What is primary hemophagocytic lymphohistiocytosis (HLH)?

Updated: Sep 16, 2020
  • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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Primary hemophagocytic lymphohistiocytosis (HLH)

Primary HLH (familial hemophagocytic lymphohistiocytosis [FHL], familial histiocytic reticulosis) [60] is a life-threatening disorder characterized by fever, enlargement of the liver (93%) and spleen (94%), rash (30%), [78] and cytopenia. [79]  Other symptoms may include enlarged lymph nodes and respiratory, cardiac, renal, and neurologic abnormalities. The neurologic symptoms can include irritability, fatigue, change in mental status, ataxia, loss of vision, abnormal muscle tone, stiff neck, seizure, cranial nerve palsies, hemiplegia, quadriplegia, and coma. The disease can manifest itself in utero, early in the neonatal period, during childhood, or, uncommonly, in adulthood. Typically, the symptoms manifest during the first months or years of life. .

The prevalence of HLH is estimated to be in 0.12-1 cases per 100,000 live births, with an equal male-to-female ratio. FHL is a heterogenous autosomal recessive disorder that is often seen in parental consanguinity. Five genetic subtypes (ie, FHL1, FHL2, FHL3, FHL 4, FHL 5), caused by genetic mutations, have been identified. The genetic cause of type 1 is still unknown. Types 2-5 are caused by mutation in PRF1. Molecular testing for FHL2 (PRF1), FHL3 (UNC13D), FHL4 (STX11), and FHL5 (STXBP2) is available.

FHL results from uncontrolled proliferation of overactivated T lymphocytes and macrophages, as well as overproduction of inflammatory cytokines and immune dysregulation. Laboratory evaluation may disclose increased liver enzymes and hemophagocytosis in the bone marrow. Elevated levels of triglycerides, ferritin, and CD25, along with evidence of hemophagocytosis and a decrease in or absence of NK cells, may be present.

The disease is rapidly progressive, and occurrence of infections during the course of FLH is common. Without appropriate treatment, the disorder can be fatal. The median survival in untreated children can be as short as a few months. Appropriate treatment, however, has brought significant improvements in survival.

Diagnosis of FHL is based on clinical findings and genetic testing. Because the disease may develop in utero, it can potentially be present at birth. Patients with nonsense mutation, including those with homozygosity for PRF, (p. Leu17 Argfs Ter 34) mutation and who are often of African descent, have tendency for onset of the disease at an earlier age. Also, in most cases, individuals with PRF1 mutations have an earlier onset of the disease than those with UNC13D mutation or patients for whom no mutations are identified. [80]

In general, those with missense mutations have later onset of their disease. [81] However, FHL is usually diagnosed in childhood and rarely in adults as an acute disease. The symptoms include prolonged fever, cytopenia, hemoglobin level less than 9 g/L (93%), platelets less than 100 X 109/L (98%), neutrophils less than 1 X 109/L (75%), increased serum ferritin levels (93%), hypofibrinogenemia (76%), and CSF pleocytosis (52%). [78]  Enlargement of liver, spleen and lymph nodes occur occasionally and are accompanied by a rash. Neurologic symptoms range from irritability, lethargy, hypotoma, hypertoma, ataxia, seizure disorder, increased intracranial pressure, hemi or quadriplegia, and cranial nerve involvement, including loss of vision. Liver dysfunction, including icterus and elevation of liver enzymes, is common; [82] hypertriglyceridemia and hypofibrinogenemia is seen as well.

HLH patients are prone to various infections. CSF may be positive for protein, increased mononuclear cells, or hemophagocytic cells. Bone marrow aspiration and biopsy typically reveals hemophagocytosis, which is the hallmark of this disease. This, however, may not be apparent early in the course. Genetic studies, as outlined above, are essential for definitive diagnosis. Cytolytic T lymphocyte (CTL)-mediated cytotoxicity can be impaired. Deficient natural killer cell (NK cell) activity is more often seen in individuals with PRF1 mutation than in those without. Immune dysregulation is one of the hallmarks of the disease, paralleling reduced or absent activity of the NK cells in most cases. CTL activity is also compromised.

Various mutations, deletions, or insertions that cause frameshift or missense mutation in perforin genes (PRF1 and PRF2), [83]  MUNC 13-4, and syntaxin 11 have been reported. These findings often appear during the first year of life and almost always appear before age 17 years. Primary HLH is linked to chromosomes 9 and 10. Genetic mutations in the perforin gene on chromosome 10 cause the disease in about 25-40% of genetically related patients. Perforin gene mutation is reported in approximately one third of HLH cases. Mutation in MUNC 13-4, a gene involved in cellular cytotoxicity that encodes for a protein that controls the fusion of the lytic granules to the plasma membranes, is associated with some FHL cases (FHL3). The mutations can be scattered over different exons but, in most cases, fall within the protein functional domain. [84] A male predominance has been reported. [85, 86] In approximately 50-75% of patients, the disease is hereditary, with an autosomal recessive trait pattern. Parental consanguinity is common. [87]

HLH is fatal if untreated. Allogeneic bone marrow transplantation is the treatment of choice. However, the HLH-94 international protocol including VP16, steroids, and cyclosporine has had excellent activity in achieving remission in most patients. When this protocol is combined with allogeneic bone marrow transplantation, more than 50% of patients can be cured. [88]

In patients with HLH, CNS disease is frequently seen. Almost 70% of patients have nonspecific abnormalities detectable with CT scan and MRI of the brain. The most common abnormalities include periventricular white matter involvement, with enlarged ventricular system, gray matter disorders, and brainstem and corpus callosum disease. Involvement of meninges is uncommon. [89]

Familial cases appear to be clustered in certain geographic areas of the world. PRF1 gene mutations are seen in whites, blacks, Japanese, Hispanics, and mixed races. Clusters of the disease have been reported in Asian, Turkish, Kurdish, Arabic, and Nordic populations. Associations with genes on other chromosomes have also been demonstrated. In a series of Japanese patients with HLH, 25% had mutations in the MUNC 13-4 gene (FHL2), a regulator of exocytosis in perforin-containing vesicles. [80] A small subgroup, dubbed FHL4, has been described in patients of Kurdish descent. A large consanguineous Kurdish kindred with 5 affected children had deletions in the syntaxin 11 gene on chromosome 6 (FLH4). Syntaxin 11 is a regulator of endocytosis. [90] This mutation is seen in approximately 21% of cases. [91] Further genetic mutations are under investigation.


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