Familial hemophagocytic lymphohistiocytosis

What causes hemophagocytic lymphohistiocytosis?

There are inherited and non-inherited (acquired) causes of hemophagocytic lymphohistiocytosis (HLH).

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.

When HLH results from an inappropriate immune response to Epstein-Barr virus or another viral illness, it may be due to a separate genetic condition called X-linked lymphoproliferative disease (XLP). XLP is caused by a mutation in the SH2D1A or XIAP gene and is inherited in an X-linked manner.

Last updated on 05-01-20

How is hemophagocytic lymphohistiocytosis diagnosed?

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:

  • Fever
  • Enlarged spleen
  • 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.

Last updated on 05-01-20

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. 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.

When HLH results from an inappropriate immune response to Epstein-Barr virus or another viral illness, it may be due to a separate genetic condition called X-linked lymphoproliferative disease (XLP). XLP is caused by a mutation in the SH2D1A or XIAP gene and is inherited in an X-linked manner.

Last updated on 05-01-20

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

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.

Last updated on 05-01-20

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, people with HLH are usually treated with chemotherapy and/or immunotherapy to destroy excess immune cells which can lead to life-threatening inflammation.

Please visit the Histiocyte Society to learn more about the treatment guidelines for HLH.

Last updated on 05-01-20

Where To Start

Cincinnati Children's Hospital - HLH

The Cincinnati Children's Hospital has an information page on Familial hemophagocytic lymphohistiocytosis. Click on the link to view this information page.

Last updated on 04-27-20

Histiocytosis Association of America HLH info page

The Histiocytosis Association of America has an information page on hemophagocytic syndromes. Click on Histiocytosis Association to view the information page.

Last updated on 04-27-20

Name: Histiocytosis Association 332 North Broadway
Pitman, NJ, 08071 , United States
Phone: +1-856-589-6606 Toll Free: 1-800-548-2758 (from US and Canada) Fax : +1-856-589-6614 Email: info@histio.org Url: https://www.histio.org/
Name: Histiocytosis Association of Canada 41 Milverton Close Waterdown, ON
L8B 0A9
Canada
Email: info@histio.ca Url: https://histiocytosis.ca/
Name: Histio UK United Kingdom Phone: 01733 309619 Url: https://www.histiouk.org/
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; Reference Link George MR.. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. June 2014; 5. 69-86. Reference Link Janka GE, Lehmberg K.. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program. 2013; 2013. 605-611. Reference Link Zhang L, Zhou J & Sokol L. Hereditary and acquired hemophagocytic lymphohistiocytosis Cancer Control. October 2014; 21(4). 301-312.

Note, these links are external searches against the National Laboratory of Medicine's drug database. You may need to adjust the search if there are no results found.

Drug Name Generic Name
Gamifant Emapalumab-lzsg

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