What is HLH?

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder of the immune system primarily affecting young infants and children. Although physicians have written about the disorder over the years, it has been only in the last few years that it has received more widespread attention. HLH is affects about 1 of every 1,000,000 children under the age of 15.

In 1985, physicians from all over the world who were interested in studying the histiocyte and disorders related to this cell created the Histiocyte Society. Thanks to their research, in part financed by the Histiocytosis Association of America (HAA) and national subgroups, we now have a better understanding of the disease, as well as dramatically improved treatments. With growing knowledge, there is also increased awareness of the disease among nonspecialized physicians.

The disease usually presents with fever and sometimes other symptoms of an infection. In many cases, a pathogen (viral, bacterial, etc.) can be identified. The human body contains many cells including T-cells and histiocytes that fight infection. The activation of these cells causes an inflammatory reaction in the body. Normally, when the pathogen has been eliminated, the inflammatory reaction is turned off, and the immune system returns to its steady state. In HLH patients, due to defect of the immune system, the inflammatory reaction persists and causes the symptoms of HLH.

What is the cause of this severe immune dysregulation?

We currently know that HLH occurs either on the basis of a genetic defect or as a secondary form with underlying diseases such as infections, cancer, or rheumatic diseases. In the primary form, also known as familial hemophagocytic lymphohistiocytosis (FHL or FHLH), defective genes are inherited from both the mother and the father (autosomal recessive inheritance). FHL is diagnosed if there is more than one affected child in the family and/or a gene defect has been determined. FHL should be suspected if the symptoms do not disappear with treatment or if symptoms recur when therapy has been stopped. The onset of FHL is usually early in life, and a persistent cure can only be achieved with BMT (bone marrow transplantation). It is important to know that infections can trigger both the familial and the secondary disease.

So far, 3 gene defects have been identified, which account for approximately 50% to 80% of the familial cases, depending on the population that has been analyzed. Two of the genes, PRF1 and UNC13D, are responsible for the synthesis of proteins, perforin, and MUNC13-4 that are involved in the killing process of infectious pathogens. They are believed to also have a function in switching off immune responses. The precise mechanism, however, is not fully understood. A third defect affecting the Syntaxin 11 (STX11) gene has so far only been detected in patients of Turkish origin. The function of the mutated protein remains to be elucidated. There remains a considerable percentage of FHL patients with no known underlying gene defect.

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