Evaluation of a tryptase depletion index for better pathologic identification of mast cell activation syndrome.

BACKGROUND: Laboratory evidence supporting diagnosis of the prevalent condition of mast cell activation syndrome (MCAS) currently includes elevated levels in blood or urine of mediators relatively specific to mast cells (MCs) and/or increased numbers of MCs in luminal gastrointestinal (GI) tract tissues. However, identification of elevated mediators is technically challenging and expensive, and controversy persists regarding the normal ranges of numbers/counts of MCs in various GI tract segments, let alone challenges in determining how many of the visualized MCs are activated. To aid diagnosis of MCAS, we developed a potential new approach for the pathologist to identify the extent of GI tract MC activation easily and inexpensively. PARTICIPANTS AND METHODS: Visualization of MCs in gastrointestinal biopsies from 251 patients vs. 95 controls using antibodies against CD117 and tryptase; MC counting per mm2; calculation of the difference between the CD117-positive MCs (identifying all MCs) vs. tryptase-positive MCs (identifying non-activated tryptase-containing MCs), which we define as the tryptase depletion index (TDI). RESULTS: Mean total MC counts did not differ significantly between patients and controls, but mean TDIs differed significantly. Non-overlapping confidence intervals at the 99.9% level identified cut-offs of TDIs between patients vs. controls of 26, 45 and 32 MCs/mm2 in gastric antrum, duodenum, and colon, respectively. CONCLUSIONS: The TDI may discriminate between MCAS patients vs. controls. If this preliminary work can be independently confirmed, the TDI may become a useful additional minor diagnostic criterion for MCAS.

Lower prevalence of vitamin D insufficiency in German patients with systemic mast cell activation syndrome compared with the general population.

Introduction The common mastocytosis variant systemic mast cell activation syndrome (MCAS) may underlie at least a subset of patients with irritable bowel syndrome (IBS). A critical role of vitamin D (VD) in the stabilization of mast cells (MCs) with deficiency of VD resulting in MC activation has been demonstrated. If so, supplementation of VD would be a potential therapeutic approach in the treatment of those IBS patients. Methods We investigated in the present study for the first time systematically whether the VD level in 100 MCAS patients differed from that in the German general population (Ggp) and made a first attempt to elucidate potential reasons for possible differences by simultaneously determining the blood levels of heparin and cholesterol. Results In contrast to the Ggp, the VD level was detected in a sufficient range (> 30 ng/mL) in 53 % of the MCAS patients (Ggp 8 %), and only 34 % had values in the range of deficiency (< 20 ng/mL; GgP 75 %). There was no correlation between VD blood level and heparin and cholesterol blood levels. Conclusions The demonstration that in the majority of MCAS patients the VD level is not in a deficient range argues against an essential contribution of VD deficiency to the high prevalence of MCAS in Germany. Our findings do not exclude the possibility of smaller effects of VD level on MC activation in vivo. However, if such effects are present, the effect sizes seem to be too small to become identifiable in the multifactorial process of disease development.

Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects.

Systemic mast cell activation syndrome is a mast cell disorder characterized by an unregulated increased activation of mast cells leading to a pathologically enhanced release of mediators. Mutations in tyrosine kinase kit which crucially determines mast cell activity have been suggested as a necessary condition for the development of a clinically symptomatic mast cell disease. At the level of mRNA in mast cell progenitor cells of 20 patients with systemic mast cell activation syndrome and of 20 gender- and age-matched healthy volunteers, the tyrosine kinase kit was investigated for genetic alterations by means of RT-PCR and direct sequencing of the amplificates. In mast cells of 13 out of these 20 patients, multiple predominantly novel potential functionally activating point mutations or complex alterations of the mRNA sequence encoding the tyrosine kinase kit were detected. In contrast, in 19 of the 20 healthy subjects, no functionally relevant alterations of c-kit transcripts were detected. The present findings support the idea that the systemic mast cell activation syndrome is a clonal disease most commonly associated with variable activating mutations in the tyrosine kinase kit.

New aspects of liver abnormalities as part of the systemic mast cell activation syndrome.

BACKGROUND/AIMS: This study was aimed at investigating the form and prevalence of liver involvement in patients with systemic mast cell activation syndrome, a possibly common subvariant of systemic mastocytosis. An attempt was made to shed light on potential mechanisms responsible for mast cell mediator-related liver abnormalities. METHODS: The methods used were clinical investigation, biochemical determination of cholesterol, transaminases and bilirubin in blood, determination of chitotriosidase by enzyme-linked immunosorbent assay technique, and quantitative reverse transcribed-polymerase chain reaction to determine chitotriosidase expression. RESULTS: An elevation of plasma cholesterol was detected in 75% of the patients; elevations of transaminases and bilirubin were determined in 40 and 36% of the patients respectively; hepatomegaly or morphological hepatic alterations were observed in 34%. Chitotriosidase level in blood as a surrogate parameter for Kupffer cell activation in the liver was unchanged. However, chitotriosidase expression in isolated mast cells was downregulated at the mRNA level. CONCLUSIONS: Hypercholesterolaemia and liver abnormalities are frequently found in patients with the mast cell activation syndrome. Hence, the mast cell activation syndrome should be considered at an early stage as a possible cause of hypercholesterolaemia and of hepatic abnormalities of unknown reason. Mast cell activation may be indicated by a reduced expression of the enzyme chitotriosidase in blood-derived mast cells as well as by an increased plasma cholesterol level.

Ureteral stones due to systemic mastocytosis: diagnostic and therapeutic characteristics.

Urolithiasis is expected to cause a considerable complication in patients with systemic mastocytosis. The aim of the present report is to demonstrate that due to pathological activation and irritability of mast cells, special features in the diagnostic investigation and therapy of urolithiasis have to be considered in patients with systemic mastocytosis. The clinical presentation, diagnostic investigation and therapeutic procedure of urolithiasis in a patient with systemic mastocytosis are described. Urolithiasis may be a significant complication of systemic mastocytosis. Non-contrast CT is the main tool for diagnosing urolithiasis after a detailed history and clinical exam. Patients with systemic mastocytosis should receive a premedication composed of a glucocorticoid and H(1)- and H(2)-histamine receptor antagonists. An increased vulnerability of mucosal tissues is expected in patients with systemic mastocytosis that may limit the options of operative and postoperative therapy. Opioids should be used cautiously for analgesia in patients with systemic mastocytosis.

Risk of solid cancer in patients with mast cell activation syndrome: Results from Germany and USA.

Background:  It has been shown repeatedly that mast cells can promote or prevent cancer development and growth. If development and/or progression of a solid cancer is substantially influenced by mast cell activity, the frequencies of occurrence of solid cancers in patients with primary mast cells disorders would be expected to differ from the corresponding prevalence data in the general population. In fact, a recent study demonstrated that patients with systemic mastocytosis (i.e., a rare neoplastic variant of the primary mast cell activation disease) have increased risk for solid cancers, in particular melanoma and non-melanoma skin cancers. The aim of the present study is to examine whether the risk of solid cancer is increased in systemic mast cell activation syndrome (MCAS), the common systemic variant of mast cell activation disease. Methods: In the present descriptive study, we have analysed a large (n=828) patient group with MCAS, consisting of cohorts from Germany and the USA, for occurrence of solid forms of cancer and compared the frequencies of the different cancers with corresponding prevalence data for German and U.S. general populations. Results: Sixty-eight of the 828 MCAS patients (46 female, 22 male) had developed a solid tumor before the diagnosis of MCAS was made. Comparison of the frequencies of the malignancies in the MCAS patients with their prevalence in the general population revealed a significantly increased prevalence for melanoma and cancers of the breast, cervix uteri, ovary, lung, and thyroid in MCAS patients. Conclusions: Our data support the view that mast cells may promote development of certain malignant tumors. These findings indicate a need for increased surveillance of certain types of cancer in MCAS patients irrespective of its individual clinical presentation.

Pharmacological treatment options for mast cell activation disease.

Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches.

Determination of plasma heparin level improves identification of systemic mast cell activation disease.

Diagnosis of mast cell activation disease (MCAD), i.e. systemic mastocytosis (SM) and idiopathic systemic mast cell activation syndrome (MCAS), usually requires demonstration of increased mast cell (MC) mediator release. Since only a few MC mediators are currently established as biomarkers of MCAD, the sensitivity of plasma heparin level (pHL) as an indicator of increased MC activation was compared with that of serum tryptase, chromogranin A and urinary N-methylhistamine levels in 257 MCAD patients. Basal pHL had a sensitivity of 41% in MCAS patients and 27% in SM patients. Non-pharmacologic stimulation of MC degranulation by obstruction of venous flow for 10 minutes increased the sensitivity of pHL in MCAS patients to 59% and in SM patients to 47%. In MCAS patients tryptase, chromogranin A, and N-methylhistamine levels exhibited low sensitivities (10%, 12%, and 22%, respectively), whereas sensitivities for SM were higher (73%, 63%, and 43%, respectively). Taken together, these data suggest pHL appears more sensitive than the other mediators for detecting systemic MC activity in patients with MCAS. The simple, brief venous occlusion test appears to be a useful indicator of the presence of pathologically irritable MCs, at least in the obstructed compartment of the body.

Gastrointestinal uptake of agmatine: distribution in tissues and organs and pathophysiologic relevance.

The authors report on (1) the absorption of agmatine from the gastrointestinal tract as an important source of this polycation in the organism, (2) its organ distribution, and (3) its putative role in liver regeneration. When rats received 0.5 microCi [(14)C]agmatine contained in 5 grams of standard rat chow after a fasting period of 24 hours, radioactivity was recovered in all organs investigated, in blood, and in urine. In the liver 67% +/- 7% of administered radioactivity was found. After partial (two-thirds) hepatectomy, administration of 250 mg and 500 mg agmatine by gavage for 6 days reduced liver regeneration at day 7 by 20% and 22%, respectively, compared with animals that received no agmatine. Agmatine is absorbed from the gastrointestinal tract, probably by means of a specific transporter. It is likely that agmatine in the chyme of the gut represents an essential source of agmatine in the tissues of the organism. An increase in the availability of gastrointestinal agmatine for absorption impairs liver regeneration and may contribute to the development of liver diseases.

Marked clinical and histologic improvement in a patient with type-1 Gaucher's disease following long-term glucocerebroside substitution. A case report and review of current diagnosis and management.

Type-1 Gaucher's disease represents the most common lysosomal storage disorder. With the introduction of enzyme replacement therapy, many of the clinical manifestations can be controlled. The functional deficiency of the lysosomal beta-glucocerebrosidase leads to deposition of glycosylceramide in the liver, spleen, and bone marrow. We report the clinical and pathologic presentation of a patient with a florid type-1 Gaucher's disease who received long-term enzyme replacement therapy, which led to marked clinical improvement. A repeat liver biopsy performed at the time of a cholecystectomy several years after initiation of enzyme replacement therapy revealed complete resolution of Gaucher cells.

[Dysferlinopathy as an extrahepatic cause for the elevation of serum transaminases]. / Dysferlinopathie als extrahepatische Ursache von Transaminasenerhöhungen.

BACKGROUND AND PURPOSE: The aim of the present report is to emphasize that the source of elevated transaminase levels, although usually indicative of hepatocellular damage, can also be of extrahepatic origin. CASE REPORT: A 42-year-old female presented with a moderate persistent elevation of the transaminases glutamic-oxaloacetic transaminase (GOT; synonym: aspartate aminotransferase [AST]) and glutamic-pyruvic transaminase (GPT; synonym: alanine aminotransferase [ALT]) in blood without any apparent clinical symptoms of liver affection. In the course of further diagnostics for clarification of a suspected liver disease, a markedly elevated activity of creatine kinase was found which, in concert with results from myography, magnetic resonance imaging (MRI) and analysis of muscle biopsies, suggested the tentative diagnosis of a distal myopathy type Miyoshi. The diagnosis was confirmed by identification of the underlying mutation in the dysferlin gene. The course of the disease has been slowly but steadily progressive; there is no therapeutic option at present. The relevance of molecular genetic analyses in the diagnostic procedure for distal myopathies, in particular dysferlinopathy, is discussed and the characteristics of this disease are summarized. CONCLUSION: In the case of persistent elevations of the serum transaminases GOT and GPT without liver disorder, a myopathy has to be taken into account as a potential extrahepatic source. In order to avoid needless nondirected expensive investigations and to prevent a delay in diagnostics, activity of serum creatine kinase should be determined which is moderately to strongly elevated in the case of myopathies. If, in particular, a dysferlinopathy is supposed, the underlying mutation should be identified to confirm the diagnosis and as a basis for current and future therapeutic interventions

Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options.

Mast cell activation disease comprises disorders characterized by accumulation of genetically altered mast cells and/or abnormal release of these cells' mediators, affecting functions in potentially every organ system, often without causing abnormalities in routine laboratory or radiologic testing. In most cases of mast cell activation disease, diagnosis is possible by relatively non-invasive investigation. Effective therapy often consists simply of antihistamines and mast cell membrane-stabilising compounds supplemented with medications targeted at specific symptoms and complications. Mast cell activation disease is now appreciated to likely be considerably prevalent and thus should be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity or patients in whom a definitively diagnosed major illness does not well account for the entirety of the patient's presentation.

Omalizumab treatment of systemic mast cell activation disease: experiences from four cases.

We report on the outcome of 4 patients with therapy-resistant systemic mast cell activation disease (MCAD) treated with the anti-IgE monoclonal antibody omalizumab in compassionate use. Two patients achieved an impressive persistent clinical response to treatment with omalizumab. In the third patient symptoms gradually improved. In the fourth patient omalizumab treatment had to be discontinued due to intolerable mast cell mediator-induced symptoms. In conclusion, omalizumab can lessen the intensity of the symptoms of systemic MCAD. Hence, omalizumab should be considered as a therapeutic option in cases of systemic MCAD that are resistant to evidence-based therapy.

[Systemic mastocytosis--definition of an internal disease]. / Die systemische Mastozytose--Standortbestimmung einer internistischen Erkrankung.

Systemic mastocytosis comprises disorders characterized by an accumulation of genetically altered mast cells in all organs and tissues due to an increased proliferation rate and reduced apoptosis of those pathologic mast cells. Release of their mediators can effectively influence organ function and can lead to systemic effects without inducing traces in routinely used laboratory parameters or imaging methods. In most cases, little invasive investigations allow diagnosing the disease and, hence, an appropriate therapy consisting of a basic medication with antihistamine and mast cell membrane-stabilizing compounds that should be supplemented, if required, by a medication adapted to individual symptoms, can be initiated. Because of the probably high prevalence of the disorder, systemic mastocytosis should be considered as a differential diagnosis in particular in the case of chronic gastrointestinal complaints such as abdominal pain/discomfort possibly associated with diarrhea, at an early stage.

Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder.

OBJECTIVE: Sequencing efforts to discover mutations in the tyrosine kinase Kit related to systemic mast cell disorders have so far been focused mainly on only a few of the 21 exons of the encoding gene c-kit, thus considerably limiting the possibility to quantitatively reveal pathogenetic relationships. The purpose of this study was to analyze and compare the total sequence of Kit tyrosine kinase at the level of the mRNAs obtained from patients with clear systemic signs of a pathologically increased mast cell mediator release and those from healthy volunteers. MATERIAL AND METHODS: Kit encoding mRNA isolated from mast cell progenitors in peripheral blood from 17 patients with a mast cell activation disorder and from 5 healthy volunteers as well as from the human mast cell leukemia cell line HMC1 was analyzed for alterations. RESULTS: Multiple novel point mutations and six isoforms of Kit which are due to alternative mRNA splicing were detected. One isoform, the insertion of a glutamine residue at amino acid position 252, was found to be a new splice variant expressed in all patients but in none of the healthy volunteers. CONCLUSIONS: Systemic mast cell activation disorder was pathogenetically characterized by two or more alterations in the Kit tyrosine kinase providing not only a means of confirming the diagnosis, but also of assessing prognosis and of starting adequate therapeutic interventions. The insertion of Q252 appears to be pathognomic for that disease, providing a novel means for the identification of chronic non-specific gastrointestinal symptoms as manifestations of a systemic mast cell activation disorder.