Associations Between Migraine, Celiac Disease, Non-Celiac Gluten Sensitivity and Activity of Diamine Oxidase
Background and pilot study: Recent reports reveal a close relationship between migraine and gastrointestinal disorders (GI), such as celiac disease (CD) and non-celiac gluten sensitivity (NCGS). CD is a genetic autoimmune disorder, which affects the mucosa of the small intestine. Gluten, found in various grains, not only plays a major role in the pathophysiology of CD and NCGS, but also aggravates migraine attacks. Another common food component, which can induce migraine headaches, is histamine. Diamine oxidase (DAO) is an enzyme, which degrades histamine. Reduced activity of DAO means reduced histamine degradation, which can cause histamine build-up and lead to various symptoms, including headaches and migraine. In this paper we propose a hypothesis, that in pathogenesis of migraine, low serum DAO activity is related to CD and NCGS. We also conducted our own pilot study of 44 patients with severe migraine in efforts to evaluate the co-presence of decreased serum DAO activity and celiac disease/NCGS in patients. 44 consecutive migraine patients were divided into 2 groups: decreased DAO activity (group 1; n = 26) and normal DAO activity (group 2; n = 18). All patients were screened for celiac disease. The diagnosis of NCGS was made after exclusion of CD, food allergies and other GI disorders in the presence of gluten sensitivity symptoms. Furthermore, dietary recommendations were given to all participants and their effects were assessed 3 months after the initial evaluation via the MIDAS (Migraine Disability Assessment) questionnaire.
Results and conclusions: Only 1 patient fit the criteria for celiac disease, rendering this result inconclusive. Pathological findings of the remainder of patients were attributed to NCGS (n = 10). 9 of 10 patients with NCGS belonged to the decreased serum DAO activity group (group 1; n = 26), suggesting a strong relationship between reduced serum DAO activity and NCGS. MIDAS questionnaire revealed, that patients with decreased serum DAO activity were more severely impacted by migraine than those with normal DAO activity, and this remained so after our interventions. Dietary adjustments significantly reduced the impact of migraine on patients’ daily activities after 3 months in both groups. We argue, that migraine, celiac disease and NCGS may benefit from treatment with a multidisciplinary approach, involving neurologists, gastroenterologists and dietitians.
Massive release of the histamine‐degrading enzyme diamine oxidase during severe anaphylaxis in mastocytosis patients
Allergy. 2019 Mar; 74(3): 583–593.
Histaminolytic activity mediated by diamine oxidase (DAO) is present in plasma after induction of severe anaphylaxis in rats, guinea pigs, and rabbits. Heparin released during mast cell degranulation in the gastrointestinal tract might liberate DAO from heparin‐sensitive storage sites. DAO release during anaphylaxis has not been demonstrated in humans.
Plasma DAO, tryptase, and histamine concentrations of four severe anaphylaxis events were determined at multiple serial time points in two patients with systemic mastocytosis. The histamine degradation rates were measured in anaphylaxis samples and in pregnancy sera and plasma with comparable DAO concentrations.
Mean DAO (132 ng/mL) and tryptase (304 ng/mL) concentrations increased 187‐ and 4.0‐fold, respectively, over baseline values (DAO 0.7 ng/mL, tryptase 76 ng/mL) during severe anaphylaxis. Under non‐anaphylaxis conditions, DAO concentrations were not elevated in 29 mastocytosis patients compared to healthy volunteers and there was no correlation between DAO and tryptase levels in mastocytosis patients. The histamine degradation rate of DAO in plasma from mastocytosis patients during anaphylaxis is severely compromised compared to DAO from pregnancy samples.
During severe anaphylaxis in mastocytosis patients, DAO is likely released from heparin‐sensitive gastrointestinal storage sites. The measured concentrations can degrade histamine, but DAO activity is compromised compared to pregnancy samples. For accurate histamine measurements during anaphylaxis, DAO inhibition is essential to inhibit further histamine degradation after blood withdrawal. Determination of DAO antigen levels might be of clinical value to improve the diagnosis of mast cell activation.
Serum levels of histamine and diamine oxidase in multiple sclerosis
Am J Clin Exp Immunol 2018;7(6):100-105 www.ajcei.us /ISSN:2164-7712/AJCEI0086352
Aryan Rafiee Zadeh1, Masih Falahatian1, Fereshteh Alsahebfosoul2
1School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; 2Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system, mostly affecting young adults. Diamine oxidase is an enzyme essential for histamine production. Histamine which is produced mostly by mast cells can have effects on different aspects of immune system via its different histamine receptors (H1R, H2R, H3R and H4R). The crucial role of diamine oxidase and histamine in immune balance has been documented in different studies and experiments both on MS patients and on experimental allergic encephalomyelitis (EAE). In this regard, we aimed to measure the level of histamine and diamine oxidase in the serum of MS patients.
A total number of 50 relapsing-remitting MS (RRMS) patients and 41 age and sex matched controls were enrolled in this study. Assessments of serum levels of histamine and diamine oxidase enzyme were performed using enzyme-linked immune sorbent assay (ELISA). Results: The serum levels of histamine and diamine oxidase in RRMS patients were lower than healthy controls (P-value = 0.00, for both).
Our research team found significant low levels of histamine and diamine oxidase in RRMS patients; however the pathogenesis of this issue was unclear.
Biogenic Amines in Plant-Origin Foods: Are they Frequently Underestimated in Low-Histamine Diets?
Foods 2018, 7(12), 205.
Low-histamine diets are currently used to reduce symptoms of histamine intolerance, a disorder in histamine homeostasis that increases plasma levels, mainly due to reduced diamine-oxidase (DAO) activity. These diets exclude foods, many of them of plant origin, which patients associate with the onset of the symptomatology. This study aimed to review the existing data on histamine and other biogenic amine contents in nonfermented plant-origin foods, as well as on their origin and evolution during the storage or culinary process. The only plant-origin products with significant levels of histamine were eggplant, spinach, tomato, and avocado, each showing a great variability in content. Putrescine has been found in practically all plant-origin foods, probably due to its physiological origin. The high contents of putrescine in certain products could also be related to the triggering of the symptomatology by enzymatic competition with histamine. Additionally, high spermidine contents found in some foods should also be taken into account in these diets, because it can also be metabolized by DAO, albeit with a lower affinity. It is recommended to consume plant-origin foods that are boiled or are of maximum freshness to reduce biogenic amine intake.
Cite this article:
Sánchez-Pérez, S.; Comas-Basté, O.; Rabell-González, J.; Veciana-Nogués, M.T.; Latorre-Moratalla, M.L.; Vidal-Carou, M.C. Biogenic Amines in Plant-Origin Foods: Are they Frequently Underestimated in Low-Histamine Diets? Foods 2018, 7, 205.
Microbial patterns in patients with histamine intolerance.
J Physiol Pharmacol. 2018 Aug;69(4). doi: 10.26402/jpp.2018.4.09. Epub 2018 Dec 9.
- First Department of Medicine, Hector Center for Nutrition, Exercise and Sports, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Erlangen, Germany.
- Second Department of Medicine, Thuringia-Clinic Saalfeld, Saalfeld/Saale, Germany.
- First Department of Medicine, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Erlangen, Germany.
- First Department of Medicine, Hector Center for Nutrition, Exercise and Sports, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Erlangen, Germany. firstname.lastname@example.org.
Histamine intolerance represents a controversially discussed disorder. Besides an impaired degradation of orally supplied histamine due to diamine oxidase (DAO) deficiency, a deranged gut flora may also contribute to elevated histamine levels. Our aim was to determine the intestinal bacterial composition in patients with proven histamine intolerance in comparison to other food intolerances and healthy controls. A total of 64 participants were included in the study, encompassing 8 patients with histamine intolerance (HIT), 25 with food hypersensitivity (FH), 21 with food allergy and 10 healthy controls (HC). All participants underwent blood testing for total and food-specific immunoglobulin E, plasma histamine and DAO serum activity. Stool samples were used to analyze stool histamine and zonulin levels and bacterial composition by 16s rRNA sequencing. No significant differences in stool histamine levels were observed, but HIT patients showed elevated levels of stool zonulin. Microbiota analysis revealed increased levels of Proteobacteria (5.4%) and a significantly reduced alpha-diversity in the HIT group (P = 0.019). On family level, HC showed a significantly higher abundance of Bifidobacteriaceae compared to other study groups (P = 0.005), with lowest levels in the HIT group (P = 0.036). Also significantly reduced abundances of the genera Butyricimonas (P = 0.026) and Hespellia (P = 0.025) were observed in the HIT patients, whereas Roseburia were significantly elevated (P = 0.021). We concluded that the altered occurrence of Proteobacteria and Bifidobacteriaceae, reduced alpha-diversity as well as elevated stool zonulin levels suggest a dysbiosis and intestinal barrier dysfunction in histamine intolerant patients, which in turn may play an important role in driving disease pathogenesis.
Histamine-reduced diet and increase of serum diamine oxidase correlating to diet compliance in histamine intolerance
Histamine-reduced diet and increase of serum diamine oxidase correlating to diet compliance in histamine intolerance.
Eur J Clin Nutr. 2018 Jul 18. doi: 10.1038/s41430-018-0260-5. [Epub ahead of print]
- Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Heinrichstrasse 31a, A-8010, Graz, Austria.
- Institute of Laboratory Medicine, General Hospital Steyr, Sierninger Straße 170, A-4400, Steyr, Austria.
- Clinical Institute of Medical and Chemical Laboratory Diagnosis, Medical University of Graz, Auenbruggerplatz 30, A-8036, Graz, Austria.
- Practice for General Internal Medicine, Dr. Theodor Körnerstrasse 19b, A-8600, Bruck, Austria. email@example.com.
Diagnosis of histamine intolerance (HIT) has been based on low serum diamine oxidase (DAO) values, functional gastrointestinal disorders and improvement of symptoms with a histamine-reduced diet (HRD). In a retrospective analysis of outpatients’ charts we identified 101 patients with HIT. After a median of 13 months, a questionnaire was distributed to the patients so that they could be classified into four diet-compliance groups. Calculated with all 101 patients we found an increase of serum DAO values due to a HRD. In the 63 patients that completed the questionnaire, we found that 50 patients had improvement of symptoms or no continuing symptoms. A significant increase of serum DAO levels was found in the patients with strict and occasional diet compliance. Therefore, we demonstrate that a HRD is not only improving symptoms in HIT, but is causing an increase in serum DAO values that correlates with the degree of diet compliance.
Circadian profiling reveals higher histamine plasma levels and lower diamine oxidase serum activities in 24% of patients with suspected histamine intolerance compared to food allergy and controls
Circadian profiling reveals higher histamine plasma levels and lower diamine oxidase serum activities in 24% of patients with suspected histamine intolerance compared to food allergy and controls.
Allergy. 2018 Apr;73(4):949-957. doi: 10.1111/all.13361. Epub 2017 Dec 15.
- Department of Medicine 1, Hector Center for Nutrition, Exercise and Sports, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
- Department of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Histamine intolerance is thought to trigger manifold clinical symptoms after ingesting histamine-rich food due to reduced activity of diamine oxidase (DAO). No study has hitherto systematically assessed daily fluctuations of histamine levels and DAO activities in symptomatic patients. The aim of the study was to investigate the presence of histamine intolerance, to therefore establish day profiles of histamine levels and DAO activities, and to compare the results between patients with suspected histamine intolerance, food allergy and healthy controls.
We determined day profiles of histamine plasma levels and DAO serum activities in 33 patients with suspected histamine intolerance, in 21 patients with proven food allergy and in 10 healthy control patients. Clinical symptoms, food intolerances and further clinical and laboratory chemical parameters were evaluated.
Twenty-four percent (8 of 33) suspected histamine-intolerant patients showed elevated histamine levels during the day. That might be caused by constantly and significantly reduced DAO activities in these patients compared to food-allergic and control patients. The remaining 25 patients presented normal histamine levels and DAO activities, but an increased prevalence of multiple food intolerances compared to the other subgroup of suspected histamine-intolerants. There was no correlation between subjective complaints and serological histamine parameters in patients with suspected histamine intolerance.
We determined by daily profiling that decreased DAO activities correlated with elevated histamine levels in a subgroup of suspected histamine-intolerants. This finding discriminates these patients from food intolerant individuals with similar clinical symptoms and strongly suggests the presence of histamine intolerance.
© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.
day profile; diamine oxidase activities; food allergy; histamine intolerance; histamine levels
Serum Diamine Oxidase in Pseudoallergy in the Pediatric Population.
Adv Exp Med Biol. 2018;1039:35-44. doi: 10.1007/5584_2017_81.
- Department of Pediatrics, Pediatric Nephrology and Allergology, Military Institute of Medicine, 128 Szaserów, 04-141, Warsaw, Poland. firstname.lastname@example.org.
- Department of Immunology and Food Microbiology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.
- Department of Regenerative Medicine and Cell Biology, Military Institute of Hygiene and Epidemiology, Warsaw, Poland.
- Department of Pediatrics, Pediatric Nephrology and Allergology, Military Institute of Medicine, 128 Szaserów, 04-141, Warsaw, Poland.
Histamine intolerance (pseudoallergy) is a poorly investigated type of food hypersensitivity. The main enzyme responsible for histamine degradation in the extracellular matrix is diamine oxidase (DAO). Disturbances in the concentration or activity of DAO may lead to the development of clinical signs of allergy. The aim of the present work was to assess the DAO concentration, peripheral blood morphology, lymphocytes phenotyping (CD3+, CD4+, CD8+, CD19+, NK cells, NKT cells, and activated T-cells), and natural regulatory Treg (nTregs) cell population (CD4+, CD25+, CD127low, and FoxP3) in 34 pediatric patients with histamine-dependent syndromes. Patients were divided into two groups: classical allergy and pseudoallergy on the basis of IgE concentration. The investigation was based on the analysis of peripheral blood samples. A significantly lower serum DAO, both total and specific IgE, concentration was found in the pseudoallergy group compared with the allergy group. There were no significant differences in blood morphology or lymphocyte populations. A similar level of nTreg lymphocytes was also found in both groups, although it was lower than that present in healthy individuals. The findings suggest that the serum DAO is responsible for the symptoms of histamine intolerance. Moreover, a general decrease in nTreg cells in comparison with healthy individuals may lead to symptom aggravation.
Allergy; Angioedema; Dermal lesions; Headache; Immunological disorders; Stomachache
A Popular myth – low-histamine diet improves chronic spontaneous urticaria – fact or fiction?
- Department of Dermatology, Clinical Center Darmstadt GmbH, Darmstadt, Germany.
- Department of Dermatology, University Medical Center of Mainz, Mainz, Germany.
- Nutrition Counselling, Main Area Allergology, Munich, Germany.
Chronic spontaneous urticaria (CsU) is a frequent dermatological disease that might last for months or years with high impact on quality of life. Known causes are autoreactive phenomena, infections or intolerances, rarely IgE-mediated allergies. One-third of CsU patients benefit from a low-pseudoallergen diet. Additionally, it is often discussed, that reducing histamine ingestion alone might improve clinical symptoms and quality of life in CsU patients despite the uncertain role of the histamine-degrading enzyme diamine oxidase (DAO).
Aim of this study was to investigate the impact of low-histamine diet on symptoms and quality of life in patients with CsU.
Patients suffering from CsU accompanied by gastrointestinal symptoms were included in the study. They underwent low-histamine diet for at least 3 weeks. During the whole study, urticaria activity score (UAS) was recorded daily in a patient’s diary. Quality of life was assessed during screening, baseline and post diet visits by completing questionnaires (DLQI and Cu-Q(2)oL). DAO activity was measured before and after elimination diet.
A total of 75% of the patients had a benefit from the low-histamine diet. Thirty-four of 56 patients (61%) reached the primary endpoint of the study, an improvement of UAS 4 of ≥3. Overall, a significant reduction from 9.05 to 4.23 points (P = 0.004) was achieved; the average reduction in a strongly affected subgroup was 8.59 points (P < 0.001). DAO activity remained stable.
Low-histamine diet is a therapeutically useful, simple and cost-free tool to decrease symptoms and increase quality of life in CsU patients with gastrointestinal involvement. Further research is needed to understand the role of diamine oxidase.
© 2016 European Academy of Dermatology and Venereology.
Tyramine and histamine risk assessment related to consumption of dry fermented sausages by the Spanish population
Tyramine and histamine risk assessment related to consumption of dry fermented sausages by the Spanish population.
- Department of Nutrition, Food Sciences and Gastronomy, XaRTA, INSA, School of Pharmacy and Food Sciences, University of Barcelona, Avinguda Prat de la Riba, 171; E-08921 Santa Coloma de Gramenet, Spain.
- IRTA-Food Safety Programme, Institute for Food and Agricultural Research and Technology, Finca Camps i Armet s/n, E-17121 Monells, Spain.
- Department of Nutrition, Food Sciences and Gastronomy, XaRTA, INSA, School of Pharmacy and Food Sciences, University of Barcelona, Avinguda Prat de la Riba, 171; E-08921 Santa Coloma de Gramenet, Spain. Electronic address: email@example.com.
Tyramine and histamine are the main dietary bioactive amines related to acute adverse health effects. Dry fermented sausages can easily accumulate high levels of these hazards and are frequently consumed in Spain. The present work aims to assess the exposure to tyramine and histamine from the consumption of dry fermented sausages by the Spanish population and to assess the risk to suffer acute health effects from this exposure. A probabilistic estimation of the exposure to these hazards was derived combining probability distributions of these amines in dry fermented sausages (n = 474) and their consumption by the Spanish population. The mean dietary exposure to tyramine and histamine was 6.2 and 1.39 mg/meal, respectively. The risk of suffering hypertensive crisis or histamine intoxication by healthy population due to tyramine or histamine intake, respectively, exclusively from dry fermented sausages, can be considered negligible. For individuals under treatment with MAOI drugs, the probability to surpass the safe threshold dose (6 mg/meal) was estimated as 34%. For patients with histamine intolerance, even the presence of this amine in food is not tolerable and it could be estimated that 7000 individuals per million could be at risk to suffer the related symptoms after consuming dry fermented sausages.
Bioactive amines; Dry fermented sausages; Histamine; Histamine intolerance; Risk assessment; Tyramine