Systemic Mastocytosis
Disease Details
Family Health Simplified
- Description
- Systemic mastocytosis is a rare disorder characterized by the accumulation of abnormal mast cells in various tissues, including the bone marrow, skin, liver, and spleen.
- Type
- Systemic mastocytosis is a type of mast cell disease characterized by the abnormal accumulation of mast cells in various tissues, including the skin, bone marrow, liver, and spleen. The type of genetic transmission for systemic mastocytosis is typically sporadic, caused by somatic mutations in the KIT gene. These mutations are not usually inherited, but rather occur spontaneously in the individual's cells during their lifetime.
- Signs And Symptoms
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When mast cells undergo degranulation, the substances that are released can cause a number of symptoms that can vary over time and can range in intensity from mild to severe. Because mast cells play a role in allergic reactions, the symptoms of mastocytosis often are similar to the symptoms of an allergic reaction. They may include, but are not limited to
Fatigue
Skin lesions (urticaria pigmentosa), itching, and dermatographic urticaria (skin writing)
"Darier's Sign", a reaction to stroking or scratching of urticaria lesions.
Abdominal discomfort
Nausea and vomiting
Diarrhea
Olfactive intolerance
Ear/nose/throat inflammation
Anaphylaxis (shock from allergic or immune causes)
Episodes of very low blood pressure (including shock) and faintness
Bone or muscle pain
Decreased bone density or increased bone density (osteoporosis or osteosclerosis)
Headache
Depression
Ocular discomfort
Increased stomach acid production causing peptic ulcers (increased stimulation of enterochromaffin cell and direct histamine stimulation on parietal cell)
Malabsorption (due to inactivation of pancreatic enzymes by increased acid)
HepatosplenomegalyThere are few qualitative studies about the effects of mastocytosis on daily life. However, a Danish study from 2018 describes the multidimensional impact of the disease on everyday life. - Prognosis
- Patients with indolent systemic mastocytosis have a normal life expectancy. The prognosis for patients with advanced systemic mastocytosis differs depending on type of disease with MCL being the most serious form with short survival.
- Onset
- Systemic mastocytosis can manifest at any age, but it is most commonly diagnosed in adults, typically in their 30s to 60s. The onset can be gradual, with symptoms often developing over several years before a diagnosis is made.
- Prevalence
- The prevalence of systemic mastocytosis is not precisely known, but it is generally considered a rare disorder. Estimates suggest it affects fewer than 1 in 10,000 people.
- Epidemiology
- The true incidence and prevalence of mastocytosis is unknown, but mastocytosis generally has been considered to be an "orphan disease"; orphan diseases affect 200,000 or fewer people in the United States. Mastocytosis, however, often may be misdiagnosed, as it typically occurs secondary to another condition, and thus may occur more frequently than assumed.
- Intractability
- Systemic mastocytosis is not considered universally intractable, but it is a chronic condition that can be very challenging to manage. Treatment focuses on symptom management and controlling the proliferation of mast cells. The severity and response to treatment can vary significantly among individuals. While some patients achieve good control of symptoms with medications, others may experience persistent and severe symptoms. In advanced forms of the disease, such as aggressive systemic mastocytosis or mast cell leukemia, the condition can be more difficult to treat and may have a poorer prognosis.
- Disease Severity
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Systemic mastocytosis varies in severity depending on the subtype:
1. **Indolent systemic mastocytosis (ISM)**: Generally less severe with a normal life expectancy. Symptoms may include skin lesions, gastrointestinal issues, and mild organ swelling.
2. **Smoldering systemic mastocytosis (SSM)**: More severe than ISM, potentially progressing to more serious forms. It can cause organ dysfunction and increased risk of anaphylaxis.
3. **Aggressive systemic mastocytosis (ASM)**: Severe and potentially life-threatening. It may involve significant organ damage, including the liver, spleen, and bone marrow.
4. **Mast cell leukemia (MCL)**: The most severe form, characterized by extensive mast cell infiltration in the blood and bone marrow. This form is life-threatening and has a poor prognosis.
5. **Mast cell sarcoma**: This is an extremely rare and very aggressive form requiring intensive treatment.
Severity in systemic mastocytosis can range from mild and manageable to severe and life-threatening, depending on the specific type and extent of organ involvement. - Healthcare Professionals
- Disease Ontology ID - DOID:349
- Pathophysiology
- Mast cells are located in connective tissue, including the skin, the linings of the stomach and intestine, and other sites. They play an important role in the immune defence against bacteria and parasites. By releasing chemical "alarms" such as histamine, mast cells attract other key players of the immune defense system to areas of the body where they are needed.Mast cells seem to have other roles as well. Because they gather together around wounds, mast cells may play a part in wound healing. For example, the typical itching felt around a healing scab may be caused by histamine released by mast cells. Researchers also think mast cells may have a role in the growth of blood vessels (angiogenesis). No one with too few or no mast cells has been found, which indicates to some scientists we may not be able to survive with too few mast cells.Mast cells express a cell surface receptor, c-kit (CD117), which is the receptor for stem cell factor (scf). In laboratory studies, scf appears to be important for the proliferation of mast cells. Mutations of the gene coding for the c-kit receptor (mutation KIT(D816V)), leading to constitutive signalling through the receptor is found in >90% of patients with systemic mastocytosis.
- Carrier Status
- Systemic mastocytosis is not typically related to carrier status as it is not a classical genetic carrier disease like cystic fibrosis or sickle cell anemia. Instead, it is often associated with somatic mutations, particularly in the KIT gene, which can occur after conception and are not inherited or passed down from parents in a carrier state.
- Mechanism
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Systemic mastocytosis is a disorder characterized by the accumulation of abnormal mast cells in multiple tissues, including the skin, bone marrow, liver, and spleen. These mast cells release excessive amounts of histamine and other mediators, leading to various symptoms such as itching, abdominal pain, anaphylaxis, and organ dysfunction.
**Mechanisms:**
1. **Mast Cell Proliferation:** The primary mechanism involves the uncontrolled proliferation and accumulation of mast cells in various organs.
2. **Mediators Release:** The accumulated mast cells release high levels of mediators like histamine, tryptase, cytokines, and leukotrienes, causing inflammatory and allergic symptoms.
**Molecular Mechanisms:**
1. **KIT Gene Mutations:** The most common molecular mechanism is mutations in the KIT gene, which encodes a receptor tyrosine kinase. The D816V mutation in the KIT gene is particularly prevalent in systemic mastocytosis cases. This mutation leads to constitutive activation of the KIT receptor, driving uncontrolled mast cell growth and survival.
2. **Signal Transduction Pathways:** The KIT D816V mutation and other activating mutations lead to the persistent activation of downstream signaling pathways, including the PI3K/AKT, RAS/RAF/MEK/ERK, and JAK/STAT pathways. These pathways are crucial for cell proliferation, survival, and differentiation, thus contributing to the pathogenesis of systemic mastocytosis.
3. **Epigenetic Modifications:** Alterations in DNA methylation and histone modifications can also play roles in the pathogenesis by affecting the expression of oncogenes and tumor suppressor genes, further promoting mast cell accumulation and survival.
Understanding these mechanisms is essential for the development of targeted therapies in treating systemic mastocytosis. - Treatment
- There is no cure for mastocytosis, but there are a number of medicines to help treat the symptoms:
- Compassionate Use Treatment
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For systemic mastocytosis (SM), treatment approaches, including compassionate use and off-label or experimental treatments, are often sought due to the rarity and complexity of the disease. Here are some options:
1. **Midostaurin (PKC412)**: While already approved for advanced systemic mastocytosis, it may also be available under compassionate use in certain situations where access is limited.
2. **Avapritinib (BLU-285)**: This is an investigational therapy targeting the KIT D816V mutation, often found in SM cases. Clinical trials and compassionate use programs may provide access.
3. **Cladribine (2-CdA)**: Although primarily used off-label, it has shown efficacy in some patients with aggressive systemic mastocytosis or mast cell leukemia.
4. **Interferon-alpha**: This medication, typically used off-label, can be considered for controlling symptoms and mast cell burden in some SM cases, especially where cytoreductive therapy is needed.
5. **KIT inhibitors**: Aside from Midostaurin and Avapritinib, other KIT inhibitors like Dasatinib and Imatinib have been explored off-label, particularly if the KIT mutation profile of the patient may respond.
6. **Masitinib**: Although primarily experimental, this KIT inhibitor is undergoing clinical trials for potential use in systemic mastocytosis, especially forms with less aggressive behavior.
Experimental treatments should ideally be accessed through clinical trials or compassionate use programs overseen by healthcare professionals. It's essential to consult a specialist in systemic mastocytosis for managing the disease and evaluating the suitability of these advanced treatment options. - Lifestyle Recommendations
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Lifestyle recommendations for systemic mastocytosis typically include:
1. **Avoid Triggers:** Identify and avoid triggers that can cause mast cell activation, such as certain foods, alcohol, insect stings, and medications (e.g., non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and certain antibiotics).
2. **Healthy Diet:** Maintain a balanced diet and avoid foods that are known to release histamine or trigger symptoms. Common problematic foods include aged cheeses, fermented foods, processed meats, and certain fruits and vegetables.
3. **Stress Management:** Practice stress-relief techniques such as yoga, meditation, or deep-breathing exercises. Stress can exacerbate symptoms.
4. **Safe Environment:** Address environmental factors by avoiding strong scents, chemicals, and temperature extremes which could trigger symptoms.
5. **Medication Adherence:** Strictly adhere to prescribed medications like antihistamines, mast cell stabilizers, or other treatments recommended by healthcare providers.
6. **Regular Monitoring:** Keep regular appointments with your healthcare provider for monitoring the condition and adjusting treatment as necessary.
7. **Medical Alert:** Consider wearing a medical alert bracelet that indicates your condition, which can be critical during emergencies.
8. **Exercise Moderation:** Engage in moderate physical activity, as extreme exercise might trigger symptoms. Warm up properly and stay hydrated.
9. **Emergency Plan:** Have an emergency plan in place, including carrying an epinephrine auto-injector if prescribed.
10. **Education:** Educate family, friends, and co-workers about the condition so they understand your needs and can provide support during emergencies.
These lifestyle adjustments can help manage symptoms and improve quality of life for individuals with systemic mastocytosis. - Medication
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Systemic mastocytosis is typically treated with medications aimed at managing its symptoms and limiting mast cell activation. These may include:
1. **Antihistamines**:
- H1 receptor blockers like cetirizine or loratadine.
- H2 receptor blockers like ranitidine or famotidine.
2. **Mast Cell Stabilizers**:
- Cromolyn sodium.
3. **Leukotriene Inhibitors**:
- Montelukast or zafirlukast.
4. **Cytoreductive Therapy**:
- Tyrosine kinase inhibitors like imatinib for those with certain mutations.
- Cladribine or interferon-alpha in more aggressive cases.
5. **Corticosteroids**:
- Used for severe symptoms or systemic involvement.
6. **Bisphosphonates**:
- For bone involvement and osteoporosis.
Treatment plans are tailored to individual patient needs and the severity of the disease. - Repurposable Drugs
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Repurposable drugs for systemic mastocytosis can include:
1. **Imatinib**: Initially developed for chronic myeloid leukemia, it has shown efficacy in treating systemic mastocytosis with specific KIT mutations.
2. **Midostaurin**: Originally used for acute myeloid leukemia, this drug has been approved for advanced systemic mastocytosis, including aggressive forms and mast cell leukemia.
3. **Ruxolitinib**: Frequently used for myelofibrosis, it may help manage symptoms related to systemic mastocytosis due to its anti-inflammatory properties.
These drugs can target specific molecular pathways involved in the disease or alleviate symptoms associated with systemic mastocytosis. - Metabolites
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For systemic mastocytosis, certain metabolites may be elevated and used as biomarkers for diagnosis and monitoring. Key metabolites include:
1. **Tryptase:** Elevated levels of serum tryptase are commonly associated with systemic mastocytosis and are used as a diagnostic marker.
2. **Histamine:** Increased levels of histamine and its metabolites can be detected in urine and may indicate mast cell activity.
3. **Prostaglandin D2:** Elevated in some patients, this is another marker of mast cell activation.
4. **Heparin:** Occasionally, heparin levels may be elevated in systemic mastocytosis.
Regular monitoring of these metabolites helps in assessing the disease's activity and response to treatment. - Nutraceuticals
- For systemic mastocytosis, there is limited clinical evidence supporting the use of nutraceuticals to manage symptoms. However, some patients may explore options such as quercetin, an over-the-counter flavonoid with anti-inflammatory properties, and curcumin, known for its anti-inflammatory and antioxidant effects. It is crucial to consult with a healthcare provider before starting any nutraceuticals, as they may interact with prescribed medications and affect disease management.
- Peptides
- Systemic mastocytosis is a disorder characterized by the accumulation of mast cells in various tissues. Peptides, particularly stem cell factor (SCF), play a significant role in mast cell growth, survival, and function. SCF binds to the KIT receptor on mast cells, promoting their proliferation. Mutations in the KIT gene, such as the D816V mutation, are often found in systemic mastocytosis, leading to uncontrolled mast cell growth and activation. This contributes to the symptoms of the disease, which can include skin lesions, gastrointestinal issues, and anaphylaxis. The involvement of peptides in the signaling pathways is a key factor in the pathogenesis of systemic mastocytosis.