Basal serum tryptase: A critical reconsideration of reference values (2023)

Basal serum tryptase in 681 healthy adults. Mathematical analysis reveals a double population of low (2–8 μg/L) or high producers (8–11.4 μg/L) with a threshold at 8 μg/L. The reference level of basal serum tryptase (BST) released by mast cells is still controversial because of the variability1, 2 in the constitutive secretion of α-tryptase. Indeed, an autosomal TPSAB1 gene replication, eventually associated with hereditary α-tryptasemia (HαT) has been observed in more than 5% of the population worldwide.3, 4 So far, ImmunoCAP™ Tryptase (ThermoFisher Scientific) is the only in vitro diagnostic kit available that measures total tryptase in human serum or plasma. The manufacturer has defined a 95th percentile reference level at 11.4 μg/L but numerous studies have reported that the BST distribution in the general population is not Gaussian and that most people display BST values much lower than 10 μg/L5 or even 8 μg/L.6 In accordance, the manufacturer has lowered its reference value but the significance of values between 8.0 and 11.4 μg/L still remains to be clarified. In a preliminary retrospective study on 831 samples analyzed in one center for diagnostic purposes (681 adults; mean age 56.0 + 16.7 years; 57.8% females) confirmed that the median BST was 4.97 [2.08; 9.48] μg/L (5th and 95th percentiles), that BST values were independent of age or gender and that they did not follow a Gaussian distribution (Table 1). Interestingly, 6 (0.9%) out of the 681 adults had a BST below the limit of detection. 4.97 [2.08; 17.4] (57.8%) 4.79 [2.1; 16.6] (42.2%) 5.47 [2.2; 17.7] NS Children teenagers (42.7%) 4.21 [2.1; 11.5] (57.3%) 5.06 [2.2; 19.1] NS 4.4 [2.0; 9.0] (56.5%) 4.6 [2.2; 8.8] (43.5%) 4.7 [2.0; 9.1] NS 4.0 [1.7; 10.2] NS 2 (3.7%) [14.9–20.0] 55.5 ± 24.4 (18–95) 3.4 [1.9; 7.3] NS (48.1%) 4.0 [2.0; 7.0] (51.9%) 3.4 [18; 10.8] NS U100 (6) U250 (50) 15.8 ± 1.62 (10–117.9) 2.6 [1.2–5.3] p < .001 (46.4%) 2.7 [1.2; 5.3] (53.6%) 2.6 [1.3; 5.1] NS 5.0 [3.2; 11.1] p = 0.0184 (20%) 5.0 [4.3-7.5] (80%) 5.0 [3.2; -11.5] NS 1(6.7%) [13,0] U250 6.0 [2.5; 13.2] p < 0.0001 (56.9%) 5.3 [2.6-9.0] NS (43.1%) 6.1 [4.2; 11.1] p = .034 2 (3.9%) [11.6–13.2] This is why we intended to clarify the reference values gathering BST data measured in healthy donors (HD) in multiple laboratories. From seven independent laboratories, a total of 636 serum BST (49.3 ± 17.9 years old, 45.6% females) was analyzed using a Phadia 250™. Median serum BST was 4.40 [2.03; 9.0] μg/L and their distribution was not Gaussian. Seven (1.1%) BST values were greater than 11.4 μg/L and three (0.47%) were undetectable (Table 1). Using a mathematical deconvolution analysis, we demonstrate that the distribution was made of two Gaussian curves overlapping one another (Figure 1A), with one centered on a median value of 5.0 [3.0; 8.0] μg/L mostly representing “low-producers” and one centered on 10.0 [9.0; 11.0] μg/L thus defining a “high-producers” (BST >8 μg/L) represented by 50 (7.9%) HD. We also observed that BST distribution was not significantly different when the measurement was performed on plasma (on 54 more adults, using a Phadia 250™) or on serum but using a UniCAP 100™ (on 27 more adults). Median BST was significantly lower 2.6 [1.2; 5.3] μg/L when measured in 56 healthy 10–18 years old teenagers (mean age 15.8 ± 1.62, 46.4% female), compared to adults (p < .001), and tended to raise up to 5.3 μg/L in HD beyond 70 years of age. On the opposite median BST was at 6.0 μg/L [2.5; 13.2] μg/L when performed in 51 healthy 3-day-old neonates, which is significantly higher than in adults (p < .0014). In 10 neonates (19.6%) BST was greater than 8 μg/L. Overall, a polynomial regression curve shows the nonlinear relationship of BST with age (Figure 1B). Individual reference remains to be referred to. We found that the non-Gaussian distribution of BST in healthy population can be explained by a two population-model in agreement with previous works considering genetic polymorphism.5, 6 Separating these two populations, 95% of HD display a BST below 8.0 μg/L while a minority of people had a BST >8.0 μg/L. This latter group could be considered as “high producers” and may present gene duplication and eventually HαT, although its correlation needs to be confirmed by genetic analysis. The 95th percentile is lower in teenagers (5.5 μg/L) and slightly higher in people older than 70 years (8.5 μg/L). In addition, our data suggest that a small minority of HD has an apparent defect in basal tryptase production that needs to be explored genetically. Fabien Francois, Brigitte Le Mauff, Luc de Chaisemartin, Thierry Tabary, Erwan Dumontet, Jean Claude Lecron, Benoit Delamare, Ahmed Boumediene, Angélique Chauvineau-Grenier, Remi Pescarmona, Lorna Garnier, Claude Lambert have contributed in getting the healthy donor data as well as technical conditions. Fabien Francois did the data collection and statistical analysis, bibliography, and part of writing. Louis Waeckel, Claude Lambert initiated the study, supervised the data collection, data analysis, and paper writing. Brigitte Le Mauff, Luc de Chaisemartin, Thierry Tabary, and Erwan Dumontet actively participated in paper writing. The author wants to acknowledge Anne Emmanuelle BERGER, lab technicians who made the tryptase dosages. The authors declare having no conflict of interest in this work and report. All tryptase dosages were performed under each participating laboratory as part of certification process. The data that support the findings of this study are available from the corresponding author upon reasonable request.