Hemophagocytic lymphohistiocytosis (HLH) is an uncommon hematologic disorder in which the immune system produces too many activated immune cells (lymphocytes) called T cells, natural killer cells, B cells, and macrophages (histiocytes). Excessive amounts of immune system proteins called cytokines are also produced.

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HLH primarily categorized as

• Familial (primary) hemophagocytic lymphohistiocytosis (FHL)
• Secondary HLH (SHLH)

FHL, an autosomal recessive disorder, is invariably fatal when untreated. It is associated with defective triggering of apoptosis and reduced cytotoxic activity, resulting in a widespread accumulation of T lymphocytes and activated macrophages.

There are four types, and each is associated with a specific gene:

• FHL1 – HPLH1
• FHL2 – PRF1
• FHL3 – UNC13D
• FHL4 – STX11
• FHL5 – STXBP2 (Syntaxin binding protein 2)/UNC18-2

Excessive production of too many activated immune cells (lymphocytes) called T cells, natural killer cells, B cells, and macrophages (histiocytes) and cytokines by the immune system causes symptoms and damages liver and spleen and causes these organs to enlarge. Familial hemophagocytic lymphohistiocytosis also destroys blood-producing cells in the bone marrow, a process called hemophagocytosis. As a result, affected individuals have low numbers of red blood cells (anemia) and a reduction in the number of blood cells involved in clotting (platelets). A reduction in platelets may cause easy bruising and abnormal bleeding.

The brain may also be affected in familial hemophagocytic lymphohistiocytosis causing various symptoms and complications.

Secondary hemophagocytic lymphohistiocytosis is usually associated with infection by viruses, bacteria, fungi, or parasites or in association with lymphoma, autoimmune disease, or metabolic disease. Acquired HLH may have decreased, normal, or increased NK cell activity.

Familial hemophagocytic lymphohistiocytosis is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Five genetic subtypes of the familial form of the disease (FHL1, FHL2, FHL3, FHL4, and FHL5) are described.

The five subtypes of FHL are each associated with a specific gene:

• FHL1 – HPLH1
• FHL2 – PRF1 (Perforin)
• FHL3 – UNC13D (Munc13-4)
• FHL4 – STX11 (Syntaxin 11)
• FHL5 – STXBP2 (Syntaxin binding protein 2)/UNC18-2

Molecular genetic testing for four of the causative genes, PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5), is available on a clinical basis.

The differential diagnosis of familial hemophagocytic lymphohistiocytosis includes

• Secondary HLH
• Macrophage-activation syndrome
• Other primary immunodeficiencies that present with hemophagocytic lymphohistiocytosis, such as X-linked lymphoproliferative disease.

• Familial hemophagocytic lymphohistiocytosis occurs in approximately 2 in 100,000 individuals worldwide.
• Signs and symptoms of familial hemophagocytic lymphohistiocytosis usually become apparent during infancy, although occasionally they appear later in life. They usually occur when the immune system launches an exaggerated response to an infection, but may also occur in the absence of infection.
• Gender distribution is equal.

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• Complications include
  • Immunodeficiency
  • Blindness
  • Coma
  • Leukemia and lymphoma
  • Posterior reversible encephalopathy syndrome

• Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment. However, long-term remission without the use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with CNS involvement.
• Without treatment, most people with familial hemophagocytic lymphohistiocytosis survive only a few months.