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 Three)

In 2009, Walker and colleagues published a paper called “Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia.”  The term “mastocytosis” as used here is not equivalent the term “mastocytosis” as in cutaneous mastocytosis or systemic mastocytosis. It is one of several papers to do so and has generated a lot of confusion as a result.

The suffix –osis is commonly used in medical terminology.  It means increase or production of something, but it also connotes that this increase results from a disease process.  Here, the author means not that these patients meet the criteria for systemic mastocytosis, which we know to be a neoplastic disease originating in the bone marrow, but that there are more mast cells than expected in these biopsies.

Excessive production of mast cells in an organ that is not the skin is the defining feature of systemic mastocytosis.  SM patients show some combination of the following characteristics: infiltration of tissue with mast cells clustered together; expression of receptors CD25 and/or CD2 on the mast cells; spindle shaped mast cells; presence of the CKIT D816V mutation; and  baseline tryptase over 20 ng/ml.  When a patient shows too many mast cells without having any of these markers, it is not called mastocytosis.  It is called mast cell hyperplasia.

Consider the following two scenarios:

Let’s imagine that you are a house builder.  For many years, you only build houses when people call your boss and say they need a house.  After your boss gets the call, she calls you to tell you to build a house for these people in the location they have requested.  Sometimes more people need houses than others, so at times you make more, and other times, you make less.  You never build houses unless your boss tells you to and you are able to build them correctly due to having the correct time and resources.  You may think that your boss is telling you to build too many houses sometimes but it is always because she is getting lots of requests from customers to build houses.

In this scenario, mast cells are house builders. They only make new mast cells when they receive appropriate signals from the body.  Sometimes your body makes more mast cells, like to fight an infection or when you have an allergic response.  But the mast cells ALWAYS wait for the correct signal from the body to make more cells.  They do not decide to make too many cells on their own.

Now let’s imagine that after years of being a house builder, you wake up one day with a compulsion to see how fast you can build a house.  Your boss calls you and says she needs one house, so you build that house and then you build four more at the same time.  Instead of building carefully one at a time, you are building five houses at the same time.  This means the houses are not built correctly.  You call your boss to say you are done with the five houses and your boss gets mad.  Where are we going to put these extra four houses?  She decides to move those four houses to another town that doesn’t have too many houses yet.  She tells you not to make too many houses again.

But you just cannot stop making houses.  Making houses is the best!  Who cares if there are little mistakes?  People can still live in them safely.  You wake up every day with a fervent need to build houses.  Your friends and family are concerned about you and stage an intervention.  You will not be moved.  You are building tons of houses at once now.  Your boss is calling you screaming at you to stop making houses because they are defective and she doesn’t have anywhere to put them.  She has been sending them to places that already have too many houses so it is getting really crowded and people are complaining.  You stop answering your boss’s calls.  These people don’t understand the importance of building houses.  No matter what anyone says to you, you will not stop making houses and they cannot make you stop.

In this scenario, the problem isn’t that the boss is telling the builder to make too many houses.  The problem here is that the builder is ignoring all the signals to stop.  This scenario represents systemic mastocytosis.  The mast cells here are making too many mast cells for the wrong reasons and they don’t work right.

I want to be very clear about something – the fact that a person has a lot of mast cells per hpf but doesn’t have markers for SM does NOT mean that these people are not suffering.  Regardless of how the mast cells ended up there in excessive populations, they will cause large scale inflammation and GI symptoms.  Nor am I saying that phenomena like mastocytosis enterocolitis or allergic mastocytic enterocolitis are definitely not mast cell diseases – it is possible that the mast cells in those cases demonstrate markers we have not yet found or that there is an error in the cells that become mast cells.  I am just describing the way these two categories are distinguished from one another at this time.  It is not my intention to disenfranchise anyone.  We are all united in the suckage that is GI symptoms as a result of mast cells.

How do you tell the difference between systemic mastocytosis and mast cell hyperplasia?  That is the purpose of the SM diagnostic criteria.  As I said before, you need to meet one major and one minor criterion, or three minor criteria, from the WHO Systemic mastocytosis criteria.  If you meet some of the criteria, but not enough for SM, that is still evidence of a clonal, proliferative mast cell disease.  This means that it is still evident that too many mast cells are being made despite signals to stop.  The state of meeting some criteria for SM but not enough for an SM diagnosis is called monoclonal mast cell activation syndrome (MMAS). This topic will be covered in detail in a later post in this series.

Many diseases involve mast cells, including various cancers and autoimmune diseases, among others. So why aren’t they considered mast cell diseases like systemic mastocytosis and mast cell activation syndrome? These are not mast cell diseases because in these situations, mast cells are getting signals to make too many mast cells and to cause inflammation.  They are the house builder when the boss is telling them to make more houses than usual, but the boss is doing that because customers need those houses.  Mast cell diseases are the house builder that has a compulsion to build houses even when they aren’t needed and everyone is telling them to stop.

Remember this distinction when you are reviewing papers and pathology reports.  The word mastocytosis is often used when they really mean mast cell hyperplasia.  Mastocytosis in proper usage means too many mast cells because the mast cells are defective.  Mast cell hyperplasia means too many mast cells because the mast cells are receiving inflammatory signals from elsewhere.