Fatal anaphylaxis in systemic mastocytosis.

A 42-year-old woman died after an episode of anaphylaxis associated with a raised serum histamine level. A diagnosis of systemic mastocytosis was established, with lymphadenopathy and hepatosplenomegaly, not associated with the usually pre-existing skin lesions of urticaria pigmentosa.     

Increased urinary methylimidazoleacetic acid (MelmAA) as an indicator of systemic mastocytosis

The urinary excretion of histamine and its main metabolite, methylimidazoleacetic acid (MelmAA), was determined in 25 adult patients with the clinical diagnosis of urticaria pigmentosa (UP). Extensive clinical and laboratory investigation, including skin histology, bone marrow examination and scintigraphy of skeleton, liver and spleen, implied systemic manifestations in 16 cases. All patients with systemic mastocytosis (SM) excreted abnormal amounts of MelmAA (>4.1 mg/24 h) and most of them 8.0 mg or more per day, while histamine excretion was increased in only nine (>40 g/24 h). Thus, the urine content of MelmAA, but not histamine, could differentiate between UP and SM. Severe pruritus was found concomitant with increased urinary MelmAA and indicated systemic mastocytosis.     

Tryptase genetics and anaphylaxis

Tryptases secreted by tissue mast cells and basophils can enter the bloodstream. In human subjects tryptases are encoded by several genes and alleles, including alpha, beta, gamma, and delta. Common variations include complete absence of alpha genes. Until recently, alpha tryptase was considered to be the major tryptase secreted at baseline and in mastocytosis. However, lack of alpha tryptase genes has little effect on circulating tryptase levels, which are now thought mainly to consist of inactive pro-beta tryptase secreted constitutively rather than stored in granules with mature tryptases. Pro-beta tryptase levels thus might reflect total body mast cell content. In contrast, mature beta tryptase can increase transiently in severe systemic anaphylaxis and confirm the diagnosis. However, it might fail to increase in food anaphylaxis or might increase nonspecifically in samples acquired after death. Thus pro- and mature beta tryptase measurements are useful but associated with false-negative and false-positive results, which need to be considered in drawing clinical conclusions in cases of suspected anaphylaxis.     

Headache as an indicator of systemic disease

Headaches can constitute a direct symptom and possibly the preliminary symptom of several autoimmune diseases and systemic vasculitis. In the majority of cases, the characteristics of the headache are not on their own sufficient to establish a certain diagnosis, which has to be based on the clinical context and on other migraine-associated signs. In practice, three main categories of headache can be indicative of systemic disease: craniofacial pain; migraine and pseudo-migraine; and headache caused by intracranial hypertension.     

Sequence of mast-cell changes in ocular anaphylaxis.

Ocular anaphylaxis was produced in rats by the injection of egg albumin into ocular adnexal tissues of immunized animals. Mast cells in the tip of the eyelid from normal, antigen-injected control and antigen-injected immunized rats were examined at 1/2, 1, 6 and 24 hr. The number of cells and their morphology was determined. All three groups had the same number of mast cells at all time intervals. Extensive mast-cell degranulation was observed at 1/2 and 1 hr in lid tips of immunized, antigen-challenged rats. By 24 hr, the mast cells appeared to have 'healed' and regranulated, although it was possible to distinguish these cells from mast cells of normal animals. We conclude that under certain conditions, mast cells participating in ocular anaphylaxis are not destroyed but survive and regenerate granules within the first 24 hr.     

Tryptase haplotype in mastocytosis: relationship to disease variant and diagnostic utility of total tryptase levels

Serum mast cell tryptase levels are used as a diagnostic criterion and surrogate marker of disease severity in mastocytosis. Approximately 29% of the healthy population lacks alpha tryptase genes; however, it is not known whether lack of alpha tryptase genes leads to variability in tryptase levels or impacts on disease severity in mastocytosis. We have thus analyzed tryptase haplotype in patients with mastocytosis, computing correlations between haplotype and plasma total and mature tryptase levels; and disease category. We found: (1) the distribution of tryptase haplotype in patients with mastocytosis appeared consistent with Hardy-Weinberg equilibrium and the distribution in the general population; (2) the disease severity and plasma tryptase levels were not affected by the number of alpha or beta tryptase alleles in this study; and (3) information about the tryptase haplotype did not provide any prognostic value about the severity of disease. Total and mature tryptase levels positively correlated with disease severity, as well as prothrombin time and partial thromboplastin time, and negatively correlated with the hemoglobin concentration.     

C4a anaphylatoxin levels as an indicator of disease activity in systemic lupus erythematosus

The use of a synthetic protease inhibitor, nafamstat mesilate, has enabled reliable estimations of in vivo complement activation to be made in systemic lupus erythematosus (SLE). Elevation of C3a anaphylatoxins was found in two out of 24 patients and elevation of C4a anaphylatoxins was found in 20 out of 24 patients, confirming that complement activation, predominantly by the classical pathway, is a common occurrence in the disease. Significantly higher levels of C4a anaphylatoxin were found in 16 patients, with more aggressive disease requiring supplementary treatment with azathioprine, while the remaining eight patients, with less severe disease, required purely steroid therapy. Very strong associations between elevated C4a anaphylatoxins and raised DNA antibody titres, C1q binding activity and low complement C4 levels were also observed, suggesting that anaphylatoxin measurement may be a sensitive additional method for monitoring disease activity in SLE.     

Diagnostic value of tryptase in anaphylaxis and mastocytosis

Serum (or plasma) levels of total and mature tryptase measurements are recommended in the diagnostic evaluation of systemic anaphylaxis and systemic mastocytosis, but their interpretation must be considered in the context of a complete workup of each patient. Total tryptase levels generally reflect the increased burden of mast cells in patients with all forms of systemic mastocytosis (indolent systemic mastocytosis, smoldering systemic mastocytosis, systemic mastocytosis associated with a hematologic clonal non-mast cell disorder, aggressive systemic mastocytosis, and mast cell leukemia) and the decreased burden of mast cells associated with cytoreductive therapies in these disorders. Causes of an elevated total tryptase level other than systemic mastocytosis must be considered, however, and include systemic anaphylaxis, acute myelocytic leukemia, various myelodysplastic syndromes, hypereosinophilic syndrome associated with the FLP1L1-PDGFRA mutation, end-stage renal failure, and treatment of onchocerciasis. Mature (beta) tryptase levels generally reflect the magnitude of mast cell activation and are elevated during most cases of systemic anaphylaxis, particularly with parenteral exposure to the inciting agent.     

Levels of mast-cell growth factors in plasma and in suction skin blister fluid in adults with mastocytosis: correlation with dermal mast-cell numbers and mast-cell tryptase.

BACKGROUND: Mast-cell accumulation has been observed in the skin and other organs of patients with systemic indolent mastocytosis (SM). The basis for this pathologic increase is not fully understood. OBJECTIVE: We sought to determine levels of mast-cell growth factors in the skin and plasma of patients with SM, patients with atopic dermatitis (AD), and healthy individuals and to correlate these levels to dermal mast-cell numbers and levels of mast-cell tryptase. METHODS: Skin suction blister fluid and plasma levels of stem-cell factor, IL-3, IL-4, IL-6, vascular endothelial growth factor, and total mast-cell tryptase were analyzed by means of ELISA. The number of mast cells was determined in a biopsy section taken from adjacent skin. RESULTS: Mast-cell numbers in the dermis were higher in patients with SM compared with numbers in patients with AD (P <.001) or in healthy control subjects (P <.0001) and correlated with tryptase levels in both skin blister fluid (P <.0001) and plasma (P <.0001). Stem-cell factor and vascular endothelial growth factor levels in the skin blister fluid and plasma of patients with SM were not significantly different from those in patients with AD or healthy control subjects. IL-3 and IL-4 levels were below the limit of detection. IL-6 levels were significantly increased in the plasma of patients with SM compared with in plasma of patients with AD (P <.002) and healthy control subjects (P <.0001) and correlated with plasma tryptase levels (P <.05) and dermal mast-cell numbers (P <.02). CONCLUSION: Because elevated levels of IL-6 could contribute to the fever, fatigue, and osteoporosis observed in patients with SM and because IL-6 is antiapoptotic for mast cells, IL-6 could potentiate the biologic consequences of this disease.     

Apnea as a manifestation of mast cell activation in an infant with mastocytosis

J Allergy Clin Immunol 1997;100:850-1.