Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder primarily
affecting young children at a very early age, but it is found in patients
of all ages. Although physicians have written about the disorder over the
years, it has only been in the last few years that it has received much
attention.
The human
body contains many types of cells which help fight infection. One type of
cell is called a histiocyte. Histiocytes are produced by the bone marrow,
and they may travel throughout the body. At a later stage these cells
remain in place within various tissues in the body. Their job is to help
destroy certain foreign materials and fight infections. This is done in
cooperation with other important cells of the immune system.
Patients
with active HLH have too many of these histiocytes, as well as lymphocytes
(another type of infection-fighting cell), both of which are categorized
as white blood cells that may cause inflammation (swelling, redness, heat,
pain and loss of function). These cells then begin to penetrate and
accumulate in good tissue and cause damage to a variety of organs. Some
possible sites of involvement include bone marrow, lymph nodes, liver,
spleen and skin. The membranes surrounding the brain, and spinal cord or
more rarely, the brain itself may be involved.
There are
two major forms of HLH. One, known as the “primary” form, is inherited
from both the mother and father. The other form of HLH is known as the
“secondary” form. In the secondary form, the disease develops secondary to
inappropriate (abnormal) activity of the immune system. This can occur
after the use of immunosuppressive therapy and/or infections. It is
important to know that even if the disease has been triggered by a virus
it may still be familial.
Familial
hemophagocytic lymphohistiocytosis (also known as FHL, FEL or FHLH) means
that this particular form of the disease is genetic. The defective gene(s)
has been inherited from both the mother and father. Families who have had
more than one child with HLH will have the diagnosis changed to FHL.
Because this form is genetic, there is a 25% risk that each young sibling
will have FHL. The onset of FHL usually occurs within the first two years
of life.
As of 2004,
two of an expected three or four defective genes believed to cause
familial HLH have been described. One genetic mutation that causes FHL
results in a deficiency of perforin, a critical protein responsible for
the function of immune cells involved in control of viral infections. The
gene is named PRF1. Perforin is required for natural-killer lymphocytes (NK
cells) and T lymphocytes (cytoxic-T cells) to fight viral infections and
also to keep the immune system, especially histiocytes, under control. A
second genetic mutation responsible for FHL involves the gene-encoding
Munc13-4 protein, which is also involved in the funct ion of NK and T
cells.
Approximately 50% of FHL in North America is caused by mutations in the
gene-encoding perforin, PRF1. In other parts of the world, it is believed
that approximately 20-30% of FHL cases are caused by the PRF1 mutation.
Perforin mutation is a particularly common cause of FHL in patients of
African descent. Cases of FHL due to the defective Munc13-4 gene have been
found worldwide, but it is not clear what percentage of FHL is due to this
gene.
