New aspects of liver abnormalities as part of the systemic mast cell activation syndrome

Alfter, Kirsten; Kügelgen, Ivar von; Haenisch, Britta; Frieling, Thomas; Hülsdonk, A.; Haars, Ulrike; Rolfs, Arndt; Noe, Gerhard; Kolck, Ulrich W.; Homann, Jürgen; Molderings, Gerhard J.

doi:10.1111/j.1478-3231.2008.01839.x

Cited by 34 publications

(18 citation statements)

References 24 publications

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“…Blinded phone interviews were conducted to identify clinical phenotypes and reported physician diagnoses among the ClinSeq participants comporting with our defined criteria (Supplementary Note). Histories focused on symptoms and conditions we identified in association with inherited elevation of tryptase levels 7 , as well as those queried in a published questionnaire for the diagnosis of mast cell activation syndrome (MCAS) 24 . Standardized questionnaires to assess for IBS (Rome III) and autonomic dysfunction (COMPASS 31) were also administered to this population.…”

Section: Methodsmentioning

confidence: 99%

Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number

et al. 2016

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Elevated basal serum tryptase levels are present in 4–6% of the general population, but the cause and relevance of such increases are unknown1, 2. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase–encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

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Section: Methodsmentioning

confidence: 99%

Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number

et al. 2016

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“…Diagnosis of MCAS was based on the proposed criteria to define MCAS [1], i.e. the typical clinical symptoms recorded in a standardized manner by our validated questionnaire [14], [15], exclusion of relevant differential diagnoses of MCAD which may present with organ- or tissue-related mast cell mediator-induced symptoms, determination of pathologically increased release of specific mast cell mediators, i.e. tryptase, heparin and histamin in blood and N-methylhistamine in urine, and in some cases detection of functionally activating genetic changes in mast cells.…”

Section: Methodsmentioning

confidence: 99%

“…This questionnaire was compiled on the basis of our previously published validated questionnaire [14], [15]. After exclusion of relevant differential diagnoses MCAD was diagnosed, if (1) 11 or more items of the questionnaire were applicable or (2) if potentially mast cell mediator-related symptoms occurred in five or more different organs and/or tissues.…”

Section: Methodsmentioning

confidence: 99%

Familial Occurrence of Systemic Mast Cell Activation Disease

et al. 2013

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Systemic mast cell activation disease (MCAD) comprises disorders characterized by an enhanced release of mast cell mediators accompanied by accumulation of dysfunctional mast cells. Demonstration of familial clustering would be an important step towards defining the genetic contribution to the risk of systemic MCAD. The present study aimed to quantify familial aggregation for MCAD and to investigate the variability of clinical and molecular findings (e.g. somatic mutations in KIT) among affected family members in three selected pedigrees. Our data suggest that systemic MCAD pedigrees include more systemic MCAD cases than would be expected by chance, i.e., compared with the prevalence of MCAD in the general population. The prevalence of MCAD suspected by symptom self-report in first-degree relatives of patients with MCAD amounted to approximately 46%, compared to prevalence in the general German population of about 17% (p<0.0001). In three families with a high familial loading of MCAD, the subtype of MCAD and the severity of mediator-related symptoms varied between family members. In addition, genetic alterations detected in KIT were variable, and included mutations at position 816 of the amino acid sequence. In conclusion, our data provide evidence for common familial occurrence of MCAD. Our findings observed in the three pedigrees together with recent reports in the literature suggest that, in familial cases (i.e., in the majority of MCAD), mutated disease-related operator and/or regulator genes could be responsible for the development of somatic mutations in KIT and other proteins important for the regulation of mast cell activity. Accordingly, the immunohistochemically different subtypes of MCAD (i.e. mast cell activation syndrome and systemic mastocytosis) should be more accurately regarded as varying presentations of a common generic root process of mast cell dysfunction, than as distinct diseases.

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“…51 Chronic alcohol consumption modifies human gut microbiota, causing endotoxemia and immune system hyperactivation, which contribute to liver disease 52 and are all the more interesting in view of the frequency of hepatic abnormalities in MCAS. 53 Alcohol has complex effects on MCs: Alcohol-related immunosuppression may be due in part to MC inhibition 54 and even apoptosis 15 by alcohol (or its metabolites), but in some circumstances alcohol and its metabolites (or preservatives such as sulfites) activate MCs, [55][56][57] which may be unsurprising given the intolerance that many patients with MCAD have for alcohol. 58,59 Dietary management is important in IBS.…”

Section: Clinical Therapeuticsmentioning

confidence: 99%