Etiologies and Short-Term Mortality in Patients with Ultraelevated Serum Ferritin

Hyperferritinemia is common in states of iron overload, inflammation, and malignancy. There is evidence that higher ferritin levels may be associated with worse outcomes in several clinical conditions. Available data have been drawn primarily from cases of serum ferritin between 1000 and 5000 ng/mL and from relatively few cases of serum ferritin >5000 ng/mL. In addition, most studies have allowed for the assignment of only a single etiology per case of hyperferritinemia, when many cases may result from a combination of multiple etiologies. This study evaluates the distribution of etiologies and short-term mortality in patients with ultrahyperferritinemia (defined as a serum ferritin concentration >5000 ng/mL).

We retrospectively identified 405 patients older than 18 years who had serum ferritin concentrations >5000 ng/mL measured within the Geisinger Health System between 2004 and 2014. For each patient, we evaluated demographics, serum ferritin concentration, contributing etiologies, and mortality at 30 days and 6 months following index serum ferritin measurement.

Ultrahyperferritinemia was caused by a combination of multiple etiologies in 51% of cases, a single etiology in 44% of cases, and an undetermined etiology in 5% of cases. The majority of all cases were the result, at least in part, of chronic blood transfusions (48%), acute liver injury (44%), malignancy (33%), myelodysplastic syndrome (11%), or end-stage renal disease (ESRD;10%). Acute liver injury accounted for the majority of cases (73%) of ultrahyperferritinemia caused by a single etiology, whereas neither myelodysplastic syndrome nor ESRD was the sole etiology for a single case. Hemophagocytic lymphohistiocytosis and macrophage activation syndrome were associated with the highest mean serum ferritin levels by far, but acute liver injury remained the most common cause of single-etiology cases across all ferritin levels and accounted for 92% of cases >20,000 ng/mL. Mortality increased substantially between 30 days and 6 months for patients with ultrahyperferritinemia caused by malignancy (from 64% to 93%) but only modestly for patients with ultrahyperferritinemia caused by acute liver injury (from 33% to 39%).

Many cases of ultrahyperferritinemia are caused by a combination of multiple distinct etiologies. Cases of ultrahyperferritinemia among patients with ESRD and myelodysplastic syndrome may be partially explained by their often concomitant chronic blood transfusions. Acute liver injury is by far the most common cause of ultrahyperferritinemia caused by a single etiology, even at the most astronomically elevated serum ferritin concentrations. Finally, patients with ultrahyperferritinemia caused by malignancy appear to have poor 30-day survival and abysmal 6-month survival.