HLH | What is Hemophagocytic Lymphohistiocytosis?

HLH can be diagnosed only with the proper tests. Blood tests include blood cell counts, liver function, infection studies, and markers of immune system activation such as ferritin and soluble IL-2 receptor levels. A bone marrow aspirate and biopsy may be performed to look for microscopic evidence of hemophagocytosis. Doctors may perform a lumbar puncture to collect cerebrospinal fluid and make sure the HLH is not affecting the brain. These latter two procedures are performed while a patient is asleep.

X-rays, CT scans, ultrasounds or MRIs may be performed.   

There are also specialized blood tests that can be done to rapidly screen patients for the genetic causes of HLH.  Detailed genetic testing should also be performed. 

Primary, or familial, HLH is caused by problems in genes that control how the immune system kills virus-infected or other abnormal cells in a person’s body.  These genes include PRF1, MUNC 13-4, STXBP2 and STX11.   

Primary HLH also occurs in some closely related inherited diseases.  These include X-linked lymphoproliferative disease (XLP), which is due to mutations in the SH2D1A gene (XLP1) or XIAP / BIRC4 gene (XLP2), Griscelli syndrome type II, which is due to mutations in the Rab27a gene, and Chediak-Higashi syndrome, which is due to mutations in the LYST gene. 

The T and NK cells in patients with primary, or familial, HLH can’t kill virus-infected or other abnormal cells in the patient’s body like they normally would.  T cells and NK cells normally do this by secreting death signals into targeted abnormal cells.   

The proteins made by the MUNC 13-4, STXBP2, STX11, Rab27a and LYST genes work like the machinery of a conveyor belt, and are responsible for the secretion of the death signals produced by T and NK cells.  The PRF1 gene makes a protein called perforin.  It works like a key that allows the secreted death signals to enter inside a targeted abnormal cell, where the death signals can work.  

SH2D1A is responsible for a more specialized mechanism of killing, and also controls how the T cells themselves die.  It is not yet entirely clear why XIAP / BIRC4 mutations cause HLH. 

Treatment is very important for patients with HLH because the condition is life-threatening. The treatments that doctors use suppress the immune system. Patients are usually treated with steroids, chemotherapy (etoposide) and/or antibody therapies that target and destroy T cells (anti-thymocyte globulin / ATG as well as alemtuzumab). Patients may receive other medications that suppress the immune system. Additionally, your doctor may give medications that help prevent and/or treat any infections.

Many patients must also have their immune systems replaced by receiving a hematopoetic (blood or bone marrow) stem cell transplant in order to be cured of HLH. Your doctor can tell you if this is the case for you or your child.