[Histamine intolerance syndrome (HIS): plethora of physiological, pathophysiological and toxic mechanisms and their differentiation]. / Histaminintoleranz-Syndrom (HIS): Vielfalt der Mechanismen von physiologischer, pathophysiologischer und toxischer Wirkung und deren Unterscheidung.

BACKGROUND: Non-immunological types of foodstuffs intolerance are reported by about 15-20% people of the population. The intolerance of histamine and to some extent of other biogenic amines (such as cadaverine, putrescine, tyramine etc.) plays an important role in the differential diagnosis of the foodstuff intolerances and has to be strictly separated from immunologically mediated foodstuffs reactions (foodstuffs allergies, 2-5% of the population). METHODS: Clinical data from the Erlangen interdisciplinary data register of allergic and chronic inflammatory gastro-intestinal diseases were analysed respecting the existence of a histamine intolerance, then classified and summarised; in addition a selective literature research was undertaken in May 2011. RESULTS: In non-immunological cases of foodstuffs intolerance, the patient's intolerance of histamine plays quite a significant role, clinically it has been exactly proven only in a small subgroup of patients by standardised blinded provocation reactions. The histamine intolerance syndrome (HIS) often presents in a non-specific manner and has to be separated from other pseudo-allergic reactions, idiopathic intolerance reactions, organic differential diagnosis (for example, chronic infections, allergies, mastocytosis etc.) as well as medicamentous adverse effects and psychosomatic reactions. CONCLUSION: The clinical picture of histamine intolerance should be definitely assured, after the exclusion of other differential diagnosis, by standardised histamine provocation. The avoidance of histamine and biogenic amines, the use of antihistaminics and the instauration of a proportionate nutrient matter are the most important therapeutic options next to a detailed education of the patient.

Analysis of immediate ex vivo release of nitric oxide from human colonic mucosa in gastrointestinally mediated allergy, inflammatory bowel disease and controls.

Nitric oxide (NO) is a local mediator in inflammation and allergy. The aim of this study was to investigate whether live incubated colorectal mucosal tissue shows a direct NO response ex vivo to nonspecific and specific immunological stimuli and whether there are disease-specific differences between allergic and chronic inflammatory bowel disease (IBD). We took biopsies (n=188) from 17 patients with confirmed gastrointestinally mediated food allergy, six patients with inflammatory bowel disease, and six control patients. To detect NO we employed an NO probe (WPI GmbH, Berlin, Germany) that upon stimulation with nonspecific toxins (ethanol, acetic acid, lipopolysaccharides), histamine (10(-8)-10(-4)M), and immune-specific stimuli (anti-IgE, anti-IgG, known food allergens) directly determined NO production during mucosal oxygenation. Non-immune stimulation of the colorectal mucosa with calcium ionophore (A23187), acetic acid, and ethanol induced a significant NO release in all groups and all biopsies. Whereas, immune-specific stimulation with allergens or anti-human IgE or -IgG antibodies did not produce significant release of NO in controls or IBD. Incubation with anti-human IgE antibodies or allergens produced a ninefold increase in histamine release in gastrointestinally mediated allergy (p<0.001), but anti-human IgE antibodies induced NO release in only 18% of the allergy patients. Histamine release in response to allergens or anti-human IgE antibodies did not correlate with NO release (r(2)=0.11, p=0.28). These data show that nonspecific calcium-dependent and toxic mechanisms induce NO release in response to a nonspecific inflammatory signal. In contrast, mechanisms underlying immune-specific stimuli do not induce NO production immediately.

Combination therapy using fexofenadine, disodium cromoglycate, and a hypoallergenic amino acid-based formula induced remission in a patient with steroid-dependent, chronically active ulcerative colitis.

Corticosteroids and 5-aminosalicylic acid are the primary standard therapy for inflammatory bowel disease. Recent immunologic data implicate an involvement of mast cell activation followed by increased histamine secretion and elevated tissue concentrations of histamine in the pathogenesis of ulcerative colitis. In the present case, the clinical course of a 35-year-old man with steroid-dependent chronic active ulcerative colitis, who did not respond to high-dose steroids, antibiotics, or azathioprine during 3 years, is reported. Clinical disease activity and established serological markers were recorded during 6 weeks of unsuccessful therapy and during the next 6 weeks, as a new nonsedative antihistaminergic drug, a mast cell stabilizer, and an hypoallergenic diet were implemented in addition to conventional therapy. Induction of remission was achieved within 2 weeks after treatment with fexofenadine, disodium cromoglycate, and an amino acid-based formula. Clinical disease activity, stool frequency, leukocytes, c-reactive protein, and orosomucoid levels in serum decreased rapidly. Daily steroid administration could be gradually reduced along with 6 weeks of this treatment. This report suggests that histamine and mast cell activity may be important pathophysiological factors responsible for persistent clinical and mucosal inflammatory activity in ulcerative colitis despite the use of steroids. In ulcerative colitis, patients unresponsive to conventional treatment, therapeutic considerations should also include an antiallergic approach when further signs of atopy or intestinal hypersensitivity are present.

Colorectal mucosal histamine release by mucosa oxygenation in comparison with other established clinical tests in patients with gastrointestinally mediated allergy.

AIM: This study evaluated colorectal mucosal histamine release in response to blinded food challenge-positive and -negative food antigens as a new diagnostic procedure. METHODS: 19 patients suffering from gastrointestinally mediated allergy confirmed by blinded oral provocation were investigated on grounds of their case history, skin prick tests, serum IgE detection and colorectal mucosal histamine release by ex vivo mucosa oxygenation. Intact tissue particles were incubated/stimulated in an oxygenated culture with different food antigens for 30 min. Specimens challenged with anti-human immunoglobulin E and without any stimulus served as positive and negative controls, respectively. Mucosal histamine release (% of total biopsy histamine content) was considered successful (positive), when the rate of histamine release from biopsies in response to antigens reached more than twice that of the spontaneous release. Histamine measurement was performed by radioimmunoassay. RESULTS: The median (range) of spontaneous histamine release from colorectal mucosa was found to be 3.2 (0.1%-25.8%) of the total biopsy histamine content. Food antigens tolerated by oral provocation did not elicit mast cell degranulation 3.4 (0.4%-20.7%, P = 0.4), while anti-IgE and causative food allergens induced a significant histamine release of 5.4 (1.1%-25.6%, P = 0.04) and 8.1 (1.5%-57.9%, P = 0.008), respectively. 12 of 19 patients (63.1%) showed positive colorectal mucosal histamine release in accordance with the blinded oral challenge responding to the same antigen (s), while the specificity of the functional histamine release to accurately recognise tolerated foodstuffs was found to be 78.6%. In comparison with the outcome of blinded food challenge tests, sensitivity and specificity of history (30.8% and 57.1%), skin tests (47.4% and 78.6%) or antigen-specific serum IgE determinations (57.9% and 50%) were found to be of lower diagnostic accuracy in gastrointestinally mediated allergy. CONCLUSION: Functional testing of the reactivity of colorectal mucosa upon antigenic stimulation in patients with gastrointestinally mediated allergy is of higher diagnostic efficacy.

Urinary excretion of N-methylhistamine as a marker of disease activity in inflammatory bowel disease.

OBJECTIVE: Mast cells are thought to participate in the pathogenesis of inflammatory bowel disease (IBD). In this study, urinary excretion of N-methylhistamine (UMH), a stable metabolite of the mast cell mediator histamine, was evaluated as an indicator of disease activity in patients with IBD. METHODS: Urinary excretion of UMH (microg/mmol creatinine x m2 body surface area) was measured by radioimmunoassay in 55 controls, 56 patients with Crohn's disease, and in 36 patients with ulcerative colitis. Excretion rates were correlated with clinical, serological, and endoscopic disease activity, disease extent, and location. RESULTS: Urinary excretion of UMH was found to be significantly elevated in IBD. Patients with active Crohn's disease (7.1 +/- 4.2, p = 0.002 vs controls) and active ulcerative colitis (8.1 +/- 4.8, p = 0.02 vs controls) had higher rates of UMH excretion than patients in remission (6.3 +/- 3.8 and 5.2 +/- 2.3, respectively) or controls (4.6 +/- 1.9). In Crohn's disease and ulcerative colitis, a significant correlation of UMH excretion with clinical disease activity was obtained (Crohn's Disease Activity Index r2 = 0.58, Clinical Activity Index r2 = 0.57, p < 0.0001). Serologically, orosomucoid showed the best positive correlation with disease activity (Crohn's Disease Activity Index r2 0.80, Clinical Activity Index r2 = 0.86, p < 0.0001), but UMH excretion was found to reflect disease activity more accurately than C-reactive protein (Crohn's Disease Activity Index r2 = 0.46, Clinical Activity Index r2 = 0.42, p < 0.0001). No association between UMH excretion and disease type or localization could be found in Crohn's disease. However, UMH excretion correlated strongly with endoscopic severity of inflammation in Crohn's disease (Crohn's Disease Endoscopic Index of Severity r2 = 0.70, p < 0.0001) or disease extent in ulcerative colitis. CONCLUSIONS: Urinary excretion of the histamine metabolite UMH is enhanced in IBD. It appears to represent an integrative parameter to monitor clinical and endoscopic disease activity in IBD, which appears to be influenced most likely by mediators released from histamine-containing cells, such as intestinal mast cell subtypes.

[Poorly tolerated or genuinely allergic? How to properly assess food allergies]. / Schlecht vertragen oder echt allergisch? Wie man Lebensmittelallergien richtig abklärt.

Massive immune reactions to certain foods may be traced back to immunological, but also to non-immunological mechanisms. The diagnostic work-up must therefore aim to distinguish an allergy from other inflammatory, neoplastic or immunoregulative disorders. The most common form of gastrointestinal-mediated allergy form are the IgE-mediated reactions of the immediate type (Type 1 allergy). The routine diagnostic investigation includes history-taking, a daily diary of foods eaten, skin tests and antibody determination. The diagnosis of an allergy is often complicated by the multitude of possible manifestation sites, a possibly localized effect, and variations in the depth of allergic processes. To confirm the diagnosis, an oral provocative test should always be performed.

[Pathobiology of dysplasia in chronic inflammatory bowel disease: Current recommendations for surveillance of dysplasia]. / Klinik und Pathobiologie von Dysplasien bei chronisch-entzündlichen Darmerkrankungen: aktuelle Empfehlungen zur Dysplasieüberwachung.

Pathobiology of dysplasia in chronic inflammatory bowel disease: Current recommendations for surveillance of dysplasia. Patients with ulcerative colitis and Crohn's disease bear an about 10- and 4-fold increased risk, respectively, for developing colorectal carcinoma. Apart from typical locations of colorectal carcinoma in the sigmoid colon and rectum other locations were also often observed, e. g. right hemicolon or multifocal distribution. Histologically colorectal neoplasms frequently present as mucinous adenocarcinoma (signet-ring cell carcinoma). The risk for neoplasm depends on extension, severity, duration and therapeutic responsiveness of chronic colonic inflammation, and it seems pathogenetically to be similar in ulcerative colitis and Crohn's disease. Colorectal carcinoma in inflammatory bowel disease arises from epithelial dysplasia. Since there are no reliable biological markers available to date, surveillance-programs continue to rely on the discovery of dysplasia (unequivocal intraepithelial neoplasia). Detection of dysplasia by colonoscopy achieves 70-85 % sensitivity.Endoscopic surveillance should start after 8 years of disease's duration in pancolitis, after 10-12 years in left- sided colitis and after 12 years in Crohn's disease of the colon, with regular intervals every 1-2 years. 3-5 biopsies should be done every 10 cm from mucosa free of inflammation. Additionally, every fine or discrete alteration of the mucosal surface should be recorded. Multiple biosies should also be taken from such minimal lesions as well as from more macroscopically suspicious areas like plaques, nodular lesions or stenosis. The clinical consequence of a positive screening for dysplasia is colectomy because of an assumed risk of cancer of about 40-70 %. Dysplasia in macroscopically suspect areas bear the highest risk of cancer (non-adenoma like dysplasia), followed by multiple high-grade lesions without a macroscopic lesion, and multiple low-grade dysplasias. Detection of single dysplastic lesions in flat mucosa should be followed by a control endoscopy after 2-6 months, and if dysplasia is seen again, colectomy is recommended.

[Stimulation of immunoglobulin E formation in chronic pancreatitis by alcohol drinking and exocrine pancreatic insufficiency]. / Stimulation der Immunoglobulin-E-Bildung bei chronischer Pankreatitis durch Alkoholaufnahme und exokrine Pankreasinsuffizienz.

Many patients with chronic pancreatitis (CP) complain of several types of food intolerance despite elimination of fat and alcohol. Since there are no data on serum immunoglobulin E (IgE) concentrations in CP, IgE concentrations in serum were detected in 97 persons with CP and 50 controls. IgE was analyzed by the use of a highly sensitive fluoro-enzyme-immunoassay. In CP, a significantly raised IgE level (mean +/- SEM; 286.1 +/- 49 KU/L; p < 0.0001) was detected compared with controls (65.2 +/- 13 KU/L). CP-patients without alcohol consumption and normal exocrine pancreatic function were found to have only slightly elevated serum IgE values (120.2 +/- 54 KU/L), whereas patients with exocrine insufficiency treated with enzyme supplementation showed an IgE level of 153.7 +/- 51 and exocrine insufficient patients without treatment of 261.0 +/- 173 KU/L (p = 0.01). IgE levels were far more elevated in the corresponding groups with continued alcohol consumption (> 25 g/day). Alcohol consuming patients with CP and normal pancreatic function had a mean serum IgE of 295.0 +/- 114 KU/L, while patients with alcohol consumption and sufficiently treated exocrine pancreatic insufficiency showed a serum IgE of 393.7 +/- 147 KU/L (p = 0.03). Non-enzyme supplemented patients with CP and exocrine pancreatic insufficiency were characterized by approximately 10-fold increased serum IgE (1080.0 +/- 313 KU/L; p = 0.001). Non-allergic, alcohol consuming patients with CP have significantly increased serum IgE values. Since patients without alcohol consumption and normal pancreatic function or sufficiently treated exocrine insufficiency showed clearly lower IgE values than non-compliant patients with manifest exocrine pancreatic insufficiency, these results are compatible with the assumption that a reduced rate of antigen digestion in exocrine pancreatic insufficiency may lead to an increased intestinal antigen load, stimulating an abnormal humoral immune response with IgE production. Alcohol may further contribute to this by damaging the mucosal barrier.

Immunoglobulin E and eosinophilic cationic protein in segmental lavage fluid of the small and large bowel identify patients with food allergy.

OBJECTIVE: Members of the general population often assume that they suffer from food allergy, but the true prevalence is low. Testing for the diagnosis of food-related hypersensitivity entails laborious procedures, including GI endoscopy. Our objective was to develop an endoscopic screening approach for food allergy. METHODS: Endoscopically guided segmental lavage was performed in 11 patients with GI allergy and in 20 controls during lower GI endoscopy of the terminal ileum, the coecum, and the rectosigmoid. Eosinophilic cationic protein (ECP) and protein were measured in native lavage fluid, and immunoglobulin E (IgE) was also measured after a 10-fold lavage concentration. RESULTS: IgE/protein in lavage fluid from the coecum (0.055 +/- 0.068 U/mg vs 0.003 +/- 0.012 U/mg; p = 0.001) and the rectosigmoid (0.134 +/- 0.170 U/mg vs 0.019 +/- 0.042 U/mg; p < 0.05) was significantly elevated in patients with GI allergy. ECP/protein was significantly elevated at the terminal ileum (22.95 +/- 37.67 microg/mg vs 7.09 +/- 7.68 microg/mg; p < 0.05) and the rectosigmoid (23.66 +/- 19.43 microg/mg vs 11.97 +/- 16.39 microg/mg; p < 0.05). The combined use of GI lavage IgE and ECP as a diagnostic test for food allergy resulted in a sensitivity of 91% and a specificity of 80%. CONCLUSIONS: In endoscopically guided segmental lavage fluid, IgE and ECP/protein are increased in patients with food allergy. These measurements seem to offer an attractive diagnostic tool and may serve as a screening method.