What causes elevated ferritin levels in patients, particularly those with a history of multiple blood transfusions, genetic disorders such as hemochromatosis, or chronic inflammation?

Causes of Elevated Ferritin

Elevated ferritin is most commonly caused by inflammation, chronic liver disease, malignancy, and infection—not iron overload—accounting for over 90% of cases in clinical practice. 1, 2

Primary Categories of Elevated Ferritin

Iron Overload Disorders (Minority of Cases)

Hereditary Hemochromatosis:

• HFE-related hemochromatosis (C282Y homozygosity or C282Y/H63D compound heterozygosity) is present in >80% of patients with clinically overt hemochromatosis 3
• Non-HFE hemochromatosis results from mutations in TFR2, SLC40A1, HAMP, or HJV genes 4, 2
• Prevalence of C282Y homozygosity is highest among non-Hispanic white persons (0.44%) 3

Transfusional Iron Overload:

• Multiple blood transfusions in conditions like thalassemia, sickle cell disease, and myelodysplastic syndromes 5
• Chronic hemolytic anemias requiring regular transfusions 6

Secondary Causes (Majority of Cases)

Liver Disease:

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury 3, 4, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome causes ferritin elevation reflecting hepatocellular injury and insulin resistance rather than true iron overload 3, 1, 4
• Viral hepatitis (hepatitis B and C) causes abnormal iron studies in approximately 50% of patients 1, 6
• Acute hepatitis and cirrhosis release ferritin from damaged hepatocytes 4

Inflammatory and Rheumatologic Conditions:

• Chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease) elevate ferritin as an acute phase reactant 3, 4
• Adult-onset Still's disease presents with extreme hyperferritinemia (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20% 4
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome causes ferritin >5,000-10,000 ng/mL with fever, cytopenias, and multiorgan dysfunction 1, 4
• Systemic inflammatory response syndrome and infections 4

Malignancy:

• Solid tumors and lymphomas elevate ferritin as a tumor marker 4, 7
• Hepatocellular carcinoma 4
• Malignancy was the most frequent condition in one large series (153/627 patients with ferritin >1000 μg/L) 7

Cellular Damage:

• Cell necrosis from muscle injury, hepatocellular necrosis, or tissue breakdown releases ferritin from lysed cells 3, 4
• Ferritin is released from necrotic or damaged cells independent of iron stores 3

Other Conditions:

• Chronic kidney disease with functional iron deficiency 1, 4
• Diabetes mellitus and metabolic syndrome 4
• Infections cause ferritin to rise acutely as part of the acute phase response 4

Critical Diagnostic Algorithm

The single most important test is transferrin saturation (TS), which must be measured simultaneously with ferritin to distinguish true iron overload from secondary causes. 1, 2

If TS ≥45% with elevated ferritin:

• Suspect primary iron overload and proceed immediately to HFE genotype testing for C282Y and H63D mutations 3, 1, 2
• This pattern suggests hereditary hemochromatosis or other iron overload disorders 1

If TS <45% with elevated ferritin:

• Iron overload is unlikely—over 90% of cases are due to secondary causes 1, 4, 2
• Evaluate for inflammation (CRP, ESR), liver disease (ALT, AST, viral hepatitis serologies), malignancy, and infection 1, 4

Risk Stratification by Ferritin Level

Ferritin <1,000 μg/L:

• Low risk of organ damage with negative predictive value of 94% for advanced liver fibrosis in hemochromatosis 1, 4

Ferritin 1,000-10,000 μg/L:

• Higher risk of advanced fibrosis/cirrhosis if iron overload is present 1, 4
• Prevalence of cirrhosis in C282Y homozygotes is 20-45% 1, 4
• Consider liver biopsy if ferritin >1,000 μg/L with elevated liver enzymes or platelet count <200,000/μL 3, 1

Ferritin >10,000 μg/L:

• Rarely represents simple iron overload 1, 4
• Suggests life-threatening conditions: adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 1, 2
• Requires urgent specialist referral 1

Common Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload, as ferritin is an acute phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of iron stores 1, 4, 2
• Do not assume iron overload when TS <45%—in the general population, iron overload is NOT the most common cause of elevated ferritin 4, 2
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests 1, 4
• Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload and requires evaluation for rheumatologic emergencies 1, 4