diagnosis

Mast cells in the GI tract: How many is too many? (Part Five)

One of the most interesting papers on mast cell burden in the GI tract evaluates patients with chronic urticaria.  The patients in this study did not have GI symptoms, but they did have skin symptoms related to consumption of trigger foods.  Mast cells were identified using antibodies to CD117 and tryptase, and were counted in five hpf and averaged.  The healthy controls for this study were from two countries in order to evaluate the effect of diet on mast cell count in healthy patients.  There was no difference between the control groups from different countries.

The control group as a whole averaged 20.2 mast cells/hpf in the stomach.  The chronic urticaria group as a whole averaged 32.4/hpf in the stomach.  This paper also assessed the mast cell count in chronic urticaria patients whose biopsies did not display any tissue damage.  In this group, mast cell count averaged 30.4/hpf. In all instances, cells were scattered and not clustered.  Mast cell count in CU patients were 61% increased compared to controls. See Table 15 for details.

In the duodenum (small intestine), the healthy control group averaged 32.5 mast cells/hpf.  The chronic urticaria group had 44.8/hpf and chronic urticaria patients with normal biopsies (not tissue damage) averaged 45.2/hpf.  Again, cells were scattered and not clustered. Mast cell count in CU patients were 37.8% increased compared to controls. See Table 16 for details.

The implication here is that even in the absence of GI symptoms, activation of mast cells in the GI tract might release enough histamine to cause urticaria.  An important feature of this paper is that it discusses “pseudoallergens”, which it describes as “non-specific histamine-release” substances. Fourteen of the patients in this study had a history of “pseudoallergen” food triggers that irritated their urticaria. In these patients, mast cell count was actually lower in the stomach than those who didn’t have food “pseudoallergen.” See quote below.

“The skin lesions of CU are caused by vasoactive mediators released through specific or non-specific mast cell degranulation in the skin or elsewhere. CU patients are particularly susceptible to the non-specific histamine-releasing effect of pseudoallergenic substances in various foods and drugs, and the success rate of pseudoallergen-free diets varies between 30 and 50%.  It is conceivable that food pseudoallergens induce non-specific mast cell degranulation, rather in the gastrointestinal tract than elsewhere. Activation of many intestinal mast cells may then result in enough histamine release to cause urticaria either directly or indirectly.” (Minnei 2006)

 

Table 15: Mast cell count in stomach of patients with chronic urticaria
Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.
Microscopy method: 400x magnification, counted in 5 hpf and averaged
Visualization: CD117 and tryptase
Sample type Study group: Chronic urticaria Study group: Chronic urticaria, biopsies normal Control group A:

Healthy controls

Stomach Average Range Average Stomach Average Range
32.4 mast cells/hpf 29.5-35.4 mast cells/hpf 30.4 mast cells/hpf 26.2-34.6 mast cells/hpf 20.2 mast cells/hpf 17.4-22.9 mast cells/hpf
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

Table 16: Mast cell count in small intestine (duodenum) of patients with chronic urticaria
Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.
Microscopy method: 400x magnification, counted in 5 hpf and averaged
Visualization: CD117 and tryptase
Sample type Study group: Chronic urticaria Study group: Chronic urticaria, biopsies normal Control group A:

Healthy controls

Duodenum Average Range Average Stomach Average Range
44.8 mast cells/hpf 39.2-50.3 mast cells/hpf 45.2 mast cells/hpf 38.4-52.1 mast cells/hpf 32.5 mast cells/hpf 29.4-35.6 mast cells/hpf
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

Ramsay DB, et al. Mast cells in gastrointestinal disease. Gastroenterology & Hepatology 2010; 6 (12): 772-777.

Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gatroenterol 2012; 18 (5): 322-326.

Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis. American Journal of Surgical Pathology 2007; 31(11): 1669-1676.

Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

Akin C, et al. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126 (6): 1099-1104.

Valent P, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012: 157 (3): 215-225.

Mast cells in the GI tract: How many is too many? (Part Four)

The 2012 study by Akhavein that described allergic mastocytic enterocolitis also performed biopsies on the stomach of patients with a history of atopic/allergic disease were biopsied.  Mast cells were identified using an antibody to CD117, the CKIT receptor found on the surface of all mast cells. The cells were counted in only 1 hpf.  On average, there were 39 mast cells/hpf with a range of 16-82 mast cells/hpf.  These cells were also scattered and not clustered.  See Table 13 for details.

Table 13: Mast cell count in stomach of patients with GI pain and dysmotility and a history of allergic disease
Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.
Stomach Study group: atopic/allergic history with abdominal pain and GI dysmotility Control group A:

No control group

Control group B:

No control group

Average Range Average Range Average Range
39 mast cells/hpf 16-82 mast cells/hpf N/A N/A N/A N/A
Diffuse, scattered cells, no clusters.

 

A 2015 publication evaluated the mast cell count in patients with chronic diarrhea for unknown reasons.  Mast cells were quantified using an antibody to CD117.  Cells were only counted in 1 hpf in the portion of the slide with the most mast cells.  The healthy control group averaged 24 mast cells/hpf, while the study group with chronic diarrhea averaged 31 mast cells/hpf. See Table 14 for details.

Table 14: Mast cell count in colon of patients with chronic diarrhea
Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.
Microscopy method: 400x magnification, mast cells counted in 1 hpf
Visualization: CD117 and tryptase (IHC)
Sample type Study group: Chronic diarrhea Control group A:

Healthy controls

Control group B:

No control group

Colon Average Range Average Range Average Range
31 mast cells/hpf 24-34 mast cells/hpf 24 mast cells/hpf 22-27 mast cells/hpf N/A N/A
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

Ramsay DB, et al. Mast cells in gastrointestinal disease. Gastroenterology & Hepatology 2010; 6 (12): 772-777.

Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gatroenterol 2012; 18 (5): 322-326.

Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis. American Journal of Surgical Pathology 2007; 31(11): 1669-1676.

Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

Akin C, et al. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126 (6): 1099-1104.

Valent P, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012: 157 (3): 215-225.

Mast cells in the GI tract: How many is too many? (Part Two)

As I mentioned in the previous post, a 2006 paper counted mast cells in the duodenum (part of the small intestine) and colon of patients with treatment resistant chronic diarrhea and compared these counts to patients with known inflammatory GI diseases and to asymptomatic healthy controls.  This paper posited that cell counts over 20 mast cells/hpf represented a distinct phenomenon called mastocytic enterocolitis.  The author felt that mastocytic enterocolitis was distinct from inflammation caused by other GI diseases, such as Crohn’s colitis, ulcerative colitis and celiac disease.

In this paper, the counts for asymptomatic controls ranged from 3-20 cells/hpf and the counts for known inflammatory GI disease ranged from 2-18 mast cells/hpf.  Patients with chronic diarrhea that resisted treatment demonstrated counts ranging from 13-35 mast cells/hpf.  Mast cells were identified by using an antibody to tryptase.

70% of patients with chronic diarrhea without a known cause had over 20 mast cells/hpf. Cells were counted in 10 hpf and averaged.  Counting in multiple fields and averaging generally gives more representative counts. Based upon this study, it was reasonable to assume that mast cells over 20/hpf was higher than normal. See Table 4 for details.

Table 4: Mast cell counts in duodenum and colon of chronic diarrhea patients (Jakate 2006)
Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.
Microscopy method: 400x magnification, mast cells counted in 10 hpf and averaged
Visualization: Tryptase (IHC)
Sample type Study group: Intractible chronic diarrhea Control group A: Inflammatory GI disease that causes chronic diarrhea (ie. Crohn’s colitis, ulcerative colitis, gluten sensitive enteropathy) Control group B: Asymptomatic, healthy controls
Duodenum and colon (counts averaged) Average Range Average Range Average Range
25.7 mast cells/hpf 13-35 mast cells/hpf 12.4 mast cells/hpf 2-18 mast cells/hpf 13.3 mast cells/hpf 3-20 mast cells/hpf

 

In a 2012 paper by Akhavein, the stomach, small intestine and colon of patients with a history of atopic/allergic disease were biopsied.  Mast cells were identified using an antibody to CD117, the CKIT receptor found on the surface of all mast cells. The cells were counted in only 1 hpf.

This paper found that the average mast cell count for biopsies from all organs was 37/hpf.  The author posited that given that these patients had a history of allergic conditions, that a count of over 40/hpf described a phenomenon called allergic mastocytic gastroenteritis that was distinct from the previous described mastocytic enterocolitis.  Cells were scattered and not clustered. There was no control group in this study.  See Table 5 and Table 6 for details.

Table 5: Mast cell count in small intestine of patients with GI pain and dysmotility and a history of allergic disease
Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.
Microscopy method: Magnification not explicitly stated, assumed 400x, mast cells counted in 1 hpf
Visualization: CD117 (IHC)
Sample type Study group: atopic/allergic history with abdominal pain and GI dysmotility Control group A:

No control group

Control group B:

No control group

Small intestine Average Range Average Range Average Range
57 mast cells/hpf 30-90 mast cells/hpf N/A N/A N/A N/A
Diffuse scattered cells, no clusters.

 

Table 6: Mast cell count in colon of patients with GI pain and dysmotility and a history of allergic disease
Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.
Microscopy method: Magnification not explicitly stated, assumed 400x, mast cells counted in 1 hpf
Visualization: CD117 (IHC)
Sample type Study group: Diarrhea predominant IBS Control group A:

Healthy controls

Control group B:

No control group

Colon Average Range Average Range Average Range
37 mast cells/hpf 1-69 mast cells/hpf N/A N/A N/A N/A
Diffuse scattered cells, no clusters.

 

A 2013 paper quantified mast cells in patients with diarrhea predominant irritable bowel syndrome and compared to healthy controls. The patients averaged 26.2 mast cells/hpf in the jejunum, part of the small intestine, while the controls averaged 17.2. Mast cells were identified using an antibody to CD117, the CKIT receptor found on the surface of all mast cells. The cells were likely counted in only 1 hpf as it was not explicitly stated. Distribution of mast cells was not described. See table 7 for details.

 

Table 7: Mast cell count in small intestine of patients diarrhea predominant irritable bowel syndrome
Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168.
Microscopy method: Magnification not explicitly stated, assumed 400x, number of hpf not explicitly stated, assumed mast cells counted in 1 hpf
Visualization: CD117 (IHC)
Sample type Study group: Diarrhea predominant IBS Control group A:

Healthy controls

Control group B:

No control group

Jejunum Average Range Average Range Average Range
26.2 ± 11.1 mast cells/hpf N/A 17.2 ± 8.8 mast cells/hpf N/A N/A N/A
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

Ramsay DB, et al. Mast cells in gastrointestinal disease. Gastroenterology & Hepatology 2010; 6 (12): 772-777.

Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gatroenterol 2012; 18 (5): 322-326.

Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis. American Journal of Surgical Pathology 2007; 31(11): 1669-1676.

Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

Akin C, et al. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126 (6): 1099-1104.

Valent P, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012: 157 (3): 215-225.

 

Mast cells in the GI tract: How many is too many? (Part One)

Let’s have a chat about the idea that 20 mast cells/hpf (high powered field) in gastrointestinal biopsy is higher than normal.

First, let’s review a few things.

The WHO diagnostic criteria for systemic mastocytosis are as follows:

Table 1: World Health Organization Criteria for Systemic Mastocytosis (2008)
  • Systemic mastocytosis is diagnosed in the presence of: 1 major and 1 minor criterion; or 3 minor criteria.
  • Biopsy specimens can be from any non-cutaneous organ (any organ that is not the skin).
Major criterion:
Multifocal, dense aggregates of mast cells (15 or more) detected in sections of bone marrow and confirmed by tryptase immunohistochemistry or other special stains:
Minor criterion:
1.       In biopsy section, more than 25% of mast cells in the infiltrate have atypical morphology, or, of all the mast cells in the smear, more than 25% are immature or atypical. (25% of the mast cells are shaped wrong.)
2.       Mast cells co-express CD117 with CD25 and/or CD2. (Mast cells show markers CD25 or CD2 on their outsides.)
3.       Detection of KIT point mutation at codon 816 in bone marrow, blood or other extracutaneous organs. (Positive for the CKIT D816V mutation.)
4.       Serum total tryptase persistently >20 ng/ml (not a valid criteria in cases of systemic mastocytosis with associated clonal non-hematologic mast-cell lineage disease). (Baseline serum tryptase over 20 ng/ml – baseline, not reaction.)

 

There are several different diagnostic algorithms floating around for mast cell activation syndrome (MCAS).  They are summarized here:

Table 2: Diagnostic algorithms for  mast cell activation syndrome (MCAS, also called mast cell activation disorder, MCAD)
  • Biopsy specimens can be from any non-cutaneous organ (any organ that is not the skin).
Molderings, Afrin 2011 Akin, Valent, Metcalfe 2010 Valent, Akin, Castells, Escribano, Metcalfe et al 2012
MCAD (mast cell activation disease, an  umbrella term including both MCAS and SM) is diagnosed if both major criteria, or one major criterion and one minor criterion, are present; following bone marrow biopsy, diagnosis is narrowed down to either SM or MCAS MCAS diagnosed if all criteria are met MCAS diagnosed if all criteria are met
Major Criteria
Multifocal of disseminated dense infiltrates of mast cells in bone marrow biopsies and/or in sections of other extracutaneous organ(s) (GI tract biopsies; CD117-, tryptase- and CD25- stained) Episodic symptoms consistent with mast cell mediator release affecting ≥2 organ systems evidenced as follows:

  • Skin: urticaria, angioedema, flushing
  • Gastrointestinal: nausea, vomiting, diarrhea, abdominal cramping
  • Cardiovascular: hypotensive syncope or near syncope, tachycardia
  • Respiratory: wheezing
  • Naso-ocular: conjunctival injection, pruritus, nasal stuffiness
Typical clinical symptoms
Unique constellation of clinical complaints as a result of a pathologically increased mast cell activity (mast cell mediator release symptom) A decrease in the frequency or severity or resolution of symptoms with antimediator therapy: H1– and H2-histamine receptor inverse agonists, antileukotriene medications (cysteinyl leukotriene receptor blockers or 5-lipoxygenase inhibitor), or mast cell stabilizers (cromolyn sodium) Increase in serum total tryptase by at least 20% above baseline plus 2 ng/ml during or within 4 h after a symptomatic period
  Evidence of an increase in a validated urinary or serum marker of mast cell activation: documentation of an increase of the marker to greater than the patient’s baseline value during a symptomatic period on ≥2 occasions or, if baseline tryptase levels are persistently >15 ng, documentation of an increase of the tryptase level above baseline value on 1 occasion. Total serum tryptase level is recommended as the marker of choice; less specific (also from basophils) are 24-hour urine histamine metabolites or PGD2 or its metabolite 11-β-prostaglandin F2. Response of clinical symptoms to histamine receptor blockers or MC-targeting agents e.g. cromolyn
  Rule out primary and secondary causes of mast cell activation and well-defined clinical idiopathic entities
Minor Criteria
Mast cells in bone marrow or other extracutaneous organ(s) show an abnormal morphology (>25%) in bone marrow smears or in histologies
Mast cells in bone marrow express CD2 and/or CD25
Detection of genetic changes in mast cells from blood, bone marrow or extracutaneous organs for which an impact on the state of activity of affected mast cells in terms of an increased activity has been proved
Evidence of a pathologically increased release of mast cell mediators by determination of the content of:

  • Tryptase in blood
  • N-methylhistamine in urine
  • Heparin in blood
  • Chromogranin A in blood
  • Other mast cell specific mediators (leukotrienes, PGD2)

 

Additionally, a questionnaire (found here: http://www.wjgnet.com/2218-6204/abstract/v3/i1/1.htm) designed to assess the likelihood of mast cell activation disease (MCAS or SM) in a patient was published in 2014 by Lawrence Afrin.  It assigns numerical values to various findings, such as mediator elevation, symptoms, clinical findings, and biopsy features.

The criteria for systemic mastocytosis can be met with a gastrointestinal biopsy showing the features listed above in Table 1.  So if you have gastrointestinal scopes and your biopsy shows mast cells with the features listed in Table 1, then that contributes to receiving a diagnosis of SM.  If you meet some of the criteria but not all of them, with a GI biopsy or otherwise, then you receive a diagnosis of monoclonal mast cell activation syndrome (MMAS), which is like a pre-SM.

A common adage in the mast cell community is that having 20 or more mast cells in a high powered field (hpf, what you see when you look through a microscope with high magnification) is diagnostic for mast cell activation syndrome.

In 2006, a paper was published called “Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.” This paper detailed a study that quantified the mast cells in biopsies of duodenum (small intestine) and colon in patients with chronic diarrhea that resisted treatment. These counts were then compared to patients who had other conditions that caused chronic diarrhea, and to some control subjects that had no GI symptoms.

Table 3: Average mast cell count per hpf in colon and duodenum (Jakate 2006)
Group Average mast cell count in colon and duodenum
Healthy control group 13.3 ± 3.5
Inflammatory GI disease control group 12.4 ± 2.3
Intractible chronic diarrhea group 25.7 ± 4.5

 

The average mast cell count in the healthy control group was 13.3/hpf.  (See Table 3 for details.) Two standard deviations from this value is approximately 20/hpf.  Two standard deviations (SD) is a statistical mechanism that allows for variation in the patient, sample or test procedure.  It is common to round to an even number.

The patients in this group were not evaluated for typical mast cell symptoms.  No information is provided regarding history of allergic or atopic disease. This paper is the origin of the idea that more than 20 mast cells/hpf in the gastrointestinal tract is considered higher than normal.

 

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

Ramsay DB, et al. Mast cells in gastrointestinal disease. Gastroenterology & Hepatology 2010; 6 (12): 772-777.

Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gatroenterol 2012; 18 (5): 322-326.

Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis. American Journal of Surgical Pathology 2007; 31(11): 1669-1676.

Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

Akin C, et al. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126 (6): 1099-1104.

Valent P, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012: 157 (3): 215-225.

 

 

 

Explain the tests: Complete blood count (CBC) with differential and platelets (Part One)

A complete blood count (CBC), also called full blood count (FBC) in some countries, is one of the most frequently ordered diagnostics.  A CBC quantifies and describes the types of cells found in the blood.  These cells include white blood cells (WBC, also called leukocytes), red blood cells (RBC, also called erythrocytes) and platelets (also called thrombocytes).

There are two commonly methods for counting blood cells, automated and manual.

In automated counting, the cells are counted by a machine called a flow cytometer.  Flow cytometers identify cells by shining a laser through a sample of the blood and using the way the light bounces off the cells to determine what kind of cells they are.   This bouncing of light is called scatter.  Flow cytometers measure forward scatter determines the diameter of a cell.  Side scatter determines granularity, how many granules are inside the cell. While this method is generally quite precise, if a cell is not shaped normally, the flow cytometer may count it incorrectly.

In manual counting, the blood is diluted and placed into a special chamber with grid lines called a hemocytometer.  The chamber is viewed under a microscope and the cells are counted by eye.  As someone who has counted lots of cell suspensions by eye, it can be hard to be exact.  This method works for red and white blood cells.

To evaluate abnormality in cell shape, a blood smear is made from the original blood sample.  A smear slide is made by smearing a thin layer of blood onto a glass slide.  Once the blood is dried on the slide, stains are then used to colorize the cells to make them easier to see and distinguish.  Giemsa is a commonly used stain for this purpose (fun fact: mast cells can be visualized with Giemsa stain).  Other stains can also be used. This method allows abnormalities in shape of red and white cells to visualized.

 

A CBC usually includes the following tests:

Total white blood cell count

  • The count of all white blood cells in a volume of blood;
  • Unit is cells/liter

Total red blood cell count

  • The count of all red blood cells in a volume of blood
  • Unit is cells/liter

Hemoglobin (Hb)

  • The amount of hemoglobin in a volume of blood
  • Unit is grams/deciliter

Hematocrit (Hct; also called packed cell volume, PCV)

  • The portion of a volume of blood that is red blood cells
  • Unit is percentage

Mean corpuscular volume (MCV)

  • The volume occupied by red blood cells in a volume of blood
  • Identifies if red cells are the right size
  • Unit is femtoliters/cell

Mean corpuscular hemoglobin (MCH)

  • The average hemoglobin in a red blood cell in a volume of blood; the amount of hemoglobin divided by the red blood cell count; mass of hemoglobin divided by number of red blood cells in a volume of blood; unit is picograms/cell
  • Mean corpuscular hemoglobin concentration (MCHC): the average concentration of hemoglobin in a volume of red blood cells; determines size of red cells; hemoglobin divided by hematocrit; unit is grams/liter

Red blood cell distribution width (RDW)

  • The amount of variation in the size of red cells
  • Can only be high or normal
  • High RDW means red cells show a wide range of size

Reticulocyte count

  • The amount of new red cells in a volume of blood
  • Unit is percentage

 

A CBC with differential and platelets will include the following tests:

Neutrophil count

  • The count of neutrophils in a volume of blood
  • Neutrophils are inflammatory cells that fight infections and initiate inflammatory response
  • Unit is cells/liter

Lymphocyte count

  • The count of lymphocytes in a volume of blood
  • B cells, T cells and NK cells are lymphocytes that detect pathogens in different ways
  • Unit is cells/liter

Monocyte count

  • The count of monocytes in a volume of blood
  • Monocytes respond to inflammatory signals and develop into specialized tissue cells
  • Unit is cells/liter

Eosinophil count

  • The count of eosinophils in a volume of blood
  • Eosinophils fight parasites and participate in allergic response
  • Unit is cells/liter

Basophil count

  • The count of basophils in a volume of blood
  • Basophils fight parasites and participate in allergic response
  • Unit is cells/liter

Platelet count

  • The count of plateletsin a volume of blood
  • Platelets stop bleeding
  • Unit is platelets/liter

Mean platelet volume (MPV)

  • The volume occupied by platelets in a volume of blood
  • Identifies if platelets are the right size
  • Unit is femtoliters/platelet

Reading list: Papers to better understand mast cells and mast cell disease

I get asked semi-regularly for literature recommendations.  This post (and the other posts marked “Reading list”) lists papers I have found helpful in understanding mast cell disease and the roles of mast cells in other diseases.

As a general rule of thumb, read the guidance documents first.  They give comprehensive overviews that include symptoms, diagnosis, treatment, statistics and so on.  Please keep in mind that at this time, there are multiple sets of diagnostic criteria for MCAS.  I have included papers here that represent the competing schools of thought on MCAS.

Enjoy!

 

Guidance documents: Overviews of mast cell diseases

  • Afrin, Lawrence B. Presentation, Diagnosis and Management of Mast Cell Activation Syndrome. 2013. Mast Cells.
  • Akin C, Valent P, Metcalfe D. Mast cell activation syndrome: Proposed diagnostic criteria. Journal of Allergy and Clinical Immunology 2010: 126 (6): 1099–1104.e4
  • Bodemer C., Hermine O., Palmérini F., Yang Y., Grandpeix-Guyodo C., Leventhal PS., Hadj-Rabia S., Nasca L., Georgin-Lavialle S., Cohen-Akenine A., Launay JM., Barete S., Feger F., Arock M., Catteau B., Sans B., Stalder JF., Skowron F., Thomas L., Lorette G.Plantin P, Bordigoni P, Lortholary O, de Prost Y, Moussy A, Sobol H, Dubreuil P. Pediatric mastocytosis is a colonal disease associated with D816V and other activating C-KIT mutations. J Invest Dermatol 2010; 130:804–815.
  • Brockow, C. Jofer, H. Behrendt and J. Ring. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy 2008, 63 ( 2):, 226–232.
  • Cardet JC, Castells M, Hamilton MJ. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.
  • Carter et al. Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis. J Allergy Clin Immunol 2015.
  • Carter MC, Escribano L, Hartmann K, Lieberman P, Nedoszytko B, Orfao A, Schwartz LB, Sotlar K, Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Sperr WR, Triggiani M, Valenta R, Horny HP, Metcalfe DD. Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal. Int Arch Allergy Immunol 2012;157:215–225.
  • Frieri, Marianne, et al. Pediatric mastocytosis: A review of the literature. Pediatr Allergy Immunol Pulmonol. Dec 1, 2013; 26(4): 175-180.
  • Georgin-Lavialle, Sophie, et al.  Mast cell leukemia.  Blood 2013;10 (11).
  • Gülen, H. Hägglund, B. Dahlén and G. Nilsson. High prevalence of anaphylaxis in patients with systemic mastocytosis – a single-centre experience. Clinical & Experimental Allergy, Volume 44, Issue 1, pages 121–129, January 2014.
  • Haenisch B, Nothen M, Molderings GJ. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.
  • Hamilton, Matthew J, et al.  Mast cell activation syndrome : A newly recognized disorder with systemic clinical manifestations.  2011, Vol 128, Issue 1, pp. 147-152.
  • Hauswirth, Alexander, et al. Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. 2004; Leuk Res 28 (3): 249-257.
  • Kettelhut BV., Metcalfe DD. Mastocytosis. J Invest Dermatol 1991; 96:115S–118S.
  • Lange M., Nedoszytko B., Górska A., Żawrocki A., Sobjanek M., Kozłowski D. Mastocytosis in children and adults: clinical disease heterogeneity. Arch Med Sci 2012; 8:533–541.
  • Lim KH, Tefferi A, Lasho TL, et al.Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009; 113(23): 5727-5736.
  • Matito, Almudena, et al. Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. 2013; PLOS One.
  • Mital A, Piskorz A, Lewandowski K, Wasag B, Limon J, Hellmann AA case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib.Eur J Haematol 2011; 86(6):531-535.
  • Molderings GJ, Brettner S, Homann J, and Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011; 4: 10.
  • Molderings GJ, Haenisch B, Bogdanow M, Fimmers R, Nöthen MM. Familial occurrence of systemic mast cell activation disease. PLoS One, 8 (2013), p. e76241
  • Molderings GJ. The genetic basis of mast cell activation disease – looking through a glass darkly. Critical Reviews in Oncology/Hematology 2014.
  • Noack F, Sotlar K, Notter M, Thiel E, Valent P, Horny HPAleukemic mast cell leukemia with abnormal immunophenotype and c-kit mutation D816V.Leuk Lymphoma 2004; 45(11): 2295-2302.
  • Pardanani A. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) Blood 2013: 121 (16).
  • Pardanini A. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. Blood 2009, 114 (18).
  • Pardanini, Animesh. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. 2013; American Journal of Hematology: 88 (7).
  • Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics 2013: 35 (5), 548–562.
  • Sperr, Wolfgang. Diagnosis, progression patterns and prognostication in mastocytosis. Expert Review of Hematology 2012: 5 (3): 261-274.
  • Uzzaman, Ashraf, et al. Pediatric-onset Mastocytosis: A long term clinical follow-up and correlation with bone marrow histopathology. Pediatr Blood Cancer. Oct 2009; 53 (4): 629-634.
  • Valent, Peter, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. 2003; Leuk Res 27 (7): 635-41.
  •  Valent et al. Chronic mast cell leukemia: A novel leukemia-variant with distinct morphological and clinical features. Leukemia Research 39 (2015) 1-5.
  • Valent, Peter, et al. How I treat patients with advanced systemic mastocytosis. 2010; Blood: 116 (26).
  • Wimazal F., Geissler P., Shnawa P., Sperr W.R., Valent P. Severe Life-Threatening or Disabling Anaphylaxis in Patients with Systemic Mastocytosis: A Single-Center Experience. Int Arch Allergy Immunol 2012; 157: 399–405.

Testing and diagnosis of mast cell disease

  • Freeman JG, Ryan JJ, Shelburne CP, Bailey DP, Bouton LA, Narasimhachari N, Domen J, Siméon N, Couderc F, Stewart JK. Catecholamines in murine bone marrowderived mast cells. J. Neuroimmunol. 2001 Oct;119(2):231-238.
  • Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunologically inducible TNF-α/cachectin. Nature 1990 Jul 19; 346:274-276.
  • Laroche D, Vergnaud MC, Sillard B, Soufarapis H, Bricard H. Biochemical markers of anaphylactoid reactions to drugs: comparison of plasma histamine and tryptase. Anesthesiol. 1991 Dec; 75(6):945-949.
  • Maclouf J, Corvazier E, Wang ZY. Development of a radioimmunoassay for prostaglandin D2 using an antiserum against 11-methoxime prostaglandin D2. Prostaglandins 1986 Jan; 31(1):123-132.
  • Pregun I, Herszényi L, Juhász M, Miheller P, Hritz I, Patócs A, Rácz K, Tulassay Z. Effect of proton-pump inhibitor therapy on serum chromogranin A level. Digestion 2011; 84:22-28.
  • Seidel H, Molderings GJ, Oldenburg J, Meis K, Kolck UW, Homann J, Hertfelder HJ. Bleeding diathesis in patients with mast cell activation disease. Thromb. Haemost. 2011 Nov; 106(5):987-989.
  • Sur R, Cavender D, Malaviya R. Different approaches to study mast cell functions.  Int. Immunopharmacol. 2007 May;7(5):555-567.
  • Takeda J, Ueda E, Takahashi J, Fukushima K. Plasma N-methylhistamine concentration as an indicator of histamine release by intravenous d-tubocurarine in humans: preliminary study in five patients by radioimmunoassay kits. Anesth. Analg. 1995; 80:1015-1017.

Neurologic aspects of mast cell activation

  • Ikuko Mohri, Masako Taniike, Hidetoshi Taniguchi, Takahisa Kanekiyo, Kosuke Aritake, Takashi Inui, Noriko Fukumoto, Naomi Eguchi, Atsuko Kushi, Hitoshi. Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in The Journal of Neuroscience 2006; 26(16):4383– 4393.
  • Rogers MP, et al. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med. 1986 Jul-Aug; 48(6):437-47.
  • Smith, Jonathan H, Butterfield, Joseph H, Pardanini, Animesh, DeLuca, Gabriele, Cutrer, F Michael. Neurologic symptoms and diagnosis in adults with mast cell disease.  Clinical Neurology and Neurosurgery 113 (2011) 570-574.

Gastrointestinal aspects of mast cell disease

  • Bedeir A, et al.  Systemic mastocytosis mimicking inflammatory bowel disease: A case report and discussion of gastrointestinal pathology in systemic mastocytosis.  Am J Surg Pathol. 2006 Nov;30(11): 1478-82.
  • Hahn, Hejin P., Hornick, Jason L.  Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis.  American Journal of Surgical Pathology. Volume 31 (11). 2007.
  • Jensen RT. Gastrointestinal abnormalities and involvement in systemic mastocytosis. Hematol Oncol Clin North Am. 2000;14:579–623.
  • Kirsten Alfter, Ivar von Ku gelgen, Britta Haenisch, Thomas Frieling, Alexandra Hu lsdonk, Ulrike Haars, Arndt Rolfs, Gerhard Noe, Ulrich W. Kolck, Jurgen Homann and Gerhard J. Molderings. New aspects of liver abnormalities as part of the systemic mast cell activation syndrome. 2009 Liver International 29(2): 181-186.
  • Lee, Jason K, et al.  Gastrointestinal manifestations of systemic mastocytosis.  World J Gastroenterol. 14(45): 7005-7008.

Mastocytic enterocolitis

  • Akhavein, A, et al.  Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility.  2012, Gastroenterology Research and Practice.
  • Hahn, Hejin P., Hornick, Jason L.  Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis.  American Journal of Surgical Pathology. Volume 31 (11). 2007.
  • Hamilton, Matthew J, et al.  Mast cell activation syndrome : A newly recognized disorder with systemic clinical manifestations.  2011, Vol 128, Issue 1, pp. 147-152.
  • Shriram Jakate, Mark Demeo, Rohan John, Mary Tobin, and Ali Keshavarzian (2006) Mastocytic Enterocolitis: Increased Mucosal Mast Cells in Chronic Intractable Diarrhea. Archives of Pathology & Laboratory Medicine: March 2006, Vol. 130, No. 3, pp. 362-367.

Mast cell disease fact sheet

Mast Cell Disease

  • Mast cell disease includes all forms of disease in which your body makes too many mast cells or those mast cells do not function correctly.
  • Mast cell disease is rare, affecting less than 200,000 people in the US.
  • 90% of mast cell disease only affects the skin (edited to add: based upon estimates of mastocytosis population – counts of MCAS/MCAD not yet available).
  • The remaining 10% is systemic disease.
  • Multiple people in a family sometimes have mast cell disease, but the heritable gene has not been identified.
  • Cutaneous and systemic mastocytosis, mast cell sarcoma and mast cell leukemia are proliferative, meaning your body makes too many mast cells.
  • Mast cell activation syndrome/mast cell activation disorder are not proliferative, meaning there is a normal amount of mast cells behaving badly.
  • Monoclonal mast cell activation syndrome is borderline for proliferation, meaning the body is thinking about making too many mast cells or is just starting to.
  • The biggest risk for most mast cell patients is anaphylaxis, a severe, life-threatening allergic reaction that can be triggered by many things.
  • There is no cure for mast cell disease, but children sometimes grow out of it for unknown reasons.

Types of mast cell disease

  • Cutaneous mastocytosis (CM) is too many mast cells in the skin.
    • This causes rashes (sometimes permanent), hiving and blistering.
    • Urticaria pigmentosa (UP), telangiectasia macularis eruptive perstans (TMEP) and diffuse cutaneous mastocytosis (DCM) are the types of cutaneous mastocytosis. (Edited to include DCM.)
    • It is diagnosed by skin biopsy.
    • You can also have mast cell symptoms that aren’t related to the skin, like nausea, vomiting, weakness, headache, palpitations, etc.
    • Solitary mastocytoma is a benign mast cell tumor usually found on the skin, but sometimes elsewhere. It is sometimes included in the cutaneous mastocytosis category.
    • Children sometimes outgrow cutaneous mastocytosis.
    • When adults develop cutaneous mastocytosis, they usually also have systemic mastocytosis.
  • Systemic mastocytosis is too many mast cells in an organ that is not the skin.
    • The bone marrow is usually where too many mast cells are found, but it is sometimes found in other organs.
    • You can have systemic mastocytosis with or without cutaneous mastocytosis.
    • It is diagnosed by biopsy of an organ other than skin. Other testing like scans and organ tests may be necessary.
    • Indolent systemic mastocytosis (ISM) is stable with no organ damage. Life span is normal.
    • Smoldering systemic mastocytosis (SSM) is progressing towards a more damaging form with some signs that organ damage is beginning. Life span may be shortened if progression is not controlled.
    • Aggressive systemic mastocytosis (ASM) is a dangerous form with organ damage that requires chemotherapy to control. Life span is shorter.
    • Mast cell leukemia (MCL) is a malignant form with organ damage that requires chemotherapy. Life span is significantly reduced.
    • Mast cell sarcoma(MCS) is a malignant form with organ damage that requires chemotherapy. Life span is significantly reduced.
  • Mast cell activation syndrome (MCAS)/ Mast cell activation disorder (MCAD) is when a normal amount of mast cells behave badly. (Edited to change mast cell activation disease to mast cell activation disorder.)
    • It is clinically similar to indolent systemic mastocytosis. Life span is normal.
    • Biopsies are negative.
  • Monoclonal mast cell activation syndrome (MMAS) is when a person meets some of the criteria for systemic mastocytosis but not all. It indicates the mast cells are starting to think about abnormal proliferation.
    • It is clinically similar to indolent systemic mastocytosis. Life span is normal.
    • Biopsies are positive for one or two minor criteria for systemic mastocytosis.

Symptoms

  • Anaphylaxis
  • Skin
    • Flushing is one of the hallmark signs of mast cell disease
    • Other skin symptoms include rashes, hives, itching, angioedema, dermatographism
  • Gastrointestinal
    • Abdominal pain, diarrhea, constipation, swelling of GI tract, difficulty swallowing
  • Neurologic
    • Headache, migraine, feeling faint, numbness, pins and needles, tremors, tics, neuropathy
  • Psychiatric
    • Depression, anxiety, memory difficulties, insomnia, sleep disorders*
  • Cardiovascular
    • Weakness, dizziness, high or low blood pressure, slow or rapid heartbeat, abnormal heart rhythm, chest pain, palpitations

*Edited to add: Psychiatric symptoms are organic symptoms of mast cell disease, rather than reactive conditions from chronic illness.

This list is not exhaustive.

Triggers

  • Many things can cause mast cell reactions or anaphylaxis in mast cell patients.
  • Allergy testing (skin prick or blood testing) is inaccurate in mast cell patients as these tests assess IgE allergies and mast cell patients often have non-IgE reactions.
  • Triggers can change over time and can include:
    • Heat, cold, or rapid change in temperature
    • Friction, especially on the skin
    • Sunlight
    • Illness, such as viral or bacterial infection
    • Exercise
    • Many foods, especially high histamine foods
    • Many preservatives and dyes
    • Many medications
    • Scents and fragrances
    • Physical stress, such as surgery
    • Emotional or psychological stress

Diagnosis: Blood and Urine Testing

  • Blood test: Serum tryptase
    • This tests for the total amount of mast cells in the body, the “mast cell burden”
    • Should be tested during a non-reactive period for baseline and during a reaction
    • Time sensitive: should be tested 1-4 hours after start of reaction
    • Normal range for adults is under 11 ng/ml. (Edited to remove out of place words “is abnormal” at the end of this statement)
    • 2 ng/ml + 20% increased from baseline is indicative of mast cell activation
    • Baseline over 20 ng/ml is a minor criteria for diagnosis systemic mastocytosis
  • 24 hour urine tests:
    • N-methylhistamine
      • Breakdown product of histamine
      • Released by mast cells when reacting
      • Very temperature sensitive
      • Sample must be refrigerated and transported on ice (unless preservative is provided)
      • Measured as a ratio of another molecule, creatinine
      • Normal range for adults is 30-200 mcg/g creatinine
      • One study found that if level was 300 mcg/g creatinine, a bone marrow biopsy was likely to be positive for systemic mastocytosis
    • D2 prostaglandin and 9a,11b-F2 prostaglandin
      • Released by mast cells when reacting
      • Very temperature sensitive
      • Sample must be refrigerated and transported on ice (unless preservative is provided)
      • Normal range for both is under 1000 ng
      • 9a,11b-F2 prostaglandin is a breakdown product of D2 prostaglandin
      • 9a,11b-F2 prostaglandin is the marker for which MCAS/MCAD patients are most often positive
      • If taking aspirin or NSAIDs, these may be discontinued five days before the test or as directed by your physician
      • Other tests sometimes done in blood include heparin, histamine, prostaglandin D2 and chromogranin A.
      • Serum tryptase and 24 hour urine n-methylhistamine, D2 prostaglandin and 9a,11b-F2 prostaglandin are the tests considered to be most reliable indicators of mast cell disease.

Diagnosis: Biopsies

  • Bone marrow biopsy
    • Obtained by bone marrow biopsy and aspiration procedure
    • Stained with Giemsa and tryptase stains
    • Tested with antibodies for CD117, CD2, CD25 and CD34
    • Looking for clusters of mast cells in groups of 15 or more
    • Looking for mast cells that are shaped abnormally, like spindles
    • DNA from the biopsy should be tested for the CKIT D816V mutation, a marker for systemic mastocytosis
  • Skin biopsy
    • Obtained by punch biopsy
    • Stained with Giemsa and tryptase stains
    • Tested with antibodies for CD117, CD2, CD25 and CD34
    • Looking for clusters of mast cells in groups of 15 or more
    • Looking for mast cells that are shaped abnormally, like spindles
    • DNA from the biopsy should be tested for the CKIT D816V mutation, a marker for systemic mastocytosis
  • GI biopsies
    • Obtained by scoping procedures
    • Stained with Giemsa and tryptase stains
    • Tested with antibodies for CD117, CD2, CD25 and CD34
    • Looking for clusters of mast cells in groups of 15 or more
    • Looking for mast cells that are shaped abnormally, like spindles
    • DNA from the biopsy should be tested for the CKIT D816V mutation, a marker for systemic mastocytosis (less likely to be positive than bone marrow biopsies)
    • Mast cells should be counted in five high powered (60X or 100X) fields and the count then averaged
    • Some researchers consider an average of more than 20 mast cells in a high powered field to be high, but this is not agreed upon
    • Some researchers consider an average of more than 20 mast cells in a high powered field to be diagnostic for mastocytic enterocolitis

Treatment

  • H1 antihistamines
    • Second generation, longer acting, non-sedating for daily use
    • First generation, shorter acting, sedating, but more potent
    • Other medications with H1 antihistamine properties like tricyclic antidepressants
  • H2 antihistamines
  • Leukotriene inhibitors
  • Aspirin, if tolerated
  • Mast cell stabilizers
    • Cromolyn
    • Ketotifen
    • Quercetin
  • Epinephrine (should be on hand in case of anaphylaxis)
  • These are baseline medications for MCAS/MCAD, MMAS and ISM cell patients. If symptoms are uncontrolled, other medications may be used off label for mast cell disease.
  • Smouldering systemic mastocytosis patients may require chemotherapy.
  • Aggressive systemic mastocytosis, mast cell leukemia and mast cell sarcoma patients require chemotherapy.

Medications to Avoid

  • Medications that cause degranulation
    • Alcohol (ethanol, isopropanol)
    • Amphoteracin B
    • Atracurium
    • Benzocaine
    • Chloroprocaine
    • Colistin
    • Dextran
    • Dextromethorphan
    • Dipyridamole
    • Doxacurium
    • Iodine based radiographic dye
    • Ketorolac
    • Metocurine
    • Mivacurium
    • Polymyxin B
    • Procaine
    • Quinine
    • Succinylcholine
    • Tetracine
    • Tubocurarine
    • Vancomycin (especially when given intravenously)
    • In some patients, aspirin and NSAIDs (please ask if your doctor if these are appropriate for you)

 

  • Medications that interfere with the action of epinephrine
    • Alpha adrenergic blockers
      • Alfuzosin
      • Atipamezole
      • Carvedilol
      • Doxazosin
      • Idazoxan
      • Labetalol
      • Mirtazapine
      • Phenoxybenzamide
      • Phentolamine
      • Prazosin
      • Silodosin
      • Tamsulosin
      • Terazosin
      • Tolazoline
      • Trazodone
      • Yohimbine
    • Beta adrenergic blockers
      • Acebutolol
      • Atenolol
      • Betaxolol
      • Bisoprolol
      • Bucindolol
      • Butaxamine
      • Carteolol
      • Carvedilol
      • Celiprolol
      • Esmolol
      • Metoprolol
      • Nadolol
      • Nebivolol
      • Oxprenolol
      • Penbutolol
      • Pindolol
      • Propranolol
      • Sotalol
      • Timolol

Please note these lists are not exhaustive and you should check with your provider before starting a new medication. A pharmacist can review to determine if a medication causes mast cell degranulation or interferes with epinephrine. This list represents the medications for which I was able to find evidence of degranulation or a-/b-adrenergic activity.

Special Precautions

  • Mast cell patients require special precautions before major and minor procedures, including radiology procedures with and without contrast or dyes
  • They must premedicate using the following procedure:
    • Prednisone 50mg orally (20 mg for children under 12): 24 hours and 1-2 hours before procedure
    • Diphenhydramine 25-50 mg orally (12.5 mg for children under 12) OR hydroxyzine 25 mg orally, 1 hour before procedure
    • Ranitidiine 150 mg orally (20 mg for children under 12): 1 hour before procedure
    • Montelukast 10 mg orally (5 mg for children under 12): 1 hour before procedure
    • This protocol was developed for the Mastocytosis Society by Dr. Mariana Castells and the original can be found at www.tmsforacure.org/documents/ER_Protocol.pdf

Common coincident conditions

  • Ehlers Danlos Syndrome (EDS), especially hypermobility type (Type III)
  • Postural orthostatic tachycardia syndrome (POTS) or other types of dysautonomia
  • Mast cell disease, EDS and POTS are often found together
  • Autoimmune diseases
  • Myeloproliferative diseases, like essential thrombocythemia and polycythemia vera
  • Eosinophilic disorders

 

 

 

What do all these words mean? (Part 2)

What does it mean if a person is CD117 positive in a biopsy? Is this bad?

In the context of mast cell disease, it usually just means that mast cells were found.

 

If CD117 is normal for mast cells, why are people sometimes “negative for CD117” on biopsies?

This sometimes happens. When you have mast cell disease, you often have more CD117 receptors on mast cells. This makes it easier for the test to find them. So when you are found to be “negative for CD117” in regards to mast cell disease, you are not truly “negative”. You just express a lower amount of CD117 receptors so the test didn’t see them.

 

I am a mast cell patient and my bone marrow biopsy was positive for CD117. How do I know that it is normal mast cells that show CD117 and not these other dangerous cells you mentioned?

You can tell by looking at the cells with special stains. Pathologists and immunohistochemistry scientists are very skilled at distinguishing one cell type from another. They can tell based upon what the cell looks like in addition to being positive for CD117.

 

If I am CD117 positive in a biopsy, does that mean I am “CKIT positive”?

No. If I could do away with one single phrase in mast cell terminology, it would be CKIT+.

CKIT+ is a term used to mean “positive for the D816V mutation in codon 816 of the CKIT gene”. It means you are positive for a mutation that has been associated with neoplastic disorders of mast cells. So when people say they are CKIT+, they mean they were found to have a mutation. They do NOT mean they were found to have CKIT/CD117 on their mast cell surfaces, because this is totally normal and is the case for everyone.

Additionally, the test to detect CD117 on a cell surface is NOT the same test used to identify the D816V mutation. That test breaks open the cells and looks for a specific mutation in the DNA sequence. They are not run at the same time.

 

Why is it important to know if I am positive for the D816V mutation (CKIT+)?

The D816V mutation changes the shape of the CKIT receptor. Due to this wrong shape, the receptor does not need SCF to bind to the receptor to tell the mast cell to live longer. In this new shape, the receptor is stuck in an “activated” position, so it is telling the cell to live longer all the time, without SCF. This is called “autoactivation”.

The D816V mutation is one of the minor criteria for systemic mastocytosis, so it is important for classification purposes. Also, it may affect your treatment plan in the unlikely situation of needing chemotherapy.

 

What is CD25?

CD25 is part of a receptor for a molecule called IL-2. Normally, mast cells do not express receptors for IL-2, which is a molecule that regulates development of T cells. When mast cells express CD25, it is an indication that the mast cell is neoplastic. Many T cells normally express CD25, so if it is on a biopsy report, keep in mind that it’s abnormal on mast cells, but not everywhere.

Presence of CD25 on mast cells is one of the minor criteria for SM.

 

What is CD2?

CD2 is an example of a “CD” molecule that is not a receptor. It is a cell adhesion molecule so it helps cells stick together. Normally, mast cells do not express CD2. When mast cells express CD2, it is an indication that the mast cell is neoplastic. Many T cells normally express CD25, so if it is on a biopsy report, keep in mind that it’s abnormal on mast cells, but not everywhere. CD2 is a less accurate indication of SM than CD25.

Presence of CD2 on mast cells is one of the minor criteria for SM.

 

What is CD30?

CD30 is a receptor for proteins associated with tumor necrosis factor. It is commonly referred to as a tumor marker, but this is not always the case. CD30 has recently been shown to be frequently positive in patients with all forms of SM (ISM, SSM, SM-AHNMD, ASM). However, on other cells besides mast cells, it may indicate lymphoma or other conditions.

 

What is CD34?

CD34 is another cell adhesion molecule. It is thought to allow stem cells to attach to proteins in the bone marrow. It is found on many progenitor cells, cells that later become other kinds of cells. Mast cells express CD34, though this tends to be lost as they move into tissues.

Initial diagnosis and treatment of mast cell activation disease: General notes for guidance

Mast cell disease is becoming more well known among both the public and medical providers, but there is still a lot of confusion regarding exactly what it is, how to diagnose and how to treat.

There are several tests that should be used when working up a patient for mast cell disease. Tryptase is the most well known of these tests, due to over 85% of patients with systemic mastocytosis (SM), a form of mast cell disease, having elevated tryptase. However, tryptase can be normal in mast cell patients, or may only be elevated during times of severe symptoms or anaphylaxis. While an elevated baseline tryptase can be used as confirmation for a mast cell disease (in the absence of frank hematologic disease), a normal tryptase test should not be used to discard the possibility of mast cell disease.

24-hour urine tests for mast cell mediators are most likely to capture evidence of mast cell activation when executed correctly. These tests measure n-methylhistamine, a metabolite of histamine, and prostaglandins D2 and F2a, which are all released by mast cells. Urine collected for this test should be kept refrigerated or on ice during collection and transport to the lab. I STRONGLY recommend communicating with the lab prior to beginning to this test to be sure that they understand the temperature requirements. The molecules being tested are not stable at room temperature and inappropriate storage can result in a negative test result in a positive patient. (For details on this topic and specific recommendations for testing, please refer to Afrin 2013).

Some providers also find utility in the measurement of other less specific mediators. Please refer to my previous post on this topic: https://www.mastattack.org/2014/10/mast-cell-mediators-recommended-testing-for-mcas-diagnosis/

Due to the well established time sensitive nature of these tests (Afrin 2013), a patient who presents a “mast cell clinical picture” and responds to typical mast cell medications may in fact have mast cell disease in the presence of negative tests.

Depending on the clinical picture, a provider may feel it necessary to order a bone marrow biopsy, skin biopsy or biopsy of another organ to determine if mast cell infiltrates are present. This is not always immediately done in the presence of positive tryptase, n-methylhistamine, D2 prostaglandin or F2a prostaglandin test and will not always affect treatment. It is common knowledge among mast cell fluent providers that a negative biopsy does not exclude mast cell disease, but it is instead used to rule in the presence of specific proliferative entities like systemic mastocytosis (Picard 2013, Molderings 2011). Furthermore, a single biopsy may fail to capture a positive specimen in a known-positive patient (Butterfield 2004).

For more specific details regarding differentiation among the diagnostic categories of mast cell disease, please refer to my previous post on this topic: https://www.mastattack.org/2014/07/diagnosis-of-mast-cell-diseases/

There are a number of well known, well tolerated medications that can be used to manage mast cell disease. First line medications include antihistamines, leukotriene inhibitors, and mast cell stabilizers (Cardet 2013, Picard 2013, Molderings 2011, Afrin 2013).

Histamine is released by activated mast cells in large quantities. Histamine acts on the body by interacting with four different types of receptors, called H1, H2, H3 and H4. Medications that block the H1 and H2 receptors are available in plentiful supply in many countries. Once diagnosed, mast cell patients generally begin daily treatment with both H1 and H2 antihistamines. Longer acting, non-sedating H1 blockers like cetirizine are typically used to provide a baseline H1 coverage. H2 coverage is achieved with medications like Zantac or Pepcid. Dosage can be increased as needed to provide effective symptom relief, and these medications are often taken in moderate to high doses by mast cell patients. It is not uncommon to take multiple drugs together to block one type of histamine receptor, but this should be managed by a provider.

Leukotrienes are also released by activated mast cells. Singulair is an example of a leukotriene inhibitor that is a common add-on for mast cell patients. This medication is not a replacement for antihistamines.

Mast cell stabilizers achieve effects by making mast cells less likely to release chemicals. Cromolyn is typically the first line mast cell stabilizer in the US. This medication can take several weeks to demonstrate its full effect, so patients and providers should be aware of this fact. Another mast cell stabilizer, ketotifen, is also available in the US through compounding pharmacies. Ketotifen is also an H1 antihistamine.

Medications should ideally be added one at a time to allow easy identification of a bad actor in the event of a med reaction. As a result, tweaking a patient’s medication regimen takes time and patience. If a patient reacts to a medication, care should be taken to determine if the medication is truly the issue or if it is an inactive ingredient in the preparation (lactose, etc).

Mast cell disease can result in a highly variable clinical picture and mast cell patients are often only diagnosed following years of investigation for other possible causes of their symptoms. For this reason, many mast cell patients have acquired a long list of diagnoses prior to a mast cell diagnosis. In some cases, these diagnoses may be accurate and co-existing. All existing prior diagnoses should be considered for their accuracy in light of a mast cell diagnosis.

Additionally, there are a number of conditions which are frequently comorbid with mast cell disease, including Ehlers Danlos syndrome, postural orthostatic tachycardia syndrome (POTS), a variety of autoimmune diseases and several digestive conditions.  Patients should be evaluated according to their clinical picture and laboratory findings.

 

References:

Afrin, Lawrence B. Presentation, Diagnosis and Management of Mast Cell Activation Syndrome. 2013. Mast Cells.

Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology 2011, 4:10.

Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Clarifications (part 1)

One of the more nuanced aspects of mastocytosis is how it affects bone structure. Previously, it was thought that only patients with systemic mastocytosis experienced bone pain, and that bone pain was always a function of increased proliferation in the marrow. This no longer appears to be the case. Some patients with non-proliferative mast cell disease have been found to experience bone pain, likely as a result of mediator activity on the outside of the bone. In particular, histamine can be very irritating to the cells on the outside of the bone.

Generally speaking, bone cells work like this:

Osteoblasts make new bone. Osteoclasts eat away (resorb) at bone so that new bone can be put in that place. When these processes aren’t balanced, you develop bone conditions.

In osteosclerosis, your body is making new bone faster than it can resorbed. In osteoporosis, your body is resorbing bone faster than new bone is made.   In osteolysis, your body is also resorbing bone faster than new bone is made, but to a much larger extent than usually seen in osteoporosis. Both osteoporosis and osteolysis can cause pathologic fractures, meaning that because your bone is weak from osteoporosis or osteolysis, the bone breaks.

Bone involvement in systemic mastocytosis is important because the type of bone involvement present can be used to stage the disease. Specifically, certain types of bone involvement can cause a person with indolent or smouldering systemic mastocytosis to be reclassified as aggressive systemic mastocytosis (ASM). Osteolysis (in which bone is eaten away) is a marker for ASM. If you have ISM or SSM and are found to have a large osteolytic lesion, you now have ASM.

More confusing is the relationship of osteoporosis to ASM. If you have ISM or SSM AND you have osteoporosis AND you have multiple fractures due to the severity of the osteoporosis (known as pathologic fractures), you are classified as having ASM. There is some debate in the community as to whether or not osteoporosis with successive pathologic fractures is a true indication of ASM. However, it is currently included in the diagnostic guidelines, and so if you meet this criteria while also having ISM or SSM, then you are classified as having ASM.

But I want to be very clear about something: the osteoporosis is NOT the factor that classifies someone as having ASM. It is the MULTIPLE FRACTURES as a result of bone disease that classifies someone as having ASM. So if you have SSM and are diagnosed with osteoporosis and have a single vertebral fracture as a result of osteoporosis, you are NOT classified as having ASM. It is easier I think to consider this “bone involvement” criterion of ASM as osteolysis or multiple fractures due to bone deterioration.

SM is well known as a possible risk factor for osteoporosis. This has been attributed by different groups to either infiltration of bone by mast cells or release of mediators, including histamine, heparin and tryptase. IL-6 levels were also shown to be proportional to disease severity and osteoporosis in mastocytosis patients (Theoharides 2002). Histamine regulates bone resorption by osteoclasts via H1 and H2 receptors (Dobigny 1997). In bone biopsies of osteoporotic patients, the number of osteoclasts is sometimes elevated and sometimes normal.

Up next: literature review of studies on bone involvement in ISM, SSM, SM-AHNMD, and ASM.

 

References:

Maurizio Rossini, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.

Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128: 344–50.

Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.

Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7

van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans & J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.