Histamine Articles 8


Histamine receptors and antihistamines: from discovery to clinical applications.
            (Cataldi et al., 2014) Download
The synthesis and the identification of histamine marked a milestone in both pharmacological and immunological research. Since Sir Henry Dale and Patrick Laidlaw described some of its physiological effects in vivo in 1910, histamine has been shown to play a key role in the control of gastric acid secretion and in allergic disorders. Using selective agonists and antagonists, as well as molecular biology tools, four histamine receptors (H1R, H2R, H3R and H4R) have been identified. The Nobel Prize in Physiology and Medicine was awarded to Daniel Bovet in 1957 for the discovery of antihistamines (anti-H1R) and to Sir James Black in 1988 for the identification of anti-H2R antagonists. Anti-H1R and anti-H2R histamine receptor antagonists have revolutionized the treatment of certain allergic disorders and gastric acid-related conditions, respectively. More recently, anti-H3R antagonists have entered early-phase clinical trials for possible application in obesity and a variety of neurologic disorders. The preferential expression of H4R by several immune cells and its involvement in the development of allergic inflammation provide the rationale for the use of anti-H4R antagonists in allergic and in other immune-related disorders.

Concomitant Prevalence of Low Serum Diamine Oxidase Activity and Carbohydrate Malabsorption.
            (Enko et al., 2016) Download
The aim of this retrospective study was to analyze the concomitant prevalence rates for lactose malabsorption (LM), fructose malabsorption (FM), and histamine intolerance (HI) in patients with so far unexplained gastrointestinal (GI) symptoms. A total of 439 outpatients, who presented unclear abdominal discomfort, underwent lactose (50 g) and fructose (25 g) hydrogen (H2) breath tests. Additionally, serum diamine oxidase (DAO) measurements were performed. Individuals with low serum DAO activity (<10 U/mL), GI symptoms, and response to histamine-free diet were diagnosed with HI. Of all 439 patients, 341 (77.7%) were found with 7 various GI conditions. In total, 94 (21.4%), 31 (7.1%), and 100 (22.8%) individuals presented LM, FM, or HI only, whereas 116 (26.4%) patients showed an overlap of GI entities investigated here. Interestingly, 89 out of 241 (36.9%) individuals with carbohydrate malabsorption were also diagnosed with HI (LM + HI: 52 [11.8%], FM + HI: 23 [5.2%], and LM + FM + HI 14 [3.2%] individuals). In conclusion different combinations of LM, FM, and HI are present in individuals with unclear abdominal discomfort/pain. In clinical practice we suggest testing for LM, FM, and additional HI in the diagnostic work-up of these patients. Depending on these various diagnoses possible, patients should get an individualized dietary advice.

Serum diamine oxidase activity is associated with lactose malabsorption phenotypic variation.
            (Enko et al., 2017) Download
OBJECTIVES:  Recently, an intermediate lactose intolerance (LI) phenotype based on the lactase gene (LCT) C/T-13910 polymorphism was proposed. However, a multifactorial genesis of LI phenotypic variation including endogenous and exogenous factors cannot be ruled out. Therefore, this study was conducted to investigate a possible association between serum diamine oxidase (DAO) and LI phenotypes in individuals with lactose malabsorption (LM). DESIGN AND METHODS:  A total of 121 ambulatory patients with LM were included in this retrospective study. The lactose hydrogen breath test (LHBT) and serum DAO activity measurements were performed on the same day. A thorough anamnesis with respect to gastrointestinal symptoms was carried out at the initial consultation. RESULTS:  In total, 44 (36.4%) patients with a serum DAO activity <10U/mL showed higher H2 levels after 60 (mean: 53.7±57.6 vs 34.5±31.7 parts per million [ppm], p=0.116), 90 (mean: 70.3±57.5 vs 52.7±41.4ppm, p=0.184) and 120min (mean: 98.9±72.5 vs 67.9±44.9ppm, p=0.012) during LHBT compared to 77 (63.6%) patients with a serum DAO activity ≥10U/mL. Individuals with a serum DAO activity <10U/mL tended to report gastrointestinal symptoms during the LHBT more often (p=0.091). CONCLUSIONS:  Our findings suggest that patients with LM and a serum DAO activity level<10U/mL had higher end-expiratory H2 levels and tended to be more symptomatic during the LHBT compared to LM patients with DAO activity levels ≥10U/mL.

Distribution, properties, and functional characteristics of three classes of histamine receptor.
            (Hill, 1990) Download
It is clear from the preceding overview of histamine receptor pharmacology that research into the pharmacology of histamine receptors is at an exciting stage of development. The rapid advance of molecular biology should soon see the structural identification and cloning of all three of the major vertebrate histamine receptors. Further work will continue toward enhancing our understanding of the control by histamine of intracellular signaling via H1- and H2-receptors, and the rapid explosion of work on the H3-receptor should begin to unravel the mechanisms underlying its actions, perhaps via effects on ionic channels. The potential role of histamine as an intracellular second messenger raises exciting possibilities, as does the search for a histamine receptor analogous to the ligand-gated ion channel in the invertebrate nervous system.


The roles of histamine and its receptor ligands in central nervous system disorders: An update.
            (Hu and Chen, 2017) Download
The neurotransmitter histamine receives less attention compared with other biogenic amines, because of its moderate action in the central nervous system (CNS). However, recent evidence suggests that histamine plays an important role in multiple CNS disorders including insomnia, narcolepsy, Parkinson's diseases, schizophrenia, Alzheimer's disease, and cerebral ischemia. New insights are emerging into the potential roles of histamine receptors as targets for the treatment of these diseases. Although some histamine related agents have failed in clinical trials, current preclinical studies suggest that this neurotransmitter may still have extensive applications in treating CNS disorders, however, advanced studies are warranted. This review summarizes findings from animal models and clinical research on the role of histamine and its receptor ligands in the brain for treatment of CNS disorders. The development of novel histamine receptor ligands and gaining an in-depth understanding of their potential mechanisms are necessary stepping stones to unlock their wide-ranging applications in the clinical arena.

Lymphatic diamine oxidase secretion stimulated by fat absorption is linked with histamine release.
            (Ji et al., 2013) Download
Diamine oxidase (DAO) is abundantly expressed in mammalian small intestine catalyzing the oxidative breakdown of polyamines and histamine. The aim of this study was to determine the relationship between stimulation of intestinal diamine oxidase secretion with intestinal fat absorption and histamine release. Conscious intestinal lymph fistula rats were used. The mesenteric lymph ducts were cannulated and intraduodenal tubes were installed for the infusion of Liposyn II 20% (an intralipid emulsion). Lymphatic DAO activity and protein secretion were analyzed by radiometric assay and Western blot, respectively. Lymphatic histamine concentration was measured by ELISA. Infusion of Liposyn II (4.43 kcal/3 ml) resulted in a ~3.5-fold increase in lymphatic DAO protein secretion and DAO activity, peaking at 1 h and lasting for 3 h. Liposyn II infusion also increased the lymphatic histamine release, a substrate for DAO. To determine the relationship of DAO release with histamine release, histamine was administered intraperitoneally (10 mg/kg) in fasting rats and resulted in a significant doubling in lymphatic DAO activity, supporting a link between histamine and DAO. In addition, ip administration of the histamine H4 receptor antagonist JNJ7777120 significantly reduced the Liposyn II-induced DAO output by 65.9%, whereas H(1) (pyrilamine maleate), H(2) (ranitidine), and H(3) (thioperamide maleate) receptor antagonists had little effect. We conclude that DAO secretion may contribute to the catabolism of histamine released during fat absorption and this is probably mediated through the histamine H(4) receptor.

Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis.
            (Johnston et al., 1992) Download
Renewed interest in the antihistamine action of ascorbic acid has emerged with the recently recognized immunosuppressive role of histamine. We examined the antihistamine effect of acute and chronic vitamin C (VC) administration and its effect on neutrophil chemotaxis in healthy men and women. In the chronic study, 10 subjects ingested a placebo during weeks 1, 2, 5 and 6, and 2 g/day of VC during weeks 3 and 4. Fasting blood samples were collected after the initial 2-week period (baseline) and at the end of weeks 4 and 6. Plasma ascorbate rose significantly following VC administration compared to baseline and withdrawal values. Neutrophil chemotaxis rose 19% (NS) during VC administration, and fell 30% after VC withdrawal, but these changes were not correlated to plasma ascorbate levels (r = 0.01). Chemotaxis was inversely correlated to blood histamine (r = -0.32, p = 0.045), and, compared to baseline and withdrawal values, histamine levels were depressed 38% following VC supplementation. Blood histamine and neutrophil chemotaxis did not change 4 hours following a single 2 g dose of ascorbic acid, although plasma ascorbate rose 150%. These data indicate that VC may indirectly enhance chemotaxis by detoxifying histamine in vivo.

Serum diamine oxidase activity as a diagnostic test for histamine intolerance.
            (Mušič et al., 2013) Download
BACKGROUND:  Histamine intolerance (HIT) is characterized by an imbalance between histamine intake and the capacity for histamine degradation. The main enzyme for metabolizing ingested histamine is diamine oxidase (DAO). Determining DAO activity in serum may be useful in diagnosing HIT. METHODS:  Over a period of 3.5 years we recruited 316 subjects with clinically suspected HIT and 55 healthy controls. Serum DAO activity was measured with a quantitative enzyme immunoassay. Twenty patients with highly reduced DAO activity went on a histamine-free diet for 6-12 months. Afterwards, their DAO activity was determined again. RESULTS:  We found that DAO activity was significantly lower in patients than in healthy control subjects (P < 0.0001). Furthermore, 54 patients had highly reduced serum DAO activity (< 40 HDU/ml). Their main symptoms involved the skin, gastrointestinal tract, respiratory system, and eyes. In all the 20 patients with highly reduced DAO activity, the main clinical symptoms typical of histamine intolerance disappeared after they adopted a histamine-free diet. Furthermore, the serum DAO activity values measured increased significantly (P < 0.0001). CONCLUSIONS:  Our results suggest that determining DAO activity in serum is a useful tool in diagnosing HIT. Furthermore, our results showed the benefit of a histamine-free diet because after the diet the majority of symptoms disappeared and the serum DAO activity significantly increased.


Role of histamine as a toxic mediator in the pathogenesis of vitiligo.
            (Panja et al., 2013) Download
BACKGROUND:  The precise cause of vitiligo is still unclear. Multiple theories have been proposed, including genetic, autoimmune, neural, and biochemical mechanisms. An immune mediated pathogenesis is indeed the most popular theory. The autoimmune hypothesis considers the role of toxic mediator that might cause an injury to the melanocytes with the release of an antigenic substance and subsequent autoimmunization. AIMS:  This study performed over a period of 10 years (February 1975 to June 1985) aims at exploring the role that histamine might play in the pathogenesis of vitiligo. MATERIALS AND METHODS:  Fifty patients with a particular type of vitiligo characterized by faint white patches occurring with significant pruritus and a history of atopy were selected and blood histamine levels were determined by Bio-Assay method. RESULTS:  Blood histamine values of patients with vitiligo of short duration and with pruritus were significantly increased in comparison with values of matched controls. CONCLUSION:  Histamine appears to play a significant role in the pathogenesis of a particular type of vitiligo characterized by faint hypopigmented patches with significant itching.

Excretion of urinary histamine and N-tele methylhistamine in patients with gastrointestinal food allergy compared to non-allergic controls during an unrestricted diet and a hypoallergenic diet.
            (Raithel et al., 2015) Download
BACKGROUND:  Patients with gastrointestinal food allergy are characterised by increased production of mast cell derived mediators upon allergen contact and present often with unspecific symptoms. The aim of this study was to evaluate urinary histamine and methylhistamine excretion in patients with food allergy and to compare their values with food-tolerant controls. METHODS:  In a retrospective case control study the urinary excretion parameters were analysed from 56 patients (40.9, 19 - 58 years) in whom later food challenge tests confirmed food allergy. During their diagnostic work-up urine was collected during a 12-h period under an unrestricted diet with staple foods and a hypoallergenic potato-rice-diet (each 2 days). Healthy controls underwent the same diet types to define normal excretion parameters. Urinary histamine and n-methylhistamine were determined by ELISA or tandem mass spectrometry, respectively, and were expressed as median (25 - 75% range, μg/mmol creatinine x m(2)BSA). RESULTS:  During unrestricted diet urinary histamine was significantly higher in gastrointestinal food allergy than healthy controls (1.42, 0.9 - 2.7 vs 0.87, 0.4 - 1.3; p < 0.0001), while the difference between both groups became marginal during potato-rice diet (1.30, 0.7 - 2.1 vs 1.05, 0.5 - 1.5; p = 0.02). N-methylhistamine was found to be significantly elevated in gastrointestinal food allergy both during unrestricted diet (7.1, 5.0 - 11.2) and potato-rice diet (5.7, 3.7 - 8.7) compared to controls (p < 0.0001). Interestingly, urinary methylhistamine excretion (p < 0.004) and clinical symptom score (p < 0.02) fell significantly when the diet was switched from unrestricted to hypoallergenic food, but was not correlated with symptom scores. CONCLUSIONS:  In gastrointestinal food allergy significantly higher levels of urine histamine and methylhistamine excretion were found under unrestricted diet, reflecting an increased secretion of histamine due to offending foods. Measurement of urinary n-methylhistamine levels may help to find out patients with increased histamine production and/or food-allergen induced clinical symptoms, respectively.

Histamine intolerance as a cause of chronic digestive complaints in pediatric patients.
            (Rosell-Camps et al., 2013) Download
INTRODUCTION:  histamine intolerance (HI) is a poorly described disease in gastroenterology that may present with predominant digestive complaints. The goals of this study include a report of two cases diagnosed in a pediatric gastroenterology clinic. MATERIAL AND METHODS:  observational, retrospective study of patients diagnosed with HI from September 2010 to December 2011 at the pediatric gastroenterology clinic of a tertiary hospital.They were deemed to have a diagnosis of HI in the presence of 2 or more characteristic digestive complaints, decreased diamino oxidase (DAO) levels and/or response to a low histamine diet with negative IgE-mediated food allergy tests. RESULTS:  sixteen patients were diagnosed. Males predominated versus females (11/5). Mean age at symptom onset was 4 years (6 months vs. 13 years and 6 months) and mean age at diagnosis was 6 years and 6 months (17 months vs. 13 years and 11 months), with an interval of 2 years and 1 month between symptom onset and diagnosis (5 months vs. 4 years). Predominant symptoms included diffuse abdominal pain (16/16), intermittent diarrhea (10/16), headache (5/16), intermittent vomiting (4/16), and skin rash (2/16). The diagnosis was established by measuring plasma diamino oxidase levels, which were below 10 kU/L (normal > 10 kU/L) in 14 cases, and symptom clearance on initiating a low histamine diet. In two patients DAO levels were above 10 kU/L but responded to diet. Treatment was based on a diet low in histamine-contaning food, and antihistamines H1 y H2 had to be added for two cases. CONCLUSIONS:  histamine intolerance is a little known disease with a potentially relevant incidence. Predominant complaints include diffuse abdominal pain, diarrhea, headache, and chronic intermittent vomiting. Its diagnosis is based on clinical suspicion, plasma DAO measurement, and response to a low histamine diet. Management with the latter provides immediate improvement.


Effects of glutamine on markers of intestinal inflammatory response and mucosal permeability in abdominal surgery patients: A meta-analysis.
            (Shu et al., 2016) Download
The present meta-analysis was carried out to determine whether supplementation with glutamine (Gln) would reduce the intestinal inflammatory response and mucosal permeability in patients undergoing abdominal surgery. The PubMed, EMBASE, Web of Science, and The Cochrane Library databases were searched for randomized controlled trials on the effects of supplementation with Gln, and published from August, 1966 to June 2014. Inclusion criteria for the meta-analysis were: i) Study design was a randomized controlled trial, ii) study included patients undergoing abdominal surgery, iii) study patients received a supplementation with Gln peptide (Ala-Gln or Gly-Gln) whereas control patients did not use any supplements, and iv) study outcomes included inflammatory markers [C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6, and IL-2 receptor] and markers of intestinal permeability [lactulose/mannitol, diamine oxidase, D(-)lactic acid, and endotoxin]. Qualities of controlled trials were assessed using the Jadad score. Meta-analyses were performed with fixed- or random-effect models depending on the heterogeneity of studies. There were 21 trials meeting the inclusion criteria. The meta-analysis revealed that the levels of CRP, TNF-α, and IL-6 in patients supplemented with Gln were significantly lower than those in control patients, whereas the levels of IL-2 receptor were increased by Gln supplementation. Gln also significantly decreased the lactulose/mannitol ratio, the levels of diamine oxidase and endotoxin, and tended to decrease the levels of cyclic D-lactic acid. In conclusion, Gln appears to effectively reduce the inflammatory response and intestinal mucosal permeability in patients after abdominal surgery.

Histamine intolerance in patients with chronic spontaneous urticaria.
            (Siebenhaar et al., 2016) Download
BACKGROUND:  Histamine intolerance and pseudoallergy to foods have been suggested to be causes of chronic spontaneous urticaria (CSU) with some patients reporting exacerbation with histamine-rich foods. OBJECTIVE:  The study aim was to identify the rate of histamine-intolerant CSU patients and to characterize the relevance of histamine intolerance as an underlying cause of CSU. METHODS:  A cohort of 157 of moderate to severe CSU patients (UAS7 ≥ 10) was asked to provide a detailed clinical history, particularly in relation to symptom development after eating histamine-rich foods. They subsequently undertook a histamine-free pseudoallergen-low diet followed by a double-blind, placebo-controlled oral histamine provocation (75 mg). RESULTS:  One third of patients (34%) had a positive history of histamine intolerance. There was no statistical difference between the mean UAS7 scores of patients with positive and negative histories (22.4 ± 1.0 vs. 22.7 ± 0.8). When kept on diet, 46% of patients responded with reduced CSU activity (UAS7 reduction of ≥7). Following double-blind, placebo-controlled oral histamine provocation, 17% of patients gave a positive weal response. There appeared to be little relationship between patient history, response to diet and the weal response to oral histamine provocation. First, the history-positive and -negative groups contained similar proportions of diet and histamine provocation weal-positive patients. Second, the diet-positive and -negative groups contained similar proportions of history-positive and histamine provocation weal-positive patients. Third, the histamine provocation weal-positive and -negative groups had similar rates of history- and diet-positive patients. Finally, only 2 of the 157 patients were positive in all three domains. CONCLUSIONS:  CSU due to histamine intolerance appears to be rare and cannot be diagnosed based on the history. The study confirms that avoidance diets low in pseudoallergens can improve urticaria symptoms, this is probably not due to the absence of dietary histamine.

Histamine and gut mucosal immune regulation.
            (Smolinska et al., 2014) Download
Histamine is a biogenic amine with extensive effects on many cell types, mediated by the activation of its four receptors (H1R-H4R). Distinct effects are dependent on receptor subtypes and their differential expression. Within the gastrointestinal tract, histamine is present at relatively high concentrations, particularly during inflammatory responses. In this review, we discuss the immunoregulatory influence of histamine on a number of gastrointestinal disorders, including food allergy, scombroid food poisoning, histamine intolerance, irritable bowel syndrome, and inflammatory bowel disease. It is clear that the effects of histamine on mucosal immune homeostasis are dependent on expression and activity of the four currently known histamine receptors; however, the relative protective or pathogenic effects of histamine on inflammatory processes within the gut are still poorly defined and require further investigation.

Histamine regulation in glucose and lipid metabolism via histamine receptors: model for nonalcoholic steatohepatitis in mice.
            (Wang et al., 2010) Download
Histamine has been proposed to be an important regulator of energy intake and expenditure. The aim of this study was to evaluate histamine regulation of glucose and lipid metabolism and development of nonalcoholic steatohepatitis (NASH) with a hyperlipidemic diet. Histamine regulation of glucose and lipid metabolism, adipocytokine production, and development of hyperlipidemia-induced hepatic injury were studied in histamine H1 (H1R(-/-)) and H2 (H2R(-/-)) receptor knockout and wild-type mice. H1R(-/-) mice showed mildly increased insulin resistance. In contrast, H2R(-/-) mice manifested profound insulin resistance and glucose intolerance. High-fat/high-cholesterol feeding enhanced insulin resistance and glucose intolerance. Studies with two-deoxy-2-[(18)F]-fluoro-d-glucose and positron emission tomography showed a brain glucose allocation in H1R(-/-) mice. In addition, severe NASH with hypoadiponectinemia as well as hepatic triglyceride and free cholesterol accumulation and increased blood hepatic enzymes were observed in H2R(-/-) mice. H1R(-/-) mice showed an obese phenotype with visceral adiposity, hyperleptinemia, and less severe hepatic steatosis and inflammation with increased hepatic triglyceride. These data suggest that H1R and H2R signaling may regulate glucose and lipid metabolism and development of hyperlipidemia-induced NASH.



Cataldi, M, et al. (2014), ‘Histamine receptors and antihistamines: from discovery to clinical applications.’, Chem Immunol Allergy, 100 214-26. PubMed: 24925401
Enko, D, et al. (2016), ‘Concomitant Prevalence of Low Serum Diamine Oxidase Activity and Carbohydrate Malabsorption.’, Can J Gastroenterol Hepatol, 2016 4893501. PubMed: 28042564
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Hill, SJ (1990), ‘Distribution, properties, and functional characteristics of three classes of histamine receptor.’, Pharmacol Rev, 42 (1), 45-83. PubMed: 2164693
Hu, W and Z Chen (2017), ‘The roles of histamine and its receptor ligands in central nervous system disorders: An update.’, Pharmacol Ther, PubMed: 28223162
Ji, Y, et al. (2013), ‘Lymphatic diamine oxidase secretion stimulated by fat absorption is linked with histamine release.’, Am J Physiol Gastrointest Liver Physiol, 304 (8), G732-40. PubMed: 23413254
Johnston, CS, LJ Martin, and X Cai (1992), ‘Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis.’, J Am Coll Nutr, 11 (2), 172-76. PubMed: 1578094
Mušič, E, et al. (2013), ‘Serum diamine oxidase activity as a diagnostic test for histamine intolerance.’, Wien Klin Wochenschr, 125 (9-10), 239-43. PubMed: 23579881
Panja, SK, B Bhattacharya, and SC Lahiri (2013), ‘Role of histamine as a toxic mediator in the pathogenesis of vitiligo.’, Indian J Dermatol, 58 (6), 421-28. PubMed: 24249891
Raithel, M, et al. (2015), ‘Excretion of urinary histamine and N-tele methylhistamine in patients with gastrointestinal food allergy compared to non-allergic controls during an unrestricted diet and a hypoallergenic diet.’, BMC Gastroenterol, 15 41. PubMed: 25888445
Rosell-Camps, A, et al. (2013), ‘Histamine intolerance as a cause of chronic digestive complaints in pediatric patients.’, Rev Esp Enferm Dig, 105 (4), 201-6. PubMed: 23859448
Shu, XL, et al. (2016), ‘Effects of glutamine on markers of intestinal inflammatory response and mucosal permeability in abdominal surgery patients: A meta-analysis.’, Exp Ther Med, 12 (6), 3499-506. PubMed: 28105083
Siebenhaar, F, et al. (2016), ‘Histamine intolerance in patients with chronic spontaneous urticaria.’, J Eur Acad Dermatol Venereol, 30 (10), 1774-77. PubMed: 27329741
Smolinska, S, et al. (2014), ‘Histamine and gut mucosal immune regulation.’, Allergy, 69 (3), 273-81. PubMed: 24286351
Wang, KY, et al. (2010), ‘Histamine regulation in glucose and lipid metabolism via histamine receptors: model for nonalcoholic steatohepatitis in mice.’, Am J Pathol, 177 (2), 713-23. PubMed: 20566747