Hemophagocytic Lymphohistiocytosis (HLH): An Update

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of immune regulation, clinically characterized by prolonged fever, cytopenias and hepatosplenomegaly. Low or absent natural killer (NK) cell and CD8+ cytotoxic T lymphocyte (CTL) cytotoxicity is one of the hallmarks of HLH. This results in ineffective infection control leading to prolonged and excessive activation of antigen presenting cells (macrophages, histiocytes) and multisystem inflammation. HLH may occur as a primary (genetic) condition due to mutations in genes important in the pathway of granule mediated cytotoxicity or as a secondary condition wherein identical clinical findings may arise secondary to infectious, rheumatological, malignant, or metabolic conditions. Primary HLH is further divided into familial HLH (FHL), in which HLH is often the presenting clinical manifestation of disease, and other genetic causes in which HLH is one of several clinical manifestations. Five different forms of FHL have so far been described; Type 1 is due to yet unidentified gene defect located on chromosome nine. Type 2 is caused by mutations in the perforin (PRF1) gene (20-40% of all FHL cases), type 3 by mutations in the Munc- 13–4 (UNC13D) gene (20-25% of all FHL cases), type 4 by mutations in the syntaxin 11 (STX11) gene (14-21% of all FHL cases) and the recently described type 5 due to mutations in the gene encoding syntaxin binding protein 2 (STXBP-2). The incidence of the five types varies significantly in different ethnic groups. Early diagnosis and initiation of immunosuppressive therapy is extremely important due to the life threatening nature of this disease. There is no single diagnostic test available for HLH and it is based on constellation of clinical manifestations and laboratory parameters which often overlap with those of severe infection and sepsis. Identification of patients with primary HLH and their underlying genetic defects require specialized laboratory tests and is important for predicting relapse and planning early therapeutic hematopoietic stem cell transplantation (HSCT). This review will focus on the pathophysiology of HLH with emphasis on FHL, clinical manifestations, diagnostic approach for rapid identification of genetic defects and important management issues.