What is the management approach for a patient with iron deficiency, elevated ferritin (Ferritin) levels, and low iron saturation?

Management of Low Iron, High Ferritin, and Low Iron Saturation

This presentation indicates functional iron deficiency (also called anemia of chronic disease or inflammation), where iron is sequestered by inflammatory processes rather than truly depleted, and requires investigation for underlying inflammatory conditions followed by intravenous iron supplementation if treatment is warranted. 1

Diagnostic Interpretation

Your laboratory pattern reveals a specific pathophysiologic state:

• When ferritin is >100 μg/L with transferrin saturation <20%, this is diagnostic of anemia of chronic disease/functional iron deficiency 1
• The elevated ferritin reflects an acute phase reactant response to inflammation, malignancy, or hepatic disease, not adequate iron stores 2
• Transferrin saturation <20% confirms iron-restricted erythropoiesis despite seemingly adequate ferritin levels 2, 1
• This pattern indicates that hepcidin (released by the liver in response to inflammation) is blocking intestinal iron absorption and sequestering iron in reticuloendothelial macrophages 2

Special Consideration for Ferritin 30-100 μg/L Range

• If your ferritin falls between 30-100 μg/L (rather than >100), this suggests combined absolute iron deficiency plus anemia of chronic disease 1
• This intermediate range requires more aggressive investigation for both blood loss and inflammatory conditions 2

Mandatory Investigations

Identify Underlying Inflammatory/Chronic Conditions

You must systematically evaluate for conditions causing functional iron deficiency: 1

• Malignancy (most common cause of markedly elevated ferritin, accounting for 153/627 cases in one series) 3
• Chronic kidney disease (affects 24-85% of CKD patients with iron deficiency) 4
• Heart failure (affects 37-61% of HF patients) 2, 4
• Inflammatory bowel disease (affects 13-90% of IBD patients) 4
• Rheumatologic disorders (adult-onset Still's disease, systemic JIA) 1, 3
• Chronic infections 3
• Hepatic disease 2

Rule Out Occult Blood Loss

Even with elevated ferritin, blood loss may coexist: 2

• NSAID use (document and discontinue if possible) 2
• Gastrointestinal evaluation: Upper endoscopy with small bowel biopsies for celiac disease (present in 2-3% of iron deficiency cases) 2
• Colonoscopy (dual pathology occurs in ~10% of cases) 2
• Helicobacter pylori testing 5
• Heavy menstrual bleeding in premenopausal women 4, 5

Additional Laboratory Assessment

• Serum creatinine and GFR (evaluate for chronic kidney disease) 2
• C-reactive protein and IL-6 (quantify inflammatory burden) 2, 6
• Complete blood count with reticulocyte count 2
• Consider soluble transferrin receptor if available (helps distinguish true iron deficiency from inflammation, though not widely available) 2

Treatment Strategy

Oral Iron is Ineffective

Do not use oral iron for functional iron deficiency—it is ineffective due to hepcidin-mediated blockade of intestinal absorption and causes unnecessary gastrointestinal side effects 1

Intravenous Iron is the Treatment of Choice

Intravenous iron should be administered for functional iron deficiency, particularly when anemia is present: 1

• IV iron has superior efficacy compared to oral iron in inflammatory states 2
• Formulations include iron sucrose and ferric carboxymaltose 2
• Hypersensitivity reactions to newer IV iron formulations are rare (<1%) 5

Condition-Specific Recommendations

Heart Failure Patients

Treat with IV iron even without anemia when ferritin <100 ng/mL OR ferritin 100-300 ng/mL with TSAT <20% 1

• Multiple trials (FAIR-HF, CONFIRM-HF) demonstrate improved exercise capacity, quality of life, and NYHA functional class 2
• Benefits include increased 6-minute walk test distance by 33-56 meters 2

Chronic Kidney Disease

• Target ferritin levels are higher for CKD patients 1
• IV iron improves hemoglobin and reduces ESA requirements 2

Cancer and Chemotherapy

• If ferritin <800 ng/mL with TSAT <20%, this represents functional iron deficiency requiring IV iron supplementation 2
• Oral iron is less effective in the cancer setting due to chronic inflammatory state 2

Erythropoiesis-Stimulating Agents (ESAs)

• Consider ESAs with concurrent IV iron supplementation for specific conditions (CKD, cancer with chemotherapy) 2
• Iron supplementation must be maintained throughout ESA therapy to optimize response 2
• Use under REMS guidelines with informed consent due to thrombotic risks 2

Monitoring Response

Reassess hemoglobin and iron studies after 4-8 weeks of treatment: 1

• Expect hemoglobin increase of 1-3 g/dL with effective IV iron therapy 2
• Repeat ferritin and transferrin saturation to guide ongoing therapy 1
• If no response, reconsider diagnosis and investigate for ongoing blood loss or uncontrolled inflammation 2

Critical Pitfalls to Avoid

• Do not rely solely on ferritin for iron status assessment in inflammatory states—always obtain transferrin saturation 1
• Do not prescribe oral iron for functional iron deficiency—it will not work and causes side effects 1
• Do not assume elevated ferritin means adequate iron stores—ferritin >100 μg/L can coexist with severe functional iron deficiency 2, 1
• Do not delay investigation for malignancy—it is the most common cause of markedly elevated ferritin 3
• Transferrin saturation is less affected by inflammation than ferritin and may be more reliable for diagnosis and prognosis, particularly in heart failure 7