indicator of iron stores in inflammation 1
• Percentage of hypochromic red cells: >10% compatible with iron deficiency 1

Step 4: Identify Underlying Cause

• In reproductive-age women: assess menstrual blood loss (38% have iron deficiency without anemia, 13% have iron-deficiency anemia) 3
• Screen for celiac disease with serological tests 4, 3
• Evaluate for gastrointestinal blood loss if indicated 4, 3
• Consider inflammatory bowel disease, chronic kidney disease, or other chronic inflammatory conditions 3

Treatment Approach

If Functional Iron Deficiency or Early Iron Deficiency:

First-line: Oral Iron

• Ferrous sulfate 325 mg daily or on alternate days 3
• Alternate-day dosing may improve absorption and tolerability 3
• Reassess in 4-8 weeks with repeat iron studies and hemoglobin 1

Indications for Intravenous Iron:

• Oral iron intolerance 3
• Impaired absorption (celiac disease, post-bariatric surgery) 3
• Chronic inflammatory conditions (inflammatory bowel disease, chronic kidney disease) 3
• Ongoing blood loss 3
• Trial dose: 50-125 mg weekly for 8-10 doses 1

If Anemia of Chronic Disease/Inflammatory Block:

• Treat the underlying inflammatory condition first 1
• If no erythropoietic response after 8-10 doses of IV iron, inflammatory block is likely and further iron should be withheld until inflammation resolves 1
• Avoid iron supplementation when ferritin >500 ng/mL with low transferrin saturation, as this reflects inflammation rather than iron need 2

Critical Pitfalls to Avoid

Do not assume normal ferritin excludes iron deficiency in a 26-year-old with potential inflammatory conditions 1. Ferritin can be falsely elevated by inflammation, masking true iron deficiency.

Do not give empiric iron without checking inflammatory markers 1. The treatment approach differs fundamentally between functional iron deficiency (responds to iron) and inflammatory block (does not respond to iron and may cause harm).

Do not overlook celiac disease 4, 3. This is a common cause of iron deficiency in young adults and requires specific serological testing.

In reproductive-age women, do not assume menstrual blood loss is the sole cause without excluding gastrointestinal pathology if anemia is present 1, 4. Investigation should be considered at any level of anemia with iron deficiency, though the urgency increases with severity.

Monitor for treatment response 1. Lack of response to oral iron after 4-8 weeks indicates either malabsorption, non-compliance, ongoing blood loss, or inflammatory block requiring reassessment 5.