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Hemophagocytic Lymphohistiocytosis

Disease Details

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Description: Hemophagocytic lymphohistiocytosis (HLH) is a severe systemic inflammatory syndrome caused by the excessive activation of immune cells, leading to organ damage and potential organ failure.
Type: Hemophagocytic lymphohistiocytosis (HLH) is an immune system disorder. There are two types of HLH: primary (or familial) and secondary (or acquired). Primary HLH is typically inherited in an autosomal recessive manner, meaning that an individual must inherit two copies of the defective gene (one from each parent) to develop the disease. Secondary HLH is usually triggered by infections, autoimmune diseases, or malignancies and is not inherited.
Signs And Symptoms: HLH as defined by the HLH-04 criteria (see below) is a descriptive diagnosis. Its individual components are non-specific.
The onset of HLH occurs before the age of one year in approximately 70 percent of cases. Familial HLH should be suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. Familial HLH is an autosomal recessive disease, hence each sibling of a child with familial HLH has a twenty-five–percent chance of developing the disease, a fifty-percent chance of carrying the defective gene (which is very rarely associated with any risk of disease), and a twenty-five–percent chance of not being affected and not carrying the gene defect.Patients with HLH, especially when untreated, may need intensive therapy. Therefore, HLH should be included in the differential diagnosis of intensive care unit patients with cytopenia and hyperferritinemia. Patients in the earlier stages of HLH are frequently hospitalized at internal medicine wards.HLH clinically manifests with fever, enlargement of the liver and spleen, enlarged lymph nodes, yellow discoloration of the skin and eyes, and a rash. Laboratory findings may include elevated triglyceride levels, low fibrinogen levels, transaminitis, and elevated ferritin levels (among others).
Prognosis: The prognosis is guarded with an overall mortality of 50%. Poor prognostic factors included HLH associated with malignancy, with half the patients dying by 1.4 months compared to 22.8 months for non-tumour associated HLH patients.Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment (i.e., IV immunoglobulin only). 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 involvement of the central nervous system (brain and/or spinal cord).
Onset: Hemophagocytic lymphohistiocytosis (HLH) can have sudden or gradual onset and can occur at any age, but it most commonly presents in infancy or early childhood. The onset can be triggered by various factors, including infections, malignancies, autoimmune diseases, and certain genetic mutations. Signs and symptoms often include fever, enlarged spleen, cytopenias, hepatic dysfunction, and neurological symptoms. Prompt diagnosis and treatment are crucial due to the rapid progression and potential for fatality.
Prevalence: Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with an estimated overall prevalence of about 1 in 50,000 to 1 in 100,000 live births.
Epidemiology: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition characterized by severe hyperinflammation due to excessive immune system activation. HLH can be classified into two main types: primary (familial) HLH and secondary (acquired) HLH.

Epidemiology:
- **Incidence:** The overall incidence of HLH varies but is estimated to be approximately 1.2 cases per million people per year.
- **Age distribution:** Although HLH can occur at any age, primary HLH typically presents in infancy or early childhood, often within the first year of life. Secondary HLH can occur in both children and adults.
- **Sex distribution:** There is no significant gender predilection in HLH.
- **Geographical variation:** Some studies suggest geographic and ethnic variations in the incidence of HLH, with higher incidences reported in areas with certain consanguineous communities.
- **Associated conditions:** Secondary HLH is frequently triggered by infections, malignancies, autoimmune diseases, or rheumatologic conditions. Viral infections, particularly Epstein-Barr virus (EBV), are common triggers.

Given the rarity and complexity of HLH, it often requires a high degree of clinical suspicion for diagnosis and prompt treatment to improve outcomes.
Intractability: Hemophagocytic lymphohistiocytosis (HLH) is considered a severe and potentially life-threatening condition that can be difficult to manage. It often requires aggressive treatments, including immunosuppressive therapy, chemotherapy, and sometimes hematopoietic stem cell transplantation. Despite available treatments, the disease can be refractory to therapy in some cases, making it challenging to control. Early diagnosis and prompt treatment are crucial for improving outcomes.
Disease Severity: Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe and potentially life-threatening condition. It is characterized by an overactive and excessive immune response, leading to organ damage. Early diagnosis and treatment are critical to manage the disease effectively and improve outcomes.
Healthcare Professionals: Disease Ontology ID - DOID:0050120
Pathophysiology: The underlying causes, either inherited or acquired, lead to an unchecked immune response when exposed to triggers. Impaired NK-cell cytotoxicity is the hallmark of HLH. All genetic defects for familial HLH are related to granule-dependent cytotoxicity. This inability to remove infected and antigen-presenting cells and terminate the immune response leads to uncontrolled proliferation and activation of the immune system with release of excessive cytokines. These cells then infiltrate organs, releasing more cytokines, which gives the clinical picture. The fever is caused by IL-1, IL-6 and TNF-alpha; the cytopenia is due to the suppressive effect on hematopoiesis by TNF-alpha and TNF-gamma. TNF-alpha and TNF-gamma may also lead to inhibition of lipoprotein lipase or stimulate triglyceride synthesis. Activated macrophages secrete ferritin and plasminogen activator leading to hyperfibrinolysis.
Carrier Status: Hemophagocytic lymphohistiocytosis (HLH) is a severe systemic inflammatory syndrome that can be inherited or acquired. Carrier status specifically pertains to the inherited (genetic) forms of HLH, known as Familial Hemophagocytic Lymphohistiocytosis (FHL). Individuals who carry one mutated copy of an HLH-related gene (such as PRF1, UNC13D, STX11, and others) are considered carriers. Carriers typically do not show symptoms of the disease but can pass the mutated gene to their offspring. If both parents are carriers, there is a 25% chance with each pregnancy that the child will inherit both mutated copies, leading to FHL.
Mechanism: Hemophagocytic lymphohistiocytosis (HLH) is a severe systemic inflammatory syndrome. The mechanism involves excessive activation and proliferation of lymphocytes and macrophages, leading to widespread immune activation and tissue damage. The result is an overproduction of inflammatory cytokines, often referred to as a "cytokine storm."

Molecular mechanisms underlying HLH typically include genetic mutations that affect the function of cytotoxic T cells and natural killer (NK) cells. Key genes implicated in familial or primary HLH include:
- PRF1 (perforin 1): Encodes perforin, a protein essential for the cytolytic activity of T cells and NK cells.
- UNC13D (Munc13-4), STX11 (syntaxin 11), and STXBP2 (Munc18-2): Involved in the exocytosis process of lytic granules in cytotoxic cells.
- RAB27A, LYST, and AP3B1: Affect granule trafficking and docking processes.

Mutations in these genes impair the ability of cytotoxic cells to kill infected or malignant cells, leading to persistent immune activation and uncontrolled inflammation, which are hallmarks of HLH.
Treatment: HLH is a description of an immunophysiologic state in time. It can be dangerous to infer a genetic impairment of granule-mediated cytotoxicity in patients, especially older children and adults, who meet any of the various criteria for HLH. Thus, like shock, one must simultaneously manage both the acute physiologic changes associated with HLH (like systemic inflammation, DIC, hepatitis, etc.) and look deeply for various underlying contributors.
The International Histiocyte Society has collected the published consensus management documents for the many contexts in which HLH occurs and they host full-text versions.Most patients who meet HLH criteria will have secondary cases. Treatment for these patients should focus on the underlying contributors. Additionally, treatment of the inflammation of HLH itself is often required.While optimal treatment of HLH is still being debated, current treatment regimes usually involve high dose corticosteroids, etoposide and cyclosporin. Intravenous immunoglobulin is also used. Methotrexate and vincristine have also been used. Other medications include cytokine targeted therapy.On 20 November 2018, the FDA approved the anti-IFN-gamma monoclonal antibody emapalumab (proprietary name Gamifant) for the treatment of pediatric and adult primary HLH.In October 2021 NHS England published Clinical Commissioning Policy: Anakinra for Haemophagocytic Lymphohistiocytosis (HLH) for adults and children in all ages, allowing Anakinra (a modified recombinant interleukin 1 receptor antagonist) to be used in the treatment of HLH.
Compassionate Use Treatment: Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening condition characterized by excessive immune activation. For compassionate use treatment, off-label, or experimental treatments for HLH, the following approaches have been explored:

1. **Etoposide:** This chemotherapeutic agent is part of the HLH-94 and HLH-2004 treatment protocols and is sometimes used in a compassionate context when standard treatments are inaccessible.

2. **Anti-thymocyte globulin (ATG):** This immunosuppressive therapy targets T-cells and is occasionally used off-label for HLH when conventional therapies fail.

3. **Alemtuzumab:** This monoclonal antibody targets CD52 on lymphocytes and has been investigated in experimental settings for its potential efficacy in HLH.

4. **Ruxolitinib:** A Janus kinase (JAK) inhibitor, ruxolitinib, has shown promise in early-phase trials and compassionate use for managing refractory HLH, though it is primarily indicated for myelofibrosis and polycythemia vera.

5. **Emapalumab:** This interferon-gamma (IFN-γ) blocking antibody has gained FDA approval for HLH under specific circumstances and can be considered a recent addition to the treatment arsenal, often used in experimental or compassionate contexts.

6. **Hematopoietic Stem Cell Transplantation (HSCT):** While not experimental, HSCT is the definitive treatment for familial or refractory HLH and can be approached as a last resort in compassionate use scenarios.

These treatments should be considered and administered by healthcare professionals familiar with HLH and its management.
Lifestyle Recommendations: For individuals with hemophagocytic lymphohistiocytosis (HLH), lifestyle recommendations primarily focus on managing symptoms and supporting overall health. Some key recommendations include:

1. **Regular Medical Follow-Up**: Regular monitoring by a healthcare provider is crucial to manage the disease and adjust treatment as necessary.
2. **Balanced Diet**: A nutritious, well-balanced diet can help support the immune system.
3. **Hydration**: Proper hydration is important for overall health.
4. **Rest**: Adequate rest and sleep are essential to help the body recover and maintain energy levels.
5. **Infection Avoidance**: Minimizing exposure to infections through good hygiene practices and avoiding large crowds can be beneficial, as individuals with HLH may have compromised immune systems.
6. **Stress Management**: Stress can negatively impact overall health, so effective stress management techniques, such as mindfulness or relaxation exercises, are recommended.
7. **Physical Activity**: Moderate physical activity may be beneficial, but it should be tailored to the individual's ability and energy levels, and done in consultation with a healthcare provider.

Regular communication with healthcare providers is critical to adjust lifestyle recommendations based on the progression and management of HLH.
Medication: Hemophagocytic lymphohistiocytosis (HLH) is often treated with a combination of medications that aim to suppress the excessive immune response. These may include immunosuppressive drugs like etoposide, corticosteroids (such as dexamethasone), and cyclosporine. In some cases, targeted treatments such as monoclonal antibodies (e.g., alemtuzumab) or bone marrow transplantation may be considered.
Repurposable Drugs: Repurposable drugs for Hemophagocytic Lymphohistiocytosis (HLH) include the following:

1. **Etoposide**: A chemotherapeutic agent used in various cancers, has shown effectiveness in treating HLH by inducing apoptosis in overactive immune cells.
2. **Dexamethasone**: A corticosteroid that suppresses inflammation and immune system activity, helping to control the hyperinflammatory state seen in HLH.
3. **Cyclosporine**: An immunosuppressive drug commonly used in organ transplantation, helps to reduce the immune system’s overactivity in HLH.
4. **Ruxolitinib**: Originally approved for myelofibrosis and polycythemia vera, this JAK1/JAK2 inhibitor can help control the overactive immune response in HLH.

These drugs can be used as part of a treatment regimen to manage the excessive immune activation characteristic of HLH.
Metabolites: In hemophagocytic lymphohistiocytosis (HLH), several metabolites can be involved or altered. These include:

1. **Ferritin**: Often elevated in HLH and used as a diagnostic marker.
2. **Soluble Interleukin-2 Receptor (sIL-2R)**: Typically increased in HLH.
3. **Cytokines**: Elevated levels of inflammatory cytokines like interferon-gamma (IFN-γ), interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α).
4. **Triglycerides**: Elevated serum triglycerides (hypertriglyceridemia) are common in HLH.
5. **Fibrinogen**: Levels are often reduced (hypofibrinogenemia).

Please specify what you mean by "nan" for more detailed information. If you intended to inquire about "nanoparticles," their role in HLH is primarily experimental and focuses on targeted therapy and drug delivery systems in research settings.
Nutraceuticals: Nutraceuticals are not a primary treatment for hemophagocytic lymphohistiocytosis (HLH). HLH requires prompt medical intervention, typically involving immunosuppressive therapies, corticosteroids, and sometimes cytotoxic drugs. If there is an underlying infection or malignancy, appropriate treatments targeting those conditions are also necessary. Nutraceuticals may be used as supportive care but should not replace conventional medical treatment.
Peptides: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition where the body's immune system becomes overly activated. Current research is exploring the role of peptides in targeting specific pathways involved in HLH to modulate the immune response. Nanotechnology, particularly nanoparticles, is being investigated for its potential to deliver therapeutic agents more effectively and precisely in HLH, thereby minimizing side effects and improving outcomes.