What are the differences between functional iron‑deficiency anemia (IDA) and absolute iron‑deficiency anemia (IDA) in terms of pathophysiology, laboratory findings, and treatment, especially in patients with chronic inflammation, chronic kidney disease (CKD), or malignancy?

Functional vs Absolute Iron Deficiency Anemia: Key Distinctions

Absolute iron deficiency reflects depleted iron stores with TSAT ≤20% and ferritin <100 ng/mL (non-dialysis/peritoneal dialysis) or <200 ng/mL (hemodialysis), while functional iron deficiency occurs when iron stores are adequate (ferritin >100 ng/mL) but iron cannot be mobilized quickly enough to meet erythropoietic demands, typically due to inflammation-mediated hepcidin elevation or ESA-stimulated erythropoiesis. 1, 2

Pathophysiology

Absolute Iron Deficiency

• Depleted total body iron stores with impaired iron delivery to erythroid marrow 2
• Results from inadequate dietary intake, malabsorption (celiac disease, bariatric surgery, autoimmune gastritis), or chronic blood loss 1
• Both serum ferritin and transferrin saturation are low, reflecting true iron depletion 3

Functional Iron Deficiency

• Adequate or elevated iron stores that cannot be mobilized to support erythropoiesis 2
• Two distinct mechanisms exist: 1
  • Inflammation-mediated iron sequestration: Chronic inflammation increases hepcidin production, which blocks iron absorption in the gut and traps iron in macrophages of the reticuloendothelial system 2, 4
  • Kinetic iron deficiency: ESA-stimulated bursts of erythropoiesis create demand that exceeds the rate of iron mobilization from stores 1, 2
• Common in chronic kidney disease (especially dialysis patients on ESA therapy), chronic heart failure (40-70% prevalence), and inflammatory bowel disease 2

Laboratory Findings

Absolute Iron Deficiency

• TSAT ≤20% 1, 3
• Ferritin <100 ng/mL (non-dialysis/peritoneal dialysis CKD) or <200 ng/mL (hemodialysis) 1, 3
• In healthy individuals without inflammation, ferritin <12 ng/mL indicates depleted stores 2
• Reticulocyte hemoglobin content decreased 1

Functional Iron Deficiency

• TSAT ≤20% (indicating insufficient iron availability for erythropoiesis) 1, 3
• Ferritin >100 ng/mL (non-dialysis) or >200 ng/mL (hemodialysis), often 100-700 ng/mL 2, 3
• Elevated erythrocyte protoporphyrin concentration due to limited iron availability for hemoglobin synthesis 2
• Increased percentage of hypochromic RBCs and reduced reticulocyte hemoglobin content 1

Critical Diagnostic Caveats

• Current diagnostic parameters have significant limitations and 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—ferritin levels up to 100 μg/L may still reflect iron deficiency in the presence of inflammation 1, 2
• Soluble transferrin receptor (sTfR) is more sensitive in inflammatory conditions where ferritin is unreliable, as it is elevated in ID but not affected by inflammation 1

Treatment Approaches

Absolute Iron Deficiency

• Oral iron monotherapy (100 mg elemental iron daily) is appropriate for patients without malabsorption or intolerance 1
• Intravenous iron is indicated for oral iron intolerance, malabsorption, or chronic inflammatory conditions 1, 2
• Hemoglobin should increase by 1-2 g/dL within 4-8 weeks of therapy 1

Functional Iron Deficiency

• Intravenous iron is strongly preferred over oral iron in most cases, especially in CKD patients on ESA therapy, as oral iron is poorly absorbed due to hepcidin-mediated blockade 2, 4
• Dosing strategy: Weekly IV iron (50-125 mg) for 8-10 doses until target hemoglobin is achieved or iron parameters normalize 2
• In chronic heart failure, IV iron has demonstrated prognostic benefit including reduced cardiovascular death, while oral iron has shown no benefit and should be avoided 1
• Maintenance therapy: Approximately 400-500 mg of supplemental iron every 3 months is needed to maintain adequate stores once target hemoglobin is reached 2

Distinguishing Functional Iron Deficiency from Inflammatory Block

• When uncertain, administer weekly IV iron (50-125 mg) for 8-10 doses as a therapeutic trial 2
• If no erythropoietic response occurs, inflammatory block is most likely, and IV iron should be discontinued until the inflammatory condition resolves 2
• This approach helps differentiate true functional iron deficiency (which responds to IV iron) from pure inflammatory anemia (which does not) 2

Monitoring and Safety

Laboratory Monitoring

• Assess hemoglobin, TSAT, and ferritin 4-8 weeks after the last infusion—do not evaluate iron parameters within 4 weeks of total dose infusion as circulating iron interferes with assays 1
• In hemodialysis patients, measure TSAT and ferritin at least every 3 months 5
• Target maintenance levels: TSAT ≥20% and ferritin ≥100 μg/L 5

Safety Thresholds

• Avoid chronically maintaining TSAT >50% or ferritin >800 μg/L in hemodialysis patients to prevent iron overload 5
• Iron overload can cause cirrhosis, diabetes, cardiomyopathy, and arthropathy 6
• Iron administration may increase infection risk, particularly with non-transferrin-bound iron promoting growth of siderophilic bacteria 5

Special Populations

Chronic Kidney Disease

• 15-72.8% of non-dialysis CKD patients have either ferritin <100 μg/L or TSAT <20% 1, 5
• Functional iron deficiency is particularly common in dialysis patients receiving ESA therapy 2, 3

Inflammatory Bowel Disease

• One-third of patients with active IBD have iron deficiency 1
• Ferritin levels up to 100 μg/L in the presence of inflammation may still reflect iron deficiency 1
• Oral iron should contain no more than 100 mg elemental iron daily; IV iron is indicated for intolerance or moderate-to-severe IDA (Hb <100 g/L) 1

Chronic Heart Failure

• 40-70% of CHF patients have functional iron deficiency due to systemic inflammation and elevated hepcidin 2
• IV iron (specifically ferric derisomaltose) is the first formulation to demonstrate statistically significant reduction in cardiovascular death 1