What may cause elevated ferritin with low transferrin saturation?

Elevated Ferritin with Low Transferrin Saturation: Causes and Clinical Significance

Elevated ferritin with low transferrin saturation (<20%) indicates either anemia of chronic disease (inflammatory iron block) or functional iron deficiency, not iron overload. 1

Understanding the Pathophysiology

The combination of elevated ferritin with low TSAT represents a paradoxical iron state where:

• Ferritin rises as an acute-phase reactant during inflammation, independent of actual iron stores 1
• Iron becomes sequestered in reticuloendothelial macrophages and hepatocytes, unavailable for erythropoiesis despite appearing adequate on ferritin measurement 1, 2
• Hepcidin elevation in response to inflammatory cytokines (IL-6, TNF-α) blocks intestinal iron absorption and traps iron in storage sites 1

This pattern has become increasingly common, with patients showing ferritin >800 ng/mL (suggesting iron overload) alongside TSAT <20% (suggesting iron deficiency). 2

Primary Causes by Clinical Context

Inflammatory and Chronic Disease States

Anemia of chronic disease (ACD) is diagnosed when ferritin >100 μg/L with TSAT <16% in the presence of biochemical or clinical inflammation. 1

Common inflammatory conditions include:

• Inflammatory bowel disease (ulcerative colitis, Crohn's disease) 1
• Chronic kidney disease, particularly in dialysis patients 1, 2
• Rheumatologic diseases (rheumatoid arthritis, systemic lupus) 1
• Active infections causing acute-phase ferritin elevation 1
• Malignancy (solid tumors, lymphomas) 1, 3

Metabolic and Liver Disease

Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome cause ferritin elevation reflecting hepatocellular injury and insulin resistance rather than true iron overload. 1

• Chronic alcohol consumption increases ferritin through hepatocellular injury 1
• Viral hepatitis (B and C) 1
• Acute hepatitis with cell necrosis 1

Functional Iron Deficiency

In chronic kidney disease patients on erythropoiesis-stimulating agents, ferritin 100-700 ng/mL with TSAT <20% represents functional iron deficiency where iron is sequestered despite adequate stores. 1, 2

This occurs when:

• Pharmacologically stimulated erythropoiesis outpaces iron mobilization from stores 1
• Iron remains trapped in reticuloendothelial cells despite erythropoietic demand 2

Mixed Iron Deficiency and ACD

When ferritin is 30-100 μg/L with TSAT <16% in the presence of inflammation, a combination of true iron deficiency and anemia of chronic disease is likely. 1

Diagnostic Algorithm

Step 1: Confirm the Pattern

• Measure fasting transferrin saturation alongside ferritin—never interpret ferritin alone 1
• TSAT <20% has high sensitivity for diagnosing absolute or functional iron deficiency 1
• Check inflammatory markers (CRP, ESR) to detect occult inflammation 1

Step 2: Rule Out Iron Overload

When TSAT <45%, iron overload is unlikely and secondary causes predominate—over 90% of elevated ferritin cases are caused by inflammation, chronic alcohol consumption, cell necrosis, tumors, or metabolic syndrome. 1

Step 3: Identify the Underlying Cause

Check complete metabolic panel including ALT, AST to assess hepatocellular injury: 1

• Elevated transaminases suggest NAFLD, alcoholic liver disease, or viral hepatitis

Assess for inflammatory conditions: 1

• In IBD: ferritin >100 μg/L with TSAT <16% indicates ACD
• Check CRP, ESR for systemic inflammation

Evaluate for chronic kidney disease: 1, 2

• Check creatinine, eGFR
• In CKD on ESAs: ferritin 100-700 ng/mL with TSAT <20% may warrant IV iron trial

Screen for malignancy if clinically indicated: 3

• Malignancy was the most frequent cause of markedly elevated ferritin (>1000 μg/L) in one large cohort

Step 4: Advanced Testing When Standard Tests Are Insufficient

Soluble transferrin receptor (sTfR) is elevated in true iron deficiency but not affected by inflammation, making it useful when ferritin interpretation is confounded. 1

Reticulocyte hemoglobin content (CHr) or equivalent (RET-He) provides direct assessment of functional iron availability to erythropoiesis. 1

Limitations:

• sTfR is also elevated with increased erythropoietic activity and ineffective erythropoiesis 1
• Both tests have limited routine availability and long turnaround times 1

Critical Clinical Pitfalls

Never diagnose iron overload based on elevated ferritin alone without confirming TSAT ≥45%. 1

Do not supplement iron when TSAT <20% with ferritin >300 ng/mL represents pure inflammatory block—iron supplementation will not improve anemia and may worsen outcomes. 1

Recognize that ferritin >1000 ng/mL with TSAT <20% in dialysis patients indicates neutrophil dysfunction has been reported, though whether this is from inflammation or functional iron deficiency remains unclear. 1

In inflammatory states, ferritin can be elevated while patients remain functionally iron deficient, as hepcidin blocks iron release from storage sites. 1

Management Based on Underlying Etiology

For Anemia of Chronic Disease (Pure Inflammatory Block)

Treat the underlying inflammatory condition—iron supplementation is contraindicated as it will not improve anemia and may promote oxidative stress and bacterial growth. 1

For Functional Iron Deficiency in CKD

In CKD patients on ESAs with ferritin 100-700 ng/mL and TSAT <20%, a trial of weekly IV iron (50-125 mg for 8-10 doses) can differentiate functional iron deficiency from pure inflammatory block. 1

• Response with hemoglobin improvement confirms functional iron deficiency 1
• No response indicates inflammatory block 1

For Mixed Iron Deficiency and ACD

When ferritin is 30-100 μg/L with inflammation present, treat both the underlying inflammatory condition and provide iron supplementation. 1

For Congestive Heart Failure Exception

In CHF patients with iron deficiency (ferritin <100 ng/mL or ferritin 100-300 ng/mL with TSAT <20%), IV iron improves functional capacity and quality of life even without anemia. 1

Laboratory Monitoring Considerations

Do not check iron parameters within 4 weeks of IV iron administration, as circulating iron interferes with assays leading to spurious results. 1

Hemoglobin should increase by 1-2 g/dL within 4-8 weeks of appropriate iron therapy. 1

In the absence of inflammation, target ferritin is 50 ng/mL regardless of sex; in inflammatory states, ferritin <100 ng/mL has only 35-48% sensitivity for iron deficiency. 1