What is the difference between absolute and functional iron deficiency in patients, and how should each be treated?

Absolute vs Functional Iron Deficiency: Key Differences and Treatment

Core Distinction

Absolute iron deficiency occurs when iron stores are depleted, while functional iron deficiency occurs when adequate iron stores exist but cannot be mobilized quickly enough to meet the demands of erythropoiesis. 1

Definitions and Diagnostic Criteria

Absolute Iron Deficiency

In CKD patients, absolute iron deficiency is defined as:

• TSAT <20% AND ferritin <100 ng/mL (for non-dialysis and peritoneal dialysis patients) 1, 2
• TSAT <20% AND ferritin <200 ng/mL (for hemodialysis patients) 1, 2
• In healthy individuals without inflammation, ferritin <12 ng/mL indicates depleted stores 1
• For surgical patients, ferritin must exceed 30 ng/mL to achieve 92% sensitivity for excluding absolute iron deficiency 1

Functional Iron Deficiency

Functional iron deficiency is characterized by:

• TSAT <20% with ferritin >100 ng/mL (non-dialysis patients) or >200 ng/mL (hemodialysis patients) 1, 2
• Iron stores are adequate or elevated, but iron cannot be released from reticuloendothelial cells fast enough to support hemoglobin synthesis 1, 3
• Commonly occurs during erythropoiesis-stimulating agent (ESA) therapy, which pharmacologically accelerates red blood cell production beyond the rate of iron mobilization 1, 3

In cancer patients, functional iron deficiency is defined as:

• TSAT 20-50% AND ferritin 30-800 ng/mL 1

Pathophysiology

Absolute Iron Deficiency

• Results from depleted total body iron stores 1, 4
• Common causes include chronic blood loss (GI bleeding, menstruation), inadequate dietary intake, malabsorption (celiac disease, post-bariatric surgery), and pregnancy 4, 5

Functional Iron Deficiency

• Two distinct mechanisms exist: inflammation-mediated iron sequestration (elevated hepcidin blocks iron release) versus kinetic iron deficiency from ESA-stimulated erythropoiesis 1, 3
• Chronic inflammation increases hepcidin production, which impairs iron absorption and mobilization from storage sites 3
• Affects 40-70% of chronic heart failure patients and is common in CKD patients receiving ESA therapy 3

Distinguishing Between Functional Iron Deficiency and Inflammatory Block

This is a critical clinical challenge, as both conditions show TSAT <20% and ferritin 100-700 ng/mL: 1

• In functional iron deficiency: Serial ferritin levels decrease during ESA therapy but remain elevated (>100 ng/mL) 1
• In inflammatory block: Abrupt increase in ferritin associated with sudden drop in TSAT 1

When uncertain, administer weekly IV iron (50-125 mg) for 8-10 doses: 1

• If no erythropoietic response occurs, inflammatory block is most likely 1
• Discontinue IV iron until the inflammatory condition resolves 1

Treatment Approaches

Absolute Iron Deficiency

Oral iron is first-line therapy for most patients: 4

• Ferrous sulfate 325 mg daily or on alternate days 4
• Effective when hepcidin levels are low, facilitating iron absorption 6
• A therapeutic trial of oral iron confirms absolute iron deficiency 1

Intravenous iron is indicated when: 4

• Oral iron intolerance or poor absorption (celiac disease, post-bariatric surgery) 4
• Ongoing blood loss 4
• Second and third trimesters of pregnancy 4

When absolute iron deficiency is detected, investigate the underlying cause: 1

• Refer to gastroenterology to rule out GI malignancy as source of chronic blood loss 1
• Measure serum creatinine and GFR if CKD is suspected 1

Functional Iron Deficiency

Intravenous iron is preferred over oral iron, especially in CKD patients on ESA therapy: 1, 3, 2

• Oral iron is ineffective because the problem is not absorption but mobilization from stores 1
• Weekly IV iron (50-125 mg) until target hemoglobin is achieved or iron parameters normalize 1, 3
• Approximately 400-500 mg of supplemental iron needed every 3 months to maintain adequate stores once target hemoglobin is reached 1

For cancer patients with functional iron deficiency: 1

• IV iron monotherapy (if ESAs are not used) or combination therapy with IV iron plus ESA 1
• Preferred IV preparations include iron dextran, ferric gluconate, iron sucrose, and ferric carboxymaltose 1
• Avoid high-molecular weight iron dextran due to increased anaphylactic risk 1

Regular monitoring is essential: 3

• Assess hemoglobin, TSAT, and ferritin levels to guide therapy 3
• Address underlying causes such as managing chronic inflammation 3

Important Caveats

Current diagnostic parameters have significant limitations: 1

• TSAT and ferritin are not reliable for estimating body iron stores or predicting response to therapy 1
• Ferritin is an acute-phase reactant, making interpretation difficult in inflammatory conditions 1
• Traditional thresholds (ferritin <12 ng/mL) are unsuitable for patients with any inflammatory process 1

Newer diagnostic tests are emerging but not yet standardized: 1

• Reticulocyte hemoglobin content indicates iron incorporation within 3-4 days of starting iron 1
• Percentage of hypochromic RBCs reflects iron availability over 2-3 months 1
• Widespread use is constrained by absence of universal clinical decision limits 1

No response to oral iron does not rule out absolute iron deficiency: 1

• May be due to patient non-compliance, ongoing blood losses exceeding oral iron absorption, or diminished GI absorption from inflammation 1
• Consider IV iron with or without ESA therapy in these cases 1