The Normal Range of Baseline Tryptase Should Be 1 to 15 ng/mL and Covers Healthy Individuals With HαT

Abstract

Physiological levels of basal serum tryptase vary among healthy individuals, depending on the numbers of mast cells, basal secretion rate, copy numbers of the TPSAB1 gene encoding alpha tryptase, and renal function. Recently, there has been a growing debate about the normal range of tryptase because individuals with the hereditary alpha tryptasemia (HαT) trait may or may not be symptomatic, and if symptomatic, uncertainty exists as to whether this trait directly causes clinical phenotypes or aggravates certain conditions. In fact, most HαT-positive cases are regarded as asymptomatic concerning mast cell activation. To address this point, experts of the European Competence Network on Mastocytosis (ECNM) and the American Initiative in Mast Cell Diseases met at the 2022 Annual ECNM meeting and discussed the physiological tryptase range. Based on this discussion, our faculty concluded that the normal serum tryptase range should be defined in asymptomatic controls, inclusive of individuals with HαT, and based on 2 SDs covering the 95% confidence interval. By applying this definition in a literature screen, the normal basal tryptase in asymptomatic controls (HαT-positive persons included) ranges between 1 and 15 ng/mL. This definition should avoid overinterpretation, unnecessary referrals, and unnecessary anxiety or anticipatory fear of illness in healthy individuals.

Keywords: Hereditary alpha tryptasemia; Mast cell activation syndromes; Mastocytosis; Tryptase.

FIGURE 1.

Synthesis of tryptases by MCs in (A) HαT-negative and (B) HαT-positive individuals. (A) In HαT-negative human MCs (~95% of the population), the tryptase locus (bottom) on each haplotype contains 4 genes encoding tryptase (TPSG1, TPSB2, TPSAB1, and TPSD1) on the short arm of chromosome 16 at p13.3. It is worth noting that, among all these genes, only TPSB2 and TPSAB1 encode for secreted (serum) tryptase isoforms. Whereas TPSB2 encodes only beta-tryptase, TPSAB1 encodes either alpha or beta isoforms. The resulting genotypes and their frequencies are presented in A. In MCs (A, top), tryptase is produced in alpha, beta, gamma, and delta subunits in the endoplasmic reticulum (ER). Although the gamma subunit is bound to granule membranes, alpha and beta monomers are continuously released as inactive pro-peptides from resting mast cells (without activation). Furthermore, beta subunits undergo sequential proteolytic cleavage (activation) to become a mature tetrameric tryptase that is stored in secretory granules of MCs (top) until degranulation occurs. (B) In HαT-positive MCs, the tryptase locus (bottom) on each haplotype still contains 1 copy of each TPSG1, TPSB2, and TPSD1, while the TPSAB1 gene is duplicated, triplicated, or even more replicated, leading to different genotypes (bottom). This results in increased synthesis of pro-alpha tryptase (top) and an increased BST level compared with MCs in HαT-negative individuals. BST, basal serum tryptase; HaT, hereditary alpha tryptasemia; MCs, mast cells.

FIGURE 2.

Serum tryptase levels in various groups of patients. Serum tryptase levels were measured in asymptomatic patients with hepatic failure (severe liver disease with clearly impaired liver function, n = 7), renal failure (n = 18), or coronavirus disease 2019 (COVID-19) infection (n = 110). In addition, serum tryptase levels were obtained in apparently healthy controls (n = 132) and pregnant women (n = 11). Tryptase genotyping was not performed in any of the patient or control groups. *P < .05 as assessed by analysis of variance.

FIGURE 3.

Longitudinal surveillance of BST concentrations in patients with mastocytosis. The BST concentrations were measured in 47 asymptomatic patients with BM mastocytosis, indolent SM, or smoldering SM at various time periods (median observation time 5 y). In all patients, the course of disease was stable and no severe mediator-related symptoms were recorded. Tryptase levels were measured by a commercial fluoroimmune enzyme assay as reported.^–,

FIGURE 4.

Kinetics of serum tryptase level during an anaphylactic reaction. A patient sensitized to Hymenoptera (wasp) venom was rechallenged by exposure to wasp venom (wasp sting). Just after reexposure to the allergen (blue arrow), tryptase is rapidly released from MCs, leading to a peak serum tryptase increase at about 1–2 h after the event. The half-life (T½) of tryptase in serum is approximately 2 h. Serum tryptase levels return to baseline within 24 h after resolution of all symptoms. The BSTwas measured before the anaphylactic event (red dashed line). UNR, proposed upper normal range threshold (15 ng/mL) (green dashed line).