Elevated Ferritin: Causes and Diagnostic Approach

Introduction to Elevated Ferritin

Elevated ferritin is most commonly caused by inflammation, chronic liver disease, malignancy, and infection, accounting for over 90% of cases in clinical practice 1
Ferritin functions as an acute phase reactant, tumor marker, and indicator of cellular damage, rising during inflammation, infection, and tissue injury independent of actual iron levels 2

Hereditary hemochromatosis (HFE-related) is characterized by C282Y homozygosity or C282Y/H63D compound heterozygosity 1, 2, 3
Non-HFE hemochromatosis is caused by mutations in TFR2, SLC40A1, HAMP, or HJV genes 1, 4
Chronic alcohol consumption increases iron absorption and causes hepatocellular injury 2, 3, 4
Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome is associated with ferritin elevation reflecting hepatocellular injury and insulin resistance rather than iron overload 1, 4

The American College of Gastroenterology recommends measuring transferrin saturation simultaneously with ferritin to distinguish true iron overload from secondary causes 1, 2, 3
If transferrin saturation is ≥45% with elevated ferritin, suspect primary iron overload and proceed to HFE genotype testing for C282Y and H63D mutations 1, 2, 3
If transferrin saturation is <45% with elevated ferritin, iron overload is unlikely, and secondary causes such as inflammation, liver disease, malignancy, and infection should be evaluated 1

The European Association for the Study of the Liver recommends risk stratification by ferritin level, with ferritin <1,000 μg/L indicating low risk of organ damage, and ferritin >10,000 μg/L suggesting life-threatening conditions such as hemophagocytic lymphohistiocytosis or adult-onset Still's disease 1, 2, 3
In chronic kidney disease patients on erythropoiesis-stimulating agents, ferritin 500-1,200 ng/mL with transferrin saturation <25% may represent functional iron deficiency that responds to IV iron therapy despite elevated ferritin 1, 4
In adult-onset Still's disease, consider measuring glycosylated ferritin fraction (<20% is 93% specific for AOSD) if ferritin rises above 4,000-5,000 ng/mL with persistent fever 1