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| {{SK}} Hemophagocytic syndrome; Familial histiocytic reticulosis; Hemophagocytic lymphohistiocytosis - familial; Erythrophagocytic lymphohistiocytosis - familial; Familial haemophagocytic lymphohistiocytosis; HLH | | {{SK}} Hemophagocytic syndrome; Familial histiocytic reticulosis; Hemophagocytic lymphohistiocytosis - familial; Erythrophagocytic lymphohistiocytosis - familial; Familial haemophagocytic lymphohistiocytosis; HLH |
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| ==Overview== | | ==[[Hemophagocytic lymphohistiocytosis overview|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.
| | ==[[Hemophagocytic lymphohistiocytosis classification|Classification]]== |
| | | ==[[Hemophagocytic lymphohistiocytosis pathophysiology |Pathophysiology]]== |
| ==Classification==
| | ==[[Hemophagocytic lymphohistiocytosis causes|Causes]]== |
| HLH primarily categorized as
| | ==[[Hemophagocytic lymphohistiocytosis differential diagnosis|Differentiating Hemophagocytic lymphohistiocytosis from other Diseases]]== |
| * Familial (primary) hemophagocytic lymphohistiocytosis (FHL)
| | ==[[Hemophagocytic lymphohistiocytosis epidemiology and demographics|Epidemiology and Demographics]]== |
| * Secondary HLH (SHLH)
| | ==[[Hemophagocytic lymphohistiocytosis natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| ===Familial forms===
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| 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.
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| There are four types, and each is associated with a specific [[gene]]:
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| * FHL1 - [[HPLH1]]
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| * FHL2 - [[PRF1]]
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| * FHL3 - [[UNC13D]]
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| * FHL4 - [[STX11]]
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| * FHL5 – [[STXBP2]] (Syntaxin binding protein 2)/UNC18-2
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| [[Image:autorecessive.jpg|thumb|center|Familial hemophagocytic lymphohistiocytosis has an autosomal recessive pattern of inheritance.]]
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| <br clear="center"/>
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| ==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]].
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| The [[brain]] may also be affected in familial hemophagocytic lymphohistiocytosis causing various symptoms and complications.
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| 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.
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| ===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.
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| Five genetic subtypes of the familial form of the disease (FHL1, FHL2, FHL3, FHL4, and FHL5) are described.
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| The five subtypes of FHL are each associated with a specific gene:
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| * FHL1 - HPLH1
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| * FHL2 - PRF1 (Perforin)
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| * FHL3 - UNC13D (Munc13-4)
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| * FHL4 - STX11 (Syntaxin 11)
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| * FHL5 – STXBP2 (Syntaxin binding protein 2)/UNC18-2
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| Molecular genetic testing for four of the causative genes, PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5), is available on a clinical basis.
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| ===Microscopic Pathology=== | |
| [[Image:Hemophagocytic_syndrome.jpg|thumb|center|Micrograph showing red blood cells within macrophages. H&E stain]] | |
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| ==Differentiating from other diseases== | |
| The differential diagnosis of familial hemophagocytic lymphohistiocytosis includes
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| * Secondary HLH
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| * [[Macrophage-activation syndrome]]
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| * Other primary immunodeficiencies that present with hemophagocytic lymphohistiocytosis, such as [[X-linked lymphoproliferative disease]].
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| ==Epidemiology and Demographics== | |
| * Familial hemophagocytic lymphohistiocytosis occurs in approximately 2 in 100,000 individuals worldwide.
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| * 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.
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| * Gender distribution is equal.
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| ==Natural History, Complications and Prognosis==
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| * Without treatment, most people with familial hemophagocytic lymphohistiocytosis survive only a few months.
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| * Complications include
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| ** [[Immunodeficiency]]
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| ** [[Blindness]]
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| ** [[Coma]]
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| ** [[Leukemia]] and [[lymphoma]]
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| * 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.
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| * Posterior reversible encephalopathy syndrome
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| ==Diagnosis== | | ==Diagnosis== |
| ===History===
| | [[Hemophagocytic lymphohistiocytosis history and symptoms|History and Symptoms]] | [[Hemophagocytic lymphohistiocytosis physical examination|Physical Examination]] | [[Hemophagocytic lymphohistiocytosis laboratory findings|Laboratory Findings]] | [[Hemophagocytic lymphohistiocytosis other diagnostic studies|Other Diagnostic Studies]] |
| Inquiry about family history may help diagnose the familial forms of Hemophagocytic lymphohistiocytosis.
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| ===Symptoms===
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| Symptoms of FHL are usually evident within the first few months of life and may even develop in utero.
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| * [[Fever]]
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| * [[Rash]] on the skin
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| * [[Abdominal pain]]
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| * Easy [[bruising]] and abnormal [[bleeding]]
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| * [[Infections]] <ref>{{cite journal |author=Fisman DN |title=Hemophagocytic syndromes and infection |journal=Emerging Infect. Dis. |volume=6 |issue=6|pages=601-608 |year=2000 |pmid=11076718 |doi= |url=http://www.cdc.gov/ncidod/eid/vol6no6/fisman.htm}}</ref>
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| * Learning deficits
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| * [[Seizure]]s
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| * Motor incoordination
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| * Vision problems
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| ===Physical Examination===
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| ====Skin====
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| * Bruising
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| ====Eye====
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| * Defective vision
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| ====Neck====
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| * [[Lymphadenopathy]]
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| * [[Neck stiffness]]
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| ====Abdomen====
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| * [[Hepatomegaly]]
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| * [[Splenomegaly]]
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| ====Extremities====
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| * [[Weakness]]
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| * [[Paralysis]]
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| ====Neurologic====
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| * Impaired muscle coordination
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| * Chronic brain failure
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| ===Laboratory Findings===
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| * Complete blood count and differential counts show - [[anemia]], [[thrombocytopenia]], [[neutropenia]]
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| * [[Cerebrospinal fluid]] ([[CSF]]) analysis shows - decreased glucose, increased cell count, increased proteins consistent with features of meningoencephalitis
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| ==Treatment== | | ==Treatment== |
| ===Medical therapy===
| | [[Hemophagocytic lymphohistiocytosis medical therapy|Medical Therapy]] | [[Hemophagocytic lymphohistiocytosis surgery|Surgery]] | [[Hemophagocytic lymphohistiocytosis cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Hemophagocytic lymphohistiocytosis future or investigational therapies|Future or Investigational Therapies]] |
| * [[Corticosteroids]]
| | ==Case Studies== |
| * [[I.V immunoglobulins]]
| | :[[Hemophagocytic lymphohistiocytosis case study one|Case #1]] |
| * [[Etoposide]]
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| * [[Cyclosporin]]
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| ===Surgical therapy=== | |
| * [[Bone marrow transplantation]]<ref>{{cite journal |author=Henter JI, Samuelsson-Horne A, Aricò M, ''et al'' |title=Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation |journal=Blood |volume=100 |issue=7 |pages=2367-2373 |year=2002 |pmid=12239144|doi=10.1182/blood-2002-01-0172 |url=http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=12239144}}</ref>
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| == References ==
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| {{reflist|2}}
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| ==External links== | | ==External links== |
| * http://www.histio.org | | * http://www.histio.org |
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| {{Hematology}} | | {{Hematology}} |
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| [[Category:Disease]] | | [[Category:Disease]] |
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| [[Category:Genetic disorders]] | | [[Category:Genetic disorders]] |
| [[Category:Autosomal recessive disorders]] | | [[Category:Autosomal recessive disorders]] |
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