Hemophagocytic Lymphohistiocytosis (HLH)

What is hemophagocytic lymphohistiocytosis (HLH)?

HLH is not a single disease. HLH is a group of rare disorders of the immune system. The immune system is the part of the body that fights infections. People with HLH become very ill, because the immune system doesn’t work properly. HLH can be caused by infections, cancer, or rheumatologic diseases.

White blood cells are the part of the immune system that fight infections. In healthy people,  certain types of white blood cells called cytotoxic T lymphocytes (CTLs) and natural killer (NK) help fight infections and cancer by making cytokines. Cytokines are chemicals that activate other immune cells. In patients with HLH, CTLs and NK cells don’t work properly. They can’t fight infections and they secrete too many cytokines which can make you sick.

Over time, the immune cells grow out of control. They damage many parts of the body, including the liver, spleen, bone marrow and brain. Without treatment, HLH can lead to severe organ damage and death.

Types of HLH

HLH occurs in two major forms:

  • Primary (or familial) HLH is an inherited version of the disease. This means it often runs in families. It typically occurs during infancy or early childhood. It is estimated that primary HLH affects around 1 in every 50,000 births.
  • Secondary (or acquired) HLH generally occurs in older children and adults. Secondary HLH is not inherited. Rather it is thought to result from a temporary disturbance of the immune system. The incidence (amount of people who get it) of secondary HLH is not known.

Causes of HLH

Primary HLH is caused by alterations (also called mutations) at specific areas within a person's genes. Genes provide the necessary instructions that our cells need to perform their different functions within our bodies.

A number of genes have been shown to be abnormal in different people with HLH. The 4 most common and recognized genes are PRF1, UNC13D, STX11 and STXBP2. Likely other genes can cause HLH and scientists are trying to discover these genes. HLH can also occur in individuals with a number of immune deficiency diseases, including X-linked lymphoproliferative disease (XLP1 or XLP2), Griscelli Syndrome, Chediak Higashi Syndrome and ITK deficiency. These immunodeficiencies are caused by genetic mutations. Together these mutations (in the genes associated with HLH and the genes associated with primary immunodeficiencies) account for most primary HLH cases.

The mechanisms leading to secondary HLH are not well understood.

How is primary HLH inherited?

With the exception of egg and sperm cells, each cell of the body normally has two working copies of each gene. One copy of each gene comes from mom and one comes from dad. Most of the time primary HLH is an autosomal recessive disorder. This means that both copies of one of these HLH-associated genes must be mutated in order for HLH to occur.

A person with primary HLH usually develops the disease because they inherit an altered copy of an HLH-associated gene from each parent. The parents are considered HLH carriers; they carry one normal and one altered copy of an HLH-associated gene in the cells of their bodies. Although they carry an altered gene copy, HLH carriers usually remain healthy and do not develop the signs and symptoms of HLH. Other forms of HLH have different types of inheritance.

Diagnosis of HLH

HLH is diagnosed when an individual meets established diagnostic criteria. Currently, these criteria include:

Presence of a known HLH-causing mutation OR five of the following eight signs and symptoms:

1.      Fever for more than 7 days

2.      Decrease in the number of blood cells (cytopenias)

3.      Enlarged spleen (splenomegaly)

4.      Elevated blood levels of triglyceride (hypertriglyceridemia) and/or decreased blood levels fibrinogen (hypofibrinogenemia)

5.      Elevated blood levels of ferritin (hyperferritinemia) ≥ 500 µg/L

6.      Elevated blood levels of soluble CD25 (IL-2Ra) ≥ 2400 U/mL

7.      Decreased or absent NK cell killing activity

8.      Presence of hemophagocytosis in bone marrow and/or cerebrospinal fluid

Most of these signs and symptoms are evaluated by simple blood tests, but need to be performed and interpreted by experts.

HLH must be recognized and treated as quickly as possible to have the best chance for cure. To diagnose this disease, specialized blood tests are often performed.

HLH Treatment

The best treatment for HLH is not known, but doctors and scientists have developed a variety of treatments that are offered depending on the underlying cause and severity of symptoms. Due to the challenging and complex nature of HLH, treatment should be discussed with or given by doctors who are familiar with the disorder. At The Children’s Hospital of Philadelphia our HLH Treatment Team will care for your child.

Primary HLH

For children with primary HLH, the first step is generally suppressing the overactive immune system. This is often done using a combination of steroids and chemotherapy, with the goal of putting the disease in remission.

After this initial treatment, children with primary HLH usually undergo allogeneic stem cell transplantation, replacing their defective immune system with a healthy one from a different person. This offers the best chance of a cure.

Secondary HLH

For children with secondary HLH, the aim is to identify and treat the underlying cause of the HLH (such as the infectious or malignant trigger). In many cases, this puts the HLH into remission. However, it is sometimes necessary to use steroids and/or chemotherapy, as in the case of primary HLH.

It should be emphasized that the severity of HLH and not its classification as primary or secondary is the deciding factor in the use of steroids and/or chemotherapy.

Selected references

Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Janka GE, Lehmberg K. Hematology Am Soc Hematol Educ Program. 2013;2013:605-11. doi: 10.1182/asheducation-2013.1.605.

Hemophagocytic Lymphohistiocytosis, Familial. Zhang K, Filipovich AH, Johnson J, et al. 2006 Mar 22 [Updated 2013 Jan 17]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.

Reviewed by David T. Teachey, MD