Signs and symptoms of hemophagocytic lymphohistiocytosis usually develop during the first months or years of life. However, in rare cases, affected people may not show symptoms until later in childhood or even into adulthood.
Increased risk for certain cancers (leukemia, lymphoma)
Many people with this condition also develop neurologic abnormalities. The neurological symptoms vary but may include irritability, fatigue, abnormal muscle tone, seizures, neck stiffness, mental status changes, ataxia, blindness, paralysis, and/or coma.
Hemophagocytic lymphohistiocytosis (HLH) is a condition in which the body makes too many activated immune cells (macrophages and lymphocytes). People with HLH usually develop symptoms within the first months or years of life which may include fever, enlarged liver or spleen, cytopenia (lower-than-normal number of blood cells), and neurological abnormalities.
HLH may be inherited in an autosomal recessive manner or it can have non-genetic causes in which case it is called acquired HLH. There are five subtypes of inherited HLH which are designated familial HLH, types 1-5. Each subtype is caused by a change (mutation) in a different gene.
The diagnosis of hemophagocytic lymphohistiocytosis (HLH) can be established if 1 and/or 2 below is fullfilled:
1. A genetic test identifying a mutation in one of the genes involved with this condition
2. At least five out of the following 8 signs or symptoms:
Cytopenia (lower-than-normal number of blood cells)
Elevated levels of triglycerides or low levels of fibrinogen in the blood
Hemophagocytosis (the destruction of certain types of blood cells by histiocytes) on bone marrow, spleen or lymph node biopsy
Decreased or absent NK cell activity
High levels of ferritin in the blood
Elevated blood levels of CD25 (a measure of prolonged immune cell activation).
Clinical genetic testing is available for the four genes known to cause familial hemophagocytic lymphohistiocytosis, types 2-5. The Genetic Testing Registry (GTR) is a centralized online resource for information about genetic tests. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
The best treatment options for hemophagocytic lymphohistiocytosis (HLH) are determined by a number of factors, including the severity of symptoms, the age of onset, and the underlying cause of the condition. In acquired HLH, it is often necessary to treat the underlying condition. For example, antibiotics or antiviral medications can be used to treat or prevent infections that may have triggered the exaggerated immune response.
All forms of HLH, including cases treated adequately, may have a high mortality rate. The long-term outlook (prognosis) of familial forms without treatment is poor, with a median survival of less than 2 months to 6 months after diagnosis. Even with treatment, only 21-26% are expected to survive 5 years. The course of the disease and life expectancy are not well studied in adults with familial HLH.
The prognosis for people with acquired HLH varies. For example, the mortality rate reportedly is lower when HLH is associated with autoimmune diseases (8–22%), and greater when it is associated with tumors (especially T-cell lymphoma).
Because affected people are being diagnosed earlier and treatment options are improving, the prognosis for people with HLH is likely to get better over time.
There are five subtypes of inherited (or familial) HLH which are designated familial HLH, types 1-5. Each subtype is caused by a change (mutation) in a different gene that helps regulate the immune system. Type 1 is due to a gene defect on chromosome 9.
Familial HLH, type 2 is caused by mutations in the PRF1 gene. Familial HLH, type 3 is caused by mutations in the UNC13D gene. Familial HLH, type 4 is caused by mutations in the STX11 gene. Familial HLH, type 5 is caused by mutations in the STXBP2 gene.
All of the genes involved with HLH normally provide instructions for proteins that help destroy or turn off activated immune cells when they are no longer needed. Changes in these genes lead to an overproduction of immune cells which results in an excessive immune response and the many signs and symptoms of familial HLH.
The acquired causes of HLH include: infection, medications that suppress the immune system, autoimmune diseases, immunodeficiencies, certain types of cancer and/or metabolic diseases.
Familial hemophagocytic lymphohistiocytosis. Genetics Home Reference. November 2014; http://ghr.nlm.nih.gov/condition/familial-hemophagocytic-lymphohistiocytosis.
Kenneth L McClain, MD, PhD. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. UpToDate. July 29, 2015;
George MR.. Hemophagocytic lymphohistiocytosis: review of etiologies and management.. J Blood Med. June 2014; 5:69-86. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062561/.
Kejian Zhang, MD, MBA, Alexandra H Filipovich, MD, Judith Johnson, MS, Rebecca A Marsh, MD, and Joyce Villanueva, MT, MBA.. Hemophagocytic Lymphohistiocytosis, Familial. GeneReviews. January 17, 2013; http://www.ncbi.nlm.nih.gov/books/NBK1444/.
Kenneth L McClain, MD, PhD. Treatment and prognosis of hemophagocytic lymphohistiocytosis. UpToDate. October 15, 2015;
Janka GE, Lehmberg K.. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment.. Hematology Am Soc Hematol Educ Program. 2013; 2013:605-611. https://www.ncbi.nlm.nih.gov/pubmed/24319239.
Zhang L, Zhou J & Sokol L. Hereditary and acquired hemophagocytic lymphohistiocytosis. Cancer Control. October 2014; 21(4):301-312.
Image: Miles Kelly Art Library, Wellcome Images. Cross section of a human lymph node