Estimating the within‐subject (CV_I) and between‐subject (CV_G) biological variation of serum tryptase

Abstract

Background: Tryptase is used as a biomarker to support the diagnosis of anaphylaxis and hematologic diseases. In the event of a mast cell activation during anaphylaxis, a temporary increase in the concentration of tryptase may be seen. On the basis of clinical studies, an increase of 2 µg/L + 20% from basis level has been proposed as significant. To evaluate the increase in tryptase levels, the within-subject (CV I ) and between-subject (CV G ) biological variations should be known. This study was conducted to estimate the biological variation of tryptase and to identify the reference change value (RCV).Methods: Blood samples were collected from healthy volunteers once a week consecutively over a 10-week period. Tryptase was measured by the use of a fluoroenzyme immunoassay (ImmunoCAP TM ; Thermo Fisher Scientific), and linear mixed-effects models were used to calculate the biological variation and RCV for both nontransformed and log-transformed tryptase.Results: Fourteen presumably healthy young adults (six males and eight females, age 23-35 years) were included. The CV I was 5.6% and the CV G was 31.5% (nontransformed data). Log-transformed data showed similar results.The analytical variation (CV A ) was 6.3% and the RCV was 23.5%. Conclusions: Young healthy adults without ongoing allergic reactions show low within-subject biological variation. Higher biological variation was observed between subjects.

Serum mast cell tryptase reference intervals in European populations

“…Gonzalez-Quintela et al 4 Norway that BST levels are stable in healthy with a within-subject variation (CV i ) reported to 5.6%. 6 In the same study marked between-individual differences of BST levels were observed, with a between-subject variation (CV g ) reported to 31.5%. This underpins the importance of evaluating tryptase (in the case of suspected mast cell activation) using each individual's own baseline tryptase, as suggested by the consensus formula of a 20% + 2 μg/L increase from BST levels.…”

Reversible Elevation of Tryptase Over the Individual's Baseline: Why is It the Best Biomarker for Severe Systemic Mast Cell Activation and MCAS?

“…The basal tryptase level is remarkably stable over time in individual healthy donors provided that no underlying disease associated with MC activation or MC expansion is present [ 16 , 17 , 18 •]. Moreover, in contrast to many other MC-derived mediators (histamine, PGD2, heparin, others), tryptase is a biologically stable protein that is not degraded, removed, or de-activated by changes in temperature, by other plasma proteins, or by short-term storage.…”

“…However, the basal serum tryptase level varies among healthy individuals, depending on the genetic background, sex, age, kidney function, and presence of an underlying disease associated with MC expansion and/or activation [ 16 , 17 , 18 •].…”

“…In those with HαT, tryptase levels are either within normal range or are elevated (> 15 ng/mL), depending on the number of extra-copies of the TPSAB1 gene, and independent of the symptoms recorded or the presence of co-morbidities. When excluding HαT carriers from the pool of healthy controls, the normal basal serum tryptase level amounts to approximately 0–11.4 ng/mL [ 16 , 17 , 18 •]. However, most HαT carriers are asymptomatic or have non-specific co-morbidities not attributable to MC activation or tryptase, so that these individuals must be included in calculating the normal range of serum tryptase levels [ 36 ].…”

“…Whereas the mature tryptase proteins are preferentially stored in the heparin-containing, secretory metachromatic granules of MC, the enzymatically inactive precursor (pro) forms of tryptase, are released continuously by resting cells, independent of the maturation stage of MC, the tissue and organ site, and the underlying pathology [ 10 , 11 , 12 •, 14 , 15 ]. As a result of steady-state release of the enzyme and its chemical stability under various conditions, the basal serum tryptase level in individual (healthy) donors is remarkably consistent, although slight variations (fluctuations) of the individual baseline have been described, especially in individuals with hereditary alpha tryptasemia (HαT), a condition leading to elevated baseline serum tryptase levels due to multiple copy numbers of TPSAB1 encoding alpha tryptase [ 16 , 17 , 18 •]. The basal serum tryptase level can also be elevated in various reactive processes and in diverse malignancies but usually remains stable in individual patients when tested over time, unless the malignancy progresses or is successfully treated [ 19 – 22 , 23 •, 24 ].…”