| Hemophagocytic lymphohistiocytosis | |
|---|---|
| Specialty | Hematology, pediatrics  |
Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome,[1] is an uncommon hematologic disorder. It is a life threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages that secrete high amounts of inflammatory cytokines.
The first case report of HLH was published in 1952.
Primary HLH, also known as familial haemophagocytic lymphohistiocytosis (FHL) or familial erythrophagocytic lymphohistiocytosis, is a heterogeneous autosomal recessive disorder found to be more prevalent with parental consanguinity.
Secondary haemophagocytic lymphohistiocytosis (acquired haemophagocytic 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 haematologic 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 [2] are each associated with a specific gene:
The onset of HLH occurs under the age of 1 year in ~70% of cases. Familial HLH should be suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. Each full sibling of a child with familial HLH has a 25% chance of developing the disease, a 50% chance of carrying the defective gene (which is very rarely associated with any risk of disease) and a 25% chance of not being affected and not carrying the gene defect.
HLH clinically manifests with fever, hepatosplenomegaly, lymphadenopathy, jaundice and a rash.
The blood count typically shows pancytopenia (anemia, neutropenia and thrombocytopenia.
The blood film may show hemophagocytosis.
The liver function tests are usually elevated.
The serum ferritin is markedly elevated.
Bone marrow biopsy shows histiocytosis[3]
The current (2008) diagnostic criteria for HLH are[4]
1. A molecular diagnosis consistent with HLH. These include the identification of pathologic mutations of PRF1, UNC13D or STX11.
OR
2. Fulfillment of five out of the eight criteria below:
Haemophagocytosis in the bone marrow, spleen or lymph nodes
Low or absent natural killer cell activity
Soluble CD25 (soluble IL-2 receptor) >2400 U/ml (or per local reference laboratory)
In addition, in the case of familial HLH, no evidence of malignancy should be apparent.
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.
Other conditions that may be confused with this condition include autoimmune lymphoproliferative syndrome.[5]
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.[6]
