The Clinical Features of Hereditary Alpha-Tryptasemia

Implications for Interdisciplinary Practice

Background: Hereditary alpha-tryptasemia (HAT) is a genetic predisposition of autosomal dominant inheritance that leads to a high normal (≥ 8–11.4 µg/L) or pathologically elevated (>11.4 µg/L) basal serum tryptase (BST) concentration. Its prevalence in the United Kingdom and France is reportedly 5%–6%; its prevalence in Germany is unknown. Symptomatic persons with HAT suffer from a complex constellation of symptoms. As described in this review, HAT is an important differential diagnosis in interdisciplinary practice.

Methods: This review is based on publications about HAT retrieved by a selective search in PubMed, on relevant presentations at scientific meetings, and on our clinical experience. We also collected our own data on the prevalence and clinical manifestations of HAT.

Results: According to the literature, HAT is very common among patients in medical centers with BST values of 8 µg/L or above (64–74%). HAT is most commonly associated with neuropsychiatric symptoms such as exhaustion (85%), depressive episodes (59%), sleep disturbances (69%), and memory impairment (59%–68%), followed by gastrointestinal symptoms such as irritable bowel (30%–60%), nausea (51%), and reflux (49%–77%). Typical mast cell–mediated symptoms, such as flushing (47%), itch (69%), urticaria (37%), and anaphylaxis (14%–28%), are reported as well. Less commonly reported are cardiovascular manifestations, such as hypotonia, dizziness, and tachycardia (34%), and joint hypermobility (28%). HAT is more common among patients with systemic mastocytosis (SM; 12%–21%). It is often associated with severe anaphylaxis induced by insect toxins or unknown triggers. The therapeutic options include treatment with antihistamines, mast-cell stabilizers, or IgE antibodies.

Conclusion: A diagnosis of hereditary alpha-tryptasemia can be strongly suspected on the basis of thorough history-taking and BST measurement and then confirmed by molecular genetic testing.

Hereditary alpha-tryptasemia (HAT), first described by Jonathan Lyons in 2016, is a genetic predisposition of autosomal-dominant inheritance that leads to elevation of basal serum tryptase (BST) (1). BST is characterized by constitutive release of tryptases from mast cells. The BST level serves as a biomarker and parameter of progression for systemic mastocytosis (SM) and as a risk marker for severe anaphylaxis (2, 3, 4).

HAT arises from additional germline copies of the gene TPSAB1 encoding the α-isoform of tryptase. These lead to increased constitutive release of α-tryptases and thus to elevated BST levels. In SM, on the other hand, elevated BST is an expression of an increase in the number of mast cells, caused in 80–95% of cases by an activating mutation of the tyrosine kinase receptor KIT (> 95% KIT-D816V mutation) followed by clonal mast cell expansion (5).

HAT phenotype expressivity is extremely variable. In a non-selected population of nine persons predisposed to HAT, three each had minimal symptoms (one manifestation), moderate symptoms (three to five manifestations), and pronounced symptoms (more than five manifestations) (1). There are no large population-based datasets on the prevalence of symptoms, and some researchers suspect that most persons predisposed to HAT exhibit no symptoms at all (6, 7).

The symptom complex in patients with symptomatic HAT includes medically unquantifiable, so-called functional manifestations such as gastrointestinal, musculoskeletal, and neuropsychiatric symptoms. The spectrum of symptoms also embraces joint hypermobility and cutaneous manifestations such as flushing, urticaria, angioedema, and itching (6, 8). HAT is associated with SM and with severe insect-venom anaphylaxis (9, 10, 11).

The broad range of symptoms underlines the role of HAT as a differential diagnosis across multiple medical specialties (allergology, gastroenterology, rheumatology, nutritional medicine, hematology and oncology, psychiatry).

The BST level should be measured in patients who display signs of these complex constellations of symptoms, especially if no causative diagnosis is apparent. This also applies to patients with severe anaphylaxis, particularly insect-venom or idiopathic anaphylaxis, and to patients with mastocytosis. Anyone with a BST concentration ≥ 8 μg/L may have HAT and should be referred to a mast cell center for further investigation.

Confirmation of HAT can be a game-changer for the patient concerned. On the one hand simple measures can be implemented to relieve the symptoms, improving their quality of life, while on the other hand the diagnosis means that in both the medical and the private environment their symptoms are recognized as being the result of a genetic predisposition.

Methods

Literature survey

We searched the PubMed database for clinical (randomized) trials, case reports, and systematic reviews published between August 2019 and October 2023 featuring the keywords “hereditary alpha-tryptasemia, basal serum tryptase, mastocytosis, venom insect allergy, anaphylaxis”. These were analyzed together with congress presentations and data from the mast cell center at University Hospital Schleswig–Holstein (UKSH), Campus Lübeck.

Data collection

To determine the prevalence of HAT, we conducted a study of patients (n = 130) who attended the allergy clinic of the Department of Dermatology at UKSH Lübeck between August 2022 and October 2023 and were found to have BST ≥ 8 µg/L on routine screening.

The symptom evaluation group comprised 87 HAT-positive patients from the prevalence cohort and 11 patients from the Department of Hematology and Oncology. All 98 of these patients with HAT tested negative for the cKIT D816V mutation in blood or bone marrow. A questionnaire based on the associated symptoms described in the literature was compiled to evaluate the symptoms (8).

Diagnosis

The diagnosis of HAT was accomplished by means of digital droplet polymerase chain reaction (ddPCR) testing of peripheral blood.

Etiopathogenesis of hereditary alpha-tryptasemia

Genetics

The tryptases released from mast cell granules correspond to the α- und β-isoforms of the gene loci TPSB2 and TPSAB1 on chromosome 16 (8). TPSB2 encodes only for β-tryptase, while TPSAB1 encodes for either an α- or a β-isoform. The two tryptase isoforms combine to determine the concentration of free tryptase (BST). The genotypes vary according to whether TPSAB1 encodes for an α- or a β-isoform (Figure 1).

Figure 1

The haplotypes and genotypes (with their prevalences) in a wild-type gene for TPSAB1 and in hereditary alpha-tryptasemia (HAT) (39). Red type: the TPSAB1 gene, which makes the difference between HAT and non-HAT. n, Variable number of copies of the TPSAB1 gene

HAT arises owing to additional copies of the gene TPSAB1 encoding for α-tryptase (1). The copy of TPSAB1 possesses stronger promoter activity than the wild-type gene and is therefore overexpressed (12). Duplication occurs most frequently (e.g., αα/β, β/β). This leads to the existence of various HAT genotypes (Figure 1).

Elevation of basal serum tryptase

The median BST across the general population is 5.1 µg/l, with around 4.3–5.9% of persons having BST concentrations above the normal range (13, 14). Typical for HAT is a BST level only slightly above normal (> 11.4 µg/L) or at the high end of normal (≥ 8–11.4 µg/L). The median BST of the patients with HAT (n = 15) in a population-based study (n = 423) was 11.7 µg/L (8.2–14.7 µg/L) (15), while that in our own patient cohort (n = 98) was 14.1 µg/L (8.0–39.0 µg/L). The BST concentration rises linearly with the number of additional α-tryptase copies; for two copies the median BST is 21.7 µg/L (16). Data from the literature and our own findings agree in showing no clear correlation of symptom severity with either number of α-tryptase copies or BST level (15).

Pathophysiology: tetramer tryptases

The observation of spontaneous formation of α/β-tryptase heterotetramers in mast cells in vitro yielded the first clues to the pathomechanisms that could be relevant for symptoms in vivo (17, 18). Persons with a preponderance of α-tryptase are more likely to form heterotetramers with β-tryptase molecules. The α/β heterotetramers activate specific receptors that cannot activated by β/β homotetramers, such as the mechanosensory receptor EMR2 and the protease-activating receptor PAR2. Subsequently vibration-induced mast cell activation and elevated vascular permeability may occur, potentially triggering anaphylaxis and inflammatory reactions (6, 16).

Prevalence of hereditary alpha-tryptasemia in the general population

The prevalence of HAT in the German general population is unknown. Studies in the UK and France have shown prevalences of 5–6%, determined by digital droplet (dd) screening for HAT in 432 neonates and in 264 healthy control probands from the CovContact study (15, 19). Prevalences of 4–6% were also found in smaller unselected cohorts (1, 9).

Prevalence in high normal and elevated basal serum tryptase

The prevalence of HAT is very high among members of the general population whose BST is pathologically elevated or at the upper end of the normal range, and both in the general population and in patients at medical centers HAT represents the commonest reason for high normal or elevated BST, accounting for 64–72% of cases (11, 12, 20). In a cohort of patients attending our allergy clinic, HAT was the most frequently occurring cause of BST ≥ 8 µg/L (67%, 87/130), followed by BST elevation of unknown origin (23%, 30/130), renal function impairment (GFR < 60 mL/min) (16%, 16/103), and SM (6%, 7/130).

Table 1 gives an overview of the differential diagnoses for BST levels ≥ 8 µg/L in our prevalence cohort together with findings from the literature (21, 22, 23, 24, 25).

Table 1

Differential diagnoses for basal serum tryptase = 8 µg/L

Prevalence by BST level

In our prevalence cohort (n = 130), 81% (70/86) of the patients with BST in the range 10–20 µg/L had HAT (Figure 2). Also in absolute terms, most patients with HAT (80%, 78/98) had BST levels of 10–20 µg/L. In the BST range 8–10 µg/L, the cause was unidentified in 77% of cases (23/30). HAT was again the predominant cause of BST levels > 20 µg/L (72%), although the proportion of patients with SM was much higher in this group (Figure 2).

Figure 2

Prevalence of HAT and other causes of BST = 8 µg/L by BST range in our allergy clinic prevalence cohort (n = 130). BST, Basal serum tryptase; GFR, glomerular filtration rate; HAT, hereditary alpha-tryptasemia; SM, systemic mastocytosis

Clinical symptoms of hereditary alpha-tryptasemia

The proportion of persons with a predisposition for HAT who actually develop symptoms of HAT is unknown. The severity of the symptoms and the number of organs involved are extremely variable. Gastrointestinal symptoms, neuropsychiatric symptoms, allergic and pseudoallergic cutaneous and systemic reactions, musculoskeletal pain, symptoms of autonomic vascular dysfunction, and connective tissue anomalies have been observed (6, 7, 8, 16).

Symptoms can become manifest at any age. Very often, patients report that the symptoms begin or are aggravated after an infection, following intake of medication (e.g., non-steroidal antirheumatic drugs or contrast medium), or in a time of emotional stress. This can be explained by the proximity of mast cells both to the external environment (skin, mucosa, bronchial system) and to sensory nerve endings, where they are activated as effector and regulatory immune cells in infections and in neural excitation of any kind (26, 27, 28).

Prevalence of individual symptoms

The symptoms most frequently observed among the patients with symptomatic HAT identified by our literature survey were neuropsychiatric manifestations such as fatigue (85%), depression (59%), sleep disorders (69%), and memory problems (59–68%). Gastrointestinal symptoms included irritable bowel (30–60%), nausea (51%), and reflux (49–77%). Other common findings were muscle and joint pain (47–66%) and typical mast cell-mediated symptoms such as flush (47%), itching (69%) and urticaria (37%) (1, 6, 29). Furthermore, functional cardiovascular disorders such as hypotension, tachycardia, and dizziness were described in 34–43% of cases, and in one cohort 28% of the patients had hypermobile joints (1, 29). Anaphylaxis was reported in 14–57% of symptomatic patients with HAT, with anaphylactic reactions to drugs in 52% of cases, foodstuffs in 29%, insect venom in 17%, and idiopathic anaphylaxis in 14% (29).

Table 2 gives an overview of the symptoms found and their prevalence in our patients with HAT from UKSH Lübeck (n = 98). Our data are in agreement with those from the literature, particularly with regard to the high rate of neuropsychiatric symptoms. The most commonly reported gastrointestinal symptom was flatulence (82%).

Table 2

The symptoms shown by patients with HAT at the mast cell center of UKSH Lübeck (n = 98)

Hereditary alpha-tryptasemia and irritable bowel symptoms

The prevalence of HAT in a group of 158 study participants with confirmed irritable bowel syndrome was 5%, corresponding to that in the general population (30). However, patients with HAT very commonly report gastrointestinal symptoms (30–89%), and 30–50% of them experience irritable bowel symptoms (8, 16, 31). Recent research supports the assumption that the abdominal symptoms in HAT represent an independent entity (30). Histological examination of samples from the duodenal and terminal ileum of patients with HAT has shown far higher numbers and much greater activity of mast cells than in symptomatic patients with Crohn’s disease or in healthy persons. Moreover, patients with HAT displayed increased intestinal epithelial permeability and caspase-1 expression following pyroptosis, reaching the same levels as in those with Crohn’s disease. In summary, these data yield preliminary evidence for the existence of a chronic inflammatory intestinal disease with the overriding involvement of mast cells.

Implications for clinical practice

BST should be measured whenever medical evaluation fails to identify the cause of irritable bowel symptoms or the symptoms do not respond adequately to treatment. If the BST level is ≥ 8 µg/L, molecular genetic testing for HAT is indicated.

Hereditary alpha-tryptasemia and systemic mastocytosis

In Europe the prevalence of HAT is two to three times higher in patients with systemic mastocytosis (SM) (12–21%) than in the general population (9, 16, 19). The association of HAT with cutaneous mastocytosis (6.5–11.5%) and with all forms of SM (indolent SM 11.7 %; smoldering SM 9.1%; advanced SM 11%) seems to be specific, because it is absent in other myeloid neoplasias (9, 19). Coexistence of HAT is associated with higher incidence and greater severity of mast cell-mediated symptoms and allergies in patients with mastocytosis (9). In particular, the prevalence of insect venom allergy is three times higher in persons with SM and HAT than in those with SM and no HAT (9, 10).

Almost without exception, patients with HAT and mastocytosis have BST levels > 20 µg/L (9). Depending on the number of α-tryptase copies, the BST concentration may even be much higher than that (2). One study showed that despite their higher median BST (50 μg/L versus 35 µg/L without HAT), patients with mastocytosis and HAT exhibit less pronounced mast cell infiltration of bone marrow and a lower blood cKIT D816V allele frequency (9). This hampers the assessment of BST levels, which is important for the classification of SM.

Implications for clinical practice

Molecular genetic testing for HAT is indicated in all patients with mastocytosis who have BST concentrations ≥ 8 µg/L.

Hereditary alpha-tryptasemia as a risk factor for severe insect-venom anaphylaxis

The prevalence of insect-venom allergy is no higher among patients with HAT than in the general population (10, 32, 33). However, HAT constitutes an independent risk factor for particularly severe reactions.

Some 78% of patients with allergic reaction to insect venom and elevated BST (> 11.4 µg/L) showed the most severe magnitude of insect-venom anaphylaxis (32). HAT was demonstrated in over half (55%) of those concerned. In a further 33%, the demonstration of the cKIT D816V mutation by ddPCR of peripheral blood pointed to the presence of SM (32). In contrast, the prevalence of SM in the general population is around 0.01% (34). This study therefore underlines the important role of SM in the severity of the reaction to insect venom, independent of HAT. This is especially true for patients with BST in the normal range, among whom the cKIT D816V mutation was demonstrated particularly frequently in the blood of of those with grade IV (18.2%) and with grade III (4.5%) reactions according to Müller, while HAT was detected extremely rarely (grade IV 0.8%, grade III 1.1%) (32). Demonstration of cKIT D816V in blood is therefore a risk marker for severe insect-venom anaphylaxis regardless of BST level.

Implications for clinical practice

Every person with insect-venom allergy should have their BST measured, and those found to have a concentration ≥ 8 µg/L should be tested for HAT and cKIT D816V. In cases of severe anaphylaxis, regardless of the BST level, peripheral blood should be tested for cKIT D816V as a sign of systemic mastocytosis (SM). The flow chart in Figure 3 shows the investigative procedure in cases of insect-venom anaphylaxis.

Figure 3

Flow chart for investigation of insect-venom anaphylaxis as recommended by the authors at he mast cell center of UKSH, Campus Lübeck. In all cases of insect-venom allergy, allergological investigation should be accompanied by determination of BST.

Treatment options

Basic treatment

The treatment of HAT is symptomatic and long-term. A combination of non-sedating H₁- and H₂-antihistamines has proved its worth, with the latter particularly effective against gastrointestinal symptoms. This treatment brings about improvement in 85% of patients with symptoms of HAT (29). As in the treatment of urticaria, it may be necessary to administer up to fourfold doses of H₁-receptor antagonists as off-label therapy (35). H₂-receptor antagonists or β-blockers may be indicated in the presence of functional tachycardia (36).

Extended basic treatment

Hardly any studies have yielded evidence on the response to extended basic treatment. In our experience, some patients’ irritable bowel symptoms are alleviated by mast-cell stabilizers such as cromoglycate or the flavonoid quercetin. Administration of ketotifen instead of an H₁-blocker may lead to relief mainly of the gastrointestinal symptoms in some cases. The leukotriene inhibitor montelukast (off-label) can be added to the basic treatment.

Treatment with anti-IgE antibodies

There are two studies on the effect of omalizumab, an IgE antibody, in symptomatic patients with HAT. In one of them (n = 13) half of the recorded symptoms were alleviated with omalizumab (37). Urticaria and anaphylaxis had response rates of 100%, and itching, nausea, flushing, fatigue, and abdominal pain also responded well (50%). The second study, with 18 patients, confirmed the response of urticaria (100%) and anaphylaxis (80%) to omalizumab (29).

Treatment of insect-venom allergy

Owing to the risk of extremely severe anaphylaxis, persons with HAT and insect-venom allergy should undergo hyposensitization. Lifelong hyposensitization is recommended in all those with high-grade anaphylaxis, mastocytosis, or BST levels exceeding the normal range (38). This recommendation thus applies to almost all persons with HAT who exhibit insect-venom allergy. An emergency kit is obligatory.

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscirpt received on 14 July 2023, revised version accepted on 20 December 2023.

Translated from the original German by David Roseveare.

Corresponding author
Prof. Dr. med. Dagmar von Bubnoff

Klinik für Dermatologie, Allergologie und Venerologie

Universitätsklinikum Schleswig-Holstein, Campus Lübeck

Exzellenzzentrum für Mastzellerkrankungen des European Competence Network Mastocytosis (ECNM)

Ratzeburger Allee 160

23538 Lübeck, Germany

Cite this as:
von Bubnoff D, Koch D, Stocker H, Ludwig RJ, Wortmann F, von Bubnoff N: The clinical features of hereditary alpha-tryptasemia—implications for interdisciplinary practice. Dtsch Arztebl Int 2024; 121: 258–64. DOI: 10.3238/arztebl.m2023.0287

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