From the Guidelines
Familial hemophagocytic lymphohistiocytosis (FHLH) is a rare, life-threatening genetic disorder of the immune system characterized by uncontrolled activation and proliferation of immune cells, particularly T lymphocytes and macrophages. This condition typically presents in infancy or early childhood, though some variants can appear later in life. In FHLH, genetic mutations impair the ability of immune cells to properly regulate themselves, leading to excessive inflammation and the inappropriate destruction of blood cells. The hallmark feature is hemophagocytosis, where macrophages abnormally engulf other blood cells.
Key Characteristics
- Symptoms include persistent high fever, enlarged liver and spleen, cytopenia (decreased blood cells), neurological abnormalities, and organ dysfunction.
- Five subtypes (FHL1-5) have been identified, each associated with specific genetic mutations affecting proteins involved in the cytotoxic function of immune cells.
- Early diagnosis is crucial but challenging due to the variable presentation that can mimic infections or other inflammatory conditions.
Treatment Approach
Treatment requires prompt immunosuppressive therapy, typically with dexamethasone and etoposide according to the HLH-2004 protocol, as suggested by 1.
- The use of etoposide is supported by studies showing its efficacy in treating both HLH and underlying neoplasms.
- Allogeneic hematopoietic stem cell transplantation is the only curative option for FHLH, as indicated by the need for a definitive treatment approach to prevent the high mortality associated with this condition 1. Without treatment, FHLH is almost universally fatal, usually within months of onset. Therefore, it is essential to prioritize aggressive and targeted therapy to improve outcomes in terms of morbidity, mortality, and quality of life.
From the Research
Definition and Characteristics
- Familial hemophagocytic lymphohistiocytosis (FHLH) is a rare, life-threatening condition characterized by immune hyperactivation and clinical signs of extreme inflammation 2.
- It is a rare immune deficiency with defective cytotoxic function, and the age at onset is usually young, with a natural course that is rapidly fatal if untreated 3.
- FHLH may present during adulthood, with clinical and genetic features that can be diagnosed based on evidence of genetic defect in one FHL-related gene 3.
Clinical Presentation
- Patients with FHLH may present with fever, pancytopenia, splenomegaly, hypertriglyceridemia, and hyperferritinemia 2.
- Clinical signs may also include liver or central nervous system disorders, especially when a lymphoproliferative disease is suspected but eventually not confirmed 3.
- FHLH can be triggered by infection, malignancy, and autoimmune disease, and may be associated with viral etiologies such as Epstein-Barr virus or Human herpesvirus-6 (HHV-6) 2, 4.
Genetic Features
- FHLH is often associated with genetic mutations in FHL-related genes, such as UNC13D, perforin, or other genes involved in cytotoxic function 2, 3.
- Genetic diagnoses may include FHL2, FHL3, FHL5, or XLP1, with FHL2 due to perforin defect being the most frequently reported subtype 3.
Treatment and Management
- Treatment of FHLH may involve antithymocyte globulins, steroids, and cyclosporin A, with the goal of inducing remission and preventing secondary relapses 5.
- Other treatment approaches may include chemo-immunotherapy followed by stem cell transplantation, especially in patients with a high risk of fatal outcome 3, 5.