Search Results (16)

Background/Objectives: Limited research has explored histamine intolerance from the perspective of primary caregivers. Our objective was to develop a practical symptom profile from the standpoint of general practice. We also aimed to gather data on the frequency and timing of disease progression and to establish a staging system. Methods: This study utilized a nonrandomized, quasi-experimental design. An in-depth interview was conducted with 217 patients involving 120 questions. To evaluate associations between food intake and symptoms, we recommended either an exclusion diet or a low-histamine diet. A follow-up questionnaire was subsequently administered. We also analyzed 3831 doctor–patient meetings involving upper respiratory symptoms. Results: Symptoms in 77 patients were associated with histamine-rich meals. The most characteristic symptoms included respiratory symptoms (95%), bloating (94%), headache (91%), fatigue (83%), postprandial drowsiness (81%), skin symptoms (81%), diarrhea/loose stool (77%), psychological symptoms (77%), dyspepsia (69%), and muscle/eyelid twitching (61%). Patients with suspected histamine intolerance visited primary care three times more often with upper respiratory symptoms than those without suspected histamine intolerance. The symptom spectrum of histamine intolerance involves multiple organ systems and occurs in distinct, repeating patterns. Symptoms can be described by their duration, sequence, and severity level, which is the key focus of this research, including visual representations. In its most severe stages, histamine intolerance may potentially involve mast cell activation. A personalized diet is associated with a gradual reduction in both the intensity and frequency of symptoms. Conclusions: The spectrum of histamine intolerance can be characterized by specific symptom patterns with defined frequencies, timelines, and symptom stages. Full article

Hypermobile Ehlers-Danlos syndrome (hEDS) is a connective tissue disorder marked by joint hypermobility, skin hyperextensibility, and tissue fragility. Recent studies have linked hEDS with mast cell activation syndrome (MCAS), suggesting a genetic interplay affecting immune regulation and infection susceptibility. This study aims to decode the genetic basis of mast cell hypersensitivity and increased infection risk in hEDS by identifying specific genetic variants associated with these conditions. We conducted whole-genome sequencing (WGS) on 18 hEDS participants and 7 first-degree relatives as controls, focusing on identifying genetic variants associated with mast cell dysregulation. Participants underwent clinical assessments to document hEDS symptoms and mast cell hypersensitivity, with particular attention to past infections and antihistamine response. Our analysis identified specific genetic variants in MT-CYB, HTT, MUC3A, HLA-B and HLA-DRB1, which are implicated in hEDS and MCAS. Protein–protein interaction (PPI) network analysis revealed significant interactions among identified variants, highlighting their involvement in pathways related to antigen processing, mucosal protection, and collagen synthesis. Notably, 61.1% of the hEDS cohort reported recurrent infections compared to 28.5% in controls, and 72.2% had documented mast cell hypersensitivity versus 14.2% in controls. These findings provide a plausible explanation for the complex interplay between connective tissue abnormalities and immune dysregulation in hEDS. The identified genetic variants offer insights into potential therapeutic targets for modulating mast cell activity and improving patient outcomes. Future research should validate these findings in larger cohorts and explore the functional implications of these variants to develop effective treatment strategies for hEDS and related mast cell disorders. Full article

Mast cell disorders range from benign proliferations to systemic diseases that cause anaphylaxis and other diverse symptoms to mast cell neoplasms with varied clinical outcomes. Mastocytosis is the pathologic process of the accumulation of abnormal mast cells in different organs, mostly driven by KIT mutations, and can present as cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma. The WHO 5th edition classification divides systemic mastocytosis into bone marrow mastocytosis, indolent systemic mastocytosis, smoldering systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. The new ICC classifies SM slightly differently. The diagnosis of SM requires the integration of bone marrow morphologic, immunophenotypic, and molecular findings, as well as clinical signs and symptoms. Moreover, understanding the wide range of clinical presentations for patients with mast cell disorders is necessary for accurate and timely diagnosis. This review provides an updated overview of mast cell disorders, with a special emphasis on SM, including the latest approaches to diagnosis, prognostic stratification, and management of this rare disease. Full article

Background: Chemical Intolerance (CI) is characterized by intolerances for chemicals, foods, and drugs with multi-system symptoms. As yet, the biomechanism remains unclear. One study reported converging lines of evidence supporting a substantive association between mast cell activation syndrome (MCAS) and CI. The purpose of this study is to (1) confirm a previous report demonstrating that 60% of MCAS patients report CI and (2) examine the parallels between symptoms and intolerances in CI and MCAS. Methods: Five hundred forty-four MCAS patients were assigned a clinical MCAS score using a validated assessment instrument and were assessed for CI using the validated Quick Environmental Exposure Sensitivity Index. Results: Our outcomes confirm the previously published study where the majority of MCAS patients also have CI. There was a clear overlap between various ICD-10 diagnostic categories and CI symptoms, providing further support for a potential shared mechanism. Conclusions: Exposures to pesticides, volatile organic compounds, combustion products, and mold have previously been reported as initiators of CI. However, until recently, little was known about the biological mechanism involved that could explain the multisystem symptoms associated with CI. This paper addresses a newly identified biomechanism for disease, which may underlie a host of “medically unexplained symptoms” triggered by xenobiotics. Full article

Mast cell activation syndrome (MCAS) is an immune disease with an estimated prevalence of 17%. Mast cell chemical mediators lead to heterogeneous multisystemic inflammatory and allergic manifestations. This syndrome is associated with various neurologic and psychiatric disorders, including headache, dysautonomia, depression, generalized anxiety disorder, and many others. Although MCAS is common, it is rarely recognized, and thus, patients can suffer for decades. The syndrome is caused by aberrant mast cell reactivity due to the mutation of the controller gene. A case series is presented herein including eight patients with significant neuropsychiatric disorders that were often refractory to standard medical therapeutics. Five patients had depression, five had generalized anxiety disorder, and four had panic disorder. Other psychiatric disorders included attention-deficit hyperactivity disorder, obsessive compulsive disorder, phobias, and bipolar disorder. All eight patients were subsequently diagnosed with mast cell activation syndrome; six had comorbid autonomic disorders, the most common being postural orthostatic tachycardia syndrome; and four had hypermobile Ehlers-Danlos syndrome. All patients experienced significant improvements regarding neuropsychiatric and multisystemic symptoms after mast-cell-directed therapy. In neuropsychiatric patients who have systemic symptoms and syndromes, it is important to consider the presence of an underlying or comorbid MCAS. Full article

Our knowledge of biology and mast cell (MC) function, as well as disorders associated with the pathologic activation of MCs, has evolved over the last few decades. Anaphylaxis, mast cell activation syndrome (MCAS), and mastocytosis are interrelated yet distinct conditions within the spectrum of mast cell activation disorders. Nevertheless, all three conditions can co-exist in one and the same patient, as pathologic MC activation is the key finding in all three. When mediator release is excessive and involves multiple systems, anaphylaxis and MCAS may occur. Furthermore, mastocytosis is a clonal disorder of MCs and often presents with anaphylaxis and MCAS. Nevertheless, in some cases, even the proliferative and accumulative features of MCs in mastocytosis can account for symptoms and disease progression. In each case, diagnosis can be only made when the diagnostic consensus criteria are fulfilled. The current article aims to provide a concise clinical update and pinpoint the main difficulties in diagnosing these puzzling disorders of MCs in medical practice. Full article

One in 20 births could be affected by hypermobile Ehlers–Danlos syndrome or Hypermobility Spectrum Disorders (hEDS/HSD); however, these are under-diagnosed and lacking research. This study aimed to examine outcomes and complications in people childbearing with hEDS/HSD. A large online international survey was completed by women with experience in childbearing and a diagnosis of hEDS/HSD (N = 947, total pregnancies = 1338). Data were collected on demographics, pregnancy and birth outcomes and complications. Participants reported pregnancies in the UK (N = 771), USA (N = 364), Australia (N = 106), Canada (N = 60), New Zealand (N = 23) and Ireland (N = 14). Incidences were higher in people with hEDS/HSD than typically found in the general population for pre-eclampsia, eclampsia, pre-term rupture of membranes, pre-term birth, antepartum haemorrhage, postpartum haemorrhage, hyperemesis gravidarum, shoulder dystocia, caesarean wound infection, postpartum psychosis, post-traumatic stress disorder, precipitate labour and being born before arrival at place of birth. This potential for increased risk related to maternal and neonatal outcomes and complications highlights the importance of diagnosis and appropriate care considerations for childbearing people with hEDS/HSD. Recommendations include updating healthcare guidance to include awareness of these possible complications and outcomes and including hEDS/HSD in initial screening questionnaires of perinatal care to ensure appropriate consultation and monitoring can take place from the start. Full article

Mast cells (MCs) are infamous for their role in potentially fatal anaphylaxis reactions. In the last two decades, a more complex picture has emerged, as it has become obvious that MCs are much more than just IgE effectors of anaphylaxis. MCs are defenders against a host of infectious and toxic aggressions (their interactions with other components of the immune system are not yet fully understood) and after the insult has ended, MCs continue to play a role in inflammation regulation and tissue repair. Unfortunately, MC involvement in pathology is also significant. Apart from their role in allergies, MCs can proliferate clonally to produce systemic mastocytosis. They have also been implicated in excessive fibrosis, keloid scaring, graft rejection and chronic inflammation, especially at the level of the skin and gut. In recent years, the term MC activation syndrome (MCAS) was proposed to account for symptoms caused by MC activation, and clear diagnostic criteria have been defined. However, not all authors agree with these criteria, as some find them too restrictive, potentially leaving much of the MC-related pathology unaccounted for. Here, we review the current knowledge on the physiological and pathological roles of MCs, with a dermatological emphasis, and discuss the MCAS classification. Full article

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often associated with various other syndromes or conditions including mast cell activation (MCA), dysmenorrhea and endometriosis, postural tachycardia (POTS) and small fiber neuropathy (SFN). The causes of these syndromes and the reason for their frequent association are not yet fully understood. We previously published a comprehensive hypothesis of the ME/CFS pathophysiology that explains the majority of symptoms, findings and chronicity of the disease. We wondered whether some of the identified key pathomechanisms in ME/CFS are also operative in MCA, endometriosis and dysmenorrhea, POTS, decreased cerebral blood flow and SFN, and possibly may provide clues on their causes and frequent co-occurrence. Our analysis indeed provides strong arguments in favor of this assumption, and we conclude that the main pathomechanisms responsible for this association are excessive generation and spillover into the systemic circulation of inflammatory and vasoactive tissue mediators, dysfunctional β2AdR, and the mutual triggering of symptomatology and disease initiation. Overall, vascular dysfunction appears to be a strong common denominator in these linkages. Full article

The incidence of food hypersensitivity has increased dramatically over the years not only among children but also in adults. Adult patients are usually less suspected of food hypersensitivity symptoms since food allergies are more typical for small children, with a tendency to outgrow the condition. The aim of this article is to increase awareness of hypersensitivity to food symptoms and their diagnosis and treatment possibilities among gastroenterologists and other health care professionals dealing with this type of patient. Symptoms of many gastrointestinal disorders, especially functional, may be driven by different types of mechanisms, and food intolerance or allergy should be considered as a potential cause. This article presents the current understanding of the epidemiology, diagnosis and treatment of immune- and non-immune-mediated food-induced diseases. Diagnosis of food hypersensitivity is based mainly on medical history, different types of sensitivity tests, e.g., hydrogen breath test, specific IgE (sIgE) serum concentration, tissue eosinophil count, skin tests and oral food challenges considered as a “gold standard” for food allergy. Elimination diet and pharmacologic treatment for allergy symptoms are first-line therapies. Eosinophilic gastrointestinal diseases are often caused by non-IgE-mediated food allergies, require endoscopic biopsy samples to confirm diagnosis and proper elimination diet often combined with steroids or proton pump inhibitor agents for treatment. Mast cell activation syndrome (MCAS) derives from pathologic reaction of mast cells with increased tryptase serum level as a marker. Symptoms may occur in the digestive, respiratory, skin, neurologic and cardiovascular system. Treatment is based on histamine type 1, type 2 (H1, H2) receptor antagonists and other mast cell stabilizing agents. Carbohydrate intolerances are the most common type of food hypersensitivity in adult patients, and an elimination diet is effective for reducing symptoms. Food additives hypersensitivity remains difficult to diagnose, but use of a diet low in chemical substances alleviates symptoms and helps to diagnose the triggering factors. Full article

Evidence continues to emerge that the social determinants of health play a role in adverse outcomes related to COVID-19, including increased morbidity and mortality, increased risk of long COVID, and vaccine adverse effects. Therefore, a more nuanced understanding of the biochemical and cellular pathways of illnesses commonly associated with adverse social determinants of health is urgently needed. We contend that a commitment to understanding adverse outcomes in historically marginalized communities will increase community-level confidence in public health measures. Here, we synthesize emerging literature on mast cell disease, and the role of mast cells in chronic illness, alongside emerging research on mechanisms of COVID illness and vaccines. We propose that a focus on aberrant and/or hyperactive mast cell behavior associated with chronic underlying health conditions can elucidate adverse COVID-related outcomes and contribute to the pandemic recovery. Standards of care for mast cell activation syndrome (MCAS), as well as clinical reviews, experimental research, and case reports, suggest that effective and cost-efficient remedies are available, including antihistamines, vitamin C, and quercetin, among others. Primary care physicians, specialists, and public health workers should consider new and emerging evidence from the biomedical literature in tackling COVID-19. Specialists and researchers note that MCAS is likely grossly under-diagnosed; therefore, public health agencies and policy makers should urgently attend to community-based experiences of adverse COVID outcomes. It is essential that we extract and examine experiential evidence of marginalized communities from the broader political–ideological discourse. Full article

For nearly a decade, case reports and series have emerged regarding dysautonomias—particularly postural orthostatic tachycardia syndrome (POTS)—presenting soon after vaccination against human papilloma virus (HPV). We too have observed a number of such cases (all following vaccination with the Gardasil product), and have found several to have detectable mast cell activation syndrome (MCAS) as well as histories suggesting that MCAS was likely present long before vaccination. We detail 11 such cases here, posing a hypothesis that HPV vaccination (at least with the Gardasil product) may have triggered or exacerbated MCAS in teenagers previously not recognized to have it. Only recently recognized, MCAS is being increasingly appreciated as a prevalent and chronic multisystem disorder, often emerging early in life and presenting with inflammatory ± allergic phenomena following from known mast cell (MC) mediator effects. There is rising recognition, too, of associations of MCAS with central and peripheral neuropathic disorders, including autonomic disorders such as POTS. Given the recognized potential for many antigens to trigger a major and permanent escalation of baseline MC misbehavior in a given MCAS patient, we hypothesize that in our patients described herein, vaccination with Gardasil may have caused pre-existing (but not yet clinically recognized) MCAS to worsen to a clinically significantly degree, with the emergence of POTS and other issues. The recognition and management of MCAS prior to vaccinations in general may be a strategy worth investigating for reducing adverse events following HPV vaccinations and perhaps even other types of vaccinations. Full article

Mast cells are essential first responder granulocytes in the innate immune system that are well known for their role in type 1 immune hypersensitivity reactions. Although mostly recognized for their role in allergies, mast cells have a range of influences on other systems throughout the body and can respond to a wide range of agonists to properly prime an appropriate immune response. Mast cells have a dynamic energy metabolism to allow rapid responsiveness to their energetic demands. However, our understanding of mast cell metabolism and its impact on mast cell activation and development is still in its infancy. Mast cell metabolism during stimulation and development shifts between both arms of metabolism: catabolic metabolism—such as glycolysis and oxidative phosphorylation—and anabolic metabolism—such as the pentose phosphate pathway. The potential for metabolic pathway shifts to precede and perhaps even control activation and differentiation provides an exciting opportunity to explore energy metabolism for clues in deciphering mast cell function. In this review, we discuss literature pertaining to metabolic environments and fluctuations during different sources of activation, especially IgE mediated vs. non-IgE mediated, and mast cell development, including progenitor cell types leading to the well-known resident mast cell. Full article

Tryptase is a serine protease that is predominantly produced by tissue mast cells (MCs) and stored in secretory granules together with other pre-formed mediators. MC activation, degranulation and mediator release contribute to various immunological processes, but also to several specific diseases, such as IgE-dependent allergies and clonal MC disorders. Biologically active tryptase tetramers primarily derive from the two genes TPSB2 (encoding β-tryptase) and TPSAB1 (encoding either α- or β-tryptase). Based on the most common gene copy numbers, three genotypes, 0α:4β, 1α:3β and 2α:2β, were defined as “canonical”. About 4–6% of the general population carry germline TPSAB1-α copy number gains (2α:3β, 3α:2β or more α-extra-copies), resulting in elevated basal serum tryptase levels. This condition has recently been termed hereditary alpha tryptasemia (HαT). Although many carriers of HαT appear to be asymptomatic, a number of more or less specific symptoms have been associated with HαT. Recent studies have revealed a significantly higher HαT prevalence in patients with systemic mastocytosis (SM) and an association with concomitant severe Hymenoptera venom-induced anaphylaxis. Moreover, HαT seems to be more common in idiopathic anaphylaxis and MC activation syndromes (MCAS). Therefore, TPSAB1 genotyping should be included in the diagnostic algorithm in patients with symptomatic SM, severe anaphylaxis or MCAS. Full article

Primary and secondary mast cell activation syndromes (MCAS) can occur in patients with mastocytosis. During the past few years our knowledge about the pathogenesis and disease-triggering mechanisms in MCAS and mastocytosis have increased substantially. Whereas mastocytosis is characterized by an accumulation of neoplastic (clonal) mast cells (MC) in various organ systems, MCAS is defined by a massive and systemic activation of these cells. Mast cells are crucial effector cells in allergic diseases, thus their elevated number and activation can cause severe anaphylactic reactions and MCAS in patients with mastocytosis. However, these cells may also degranulate spontaneously or degranulate in response to non-allergic triggers leading to clinical symptoms. In mastocytosis patients, such symptoms may lead to the diagnosis of a primary MCAS. The diagnosis of a concomitant allergy in mastocytosis patients is challenging. In these patients, a mixed form (primary and secondary) of MCAS may be diagnosed. These patients may also suffer from life-threatening anaphylactic reactions when exposed to allergens. In these cases, the possibility of severe side effects of in vivo provocations can sometimes also limit diagnostic evaluations. In the current article, we discuss the diagnosis and management of patients suffering from mastocytosis and concomitant MCAS, with special emphasis on novel diagnostic tests and management, including allergen microarrays, recombinant allergen analysis, basophil activation tests, optimal prophylaxis, and specific therapies. Full article