Biomolecules 2022, 12, 454. https://doi.org/10.3390/biom12030454
Ying Zhao 1,2,† , Xiaoyan Zhang 1,2,† , Hengxi Jin 2 , Lu Chen 1,2, Jiang Ji 1,2,* and Zhongwei Zhang 3,*
1 Department of Dermatology, The Second Affiliated Hospital of Soochow University, Suzhou 215000, China;
firstname.lastname@example.org (Y.Z.); email@example.com (X.Z.); firstname.lastname@example.org (L.C.)
2 Department of Dermatology and Venereology, Suzhou Medical College of Soochow University,
Suzhou 215000, China; email@example.com
3 Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University,
Nantong 226001, China
*Correspondence: firstname.lastname@example.org (J.J.); email@example.com (Z.Z.); Tel.: +86-0512-6778-3484 (J.J.)
† These authors contributed equally to this work.
Download th review here
Histamine intolerance (HIT) is a common disorder associated with impaired histamine metabolism. Notwithstanding, it is often misdiagnosed as other diseases because of its lack of specific clinical manifestations. HIT did not gain traction until the early 21st century. In this review, we will focus on the latest research and elaborate on the clinical manifestations of HIT, including its manifestations in special populations such as atopic dermatitis (AD) and chronic urticaria (CU), as well as the latest understanding of its etiology and pathogenesis. In addition, we will explore the latest treatment strategies for HIT and the treatment of specific cases.
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.
Impaired resolution of wheals in the skin prick test and low diamine oxidase blood level in allergic patients
Aneta Wagner1, Krzysztof Buczyłko2, Hanna Zielińska-Bliźniewska1, Waldemar Wagner3
1Allergology and Respiratory Rehabilitation Department, Medical University of Lodz, Lodz, Poland
2NZOZ Allergology Center, Lodz, Poland
3Laboratory of Cellular Immunology, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland
Adv Dermatol Allergol 2019; XXXVI (5): 538–543
Introduction: Histamine is the major mediator of IgE- and non-IgE-mediated allergic reactions upon allergen or
hapten contact. Reduced histamine degradation capacity was associated with atopic eczema as well as with nonimmunological
histamine intolerance. Higher blood serum histamine level concomitant with decreased intestinal
diamine oxidase activity were observed in patients with food allergy.
Aim: To evaluate the relationship between patients’ blood diamine oxidase (DAO) activity/histamine status and
their reactivity to time-resolved histamine skin prick test in respect to vulnerability to allergic diseases.
Material and methods: Fifty-three patients were examined with skin prick tests (SPT) and patch tests for suspected
presence of either IgE- or non-IgE-mediated allergy. All individuals were skin prick tested with histamine and the
resolution of the wheal was monitored for 50 min. Blood DAO activity and histamine concentration were measured
with a radio-extraction radioimmunoassay.
Results: Time-resolved histamine skin prick testing revealed presence of wheals which were 35% larger in diameter
in 47% of examined subjects at 20 min of the test. These patients exhibited significantly compromised time-course
wheal resolution (wheal ≥ 3 mm at 50 min) compared to a group of patients with the normal-rate of wheal resolution
(wheal = 0 mm at 50 min). Within a group of subjects exhibiting impaired wheal resolution, 61% of patients
were diagnosed allergic compared to 50% in a group of patients with a normal rate of wheal resolution. Finally,
allergic patients were characterized by a significantly lower DAO activity and higher histamine content compared
to healthy subjects.
Conclusions: The results of this study indicate that patients with IgE- or non-IgE-mediated allergy are likely to
have low DAO blood activity and may concomitantly suffer from histamine intolerance. Furthermore, our results
suggest that allergic patients are more likely to develop an excessive SPT reaction. Our results emphasize caution
in interpretation of the SPT results in allergic patients with diagnosed histamine intolerance or histamine/DAO
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.
Diamine Oxidase Supplementation in Chronic Spontaneous Urticaria: A Randomized, Double-Blind Placebo-Controlled Study
Diamine Oxidase Supplementation in Chronic Spontaneous Urticaria: A Randomized, Double-Blind Placebo-Controlled Study.
Int Arch Allergy Immunol. 2018;176(3-4):268-271. doi: 10.1159/000488142. Epub 2018 Apr 26.
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS Ospedale San Raffaele, Milan, Italy.
- Università Vita-Salute San Raffaele, Milan, Italy.
- Unit of Cellular and Molecular Allergology, IRCCS Ospedale San Raffaele, Milan, Italy.
Diamine oxidase (DAO) catabolizes and inactivates histamine, a key player in a wide range of invalidating conditions, such as migraine and chronic spontaneous urticaria (CSU). The highest expression of DAO occurs in the gastrointestinal tract, possibly to control the burden of histamine intake from food.
Here, we tested the hypothesis that a 30-day oral supplementation with DAO (1 capsule b.i.d., 15 min before a meal) could reduce the severity of CSU as estimated by the 7-Day Urticaria Activity Score (UAS-7). The study was designed as a double-blind, placebo-controlled, crossover investigation of 22 patients with CSU incompletely controlled by first-line antihistamine therapy.
Twenty patients completed the study. Supplemental therapy with DAO caused a 3.8 ± 1.2 point mean ± SEM UAS-7 score reduction in patients with low serum DAO levels at time 0 (p = 0.041 compared to placebo). The degree of UAS-7 improvement was inversely correlated with the levels of basal DAO (p = 0.019). Patients receiving DAO supplementation were able to slightly reduce their daily antihistamine dose (p = 0.049).
These data suggest that DAO may be involved in the pathogenic cascade of CSU and that DAO supplementation could be effective for symptom relief in patients with low DAO levels in serum.
© 2018 S. Karger AG, Basel.
Chronic spontaneous urticaria; Diamine oxidase; Histamine; Histamine intolerance
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
A Histamine-Free Diet Is Helpful for Treatment of Adult Patients with Chronic Spontaneous Urticaria.
In adult patients with chronic urticaria (CU), the prevalence of food allergy is low compared to childhood patients. However, there are many patients who report food-related aggravation of CU, and some of them may have histamine intolerance.
The aim of this study was to evaluate the role of ingested histamine and to investigate the effect of a histamine-free diet in adult patients with CU.
Twenty-two adult patients with CU were enrolled. Foods with high amounts of histamine were prohibited to all patients for four weeks. The degree of severity of the urticaria was evaluated using the urticaria severity score (USS) and urticaria activity score (UAS). Plasma histamine levels and diamine oxidase (DAO) activity were determined and compared before (baseline) and after the histamine-free diet.
Twenty-two adult patients were recruited and completed four weeks of histamine-free diet. The USS and UAS scores each showed significant differences before and after the histamine-free diet (p=0.010, p=0.006). There was a significant reduction in plasma histamine level after the histamine free-diet, compared with baseline (p=0.010). However, DAO activity did not change after the histamine-free diet (p=0.165).
Our study suggested that ingested histamine might be related to CU severity and that a histamine-free diet is helpful for treatment of adult patients with CU.
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: firstname.lastname@example.org.
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