Hemophagocytic lymphohistiocytosis
Encyclopedia
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.
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:
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.
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, hepatosplenomegaly
Hepatosplenomegaly
Hepatosplenomegaly is the simultaneous enlargement of both the liver and the spleen . Hepatosplenomegaly can occur as the result of acute viral hepatitis or infectious mononucleosis, or it can be the sign of a serious and life threatening lysosomal storage disease...
, lymphadenopathy
Lymphadenopathy
Lymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....
, jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
and rash, with laboratory
Medical laboratory
A medical laboratory or clinical laboratory is a laboratory where tests are done on clinical specimens in order to get information about the health of a patient as pertaining to the diagnosis, treatment, and prevention of disease.-Departments:...
findings of lymphocytosis
Lymphocytosis
Lymphocytosis is an increase in the number or proportion of lymphocytes in the blood, usually detected when a complete blood count is routinely obtained. Lymphocytes normally represent 20 to 40% of circulating white blood cells...
and histiocytosis
Histiocytosis
In medicine, histiocytosis refers to an excessive number of histiocytes, , and is typically used to refer to a group of rare diseases which share this as a characteristic...
, and the pathologic finding of hemophagocytosis
Hemophagocytosis
Hemophagocytosis is phagocytosis by histiocytes of erythrocytes, leukocytes, platelets, and their precursors in bone marrow and other tissues.It is part of the presentation of hemophagocytic lymphohistiocytosis....
. Pancytopenia
Pancytopenia
Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
(anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
, and thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
), markely elevated serum ferritin
Ferritin
Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals...
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 - HPLH1HPLH1HPLH1 is a protein associated with hemophagocytic lymphohistiocytosis type 1....
- FHL2 - PRF1 (PerforinPerforinPerforin-1 is a protein that in humans is encoded by the PRF1 gene.- Function :Perforin is a cytolytic protein found in the granules of CD8 T-cells and NK cells. Upon degranulation, perforin inserts itself into the target cell's plasma membrane, forming a pore. The lytic membrane-inserting part...
) - FHL3 - UNC13DUNC13DProtein unc-13 homolog D, also known as munc13-4, is a protein that in humans is encoded by the UNC13D gene.- Function :Munc13-4 is a member of the UNC13 family, containing similar domain structure as other family members but lacking an N-terminal phorbol ester-binding C1 domain present in other...
(Munc13-4) - FHL4 - STX11STX11Syntaxin 11, also known as STX11, is a human gene that is a member of the t-SNARE family.-Interactions:STX11 has been shown to interact with SNAP-25 and SNAP23.-See also:* Hemophagocytic lymphohistiocytosis-Further reading:...
(Syntaxin 11) - FHL5 – STXBP2 (Syntaxin binding protein 2Syntaxin binding protein 2Syntaxin-binding protein 2 is a protein that in humans is encoded by the STXBP2 gene.-Further reading:...
)/UNC18-2
The differential diagnosis of FHL includes secondary HLH and macrophage-activation syndrome
Macrophage-activation syndrome
Macrophage-activation syndrome is a severe, potentially life-threatening, complication of several chronic rheumatic diseases of childhood. It occurs most commonly with systemic-onset juvenile idiopathic arthritis , which is also known as Still's disease...
or other primary immunodeficiencies that present with hemophagocytic lymphohistiocytosis, such as X-linked lymphoproliferative disease
X-linked lymphoproliferative disease
X-linked lymphoproliferative disease is a lymphoproliferative disorder.-XLP1:There is a mutation on the X-chromosome that has been found to be associated with a T- and NK-cell lymphoproliferative disorder. The mutation is on the long arm of the chromosome, at position 25, which is denoted as Xq25...
.
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.