Elevated serum ferritin is not specific for hemophagocytic lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal, syndrome of excessive and ineffective activation of the immune system. The majority of the reported data on HLH is from pediatric patients and lacks specificity. This makes HLH diagnosis challenging especially in adults where HLH is triggered by many conditions and can resemble many disease entities. Elevated ferritin is one of the diagnostic criteria for HLH. We determined the conditions associated with elevated ferritin at our medical center to assess how specific ferritin is for predicting HLH. We retrospectively reviewed all ferritin results >10,000 μg/L in pediatric and adult patients. The most common condition associated with elevated ferritin was hematologic malignancy in adults (25.7%) and HLH in pediatric patients (48.9%). HLH was diagnosed in 14.2% of adults and 48.9% of children with ferritin >10,000 µg/L. Hyperferritinemia occurs in a variety of conditions and is not specific for adult or pediatric HLH. Common causes of elevated ferritin should be considered before entertaining the possibility of HLH, especially in adult patients.

Brucellosis accompanied by haemophagocytic lymphohistiocytosis and multiple splenic abscesses in a patient with depression

“…In our case, Brucella-induced haemophagocytic syndrome was suggested by the presence of six of these criteria including fever, splenomegaly, cytopenia (neutropaenia, thrombocytopenia and anaemia), bone marrow haemophagocytosis, hypertriglyceridaemia and hyperferritinaemia exceeding 70 000. HLH was identified in 48.9% of children and 14.2% of adults with ferritin >10 000 µg/L 10. Other factors associated with this syndrome were not examined in our case.…”

Reevaluating the role of ferritin in the diagnosis of adult secondary hemophagocytic lymphohistiocytosis

“…This is problematic for several reasons: first, because the diagnosis of this disease is based on the somewhat arbitrary inclusion criteria for a single clinical trial rather than on any real‐world clinical data; second, because pediatric primary HLH is likely a vastly different disease from adult secondary HLH, and the use of uniform diagnostic criteria for these disparate entities makes little sense; and third, because ferritin, though certainly an exquisite marker of inflammation, is a highly non‐specific one . Notably, HLH‐2004 reported a sensitivity of 84% for their ferritin cutoff however reported no associated specificity …”

“…Recently, data have been emerging which call into question the specificity and relevance of several of the HLH‐2004 criteria among adults with suspected secondary HLH . Much of these data have focused on the criterion of serum ferritin, a non‐specific marker of inflammation which, when markedly abnormal, is often a primary driver of HLH workups among hospitalized patients . Studies examining serum ferritin thresholds >3000 ng/mL, 4000 ng/mL, 10 000 ng/mL, and 50 000 ng/mL have demonstrated that hyperferritinemia lacks specificity for HLH .…”

Limitations of HLH‐2004 criteria in distinguishing malignancy‐associated hemophagocytic lymphohistiocytosis

“…The criteria largely consist of nonspecific markers of inflammation. These include the findings that are often mistakenly considered more specific for HLH, such as elevated soluble IL2 receptor (sIL2R) and hemophagocytosis . Rubin et al also recently demonstrated that the NK cell cytolytic assay is neither efficient nor reliably diagnostic for primary HLH, with a sensitivity of 60% and a specificity of 72% .…”