Hemophagocytic lymphohistiocytosis

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at October 22, 2016
StartDiseasesHemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis or HLH is a serious disease caused by genetic mutations. In order to inherit most types of HLH, both parents have to have the defective gene. This type of HLH is called primary HLH. Hemophagocytic lymphohistiocytosis can affect people of all ages and ethnic groups, but there’s one type, linked to the X chromosome, that only affects boys. The disease can also be acquired by a person who has an immune deficiency, cancer, or another disease that disrupts their metabolism. HLH is rare, and medical researchers do not know how many people have it.

Contents

Definition & Facts

In HLH, the immune system does not work the way it should. Normally, proteins made by the genes enter diseased cells and destroy them. They also give instructions to immune cells who have completed their job to die. This process does not occur properly among those with hemophagocytic lymphohistiocytosis.

Two types of white blood cells: T cells and natural killer cell (NK) cells, do not do their job of destroying cells that are infected with viruses or are abnormal. They don’t even do the job of destroying the immune cells when their task is completed.

Normally, NK, or natural killer cells are cytotoxic, which means their interiors have molecules such as perforin and granzymes. When the NK cell come close to a cell that needs to be killed, the perforin punches holes in the membrane of the targeted cell so granzymes and other molecules can enter and cause the cell to destroy itself. It is important that the cell destroy itself rather than be destroyed from the outside. If a cell destroys itself, it also destroys the virus inside of it.

T-cells circulate around the body. One of two types of T-cells are called killer T-cells. These cells are able to discern what is inside of another cell simply by "seeing" what’s on its surface. They hunt down and kill cells that are infected or malignant. T-cells directly kill sick cells and support other immune cells that eat pathogens or make antibodies. A T-cell can remember a pathogen for decades, which gives a person immunity.

With HLH, these normal processes don’t work. Because of this, the immune system is stimulated to the point where it starts to attack various bodily systems. It produces too many cytokines, which normally regulate the immune function. This results in hypercytokinemia, a condition that is destructive to many organs of the body, including the brain, the lungs, the heart, and the digestive system. Doctors can actually see the white blood cells devouring healthy cells under a microscope. This action is called hemophagocytosis and gives the disease its name.

Symptoms & Complaints

The symptoms of hemophagocytic lymphohistiocytosis can be difficult to diagnose because so many of the bodily systems are under attack that the disease can mimic other diseases. Symptoms include:

Doctors need to see at least five of these symptoms before they suspect that the patient has HLH.

Causes

There are five subtypes of HLH, caused by genetic mutations on the MURC 13-4, STX11, PRF1 gene, or STXBP2 genes. Less frequently, the disease is caused by mutations on the XIAP/BIRC4 gene. Hemophagocytic lymphohistiocytosis can also occur in similar diseases such as X-linked lymphoproliferative disease, or XCP.

Diagnosis & Tests

Blood tests are the main way to diagnose HLH. The doctor orders tests to check the patient’s blood cell counts, liver function tests, ferritin and soluble IL-2 receptor levels.

Ferritin is a protein found in the blood cells that lets the doctor know how much iron is in the blood. Low ferritin levels indicate an iron deficiency. Elevated IL-2 receptor levels are found in patients who have weakened immune systems. CD25 levels, which are related to IL-2 receptor levels, also let a doctor know that the patient’s immune system is stressed.

Sometimes, a bone marrow biopsy is necessary to diagnose HLH. Imaging tests like computed tomography (CT) scans, X-rays, and magnetic resonance imaging (MRI)s are also used as the doctor searches for infections and diseases that are likely to be complications of HLH. The patient can also have genetic testing to see if the defective genes responsible for HLH are present. 

Treatment & Therapy

Treatment of HLH involves giving the patient drugs to suppress their immune system. This may involve corticosteroids plus chemotherapy drugs such as etoposide/VP-16. The patient can also undergo antibody therapy that kills T-cells. If the patient is suffering from an illness that is a complication of HLH, they are treated for the illness. 

Some patients undergo a type of bone marrow transplant to replace their old, defective immune system. This is called a hematopoietic cell transplantation, or HCT which transplants hematopoietic stem cells and progenitor cells into the patient. Hematopoietic stem cells are cells that turn into blood cells. Progenitor cells are a somewhat more advanced form of stem cell.

The stem and progenitor cells are taken from the bone marrow or peripheral blood, which is simply the blood that’s circulating around the body and is not stored in an organ. The patient’s old immune system is destroyed through chemotherapy or radiation, and then the new cells are given to them through an IV line. This basically cures the HLH.

There are several sources for the progenitor cells. They can come from an identical twin, in which case there's no risk of rejection. They can come from a parent, a regular sibling or a stranger who is a match for the patient. This last, however, is quite uncommon.

The lifespans of patients who have HCT are considerably longer than those patients who do not have the therapy. A person whose HLH is not treated often dies within six months of their diagnosis. Even a person who receives treatment that doesn’t involve HCT has a 21 to 26 percent chance of surviving for five years. 

Prevention & Prophylaxis

Hemophagocytic lymphohistiocytosis cannot be prevented at this time, though genetic tests are available to people who suspect they might be genetic carriers of the faulty genes.