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familial hemophagocytic lymphohistiocytosis

Tuesday 22 February 2005

Definition: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, fatal disorder of early infancy.

Hemophagocytic lymphohistiocytosis (HLH) is also known as the autosomal recessive familial hemophagocytic lymphohistiocytosis (FHL), familial erythrophagocytic lymphohistiocytosis (FEL), and viral-associated hemophagocytic syndrome (VAHS).

This aggressive and potentially life-threatening disease most often affects infants from birth to 18 months of age, but cases in older children and adults have been reported.

Usually, primary HLH denotes the presence of an underlying genetic disorder, but secondary HLH denotes the presence of HLH phenomenon occurring secondary to another condition (eg, viral or fungal infections).

Familial hemophagocytic lymphohistiocytosis (FHL) is transmitted in an autosomal recessive manner, affects approximately 1 in every 50,000 live births, and typically presents in infancy or early childhood.

It is genetically heterogeneous and is associated with mutations in genes encoding perforin (PRF1), hMunc13-4 (UNC13D), and syntaxin 11 (STX11), resulting in defective cytotoxic granules or impairment of their release from cytotoxic T cells and natural killer (NK) cells.

FHL is rapidly progressive and fatal, but if diagnosed early, treatable with immunosuppressive chemotherapy and allogeneic stem cell transplantation.

FHL typically presents with fever, organomegaly, and cytopenia(s). However, the clinical presentation, laboratory findings and histopathology can be variable, nonspecific, and overlap with other disorders, making its early recognition challenging; many patients undergo irreversible organ damage or succumb to the disease before a diagnosis is established.

Patients afflicted with FHL are often profoundly ill at presentation and a prompt, effective treatment is dependent upon an early diagnosis.

As hepatomegaly and hepatic dysfunction occur early in the disease, the liver is frequently biopsied for diagnosis. Hepatomegaly and hepatic dysfunction, including elevated serum transaminases and bilirubin, cholestasis, and coagulopathy typically occur early in the disease and are associated with marked hematologic and/or neurological abnormalities. In rare instances acute hepatic failure may dominate the clinical picture, which in combination with hyperferritinemia, may mimic neonatal hemochromatosis. (see "liver in FHL")

Nota bene: Hemophagocytic lymphohistiocytosis (HLH) is observed in a group of diseases characterized by an activation of the immune system that results in an uncontrolled expansion of cytotoxic lymphocytes and histiocytes, hemophagocytosis, hypersecretion of proinflammatory cytokines, and multiorgan damage. It comprises a group of diseases that can be inherited and/or induced by infection, malignancy, drug reaction, inborn error of metabolism, or immune dysfunction.

Synopsis

- sudden-onset fever
- visceral lymphohistiocytic infiltration
- meningeal lymphohistiocytic infiltration
- hepatic anomalies (liver in FHL) (#20442642#)

  • hepatic failure
  • hepatosplenomegaly
  • hepatorenal failure
  • portal infiltrates of T lymphocytes
  • portal infiltrates of histiocytes
  • periportal infiltrates of T lymphocytes
  • periportal infiltrates of histiocytes
  • activation of the hepatic mononuclear phagocytic system
  • focal hemophagocytosis
  • loss of interlobular bile ducts (biliary ductopenia)
  • paucity of bile ducts (biliary ductopenia)

- cytophagic histiocytic panniculitis (#17601962#)

Loci

- FHL1 (9q21.3-q22 - MIM.267700)
- FHL2 (10q22 - MIM.603553): mutation in the gene PRF1, encoding perforin (MIM.170280)
- FHL3 (17q25.1 - MIM.608898): mutation in the UNC13D gene (MUNC13-4, Munc 13-4) (MIM.608897)
- FHL4 (6qq24 - MIM.603552): mutations in the STX11 gene, the syntaxin-11 (MIM.605014)
- FHL5 (MIM.613101) : mutation in the STXBP2 gene, encoding the syntaxin-binding protein-2 (MIM.601717), which is an interaction partner of STX11.

Differential diagnosis

- Omenn syndrome (familial reticuloendotheliosis with eosinophilia) (MIM.603554)

- Faisalabad histiocytosis (hemophagocytic lymphohistiocytosis with sensorineural deafness and joint contractures) (MIM.602782)

- Griscelli disease: GS1 (MIM.214450), GS2 (MIM.607624), GS3 (MIM.609227)

Before the definition of mutations in the RAG1 (MIM.179615) and RAG2 (MIM.179616) genes, both of which map to 11p, Omenn syndrome (familial reticuloendotheliosis with eosinophilia; MIM.603554) was not thought to be clearly distinct from other reported cases of hemophagocytic lymphohistiocytosis.

A form of histiocytosis associated with sensorineural deafness and joint contractures, referred to as Faisalabad histiocytosis (MIM.602782), has been mapped to 11q25.

Further genetic heterogeneity in familial hemophagocytic lymphohistiocytosis (FLH) was suggested by a study in which FHL in 2 unrelated Canadian families with affected first cousins was not linked to 9q21.3-q22 or 10q21-q22 (Graham et al., 2000).

Pathophysiology

Studies have suggested that the central abnormality in HLH is cytokine dysfunction, which is further leading to an uncontrolled accumulation of activated T-lymphocytes and activated histiocytes in many organs. Cytokines that have been found at extremely high levels in HLH patient plasma include interferon-gamma , TNF-alpha , interleukin (IL)-6, IL-10, IL-12, and soluble IL-2 receptor (CD25).

Studies have also demonstrated a depressed or non-existent natural killer (NK)-cell and cytotoxic T cell activity in HLH patients. Defective NK cell function is associated with decreased amounts of the pore-forming protein, perforin, which may also be important in regulating T cell function.

The importance of perforin expression, as well as the cytotoxic function of T and NK cells in HLH has been documented. HLH patients have been found to lack intracellular perforin in cytotoxic cell types.

A murine model of HLH with perforin-deficient mice has been developed in which the CD8(+) T cells were shown to be critical in causing HLH. Besides perforin, defects in two other proteins of the cytolytic pathway have been associated with defective T cell control and HLH.

The MUNC13-4 protein is important for packaging of the cytolytic granzymes. Patients with the Griscelli syndrome often develop HLH and have been shown to lack a protein rab27a that controls secretion of lytic granules.

Studies have demonstrated that MUNC 13-4 must link with rab27a to allow fusion of secretory granules with the plasma membrane.

Patients with Chediak-Higashi syndrome also have a high frequency of HLH.

In these patients the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) does not move from secretory lysozomes to the cell membrane.

Another cellular defect in HLH relates to defective apoptosis, as less spontaneous activation of caspase-3-like enzymes was found in activated lymphocytes of some HLH patients.

Clinical and pathologic findings

Initial presentation - Early clinical signs may include fever, hepatomegaly, splenomegaly, neurologic symptoms, rash, and lymphadenopathy. Many of HLH patients have clinical and radiologic findings similar to the acute respiratory distress syndrome, with alveolar-interstitial opacities and pleural effusions. The initial presentation of HLH may simulate a number of common conditions such as febrile illness, multiple organ failure syndrome, etc.

Pathologic findings - The pathologic findings of HLH result from the aggressive proliferation of normal histiocytes and T-lymphocytes in various tissues.

Hemophagocytosis of red cells (erythrophagocytosis), other white blood cells, or platelets in the bone marrow, spleen, or lymph nodes is the key diagnostic finding. Infiltration of the liver and bone marrow with histiocytes and the antiproliferative effects of cytokines result in damage to these organs.

Diagnostic Criteria for HLH

Since HLH is often fatal, one must have a high index of suspicion of HLH for patients who present with several of the following: high fevers, maculopapular rash, failure to thrive, central nervous system symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, coagulopathy, abnormal liver function tests, and high serum ferritin.

Major criteria:

Fever: Peak temperature >38.5ºC for seven or more days.
Splenomegaly: Spleen palpated >3 cm below the left costal margin.
Cytopenia involving two or more cell lines: hemoglobin <9.0 g/dL, or platelets <100,000/µL, or absolute neutrophil count <1,000/µL.
Hypertriglyceridemia or hypofibrinogenemia: fasting triglycerides >2.0 mmol/L, or more than 3 standard deviations (SD) above the normal value for age, or fibrinogen <1.5 g/L, or more than 3 SD below the normal value for age.
Hemophagocytosis: demonstrated in bone marrow, spleen, or lymph node. No evidence for malignancy.

Alternative criteria:

Low or absent natural killer.
Serum ferritin level >500 µg/L.
Soluble CD25 (sIL-2 receptor) >2400 U/mL.
The diagnosis of HLH requires the presence of all five major criteria. Either criterion (a) or a combination of criteria (b) and (c) may substitute for one of the major criteria. If a patient meets only four criteria and the clinical suspicion for HLH is high, one must initiate appropriate treatment, as delays may be fatal.

Specialized testing - Some of the following tests may be helpful in supporting the diagnosis, including histologic evidence of chronic persistent hepatitis, low natural killer cell activity, coagulopathy with markedly prolonged activated partial thromboplastin time, and increased concentrations of circulating soluble interleukin (IL)-2 (sIL-2R) receptor (sCD25). Serum NSE (neuron-specific enolase) levels were found to be inversely proportional to the platelet count, and sequential changes in NSE levels appeared to reflect the clinical course. The soluble hemoglobin-haptoglobin scavenger receptor CD163 levels track closely with disease activity and correlate with serum ferritin.

Treatment

HLH-94 protocol - This protocol included induction therapy with dexamethasone, etoposide (VP-16), cyclosporine (started at week 9), and intrathecal methotrexate, followed by pulses of dexamethasone and VP-16 for up to one year. Results of this study showed an overall survival of 55 percent at a median follow-up of 3.1 years.

HLH-2004 protocol - A new version of the HLH treatment program was initiated in January, 2004. This protocol can be obtained from the Histiocytosis Association of America.

Hematopoietic cell transplantation - Allogeneic hematopoietic cell transplantation (HCT) seems to provide the best overall cure rate for HLH patients. HCT is indicated in patients who have homozygous mutations in the various genes associated with HLH, those who responded poorly to the initial eight weeks of therapy, and those with CNS disease.

See also

- macrophagic activation syndrome

  • erythrophagocytosis
  • hemophagocytosis

References

- Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases. Rohr J, Beutel K, Maul-Pavicic A, Vraetz T, Thiel J, Warnatz K, Bondzio I, Gross-Wieltsch U, Schündeln M, Schütz B, Woessmann W, Groll AH, Strahm B, Pagel J, Speckmann C, Janka G, Griffiths G, Schwarz K, zur Stadt U, Ehl S. Haematologica. 2010 Dec;95(12):2080-7. PMID: #20823128# [Free]

- Pathology of the liver in familial hemophagocytic lymphohistiocytosis. Chen JH, Fleming MD, Pinkus GS, Pinkus JL, Nichols KE, Mo JQ, Perez-Atayde AR. Am J Surg Pathol. 2010 Jun;34(6):852-67. PMID: #20442642#

- Cytophagic histiocytic panniculitis with fatal haemophagocytic lymphohistiocytosis in a paediatric patient with perforin gene mutation. Chen RL, Hsu YH, Ueda I, Imashuku S, Takeuchi K, Tu BP, Chuang SS. J Clin Pathol. 2007 Oct;60(10):1168-9. PMID: #17601962#

- Hong W. Cytotoxic T lymphocyte exocytosis: bring on the SNAREs! Trends Cell Biol. 2005 Dec;15(12):644-50. PMID: #16260137#

- Kapelari K, Fruehwirth M, Heitger A, Konigsrainer A, Margreiter R, Simma B, Offner FA. Loss of intrahepatic bile ducts: an important feature of familial hemophagocytic lymphohistiocytosis. Virchows Arch. 2005 Jun;446(6):619-25. PMID: #15906086#

- Kakkar N, Vasishta RK, Banerjee AK, Marwaha RK, Thapa BR. Familial hemophagocytic lymphohistiocytosis: an autopsy study. Pediatr Pathol Mol Med. 2003 May-Jun;22(3):229-42. PMID: #12746174#

- de Saint Basile G, Fischer A. The role of cytotoxicity in lymphocyte homeostasis. Curr Opin Immunol. 2001 Oct;13(5):549-54. PMID: #11544002#

- Ost A, Nilsson-Ardnor S, Henter JI. Autopsy findings in 27 children with haemophagocytic lymphohistiocytosis. Histopathology. 1998 Apr;32(4):310-6. PMID: #9602326#

- Favara BE. Hemophagocytic lymphohistiocytosis: a hemophagocytic syndrome. Semin Diagn Pathol. 1992 Feb;9(1):63-74. PMID: #1561489#

- Wieczorek R, Greco MA, McCarthy K, Bonetti F, Knowles DM 2nd. Familial erythrophagocytic lymphohistiocytosis: immunophenotypic, immunohistochemical, and ultrastructural demonstration of the relation to sinus histiocytes. Hum Pathol. 1986 Jan;17(1):55-63. PMID: #3080365#

- Akima M, Sumi SM. Neuropathology of familial erythrophagocytic lymphohistiocytosis: six cases and review of the literature. Hum Pathol. 1984 Feb;15(2):161-8. PMID: #6698535#