Serum Ferritin is a sensitive screening parameter to diagnose hemophagocytic lymphohistiocytosis (HLH) in critically ill patients but lacks specificity. Immunoassays used in clinical laboratories recognize solely the L subunit of ferritin. However, the proportion of the H subunit has been suggested to also increase during these hyperinflammatory conditions.To improve the specificity of the assay, we developed a targeted LC-MS/MS method to quantify both L and H subunits of ferritin in human serum (FeL and FeH respectively). We assessed the diagnostic performances of FeL and FeH in a cohort of critically patients with hyperferritinemia (n=50) including 22 patients with HLH and 7 patients with macrophage activation-like syndrome (MALS). The optimal cutoff value of FeL and FeH (with the highest Youden index) was obtained by receiver operating characteristic curve analysis comparing the patients with HLH and MALS to those with unconfirmed HLH, sepsis, severe sepsis and septic shock.

We found that at equivalent FeL levels, the serum FeH to total Ferritin ratio increased significantly in patients with HLH and macrophage activation-like syndrome compared to patients with sepsis (p<0.05). We defined a cut-off of FeH to total Ferritin of 6 and a cut-off of FeL levels of 4465 µg/L, predictable of HLH and MALS. We observed that the ratio of FeH to total Ferritin was able to better identify HLH and MALS compared to FeL levels. By setting the diagnostic sensitivity to 93%, we observed an increased specificity of 86% for the ratio of FeH to Ferritin compared to 67% for FeL.

These results support the value of the FeH to total Ferritin ratio to diagnose patients with HLH and to better stratify septic patients in order to optimize new targeted therapeutic strategies.

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2025
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