What are the implications of hyperferritinemia?

Implications of Hyperferritinemia (Ferritin 402)

A ferritin level of 402 μg/L warrants further evaluation for underlying causes, with the most common etiologies being inflammation, chronic alcohol consumption, metabolic syndrome, and liver disease rather than primary iron overload. 1

Common Causes of Hyperferritinemia

• The most common causes of hyperferritinemia in outpatients include chronic alcohol consumption, inflammation, cell necrosis, tumors, and non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome, accounting for over 90% of cases 1
• Inflammatory conditions such as viral hepatitis, rheumatologic diseases, and infections can elevate ferritin as an acute phase reactant 2
• Alcoholic liver disease is a significant cause of hyperferritinemia due to alcohol's disruption of iron metabolism by downregulating hepcidin transcription 3
• Metabolic syndrome and NAFLD are increasingly common causes of elevated ferritin levels 1
• Malignancies, particularly hematologic malignancies, can cause significant hyperferritinemia 4, 5

Diagnostic Approach

Initial Assessment

• The first step in evaluating hyperferritinemia is to check transferrin saturation (TS) along with serum ferritin 1, 2
• If TS ≥45% and/or ferritin is elevated, proceed with further evaluation for potential iron overload 1
• If TS <45%, focus on evaluating non-iron overload causes such as inflammation, liver disease, and metabolic disorders 2

Further Evaluation Based on Transferrin Saturation

1. If TS ≥45%:

   • Consider HFE genetic testing for C282Y and H63D mutations 6
   • C282Y homozygosity is the most common genotype associated with hereditary hemochromatosis 1

2. If TS <45%:

   • Evaluate for inflammatory conditions (check CRP, ESR) 2
   • Assess liver function (ALT, AST) 2
   • Screen for metabolic syndrome (lipid panel, glucose) 1
   • Consider alcohol history and consumption patterns 3

Clinical Significance Based on Ferritin Level

• A ferritin level of 402 μg/L is mildly elevated but below the threshold of 1000 μg/L that would suggest significant risk for cirrhosis in hereditary hemochromatosis 6, 1
• Ferritin >1000 μg/L with elevated liver enzymes and platelet count <200,000/μL predicts cirrhosis in 80% of C282Y homozygotes 1
• Extremely high ferritin levels (>10,000 μg/L) may suggest adult-onset Still's disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome 4, 7

Management Considerations

• For confirmed hereditary hemochromatosis with elevated ferritin, therapeutic phlebotomy to achieve ferritin <50 μg/L is recommended 2
• For secondary causes (inflammation, alcohol, metabolic syndrome), treating the underlying condition rather than the elevated ferritin itself is recommended 2
• Avoid iron supplementation in patients with elevated ferritin unless there is evidence of iron deficiency with low transferrin saturation 2
• In chronic alcohol users, abstinence from alcohol should be the first intervention, as ferritin levels may normalize after cessation 3

Important Clinical Pearls

• Serum ferritin has high sensitivity but low specificity for iron overload, as it can be elevated in many inflammatory conditions 1
• In the general population, iron overload is not the most common cause of elevated ferritin 1, 5
• Multiple underlying conditions can contribute to hyperferritinemia in a single patient, with higher ferritin levels often associated with multiple etiologies 5
• The decision to treat hyperferritinemia should be based on the underlying cause rather than the ferritin level alone 8