What causes elevated ferritin levels in adults, particularly those with a family history of hemochromatosis or other iron metabolism disorders?

What Causes Elevated Ferritin Levels

Elevated ferritin is caused by non-iron overload conditions in over 90% of cases, including chronic alcohol consumption, inflammation, cell necrosis, tumors, and metabolic syndrome/NAFLD—not hereditary hemochromatosis. 1

Primary Diagnostic Framework

The key to understanding elevated ferritin is recognizing that ferritin is an acute phase reactant that rises during inflammation, infection, liver disease, and tissue injury independent of actual iron stores. 1 This means most elevated ferritin levels do not indicate iron overload.

Most Common Causes (>90% of Cases)

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury 1, 2
• Inflammation from any source (infections, rheumatologic diseases, systemic inflammatory response syndrome) 1
• Cell necrosis from muscle injury, hepatocellular necrosis, or tissue breakdown 1
• Tumors including solid tumors, lymphomas, and hepatocellular carcinoma 1
• Metabolic syndrome/NAFLD where ferritin reflects hepatocellular injury and insulin resistance rather than iron overload 1

Liver Disease Causes

• Alcoholic liver disease through multiple mechanisms including increased iron absorption and liver injury 1, 2
• Viral hepatitis B and C 1, 2
• Non-alcoholic fatty liver disease (NAFLD) 1, 2
• Acute hepatitis 1

Inflammatory and Rheumatologic Conditions

• Adult-onset Still's disease (AOSD) causes extreme hyperferritinemia (4,000-30,000 ng/mL, occasionally up to 250,000 ng/mL) with glycosylated ferritin fraction <20% 1
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 1, 3
• Chronic rheumatologic diseases 1
• Systemic inflammatory response syndrome 1

Malignancy

• Solid tumors 1
• Lymphomas 1
• Hepatocellular carcinoma 1

In a large academic medical center study of 627 patients with ferritin >1000 μg/L, malignancy was the most frequent cause (153/627), followed by iron-overload syndromes (136/627), with only 6 cases of AOSD, systemic juvenile idiopathic arthritis, or hemophagocytic lymphohistiocytosis 3

Iron Overload Disorders (Minority of Cases)

Hereditary Hemochromatosis

• HFE-related hemochromatosis with C282Y homozygosity or C282Y/H63D compound heterozygosity 1, 2, 4
• Non-HFE hemochromatosis with mutations in TFR2, SLC40A1, HAMP, or HJV genes 1, 2

Critical point: In patients with family history of hemochromatosis, HFE genetic testing should be pursued if transferrin saturation ≥45% 1, 4

Secondary Iron Overload

• Transfusional iron overload in patients with chronic transfusion requirements 2, 5
• Hematologic disorders including thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, or pyruvate kinase deficiency 4

Other Causes

• Chronic kidney disease 1
• Diabetes mellitus 1
• Infections (ferritin rises as part of acute phase response) 1, 2

Critical Diagnostic Distinction

The single most important test is transferrin saturation (TS), which must be measured simultaneously with ferritin. 1, 6

• If TS ≥45%: Suspect primary iron overload and proceed with HFE genetic testing 1, 6
• If TS <45%: Iron overload is unlikely and secondary causes predominate 1, 6

This distinction is crucial because in the general population, iron overload is NOT the most common cause of elevated ferritin. 1

Risk Stratification by Ferritin Level

• Ferritin <1,000 μg/L: Low risk of organ damage (negative predictive value 94% for advanced liver fibrosis in hemochromatosis) 1, 6
• Ferritin 1,000-10,000 μg/L: Higher risk of advanced fibrosis/cirrhosis if iron overload is present (20-45% prevalence of cirrhosis in C282Y homozygotes) 1, 6
• Ferritin >10,000 μg/L: Rarely represents simple iron overload; most commonly due to chronic transfusion (35%), liver disease (27%), or hematologic malignancy (16%) 1, 5

Common Pitfalls to Avoid

• Never use ferritin alone without transferrin saturation to diagnose iron overload 1, 6
• Do not assume iron overload when TS <45% 1
• Do not overlook liver biopsy in patients with ferritin >1000 μg/L and abnormal liver tests 1, 6
• Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload 1, 5
• Do not fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1