Urinary Histamine Levels Research Articles

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Urinary leukotrienes and histamine in patients with varying severity of acute dengue.

Vascular leak is a hallmark of severe dengue, and high leukotriene levels have been observed in dengue mouse models, suggesting a role in disease pathogenesis. We sought to explore their role in acute dengue, by assessing levels of urinary LTE4 and urinary histamine in patients with varying severity of acute dengue. Urinary LTE4, histamine and creatinine were measured by a quantitative ELISA, in healthy individuals (n = 19), patients with dengue fever (DF = 72) and dengue haemorrhagic fever DHF (n = 48). The kinetics of LTE4 and histamine and diurnal variations were assessed in a subset of patients. Urinary LTE4 levels were significantly higher (p = 0.004) in patients who proceed to develop DHF when compared to patients with DF during early illness (≤ 4 days) and during the critical phase (p = 0.02), which continued to rise in patients who developed DHF during the course of illness. However, LTE4 is unlikely to be a good biomarker as ROCs gave an AUC value of 0.67 (95% CI 0.57 and 0.76), which was nevertheless significant (p = 0.002). Urinary LTE4 levels did not associate with the degree of viraemia, infecting virus serotype and was not different in those with primary vs secondary dengue. Urinary histamine levels were significantly high in patients with acute dengue although no difference was observed between patients with DF and DHF and again did not associate with the viraemia. Interestingly, LTE4, histamine and the viral loads showed a marked diurnal variation in both patients with DF and DHF. Our data suggest that LTE4 could play a role in disease pathogenesis and since there are safe and effective cysteinyl leukotriene receptor blockers, it would be important to assess their efficacy in reducing dengue disease severity.

Urinary N-methyl histamine levels relate to the presence of angioedema and decrease with the duration of chronic urticaria

Chronic urticaria (CU) defined as hives lasting more than 6 weeks1 is a challenging disease to treat due to its unpredictable nature, the lack of prognostic predictors, and minimal data on predictors of treatment response. CU affects between 0.5% and 5% of the population with the estimated incidence rate of 1.4% per year.1 Quality of life of patients with CU is significantly poor2 with associated angioedema (in approximately 40% of cases3) perceived as a particularly alarming symptom. Hives commonly last 3-5 years with 85% of patients reporting resolution of urticaria within 5 years.

AB0617 Bone involvement in systemic mastocytosis: cases review

BackgroundSystemic mastocytosis is a clonal disease of mast cell progenitors in bone marrow which causes abnormal growth and accumulation of mast cells in skin and other organs. Bone involvement occurs...

Effect of Anti-Siglec-F Antibody and Reactive Oxygen Species Blocking on Histamine Release in Urinary Bladder of Ovalbumin-Treated Mice

PurposeSialic acid-binding Ig-like lectin (Siglec) is an immune inhibitory receptor that plays a role in the negative regulation of the activation of immune cells. This study aimed to evaluate the effects of anti-Siglec-F on plasma and urinary histamine levels in ovalbumin (OVA)-challenged urinary bladder in mice.MethodsThirty BALB/c mice were used. In group I (control group, n=5), mice were sensitized with OVA and challenged with saline. In group II (OVA challenge group, n=5), OVA was used for intraperitoneal sensitization and intravesical challenge. The challenged mice in group III (control immunoglobulin G [IgG] group, n=5) and those in group IV (anti-Siglec-F group, n=5) were intraperitoneally pretreated with rabbit control IgG or anti-Siglec-F antibody, respectively. In groups V (N-acetylcysteine [NAC] in OVA challenge group, n=5) and VI (control NAC only, n=5), mice were pretreated with NAC.ResultsUrinary histamine concentrations were significantly higher 7 days after intravesical OVA challenge (P<0.01), whereas plasma histamine levels were not. Pretreatment with anti-Siglec-F antibody significantly prevented the increase in urinary histamine release (P<0.05), whereas pretreatment with the IgG antibody control did not. Also, pretreatment of the OVA challenge group with NAC did not affect the histamine concentration in either urine or plasma.ConclusionsSystemic anti-Siglec-F treatment showed anti-allergic effects at least on local histamine release, particularly in the lower urinary bladder.

Urticaria Associated With Parenteral Nutrition

We report a 53-year-old female patient with short bowel syndrome who developed urticaria after administration of cyclic parenteral nutrition (PN). The urticaria occurred 2 hours into the 12-hour nocturnal infusion and resolved completely 1 hour after discontinuation of the PN infusion. The urticaria occurred despite removing lipids from the 3-in-1 PN solution. The urticaria did not occur when the multivitamin preparation was removed from the PN. Upon rechallenge with a PN solution containing a multivitamin, the urticaria reoccurred. Prick skin testing using the multivitamin in increasing aliquots was negative. Serum tryptase and 12-hour urinary histamine level during PN infusion containing the multivitamin was unchanged compared with baseline measurements. The patient had no allergic reaction using a similar dose of an oral multivitamin. This case illustrates that allergic reactions from PN infusion may occur and that the multivitamin preparation can be the cause.

The presence of membrane-bound stem cell factor on highly immature nonmetachromatic mast cells in the peripheral blood of a patient with aggressive systemic mastocytosis

Background: Systemic mastocytosis is characterized by mast cell infiltration of bone marrow and tissues in the absence of identified circulating bone marrow–derived progenitors. A 58-year-old man was first seen with aggressive systemic mastocytosis manifested by urticaria pigmentosa, hepatosplenomegaly, generalized bone lesions, anemia, thrombocytopenia, monoclonal gammopathy, and increased urine histamine levels. OBJECTIVES AND METHODS: A rapidly progressive anemia and thrombocytopenia dictated a splenectomy. We sought to identify the mast cell progenitors in the peripheral blood and to provide evidence of their maturation in tissues with immunohistochemical and ultrastructural analyses. Results: The peripheral blood contained 1% to 3% nonmetachromatic mononuclear cells with eccentric nuclei that expressed the mast cell proteases, tryptase and carboxypeptidase A, along with c- kit, stem cell factor (SCF), and high-affinity IgE receptor (FcϵRI), but not chymase. Similar mononuclear cells colocalized in the spleen and lymph nodes with mature, metachromatic mast cells that expressed tryptase, chymase, carboxypeptidase A, c- kit, SCF, and FcϵRI. Electron microscopy disclosed, at each site, a mature mast cell population with electron-dense, scroll-poor granules. Conclusions: The peripheral blood of a patient with aggressive systemic mastocytosis contained immature mononuclear cells of the mast cell lineage that express c- kit, SCF, tryptase, carboxypeptidase A, and FcϵRI. These cells were also found in the skin, spleen, and lymph nodes where they presumably expand, differentiate, and mature, assuming the mast cell phenotype for those tissues characterized by metachromasia, expression of a full range of mast cell–related secretory granule proteases, and ultrastructural appearance. The presence of SCF on the surface membrane of the circulating, highly immature mast cells suggests an autocrine regulation of the c- kit–SCF interaction. (J A LLERGY C LIN I MMUNOL 1996;98:831-40.)

Dimethyl sulfoxide does not trigger urine histamine release in interstitial cystitis

Dimethyl sulfoxide (DMSO), an agent that provides symptomatic relief in patients with interstitial cystitis (IC) works via an unknown mechanism. We investigated whether DMSO acts as a chemical stimulant of mast cell degranulation. A radioimmunoassay (RIA) specific for histamine was used to test this hypothesis. Twelve women with strictly diagnosed IC were treated with intravesical instillations of DMSO. Treatments were repeated at varying intervals, and each patient received three to six treatments. Urine histamine levels were measured before and after each intravesical instillation of DMSO. Dilutional effects of DMSO were corrected for by conversion of urine histamine concentration to urine histamine:creatinine ratio. The RIA was unaffected by the addition of DMSO to urine. No consistent change in the urine histamine:creatinine ratio following DMSO instillation was found. Trend analysis revealed no trend in the histamine:creatinine ratio with time. The relief of symptoms reported in 50% to 77% of patients treated with intravesical DMSO is not related to detectable mast cell release of histamine. Other mechanisms of action must be investigated to explain the beneficial effect of this agent.

Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma

Background: A subset of patients with asthma experience adverse nasoocular reactions after ingestion of aspirin or agents that inhibit cyclooxygenase. Recent evidence has implicated the leukotrienes in the nasoocular reaction, but the cellular sources and mechanism of activation are unknown. We used nasal lavage with and without a 5-lipoxygenase inhibitor; zileuton, to define the role of leukotrienes and to profile nasal cellular activation during this reaction. Methods: A group of eight patients with asthma shown to have adverse reactions to aspirin documented by a 15% or greater decrease in forced expiratory volume in 1 second, accompanied by an elevation in urinary leukotriene E4 after ingestion of aspirin, received aspirin or placebo in a study with a crossover design. Nasal symptoms and nasal tryptase, histamine, leukotriene, and eosinophil cationic protein levels were evaluated. Serum tryptase and urinary histamine levels were also assessed. Subjects were then randomized to receive a week of treatment with zileuton or placebo, according to a double-blind, crossover design followed by aspirin challenge and measurement of the same mediators. Results: Aspirin ingestion produced a marked increase in nasal symptoms from a baseline symptom score of 2.1 ± 0.7 to a maximum of 8.4 ± 1.2 (p < 0.0007). Aspirin ingestion produced a mean maximal increase in nasal tryptase of 3.5 ± 2.6 ng/ml whereas placebo ingestion produced a mean maximal increase of 0.1 ± 0.2 ng/ml (p < 0.05, aspirin vs placebo). Mean maximal nasal histamine increased 1.73 ± 1.16 ng/ml versus 0.08 ± 0.08 ng/ml from baseline (p < 0.05, aspirin vs placebo). Aspirin produced a mean maximal increase in nasal leukotriene value of 152 pg/ml versus a 16 pg/ml decrease after placebo ingestion (p < 0.05). Zileuton treatment blocked the increase in nasal symptoms after aspirin ingestion (maximum nasal symptom score of 1.6 ± 0.6 with zileuton vs 5.5 ± 0.9 with placebo [p < 0.0053]). It also blocked the rise in nasal tryptase (p = 0.011) and nasal leukotriene (p < 0.05) levels after aspirin ingestion. Zileuton treatment had no significant effect on the recovery of nasal histamine. Conclusion: The increase in nasal symptoms in aspirin-sensitive patients with asthma after aspirin ingestion is associated with increases in nasal tryptase, histamine, and cysteinyl leukotriene levels. This mediator profile is consistent with mast cell activation during the nasal response to aspirin and suggests that 5-lipoxygenase products are essential for the nasal response to aspirin. (J ALLERGY CLIN IMMUNOL 1994;94:1046-56.)

Stimulated Release of Urine Histamine in Interstitial Cystitis

The diagnosis of interstitial cystitis is primarily made based on clinical and cystoscopic findings with exclusion of other bladder diseases. Despite all of the efforts at definitive identification, interstitial cystitis lacks universal objective findings. Mast cell activation with associated histamine release has been postulated as an etiological factor leading to the symptom complex associated with interstitial cystitis. To investigate this hypothesis, a 3-step controlled prospective study was conducted.In step 1 reliability of urine histamine assay was critically examined, and the assay was established to be simple, reliable and valid. In step 2 random spot urine histamine levels (basal state) were measured in 25 noninterstitial cystitis and 15 interstitial cystitis patients (22.1 ± 0.95ng./ml. versus 19.2 ± 1.19ng./ml.). There was no significant difference in the random urine histamine levels between the 2 groups (p >0.05). In step 3 urine histamine levels were measured before and after hydrodistention (acute stimulation) in 7 noninterstitial cystitis controls and 6 newly diagnosed interstitial cystitis patients under general anesthesia. The urine histamine-to-creatinine ratio was used to correct for the dilutional effect of normal saline used during hydrodistention. The urine histamine-to-creatinine ratios of the control group showed no significant difference before and after hydrodistention. However, the difference in the urine histamine-to-creatinine ratios of the interstitial cystitis group compared to the controls before and after hydrodistention was highly significant (p <0.001). Although measurement of random spot urine histamine alone (basal state) was not found useful to make the diagnosis of interstitial cystitis, measurement of urine histamine before and immediately after hydrodistention (acute stimulation) may become an important objective parameter to assist in the diagnosis of interstitial cystitis.

Seronegative juvenile rheumatoid arthritis and mast cell-associated gastritis.

We describe 4 children with seronegative inflammatory arthritis who had persistent, severe nausea and abdominal pain over several months, in spite of vigorous medical therapy, including antacids and histamine H2 receptor antagonists. Endoscopy and biopsy of gastric and duodenal mucosa showed antral gastritis and an increased number of mast cells in 3 of the 4 patients. In the fourth patient, urinary histamine levels were elevated. These findings suggest an association between inflammatory arthritis and localized mast cell disease in some individuals. Further studies are needed to determine whether this association represents an independent syndrome or whether mast cell-related disease is secondary to long-term treatment with nonsteroidal antiinflammatory drugs in children with mild arthritis.

A synergism of antigen challenge and severe magnesium deficiency on blood and urinary histamine levels in rats.

The effects of severe and moderate magnesium (Mg) deficiency on blood and urinary histamine were studied in 36 male weanling Sprague-Dawley rats with or without IgE-stimulating antigen challenge. The rats were divided into six groups: two each on 50 (severely deficient), 300 (moderately deficient), and 2000 (control) ppm Mg diets without and with immunization with ovalbumin challenge on days 0, 14, and 29. Unimmunized severely Mg-deficient rats had significantly elevated urinary histamine which returned to normal by 22 days, but whole blood histamine was still significantly elevated at 36 days. Both blood and urinary histamine of immunized severely Mg-deficient rats were significantly higher than those of all the other groups throughout the study, particularly after the antigen challenge. There was a synergism of antigen challenge and severe Mg deficiency on blood and urinary histamine levels. The results suggest that severe Mg deficiency can aggravate diseases which are caused by abnormal histamine release after exposure to an IgE-stimulating antigen.

Inhibition of mediator release in systemic mastocytosis is associated with reversal of bone changes

A 59-year-old male presented with systemic mastocytosis with extensive skeletal involvement resulting in vertebral compression fractures and bone pain. Histomorphometric analysis of bone revealed increased mast cells, elevated static parameters of bone resorption, and low bone formation. Serum calcium, phosphorus, and alkaline phosphatase were normal; however, serum 1,25-dihydroxyvitamin D3 and osteocalcin levels were low. Histamine levels in plasma and urine were elevated. Following therapy with ketotifen, the patient had resolution of bone pain along with decreased flushing and pruritus. Elevated plasma and urine histamine levels normalized, as did 1,25-dihydroxyvitamin D3 and osteocalcin levels. Indices of low bone formation improved on therapy. Eroded surfaces improved but remained elevated. This case is the first demonstration that bone symptoms and histomorphometric change in systemic mastocytosis are reversed with inhibition of mast cell degranulation. The role of mast cells and their products in bone metabolism is poorly understood, but the therapy of bone disease in systemic mastocytosis should include inhibition of the release of mast cell products along with the use of histamine antagonist.

A double-blind, placebo-controlled, crossover trial of ketotifen versus hydroxyzine in the treatment of pediatric mastocytosis

To asses the efficacy of ketotifen (Zaditen; Sandoz Pharmaceuticals, Basel, Switzerland) for the treatment of pediatric mastocytosis, eight children who exhibited symptoms as a result of mastocytosis were enrolled in a 12-week, double-blind, placebo-controlled, crossover trial of ketotifen versus hydroxyzine (Atarax; Roerig, New York, N.Y.). Efficacy of each drug was assessed by daily symptom scores and plasma- and 24-hour urine-histamine levels. After completion of the study, symptom scores revealed that seven of the eight children exhibited a greater reduction in symptoms while they were receiving hydroxyzine ( p < 0.05). The symptoms most likely to improve with treatment with hydroxyzine were flushing and abdominal pain. Analysis of plasma- and 24-hour urine-histamine levels at the beginning and end of each trial period of each drug revealed no significant differences ( p > 0.20). Changes in 24-hour urine-histamine levels, but not plasma-histamine levels, correlated with changes in symptom scores. We conclude that ketotifen offers no advantage over hydroxyzine in the treatment of pediatric mastocytosis.

Effect of continuous administration of nicotine on urinary histamine and Nτ-methylhistamme levels in the guinea pig

The effect of continuous subcutaneous administration of S-(−)- and R-(+)-nicotines on urinary excretion levels of histamine and N τ -methylhistamine in guinea pigs, over a 23-day period, has been studied. Urinary levels of these endogenous compounds were measured utilizing paired-ion reversed-phase high performance liquid chromatography with flow-through electrochemical detection. Urinary histamine levels of animals that had been administered either of these nicotine isomers were not significantly different from control values. Initial levels of urinary N τ -methylhistamine (days 2–3) in R-(+)- and S-(−)-nicotine-treated animals were, 2-fold and 8-fold higher, respectively than control levels but in both cases these levels returned to control values over the remainder of the time course examined (days 6–23). These results suggest that exposure to S-(−)-nicotine results in initial histamine release and/or inhibition of histamine uptake. However, longer term exposure to S-(−)-nicotine may not result in significantly altered levels of circulating histamine.

Urine-histamine levels in patients with hereditary angioedema (HAE)

Hereditary angioedema (HAE) is defined clinically by recurrent, self-limited episodes of angioedema. The disease is defined biochemically by a deficiency in the functional activity of C1 esterase inhibitor. To date, the actual serum or tissue mediator(s) responsible for the angioedematous lesion remains controversial. Although antihistaminics have been clearly demonstrated to have no efficacy in the long-term treatment of this disorder, instances of elevated urine-histamine levels in patients with HAE raises the possibility of a role for histamine in the pathophysiology of this disease. Urine samples were collected from 28 asymptomatic and from 11 symptomatic patients with HAE. The urine-histamine levels were compared with levels of 41 normal control subjects. With the exception of one asymptomatic patient with HAE whose diagnoses also included rheumatoid arthritis and secondary Sjögren's syndrome, the urinehistamine levels from asymptomatic patients with HAE were similar to values obtained from normal control subjects. Except for data from two patients with HAE, urine-histamine levels from symptomatic patients with HAE were also indistinguishable from levels of normal volunteers. These data suggest that the vast majority of patients with HAE have normal urine-histamine levels both during and between attacks. Consequently, histamine is unlikely to play a pathophysiologic role in HAE.

Plasma histamine concentrations in evaluation of pediatric mastocytosis

Mastocytosis is a disease characterized by an increase in the number of tissue mast cells and a concomitant increase in mast cell-derived mediators. In pediatric mastocytosis, the predominant cutaneous forms are urticaria pigmentosa and diffuse cutaneous mastocytosis. In the less commonly diagnosed systemic mastocytosis, abnormal mast cell accumulations may be found in the gastrointestinal tract, liver, spleen, and bone marrow? Adults with mastocytosis have elevated plasma and urine histamine levels 25 that correlate with the extent of bone involvement and basal gastric acid output, a'5 In contrast, little is known concerning histamine values in children with this disease. To determine whether plasma histamine concentrations are elevated in children with mastocytosis, and to assess the relationship of plasma histamine levels to the category and severity of disease, the information obtained during the routine evaluation of children with mastocytosis was correlated with plasma histamine measurements. METHODS Nine children aged 3 months to 8 years who were referred over 9 months to the National Institutes of Health with a tentative diagnosis of mastocytosis were examined to confirm the diagnosis and to assess the extent of disease. Medical evaluation consisted of a history, physical examination, laboratory studies (complete blood cell count with differential, serum chemistry, serum immunoglobulins, urinalysis), and posterior iliac crest bone marrow examination. 6 Additional diagnostic studies were performed if the patient's history or physical examination suggested systemic involvement. Informed consent was obtained for specific procedures as required by the NIH Clinical Center.

Elevated urinary histamine in the hyperimmunoglobulin E and recurrent infection (Job's) syndrome: Association with eczematoid dermatitis and not with infection

To test the hypothesis that IgE-mediated release of histamine may be, in part, responsible for the abnormal inflammatory response observed in the hyperimmunoglobulin E (HIE) and recurrent infection syndrome, urine and plasma histamine levels were measured. Twenty-four-hour urinary histamine concentrations from 15 patients with HIE (23.7 ± 6.9 μg/24 hr) were significantly elevated ( p < 0.001) compared to a large historical control population (10.5 ± 0.7 μg/24 hr; n = 97). However, urinary histamine levels in HIE were much less abnormal ( p < 0.01) than in five patients with biopsy-proven systemic mastocytosis (159 ± 62 μg/24 hr) and were not significantly elevated when levels were compared to 13 concurrently studied normal subjects (10.1 ±1.7 μg/24 hr) and nine patients with chronic granulomatous disease (8.1 ± 1.2 μg/24 hr). Overall, there was no clear relationship between urine histamine values and the presence of infection as well as no significant correlation between urine histamine and total IgE or anti- Staphylococcus aureus IgE. However, urine histamine levels in a subgroup of six patients with HIE with chronic eczematoid dermatitis (42.4 ± 12.5 μg/24 hr) were elevated compared with values from the historical control subjects ( p < 0.001), the concurrent control subjects ( p < 0.01), the patients with chronic granulomatous disease ( p < 0.01), and five patients with HIE who did not have skin manifestations (4.6 ±1.1 μg/24 hr; p < 0.05). In related studies, plasma histamine levels were normal (<500 pg/ml) in 19 samples from eight patients with HIE. Thus, histamine is moderately increased in the urine of patients with HIE and is not increased in the plasma. Elevated urine histamine excretion in HIE appears to be related to the presence of eczematoid dermatitis and not to the presence of infection. Therefore, it appears unlikely that abnormal histamine release plays an important role in the pathophysiology of recurrent infections in patients with HIE.

Comparison of the therapeutic efficacy of cromolyn sodium with that of combined chlorpheniramine and cimetidine in systemic mastocytosis. Results of a double-blind clinical trial

Both antihistamines and cromolyn sodium have been suggested for the treatment of systemic mastocytosis. To determine If one drug regimen was superior to the other, eight patients with systemic mastocytosis were admitted to a double-blind, double-crossover study in which the therapeutic efficacy of cromolyn sodium was compared with that of a combination of chlorpheniramine and cimetidine. Response to therapy was assessed by the patients using symptom scores and by the attending physicians during clinic examinations in addition to sequential plasma and urinary histamine determinations. in the six patients who completed the trial, the patient symptom scores and the physician evaluations indicated that there was no advantage of one drug regimen over the other. Plasma and urinary histamine levels, markedly elevated in most of the patients, were not consistently altered by administration of either cromolyn sodium or the combined antihistamines. Thus, cromolyn sodium and the combined antihistamines were indistinguishable when used for the symptomatic treatment of systemic mastocytosis, and neither regimen altered systemic histamine levels.

Histamine metabolism in patients with histidinemia: determination of urinary levels of histamine, N tau-methylhistamine, imidazole acetic acid, and its conjugate(s).

Histamine metabolism in histidinemic patients was studied by measuring the urinary levels of histamine and its metabolites. The urinary excretions of histamine, N tau-methylhistamine, imidazole acetic acid, and its conjugate(s) were higher in patients with histidinemia than in controls, and these levels of excretion were correlated with the plasma histidine level. The urinary histamine levels of patients with eczema-like dermatitis were twice that of those without dermatitis. The urinary excretion of 3-methylhistidine showed a close correlation with the urinary histidine excretion. Thus, it was concluded that histamine metabolism is higher in histidinemic patients than in normal controls.