What is the most likely explanation for a markedly elevated ferritin level combined with a low transferrin saturation?

High Ferritin with Low Transferrin Saturation

The most likely explanation for markedly elevated ferritin combined with low transferrin saturation is anemia of chronic disease (ACD) or functional iron deficiency, where inflammation drives hepcidin-mediated iron sequestration in reticuloendothelial stores, making iron unavailable for erythropoiesis despite adequate or elevated total body iron. 1

Pathophysiology

Inflammatory cytokines (IL-6, TNF-α) stimulate hepcidin production, which blocks ferroportin-mediated iron release from macrophages and hepatocytes, trapping iron in storage sites. 1 This creates a paradox: ferritin rises as both an acute-phase reactant and a marker of sequestered iron, while transferrin saturation falls because circulating iron available for red cell production is depleted. 2

Ferritin behaves as an acute-phase reactant during inflammation, independent of true iron stores, and can be elevated in liver disease, malignancy, tissue necrosis, and metabolic syndrome. 2, 1 The iron shift from circulation and parenchymal cells to the reticuloendothelial system (RES) is reflected by increased ferritin levels and decreased TSAT. 2

Diagnostic Criteria

An elevated ferritin together with TSAT < 20% indicates anemia of chronic disease or functional iron deficiency, not iron overload. 1 Specifically:

• ACD is diagnosed when ferritin > 100 µg/L and TSAT < 16% in the presence of biochemical or clinical inflammation. 1
• TSAT < 20% has high sensitivity for detecting absolute or functional iron deficiency. 1
• Never diagnose iron overload based solely on ferritin; confirm TSAT ≥ 45% before labeling overload. 1

If TSAT < 45%, iron overload is excluded with >90% certainty, and the elevated ferritin reflects inflammation, alcohol, cell necrosis, tumors, or metabolic syndrome. 1

Common Clinical Contexts

Condition	Typical Pattern	Key Diagnostic Features
Inflammatory Bowel Disease	Ferritin > 100 µg/L, TSAT < 16%	Assess CRP/ESR; reflects ACD [1]
Chronic Kidney Disease (on ESAs)	Ferritin 100–700 ng/mL, TSAT < 20%	Functional iron deficiency; consider IV iron trial [1]
Rheumatologic diseases (RA, SLE)	Elevated ferritin, low TSAT	Inflammation-driven iron block [1]
Active infection	Acute-phase ferritin rise, low TSAT	Check inflammatory markers [1]
Malignancy	Markedly high ferritin, low TSAT	Exclude iron overload; treat underlying cancer [1,3]
Metabolic/liver disease (NAFLD, alcoholic hepatitis)	Ferritin elevation, TSAT < 20%	Transaminases help differentiate [1]

In a large tertiary-care study, malignancy was the most frequent cause of ferritin > 1000 µg/L (153/627 cases), followed by iron-overload syndromes (136/627). 3 Only 6 cases were rheumatologic hyperferritinemic syndromes (adult-onset Still's disease, systemic JIA, or hemophagocytic lymphohistiocytosis), with average ferritin 14,242 µg/L. 3

Diagnostic Algorithm

Step 1 – Confirm the pattern

Measure fasting TSAT together with ferritin; assess CRP/ESR for occult inflammation. 1 If TSAT < 45%, iron overload is unlikely. 1

Step 2 – Exclude iron overload

If TSAT < 45%, >90% of cases are due to inflammation, alcohol, cell necrosis, tumors, or metabolic syndrome—not iron overload. 1

Step 3 – Identify the underlying cause

• Check liver panel (ALT/AST) for NAFLD, alcoholic hepatitis, or viral hepatitis. 1
• Evaluate for IBD, rheumatologic disease, infection, or malignancy. 1
• In CKD on ESAs, consider functional iron deficiency and plan an IV-iron trial. 1
• Assess alcohol consumption and metabolic risk factors (obesity, insulin resistance). 1

Step 4 – Advanced testing when ferritin is ambiguous

• Soluble transferrin receptor (sTfR) rises in true iron deficiency and is not affected by inflammation; sTfR levels remain mostly normal in functional iron deficiency, helping identify concomitant absolute iron deficiency in patients with inflammation. 2, 1
• Reticulocyte hemoglobin content (CHr/RET-He) directly reflects functional iron availability for erythropoiesis. 2, 1

Management Strategies

Pure ACD (inflammatory block)

Treat the underlying inflammatory condition; iron supplementation is contraindicated because it does not improve anemia and may increase oxidative stress or infection risk. 1 The iron is sequestered by hepcidin, and supplementation will not mobilize it. 1

Functional iron deficiency in CKD

Conduct a trial of weekly IV iron (50–125 mg for 8–10 doses). 1 Hemoglobin rise confirms functional deficiency; lack of response indicates predominant inflammatory block. 1 IV iron bypasses hepcidin-mediated blockade of intestinal iron absorption. 1

Mixed iron deficiency + ACD

Simultaneously address inflammation and provide iron supplementation. 1 In this scenario, sTfR measurement is particularly useful because it remains elevated in true iron deficiency but normal in pure functional iron deficiency. 2

Congestive heart failure with iron deficiency

IV iron improves functional capacity and quality of life even without anemia when ferritin < 100 ng/mL or 100–300 ng/mL with TSAT < 20%. 1

Monitoring and Follow-Up

• Avoid re-checking iron studies within 4 weeks of IV iron administration because circulating iron interferes with assays. 1
• Expected hemoglobin response: Increase of 1–2 g/dL within 4–8 weeks of appropriate iron therapy. 1
• Target ferritin levels: In non-inflamed states, < 50 ng/mL indicates deficiency; in inflammation, ferritin < 100 ng/mL has only 35–48% sensitivity for true iron deficiency, so rely on TSAT and functional tests. 1

Critical Pitfalls to Avoid

• Do not diagnose iron overload based on ferritin alone. Ferritin is an acute-phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores. 2, 1
• Do not assume iron overload when TSAT < 45%. In the general population, iron overload is NOT the most common cause of elevated ferritin. 1
• Do not give oral iron in functional iron deficiency with active inflammation because hepcidin blocks intestinal absorption; IV iron is required. 1
• Recognize that ferritin up to 100–300 ng/mL may still indicate true iron deficiency in inflammatory conditions because ferritin is artificially elevated by inflammation. 1
• In CKD patients with ferritin > 800 ng/mL and TSAT < 20%, the scenario suggests functional iron deficiency despite apparent iron overload, and a trial of IV iron may still be beneficial. 4