Extreme hyperferritinemia: Causes and impact on diagnostic reasoning

Objectives: Hyperferritinemia can be a result of inflammation, infection, chronic iron overload, or other uncommon pathologies including hemophagocytic lymphohistiocytosis (HLH). There is a historical association between extreme hyperferritinemia and HLH, but in reality HLH is associated with a minority of hyperferritinemic states. Methods: We identified conditions most associated with hyperferritinemia by identifying 65, 536 serum ferritin levels at the University of Minnesota Hospital over a five-year period, with 86 values higher than 10, 000 ng/mL. Pediatric patients comprised 22% of this population, and adults, 78%. Results: The majority of cases in both populations with hyperferritinemia were due to chronic transfusion (35%), followed by liver disease (27%), and hematologic malignancy (16%). Solid malignancies, infection, macrophage activation syndrome, and primary and secondary HLH comprised the remaining (22%). Conclusions: Although this supports the relationship between extreme hyperferritinemia and HLH, it maintains that the positive predictive value of hyperferritinemia for HLH is quite low, and one should consider more common explanations before suspecting HLH.