Francesca Crupi1,2,3
Francesco Mannelli- 1Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze, Firenze, Italy
- 2SOD Ematologia, Università di Firenze, AOU Careggi, Firenze, Italy
- 3Centro Ricerca e Innovazione Malattie Mieloproliferative (CRIMM), AOU Careggi, Firenze, Italy
Serum tryptase level has long been used as a biomarker in clinical practice to suspect mast-cell associated disorders. Basal serum tryptase (BST) above 20 ng/ml represents a minor criterion according to WHO and ICC for the diagnosis of systemic mastocytosis (SM) although normal BST value does not exclude the diagnosis. Nevertheless, BST can be elevated also due to non-SM related diseases as well as hereditary alpha-tryptasemia (HαT), an autosomal dominant germline condition that consists in the increase of the number of copies of the TPSAB1 gene encoding the alpha isoform of tryptase. The prevalence of HαT is estimated at around 5% of the general population. Individuals with HαT genotype can be asymptomatic; however, some of them can experience a range of symptoms with a large variability in type and severity, posing a problem of differential diagnosis with SM. The increasing awareness on a potentially SM underlying diverse clinical manifestations has led to excessive BST testing by several specialists, a trend that risks over interpreting some borderline results. The interpretation of elevated BST should thus be carefully appraised in specific clinical contexts on individual basis. This review is intended to examine the existing literature on this topic and offers a guide for interpreting the BST to rationalize the application of invasive diagnostic procedures.
Introduction
Systemic mastocytosis (SM) is a rare haematological disease characterized by the abnormal accumulation and expansion of neoplastic mast cells (MCs) in one or more extracutaneous organs, leading to widely heterogeneous clinical manifestations. The clinical picture is primarily due to the inappropriate release of MC mediators. On the other hand, in advanced variants (AdvSM), massive MCs infiltration and organ dysfunction are observed (1–3).
Due to the frequently blurred presentation of mediator-related symptoms, with large overlap with several non-SM disorders, patients often consult multiple specialists before being diagnosed. A further challenge is represented by the need of invasive diagnostics, inclusive of bone marrow biopsy, to get or reliably exclude the presence of a MC disorder. The reticence of patients, especially when a- or pauci-symptomatic, to undergo such diagnostic path leads clinicians to request tests in PB, i.e., basal tryptase level (BST) and KIT variant, the results of which can often be misleading if not properly considered in the specific setting.
On the other hand, the increasing awareness on a potentially SM underlying diverse clinical manifestations has led to excessive BST testing by several specialists, a trend that risks overinterpreting some borderline results. That is even more relevant considering the growing knowledge of hereditary alpha-tryptasemia (HαT), a germline condition causing increase in BST with not fully elucidated clinical consequences (4–6).
The aim of this work is to provide key indications that should raise suspicion of SM and, specifically, to assess the interpretation of BST with the intent of rationalizing invasive diagnostics. We discuss specific contexts in which to integrate the finding of altered BST, highlighting when it may serve as a red flag for diagnosis, and conversely examining situations in which its value alone should not support diagnostic suspicion.
Updates in diagnosis and subclassification of systemic mastocytosis
Classification and diagnostic criteria of SM were recently refined by the 2022 International Consensus Classification (ICC) (7) and the 5th edition of the World Health Organization (WHO) classification (8) by incorporating the most recent clinical updates and advances especially in molecular genetics (Table 1).
Table 1. Updates in classification of mastocytosis according to 2022 ICC and WHO 5th edition.
SM was categorized into five distinct subtypes: indolent (ISM), smoldering (SSM), aggressive (ASM), associated to another haematological/myeloid neoplasm (SM-AHN), and mast cell leukemia (MCL). Although formally not recognized as an independent subtype, the acknowledgement of peculiar features for well-differentiated SM (WDSM) (9), previously described by the Spanish group (10), led to more comprehensive diagnostic criteria to include these forms, often featured by non-canonical KIT variants. Meanwhile, both classifications have defined bone marrow mastocytosis (BMM), a separate variant according to the WHO (8) and a subtype of ISM according to the ICC (7).
Demonstration of multifocal infiltrates of tryptase- or CD117-positive MCs (≥15 mast cells in aggregates) in BM or other extracutaneous organs remained the major diagnostic criterion. The combination with which major and minor criteria meet a full SM diagnosis differs slightly between ICC and WHO. While the WHO (8) requires one major and one minor criterion, or three minor criteria, the ICC (7) is less stringent as it requires only the major criterion or three minor criteria.
Furthermore, minor criteria have been revised in both classifications. The aberrant MC phenotype now includes also CD30 expression beside the positivity of CD2 and/or CD25. The presence of any KIT-activating variants, in addition to the canonical D816V, has also been considered. As regards BST, in the WHO classification, its value should be adjusted in case of HαT, if known, while for the ICC the value of BST is waived in the context of SM-AHN. B and C findings reflect the burden of the disease and organ impairment, respectively, and continue to be the key for establishing an accurate subclassification of SM clinical variants. While C-findings remained essentially unchanged, B-findings have been slightly modified, as WHO has embedded a variant allele frequency (VAF) >10% of the KIT D816V variant (8), and ICC has simplified the definition of cytopenia (not meeting the criteria for C-findings) or cytosis (7).
Hereditary alpha tryptasemia and mastocytosis: a clinical interaction?
Tryptase production depends on the regulation of four genes, among which TPSAB1 and TPSB2 encode the two major secreted isoforms, that are α- and β-tryptase. Around a decade ago, Lyons et al. (4, 11) first described a genetic trait known as HαT, an autosomal dominant condition resulting from the multiplication of the TPSAB1 gene (Figure 1) encoding the alpha isoform of tryptase. Further studies have elucidated as the number of TPSAB1 copies determined an increase in α-tryptase levels, on turn ultimately leading to elevated BST, each additional copy number adding approximately 9–10 ng/ml to the basal BST levels (12, 13). The increased production of α-tryptase leads to enhanced formation of α/β-tryptase heterotetramers. Recent studies have shown that in individuals with HαT, these heterotetramers increase vascular permeability by cleaving and activating protease-activated receptor-2 (PAR2) on endothelial cells, resulting in increased vascular leakage (14, 15). Furthermore, heterotetramers have been shown to cleave a subunit of the epidermal growth factor-like module-containing mucin-like hormone receptor-like 2 (EMR2) in vivo thus causing a decrease in the threshold for vibration-induced MC degranulation (16). These factors have been hypothesized to contribute to hypotension and other systemic reactions in subjects with HαT, potentially accounting for a higher prevalence of HαT among individuals with grade IV Muller anaphylaxis compared to those with less severe forms of anaphylaxis (12, 17). Such correlations are still a matter of debate and need confirmation in larger datasets.
Figure 1. Possible combinations of genotypes for TPSB2 and TPSAB1. Adapted from Sordi et al. JACI, 2023.
Of interest, the presence of HαT has been investigated as a potential additive trigger for clinical manifestations in SM patients, as severe episodes were twice more frequent in individuals with both SM and HαT than in those with SM but without HαT (17, 18). In spite of a lower burden of disease, HαT+ SM patients displayed a propensity to higher rate of mediator-related symptoms, that supported the role of HαT as a clinical amplifier in this clinical context (19).
These aspects must be considered given the significant prevalence of HαT in the general population, estimated at around 5% (20, 21) and in patients with SM, where it can reach up to 12%–20% (17, 19, 22, 23).
Tryptase in suspected SM: the interference by HαT
As anticipated, BST is used as one of the main biomarkers in the suspicion of SM and represents a minor criterion for diagnosis when its value exceeds 20 ng/ml (7, 8).
BST normal values have been established in the range of 1 to 11.5 ng/ml (20, 24), maintaining a consistent level in healthy individuals due to the balance between storage and release from MCs (25, 26). However, several reasons other than SM can increase BST, including pregnancy, chronic kidney disease, other myeloid neoplasms and HαT (27).
The need for BST testing and its interpretation thus requires a critical and context-dependent approach for making it a reliable diagnostic tool, while over testing and out-of-context mere consideration of abnormal values risk to be misleading.
In the work-up of anaphylaxis, BST levels raise significantly after the episode due to the considerable release by MC and is expected to turn to the baseline value at least after 24 h (28, 29). The 2012 proposal for mast cell activation syndrome (MCAS) by Valent et al. (30) recommends that an increase in BST levels of more than “20% + 2” (measured within 4 h from symptom onset) should be considered highly suggestive of MCAS. This so-called “20% + 2 formula” was subsequently validated by several studies (31–33). However, a recent study suggested this approach to be not sufficiently performant when applied to patients with HαT and/or SM. These authors proposed an acute tryptase value/BST ratio of 1.685 to improve specificity while maintaining high sensitivity (34). Based on these premises, the need for repeating the tryptase measurement at a reasonable distance from symptom onset, at least two or more days after the event, has clearly emerged (35). If BST value remains persistently elevated and other possible causes are excluded, SM should be suspected, especially if a REMA score of ≥2 is present (36).
The need for operational thresholds for BST (i.e., >20 ng/ml and >200 ng/ml as a minor diagnostic criterion for SM and a B-finding for SSM, respectively) is challenged by the potential presence of an underlying HαT, as it has been well established that the copy number of the TPSAB1 gene correlates with BST values. A recent proposal (10), also received by the 5th WHO classification (8), suggested normalizing BST value by dividing it by the number of extra copies of the TPSAB1 gene, encoding alpha tryptase, plus one. In addition to this, three other methods of correction have been proposed (5, 13, 23) (Table 2). All these attempts to adjust the value of BST for HαT are empirical and still to be validated prospectively. In the meantime, to draw a clear line in this debate, the European Competence Network on Mastocytosis (ECNM) and the American Initiative in Mast Cell Diseases (AIM) established that the normal BST range should be set at 1–15 ng/ml, including asymptomatic individuals with HαT (35). This proposal thus recommends that, in asymptomatic patients, BST values up to 15 ng/ml should be considered normal to avoid unnecessary referrals and investigations, as well as unjustified worries in interested individuals.
Table 2. Available formulae for normalize basal serum tryptase (BST) value according to HαT genotype.
Analysis of KIT D816V variant in peripheral blood
Over 90% of SM cases harbor the KIT D816V variant, that leads to the constitutive activation of the receptor tyrosine kinase CD117, on turn responsible for MC survival, proliferation, and differentiation (37, 38). Although KIT variants detection has represented a technical challenge for years due to the low fraction of pathological cells in most SM cases, significant improvements have been made in recent years. Several techniques have been developed with progressive improvement in sensitivity. Sanger sequencing was the first methodology used, affected by a low sensitivity (around 10%–20%). This was followed by the implementation of RT-PCR, which offers high sensitivity (0.05%) but lacks standardization due to the absence of a universally accepted calibrator. Peptide nucleic acid (PNA)-mediated PCR offers high specificity by blocking the amplification of wild-type sequences but has limited sensitivity in detecting low-frequency mutations (39). Therefore, it was subsequently replaced by allele-specific oligonucleotide quantitative PCR (ASO-qPCR), which allows for highly sensitive and quantitative detection of KIT D816V variant, making it more suitable in samples with a low mutant allele burden (40). Another standardized method for KIT mutation detection is droplet digital PCR (ddPCR), which partitions the target nucleic acid into thousands of nanoliter-sized droplets to enable highly accurate, absolute quantification of DNA molecules without the need for calibration standards (41). Currently, the gold standard techniques are ASO-qPCR or, preferably, droplet digital PCR (ddPCR), both of which achieve a sensitivity of 0.001% (42). Next-generation sequencing (NGS) provides a sensitivity of 1%–5%; however, it remains valuable for detecting rare, non-canonical KIT-activating variants (38).
Due to the lack of standardization and the known low variant burden in patients with ISM, it has been repeatedly argued that variant analysis should not be performed on peripheral blood (PB), as a negative result cannot reliably exclude the diagnosis of SM (43, 44). Nonetheless, the increased sensitivity of the methodology has shown comparable results for mutational testing on BM and PB, with a discordance rate ranging from 5% to 10% (40, 42, 45, 46). Additionally, in a recent post hoc analysis of the PIONEER trial on the use of avapritinib in symptomatic ISM, the central ddPCR assay method detected the KIT D816V variant in 37/39 (95%) of PB samples compared with 11/39 (28%) analyzed by NGS and 30/39 (80%) of PB samples analyzed locally (47), a pattern that confirms a linearity between the sensitivity of the technique and the rate of positivity. Therefore, if one wishes to initiate a patient into diagnostic procedures in this context, an accurate knowledge of the local performance of available methodologies is necessary.
A further interaction regards the correlation between BST levels and differences in detecting KIT variants in PB. The negative predictive value was approximately 40% in patients with BST levels between 5 and 30 ng/ml (46). In a recent retrospective study, the sensitivity of diagnostic assays for KIT D816V was further refined according to specific BST thresholds (≥11.5 ng/ml, ≥20 ng/ml and BST elevated due to HαT genotype) and REMA score ≥ 2. Sensitivity of PB testing was higher for BST ≥ 11.5 ng/ml and BST elevated based on genotype, while specificity was highest for BST elevated based on genotype (48). Similarly, Navarro et al. found a correlation between the percentage of KIT D816V-mutated cells in both PB and BM and BST levels (49).
However, tryptase represents only a minor diagnostic criterion, and a normal BST value does not exclude a diagnosis of SM, as evidenced by patients with BMM, who often present with normal BST levels (50–52). This highlights the importance of considering situations highly suspected for SM in which a direct bone marrow evaluation, including KIT variants analysis, should be preferred regardless of BST value (i.e., REMA score ≥ 2, MIS onset in adulthood).
The incorporation of tryptase level in scoring models for SM
Only a small subset of SM patients (approximately 10%) present with an aggressive variant, with clinical manifestations primarily dictated by the presence of C-findings (53). In these cases, the diagnostic challenge stems from the clinical overlap with other diseases, obviously enhanced by the rarity of the disease, which can divert initial investigations towards more common causes. However, once SM is suspected, the high burden of MC infiltration, along with generally elevated tryptase levels, make the diagnosis relatively simple to establish.
Conversely, most cases of ISM present a clinical picture dominated by mediator-related symptoms, including cutaneous, gastrointestinal, musculoskeletal, and neurocognitive manifestations (54–56). When mastocytosis in the skin (MIS) appears in adult patients, it is strongly associated with a systemic form, unlike in pediatric cases, where skin lesions spontaneously regress during puberty in the vast majority of patients (57, 58). Additionally, greater than 50% of patients experience severe anaphylaxis, especially in reaction to Hymenoptera venom (59, 60). On the other hand, the prevalence on SM sets around 10% in patients experiencing anaphylaxis after Hymenoptera sting (21, 61) and 5% of all cases of anaphylaxis (62, 63). The REMA score, developed by the Spanish Network on Mastocytosis, is a diagnostic tool capable of predicting the probability of SM in patients with anaphylaxis and include BST as one of the key variables (36).
The NICAS score added the analysis of KIT D816V in PB, as assessed by ASO-qPCR, to the already existing parameters (slightly modifying clinical findings and BST levels) (64). In this model, the demonstration of a clonal disease in PB by the detection of KIT variant is clearly dominant when positive, but its incorporation is far less useful with negative results.
The ECNM proposed two algorithms for the recognition of underlying SM disorders in patient presenting with anaphylaxis. For adult patients with MIS, BM biopsy is generally recommended regardless of other findings. On the other hand, for patients without MIS, a BM biopsy is recommended when BST is greater than 25–30 ng/ml, when REMA score is ≥2, or when a KIT D816V variant is detected in PB (62).
Frequently, the clinical picture can be characterized by other, less specific manifestations, as gastrointestinal symptoms (i.e., epigastralgia, abdominal pain, meteorism, and diarrhea) fatigue, neurologic and/or neuropsychiatric manifestations (including depression, anxiety, headaches, and cognitive impairment such as lack of concentration). In all these cases, the recommendations for testing BST are not standardized (53–55, 65).
Several scoring systems (Table 3) have been developed to predict clonality in cases that are less characteristic than anaphylaxis. Fuchs et al. proposed a model for patients with MIS incorporating BST values as well as the presence of mediator-related symptoms (66). Among these, osteoporosis is probably the most easily identifiable and showed a prevalence of 15%–30% (67, 68). These data have justified the development of a score specific for this setting (OSTEO-score) with increased sensitivity when BST levels were corrected for the presence of HαT (69).
Table 3. Summary of the scoring systems evaluated in this review.
Of interest, a recent study addressed the issue of distinguishing SM patients from individuals with HαT, in view of the described overlap of some clinical symptoms. The study showed that the urinary metabolites of mediators (i.e., methylhistamine, prostaglandin F2-alpha, and leukotriene E4) were higher in SM cases than in subjects with symptomatic HαT. Although promising for their potential aid in a debated matter, these results require further validation (70).
Conclusions
The growing knowledge of HαT and eventually the increasingly wider use of genotyping in clinical practice could contribute to improving the diagnosis of SM, downsizing the confounding factor of high BST levels in patients with an unclear presentation of a clonal MC disorder. Moreover, the increased sensitivity of the diagnostic assays for KIT D816V variant is expected to improve the diagnostic algorithm in SM, especially in patients with equivocal symptoms, allowing to spare invasive procedures such as bone marrow biopsy. In this context, patients with a low REMA score (i.e., <2), no clear mediator-related symptoms (also according to the other predictive scores), and elevated BST alone could benefit from an initial evaluation of the KIT D816V variant in PB, along with the investigation of the HαT genotype (48). With negative KIT result and confirmation of HαT genotype, the suspicion of SM could be reasonably excluded (Figure 2).
Figure 2. Basic algorithm for patients with suspected SM. In patients with REMA score ≥2 and/or typical skin lesions and/or suggestive signs of SM, a BM examination should be performed to confirm or exclude SM regardless of BST value. In absence of these findings within BST value >15 ng/ml, we suggested an initial evaluation of KIT D816V in PB and (if available) HαT testing. When KIT D816V is detectable, BM study is recommended. BST, basal tryptase level; REMA, red Espanola de Mastocitosis; MIS, mastocytosis in the skin; SM, systemic mastocytosis; HαT, hereditary alpha tryptasemia; TPSAB1, tryptase alpha/beta 1; PB, peripheral blood; BM, bone marrow.
Nevertheless, despite the undisputable increase in accuracy in detecting KIT variants in PB, major limitations remain. Several studies have shown that patients with a very low disease burden, who usually fail to meet a full diagnosis of SM and are classified as clonal mast cell activation syndrome (MMAS/cMCAS), display the greatest discrepancies in KIT analysis between BM and PB (49). These cases remain a grey zone that deserves further clarification because of the potentially relevant clinical implications, in terms of prevention of anaphylaxis, prescription of epinephrine and lifelong allergen-specific immunotherapy. A rationale use of BST and genetic testing in the different clinical settings is the premise to balance the application of invasive diagnostics to the actual probabilities of underlying SM disorders.
Author contributions
FC: Conceptualization, Writing – original draft. JC: Writing – original draft. FM: Conceptualization, Writing – review & editing.
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References
1. Leguit RJ, Wang SA, George TI, Tzankov A, Orazi A. The international consensus classification of mastocytosis and related entities. Virchows Arch. (2023) 482:99–112. doi: 10.1007/s00428-022-03423-3
2. Ustun C, Keklik Karadag F, Linden MA, Valent P, Akin C. Systemic mastocytosis: current Status and challenges in 2024. Blood Adv. (2025) 9(9):2048–62. doi: 10.1182/bloodadvances.2024012612
3. Valent P, Akin C, Sperr WR, Horny H-P, Arock M, Metcalfe DD, et al. New insights into the pathogenesis of mastocytosis: emerging concepts in diagnosis and therapy. Annu Rev Pathol Mech Dis. (2023) 18:361–86. doi: 10.1146/annurev-pathmechdis
4. Lyons JJ. Hereditary alpha tryptasemia: genotyping and associated clinical features. Immunol Allergy Clin North Am. (2018) 38:483–95. doi: 10.1016/J.IAC.2018.04.003
5. Lyons JJ. Inherited and acquired determinants of serum tryptase levels in humans. Ann Allergy Asthma Immunol. (2021) 127:420–6. doi: 10.1016/j.anai.2021.06.019
6. Beyens M, Toscano A, Ebo D, Gülen T, Sabato V. Diagnostic significance of tryptase for suspected mast cell disorders. Diagnostics. (2023) 13:3662. doi: 10.3390/diagnostics13243662
7. Arber DA, Orazi A, Hasserjian RP, Borowitz MJ. International consensus classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data. Blood. (2022) 140:1200–28. doi: 10.1182/blood.2022015850
8. Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the world health organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. (2022) 36:1703–19. doi: 10.1038/s41375-022-01613-1
9. Álvarez-Twose I, Jara-Acevedo M, Morgado JM, García-Montero A, Sánchez-Muñoz L, Teodósio C, et al. Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis. J Allergy Clin Immunol. (2016) 137:168–178.e1. doi: 10.1016/j.jaci.2015.05.008
10. Valent P, Akin C, Hartmann K, Alvarez-Twose I, Brockow K, Hermine O, et al. Updated diagnostic criteria and classification of mast cell disorders: a consensus proposal. Hemasphere. (2021) 5:E646. doi: 10.1097/HS9.0000000000000646
11. Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. (2016) 48:1564–9. doi: 10.1038/ng.3696
12. Wu R, Lyons JJ. Hereditary alpha-tryptasemia: a commonly inherited modifier of anaphylaxis. Curr Allergy Asthma Rep. (2021) 21:33. doi: 10.1007/s11882-021-01010-1
13. Chovanec J, Tunc I, Hughes J, Halstead J, Mateja A, Liu Y, et al. Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms. Blood Adv. (2023) 7:1796–810. doi: 10.1182/bloodadvances.2022007936
14. Le QT, Lyons JJ, Naranjo AN, Olivera A, Lazarus RA, Metcalfe DD, et al. Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia. J Exp Med. (2019) 216:2348–61. doi: 10.1084/jem.20190701
15. Shin H, Lyons JJ. Alpha-tryptase as a risk-modifying factor for mast cell–mediated reactions. Curr Allergy Asthma Rep. (2024) 24:199–209. doi: 10.1007/s11882-024-01136-y
16. Sprinzl B, Greiner G, Uyanik G, Arock M, Haferlach T, Sperr WR, et al. Genetic regulation of tryptase production and clinical impact: hereditary alpha tryptasemia, mastocytosis and beyond. Int J Mol Sci. (2021) 22:1–22. doi: 10.3390/ijms22052458
17. Lyons JJ, Chovanec J, O’Connell MP, Liu Y, Šelb J, Zanotti R, et al. Heritable risk for severe anaphylaxis associated with increased α-tryptase–encoding germline copy number at TPSAB1. J Allergy Clin Immunol. (2021) 147:622–32. doi: 10.1016/j.jaci.2020.06.035
18. Li JY, Ryder CB, Zhang H, Cockey SG, Hyjek E, Moscinski LC, et al. Review and updates on systemic mastocytosis and related entities. Cancers. (2023) 15:5626. doi: 10.3390/cancers15235626
19. Sordi B, Vanderwert F, Crupi F, Gesullo F, Zanotti R, Bonadonna P, et al. Disease correlates and clinical relevance of hereditary α-tryptasemia in patients with systemic mastocytosis. J Allergy Clin Immunol. (2023) 151:485–493.e11. doi: 10.1016/j.jaci.2022.09.038
20. Waters AM, Park HJ, Weskamp AL, Mateja A, Kachur ME, Lyons JJ, et al. Elevated basal serum tryptase: disease distribution and variability in a regional health system. J Allergy Clin Immunol Pract. (2022) 10:2424–2435.e5. doi: 10.1016/j.jaip.2021.12.031
21. Bonadonna P, Nalin F, Olivieri F. Hereditary alpha-tryptasemia. Curr Opin Allergy Clin Immunol. (2022) 22:277–82. doi: 10.1097/ACI.0000000000000849
22. Greiner G, Sprinzl B, Górska A, Ratzinger F, Gurbisz M, Witzeneder N, et al. Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis. Blood. (2021) 137:238–47. doi: 10.1182/BLOOD.2020006157
23. Chollet MB, Akin C. Hereditary alpha tryptasemia is not associated with specific clinical phenotypes. J Allergy Clin Immunol. (2022) 149:728–735.e2. doi: 10.1016/j.jaci.2021.06.017
24. Francois F, Mauff BL, Waeckel L, de Chaisemartin L, Tabary T, Dumontet E, et al. Basal serum tryptase: a critical reconsideration of reference values. Allergy. (2023) 78:3003–6. doi: 10.1111/all.15790
25. Schwartz LB. Tryptase from human mast cells: biochemistry, biology and clinical utility. Monogr Allergy. (1990) 27:90–113.2084539
26. Schwartz LB, Min H-K, Ren S, Xia H-Z, Hu J, Zhao W, et al. Tryptase precursors are preferentially and spontaneously released, whereas mature tryptase is retained by HMC-1 cells, Mono-Mac-6 cells, and human skin-derived mast cells 1. J Immunol. (2003) 170:5667–73. doi: 10.4049/jimmunol.170.11.5667
27. Lee AYS. Elevated serum tryptase in non-anaphylaxis cases: a concise review. Int Arch Allergy Immunol. (2020) 181:357–64. doi: 10.1159/000506199
28. Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. (1987) 316:1622–6. doi: 10.1056/NEJM198706253162603
29. Schwartz LB, Yunginger JW, Miller J, Bokhari R, Dull D. Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis. J Clin Invest. (1989) 83:1551–5. doi: 10.1172/JCI114051
30. Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol. (2012) 157:215–25. doi: 10.1159/000328760
31. Baretto RL, Beck S, Heslegrave J, Melchior C, Mohamed O, Ekbote A, et al. Validation of international consensus equation for acute serum total tryptase in mast cell activation: a perioperative perspective. Allergy. (2017) 72:2031–4. doi: 10.1111/all.13226
32. Vitte J, Amadei L, Gouitaa M, Mezouar S, Zieleskiewicz L, Albanese J, et al. Paired acute-baseline serum tryptase levels in perioperative anaphylaxis: an observational study. Allergy. (2019) 74:1157–65. doi: 10.1111/all.13752
33. Valent P, Bonadonna P, Hartmann K, Broesby-Olsen S, Brockow K, Butterfield JH, et al. Why the 20%+2 tryptase formula is a diagnostic gold standard for severe systemic mast cell activation and mast cell activation syndrome. Int Arch Allergy Immunol. (2019) 180:44–51. doi: 10.1159/000501079
34. Mateja A, Wang Q, Chovanec J, Kim J, Wilson KJ, Schwartz LB, et al. Defining baseline variability of serum tryptase levels improves accuracy in identifying anaphylaxis. J Allergy Clin Immunol. (2022) 149:1010–1017.e10. doi: 10.1016/j.jaci.2021.08.007
35. Valent P, Hoermann G, Bonadonna P, Hartmann K, Sperr WR, Broesby-Olsen S, et al. The normal range of baseline tryptase should be 1 to 15 ng/ml and covers healthy individuals with HαT. J Allergy Clin Immunol Pract. (2023) 11:3010–20. doi: 10.1016/j.jaip.2023.08.008
36. Alvarez-Twose I, González-de-Olano D, Sánchez-Muñoz L, Matito A, Morgado J, Jara-Acevedo M, et al. Validation of the REMA score for predicting systemic mastocytosis in patients with mast cell activation disorders. J Allergy Clin Immunol. (2011) 127:AB248–AB248. doi: 10.1016/j.jaci.2010.12.988
37. Valent P, Spanblochl E, Sperr W, Sillaber C, Zsebo K, Agis H, et al. Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell Factor/kit-ligand in long-term culture. Blood. (1992) 80:2237–45. doi: 10.1182/BLOOD.V80.9.2237.2237
38. Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G, Escribano L, et al. KIT Mutation analysis in mast cell neoplasms: recommendations of the European competence network on mastocytosis. Leukemia. (2015) 29:1223–32. doi: 10.1038/leu.2015.24
39. Kristensen T, Vestergaard H, Møller MB. Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay. J Mol Diagn. (2011) 13:180–8. doi: 10.1016/j.jmoldx.2010.10.004
40. Jara-Acevedo M, Teodosio C, Sanchez-Muñoz L, Álvarez-Twose I, Mayado A, Caldas C, et al. Detection of the KIT D816V mutation in peripheral blood of systemic mastocytosis: diagnostic implications. Mod Pathol. (2015) 28:1138–49. doi: 10.1038/modpathol.2015.72
41. Huggett JF, Cowen S, Foy CA. Considerations for digital PCR as an accurate molecular diagnostic tool. Clin Chem. (2015) 61:79–88. doi: 10.1373/clinchem.2014.221366
42. Greiner G, Gurbisz M, Ratzinger F, Witzeneder N, Simonitsch-Klupp I, Mitterbauer-Hohendanner G, et al. Digital PCR: a sensitive and precise method for KIT D816V quantification in mastocytosis. Clin Chem. (2018) 64:547–55. doi: 10.1373/clinchem.2017.277897
43. Pardanani A. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage). Blood. (2013) 121:3085–94. doi: 10.1182/blood-2013-01-453183
44. Valent P, Akin C, Escribano L, Födinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Invest. (2007) 37:435–53. doi: 10.1111/j.1365-2362.2007.01807.x
45. Kristensen T, Vestergaard H, Bindslev-Jensen C, Mortz CG, Kjaer HF, Ollert M, et al. Prospective evaluation of the diagnostic value of sensitive KIT D816V mutation analysis of blood in adults with suspected systemic mastocytosis. Allergy. (2017) 72:1737–43. doi: 10.1111/all.13187
46. De Puysseleyr LP, Ebo DG, Elst J, Faber MA, Poorten MV, Van Gasse AL, et al. Diagnosis of primary mast cell disorders in anaphylaxis: value of KIT D816V in peripheral blood. J Allergy Clin Immunol Pract. (2021) 9:3176–3187.e3. doi: 10.1016/j.jaip.2021.04.062
47. George TI, Hoehn G, Lin H-M, Miller S, Akin C. Increased detection of KIT D816V mutation in peripheral blood samples from patients with indolent systemic mastocytosis (ISM) in the phase 2 pioneer study using a high sensitivity droplet digital (dd) PCR assay compared with next generation sequencing (NGS). Blood. (2020) 136:7–8. doi: 10.1182/blood-2020-136930
48. Mcmurray JC, Pacheco CS, Schornack BJ, Sun X, Brunader JA, Scott AE, et al. Standardized indolent systemic mastocytosis evaluations across a health care system: implications for screening accuracy. Blood. (2024) 144(4):408–19. doi: 10.1182/blood.2023023347
49. Navarro-Navarro P, Álvarez-Twose I, Pérez-Pons A, Henriques A, Mayado A, García-Montero AC, et al. KIT D816v mutation in blood for the diagnostic screening of systemic mastocytosis and mast cell activation syndromes. Allergy. (2023) 78:1347–59. doi: 10.1111/all.15584
50. Álvarez-Twose I, Zanotti R, González-De-Olano D, Bonadonna P, Vega A, Matito A, et al. Nonaggressive systemic mastocytosis (SM) without skin lesions associated with insect-induced anaphylaxis shows unique features versus other indolent SM. J Allergy Clin Immunol. (2014) 133:520–8. doi: 10.1016/j.jaci.2013.06.020
51. Zanotti R, Bonifacio M, Lucchini G, Sperr WR, Scaffidi L, van Anrooij B, et al. Refined diagnostic criteria for bone marrow mastocytosis: a proposal of the European competence network on mastocytosis. Leukemia. (2022) 36:516–24. doi: 10.1038/s41375-021-01406-y
52. Zanotti R, Bonadonna P, Bonifacio M, Artuso A, Schena D, Rossini M, et al. Isolated bone marrow mastocytosis: an underestimated subvariant of indolent systemic mastocytosis. Haematologica. (2011) 96:482–4. doi: 10.3324/haematol.2010.034553
53. Pardanani A. Systemic mastocytosis in adults: 2023 update on diagnosis, risk stratification and management. Am J Hematol. (2023) 98:1097–116. doi: 10.1002/ajh.26962
54. Pyatilova P, Bernstein JA, Aulenbacher F, Borges MS, Dimitrijević S, Hoehn G, et al. The diagnostic workup for systemic mastocytosis differs from consensus recommendations: results of a worldwide survey. World Allergy Organ J. (2023) 16:100838. doi: 10.1016/j.waojou.2023.100838
55. Pyatilova P, Akin C, Alvarez-Twose I, Arock M, Bonadonna P, Brockow K, et al. Refined treatment response criteria for indolent systemic mastocytosis proposed by the ECNM-AIM consortium. J Allergy Clin Immunol Pract. (2022) 10:2015–24. doi: 10.1016/j.jaip.2022.05.037
56. Jennings S, Russell N, Jennings B, Slee V, Sterling L, Castells M, et al. The mastocytosis society survey on mast cell disorders: patient experiences and perceptions. J Allergy Clin Immunol Pract. (2014) 2:70–6. doi: 10.1016/j.jaip.2013.09.004
57. Kettelhut BV, Metcalfe DD. Pediatric mastocytosis. Ann Allergy. (1994) 73:197–202; quiz 202–7.8092552
58. Berezowska S, Flaig MJ, Ruëff F, Walz C, Haferlach T, Krokowski M, et al. Adult-onset mastocytosis in the skin is highly suggestive of systemic mastocytosis. Mod Pathol. (2014) 27:19–29. doi: 10.1038/modpathol.2013.117
59. Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy. (2008) 63:226–32. doi: 10.1111/j.1398-9995.2007.01569.x
60. Matito A, Alvarez-Twose I, Morgado JM, Sánchez-Muñoz L, Orfao A, Escribano L. Anaphylaxis as a clinical manifestation of clonal mast cell disorders. Curr Allergy Asthma Rep. (2014) 14:450. doi: 10.1007/s11882-014-0450-8
61. Bonadonna P, Zanotti R, Pagani M, Caruso B, Perbellini O, Colarossi S, et al. How much specific is the association between hymenoptera venom allergy and mastocytosis? Allergy. (2009) 64:1379–82. doi: 10.1111/j.1398-9995.2009.02108.x
62. Valent P, Akin C, Bonadonna P, Hartmann K, Brockow K, Niedoszytko M, et al. Proposed diagnostic algorithm for patients with suspected mast cell activation syndrome. J Allergy Clin Immunol Pract. (2019) 7:1125–1133.e1. doi: 10.1016/j.jaip.2019.01.006
63. González-de-Olano D, Esteban-López MI, Alonso-Díaz-de-Durana MD, González-Mancebo E, Prieto-García A, Gandolfo-Cano M, et al. Frequency of clonal mast cell diseases among patients presenting with anaphylaxis: a prospective study in 178 patients from 5 tertiary centers in Spain. J Allergy Clin Immunol Pract. (2019) 7:2924–2926.e1. doi: 10.1016/j.jaip.2019.05.027
64. Carter MC, Desai A, Komarow HD, Bai Y, Clayton ST, Clark AS, et al. A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis. J Allergy Clin Immunol. (2018) 141:180–188.e3. doi: 10.1016/j.jaci.2017.05.036
65. Vermeiren MR, Kranenburg LW, van Daele PLA, Gerth van Wijk R, Hermans MAW. Psychological functioning and quality of life in patients with mastocytosis. Ann Allergy Asthma Immunol. (2020) 124:373–378.e2. doi: 10.1016/j.anai.2019.12.020
66. Fuchs D, Kilbertus A, Kofler K, Bubnoff v, Shoumariyeh N, Zanotti K, et al. Scoring the risk of having systemic mastocytosis in adult patients with mastocytosis in the skin. J Allergy Clin Immunol Pract. (2021) 9:1705–1712.e4. doi: 10.1016/j.jaip.2020.12.022
67. van der Veer E, van der Goot W, de Monchy JGR, Kluin-Nelemans HC, van Doormaal JJ. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy. (2012) 67:431–8. doi: 10.1111/j.1398-9995.2011.02780.x
68. Degboé Y, Eischen M, Nigon D, Apoil P-A, Mailhol C, Tournier E, et al. Prevalence and risk factors for fragility fracture in systemic mastocytosis. Bone. (2017) 105:219–25. doi: 10.1016/j.bone.2017.09.005
69. Tanasi I, Crosera L, Taus F, Orsolini G, Adami G, Olivieri F, et al. Underlying systemic mastocytosis in patients with unexplained osteoporosis: score proposal. Bone. (2024) 186:117141. doi: 10.1016/j.bone.2024.117141
Keywords: tryptase, mastocytosis, mast cell disorder, KIT, tryptasemia
Citation: Crupi F, Caroprese J and Mannelli F (2025) Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis. Front. Allergy 6:1592001. doi: 10.3389/falgy.2025.1592001
Received: 11 March 2025; Accepted: 25 April 2025;
Published: 12 May 2025.
Edited by:
Peter Kopac, University Clinic of Pulmonary and Allergic Diseases Golnik, SloveniaReviewed by:
Nathalie Acevedo, University of Cartagena, ColombiaMatija Rijavec, University Clinic of Pulmonary and Allergic Diseases Golnik, Slovenia
Copyright: © 2025 Crupi, Caroprese and Mannelli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Francesco Mannelli, ZnJhbmNlc2NvLm1hbm5lbGxpQHVuaWZpLml0