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Hemophagocytic lymphohistiocytosis

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Other Names for this Disease

  • Familial erythrophagocytic lymphohistiocytosis
  • Familial hemophagocytic lymphohistiocytosis
  • Familial histiocytic reticulosis
  • FHL
  • HLH
See Disclaimer regarding information on this site. Some links on this page may take you to organizations outside of the National Institutes of Health.

Overview

What is hemophagocytic lymphohistiocytosis?

What are the signs and symptoms of hemophagocytic lymphohistiocytosis?

What causes hemophagocytic lymphohistiocytosis?

Is hemophagocytic lymphohistiocytosis inherited?

Is genetic testing available for hemophagocytic lymphohistiocytosis?

How is hemophagocytic lymphohistiocytosis diagnosed?

How might hemophagocytic lymphohistiocytosis be treated?

What is the long-term outlook for people with hemophagocytic lymphohistiocytosis?

What is hemophagocytic lymphohistiocytosis?

Hemophagocytic lymphohistiocytosis (HLH) is a condition in which the body makes too many activated immune cells (macrophages and lymphocytes).[1] 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.[2][3] 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 genetic cause of type 1 is currently unknown. Types 2-5 are caused by mutations in the PRF1 gene, the UNC13D gene, the STX11 gene and the STXBP2 gene, respectively.[4] Treatment depends on a number of factors, including the severity of symptoms, the age of onset, and the underlying cause of the condition.[4][5]
Last updated: 11/9/2014

What are the signs and symptoms of hemophagocytic lymphohistiocytosis?

The signs and symptoms of hemophagocytic lymphohistiocytosis typically 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. The features of this condition may include:[1][4][2][3]
  • Fever
  • Enlarged liver and/or spleen
  • Skin rash
  • Lymph node enlargement
  • Breathing problems
  • Easy bruising and/or abnormal bleeding
  • Kidney abnormalities
  • Heart problems
  • 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.[4][1]
Last updated: 11/9/2014

What causes hemophagocytic lymphohistiocytosis?

There are inherited and non-inherited (acquired) causes of hemophagocytic lymphohistiocytosis (HLH).[6][3]

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 that helps regulate the immune system. The genetic cause of familial HLH, type 1 is currently unknown. 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.[4] 

All of the genes that cause HLH serve as the instructions for proteins that help destroy or turn off activated immune cells that 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.[7][6][3]

The acquired causes of HLH include: infection, medications that suppress the immune system, autoimmune diseases, immunodeficiencies, certain types of cancer and/or metabolic diseases.[3][6]
Last updated: 11/10/2014

Is hemophagocytic lymphohistiocytosis inherited?

Hemophagocytic lymphohistiocytosis (HLH) may be inherited or acquired (due to non-genetic factors).

Familial HLH is inherited in an autosomal recessive manner.[4] This means that to be affected, a person must have a change (mutation) in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Acquired HLH is not inherited. The non-genetic causes of HLH include: infection, medications that suppress the immune system, autoimmune diseases, immunodeficiencies, certain types of cancer and/or metabolic diseases.[3][6]
Last updated: 11/10/2014

Is genetic testing available for hemophagocytic lymphohistiocytosis?

Yes. Clinical genetic testing is available for the four genes known to cause familial hemophagocytic lymphohistiocytosis, types 2-5. Carrier testing for at-risk relatives and prenatal testing are possible if the two disease-causing mutations in the family are known. Molecular genetic testing is not available for familial hemophagocytic lymphohistiocytosis, type 1 because the genetic cause is currently unknown.[4]

Genetic testing is not available for acquired HLH because it is caused by non-genetic factors.

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.
Last updated: 11/10/2014

How is hemophagocytic lymphohistiocytosis diagnosed?

A diagnosis of hemophagocytic lymphohistiocytosis (HLH) is based on the presence of certain signs and symotoms. A person is considered affected by this condition if they have at least five of the following symptoms:[4][8]
  • Fever
  • Enlarged spleen
  • Cytopenia (lower-than-normal number of blood cells)
  • Elevated levels of triglycerides or 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)
The diagnosis of familial HLH, types 2-5 can be confirmed with genetic testing.[4]
Last updated: 11/10/2014

How might hemophagocytic lymphohistiocytosis be treated?

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, antiobiotics or antiviral medications can be used to treat or prevent infections that may have triggered the exaggerated immune response. Allogeneic hematopoietic cell transplantation is considered a cure for familial HLH. It is often recommended that people with confirmed or suspected familial HLH undergo this treatment as early in life as possible. Prior to hematopoietic cell transplanation, affected people are usually treated with chemotherapy and/or immunotherapy to destroy excess immune cells which can lead to life-threatening inflammation.[4][5][3]
Last updated: 11/10/2014

What is the long-term outlook for people with hemophagocytic lymphohistiocytosis?

Without treatment hemophagocytic lymphohistiocytosis (HLH) can be fatal. The prognosis for people with HLH who undergo treatment depends on many factors, including the severity of symptoms, the age of diagnosis, and the underlying cause of the condition. For example, people with neurological symptoms, diagnosis before age 6 months, high blood ferritin levels, or cancer-associated HLH tend to have worse prognoses. 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.[5][8]
Last updated: 11/10/2014

References
  1. Familial hemophagocytic lymphohistiocytosis. Genetics Home Reference. January 2011; http://ghr.nlm.nih.gov/condition/familial-hemophagocytic-lymphohistiocytosis. Accessed 7/22/2011.
  2. Kenneth L McClain, MD, PhD. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. UpToDate. August 27, 2014; http://www.uptodate.com/contents/clinical-features-and-diagnosis-of-hemophagocytic-lymphohistiocytosis?source=see_link. Accessed 11/9/2014.
  3. George MR.. Hemophagocytic lymphohistiocytosis: review of etiologies and management.. J Blood Med. June 2014; 5:69-86. Accessed 11/9/2014.
  4. 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, 2013; http://www.ncbi.nlm.nih.gov/books/NBK1444/. Accessed 11/7/2014.
  5. Kenneth L McClain, MD, PhD. Treatment and prognosis of hemophagocytic lymphohistiocytosis. UpToDate. April 1, 2014; http://www.uptodate.com/contents/treatment-and-prognosis-of-hemophagocytic-lymphohistiocytosis?source=see_link. Accessed 11/9/2014.
  6. Janka GE, Lehmberg K.. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment.. Hematology Am Soc Hematol Educ Program. 2013; 2013:605-611. Accessed 11/10/2014.
  7. Familial hemophagocytic lymphohistiocytosis. Genetics Home Reference. January 2011; http://ghr.nlm.nih.gov/condition/familial-hemophagocytic-lymphohistiocytosis. Accessed 11/26/2012.
  8. Zhang L, Zhou J, Sokol L. Hereditary and acquired hemophagocytic lymphohistiocytosis. Cancer Control. October 2014; 21(4):301-312. Accessed 11/10/2014.


Other Names for this Disease
  • Familial erythrophagocytic lymphohistiocytosis
  • Familial hemophagocytic lymphohistiocytosis
  • Familial histiocytic reticulosis
  • FHL
  • HLH
See Disclaimer regarding information on this site. Some links on this page may take you to organizations outside of the National Institutes of Health.