Mastocytosis is characterized by the proliferation of clonal mast cells and its clinical features include flushing, pruritus, abdominal pain, diarrhea, hypotension, and anaphylaxis. The predominant form of cutaneous mastocytosis (CM) is urticaria pigmentosa (UP). Other forms of CM include diffuse CM and mastocytomas. Systemic mastocytosis (SM) is characterized by multifocal mast cell infiltrates in the bone marrow and other organs, and is subcategorized following World Health Organization (WHO) criteria. One minor criterion for the diagnosis of SM is a serum tryptase >20 ng/mL, which generally reflects mast cell expansion and is a useful marker of mast cell activation by established criteria. Other mediators where no such criteria have been proposed include heparin, histamine, and prostaglandin D2 and some authors have suggested that chromogranin A (CgA) should be among these markers based on limited data. In particular, serum levels of CgA have been reported as fairly specific to mast cells when evaluating patients for mast cell activation disorder (MCAD) when other causes of elevated chromogranin levels are excluded. Proton pump inhibitor (PPI) use is associated with an increase in CgA levels, as acid suppression by PPIs promotes hypergastrinemia that leads to increased CgA. Patients with mastocytosis are frequently treated with these agents to control symptoms related to mast cell-driven acid hypersecretion. We thus prospectively determined serum CgA, gastrin, and tryptase levels in 20 adults and 17 pediatric patients diagnosed with mastocytosis based on WHO criteria. All patients had symptoms consistent with mast cell activation, such as flushing, pruritus, abdominal pain, diarrhea, hypotension, and anaphylaxis. Serum CgA, gastrin, and tryptase levels were obtained in all patients. Bone marrow, skin, and small intestinal biopsies were obtained from adult patients with indolent systemic mastocytosis (ISM). Samples were fixed and stained for tryptase and CgA. HMC1.1, HMC1.2, and LAD2 human mast cell lines and the pancreatic beta islet cell carcinoma line, QGP-1, were used to determine relative quantitative expression of CgA using RT-PCR and western blotting. The adult cohort consisted of 10 female and 10 male patients with ISM, with a median age of 52.8 years and a tryptase level of 32.0 ng/mL. Serum CgA median, 25th and 75th interquartile range (IQR) were 65.0, 38.3, and 135 ng/mL, respectively. Because patients with ISM are often treated with PPIs and H2 antagonists, we divided the patients according to medication use. The median, 25th, and 75th IQR CgA serum values for those taking neither H2 antagonists or PPIs were 40.5, 32.5, and 59.8 ng/mL, respectively (n = 6); for those on H2 antagonists alone were 68.0, 46.0, and 107 ng/mL, respectively (n = 9); and for those taking H2 blockers and PPIs were 508, 300, and 824 ng/mL, respectively (n = 5). We determined a significant difference in CgA serum values when comparing the no medication group (P < .001) and the H2 antagonist group (P < .05) with those taking both PPIs and H2 antagonists but not when comparing the no medication with those taking H2 antagonists alone. Tryptase levels and D816V allelic frequency were not associated with H2 antagonist or PPI. These data are consistent with the conclusions that adult patients with mastocytosis not taking PPIs have serum CgA levels within the normal reference range and that the serum levels of CgA are significantly influenced by the use of PPIs. Serum gastrin levels correlated with CgA levels (P = .020, r = 0.51). However, CgA and tryptase levels did not correlate. CgA levels were similarly measured in patients with pediatric mastocytosis. All had mediator-related symptoms and CgA levels within the normal range. Also consistent with adult data, we found a positive correlation of CgA with gastrin (P = .029, r = 0.83), but not between tryptase and CgA. Representative marrow, duodenum, and skin biopsy staining for CgA were essentially negative compared with positive controls. Bone marrow staining with tryptase revealed focal mast cell aggregates with corresponding negative staining for CgA. Skin biopsy showed similar results. Tryptase staining of the duodenum in a patient with severe gastrointestinal (GI) symptoms who is also treated by PPI highlighted the presence of mast cells in the lamina propria with no significant CgA staining. The relative expression of chromogranin by qPCR and western blotting in mast cell lines compared with positive control (QGP-1 cells) was low. We thus determined that CgA is largely not identified in mast cell infiltrates in the bone marrow, skin, and GI tract, and serum levels are within the normal reference range in patients with pediatric and adult mastocytosis, whereupon all of these patients exhibited an elevated CgA. Serum tryptase levels and D816V frequencies in peripheral blood, regardless of medication usage, did not associate with CgA levels. We found that the use of PPIs is the cause of elevated serum CgA in patients with mastocytosis. These results, coupled with the immunohistochemical data, demonstrate that mast cells are not a significant systemic source of serum CgA. Therefore, we recommend that serum CgA not be used as a biomarker of mast cell disease. Clonal mast cell disorders are known to occur in a subset of patients with systemic reactions to Hymenoptera stings. This observation has prompted the question of whether clonal mast cell disorders also occur in patients with idiopathic anaphylaxis (IA). In collaboration with Dr. Carter, we sought to determine the prevalence of clonal mast cell disorders among patients with IA, criteria to identify those patients who require a bone marrow biopsy, and whether the pathogenesis of IA involves a hyperresponsive mast cell compartment. We analyzed prospectively enrolled patients with IA (3 episodes/y) who then underwent a medical evaluation that included a serum tryptase determination, allele-specific quantitative PCR (ASqPCR) for the KIT D816V mutation, and a bone marrow examination. Mast cells were cultured from peripheral blood CD34+ cells and examined for releasability after FcRI aggregation. Results showed that clonal mast cell disease was diagnosed in 14% of patients referred with IA. ASqPCR for the KIT D816V mutation was a useful adjunct in helping identify those with systemic mastocytosi, but not monoclonal mast cell activation syndrome. A modified overall clonal prediction model was developed by using clinical findings, a serum tryptase determination, and ASqPCR. There was no evidence of a hyperresponsive mast cell phenotype in patients with IA. We concluded that patients with clonal mast cell disease can present as having IA. Distinct clinical and laboratory features can be used to select those patients more likely to have an underlying clonal mast cell disorder (monoclonal mast cell activation syndrome or systemic mastocytosis) and thus candidates for a bone marrow biopsy.

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Hanjra, Pahul; Lee, Chyi-Chia R; Maric, Irina et al. (2018) Chromogranin A is not a biomarker of mastocytosis. J Allergy Clin Immunol Pract 6:687-689.e4
Carter, Melody C; Desai, Avanti; Komarow, Hirsh D et al. (2018) A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis. J Allergy Clin Immunol 141:180-188.e3
Carter, Melody C; Clayton, Sarah T; Komarow, Hirsh D et al. (2015) Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis. J Allergy Clin Immunol 136:1673-1679.e3
Maric, Irina (2015) CD30-targeting drugs: cure for mastocytosis? Blood 126:2771-3
Carter, Melody C; Metcalfe, Dean D; Clark, Alicia S et al. (2015) Abnormal bone marrow histopathology in paediatric mastocytosis. Br J Haematol 168:865-73
Chan, Eunice Ching; Bai, Yun; Kirshenbaum, Arnold S et al. (2014) Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype. J Allergy Clin Immunol 134:178-87
Lyons, Jonathan J; Sun, Guangping; Stone, Kelly D et al. (2014) Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities. J Allergy Clin Immunol 133:1471-4
Bai, Y; Bandara, G; Ching Chan, E et al. (2013) Targeting the KIT activating switch control pocket: a novel mechanism to inhibit neoplastic mast cell proliferation and mast cell activation. Leukemia 27:278-85
Chan, Eunice Ching; Bai, Yun; Bandara, Geethani et al. (2013) KIT GNNK splice variants: expression in systemic mastocytosis and influence on the activating potential of the D816V mutation in mast cells. Exp Hematol 41:870-881.e2
Wilson, Todd M; Maric, Irina; Simakova, Olga et al. (2011) Clonal analysis of NRAS activating mutations in KIT-D816V systemic mastocytosis. Haematologica 96:459-63

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