Hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is an uncommon hematologic disorder that, typically, clinically manifests as fever, hepatosplenomegaly, lymphadenopathy, jaundice and rash, with laboratory findings of lymphocytosis and histiocytosis, and the pathologic finding of hemophagocytosis. Pancytopenia (anemia, neutropenia, and thrombocytopenia), markely elevated serum ferritin levels, and abnormal liver enzymes are frequently present.

Types
Primary HLH, also known as familial hemophagocytic lymphohistioctosis (FHL) or familial erythrophagocytic lymphohistiocytosis, is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity. Secondary hemophagocytic lymphohistiocytosis (i.e., acquired hemophagocytic lymphohistiocytosis) occurs after strong immunologic activation, such as that which can occur with systemic infection, immunodeficiency, or underlying malignancy. Both forms are characterized by the overwhelming activation of normal T lymphocytes and macrophages, invariably leading to clinical and hematologic alterations and death in the absence of treatment.

Five genetic subtypes (FHL1, FHL2, FHL3, FHL4, and FHL5) are described, with an estimated prevalence of one in 50,000 and equal gender distribution. Molecular genetic testing for four of the causative genes, PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5), is available on a clinical basis. Symptoms of FHL are usually evident within the first few months of life and may even develop in utero. However, symptomatic presentation throughout childhood and even into young adulthood has been observed in some cases.

The five subtypes of FHL are each associated with a specific gene:
 * FHL1 - HPLH1
 * FHL2 - PRF1 (Perforin)
 * FHL3 - UNC13D (Munc13-4)
 * FHL4 - STX11 (Syntaxin 11)
 * FHL5 – STXBP2 (Syntaxin binding protein 2)/UNC18-2

The differential diagnosis of FHL includes secondary HLH and macrophage-activation syndrome or other primary immunodeficiencies that present with hemophagocytic lymphohistiocytosis, such as X-linked lymphoproliferative disease.

The diagnosis of acquired, or secondary, HLH is usually made in association with infection by viruses, bacteria, fungi, or parasites or in association with lymphoma, autoimmune disease, or metabolic disease. Acquired HLH may have decreased, normal, or increased NK cell activity.

Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment (i.e., IV immunoglobulin only). However, long-term remission without the use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with CNS involvement.