Hemophagocytic lymphohistiocytosis: review of etiologies and management

George, Melissa R

The diagnosis of FHL or secondary HLH is based on a number of clinical signs and laboratory findings. Due to the relatively nonspecific nature of the clinical signs and symptoms, and significant overlap with other illnesses, diagnosis is often delayed. The official diagnosis of HLH, established by the Histiocyte Society, is based on fulfilling one or both of the following criteria: 1. A molecular diagnosis consistent with HLH 2. Five out of the following nine diagnostic criteria for HLH: fever, splenomegaly, cytopenias (affecting two or more of three lineages in the peripheral blood), hypertriglyceridemia, hypofibrinogenemia, elevated ferritin, hemophagocytosis in bone marrow/spleen/ lymph nodes, low or absent natural killer (NK)-cell activity, or elevated soluble CD25 (interleukin [IL]-2 receptor). 7, 8 All of the clinical and laboratory findings are readily linked to the pathophysiology of HLH. Fever is the result of high IL levels. Splenomegaly is the direct result of infiltration by lymphocytes and macrophages. Cytopenias can be explained by high concentrations of tumor necrosis factor (TNF)-α and interferon (IFN)-γ, as well as direct hemophagocytosis. High triglycerides are secondary to decreased lipoprotein lipase activity initiated by increased TNF-α levels. Elevated ferritin .10,000 µg/L has been demonstrated to be 90% sensitive and 96% specific for HLH. [9] [10] [11] [12] Ferritin is believed to accumulate during the antiinflammatory process of macrophage scavenging of heme via the CD163 receptor. High concentrations of soluble IL-2 receptor are produced by activated lymphocytes. 13 A summary of clinical and laboratory findings is provided in Table 1 .