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Lisa Klimas

I'm a 35 year old microbiologist and molecular biologist with systemic mastocytosis, Ehlers Danlos Syndrome, Postural Orthostatic Tachycardia Syndrome, Adrenal Insufficiency, and an assortment of other chronic health issues. My life is pretty much a blast.

The Sex Series – Part Three: Allergic reactions of the vagina and vulva

Most of what I said about kissing applies to genitally penetrating intercourse, too.  It is not uncommon for people to develop hives as a result of the vibration, pressure, heat and friction of intercourse. Swelling after sex, called postcoital edema, is also not unusual.  Sex is also a known trigger for asthma and rhinitis.  Several aspects of sex, including the heat and emotion, can activate the autonomic nervous system and cause release of mast cell mediators.  Importantly, studies have revealed that the allergic effects of sex are not due to the physical exertion (ie. exercise anaphylaxis).

While local reactions are more common, there is precedent for sex causing multisystem allergic response or anaphylaxis.  The person receiving the vaginal penetration is more likely to have anaphylaxis following sex, especially if they are strongly sensitized to food or medications.  Seminal fluid can contain food or drug allergens.  Aspirin and penicillin derivatives have been reported to cause allergic reactions from sex, called postcoital hypersensitivity. Transfer of pollens from the clothes or skin of the partner can also cause allergic reactions.

One product we have not yet discussed that can cause contact dermatitis and anaphylaxis is condoms. 25% of reactions to latex condoms cause hives over large portions of the body, angioedema and respiratory symptoms. There are latex alternative condoms, but many patients react to those as well.

Vaginally penetrating intercourse often causes microscopic tearing, mostly due to inadequate lubrication.  As a former sex educator, if you think you are using enough lubrication, you are not.  It is my personal experience that water based lubricants are better tolerated by most allergy patients for vaginal intercourse.  Silicone lubricant is popular because it’s not absorbed by the body and is therefore slicker, whereas water based lubricant often requires reapplication.  But that’s okay.  That’s why you get a whole bottle.

Contributing to the insufficient lubrication is the fact that most people don’t engage in long enough foreplay.  Foreplay provides a number of benefits: it increases naturally secreted vaginal lubrication, increases blood flow to the vagina and tells the cervix to get out of the way. 20 minutes of foreplay is often recommended as a rule of thumb in order to get the vagina in order before penetrating intercourse.

Moisture, friction and heat can cause the vulvar skin to break down. Estrogen plays a large role in keeping this tissue strong and undamaged.  Urine on the skin can cause contact dermatitis.  Malnutrition and history of genital infections can also contribute towards the reactivity of the tissue. It is also possible to be IgE positive for Candida albicans, a yeast that lives normally in the vagina.  Inflammation can upset the balance of the normal flora, resulting not only in vaginal infections but a literal allergy to Candida.

References:

Schlosser BJ. Contact dermatitis of the vulva. Dermatol Clin 2010: 28; 697-706.

Moraes PSA, Taketomi EA. Allergic vulvovaginitis. Ann Allergy Asthma Immunol 2000; 85: 253-267.

Chen WW, Baskin M. A 33-year-old woman with burning and blistering of perivaginal tissue following sexual intercourse. Annals of Allergy, Asthma & Immunology 2004; 93: 126-130.

Harlow BL, He W, Nguyen RHN. Allergic reactions and risk of vulvodynia. Ann Epidemiol 2009; 19: 771-777.

Liccardi G, et al. Intimate behavior and allergy: a narrative review. Annals of Allergy, Asthma & Immunology 2007; 99: 394-400.

Sonnex C. Genital allergy. Sex Transm Infect 2004; 80: 4-7.

The Sex Series – Part Two: Contact dermatitis

Symptoms affecting the genitalia as a result of vaginally penetrating intercourse are not uncommon.  Today we are going to talk about allergic and irritant reactions to products. There are other kinds of symptoms to vaginally penetrating intercourse that we will get to later on in this series.

It is not unusual for people to use specific products only in advance of having sex.  This includes things like lubrication, pleasure creams, and products for shaving and removal of hair.  Contact dermatitis can arise as a result of these products.

Contact dermatitis is inflammation of the skin following contact with a substance that irritates or generates an allergic reaction.  In case it’s not obvious, genital tissue is much more sensitive than other parts of the body.  Irritant contact dermatitis of the vulva is more common than true allergic dermatitis there.

Common irritant triggers include hygiene products like soap, shower gel, and sanitary napkins, spermicides, diaphragms, and sexual lubricants.  In some people, these triggers can also generate a true allergic dermatitis.  Additional triggers commonly associated with allergic contact dermatitis regularly include neomycin, -caine anesthetics and nickel.

Contact dermatitis of the genital (and other) areas can cause a wide range of reactions from mildly irritating to very severe.  Symptoms can include redness, swelling, itching, burning and pain, and can cause chronic thickening of the skin, fissuring of the skin, weeping of the skin and blistering.  In most patients, the substance responsible for the reaction is identified via skin patch testing.  I would not expect this to be reliable in mast cell patients given the inherently reactive nature of our skin.

Irritant contact dermatitis often shows symptoms shortly after product use. True allergic contact dermatitis is a delayed type IV hypersensitivity reaction and can take 2-3 days to appear. Many patients are able to identify the trigger by removing products and symptom resolution upon doing so. Some genital hygiene products include alcohol.  Many more include propylene glycol, a well defined trigger for vulvar dermatitis.  Products that contain sugar and/or change the pH of the internal vaginal environment disturb the natural microbial flora, causing inflammation and increased risk of infection later.

It is also possible for products used by the partner to transfer during vaginal penetration.  If the penetration is made by part of the body and not a toy, transfer can happen in either direction. For persons using toys for external or internal stimulation, it is also possible to react to the material of the product. Something to consider is that many companies sell products to clean up after sex, either to clean genitalia, toys or both.  Please look carefully at the ingredients included in those products.  Additionally, please ensure that any toys used are cleaned before and after use.

 

References:

Schlosser BJ. Contact dermatitis of the vulva. Dermatol Clin 2010: 28; 697-706.

Moraes PSA, Taketomi EA. Allergic vulvovaginitis. Ann Allergy Asthma Immunol 2000; 85: 253-267.

Chen WW, Baskin M. A 33-year-old woman with burning and blistering of perivaginal tissue following sexual intercourse. Annals of Allergy, Asthma & Immunology 2004; 93: 126-130.

Harlow BL, He W, Nguyen RHN. Allergic reactions and risk of vulvodynia. Ann Epidemiol 2009; 19: 771-777.

Liccardi G, et al. Intimate behavior and allergy: a narrative review. Annals of Allergy, Asthma & Immunology 2007; 99: 394-400.

Sonnex C. Genital allergy. Sex Transm Infect 2004; 80: 4-7.

The Sex Series – Part One: Kissing and allergic reactions

The avenues by which a person can suffer symptoms as a result of sex are almost endless.  I am asked often about the mechanism by which mast cell patients can react to foreplay or intercourse. The reason it has taken so long to put this series together is not because of a dearth of information, but because there is so much.  The research on this topic is deep, if not always to the point: Why do some people react badly to having sex?

There are a number of reasons why sex can cause allergic symptoms, which explains why intimacy is often fraught with anxiety for mast cell patients.  So let’s start with the entry level: kissing.

It is widely accepted that kissing can transfer allergens via saliva, or contact between skin or oral mucosa.  Allergic reaction after kissing is not even especially unusual.  5-12% of IgE food allergic patients have had at least one reaction after kissing.  Peanuts, walnuts, and tree nuts are the most common offenders.  Rash around the mouth, hives around the mouth, flushing, angioedema of lips, mouth, tongue and throat, wheezing and hives all over the body have all been reported in this situation.  Usually symptoms present within minutes, but there are literature references to reactions developing up to three hours later.

In a group of 26 volunteers that ate peanut butter, the protein reached its highest concentration in saliva five minutes after consumption.  After an hour, the protein was undetectable.  Several methods for clearing the protein were tested.  Brushing teeth, rinsing mouth, or both, waiting an hour after consumption, and waiting an hour and then chewing gum, all reduced protein concentration by over 80%.  However, waiting one hour after eating was still the most effective way to clear the protein from the mouth.

Though much less common than transfer of food allergens, it is possible to transmit medications via saliva. In literature, all reports of this phenomenon involve ingestion of β-lactam antibiotics, including penicillin derivatives.  In these cases, the patients had symptoms of oral allergy syndrome with hives over large parts of the body.

The quality of the kissing is certainly a factor.  How deep is it?  How much hard? How much friction?  How wet?  Mast cell patients often react to physical stimuli like this.  It’s not hard to imagine a situation where the pressure and heat of kissing cause local mast cell degranulation.   I found a (non-scientific) article describing a woman with aquagenic urticaria who reacts to kissing because it’s wet.  For patients allergic to sweat, that could also cause a kissing reaction.

I feel like I should throw out there that you can react to allergens returned to the mouth by vomit.  Mostly because there isn’t really anywhere else to put it.  So it’s here.  The warning about vomit is in the kissing post.  How did this get to be my life?

BUT GUESS WHAT GUYS?!?!?!? Kissing can also be good for allergy patients.  One study reported that that kissing decreased wheal response (the formation of red swollen areas) was decreased 28-34% in patient allergic to dust mite and Japanese cedar pollen.  This patient group had allergic rhinitis and atopic dermatitis.  It didn’t decrease the response to injection of histamine, which means the benefit from kissing in this study is not directly blocking histamine.  Plasma levels of neurotrophins were decreased in these patients.  Neurotrophins have a complex relationship to mast cells, so it’s possible that neurotrophins block something that tells mast cells to release histamine.

I know everyone wants to know – how can I kiss safely? So hang in there, because it’s coming.  Along with the answers to all of the “embarrassing” sex questions I have ever been asked.

References:

Liccardi G, et al. Intimate behavior and allergy: a narrative review. Annals of Allergy, Asthma & Immunology 2007; 99: 394-400.

Maloney JM, et al. Peanut allergen exposure through saliva: assessment and interventions to reduce exposure. J Allergy Clin Immunol 2006; 118: 719-724.

Liccardi G, et al. Drug allergy transmitted by passionate kissing. Lancet 2002; 359: 1700.

Sonnex C. Genital allergy. Sex Transm Infect 2004; 80: 4-7.

 

 

 

 

 

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

One study assessed whether mast cell count would be influenced depending on which part of the organ biopsies were taken from. While the difference in count was not large, it is worth considering that these counts all straddle the cut off of 20 mast cells/hpf.  This means that patients with the same GI symptoms could have biopsies with over or under 20/hpf depending on the site of the biopsy.  See Table 24 for details.

Table 24: Effect of sampling site on mast cell count/hpf in colon of chronic diarrhea patients
Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gastroenterol 2012; 18 (5): 322-326.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: Tryptase (IHC), toluidine blue
Rectum Sigmoid Descending colon Transverse colon Ascending colon Cecum
20.5±5 18.3±3.5 22.6±3.9 20.7±4.9 25.5±6.7 22.1±4.9

 

The same paper also looked at effect of season on mast cell count.  There was no significant difference, but again, the range of biopsies in each season straddles the 20/hpf line. See Table 25 for details.

Table 25: Effect of season on mast cell count in colon of diarrhea patients
Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gastroenterol 2012; 18 (5): 322-326.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: Tryptase (IHC), toluidine blue
Spring Summer Fall Winter
20.6±4.7 24.2±4.9 19.5±3.9 20.3±4.9

 

The most telling portion of this study compared mast cell counts when using a simple stain (toluidine blue) and when using IHC (antibody for tryptase) to find mast cells in biopsies.  Mast cells are not easy to see on biopsy.  They require special stains, and even then, they are hard to see.  Immunohistochemistry (IHC) uses antibodies to identify markers on cells that are easier to see with a microscope.  It is not uncommon for unfamiliar doctors to refuse the use of IHC testing (which usually includes CD117, CD25, CD2 or tryptase) in lieu of commonly available stains in the lab.  However, even stains that visualize mast cells are inferior to IHC methods.  In biopsies taken from all parts of the colon, toluidine blue staining showed less than half of the mast cells visualized using IHC for tryptase.  This means that when IHC testing isn’t ordered, counts reported by simple staining are much lower than the true count. See Table 26 for details.

Table 26: Comparison of mast cell count in biopsies stained with toluidine blue and with tryptase antibody (IHC)
Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gastroenterol 2012; 18 (5): 322-326.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: Tryptase (IHC) and toluidine blue
Staining method Rectum Sigmoid Descending colon Transverse colon Ascending colon Cecum
IHC 20.5±5 18.3±3.5 22.6±3.9 20.7±4.9 25.5±6.7 22.1±4.9
Toluidine blue 8.5±0.7 6.8±1.2 10.3±4.2 10.3±3.5 12.5±5 8.1±2.9
% of cells identified by IHC seen by toluidine blue staining 41% 37% 46% 50% 49% 37%

 

There are other factors that contribute to lack of consensus in mast cell counts in GI tissue. One of the biggest causes is that not all labs use standard size high powered fields.  HPF is usually 0.25mm2, but it is not uniform throughout the research world.  Many papers don’t even provide the size of their high powered fields.  More than that, many papers report mast counts per mm2 without providing conversion factors so it’s not always possible to compare results from one paper to another.  There were some papers I wanted to use for this series that I couldn’t because I couldn’t be sure that I could convert their mast cells/mm2 confidently to mast cells/hpf.

Together with the fact that number of hpf counted, methods of biopsy slide preparation, stains and IHC antibodies are variable, it is hard to get a real understanding of whether the cut off of 20 mast cells/hpf is meaningful.  It is my finding that there are a number of conditions that cause mast cells/hpf to be higher than controls in an experiment.  It is also my finding that in some experiments, control subjects have baseline mast cell counts over 20 mast cells/hpf. It is reasonable to assume that inflammatory GI conditions can cause mast cell hyperplasia.  But the fact that chronic urticaria patients often have mast cell counts higher than control subjects is also telling.  It speaks to the fact that an allergic process can elevate mast cell counts in a space where there is no appreciable symptomology. If patients have reactions to “pseudoallergens” as described in that paper, then it is possible that these reactions could drive the increase in mast cell count in the GI tract.  If this is true, then the many mast cell patients who have “pseudoallergen” responses could see an increase in GI mast cell burden as a result of their mast cell disease.

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 seven)

The 2014 Doyle paper provides mast cell counts in colon biopsies for healthy controls, MCAS, and IBS. Mast cells were identified using antibodies for tryptase, CD117, CD25 and CD30 (IHC). Mast cells were counted in both one HPF in the densest portion of the slide and in five HPF and averaged.  In the densest portion of the slide, mast cell counts were higher in 1 HPF than in the average of 5 HPF.  Differences in methodology such as this can contribute to lack of consensus on what constitutes too many mast cells. See Table 21 for details.

Table 21: Comparison of mast cell count in 1 HPF and in the average of 5 HPF
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.
Microscopy method: 400x magnification, mast cells counted in 1 hpf
Visualization: IHC for tryptase, CD117, CD25 and CD30
HPF Control group A:

Healthy controls

 Control group B:

MCAS

 Control group C:

IBS
Average Range Average Range Average Range
Average of 5 hpf 19 mast cells/hpf 7-39 mast cells/hpf 20 mast cells/hpf 12-31 mast cells/hpf 23 mast cells/hpf 9-45 mast cells/hpf
1 hpf 26 mast cells/hpf 11-55 mast cells/hpf 28 mast cells/hpf 14-48 mast cells/hpf 30 mast cells/hpf 13-59 mast cells/hpf

 

Other papers also investigated factors that could contribute to differences in mast cell counts. The 2015 Sethi paper evaluated differences in GI mast cell counts between men and women.  Women had  marginally higher counts in both IBS and control groups. See Table 22 for details.

Table 22: Difference in mast cell count between men and women with chronic diarrhea and asymptomatic controls
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 5 hpf and averaged
Visualization: CD117 (IHC)
Sample type Study group: Women Study group: Men Control group: Women Control group: Men
Colon Average Range Average Range Average Range Average Range
30 mast cells/hpf 27-34 mast cells/hpf 27 mast cells/hpf 24-31 mast cells/hpf 24 mast cells/hpf 22-37 mast cells/hpf 21 mast cells/hpf 19-24 mast cells/hpf
Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

One paper looked at the difference in mast cell count in the rectum of healthy patients over the age of 55 and under.  Please note that these counts were made using a much lower magnification than other papers in this series, so mast cell counts are not directly comparable. Mast cells were identified using antibodies to tryptase (IHC). See Table 23 for details.

Table 23: Differences in GI mast cell count in healthy patients over and under 55 years of age.
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.
SPECIAL NOTE: THESE COUNTS WERE MADE AT HALF THE MAGNIFICATION OF OTHER PAPERS IN THIS SERIES.  THESE MAST CELL COUNTS ARE NOT DIRECTLY COMPARABLE TO OTHER STUDIES.
200x magnification, number of hpf not explicitly stated, assumed mast cells counted in 1 hpf
Visualization: Tryptase (IHC)
Sample type Study group: Healthy, over 55 years old Study group: Healthy, under 55 years old Control group B:

No control group
Rectum Average Range Average Range Average Range
40.5 ± 2.4 mast cells/hpf 51.7 ± 4.1 mast cells/hpf N/A N/A

 

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 six)

A 2007 paper assessed the reliability of CD25 on GI mast cells as a marker of systemic mastocytosis. This study determined mast cell burden in stomach, small intestine and colon of patients with SM and compared it to patients with urticaria pigmentosa, various inflammatory GI conditions and healthy controls. Mast cells were detected using antibodies for tryptase and CD25 (IHC) and counted in 10 hpf and averaged.

In the stomach, SM patients averaged 57 mast cells/hpf, compared to 14/hpf for urticaria pigmentosa patients; 23.7/hpf for other inflammatory GI conditions; and 12/hpf for healthy controls.  Conditions other than SM that caused over 20 mast cells/hpf in the stomach were H. pylori positive gastritis and bile reflux esophagus.  Some healthy controls also had a count of 20/hpf or higher. See Table 17 for details.

In the small intestine, SM patients averaged 175 mast cells/hpf; urticaria pigmentosa, 22 mast cells/hpf; other inflammatory GI conditions, 20.3 mast cells/hpf; and healthy controls, 27 mast cells/hpf in the duodenum and 32 mast cells/hpf in the terminal ileum. Conditions other than SM that caused over 20 mast cells/hpf in the small intestine were peptic duodenitis, celiac disease, irritable bowel syndrome and eosinophilic enteritis.  See Table 18 for details.

In the colon, SM patients averaged 209 mast cells/hpf; urticaria pigmentosa, 13/hpf; other inflammatory GI conditions, 20.4/hpf; and healthy controls, 21/hpf. Conditions other than SM that caused over 20 mast cells/hpf in the colon were ulcerative colitis, Crohn’s colitis, lymphocytic colitis, irritable bowel syndrome and parasitic infection.  See Table 19 for details.

Table 17: Mast cell count in stomach of patients with systemic mastocytosis
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.
Microscopy method: 400x magnification, mast cells counted in 10 hpf and averaged
Visualization: Tryptase and CD25 (IHC)
Sample type Study group: Systemic mastocytosis Study group: Urticaria pigmentosa Study group: Inflammatory GI conditions Control group A:Healthy control
Stomach Average Range Average Range Average Range Average Range
57 mast cells/hpf 24-90 mast cells/hpf 14 mast cells/hpf 10-17 mast cells/hpf 23.7 mast cells/hpf 6-23.3 mast cells/hpf 12 mast cells/hpf 5-21 mast cells/hpf
Clusters/dense infiltrates or confluent sheets. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

Table 18: Mast cell count in small intestine of patients with systemic mastocytosis
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.
Microscopy method: 400x magnification, mast cells counted in 10 hpf and averaged
Visualization: Tryptase and CD25 (IHC)
Sample type Study group: Systemic mastocytosis Study group: Urticaria pigmentosa Study group: Inflammatory GI conditions Control group A:Healthy control
Small intestine Average Range Average Range Average Range Average Range
175 mast cells/hpf 74-339 mast cells/hpf 22 mast cells/hpf 12-32 mast cells/hpf 20.3 mast cells/hpf 17.5-33 mast cells/hpf 27 mast cells/hpf(duodenum)32 mast cells/hpf (terminal ileum) 4-51 mast cells/hpf (duodenum)21-40 mast cells/hpf (terminal ileum) 

 
Clusters/dense infiltrates or confluent sheets. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

Table 19: Mast cell count in colon of patients with systemic mastocytosis
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.
Microscopy method: 400x magnification, mast cells counted in 10 hpf and averaged
Visualization: Tryptase and CD25 (IHC)
Sample type Study group: Systemic mastocytosis Study group: Urticaria pigmentosa Study group: Inflammatory GI conditions Control group A:Healthy control
Colon Average Range Average Range Average Range Average Range
209 mast cells/hpf 110-301 mast cells/hpf 13 mast cells/hpf 8-19 mast cells/hpf 20.4 mast cells/hpf 12.1-33.4 mast cells/hpf 21 mast cells/hpf 10-31 mast cells/hpf
Clusters/dense infiltrates or confluent sheets. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters. Diffuse scattered cells, no clusters.

 

Table 20: Inflammatory GI conditions associated with mast cell over 20/hpf in at least one biopsy
Stomach Small intestine Colon
Gastritis from H. pylori infection Peptic duodenitis Ulcerative colitis
Bile reflux gastropathy Celiac disease Crohn’s disease colitis
Healthy stomach tissue Irritable bowel syndrome Collagenous colitis
Eosinophilic enteritis Lymphocytic colitis
Healthy duodenum and ileum Irritable bowel syndrome
Parasitic worm infection
Eosinophilic colitis
Healthy colon tissue

 

A 2014 paper (Doyle 2014) summarized results of GI biopsies from various locations for patients with systemic mastocytosis.  Mast cell count in SM patients ranged from 20-278/hpf, with an average of 116/hpf. Most biopsies in SM patients contained clusters of mast cells or confluent sheets. 25% of positive biopsies had only one cluster of mast cells. 21% showed multiple clusters within a biopsy while other biopsies from the same region showed no mast cells.  Three biopsies from SM patients showed dispersed cells that were CD25+.

In actual practice, many doctors do not take a variety of biopsies, especially if there is no gross abnormality visualized during scoping.  This highlights the need to test for CD25. It also provides evidence that while clustering is a defining characteristic of SM, in some tissue spaces, clustering may be absent despite being present elsewhere in the same organ.

Positivity for some markers associated with systemic mastocytosis, but not enough to receive a diagnosis of SM per WHO criteria, yields a diagnosis of monoclonal mast cell activation syndrome (MMAS).  Patients with MMAS display clonality of mast cells despite not meeting criteria for SM.  In research circles, MMAS is sometimes referred to as preclinical SM.  It is possible that MMAS represents a very early stage of SM.  MMAS is managed the same way as SM and markers of clonality (25% or more mast cells in a hpf spindle shaped, positivity for CD25 and/or CD2 receptor(s), clustering of mast cells in groups of 15 or more, positivity for CKIT D816V mutation, serum tryptase baseline of 20 ng/ml or higher) should be taken seriously as an indication of proliferative mast cell disease.

 

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 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.

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.

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