Health Library

Hemophagocytic Lymphohistiocytosis (HLH)

What Are the Types of HLH?

There are two types of HLH. “Primary,” or “familial,” HLH is caused by an inherited problem of the immune system. “Secondary” HLH can occur when the immune system is disturbed (e.g., infections), but not necessarily because of an inherited condition. Both types of HLH are life-threatening. HLH can lead to liver failure, breathing problems, inflammation in the brain, and the inability to fight infection.

HLH happens more often in infants and children. But it can occur at any age, including in the teenage years and adulthood.

HLH is considered a rare disease. Statistics say it occurs in about one in 50,000 children. Because of that, many healthcare providers are unfamiliar with its symptoms, and it often goes undiagnosed for too long.

What Are the Symptoms of HLH?

HLH can be challenging to diagnose because the initial symptoms may mimic common infections. Symptoms of HLH that you may notice in your child include:

• Persistent fevers
• Rash
• Yellowish-looking skin and eyes (jaundice)
• Coughing, trouble breathing
• Seizures
• Altered mental status

Other issues that your child’s doctor may find include:

• Hepatitis
• Liver failure
• Low blood counts
• Enlarged liver
• Enlarged spleen

How is HLH Diagnosed?

Because HLH is so rare, many healthcare providers don’t recognize its symptoms. HLH can “look like” certain cancers in the early stages of the illness. For these reasons, the disease often is misdiagnosed or goes undiagnosed for too long.

HLH can only be diagnosed with proper blood tests in the appropriate clinical setting. Doctors might collect some fluid from the spinal canal to look for HLH in the brain. It is important to remember certain malignancies (including leukemia and lymphoma) can mimic HLH, therefore these conditions should be appropriately investigated during the work-up of a suspected patient with HLH.

Doctors must use the following tests to diagnose HLH and develop a personalized treatment plan.

• Blood tests. These include blood cell counts, liver function, infection studies, and markers of immune system activation, such as ferritin and soluble IL-2 receptor levels.
• Bone marrow aspirate and biopsy (taking samples from the patient’s bone marrow, the organ that makes blood)
• Lumbar puncture. Doctors do this to collect cerebrospinal fluid to see if HLH is affecting the brain.
• Imaging studies. These can include X-rays, Computed tomography (CT) scans, ultrasound or magnetic resonance imaging (MRI).
• Detailed genetic testing

What Genetic Conditions Cause HLH?

“Primary” or “familial” HLH is caused by inherited 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, MUNC13-4, 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 gene (XLP2)
• Griscelli syndrome type II, which is due to mutations in the Rab27a gene
• Chediak-Higashi syndrome, which is due to mutations in the LYST gene.

“Secondary” HLH can occur when the immune system is disturbed (e.g., infections), but not necessarily because of an inherited condition.

Why Do These Conditions Result in HLH?

The T and NK cells in patients with primary HLH can’t kill virus-infected or other abnormal cells like they normally would. T cells and NK cells usually do this by secreting death signals into targeted abnormal cells. When they can’t do this they get ‘overexcited’ and this leads to severe and unusual inflammation.

The proteins made by the MUNC13-4, 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 killing mechanism and controls how the T cells themselves die. It is not yet entirely clear why XIAP mutations cause HLH.

How is HLH Treated?

Prompt treatment is very important for patients with HLH, as the condition is often fatal. The first treatments are typically used to stop the inflammation in the body. These treatments suppress the immune system which helps decrease the damage to a patient’s body.

Treatment may include:

• Steroids plus chemotherapy to calm down the hyper-inflammation
• Antibody therapy that blocks certain inflammatory proteins, or that destroys T cells which make these proteins
• Medicines that suppress the immune system
• Medicines to help treat any infections that are present and to prevent new infections

With treatment, HLH may come under control after a few weeks. However, it may flare again later, especially as treatment is decreased and a patient may need further treatment.

Often, patients with primary HLH may need a bone marrow transplant (BMT). Often patients who have a successful BMT go on to lead full, productive lives.