Histamine synthesis in man: inhibition by 4-bromo-3-hydroxybenzyloxyamine.

Oral administration of 4-bromo-3-hydroxybenzyloxyamine to normal humans resulted in decreased urinary excretion of histamine; the normal increase in urinary levels of histamine after oral histidine loading was prevented. In two patients having systemic mastocytosis, additional evidence of inhibition of biosynthesis of histamine included marked reduction in symptoms attributed to histamine, and prevention of symptomatic exacerbation associated with histidine loading.

Decreased urinary histamine metabolite after successful PUVA treatment of urticaria pigmentosa.

The effect of PUVA therapy on pruritus, the skin mast cell population and histamine metabolism has been studied in 3 patients with urticaria pigmentosa and manifestations of systemic mastocytosis. Relief of itch was found concomitant with a significant decrease of the major histamine metabolite 1-methyl-4-imidazoleacetic acid in the urine. The decrease occurred during the first 2 mo after starting PUVA therapy and was sustained during an observation period of 3 mo after discontinuation of the treatment. At this time a reduction of the number of mast cells was found in skin biopsy specimens. No evidence of acute histamine release in association with PUVA treatment was obtained. These results suggest that this effective new treatment for urticaria pigmentosa reduces the histamine turnover in the skin by inhibiting mast cell proliferation.

Increased formation of thromboxane in vivo in humans with mastocytosis.

Clinical manifestations of mastocytosis are mediated, at least in part, by release of the mast cell mediators histamine and prostaglandin D2. It has been previously reported that in addition to prostaglandin D2, mast cells produce other eicosanoids, including thromboxane. Nonetheless, little information exists regarding the formation of other prostanoids in vivo. The most accurate method to examine the systemic production of eicosanoids in vivo is the quantitation of urinary metabolites. We previously developed a highly accurate assay employing mass spectrometry to measure a major urinary metabolite of thromboxane, 11-dehydro-thromboxane B2, in humans. We utilized this assay to quantitate thromboxane production in 17 patients with histologically proven mastocytosis. We report that thromboxane formation was significantly increased (>2 SD above the mean) in at least one urine sample from 65% of patients studied. Of these, 91% of patients with documented systemic involvement had elevated thromboxane generation. In addition, endogenous formation of thromboxane was highly correlated with the urinary excretion of the major urinary metabolite of prostaglandin D2 (r = 0.98) and Ntau-methylhistamine (r = 0.91), suggesting that the cellular source of increased thromboxane in vivo could be the mastocyte. Enhanced thromboxane formation in patients with this disorder is unlikely to be of platelet origin as other markers of platelet activation, platelet factor 4 and beta-thromboglobulin, were not increased in three patients with marked overproduction of thromboxane. Furthermore, the recovery of 11-dehydro-thromboxane B2 excretion in two patients after the administration of aspirin occurred significantly more rapidly than the recovery of platelet thromboxane generation. These studies, therefore, report that thromboxane production is significantly increased in the majority of patients with mastocytosis that we examined and provide the basis to elucidate the role of this eicosanoid in disorders of mast cell activation.

Patterns of skeletal scintigraphy and their relationship to plasma and urinary histamine levels in systemic mastocytosis.

Scintigraphic findings in ten cases of systemic mastocytosis are described. Four radionuclide bone patterns were noted: normal, unifocal, multifocal, and diffuse. Compared with radiographic surveys, bone images were better able to show the widespread skeletal involvement in patients with diffuse disease, and to detect a greater number of focal lesions. Serum calcium, phosphorus, and bone-derived alkaline phosphatase, as well as urinary calcium, phosphorus, and hydroxyproline levels, were usually within normal limits even when the bone scintigrams were clearly abnormal. Plasma and urinary histamine levels were highest in patients whose bone images detected widespread skeletal involvement. In systemic mastocytosis, not only does scintigraphy document active bone disease more effectively than laboratory studies of bone metabolism and radiographs of bone, but it also appears to reflect the general severity of the disease process.

Urticaria pigmentosa. Systemic evaluation and successful treatment with topical steroids.

Nine patients with adult-onset urticaria pigmentosa were studied for the incidence of extracutaneous mast cell involvement and the efficacy of potent topical corticosteroid therapy for cutaneous lesions. Seven of the nine patients had increased mast cells in the marrow biopsy specimens, and five patients had focal aggregates of mast cells. The bone scan was abnormal in one patient. Liver-spleen scans revealed a shift of colloid uptake from liver to spleen in four patients. No abnormal gastrointestinal tract roentgenograms were obtained. Urinary histamine metabolites correlated with nodular bone marrow involvement, but not with other parameters. Results of the psychoneurologic testing revealed significant deviation from the norm with a verbal memory deficit in all nine patients and abnormalities on the Minnesota Multiphasic Personality Inventory in four patients. All nine patients were treated with 0.05% betamethasone dipropionate ointment under occlusion over half of the body nightly for 6 weeks. Seven of nine patients treated responded with almost complete resolution of their lesions. Hypothalamic pituitary adrenal axis suppression was evaluated with intramuscular cosyntropin stimulation and metyrapone administration during treatment. Only two patients, both of whom used the medication improperly, developed transient abnormalities. Slow return of lesions was noted 6 months after completion of therapy. Remissions could be lengthened with single weekly applications of topical steroids. Systemic involvement is frequent in patients with cutaneous mast cell disease and it is best demonstrated by bone marrow biopsy. Mast cell lesions can be safely and effectively treated with topical steroids in motivated patients.

Determination of N tau-methylimidazoleacetic acid (a histamine metabolite) in urine by gas chromatography using nitrogen-phosphorus detection.

N tau-Methylimidazoleacetic acid, the quantitatively most important metabolite of histamine, was isolated from urine by ion exchange chromatography. After esterification with 2-propanol and extraction, N tao-methylimidazoleacetic acid was analyzed by capillary gas chromatography with nitrogen-phosphorus detection, using N tao-ethylimidazoleacetic acid as internal standard. The synthesis of this internal standard is described. In contrast to the methods hitherto described, this method is appropriate for use in clinical chemical laboratories. Normal 24-h excretion ranged from 8.3 to 18.5 mumol (n = 20). Five patients with mastocytosis, a patient with chronic myelocytic leukemia and a patient after an anaphylactoid reaction on acetylsalicylic acid showed highly elevated values.

Comparative evaluation of the radioenzymatic method for the determination of urinary histamine with a mass spectrometric assay.

Considerable inaccuracy and unreliability have recently been demonstrated to be associated with the widely used radioenzymatic methods for the determination of histamine in biological fluids. Urine appears to inhibit the methylation of histamine by histamine N-methyltransferase such that the radioenzymatic assay underestimates the concentration of histamine present in urine. Directly comparing the radioenzymatic assay with a recently developed reference method using mass spectrometry for the determination of urinary histamine, up to 34-fold differences in the levels of urinary histamine were found with the two methods.

Urinary excretion of histamine, methylhistamine (1-MeHi) and methylimidazoleacetic acid (MeImAA) in mastocytosis: comparison of new HPLC methods with other present methods.

New HPLC-methods for the determination of histamine, 1- MeHi and MeImAA in human urine were compared with methods presently at use in our laboratory, the enzymatic double-isotope assay for histamine, the DNFB-method for 1- MeHi and the semiquantitative estimation of MeImAA by thin layer chromatography (TLC). A fairly good agreement between the methods was obtained for the measurement of histamine and 1- MeHi , although there was a rather large random error probably due to poor precision of the present methods. The TLC-method for MeImAA used so far overestimated by about 20% the HPLC-values, probably due to inaccurate correction for recovery by the internal standard technique. There was found to be a strong correlation between the urinary excretion of 1- MeHi and MeImAA in mastocytosis patients and the molar ratio MeImAA /1- MeHi appeared significantly higher compared to normal controls and patients with chronic granulocytic leukemia indicating in general a more efficient histamine catabolism in mastocytosis.

Improved diagnosis of mastocytosis by measurement of urinary histamine metabolites.

In an attempt to facilitate the diagnosis of mastocytosis, we measured the urinary excretion of histamine and two of its main metabolites (N tau-methylhistamine and N tau-methylimidazoleacetic acid) in eight adults with this disorder. All patients had above-normal values for the metabolites of histamine, whereas only three had above-normal values for histamine. In both 24-hour and randomly voided urine specimens, the determination of histamine metabolites is more specific and sensitive for the diagnosis of mastocytosis than the determination of histamine itself.

Oral disodium cromoglycate in mastocytosis.

Oral disodium cromoglycate was found useful for the treatment of gastrointestinal manifestations of mastocytosis in 2 patients with systemic disease. The urinary excretion of histamine in these 2 patients decreased following treatment. Oral disodium cromoglycate had no effect on cutaneous symptoms, either in these 2 patients nor in 2 other patients with urticaria pigmentosa without signs of systemic mastocytosis. In the latter 2 patients the urinary excretion of histamine was unaffected. Treatment was given for 4 to 6 weeks and the dose of disodium cromoglycate was 100 mg four times daily in the 3 adult patients and 100 mg three times daily in the fourth patient, an 8-year-old boy.

Determination of N tau-methylhistamine in urine by gas chromatography using nitrogen-phosphorus detection.

The determination of N tau-methylhistamine in urine, using gas chromatography with nitrogen-phosphorus detection and the homologue N tau-ethylhistamine as internal standard, is described. A comparison between the present method and a previously described stable isotope dilution mass fragmentographic method resulted in a regression line of Y = 0.023 + 0.944X mumol/l with a correlation coefficient of 0.996. The 24-h excretions of 35 normal adults on a free diet ranged from 0.4 to 1.8 mumol. Patients with mastocytosis, chronic myelocytic leukemia, anaphylactic reactions and a patient after bronchial provocation showed above normal values.

Urticaria pigmentosa treated with oral disodium cromoglycate.

4 patients with urticaria pigmentosa were treated with oral disodium cromoglycate (DSCG) for 2 months. During the treatment urine excretion of the main histamine metabolite, 1,4-methylimidazoleacetic acid (MIAA), was determined, and sequential skin biopsies were examined. DSCG was found to have beneficial effect on pruritus and whealing in 3 patients. The one treatment failure was in a patient without pruritus. The skin lesions remained unchanged. DSCG treatment had no effect on MIAA excretion or on the number of mast cells found in the skin biopsies.

Urticaria pigmentosa. Histaminuria and treatment.

We present the case of an adult patient with urticaria pigmentosa. The sudden presence of severe symptomatology (symptoms to mast cell mediators release), made us think of evaluating extracutaneous affection. Our results are consistent with recent reports in the medical literature. We have confirmed an increase of conjugated histamine levels (methyl-histamine) during the attack and its return to normal values after the treatment. For these reasons we comment on the importance of histamine levels in diagnosis and treatment control. The gastrointestinal biopsy suggestive of mastocytosis; the severe clinical manifestations, and the histamine metabolite levels during the clinical course, led us to include this case in the group of "indolent SMCD" according to the TRAVIS classification.

Metabolic fate of radiolabeled prostaglandin D2 in a normal human male volunteer.

50 microCi of [3H]prostaglandin D2 tracer (100 Ci/mmol) was infused intravenously into a normal human male volunteer. 75% of the infused radioactivity was excreted into the urine within 5 h. This urine was added to urine obtained from two mastocytosis patients with marked overproduction of prostaglandin D2. Radiolabeled prostaglandin D2 urinary metabolites were chromatographically isolated and purified and subsequently identified by gas chromatography-mass spectrometry. 25 metabolites were identified. 23 of these compounds comprising 37% of the recovered radioactivity had prostaglandin F-ring structures, and only two metabolites comprising 2.7% of the recovered radioactivity retained the prostaglandin D-ring structure. The single most abundant metabolite identified was 9,11-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid which was isolated in a tricyclic form as a result of formation of a lower side chain hemiketal followed by lactonization of the terminal carboxyl and the hemiketal hydroxyl. Different isomeric forms of several prostaglandin F-ring metabolites were identified. An isomer of prostaglandin F2 alpha was also excreted intact into the urine as a metabolite of prostaglandin D2. 15 PGF-ring compounds were treated with n-butylboronic acid and 13 failed to form a boronate derivative, suggesting that the orientation of the hydroxyl group at C-11 in these 13 metabolites is beta. This study documents that prostaglandin D2 is metabolized to prostaglandin F-ring metabolites in vivo in humans. These results also bring into question the accuracy of quantifying prostaglandin F2 alpha metabolites as a specific index of endogenous prostaglandin F2 alpha biosynthesis, as well as quantifying urinary prostaglandin F2 alpha as an accurate index of renal production of prostaglandin F2 alpha.

Detection of the major urinary metabolite of prostaglandin D2 in the circulation: demonstration of elevated levels in patients with disorders of systemic mast cell activation.

The symptoms and hemodynamic alterations that accompany episodes of systemic mast cell activation have been largely attributed to excessive prostaglandin (PG)D2 release. Quantification of the major urinary metabolite of PGD2 has been invaluable in elucidating a role for PGD2 in these clinical entities and in the biochemical evaluation of systemic mastocytosis. With the use of a modified mass spectrometric assay for the major urinary metabolite of PGD2, this metabolite was detected in plasma from 10 normal volunteers (3.5 +/- 1.4 pg/ml). Ingestion of niacin, which induces endogenous release of PGD2, increased plasma levels of this metabolite 6.3 to 33 times above the upper limit of normal by 2 hours. Thereafter, levels declined gradually but remained elevated for up to 6 to 8 hours. In contrast, circulating levels of 9 alpha, 11 beta-PGF2, the initial metabolite of PGD2, peaked by 30 minutes and returned to baseline by 2 hours. The clinical utility of measuring the major urinary metabolite in the circulation was demonstrated by detection of markedly increased levels in plasma and serum from patients with systemic mastocytosis and a patient with a severe type I allergic reaction. Thus in the biochemical evaluation of episodes of systemic mast cell activation and endeavors to further elucidate the role of PGD2 in human disease, there are kinetic advantages of measuring the major urinary metabolite of PGD2 in the circulation. One particular advantage is the evaluation of clinical events, which only in retrospect are suspected to be associated with excessive release of PGD2, yet plasma or serum was obtained proximate to the event.

Value of urinary N-methylhistamine measurements in childhood mastocytosis.

BACKGROUND: Histamine is an indicator of mast cell activation. N-methylhistamine (NMH) is a metabolite of histamine that can be measured in urine. OBJECTIVE: Our purpose was to assess the usefulness of determining urinary NMH levels for the diagnosis and follow-up of patients with mastocytosis. METHODS: Urinary NMH levels were determined in 44 patients and were correlated with disease activity and extension. The control group consisted of 24 children without mastocytosis or any other skin disease. RESULTS: A significant negative correlation was found between NMH and age in patients with active mastocytosis and in the control group. Adjusted for age, NMH values were significantly higher in patients with active mastocytosis. There was a significant difference in NMH values between patients with diffuse cutaneous mastocytosis, patients with active urticaria pigmentosa, and patients with active mastocytomas. However, there was a substantial overlap of NMH values in the different subgroups. CONCLUSION: Urinary NMH values tend to decrease with age. Urinary NMH values correlated with the extent and the activity of the disease. High NMH values suggest more extensive involvement.