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Diaminoxidase keine diagnostische Hilfe bei Histaminintoleranz
Abstract
Although exact numbers on the prevalence of histamine intolerance are lacking, it seems to be on a rise during the last years. The estimated prevalence in the population is 3%. This is particularly true for middle-aged female patients. A deficiency of 1 of the histamine metabolizing enzymes, diamine oxidase (DAO) has been postulated as the main causal factor. Recently, a commercial radioimmunoassay for determination of DAO activity has been launched. To evaluate the clinical impact of this assay for the diagnosis of histamine intolerance, we performed a prospective, multicentre study in 207 adult patients. In 77 patients, a diagnosis of histamine intolerance was made based on clinical criteria, in 67 a diagnosis "in question", and 61 healthy patients without anamnestic evidence for histamine intolerance served as a control. Interestingly, no correlation between diamine oxidase serum levels and clinical status could be found in any of the 3 groups. We, therefore, recommend further investigations, before determination of DAO serum activity should be used as a screening tool for the diagnosis of histamine intolerance.
... Similar contradictory results on the usefulness of DAO measurements in diagnosing HIT have been reported previously since certain studies: Töndury et al. (2008) [18], Kofler et al. (2009) [19], and Schnoor et al. (2013) [20] concluded that there was no significant association between the clinical history of patients displaying typical symptoms of histamine intolerance and blood DAO activity values. These studies suggest that until further research validates its effectiveness, this technique as a routine diagnostic tool cannot be recommended. ...
... Similar contradictory results on the usefulness of DAO measurements in diagnosing HIT have been reported previously since certain studies: Töndury et al. (2008) [18], Kofler et al. (2009) [19], and Schnoor et al. (2013) [20] concluded that there was no significant association between the clinical history of patients displaying typical symptoms of histamine intolerance and blood DAO activity values. These studies suggest that until further research validates its effectiveness, this technique as a routine diagnostic tool cannot be recommended. ...
Histamine intolerance (HIT) is a clinical condition caused by decreased intestinal degradation of ingested histamine, primarily due to reduced enzyme diamine oxidase (DAO) activity, leading to histamine accumulation and causing various clinical manifestations. The measurement of serum DAO is commonly used as the main diagnostic test for HIT, although its diagnostic use is still uncertain. In this retrospective study, we aimed to assess the validity of DAO determination in patients with clinically suspected HIT. We measured DAO levels in 249 patients with suspected HIT and 50 healthy adult controls without HIT-related problems. Based on five clinical criteria, we divided patients into two groups: high (all five inclusion criteria; 41 patients) and low probability of HIT (≤4 inclusion criteria; 208 patients). Patients with a “high probability of HIT” had the lowest DAO (median: 8 U/mL, IQR: 6–10) in comparison to patients with a “low probability of HIT (median: 10 U/mL, IQR: 7–16, p = 0.0006) and healthy controls (median: 18 U/mL, IQR: 14–22, p < 0.0001). The specificity and sensitivity for DAO levels < 3/< 10 U/mL (manufacturer’s set cut-off) to discriminate between patients with ‘‘high probability of HIT’’ and healthy controls were 100%/92% and 2%/71%. On the other hand, the specificity and sensitivity to discriminate between patients with ‘‘high probability of HIT’’ and ‘‘low probability of HIT’’ were 97%/61% and 2%/71%, respectively. Serum DAO determination represents an additional asset to the diagnosis of HIT based on clinical evaluation and assessment, but the diagnosis should not solely rely on DAO measurements.
... Multiple sets of clinical criteria for HIT diagnosis have been proposed in the literature with the aim of minimizing the confounding effects of other conditions, such as food intolerances [35,41,42], irritable bowel syndrome [43][44][45][46], and non-celiac gluten sensitivity [19,47,48]. In the absence of a universal definition of HIT, a reliable comparison among distinct cohorts remains challenging [49]. In addition, there is also limited knowledge about the possible compensatory mechanisms accounting for the coexistence of low DAO levels and the absence of symptoms among healthy subjects as well as on the potential role of pathogenic mechanisms other than DAO deficiency in patients with HIT and higher DAO levels. ...
... In addition, there is also limited knowledge about the possible compensatory mechanisms accounting for the coexistence of low DAO levels and the absence of symptoms among healthy subjects as well as on the potential role of pathogenic mechanisms other than DAO deficiency in patients with HIT and higher DAO levels. Regarding this aspect, it might be well-accepted that serum DAO levels alone cannot substitute accurate history taking and conventional allergy and gastroenterological workup to rule out alternative diagnoses [49]. Indeed, data from this study further highlight that accurate pre-test stratification of patients might enhance the diagnostic significance of DAO measurement, which might be more fit to identify patients with distinct degrees of symptom severity and treatment susceptibility within the spectrum of HIT rather than surrogating other tools for HIT diagnosis [10,24,26]. ...
Background:
Histamine Intolerance (HIT) is a multifaceted pseudoallergic disorder possibly due to defective histamine metabolism. Diamine oxidase (DAO) contributes to histamine degradation and can be measured in the serum. The role of DAO measurement in the diagnostic work-up of HIT still remains unclear, and conflicting results have been reported in the literature. Therefore, we aimed to evaluate the possible clinical usefulness and consistency of DAO value ranges as provided by the assay manufacturer and verify whether they could predict the response to treatment.
Methods:
We retrospectively analyzed 192 outpatients with HIT symptoms and measured serum DAO values at baseline. Patients were prescribed either with low-histamine diet and/or enzymatic supplementation according to symptom severity and re-evaluated six to eight months later. Patients were stratified into three groups according to DAO levels: <3 U/mL, 3-10 U/mL, and >10 U/mL. HIT severity was assessed on a scale of 1 to 5 before and after treatment.
Results:
A total of 146 patients completed the study. Gastrointestinal and cutaneous symptoms, often associated with headache, were more frequent in subjects with DAO < 10 U/mL. Symptom severity and DAO ranges were correlated. Patients with intermediate DAO levels (3-10 U/mL) showed a more complex clinical phenotype but also a more significant improvement in symptom severity (score reduction 50%, interquartile range (IQR) = 33-60%) when compared to patients with low DAO (40%, IQR = 20-60%; p = 0.045) or high DAO (33%, IQR = 0-50%; p < 0.001). Complex clinical phenotypes were also more frequent in patients with intermediate DAO levels.
Conclusions:
HIT is characterized by typical symptoms and low levels of DAO activity. Symptom severity was associated with the degree of DAO deficiency. Patients with DAO values between 3 and 10 U/mL show the best response to treatment (low-histamine diet and/or DAO supplementation). DAO value could arguably be considered as a predictor of clinical response to treatment. Prospective studies are needed to confirm these data.
... Other limitations would be the cross-sectional design without a control group, the lack of other determinations (IgE, histamine, allergens), the lack of follow-up, or the lack of repeated DAO activity levels in the same patient [37,38]. The strengths are the measurement of the NPIF and to relate it for the first time with DAO activity and histamine intolerance in AR, but even the analysis of DAO activity has been called into question as a diagnostic method for histamine intolerance [10,25,29,30,39]. This study opens up a range of possibilities, but the degree of the relationship found might not be enough to define the real link between DAO activity and AR severity. ...
... However, DAO activity could be considered in the future as a biomarker to differentiate between severity groups. On the other hand, there is some controversy about which measure is the best to assess DAO, whether its levels or its activity [19,25,29,39,40,41,42]. This work demonstrates that the same conclusions are not applicable for both parameters. ...
Aim:
To analyze the diamine oxidase (DAO), the main catabolic enzyme of histamine, degradation activity and its relation with symptoms of persistent allergic rhinitis.
Methods:
In this descriptive and analytical observational study, we collected DAO activity levels and the nasal peak inspiratory flow.
Results:
Enzymatic activity deficit in 108 patients was 46.3% (95% CI, 0.44 - 0.63), 33.33% in mild and 47.92% in moderate/severe rhinitis (p = 0.376). The nasal peak inspiratory flow in patients with a deficit in DAO activity was 76.30 ± 28.40 L/min compared to 93.62 ± 37.50 L/min in patients with normal enzymatic activity (p = 0.010).
Conclusions:
It seems that the lower the catabolic activity of DAO, the lower the nasal peak inspiratory flow observed. Although DAO activity levels could be a severity biomarker in allergic rhinitis, a cause-effect association cannot be concluded. The enzyme could be another actor in the pathophysiology of allergic rhinitis.
... Other limitations would be the cross-sectional design without a control group, the lack of other determinations (IgE, histamine, allergens), the lack of follow-up, or the lack of repeated DAO activity levels in the same patient [37,38]. The strengths are the measurement of the NPIF and to relate it for the first time with DAO activity and histamine intolerance in AR, but even the analysis of DAO activity has been called into question as a diagnostic method for histamine intolerance [10,25,29,30,39]. This study opens up a range of possibilities, but the degree of the relationship found might not be enough to define the real link between DAO activity and AR severity. ...
... However, DAO activity could be considered in the future as a biomarker to differentiate between severity groups. On the other hand, there is some controversy about which measure is the best to assess DAO, whether its levels or its activity [19,25,29,39,40,41,42]. This work demonstrates that the same conclusions are not applicable for both parameters. ...
Introducción: La rinitis es una inflamación del revestimiento mucoso de la nariz que se caracteriza por rinorrea, estornudos, prurito nasal y congestión. La fisiopatología del prurito sigue sin conocerse con exactitud. Muchos mediadores han sido puestos en relación, siendo la histamina uno de los persistentes candidatos y el más estudiado a lo largo de décadas. La diamino oxidasa es la enzima más importante en el metabolismo de la histamina ingerida. La intolerancia a la histamina resulta de un desequilibrio de la histamina acumulada y la capacidad para su degradación causado por un fallo en la función enzimática de la diamino oxidasa. Este hecho podría ser el causante de un agravamiento de la rinitis. El objetivo de este estudio es identificar la prevalencia de déficit en la actividad de la enzima diamino oxidasa en pacientes con rinitis alérgica.
Material y métodos: Estudio observacional de tipo transversal en el que a pacientes diagnosticados de rinitis alérgica se les realizó una extracción sanguínea para estimar la actividad de la enzima diamino oxidasa, así como medir el peak flow nasal inspiratorio y la calidad de vida mediante el test SPRINT-15.
Resultados: 38 pacientes fueron reclutados. El 55,26% presentaban déficit de actividad enzimática. El peak flow nasal inspiratorio obtuvo una media de 95,92 L/min, siendo de 86,42 L/min para los pacientes con déficit frente a 107,64 L/min para los que tenían una actividad enzimática normal (p =0,02).
Discusión: El déficit de actividad diamino oxidasa se asocia a una menor capacidad nasal inspiratoria.
... Other limitations would be the cross-sectional design without a control group, the lack of other determinations (IgE, histamine, allergens), the lack of follow-up, or the lack of repeated DAO activity levels in the same patient [37,38]. The strengths are the measurement of the NPIF and to relate it for the first time with DAO activity and histamine intolerance in AR, but even the analysis of DAO activity has been called into question as a diagnostic method for histamine intolerance [10,25,29,30,39]. This study opens up a range of possibilities, but the degree of the relationship found might not be enough to define the real link between DAO activity and AR severity. ...
... However, DAO activity could be considered in the future as a biomarker to differentiate between severity groups. On the other hand, there is some controversy about which measure is the best to assess DAO, whether its levels or its activity [19,25,29,39,40,41,42]. This work demonstrates that the same conclusions are not applicable for both parameters. ...
Introducción: La rinitis es una inflamación del revestimiento mucoso de la nariz que
se define por su presentación clínica, caracterizada por cinco síntomas cardinales:
rinorrea, estornudos, prurito nasal y congestión. La fisiopatología del prurito sigue sin
conocerse con exactitud. Muchos mediadores han sido puestos en relación, siendo la
histamina uno de los persistentes candidatos y el más estudiado a lo largo de décadas.
La diamino oxidasa es la enzima más importante en el metabolismo de la histamina
ingerida. La intolerancia a la histamina pertenece al grupo de reacciones de hipersensibilidad no IgE-mediadas que resulta de un desequilibrio de la histamina acumulada y la capacidad para su degradación causado por un fallo en la función enzimática de la DAO. Este hecho podría ser el causante de un agravamiento de la rinitis. El objetivo
de este estudio es identificar la prevalencia de déficit en la actividad de la enzima
diamino oxidasa en pacientes con rinitis.
Material y métodos: Fase de reclutamiento del estudio “Tratamiento con diamino-oxidasa
en pacientes con rinitis: un ensayo clínico aleatorizado, controlado y doble ciego
para comprobar la eficacia y seguridad (Estudio DAO-RIN)”. Se reclutaron pacientes
diagnosticados de rinitis alérgica y no alérgica con pruebas cutáneas realizadas y se
realizó estimación de actividad de la diamino oxidasa.
Resultados: 45 pacientes fueron reclutados, 24 con rinitis no alérgica y 21 con rinitis
alérgica.El peak fl ow nasal inspiratorio en rinitis no alérgica obtuvo una media de
92,08 L/min y de 96,19 L/min para rinitis alérgica. Los valores de diamino oxidasa
fueron 107,63 HDU/L frente 82,95 HDU/L.
Discusión: Parece existir una menor actividad de la enzima diamino oxidasa en pacientes
con rinitis alérgica, coincidiendo esto a su con un menor valor de peak flow nasal inspiratorio.
... Es gibt kein zuverlässiges, etabliertes Para meter für die Diagnose eines Histamininto leranzsyndroms. Die diagnostische Bedeutung einer DAO Bestimmung in Blut wird kontrovers disku tiert [11, 12]. Einige Laboratorien geben sol che Angaben bei der DAOBestimmung ab: – DAO < 3 U/ml: sehr geringe Enzymak tivität, – DAO 3 – 10 U/ml: mittlere Enzymakti vität, – DAO > 10 U/ml: normale Enzymaktivi tät. ...
... Wie zwei Studien, basierend auf der Anamnese mit allergieähnlichen Symptomen nach Auf nahme von histaminreichen Nahrungsmitteln gezeigt haben, bietet die Bestimmung der DAOAktivität im Serum in der alltäglichen klinischen Praxis wegen großen Überlap pungen keine Hilfestellung für die Diagnose einer Histaminintoleranz. Bei den drei Grup pen von gesunden Probanden, Patienten mit möglicher Histaminintoleranz und Patien ten mit anamnestisch sehr wahrscheinlicher Histaminintoleranz kamen sowohl tiefe wie normale als auch erhöhte Werte vor [11, 12]. Seit November 2011 steht gemäß Anga ben der Schweizerischen Interessengemein schaft HistaminIntoleranz (SIGHI) (www. ...
... The different approaches include the determination of DAO activity in serum or an intestinal biopsy sample, the identification of certain SNVs in the DAO-encoding gene, the application of a variant of the intradermal skin allergy test (histamine 50-skin-prick test), and the determination of histamine metabolites in urine samples [3,12,18,19]. In the last decade, measuring serum DAO activity has been frequently used for the complementary routine clinical diagnosis of this enzymatic deficiency, but the evidence for its utility in the diagnosis of histamine intolerance is neither abundant nor conclusive [20][21][22][23][24][25][26]. This controversy is highlighted in different articles recently published that emphasize the need for more research to verify the diagnostic value of serum DAO activity for histamine intolerance [25,26]. ...
A retrospective pilot study was carried out to investigate the prevalence of four variants of the diamine oxidase (DAO) encoding gene (AOC1) in Caucasian adults with symptoms of histamine intolerance. In a cohort of 100 patients and 100 healthy individuals, DAO-encoding gene non-synonymous Single Nucleotide Variations (SNVs) were genotyped by multiplex single-nucleotide primer extension (SNPE) and capillary electrophoresis, and serum DAO activity was analyzed with a radio-extraction assay. The study found that 79% of individuals with symptoms of histamine intolerance harbored one or more of the four SNVs associated with reduced DAO activity. No significant differences were found in the prevalence of any variant between the group of patients and healthy controls. However, when considering the status of the alleles associated with DAO deficiency, more homozygous alleles were observed in histamine-intolerant patients. Moreover, a slightly but statistically higher percentage of patients had a high genetic risk score, reflecting the cumulative effect of carrying multiple DAO deficiency-associated gene variants and a high load of risk alleles (homozygous). A relationship between serum DAO activity and the genetic load of one specific SNV was observed, with DAO activity being significantly lower in patients homozygous for rs2052129. These results potentially support that carrying multiple DAO deficiency-associated gene variants and a high load of risk alleles (homozygous) is more relevant than the mere presence of one or more SNVs. Further studies are needed to determine the predictive value of these DAO-encoding gene variants.
... In a prospective study of subjects with clinically suspected histamine intolerance, DAO levels were significantly lower compared to levels in control subjects [12], but the reliability of measurement of DAO activity in serum has also been questioned. In one case control study, no correlation between serum levels of DAO and clinical status of histamine intolerance was found [13]. A recently published cohort study with a retrospective design found low levels of DAO to be a reliable biomarker for histamine intolerance [10]. ...
Histamine intolerance (HIT) is a common adverse reaction to food where elimination and reintroduction of histamine-rich food is part of the investigation. Analysis of the enzyme diamine oxidase (DAO) is sometimes used as an additional tool for diagnosis. This study aimed to describe the distribution of DAO in a large representative cohort of adults and to determine the association between DAO activity and possible associated factors. The study is based on the population-based West Sweden Asthma Study and includes 1051 subjects. Subjects underwent structured interviews including questions on demography, asthma, allergy symptoms, and lifestyle factors. Subjects were assessed for specific-IgE-antibodies and measurement of DAO activity in serum. Previously suggested cut-off levels for low values (<3 U/mL), normal values (>10 U/mL), and median levels of DAO were used. In the group of 1051 subjects, only a few presented reactions upon histamine intake, whereas 44% presented DAO levels below the suggested normal cut-off levels. BMI and age were shown to have an impact on DAO activity among women with increasing activity of DAO with increasing BMI and age. Among men, only increasing age was seen to have an impact on DAO levels. There was no difference in DAO levels with different sensitization status to common foods or airborne allergens. No association between DAO levels and reported symptoms to histamine-rich foods could be found. In conclusion, the determination of the DAO enzyme needs to be re-evaluated and may not be used as a valuable tool for histamine intolerance using current cut-off values. Further studies are needed to improve the use of DAO as a biomarker for histamine intolerance.
... Finally, only 17% of the patients included in the study were men, and it is possible that this introduced selection bias, affecting the results. The strengths of this study include the physiological basis previously demonstrated in the literature, on which the hypothesis was based; the evaluation of the NPIF; and the first ever investigation of the relationship between histamine intolerance and DAO activity in IR patients [31,33,36,54,55]. ...
Idiopathic rhinitis represents more than 50% of non-allergic rhinitis, a heterogeneous group that involves the symptomatic inflammation of the nasal mucosa. The TRPV1 receptor of unmyelinated C-type neurons appears to be involved in its pathophysiology. Histamine, whose main catabolic enzyme is DAO, is one of the mediators that can activate this receptor. The failure of DAO causes an increase in the level of histamine in the body and, consequently, the activation of TRPV1. The objective was to investigate the existence of a DAO enzyme activity deficit in idiopathic rhinitis and its correlation with symptoms. A cross-sectional study was conducted in 116 idiopathic rhinitis patients, and DAO activity, nasal peak inspiratory flow, and rhinitis severity were recorded. The prevalence of a DAO activity deficit was 41.38% (95%CI 0.33–0.50; p = 0.05). The DAO activity in patients with mild rhinitis was 52.93 ± 8.72 HDU/mL, in those with moderate rhinitis it was 120.33 ± 71.63 HDU/mL, and in those with severe rhinitis it was 92.58 ± 27.75 HDU/mL (p = 0.006). The NPIF in patients with a DAO activity deficit was 107.92 ± 34.05 L/min, compared to 72.35 ± 27.16 L/min in patients with normal enzymatic activity (p < 0.001), demonstrating a linear correlation between activity levels and nasal obstruction (−0.45; p < 0.001). Therefore, patients with a DAO deficiency and idiopathic rhinitis could present a milder disease course, because the repeated and continuous activation of TRPV1 led to a partial or total decrease in their response (desensitization). This new theory represents a different perspective for the study of idiopathic rhinitis and its relationship with TRPV1, with the regulation or modulation of the desensitization of TRPV1 being an important therapeutic target for patients with idiopathic rhinitis in the future.
... Some studies have proposed that determining blood DAO activity may be helpful in identifying subjects with symptoms associated with histamine intolerance [63,83,84]. In contrast, three studies did not find a significant relationship between the clinical history of patients with typical symptoms of histamine intolerance and blood DAO activity values, concluding that this technique cannot be recommended as a diagnostic tool in routine clinical practice until studies have validated its effectiveness [98][99][100]. Moreover, the work performed by Schnoor et al. also reported a high interassay variation in DAO activity values that made the proper classification of histamine-intolerant subjects impossible [100]. ...
Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that was described at the beginning of the 21st century. Although interest in histamine intolerance has considerably grown in recent years, more scientific evidence is still required to help define, diagnose and clinically manage this condition. This article will provide an updated review on histamine intolerance, mainly focusing on its etiology and the existing diagnostic and treatment strategies. In this work, a glance on histamine intoxication will also be provided, as well as the analysis of some uncertainties historically associated to histamine intoxication outbreaks that may be better explained by the existence of interindividual susceptibility to ingested histamine.
... Bei Verdacht auf Unverträglichkeit gegenüber oral aufgenommenem Histamin stehen keine objektiven Laborparameter zur Dia gnose zur Verfügung [1]. Auch die Messung des Diaminoxidase-Spiegels im Serum und die Histamin-Bestimmung im Plasma haben sich nicht als aussagekräftig erwiesen [7,8,9,10]. Tatsächlich ist es fraglich, ob das Serum zur Messung der Diaminoxidase überhaupt geeignet ist [11]. ...
The so-called histamine intolerance is a popular disorder which is most often selfdiagnosed. As the diagnosis mainly depends on self-reporting of clinical symptoms it is mandatory to make sure that reproducibility, a prerequisite for an adverse reaction, is present. A dietetic approach is only reasonable if ingested histamine does indeed elicit objective and provocable reactions. If histamine intolerance is confirmed, an individual therapeutic strategy is required.
... Diagnosis based on measurement of DAO enzyme activity in the blood cannot be considered conclusive. Results of several studies suggest that the DAO values of affected and healthy individuals are comparable [29,30]. Using DAO-specific monoclonal antibodies, it was not possible to detect relevant amounts of DAO in serum. ...
Nahrungsmittelunverträglichkeiten sind objektiv nachweisbar deutlich seltener als subjektiv empfunden. Insbesondere zum wissenschaftlichen Kenntnisstand nicht allergischer Überempfindlichkeitsreaktionen bestehen große Defizite. Ein Beispiel ist die Histaminunverträglichkeit, die aufgrund der starken Thematisierung in den Medien und im Internet von Betroffenen oftmals als Auslöser ihrer Gesundheitsbeschwerden vermutet wird. Die wissenschaftliche Evidenz für die postulierten Zusammenhänge ist begrenzt, eine verlässliche Laborbestimmung zur definitiven Diagnose nicht vorhanden. Die vorliegende Stellungnahme der Arbeitsgruppe Nahrungsmittelallergie der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI) in Zusammenarbeit mit dem Ärzteverband Deutscher Allergologen (AeDA), der Pädiatrischen Allergologie und Umweltmedizin (GPA) sowie der Schweizerischen Gesellschaft für Allergologie und Immunologie (SGAI) beleuchtet die Datenlage für das Krankheitsbild der Unverträglichkeit gegenüber oral aufgenommenem Histamin, fasst wichtige Aspekte und deren Konsequenzen zusammen und schlägt ein praktikables diagnostisches und therapeutisches Vorgehen vor.
... Diagnosis based on measurement of DAO enzyme activity in the blood cannot be considered conclusive. Results of several studies suggest that the DAO values of affected and healthy individuals are comparable [29,30]. Using DAO-specific monoclonal antibodies, it was not possible to detect relevant amounts of DAO in serum. ...
Chronic urticaria, recurrent angioedema and non-allergic asthma have all been associated with pseudoallergic reactions to food ingredients. For atopic dermatitis and diseases of the gastrointestinal tract, this association is controversial. Pseudoallergic reactions can be elicited by additives as well as by natural food ingredients. An altered histamine metabolism may be associated with pseudoallergy.
Acute urticaria or a short episode of angioedema is not an indication for exhaustive evaluation. If basic diagnostic screening is negative in chronic urticaria, a low-pseudoallergen diet can be considered. Skin and serological tests are not objective diagnostic parameters for pseudoallergic reactions. The severity of symptoms should be documented while the patient is on a low-pseudoaller-gen diet.
Oral provocation with additives leads to reproducible symptoms only in a few cases. Therefore, if a low-pseudoallergen diet brings improvement, the patient is then exposed to a pseudoallergen-rich "super meal". After a positive reaction to the "super meal" the challenge with additives takes place in the form of collective group exposition. When the patient has asthma or a history of anaphylac-toid reactions, testing with individual substances in carefully increasing dosages is required.
The suspicion of adverse reactions against histamine can be confirmed by a challenge with histamine dihydrochloride. In the case of respiratory symptoms, provocation by inhalation should be considered. Objectifying symptoms especially in gastrointestinal diseases is mandatory and should include double-blind placebo-controlled food challenge, if possible.
“Histamine intolerance” is often based on a self-diagnosis. Due to the known range of reactions that can be mediated by the messenger substance histamine, it is postulated that food histamine can trigger the same reactions. Results of studies with double-blind, placebo-controlled oral provocation tests do not confirm this, but rather show that orally administered histamine does not trigger reproducible reactions and that symptoms often occur after placebo, indicating a strong nocebo effect. Without reproducibility, however, the definition for an adverse reaction to food is not fulfilled. As many sufferers are severely affected by their self-diagnosis due to a massive restriction of their food choice, quality of life, and social interaction, allergy societies in German-speaking countries have published a guideline which describes a pragmatic diagnostic and therapeutic approach. The primary aim is to alleviate symptoms by improving digestive function and to expand the choice of foods, rather than to exclude the suspected diagnosis. Collaboration with a dietician/nutritionist with allergological expertise is therefore strongly recommended.
Background:
Histamine intolerance (HIT) is frequently diagnosed in patients with polysymptomatic otherwise unexplained symptoms.
Objectives:
To exclude HIT by single-blind placebo-controlled histamine challenge (SBPCHC), to study clinical features of patients with positive challenge and to examine the predictability of HIT by biomarkers.
Methods:
SBPCHC was performed in fifty-nine patients with suspected HIT. History and clinical data, including serum diaminooxidase (DAO) and histamine skin test wheal size of patients with positive vs. negative SBPCHC were compared.
Results:
Patients were predominantly middle-aged females (84.7 %). Three-quarters reported improvement, but never resolution of symptoms during histamine-low diet. Histamine provocation was safe; only one patient was treated with antihistamines. Thirty-seven patients (62.7 %) displayed symptoms to placebo. HIT was excluded in 50 patients (84.7 %). Objective symptoms occurred in four out of 59 cases (6.8 %) after histamine, but not after placebo challenge. These were diagnosed with"plausible HIT", since reactions occurring by chance could not be excluded. Another five patients (8.5 %) were diagnosed with "possible HIT" after case-dependent detailed analysis. Patients with plausible/possible HIT had reported more gastrointestinal symptoms (p=0.01), but comparable diet response and equal histamine skin prick test wheal sizes to those without HIT. Serum DAO activity tended to be lower in patients with HIT (p=0.08), but was highly variable in those without, limiting its value as biomarker.
Conclusions:
SBPCHC disproves HIT in the majority of patients. Placebo-controlled challenges are needed as placebo reactions were frequent. Gastrointestinal symptoms after food intake and reduced DAO levels are markers for HIT, however, specificity is not sufficient enough for making the diagnosis.
Histamine is a biogenic amine involved in important physiological activities in the organism, but its ingestion through food is associated with the onset of health disorders. Histamine intoxication, previously known as scombroid fish poisoning, is caused by the intake of foods with high levels of histamine. According to official European Union reports, more than 90% of the outbreaks registered in the last years were caused by the consumption of fish and seafood products. Histamine intolerance, on the other hand, arises when histamine degradation is impaired, mainly by a lower diamine oxidase (DAO) activity. Some of the uncertainties classically associated with histamine intoxication may be explained by this enzymatic deficit in a sensitive population. This chapter reviews the adverse effects of histamine from food within a risk analysis framework, focusing specifically on the components of risk assessment and management.
Histamine plays a major role in inflammation associated with many different diseases, including allergies, autoimmune diseases and cancer, but it also has important physiological effects. Although mast cells and basophils are the main sources of histamine it can be differentially produced and released by enterochromaffin-like cells, certain nerve cells, and even neutrophils in certain pathological settings. This chapter highlights the recent developments regarding the major contributions of histamine to inflammation by acting not only through H1-receptors (H1R) but also H2R and H4R. These receptors determine both the severity of inflammation and also have immunomodulatory effects in various lymphocytes. Recent evidence also suggests a dual role for histamine in various autoimmune inflammatory disease and certain cancers, where differential receptor expressions for the amine determine the severity of these diseases but also play a role in tumour surveillance.
Adverse food reactions are far more often perceived than objectively verified. In our scientific knowledge on non-allergic adverse reactions including the so called histamine intolerance, there are large deficits. Due to the fact that this disorder is increasingly discussed in the media and the internet, more and more people suspect it to be the trigger of their symptoms. The scientific evidence to support the postulated link between ingestion of histamine and adverse reactions is limited, and a reliable laboratory test for objective diagnosis is lacking. This position paper by the “Food Allergy” Working Group of the German Society for Allergology and Clinical Immunology (DGAKI) in collaboration with the German Association of Allergologists (AeDA), the Society for Pediatric Allergology and Environmental Medicine (GPA), and the Swiss Society for Allergology and Immunology (SGAI) reviews the data on the clinical picture of adverse reactions to ingested histamine, summarizes important aspects and their consequences, and proposes a practical diagnostic and therapeutic approach.
Immunologically mediated hypersensitivity to foods is defined as food allergy, mainly due to immunglobulins of class E (IgE) triggering immediate reactions (type I hypersensitivity) with possible involvement of mucosa, skin, airways, intestinal tract, and the vascular system. Primary food allergy is based on (early) IgE sensitization against animal (e. g., cow’s milk, hen’s eggs) or plant proteins (e. g. peanut, hazelnut or wheat). In the case of secondary food allergies, IgE against pollen proteins (e. g., birch) reacts to structurally related food proteins (with cross-reactions to stone and pit fruits). Non-immunological food intolerance reactions are mostly based on carbohydrate malassimilation (e. g., lactose intolerance, fructose malabsorption) and are rarely due to pseudo-allergies (e. g., flavors, dyes, preservatives) primarily in patients with chronic urticaria. Common intestinal symptoms are mainly due to functional disorders (e. g., irritable bowel disease), rarely because of inflammatory intestinal diseases (e. g., celiac disease). Histamine intolerance, gluten hypersensitivity, and so-called food type III hypersensitivities are controversial diagnoses. The aforementioned disease entities/models are of variable importance for the affected individuals, the public health system, and society in general.
Searching the internet for an explaination of recurring symptoms, many people come across the so-called histamine intolerance disorder. Also many practitioners like to diagnose this disorder without making sure that reproducibility, a prerequisite for an adverse reaction, is present. Consequently, presumably affected persons are often advised to follow a low-histamine diet. Depending on the source of information, these diets often avoid a huge variety of foods containing more or less histamine, which has a considerable impact on patient quality of life. While most persons benefit from such a diet in the beginning – this might be due to the change in dietary habits or the expectation of symptom improvement by dieting – in the long run the expected loss of symptoms will not happen. Underlying a diminished capacity for histamine degradation, the lack of partial or complete symptom improvement might be due to the fact that endogenous histamine release is responsible for reactions. The role of ingested histamine is discussed controversially. However, it is more than obvious that the histamine content of a certain food alone is not enough to predict its tolerance.
If histamine intolerance is suspected, an individual diagnostic and therapeutic procedure is mandatory in order to minimize avoidance and to preserve a high quality of life. Ideally this is done in a close cooperation between allergologists and nutritionists/dieticians.
EC number 1.4.3.22 Systematic name histamine:oxygen oxidoreductase (deaminating) Recommended name diamine oxidase Synonyms AGAO [42,61] Amine oxidase [61,65] BSAO [51] Copper amine oxidase [64] DAO [40,44,47,49,52,53,55,56,60,62,66] Diamine oxidase [40,43,44,60,62,63] ELAO [46,51] GPAO [46] LCAO [37,54] LSAO [46,48,51] PKAO [51] PPLO [42] PSAO [42,43,51,54,64] hDAO [63] histaminase [59] histamine oxidase [39] pea seedling amine oxidase [64] rhDAO [42] Additional information ( the enzyme is a member of the coppercontaining amine oxidase, CAO, family of enzymes [66]) [66]
Low-histamine diets are very popular and often self-imposed among people suspecting histamine intolerance. Most of these diets avoid a huge variety of foods containing more or less histamine, which has a considerable impact on their quality of life, but in most cases no long-term benefit. Underlying a diminished capacity for histamine degradation, the lack of partial or complete symptom improvement might be due to the fact that endogenous histamine release could also be responsible for symptoms. The role of ingested histamine-below the level for intoxication-is discussed controversially. However, it is obvious that the histamine content of a certain food alone is not enough to predict its tolerance. If histamine intolerance is suspected, an individual diagnostic and therapeutic procedure is mandatory in order to minimize avoidance and to preserve a high quality of life. Ideally this is done in a close cooperation between allergists and nutritionists.
Background. Histamine intolerance results from an imbalance between histamine intake and degradation. In healthy persons, dietary histamine can be sufficiently metabolized by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity. Diamine oxidase (DAO) is the key enzyme in degradation. Histamine elicits a wide range of effects. Histamine intolerance displays symptoms, such as rhinitis, headache, gastrointestinal symptoms, palpitations, urticaria and pruritus.
Objective. Diagnosis of histamine intolerance until now is based on case history; neither a validated questionnaire nor a routine test is available.
It was the aim of this trial to evaluate the usefullness of a prick-test for the diagnosis of histamine intolerance.
Methods. Prick-testing with 1% histamine solution and wheal size-measurement to assess the relation between the wheal in prick-test, read after 20 to 50 minutes, as sign of slowed histamine degradation as well as history and symptoms of histamine intolerance.
Results. Besides a pretest with 17 patients with HIT we investigated 156 persons (81 with HIT, 75 controls): 64 out of 81 with histamine intolerance(HIT), but only 14 out of 75 persons from the control-group presented with a histamine wheal ≥3 mm after 50 minutes (P < .0001).
Conclusion and Clinical Relevance. Histamine-50 skin-prickt-test offers a simple tool with relevance.
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