Hemophagocytic lymphohistiocytosis
| Hemophagocytic lymphohistiocytosis | |
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| Light microscopic image of bone marrow showing stromal macrophages containing numerous red blood cells in their cytoplasm | |
| ICD-10 | D76.1 |
| ICD-9 | 288.4 |
| OMIM | 267700 603552 |
| DiseasesDB | 31418 |
| MeSH | D051359 |
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Hemophagocytic lymphohistiocytosis Microchapters |
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Differentiating Hemophagocytic lymphohistiocytosis from other Diseases |
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Hemophagocytic lymphohistiocytosis On the Web |
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American Roentgen Ray Society Images of Hemophagocytic lymphohistiocytosis |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]
Synonyms and keywords: Hemophagocytic syndrome; Familial histiocytic reticulosis; Hemophagocytic lymphohistiocytosis - familial; Erythrophagocytic lymphohistiocytosis - familial; Familial haemophagocytic lymphohistiocytosis; HLH
Overview
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.
Classification
HLH primarily categorized as
- Familial (primary) hemophagocytic lymphohistiocytosis (FHL)
- Secondary HLH (SHLH)
Familial forms
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
Pathophysiology
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.
Genetics
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.
Microscopic Pathology
Differentiating from other diseases
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.
Epidemiology and Demographics
- 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.
Natural History, Complications and Prognosis
- Without treatment, most people with familial hemophagocytic lymphohistiocytosis survive only a few months.
- Complications include
- 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.
- Posterior reversible encephalopathy syndrome
Diagnosis
History
Inquiry about family history may help diagnose the familial forms of Hemophagocytic lymphohistiocytosis.
Symptoms
Symptoms of FHL are usually evident within the first few months of life and may even develop in utero.
- Fever
- Rash on the skin
- Abdominal pain
- Easy bruising and abnormal bleeding
- Infections [1]
- Learning deficits
- Seizures
- Motor incoordination
- Vision problems
Physical Examination
Skin
- Bruising
Eye
- Defective vision
Neck
Abdomen
Extremities
Neurologic
- Impaired muscle coordination
- Chronic brain failure
Laboratory Findings
- Complete blood count and differential counts show - anemia, thrombocytopenia, neutropenia
- Cerebrospinal fluid (CSF) analysis shows - decreased glucose, increased cell count, increased proteins consistent with features of meningoencephalitis
Treatment
Medical therapy
Surgical therapy
References
- ↑ Fisman DN (2000). "Hemophagocytic syndromes and infection". Emerging Infect. Dis. 6 (6): 601–608. PMID 11076718.
- ↑ Henter JI, Samuelsson-Horne A, Aricò M; et al. (2002). "Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation". Blood. 100 (7): 2367–2373. doi:10.1182/blood-2002-01-0172. PMID 12239144.
External links