Elevated tryptase levels are crucial markers in diagnosing conditions related to mast cell activation, including anaphylaxis, allergies, and mastocytosis.
High tryptase can indicate severe systemic reactions such as anaphylaxis, where it reflects acute mast cell degranulation often triggered by allergens. In mastocytosis, elevated tryptase levels signify an abnormal proliferation of mast cells, which can lead to more persistent elevations.
Understanding these levels helps diagnose mast cell activation syndrome, especially when there is a significant increase from baseline levels following an allergic reaction, suggesting excessive mast cell activity. Proper assessment of tryptase is essential for managing and diagnosing these conditions, emphasizing its role in indicating the severity and extent of mast cell involvement in allergic responses and systemic disorders.
Low tryptase levels suggest a decreased risk of mast cell activation, mastocytosis, and anaphylaxis.
Standard Range: < 11.0 µg/L
The ODX Range: < 8 µg/L
Low tryptase is associated with a low risk of tryptasemia, mast cell activation, and anaphylaxis.
High tryptase levels are associated with anaphylaxis (Mateja 2022), IgE-mediated allergies, mast cell activation, bone marrow disorders and neoplasms, mastocytosis, hereditary alpha-tryptasemia (HaT), other genetic factors (Valent 2024), chronic inflammatory disease, infection, obesity (Valent 2023), chronic renal failure, parasitic infection, eosinophilic gastroenteritis, eosinophilic esophagitis, inflammation, and cardiovascular disorders (Lee 2020).
Tryptases are serine protease enzymes produced primarily by mast cells and in smaller amounts by basophils. Basal serum tryptase (BST) levels reflect the total body burden of mast cells, while an acute increase over basal (over baseline) indicates severe systemic mast cell activation (MCA) and likely anaphylaxis. Symptoms of anaphylaxis may include severe hypotension, collapse, itching, allergic asthma, edema, skin rash, abdominal pain, nausea, and vomiting (Valent 2024).
Serum tryptase is essential for documenting mast cell activation. Serum tryptase will increase and peak approximately 60 minutes after a triggering event and can remain elevated for three hours or longer. Tryptase elevation in mast cell activation is associated with a drop in blood pressure and symptoms involving the skin, GI tract, respiratory tract, and cardiovascular system. Anaphylaxis involves at least two organ systems and can be severe and even fatal (Gulen 2024).
Severe mast cell activation and anaphylaxis are most commonly associated with IgE-mediated allergies. The 20 + 2 rule is considered the gold standard for evaluating mast cell activation as it takes into account basal and acute tryptase levels. A tryptase increase of at least 20% + 2 µg/L above basal reflects severe mast cell activation and is considered a specific indicator of mast cell activation syndrome (MCAS). Basal tryptase can vary depending on gender, age, kidney function, underlying mast cell-related disorders, including cutaneous and systemic mastocytosis, and genetic factors, such as hereditary alpha-tryptasemia (HaT). However, elevated BST can also be seen with chronic renal failure, parasitic infection, and bone marrow disorders, including myeloproliferative neoplasms and myelodysplastic syndromes. A tryptase above 15 µg/L is likely associated with systemic mast cell activation or genetically elevated baseline tryptase. Aggressive systemic mastocytosis and mast cell leukemia may be associated with tryptase levels of 500-1,000 µg/L and above (Valent 2024).
Elevated tryptase in renal failure is likely due to kidney inflammation and injury due to local mast cells. Tryptase above 17.3 µg/L may be seen with chronic renal failure with levels increasing as kidney function decreases. Anaphylactic shock is associated with markedly elevated tryptase with levels exceeding 74 µg/L, while levels of 15 µg/L and above can be seen with urticaria/angioedema without anaphylaxis. Chronically elevated tryptase can also be associated with acute coronary syndrome, major adverse cardiovascular events, eosinophilic gastroenteritis, and eosinophilic esophagitis characterized by abdominal pain, urticaria, asthma, and arthralgia. Tryptase can promote inflammation, chemotaxis, and fibroblast proliferation (Lee 2020).
Chronic inflammatory disease, chronic infection, and obesity may be associated with basal serum tryptase levels of up to 25 µg/L. Researchers emphasize that serum tryptase must be evaluated in conjunction with symptoms and clinical presentation. An out-of-range level without concurrent symptoms may not be diagnostically relevant. Individual BST should be determined whenever possible. A BST of up to 15 µg/L may be maintained without adverse effects. Diagnosis of mast cell activation syndrome requires an increase in baseline tryptase of at least 120% + 2 µg/L, clinical symptoms, and relief from therapeutic intervention (Valent 2023).
The WHO considers a basal serum tryptase above 20 µg/L a minor criterion for diagnosing systemic mastocytosis, a level that may trigger a bone marrow biopsy for symptomatic individuals. However, genetic testing for hereditary alpha-tryptasemia should be undertaken first to avoid potentially unnecessarily invasive procedures. HaT accounts for most elevations in basal serum tryptase and can magnify hypersensitivity reactions. An individual with a BST of 8 µg/L or more should be worked up for HaT. A review of NIH tryptase genotyping data found that 97.3% of individuals with a BST between 8 and 11.4 µg/L had HaT or clonal mast cell disease (MCD) (Chovanec 2023). A retrospective study of 109 individuals found that 63,8% of those with a BST of 11.5 µg/L or above had HaT, 20.7% had clonal myeloid disorders, and 12.1% had chronic kidney disease (Waters 2022).
Less than 5% of the general population is expected to have a BST above 8 µg/L (Chovanec 2023), while the median BST for individuals without HaT or indolent systemic mastocytosis (ISM) is 4.1 µg/L. Calculating the acute to basal/baseline serum tryptase ratio can help identify anaphylaxis, including in individuals with HaT or ISM. A ratio above 1.685 improves specificity for anaphylaxis when assessing these subjects, and a threshold of 1.374 is comparable to the gold standard of 20% +2 µg/L above basal for identifying severe mast cell activation (Mateja 2022). A threshold ratio of 1.5 or above may be associated with food allergy-related anaphylaxis (Wongkaewpothong 2014). The acute to basal tryptase ratio can be calculated and interpreted at https://triptase-calculator.niaid.nih.gov/ (NIH TRIPTASE).
A comprehensive evaluation of elevated tryptase should include a series of measurements over to time to determine basal/baseline levels and individual variability (Pongdee 2022).
Genetic tryptasemia testing may be indicated in those with a BST of 8 µg/L or above with severe allergic reactions, cutaneous flushing, itching, chronic pain, connective tissue abnormalities, and/or a diagnosis of MCAS, postural orthostatic tachycardia syndrome (dysautonomia), gastroparesis, or Ehlers-Danlos Syndrome (genebygene.com/tryptase).
Serum tryptase guide (Weiler 2019):
Hereditary alpha-tryptasemia: Baseline tryptase above 8 µg/L
Mast cell activation syndrome: Acute tryptase 20% + 2 µg/L above basal
Systemic mastocytosis: Baseline tryptase above 20 µg/L in 75% of cases
AERD (Acute aspirin or NSAID-triggered
systemic anaphylaxis): Acute tryptase 20% + 2 µg/L above basal
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Chovanec, Jack et al. “Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms.” Blood advances vol. 7,9 (2023): 1796-1810. doi:10.1182/bloodadvances.2022007936
Genebygene.com/tryptase Tryptase Copy Number Variation Testing.
Gulen, Theo. “Using the Right Criteria for MCAS.” Current allergy and asthma reports vol. 24,2 (2024): 39-51. doi:10.1007/s11882-024-01126-0 This article is licensed under a Creative Commons Attribution 4.0 International License
Lee, Adrian Y S. “Elevated Serum Tryptase in Non-Anaphylaxis Cases: A Concise Review.” International archives of allergy and immunology vol. 181,5 (2020): 357-364. doi:10.1159/000506199
Mateja, Allyson et al. “Defining baseline variability of serum tryptase levels improves accuracy in identifying anaphylaxis.” The Journal of allergy and clinical immunology vol. 149,3 (2022): 1010-1017.e10. doi:10.1016/j.jaci.2021.08.007
NIH Total Rise in Peripheral Tryptase After a Systemic Event (TRIPTASE) https://triptase-calculator.niaid.nih.gov/
Pongdee, Thanai, and Mariana Castells. “Elevated Tryptase: Conditions and Pitfalls.” The journal of allergy and clinical immunology. In practice vol. 10,9 (2022): 2436-2437. doi:10.1016/j.jaip.2022.06.028
Valent, Peter et al. “The Normal Range of Baseline Tryptase Should Be 1 to 15 ng/mL and Covers Healthy Individuals With HαT.” The journal of allergy and clinical immunology. In practice vol. 11,10 (2023): 3010-3020. doi:10.1016/j.jaip.2023.08.008
Valent, Peter et al. “Reversible Elevation of Tryptase Over the Individual's Baseline: Why is It the Best Biomarker for Severe Systemic Mast Cell Activation and MCAS?.” Current allergy and asthma reports vol. 24,3 (2024): 133-141. doi:10.1007/s11882-024-01124-2
Waters, Aubri M et al. “Elevated Basal Serum Tryptase: Disease Distribution and Variability in a Regional Health System.” The journal of allergy and clinical immunology. In practice vol. 10,9 (2022): 2424-2435.e5. doi:10.1016/j.jaip.2021.12.031
Weiler, Catherine R et al. “AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management.” The Journal of allergy and clinical immunology vol. 144,4 (2019): 883-896. doi:10.1016/j.jaci.2019.08.023
Wongkaewpothong, Patcharaporn et al. “The utility of serum tryptase in the diagnosis of food-induced anaphylaxis.” Allergy, asthma & immunology research vol. 6,4 (2014): 304-9. doi:10.4168/aair.2014.6.4.304