What are the causes of hyperferritinemia?

Causes of Hyperferritinemia

Primary Classification Framework

Hyperferritinemia is caused by non-iron overload conditions in over 90% of outpatient cases, with chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD being the dominant etiologies. 1

The critical first step is measuring transferrin saturation (TS) alongside ferritin to distinguish true iron overload (TS ≥45%) from secondary hyperferritinemia (TS <45%). 1, 2

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Most Common Causes (>90% of Cases)

Metabolic and Liver-Related

• Non-alcoholic fatty liver disease (NAFLD)/Metabolic syndrome: The most prevalent cause in modern practice, reflecting hepatic inflammation and insulin resistance rather than iron accumulation 1, 3
• Chronic alcohol consumption: Causes direct hepatocellular injury and ferritin release 1, 4
• Viral hepatitis (B and C): Associated with chronic liver inflammation 1, 4
• Acute hepatitis: Can cause dramatic ferritin elevation from hepatocyte necrosis 1

Inflammatory Conditions

• Systemic inflammatory response syndrome: Ferritin acts as an acute phase reactant 1
• Adult-onset Still's disease (AOSD): Characterized by extreme hyperferritinemia (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20% 5, 1
• Hemophagocytic lymphohistiocytosis: Associated with extreme hyperferritinemia 6, 7
• Infections: Cause acute ferritin elevation as part of inflammatory response 1

Malignancy

• Solid tumors: Release ferritin through cell necrosis 1
• Lymphomas: Associated with elevated ferritin 1
• Hepatocellular carcinoma: Can cause marked hyperferritinemia 1

Cell Necrosis

• Muscle damage: Rhabdomyolysis or severe myositis 1
• Hepatocellular necrosis: From any acute liver injury 1

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Iron Overload Causes (When TS ≥45%)

Primary (Hereditary) Hemochromatosis

• HFE-related hemochromatosis: C282Y homozygosity or C282Y/H63D compound heterozygosity 1, 6
• Non-HFE hemochromatosis: Mutations in TFR2, SLC40A1 (ferroportin), HAMP (hepcidin), or HJV (hemojuvelin) genes 1, 8, 9
• Hyperferritinemia-cataract syndrome: L-ferritin gene mutation without iron overload 8, 9
• Aceruloplasminemia: Ceruloplasmin gene mutation with neurological symptoms 9

Secondary Iron Overload

• Chronic transfusion therapy: Most common cause of extreme hyperferritinemia (>10,000 ng/mL), accounting for 35% of such cases 7
• Thalassemia syndromes: From both ineffective erythropoiesis and transfusions 6
• Myelodysplastic syndrome: Causes transfusion-dependent iron overload 6
• Sickle cell disease: Particularly in chronically transfused patients 6
• Sideroblastic anemias: Ineffective erythropoiesis leads to iron accumulation 6

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Diagnostic Algorithm

Step 1: Measure Transferrin Saturation

• If TS <45%: Iron overload is unlikely; investigate secondary causes (inflammation, liver disease, malignancy, metabolic syndrome) 1, 2
• If TS ≥45%: Proceed to HFE genetic testing for C282Y and H63D mutations 1, 2

Step 2: Risk Stratification by Ferritin Level

• <1,000 μg/L: Low risk of organ damage; negative predictive value of 94% for advanced fibrosis 1
• 1,000-10,000 μg/L: Higher risk of cirrhosis if iron overload present (20-45% in C282Y homozygotes) 1
• >10,000 μg/L: Rarely represents simple iron overload; consider chronic transfusion (35%), liver disease (27%), hematologic malignancy (16%), or HLH 1, 7

Step 3: Additional Testing Based on Clinical Context

• Check inflammatory markers: CRP, ESR to detect occult inflammation 1
• Liver function tests: AST, ALT, albumin to assess hepatocellular injury 5, 1
• Complete blood count: To identify hematologic disorders 6
• Glycosylated ferritin: If AOSD suspected (fraction <20% is 93% specific when combined with 5-fold ferritin elevation) 5

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Critical Clinical Pearls

Ferritin has high sensitivity but low specificity for iron overload—it rises in numerous inflammatory conditions independent of iron stores. 1 Never use ferritin alone without transferrin saturation to diagnose iron overload. 1, 2

In inflammatory states, ferritin rises acutely while transferrin saturation often drops, creating a pattern of elevated ferritin with low TS that indicates inflammatory iron block rather than true iron excess. 1

Extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload—the positive predictive value for HLH is quite low despite historical associations, with chronic transfusion, liver disease, and hematologic malignancy being far more common. 7

In chronic kidney disease, ferritin 500-1,200 μg/L with TS <25% may represent functional iron deficiency that responds to IV iron therapy despite seemingly adequate ferritin levels. 1, 3

For AOSD specifically, serum ferritin correlates with disease activity and often normalizes with remission, making it useful for monitoring. 5