HLH Center of Excellence

HLH can be challenging to diagnose because the initial symptoms may mimic common infections.  Symptoms of HLH may include: 

• Persistent fevers
• Rash
• Enlarged liver
• Enlarged spleen
• Enlarged lymph nodes
• Anemia
• Low platelets
• Low white blood cells
• Jaundice
• Hepatitis
• Liver failure
• Respiratory issues (coughing, respiratory distress)
• Seizures
• Altered mental functions 

HLH can only be diagnosed with the proper blood tests.  Blood tests may include looking at blood cell counts, liver function numbers, and markers of immune system activation such as ferritin and soluble IL-2 receptor levels.  A sample of bone marrow may be obtained to look for hemophagocytosis.  Doctors may collect some fluid from the spinal canal to look for HLH affecting the brain. 

X-rays, CT scans, ultrasounds or MRIs may be performed.  Your doctor may also perform testing to look for infections that can be associated with HLH.   

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 / 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.  XIAP / BIRC4 mutations can also be considered as a cause of familial HLH.   

HLH also occurs in some closely related 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 cells and NK cells in patients with primary / 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 out of T cells and NK cells.  The PRF1 gene makes a protein called perforin.  It works like a key, and 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, as the condition is life-threatening.  The treatments that doctors use suppress the immune system.  Patients are usually treated with steroids plus chemotherapy (etoposide / VP-16) and / or an antibody therapy that destroys the T cells (called anti-thymocyte globulin or ATG).  Patients may receive other medications that suppress the immune system.  Additionally, your doctor may give medications that help treat any infections that are present, or that prevent new infections from occurring.   

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