Understanding Hereditary Alpha Tryptasemia (HAT)
- Dr. Harold Pierre
- 7 days ago
- 12 min read
Updated: 2 days ago
A Hidden Cause of Chronic Symptoms
If you've been dealing with unexplained chronic symptoms like abdominal pain, flushing, fatigue, or recurrent allergic reactions, you might have a condition called Hereditary Alpha Tryptasemia (HAT). Despite being discovered relatively recently in 2016, HAT is surprisingly common and may explain symptoms that have puzzled both patients and doctors for years.
As an anesthesiologist, it's crucial that I understand the immunology of mast cell diseases because of the risks for anaphylaxis during anesthesia care. As an addiction medicine specialist, to determine if my patient is experiencing withdrawal, medication reaction, or something cryptic like HAT. I've been fortunate to care for multiple Mast Cell Activation Syndrome patients for surgery, addiction treatment, and pain management. Today, I am presenting all of the pertinent information about HAT.
What is Hereditary Alpha Tryptasemia?
HAT is a genetic trait caused by having extra copies of the TPSAB1 (Tryptase Alpha/Beta-1) gene which is the alpha tryptase gene, which produces alpha tryptase - an enzyme stored in mast cells. Mast cells are immune cells that play crucial roles in allergic reactions and inflammation. When you have extra gene copies, your body produces more tryptase, leading to elevated tryptase levels in your blood and potentially causing various symptoms.
The condition follows an autosomal dominant inheritance pattern, meaning you only need one copy of the altered gene from either parent to have HAT. HAT affects an estimated 4-6% of the general population, making it common. Importantly, HAT is the most common cause of elevated serum tryptase levels, accounting for 64%-72% of all cases where people have pathologically elevated basal serum tryptase. However, many people with HAT have no symptoms at all, while others experience a wide range of issues that can significantly impact their quality of life.
Common Clinical Features of HAT
Important to understand: HAT doesn't affect everyone the same way. Research shows that roughly one-third of individuals with HAT have no symptoms at all, one-third have mild to moderate symptoms, and one-third experience significant symptoms that impact their daily lives. If you have HAT but feel fine, that's completely normal and doesn't require treatment.
Why Some People Have Symptoms and Others Don't
Scientists don't fully understand why HAT causes symptoms in some people but not others, even when they have similar tryptase levels. Factors that may influence symptom severity include:
Other genetic variations
Environmental triggers
Coexisting conditions like EDS (Ehlers-Danlos Syndrome) or MCAS (Mast Cell Activation Syndrome)
Individual sensitivity to tryptase and mast cell mediators
For Those Who Do Have Symptoms
If you're among those who experience symptoms, they can affect multiple body systems:
Gastrointestinal Issues
Chronic abdominal pain and cramping
Gastroesophageal reflux (heartburn)
Diarrhea or alternating bowel habits
Nausea and bloating
Symptoms resembling irritable bowel syndrome (IBS)
Food intolerances
Skin and Allergic Symptoms
Frequent flushing episodes
Chronic itching (pruritus)
Hives or rashes
Increased sensitivity to triggers like heat, stress, or physical pressure
Allergic rhinitis
Atopic dermatitis
Common specific triggers for skin symptoms:
Vibration and mild trauma: These are the most frequently reported triggers for flushing and skin reactions in HAT patients
Physical pressure or friction on the skin
Temperature changes (especially heat)
Emotional stress or anxiety
Certain medications or foods
Systemic Symptoms
Chronic fatigue
Joint and muscle pain
Headaches
Brain fog or cognitive difficulties
Mood changes and anxiety
Severe Allergic Reactions
Increased risk of anaphylaxis (although the literature is mixed on this)
More severe reactions to insect stings (note: HAT patients don't have higher rates of venom anaphylaxis than the general population, but when reactions do occur, they tend to be more severe)
Drug or food allergies
Idiopathic (unexplained) anaphylaxis
Important for HAT patients: If you experience anaphylaxis, standard diagnostic criteria may not apply to you. Your doctor should use HAT-specific guidelines to confirm whether you had a true anaphylactic reaction.
The Connection to Other Conditions: Understanding HAT, MCAS, and Mastocytosis
One of the most confusing aspects of HAT is how it relates to other mast cell diseases. Many patients and even some doctors struggle to understand the differences and overlaps between HAT, Mast Cell Activation Syndrome (MCAS), and mastocytosis. Here's what you need to know:
HAT vs. MCAS vs. Mastocytosis: Key Differences
Hereditary Alpha Tryptasemia (HAT):
What it is: A genetic condition with inherited extra copies of the TPSAB1 gene
Tryptase levels: Elevated baseline (usually 8-50 ng/mL)
Mast cell numbers: Normal number of mast cells
Inheritance: Autosomal dominant genetic
Symptoms: Variable - some people have no symptoms, others have significant issues
Mast Cell Activation Syndrome (MCAS):
What it is: Abnormal activation of otherwise normal mast cells
Tryptase levels: May be normal or elevated
Mast cell numbers: Normal number of mast cells
Cause: Often unknown (can be secondary to other conditions)
Symptoms: Range of symptoms of mast cell activation (flushing, GI issues, anaphylaxis)
Systemic Mastocytosis (SM):
What it is: Too many abnormal mast cells in the body
Tryptase levels: Usually very high (often >20 ng/mL)
Mast cell numbers: Increased, often with abnormal appearance
Genetic marker: Usually has c-KIT D816V mutation
Symptoms: Can include skin lesions, bone problems, organ involvement
How These Conditions Can Overlap
HAT + MCAS:
HAT can trigger MCAS - the extra tryptase may make mast cells more likely to activate inappropriately
People with HAT have a higher risk of developing secondary MCAS
Having both conditions can make symptoms more severe and harder to manage
Treatment often requires addressing both the underlying HAT and the mast cell activation
HAT + Mastocytosis:
HAT is found in 12-21% of patients with mastocytosis (2-3 times higher than the general population)
Having both conditions significantly increases the risk of severe anaphylaxis
Patients with both HAT and mastocytosis are 3 times more likely to have venom allergies
These patients need especially careful monitoring and emergency planning
HAT + Eosinophilic Gastrointestinal Disorders (EGID):
Patients with EGID often have higher baseline tryptase levels, which may be partly due to HAT
This connection may explain some of the gastrointestinal symptoms experienced by HAT patients
More research is needed to understand this relationship
HAT + Connective Tissue Disorders:
Some patients with HAT also have connective tissue disorders like Ehlers-Danlos Syndrome (EDS), though the relationship between these conditions is still being studied
When present together, both conditions may contribute to chronic pain and other symptoms
Triple Risk: HAT + SM + IgE Allergies:
This combination creates the highest risk for severe mast cell activation syndrome
Requires aggressive management and emergency preparedness
Often needs treatment from multiple specialists
Diagnostic Complexity: Why Testing Matters
If you have elevated tryptase (>15 ng/mL), your doctor should test for:
HAT first (using genetic testing)
c-KIT D816V mutation (for mastocytosis)
Bone marrow biopsy may be needed if other tests are inconclusive
Why this order matters:
HAT is the most common cause of elevated tryptase
Having HAT changes how doctors interpret other test results
Treatment strategies differ depending on which conditions you have
Treatment Considerations When Conditions Overlap
Having multiple mast cell conditions requires:
More aggressive treatment: Single medications may not be enough
Specialist coordination: You may need an allergist, hematologist, and gastroenterologist working together
Enhanced emergency planning: Higher risk of severe reactions
Regular monitoring: Tryptase levels and symptoms need closer tracking
What This Means for You
If you suspect you have mast cell issues:
Don't self-diagnose: These conditions require specific testing to distinguish
Find an experienced specialist: Not all doctors understand these overlapping conditions
Be patient with testing: Getting the right diagnosis may take time and multiple tests
Keep detailed records: Symptom patterns can help doctors understand which conditions you might have
Red flags that suggest multiple conditions:
Very high tryptase levels (>20 ng/mL) with family history of elevated tryptase
Severe reactions that seem out of proportion to triggers
Multiple family members with similar symptoms
Symptoms that don't respond well to standard MCAS treatments
Understanding these relationships is crucial because having overlapping conditions often means you need more comprehensive treatment and monitoring than someone with just one mast cell disorder.
Diagnosis: Getting Tested for HAT
The Diagnostic Process
Getting diagnosed with HAT typically follows a step-by-step approach:
Step 1: Initial Tryptase Testing Your doctor will order a baseline blood tryptase test. Normal levels are typically under 11.4 ng/mL, but HAT should be considered if levels are 8 ng/mL or higher, especially with symptoms. If your tryptase is elevated (≥11.5 ng/mL), additional testing is needed.
Step 2: Rule Out Other Causes Before testing for HAT, doctors need to check for other causes of elevated tryptase:
Kidney function tests (kidney problems can raise tryptase)
Complete blood count (to check for blood disorders)
Testing for systemic mastocytosis, including the c-KIT D816V mutation
Step 3: HAT Genetic Testing If other causes are ruled out, genetic testing using digital droplet PCR (ddPCR) can definitively diagnose HAT by detecting extra copies of the TPSAB1 gene. This test has 100% sensitivity and 90% specificity.
Special Considerations for Anaphylaxis
If you've had anaphylaxis (severe allergic reactions), doctors use specific formulas to determine if your reaction was genuine. This is especially important for HAT patients because standard criteria may not work correctly.
Standard anaphylaxis confirmation (may not be accurate for HAT patients):
Traditional formula: If your tryptase during a reaction is higher than (1.2 × your baseline tryptase + 2), it suggests true anaphylaxis
HAT-specific anaphylaxis confirmation (more accurate):
New formula: If your (acute tryptase ÷ baseline tryptase) ratio is 1.685 or higher, it indicates anaphylaxis
This formula works better for people with HAT and systemic mastocytosis
It has higher specificity and sensitivity than the traditional formula
Why this matters for HAT patients:
Your baseline tryptase is already elevated, so traditional formulas may miss true anaphylaxis
Some anaphylactic reactions (especially food-induced) may not always cause tryptase to rise significantly
Accurate diagnosis is crucial for proper emergency planning and treatment decisions
Important timing for tryptase testing:
Acute tryptase should be drawn 30 minutes to 2 hours after symptom onset
If you don't have a known baseline, a tryptase level 24 hours after symptoms resolve can serve as your baseline
When to Get Tested
Consider asking about HAT testing if you have:
Baseline tryptase ≥8 ng/mL with unexplained symptoms
Recurrent signs of mast cell activation (flushing, abdominal pain, idiopathic anaphylaxis) without a clear cause
Family history of similar symptoms or elevated tryptase
Suspected systemic mastocytosis but negative c-KIT testing
Severe reactions to insect stings or unexplained anaphylaxis
Multiple chronic symptoms affecting digestion, skin, or energy levels
What Your Results Mean
Negative HAT test: Your doctor may investigate other causes like mastocytosis or kidney problems
Positive HAT test: The number of extra gene copies often correlates with tryptase levels:
1 extra copy: ~15 ng/mL average
2 extra copies: ~24 ng/mL average
4 extra copies: ~37 ng/mL average
Important note: Some people with HAT are completely asymptomatic and don't need genetic testing unless they have symptoms, family planning concerns, or are being evaluated for other medical reasons. Having HAT without symptoms doesn't require any treatment or lifestyle changes.
Treatment Options and Management
Setting realistic expectations: Currently, there's no cure for HAT, and all available treatments are palliative - meaning they help manage symptoms but don't address the underlying genetic cause. While many patients do find significant relief, it's important to understand that treatment often requires patience, trial and error, and ongoing management rather than a quick fix.
Current Treatment Limitations
Before looking at treatment options, it's important to understand the current limitations:
Limited drug options: Beyond antihistamines and a few other medications, there are relatively few proven treatments specifically for HAT
Individual variation: What works well for one person may not work for another, even with similar symptoms
Symptom management vs. cure: All current treatments focus on controlling symptoms rather than correcting the genetic cause
Long-term strategies unclear: For patients with mild to moderate symptoms, optimal long-term management approaches are still being studied
Trial and error process: Finding the right combination of treatments often takes time and multiple attempts
Medications
Important note: Response rates vary significantly between individuals, and these medications provide symptom relief rather than addressing the underlying genetic cause.
Antihistamines: H1 and H2 blockers (like cetirizine and famotidine) can help control allergic symptoms
Often the first-line treatment
Combination therapy (H1 + H2) may be more effective than single agents
May provide significant relief for some patients, minimal relief for others
Mast cell stabilizers: Cromolyn sodium and my favorite ketotifen may help with gastrointestinal symptoms
Can be particularly helpful for intestinal symptoms
Response is variable and may take weeks to see full effects
Omalizumab: This biologic medication, FDA approved for asthma, has shown promising results in studies
Response rates of 100% for urticaria and 80-100% for anaphylaxis in some small studies
However, it's extremely expensive and insurance approval is required
Not effective for all patients or all symptom types
Long-term effects and optimal duration of treatment are still being studied
Lifestyle Management
Trigger identification and avoidance: Keep a detailed symptom diary to identify your personal triggers. Common triggers include:
Physical triggers: Vibration (from exercise equipment, car rides, power tools), mild trauma or pressure, temperature extremes
Emotional triggers: Stress, anxiety, excitement
Food triggers: Alcohol, spicy foods, histamine-rich foods, individual food sensitivities
Environmental triggers: Strong scents, chemicals, allergens
Medical triggers: Certain medications, contrast dyes, surgical procedures
Emergency preparedness: Carry epinephrine auto-injectors if you've had severe reactions
Stress management: Techniques like meditation, deep breathing, or therapy can help reduce mast cell activation
Physical modifications:
Choose low-vibration exercise options if vibration triggers symptoms
Use gentle skincare products and avoid harsh scrubbing
Dress in loose, soft fabrics to minimize skin irritation
Dietary modifications: Some patients benefit from low-histamine diets or avoiding specific personal food triggers
Emerging Treatments
Realistic timeline: While research is promising, most of these treatments are still in early stages and may not be available for several years.
Research is ongoing into new therapies, including:
Lirentelimab : An antibody targeting the Siglec-8 receptor on mast and eosinophil cells. It acts like a "kill switch"
Anti-tryptase antibodies: Could directly neutralize excess tryptase (early research stage)
Targeted therapies: Based on better understanding of mast cell biology (research phase)
Important considerations for emerging treatments:
Clinical trials may have strict eligibility criteria
Safety and efficacy data are still being collected
Timeline from research to availability can be years or decades
Not all experimental treatments will prove effective or safe
Living with HAT: What to Expect
The Variability Challenge
One of the most frustrating aspects of HAT is its unpredictability. Symptoms can vary dramatically between individuals and even within the same person over time. Some people with HAT live normal lives with minimal symptoms, while others experience daily challenges.
Building Your Healthcare Team
Managing HAT often requires a multidisciplinary approach, as complex conditions typically benefit from coordinated care across multiple specialties:
Allergist/Immunologist: For allergy management and tryptase monitoring
Gastroenterologist: For digestive symptoms
Rheumatologist: If you have joint hypermobility or EDS
Pain specialist: For chronic pain management if needed
Mental health provider: For coping strategies and psychological support
Geneticist: For family planning considerations
Having team members who communicate with each other and coordinate your care can lead to better outcomes than seeing specialists in isolation.
The Importance of Self-Advocacy
Because HAT is relatively new to medicine, many healthcare providers aren't familiar with it. Being informed about your condition and bringing research to appointments can be crucial for getting proper care. Bring your records from your immunologist or blood test results to your appointments with new doctors.
Hope for the Future
Research into HAT is advancing rapidly. Scientists are working to better understand:
Why some people with HAT have symptoms while others don't
How tryptase levels correlate with symptom severity
New therapeutic targets for more effective treatments
The relationship between HAT and other chronic conditions
Taking the Next Step
If you suspect you might have HAT, consider these steps:
Track your symptoms: Keep a detailed diary of symptoms, triggers, and patterns
Get baseline tests: Ask your doctor for a blood tryptase level
Find a knowledgeable provider: Seek out an allergist or immunologist familiar with mast cell disorders
Connect with others: Join HAT support groups or mast cell disorder communities for advice and support. Start with the Mast Cell Disease Society
Remember, having a genetic condition like HAT doesn't define you, but understanding it can be the key to finally getting the answers and treatment you've been searching for. Many people report significant improvement in their quality of life once they understand their condition and begin appropriate management.
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About the author:
Harold Pierre, MD, is a board-certified anesthesiologist, board-certified addiction medicine specialist, and a concierge addiction doctor with over 26 years of experience. He is board-certified by the American Board of Anesthesiology and the American Board of Preventive Medicine, and has extension experience managing hormones, pain, addiction, and their intersection. He is licensed in Florida, Texas, Oklahoma, South Carolina, Louisiana, and Arizona. If you are seeking care, you may schedule an appointment with him by calling or texting 918-518-1636. LinkedIn
*Disclaimer: This blog post is for informational purposes only and is not intended as a substitute for professional medical advice, diagnosis, or treatment. Always seek the guidance of your doctor or other qualified health provider with any questions you may have regarding your health or a medical condition before making any changes. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
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