Hereditary Alpha-Tryptasemia: Uncover Symptoms, Diagnosis Secrets & Effective Management Tips!

Hereditary alpha-tryptasemia (HαT) is a genetic condition characterized by an increased copy number of the TPSAB1 gene, which encodes for alpha-tryptase. This leads to elevated basal serum tryptase (BST) levels. Affecting approximately 5% of certain populations, particularly those of Caucasian descent, HαT is inherited in an autosomal dominant manner, meaning that inheriting one extra copy of the gene from a parent is enough to manifest the trait. This article delves into the symptoms, diagnosis, and management of HαT, providing a comprehensive overview for patients and healthcare professionals alike.

The Genetic Basis of HαT

The genetic change responsible for HαT involves one or more extra copies of the TPSAB1 gene, a structural variant impacting the number of copies of the gene rather than the genetic sequence itself. The TPSAB1 gene resides on chromosome 16, and its autosomal dominant inheritance pattern results in elevated basal serum tryptase (BST) levels, typically exceeding 8 ng/mL. It's worth noting that elevated BST levels in the general population (usually defined as greater than 11.4 ng/mL) occur in approximately 6% of Western populations, with HαT accounting for over 90% of these cases. Significant kidney disease accounts for another ~7% of people with elevated BST, and rare conditions including but not limited to clonal myeloid diseases such as mastocytosis account for the remainder of individuals.

The Role of Tryptase and Mast Cells

Tryptase, an enzyme primarily produced by mast cells and, to a lesser extent, basophils, plays a crucial role in allergic reactions. Mast cells originate in the bone marrow but migrate to tissues, particularly the skin and the lining of the gastrointestinal and respiratory tracts, where they mature. Tryptase, one of the most abundant proteins in mast cells, is a protease that requires assembly from four pro-tryptase building blocks into active "mature" tetramers. These mature tryptases are stored in secretory granules along with other molecules like histamine, which contribute to immediate allergic reaction symptoms.

Under normal conditions, the release of these powerful granules is highly regulated and requires significant stimulation. During anaphylaxis, serum tryptase levels can help confirm mast cells as the cause, although tryptase levels don't always increase during allergic reactions. Mast cells constantly release moderate amounts of pro-tryptases into the surrounding area, which then pass into the peripheral blood, where they can be measured. In individuals with HαT, the extra copies of the TPSAB1 gene lead to increased production of α-tryptase and elevated BST. It's important to note that increases in BST measured in peripheral blood are not evidence of mast cells releasing granule contents, and mature tryptases are not detectable in BST samples from individuals with HαT.

Symptoms Associated with HαT

Initial studies identified multisystem complaints or symptoms among family members with HαT that were coinherited with elevated BST. These symptoms include skin flushing, itching, and recurrent hives; abdominal pain and bloating (IBS-like symptoms); anaphylaxis to various causes, especially stinging insects; connective tissue abnormalities like joint hypermobility and retained primary teeth; and autonomic nerve dysfunction symptoms such as changes in blood pressure or heart rate.

Read also: Managing HS with Diet

It's important to acknowledge that referral biases inherent in studies from institutions focusing on genetic and/or mast cell-related disorders may influence the reported symptoms. However, studies have demonstrated that a significant portion of individuals with HαT experience a range of symptoms, including anaphylaxis (particularly to stinging insects), connective tissue abnormalities, autonomic dysfunction symptoms, eosinophilic gastrointestinal disease, food intolerances, chronic pain, and fatigue. Of these, systemic reactions to stinging insects, skin flushing and itching, IBS-like abdominal complaints, retained primary teeth, and symptoms of autonomic dysfunction were significantly increased among individuals with HaT.

HαT and Anaphylaxis

Individuals with HαT have a higher likelihood of experiencing more severe anaphylaxis, particularly in response to stinging insects. Studies have revealed that the frequency of HαT among venom allergic individuals presenting with severe anaphylaxis is approximately double that of the general population or those with milder reactions. While HαT doesn't appear to be a risk factor for venom allergy, it roughly doubles the chance of having a severe systemic reaction in venom-allergic patients.

HαT has also been found to be more common among patients with systemic mastocytosis (SM) and idiopathic anaphylaxis, with frequencies approximately three times higher than in the general population. Moreover, the frequency of anaphylaxis in patients with both SM and HαT is approximately doubled compared to patients with SM alone. This increased prevalence of HαT in SM patients may be due to a detection bias, where individuals with both conditions are more likely to be symptomatic and seek medical attention.

Research has also indicated moderate increases in mast cell numbers in the bone marrow and GI lining of symptomatic individuals with HαT compared to healthy volunteers or patients with similar symptoms who do not have HαT. This suggests that extra α-tryptase may affect mast cell growth or survival. Despite these findings, HαT alone is not associated with a clinically relevant increase in the risk of developing SM.

Gastrointestinal Complaints and Immune Cell Differences

While IBS-like symptoms are frequently reported in individuals with HαT, studies have shown that HαT is not a risk factor for classical IBS. However, individuals with GI symptoms and HαT exhibit an unusual kind of inflammation called pyroptosis in the gastrointestinal lining, comparable to what is seen in celiac disease and treated Crohn's disease. These inflammatory changes are associated with immunologic changes in the GI lining and peripheral blood, including increased numbers of mast cells.

Potential Mechanisms Underlying Symptoms

The mechanisms by which α-tryptase contributes to HαT symptoms remain unclear. One hypothesis involves the composition of mature tryptase tetramers. While mature tryptases containing four β-tryptase subunits are enzymatically active, those with four α-tryptase subunits have minimal enzymatic activity. However, the existence of heterotetramers containing both α-tryptase and β-tryptase subunits has been discovered. These heterotetramers can cut specific proteins, including stimulating receptors on mast cells and endothelial cells, potentially contributing to mast cell activation or increased blood vessel leakiness.

Another explanation is that the increased numbers of mast cells that multiple studies have reported in bone marrow and in the GI epithelium based upon these findings, or the increased prevalence among SM patients. Additional mechanism(s) potentially underlying all of these findings are active areas of research.

Diagnosing HαT

The first step in diagnosing HαT is measuring total serum tryptase levels, which are typically above 8 ng/mL in most individuals with HαT. Tryptase genotyping by ddPCR should be considered in symptomatic individuals with elevated basal serum tryptase levels, and is currently the only test available to confirm the diagnosis of HαT. Correct interpretation of tryptase genotyping can be a challenge even for doctors.

Management and Lifestyle Adjustments

Managing HαT involves a comprehensive approach that includes identifying and avoiding triggers, managing symptoms with appropriate medications, and adopting lifestyle adjustments to promote overall well-being.

Identifying and Avoiding Triggers

Mast cell activation can be triggered by various substances and events, including foods, food additives, inhaled chemicals, medications/supplements, and temperature changes. These triggers can cause symptoms similar to IgE-mediated allergies. Keeping a diary to track symptoms, food intake, experiences, and feelings can help identify potential triggers.

Medications and Emergency Preparedness

Doctors may recommend medications to help control symptoms. Antihistamines are commonly used to treat mast cell diseases. For individuals at risk of severe systemic reactions, carrying epinephrine at all times is crucial. Epinephrine is the first-line treatment for anaphylaxis and should be administered at the first sign of symptoms. A Medical ID bracelet can also be beneficial, alerting others to the risk of anaphylaxis and providing instructions in case of an emergency.

Lifestyle Modifications

Several lifestyle modifications can help manage HαT symptoms and improve overall quality of life:

Temperature Control: Be mindful of sudden or extreme temperatures, as some individuals with mast cell disease are sensitive to heat or cold. Wear appropriate clothing and use temperature control measures during bathing and other activities.
Regular Exercise: Engage in regular physical activity to reduce stress levels and improve overall well-being. Choose enjoyable activities like walking, swimming, or biking, and consider low-impact exercises if vigorous activity triggers symptoms.
Stress Management: Find ways to relax and manage stress, as stress can worsen mast cell disease symptoms. Consider activities like reading, drawing, or spending time with loved ones.
Balanced Diet: Eating a balanced diet with plenty of fruits, vegetables, and whole grains can support a strong immune system. Some individuals may need to avoid alcohol, as it can trigger mast cell disease symptoms.

Additional Resources

The Mast Cell Disease Society offers a wealth of patient education resources. Connecting with support groups or online communities can provide valuable peer support and information.

The Role of Nutrition

While hereditary alpha tryptasemia (HαT) is primarily a genetic condition affecting mast cell activity and tryptase levels, nutrition can play a supportive role in managing symptoms and overall well-being. There isn't a specific "HαT diet," but certain dietary strategies can help minimize triggers and support a balanced immune response.

Identifying Food Triggers

One of the most important aspects of nutrition in HαT is identifying and avoiding individual food triggers. Mast cells can be activated by a wide range of foods and food additives, leading to gastrointestinal symptoms, skin reactions, and other issues. Common culprits include:

High-histamine foods: These foods naturally contain high levels of histamine, which can further activate mast cells. Examples include aged cheeses, fermented foods (sauerkraut, kimchi), smoked meats, alcohol (especially red wine and beer), avocados, eggplant, spinach, tomatoes, and certain seafood.
Histamine-liberating foods: These foods don't contain high levels of histamine themselves, but they can trigger mast cells to release histamine. Examples include citrus fruits, bananas, strawberries, chocolate, shellfish, and food dyes.
Other potential triggers: Individual sensitivities vary, so it's important to be aware of other foods that may trigger symptoms. Common examples include dairy products, gluten-containing grains, legumes, nuts, seeds, and artificial sweeteners.

Strategies for identifying food triggers:

Elimination diet: This involves removing suspected trigger foods from your diet for a period of time (usually 2-4 weeks) and then gradually reintroducing them one at a time to monitor for symptoms.
Food diary: Keeping a detailed record of what you eat and any symptoms you experience can help you identify patterns and potential trigger foods.
Allergy testing: While standard allergy tests (skin prick tests and blood tests) primarily detect IgE-mediated allergies, they may not be helpful for identifying mast cell-related food triggers. However, they can help rule out IgE-mediated allergies to certain foods.
Working with a registered dietitian: A registered dietitian can help you develop a personalized elimination diet plan, interpret food diary results, and ensure that you're meeting your nutritional needs while avoiding trigger foods.

Anti-Inflammatory Diet

Since HαT is often associated with inflammation, adopting an anti-inflammatory diet can be beneficial. This involves focusing on whole, unprocessed foods that are rich in nutrients and antioxidants. Key components of an anti-inflammatory diet include:

Fruits and vegetables: These are packed with vitamins, minerals, and antioxidants that can help reduce inflammation. Focus on a variety of colors, including leafy greens, berries, colorful peppers, and cruciferous vegetables.
Healthy fats: Omega-3 fatty acids, found in fatty fish (salmon, tuna, mackerel), flaxseeds, chia seeds, and walnuts, have anti-inflammatory properties.
Lean protein: Choose lean sources of protein such as poultry, fish, beans, and lentils.
Whole grains: Opt for whole grains like brown rice, quinoa, and oats over refined grains like white bread and pasta.

Nutrients that Support Mast Cell Stabilization

Some nutrients may help stabilize mast cells and reduce their reactivity. While more research is needed, these nutrients may be worth incorporating into your diet:

Quercetin: This flavonoid is found in onions, apples, berries, and broccoli. It has antioxidant and anti-inflammatory properties and may help stabilize mast cells.
Vitamin C: This vitamin is found in citrus fruits, berries, and bell peppers. It acts as an antioxidant and may help reduce histamine levels.
Vitamin D: This vitamin is important for immune function and may help regulate mast cell activity.
Magnesium: This mineral is found in leafy greens, nuts, and seeds. It may help reduce mast cell degranulation.

Considerations

Individualized approach: It's important to remember that everyone is different, and what works for one person with HαT may not work for another. It's essential to work with a healthcare professional to develop a personalized nutrition plan that meets your individual needs and addresses your specific symptoms.
Nutrient deficiencies: Restrictive diets can increase the risk of nutrient deficiencies. It's important to ensure that you're getting all the nutrients you need, either through diet or supplementation.
Long-term sustainability: The most effective dietary approach is one that you can stick with long-term. Focus on making gradual, sustainable changes to your diet rather than making drastic, unsustainable changes.

By understanding the role of nutrition in HαT and working with a healthcare professional, you can develop a dietary strategy that helps manage your symptoms and improve your overall quality of life.

tags: #hereditary #alpha #tryptasemia #nutrition