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.
Association of Diamine oxidase (DAO) variants with the risk for migraine from North Indian population
Association of Diamine oxidase (DAO) variants with the risk for migraine from North Indian population
Sukhvinder Kaura,⁎, Arif Alib, Yaser Siahbalaeic, Uzair Ahmadc, Fazila Nargisc, A.K. Pandeyd,
a UGC-PDF, Gene Expression Lab, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
b UGC-BSR-FF, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
c Department of Biosciences, Jamia Millia Islamia, New Delhi, India
d Head, Department of Physiology, ESIC Medical College & Hospital, Faridabad, India
e NC Medical College & Hospital, Panipat, India
A B S T R A C T
Background: Migraine is a common neurovascular disorder affected by various levels of neurotransmitters. Low histamine metabolism is also related with pathophysiology of migraine. As diamine oxidase (DAO) gene variants are linked with higher levels of histamine in migraine patients, we investigated the possible relationship of two variants rs2052129 and rs10156191of this gene with migraine risk in North Indian population.
Methods: A case-control study for 250 migraine patients and 250 matched healthy controls was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Results: We found statistically significant differences in allelic frequencies of rs2052129 (p = .009, OR = 1.462; 95% CI: 1.098–1.947) and rs10156191 (p = .019, OR = 1.430; 95% CI: 1.060–1.928) variants in DAO gene. For rs1015691, we were able to show statistically significant association at all genotypic, dominant and allelic levels in both MA (for T allele, p = .020; OR = 1.662, 95% CI: 1.083–2.551) as well as in female subgroup (for T allele, p = .025, OR = 1.460; 95% CI: 1.049–2.033). But no such significant association was found in clinical sub grouping of migraine in rs2052129 as p > .05. However in gender analysis, protective effect of T allele in male migraine patients for rs2052129 (OR < 1) was found.
Conclusions: Our findings clearly indicated that female patient with rs10156191T allele and in MA subgroup showed an increased risk for migraine. Our data also indicated that rs2052129T variant showed a significant role in migraine susceptibility of this population.
Migraines appear more likely to be caused by histamine rather than ethanol.
Eur J Neurol. 2019 May 20. doi: 10.1111/ene.14003. [Epub ahead of print]
1General Internal Medicine Practice, Dr. Theodor Körnerstrasse 19b, 8600, Bruck, Austria.2Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Auenbruggerplatz 36, 8036, Graz, Austria.
We read with interest the manuscript by Onderwater et al. that reported on alcoholic beverages as a trigger factor for migraines . Although, epidemiological studies have found a correlation between alcohol intake and headaches, a specific pathophysiologic mechanism of this headache remains unidentified . Particularly red wine was documented as the most common trigger for migraines in this evaluated population . Most commonly found biogenic amines in wine – histamine, tyramine, phenylethylamine, putrescine, cadaverine, spermidine, serotonin, tryptamine, agmatine – and, flavonoids have suspected relevance for migraines and this implies that ethanol seems not to be the main culprit for the headaches . This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Alcohol; Diamine oxidase; Headache; Histamine intolerance; MigrainePMID: 31106460 DOI: 10.1111/ene.14003
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.
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.
Low-histamine diet supplemented with exogenous diamine oxidase enzyme is useful for treating migraine in patients with DAO Deficiency
Low-histamine diet supplemented with exogenous diamine oxidase enzyme is useful for treating migraine in patients with DAO Deficiency.
Ann Nutr Metab 2018;73 (suppl 2); 1-93
A.Duelo; M.Berbel; H.Mantecon-Laviguerie; O.Comas-Basté; M.L.Latorre-Moratalla; M.T.Veciana-Noguès; M.C.Vidal-Carou.
Departament of Nutrition, Instituto Clónico del Déficit de DAO (ICDDAO), Sant Cugat del Vallés. Spain; Departament de Nutrició, Ciències de l’Alimentació i Gastonomia. Facultat de Farmàcia i Ciències de l’Alimentació.INSA-UB.XaRTA.Universitat de Barcelona.Santa Coloma de Gramanet. Spain
Spanish Nutrition Society SEÑ and the Catalan Association of Food Science (ACCA), Barcelona, Spain, june 27-29, 2018
Low-histamine diets and/or exogenous diamine oxidase (DAO) supplementation are currently used to treat symptoms of histamine intolerance (IH), a disorder in histamine homeostasis that increases its plasma levels, mainly dou to DAO deficiency. Headache is the most recognized symptoms.
To assess the effectiveness of a low-histamine diet plus a DAO enzyme supplement on the remision of migraine in subjects with DAO deficiency.
An intervention study was carried out in 212 individuals with a migraine diagnosis by a neurologist according to the International Classification of Headache Disorders and wih DAO deficiency (DAO <80 HDU/ml). Subjects followed a 3-month low-histamine diet based on the exclusion of foods considered rich in histamine or other biogenic amines and usually related to the onset of HI symptoms, such as fermented products (cheese, dry-fermented sausage, wine, beer), semi-preserved and canned fish, shellfish, certain fruits and vegetables (spinach, tomato, egg-plant, avocado, citrus, bananas, strawberries, pineapple, nuts) and chocolate. A DAO supplement was administrered before break-fast, lunch and dinner. Outcomes assessed were duration and number of attacks and perception of pain intensity with a score-scale fom 0 (absence) to 10.
Most subjects showed and improvement in migraines after the 3-month treatment: 34.9% reported complete remission and another 35.8% had a reduced number of migraines episodes per month of less duration and pain intensity. The treatment was less successful in 29.3% of patients. On average, when comparing baseline and final values after treatment, all outcomes were significantly reduced: 8 to 2 attacks per month, 24 to 3 hours of pain and 8 to 4 in pain intensity scoring.
A low-histamine diet supplemented with the DAO enzyme for three months was useful in reducing the number of attacks, duration and intensity of pain in migraineous patients with DAO deficiency.
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
Pregnancy-associated diamine oxidase originates from extravillous trophoblasts and is decreased in early-onset preeclampsia
Pregnancy-associated diamine oxidase originates from extravillous trophoblasts and is decreased in early-onset preeclampsia
Sci Rep. 2018 Apr 20;8(1):6342. doi: 10.1038/s41598-018-24652-0.
- Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, Vienna, Austria.
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
- Department of Obstetrics and Gynaecology, Division of General Gynaecology and Gynaecologic Oncology, Medical University of Vienna, Vienna, Austria.
- Forensic Toxicology, Clinical Institute of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
- Children’s Cancer Research Institute, Vienna, Austria.
- Section for Medical Statistics (IMS), Center of Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
- Gynmed Clinic, Vienna, Austria.
- Division of Maternal and Fetal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States.
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. firstname.lastname@example.org.
- Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, Vienna, Austria. email@example.com.
Human extravillous trophoblast (EVT) invasion of the pregnant uterus constitutes a pivotal event for the establishment of the maternal-fetal interface. Compromised EVT function manifesting in inadequate arterial remodeling is associated with the severe pregnancy disorder early-onset preeclampsia (eoPE).
Recent studies suggest that EVTs invade the entire uterine vasculature including arteries, veins and lymphatics in the first trimester of pregnancy. We therefore hypothesized that EVT-derived factors accumulate in the circulation of pregnant women early in gestation and may serve to predict eoPE.
In contrast to published literature, we demonstrate that placenta-associated diamine oxidase(DAO) is not expressed by maternal decidual cells but solely by EVTs, especially when in close proximity to decidual vessels.
Cultures of primary EVTs express and secret large amounts of bioactive DAO.
ELISA measurements indicate a pregnancy-specific rise in maternal DAO plasma levels around gestational week (GW) 7 coinciding with vascular invasion of EVTs.
Strikingly, DAO levels from eoPE cases were significantly lower (40%) compared to controls in the first trimester of pregnancy but revealed no difference at mid gestation. Furthermore, DAO-containing pregnancy plasma rapidly inactivates pathophysiologically relevant histamine levels.
This study represents the first proof of concept suggesting EVT-specific signatures as diagnostic targets for the prediction of eoPE.
Low serum diamine oxidase (DAO) activity levels in patients with migraine.
J Physiol Biochem. 2018 Feb;74(1):93-99. doi: 10.1007/s13105-017-0571-3. Epub 2017 Jun 17.
- Department of Neurology, Hospital General de Catalunya, C/ Pere i Pons 1, 08915, Sant Cugat del Vallès, Spain.
- Department of Basic Sciences, Universitat Internacional de Catalunya, C/ Pere i Pons 1, 08915, Sant Cugat del Vallès, 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, 08921, Santa Coloma de Gramenet, Spain.
- Department of Nutrition, Instituto Clínico del Déficit de DAO (ICDDAO), C/ Pere i Pons 1, 08195, Sant Cugat del Vallès, 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, 08921, Santa Coloma de Gramenet, Spain. firstname.lastname@example.org.
Histamine intolerance is a disorder in the homeostasis of histamine due to a reduced intestinal degradation of this amine, mainly caused by a deficiency in the enzyme diamine oxidase (DAO). Among the several multi-faced symptoms associated with histamine intolerance, headache is one of the most recognized and disabling consequences. The aim of this study was to determine the prevalence of DAO deficiency in patients with a confirmed migraine diagnosis according to the current International Headache Society (IHS) and in non-migraine subjects. DAO activity was assessed in a total of 198 volunteers recruited at the Headache Unit of the Hospital General de Catalunya, 137 in the migraine group and 61 as a control group. DAO enzyme activity in blood samples was determined by ELISA test. Values below 80 HDU/ml (Histamine Degrading Unit/ml) were considered as DAO deficient. Mean value of DAO activity from migraine population (64.5 ± 33.5 HDU/ml) was significantly lower (p < 0.0001) than that obtained from healthy volunteers (91.9 ± 44.3 HDU/ml). DAO deficiency was more prevalent in migraine patients than in the control group. A high incidence rate of DAO deficiency (87%) was observed in the group of patients with migraine. On the other hand, 44% of non-migranous subjects had levels of DAO activity lower than 80 HDU/ml. Despite the multifactorial aetiology of migraine, these results seem to indicate that this enzymatic deficit could be related to the onset of migraine.
Diamine oxidase (DAO); Headache; Histamine; Histamine intolerance; Migraine