Histamine and histamine intolerance

Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. Histamine is a biogenic amine that occurs to various degrees in many foods. In healthy persons, dietary histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of histamine toxicity. Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular histamine after mediator release. Conversely, histamine N-methyltransferase, the other important enzyme inactivating histamine, is a cytosolic protein that can convert histamine only in the intracellular space of cells. An impaired histamine degradation based on reduced DAO activity and the resulting histamine excess may cause numerous symptoms mimicking an allergic reaction. The ingestion of histamine-rich food or of alcohol or drugs that release histamine or block DAO may provoke diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in patients with histamine intolerance. Symptoms can be reduced by a histamine-free diet or be eliminated by antihistamines. However, because of the multifaceted nature of the symptoms, the existence of histamine intolerance has been underestimated, and further studies based on double-blind, placebo-controlled provocations are needed. In patients in whom the abovementioned symptoms are triggered by the corresponding substances and who have a negative diagnosis of allergy or internal disorders, histamine intolerance should be considered as an underlying pathomechanism.     

Serum Diamine Oxidase Values,Indicating Histamine Intolerance,Influence Lactose Tolerance Breath Test Results

Lactose intolerance (LIT) is one of the major causes of irritable bowel syndrome (IBS) spectrum complaints. Differences in inadequate lactose digestion are described as various LIT phenotypes with basically unknown pathophysiology. In LIT patients, we retrospectively assessed the effect of histamine intolerance (HIT) on expiratory hydrogen (H₂) during H₂ lactose breath tests. In a retrospective evaluation of charts from 402 LIT patients, 200 patients were identified as having only LIT. The other 202 LIT patients were found to additionally have diamine oxidase (DAO) values of <10 U/mL, which indicates histamine intolerance (HIT). To identify HIT, standardized questionnaires, low serum DAO values and responses to a histamine-reduced diet were used. Patients were separated into three diagnostic groups according to the result of H₂ breath tests: (1) LIT, with an H₂ increase of >20 parts per million (ppm), but a blood glucose (BG) increase of >20 mg/dL, (2) LIT with an H₂ increase of 20 ppm in combination with a BG increase of <20 mg/dL, and (3) LIT with an exhaled H₂ increase of <20 ppm and BG increase of <20 mg/dL. Pairwise comparison with the Kruskal Wallis test was used to compare the areas under the curve (AUC) of LIT and LIT with HIT patients. Exhaled H₂ values were significantly higher in H₂ > 20 ppm and BG < 20 mg/dL patients with LIT and HIT (p = 0.007). This diagnostic group also showed a significant higher number of patients (p = 0.012) and a significant higher number of patients with gastrointestinal (GI) symptoms during H₂ breath tests (p < 0.001). Therefore, low serum DAO values, indicating HIT, influence results of lactose tolerance breath tests.     

Toward Oral Supplementation of Diamine Oxidase for the Treatment of Histamine Intolerance

A new diamine oxidase (DAO-1) was discovered recently in the yeast Yarrowia lipolytica PO1f and investigated for its histamine degradation capability under simulated intestinal conditions. DAO-1 was formulated together with catalase as a sucrose-based tablet. The latter (9 × 7 mm; 400 mg) contained 690 nkat of DAO-1 activity, which was obtained from a bioreactor cultivation of a genetically modified Y. lipolytica with optimized downstream processing. The DAO-1 tablet was tested in a histamine bioconversion experiment under simulated intestinal conditions in the presence of food constituents, whereby about 30% of the histamine was degraded in 90 min. This amount might already be sufficient to help people with histamine intolerance. Furthermore, it was found that the stability of DAO-1 in a simulated intestinal fluid is influenced distinctively by the presence of a food matrix, indicating that the amount and type of food consumed affect the oral supplementation with DAO. This study showed for the first time that a microbial DAO could have the potential for the treatment of histamine intolerance by oral supplementation.     

Increasing Expiratory Hydrogen in Lactose Intolerance Is Associated with Additional Food Intolerance/Malabsorption

Single and/or combined food intolerance/malabsorption may cause nonspecific, functional gastrointestinal (GI) complaints. In lactose-intolerant patients we evaluated the influence of additional food intolerance/malabsorption with hydrogen (H₂) breath tests. In a retrospective analysis of charts from 279 lactose-intolerant patients, we found 128 patients with only lactose intolerance (LIT). Then, we identified 106 LIT patients with additional histamine intolerance (HIT). Additionally, 45 LIT and HIT patients also had fructose malabsorption (FM). A hydrogen (H₂) breath test was performed to evaluate LIT and FM. A serum diamine oxidase value of <10 U/mL and a response to a histamine-reduced diet was used to identify HIT. Using pairwise comparison with the Kruskal–Wallis test to associate the area under the curve (AUC) of LIT patients and, LIT with HIT, to LIT with HIT and FM it was found, that the exhaled hydrogen values were significantly higher in patients with two-fold and triple combined food intolerance/malabsorption (p < 0.004 and p < 0.001, respectively). Within the pool of 170 LIT patients with >20 ppm increase of expiratory H₂ from baseline, there were 74 LIT-only patients, 60 LIT with HIT patients, and 36 LIT patients with additional HIT and FM. With the Kruskal–Wallis test AUCs demonstrated a significant difference between all three groups (p = 0.024). In patients with LIT, the presence of additional food intolerance/malabsorption, significantly increases expiratory H₂ values. We demonstrate evidence, which may suggest HIT to embody an own GI disorder as food intolerance/malabsorption.     

Histamine Intolerance—The More We Know the Less We Know. A Review

The intake of food may be an initiator of adverse reactions. Food intolerance is an abnormal non-immunological response of the organism to the ingestion of food or its components in a dosage normally tolerated. Despite the fact that food intolerance is spread throughout the world, its diagnosing is still difficult. Histamine intolerance (HIT) is the term for that type of food intolerance which includes a set of undesirable reactions as a result of accumulated or ingested histamine. Manifestations may be caused by various pathophysiological mechanisms or a combination of them. The problem with a “diagnosis” of HIT is precisely the inconstancy and variety of the manifestations in the same individual following similar stimuli. The diagnosing of HIT therefore requires a complex time-demanding multidisciplinary approach, including the systematic elimination of disorders with a similar manifestation of symptoms. Among therapeutic approaches, the gold standard is a low-histamine diet. A good response to such a diet is considered to be confirmation of HIT. Alongside the dietary measures, DAO supplementation supporting the degradation of ingested histamine may be considered as subsidiary treatment for individuals with intestinal DAO deficiency. If antihistamines are indicated, the treatment should be conscious and time-limited, while 2nd or 3rd generation of H₁ antihistamines should take precedence.     

Can Lactose Intolerance Be a Cause of Constipation? A Narrative Review

Lactose intolerance and constipation are common in children and impact everyday life, not only for patients but also their families. Both conditions can be comorbid with other diseases or form a part of their clinical presentation, but constipation is not usually associated with lactose intolerance. The typical symptoms of lactose intolerance include abdominal pain, bloating, flatus, diarrhoea, borborygmi, and less frequently nausea and vomiting. In approximately 30% of cases, constipation can be a symptom of lactose intolerance. Constipation is characterized by infrequent bowel movements, hard and/or large stools, painful defecation, and faecal incontinence, and is often accompanied by abdominal pain. This paper provides a narrative review on lactose intolerance, its epidemiology, pathogenesis, the correlation between lactose intolerance and constipation in children, and potential mechanisms of such association.     

Histaminintoleranz – wirklich eine Unverträglichkeit im Sinne einer reproduzierbaren Gesundheitsstörung auf definierte Auslöser?

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.     

Basal Serum Diamine Oxidase Levels as a Biomarker of Histamine Intolerance: A Retrospective Cohort Study

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.     

Low-Histamine Diets: Is the Exclusion of Foods Justified by Their Histamine Content?

A low-histamine diet is currently the most advised strategy to prevent the symptomatology of histamine intolerance. Conceptually, these diets should be founded on the exclusion of histamine-containing foods, although a certain disparity is found within the list of excluded foods in accordance with the different low-histamine diets available in the literature. This study aimed to critically review low-histamine diets reported in the scientific literature, according to the histamine and other biogenic amine contents of the excluded foods. A total of ten scientific studies that provided specific recommendations on the foods that must be avoided within the framework of a low-histamine diet were found. Overall, the comparative review brought out the great heterogenicity in the type of foods that are advised against for histamine intolerant individuals. Excluded foods were, in most cases, different depending on the considered diet. Only fermented foods were unanimously excluded. The exclusion of 32% of foods could be explained by the occurrence of high contents of histamine. The presence of putrescine, which may interfere with histamine degradation by the DAO enzyme at the intestinal level, could partly explain the reason why certain foods (i.e., citrus fruits and bananas) were also frequently reported in low-histamine diets. Finally, there was a range of excluded foods with an absence or very low levels of biogenic amines. In this case, certain foods have been tagged as histamine-liberators, although the mechanism responsible has not yet been elucidated.     

Histamine plasma levels and elimination diet in chronic idiopathic urticaria

OBJECTIVE: The aim of this study was to evaluate the effects of an oligoantigenic and histamine-free diet on patients affected with chronic idiopathic urticaria (CIU). DESIGN: Ten patients with chronic idiopathic urticaria were prescribed an oligoantigenic and histamine-free diet for 21 days, followed by serial and controlled reintroduction of foods during a further 70 days. Modification in clinical illness as well as histamine plasma levels, post-heparin plasma diamine oxidase (DAO) and intestinal permeability were evaluated. RESULTS: The oligoantigenic and histamine-free diet induced a significant improvement of symptoms (P<0.05). Moreover, CIU patients on free diet showed higher histamine plasma levels (P<0. 05 vs post-diet and vs controls) that fell to control levels during the oligoantigenic and histamine-free diet. Post-heparin plasma diamine oxidase values were slightly reduced and were unchanged during the diet as well as intestinal permeability, which was always normal in all patients. CONCLUSIONS: These data suggest that histamine plays a major role in chronic idiopathic urticaria. The finding of normal intestinal permeability suggests that a morphological damage of intestinal mucosa should be excluded in these patients. However, the presence of low levels of post-heparin plasma diamine oxidase may indicate a subclinical impairment of small bowel enterocyte function that could induce a higher sensitivity to histamine-rich or histamine-producing food. European Journal of Clinical Nutrition (2000) 54, 155-158     

Diabetes mellitus in children

The review is covering different forms of diabetes mellitus occurring in children and adolescents. Main characteristics of childhood diabetes are based on the continuous changes in growth and development of children. The review is focusing on the diagnostics, epidemiology, etiopathogenesis and natural course of type 1 diabetes, the dominant form in the pediatric age group. Insulin treatment, nutritional management and education, including age related special problems are covered. Due to space limitations, acute and late complications, as well as possible prevention of type 1 diabetes are shortly mentioned. Beside type 1 diabetes, other forms of carbohydrate intolerance occurring in children are also also included. Among those, special emphasis is put on type 2 diabetes, due to its increasing incidence in children and adolescents parallel to the increased prevalence of childhood obesity.     

肺炎支原体的耐药机制及治疗

肺炎支原体（MP）为常见的儿童呼吸道感染病原体之一.随着大环内酯类抗菌药物的广泛应用,耐大环内酯抗菌药物菌（MRMP）呈上升趋势,MRMP感染人群已向成年人蔓延.MRMP较敏感菌株导致感染个体的临床症状持续时间长,肺外并发症发病率高.笔者拟就肺炎支原体流行病学、耐药机制及MRMP的治疗,综述如下.     

Alcohol-histamine interactions.

Alcohol and histamine metabolic pathways in the body have the common enzymes aldehyde dehydrogenase and aldehyde oxidase. The metabolite of ethanol, acetaldehyde, can effectively compete with the metabolites of histamine, methylimidazole acetaldehyde, and imidazole acetaldehyde. At the periphery, alcohol and acetaldehyde liberate histamine from its store in mast cells and depress histamine elimination by inhibiting diamine oxidase, resulting in elevated histamine levels in tissues. Histamine mediates alcohol-induced gastric and intestinal damage and bronchial asthma as well as flushing in Orientals. On the other hand, alcohol provokes food-induced histaminosis and histamine intolerance, which is an epidemiological problem. There are many controversial reports concerning the effect of H2 receptor antagonists on ethanol metabolism and the activity of alcohol dehydrogenase in the stomach. In addition, alcohol affects histamine levels in the brain by modulating histamine synthesis, release, and turnover. Histamine receptor antagonists can affect ethanol metabolism and change the sensitivity of animals to the hypnotic effects of alcohol. In contrast to other neurotransmitters, the involvement of the brain histamine system in the mechanisms of the central actions of alcohol and in the pathogenesis of alcoholism is poorly studied and understood.     

Dietary treatment of lactose intolerance in infants and children

During the past several years there have been many reports of alternative dietary therapies for primary and secondary lactose intolerance. We have learned that it is useful to feed through most episodes of mild diarrhea that previously would have been treated with clear liquid diets. Infant formulas, including both soy-protein and hydrolysate formulas with specially designed carbohydrate, protein, and fat components, are available to treat the infant with diarrheal syndromes and secondary lactase deficiency. Also, the diet can be supplemented with lactase. Specialized lactose-reduced products as well as cultured and fermented dairy products may be used in varying degrees for lactose-intolerant children. The ingestion of milk with food and fiber components in the diet has also been shown to improve symptoms of lactose intolerance. This review summarizes the essentials of diagnosis of and dietary therapy for lactose intolerance. Our findings indicate that a number of specialized formulas and products are available for successful dietary management of lactose intolerance in infants and children.     

阻塞性呼吸睡眠暂停综合征在儿科的研究进展

儿童阻塞性呼吸睡眠暂停综合征与成人相比,有许多共同特征,但又有其显著的特点.该文从儿童阻塞性呼吸睡眠暂停综合征的病因、病理生理、流行病学、临床表现、诊断以及治疗上,对该病目前研究的进展进行阐述.治疗主要以减轻或缓解打鼾、低氧血症、呼吸暂停及睡眠紊乱为主,多采用扁桃体或腺样体切除术、持续正压通气、消除过敏原、减肥、氧疗等措施.     

Guillain-Barré syndrome

Guillain-Barré syndrome is the most common paralytic illness affecting children and adolescents in countries with established immunization programs. The term is currently used to encompass a group of disorders in which an autoimmune response occurs days or weeks after an antecedent infection or event (e.g., immunization) and results in an acute polyradiculoneuropathy with flaccid weakness, areflexia, and increased cerebrospinal fluid protein. This chapter reviews the epidemiology, clinical presentation, diagnostic criteria, pathogenesis, treatment, and outcome of this condition.     

Advances in celiac disease and gluten-free diet

Celiac disease is becoming an increasingly recognized autoimmune enteropathy caused by a permanent intolerance to gluten. Once thought to be a rare disease of childhood characterized by diarrhea, celiac disease is actually a multisystemic disorder that occurs as a result of an immune response to ingested gluten in genetically predisposed individuals. Screening studies have revealed that celiac disease is most common in asymptomatic adults in the United States. Although considerable scientific progress has been made in understanding celiac disease and in preventing or curing its manifestations, a strict gluten-free diet is the only treatment for celiac disease to date. Early diagnosis and treatment, together with regular follow-up visits with a dietitian, are necessary to ensure nutritional adequacy and to prevent malnutrition while adhering to the gluten-free diet for life. The purpose of this review is to provide clinicians with current updated information about celiac disease, its diverse clinical presentation and increased prevalence, the complex pathophysiology and strong genetic predisposition to celiac disease, and its diagnosis. This review focuses in detail on the gluten-free diet and the importance of intense expert dietary counseling for all patients with celiac disease. Recent advances in the gluten-free diet include food allergen labeling as well as the US Food and Drug Administration's proposed definition of the food-labeling term gluten-free. The gluten-free diet is complex and patients need comprehensive nutrition education from a skilled dietitian.     

A diagnostic decision rule for management of children with meningeal signs

In a previous study we devised a diagnostic decision rule to improve management of children with meningeal signs, suspected of having bacterial meningitis. The decision rule aimed to guide decisions on (1) whether a lumbar puncture is necessary in children with meningeal signs, and (2) which children need hospitalisation and empirical antibiotic treatment for bacterial meningitis. In this study we assessed the validity of this rule in an external population of four (paediatric) hospitals in The Netherlands. The decision rule included two scoring algorithms using symptoms, signs and quickly available blood and cerebrospinal fluid (CSF) laboratory tests. To evaluate the discriminative value of both algorithms, the absolute numbers of correctly diagnosed patients and the area under the receiver operator characteristic curve were estimated, and compared with the results from the original population (n = 360). In a 18 month period, we included 226 children, median age 2.2 years, who visited the emergency department with meningeal signs. Bacterial meningitis was present in 25 (11%). Using the scoring algorithms patients could be categorised in groups of increasing risk of bacterial meningitis. The discriminative values of the clinical and CSF algorithm in this new population were similar to those in the original population. In the total population of 586 children with meningeal signs, the rule selected 205 children (35%) who did not need a lumbar puncture and 366 children who did not need empirical treatment (62%). In conclusion, this diagnostic rule performed well in a new population of children with meningeal signs. This diagnostic decision rule is a valuable tool for the clinician when deciding to treat these children for bacterial meningitis and thus improving their management.