What are mast cells and why should I be interested? More on mastocytic enterocolitis and a link to refractory Celiac disease.

Why should you be interested in mast cells?

Do you have unexplained or poorly controlled symptoms? Do you have severe allergies and/or suspected food intolerance or sensitivity resulting in various health problems. Are your health problems difficult to shake, reverse, or are they being blamed on poorly understood diseases? Have you been told you have irritable bowel syndrome (IBS) but have had little improvement with the treatments offered or recommended to you?

Then you should be interested in learning more about mast cells. A mast cell problem might very well be the cause. They are, at least, likely to be contributing to your feeling ill. They are known to cause severe allergies, unexplained or difficult to treat symptoms effecting numerous parts of the body. The good news is that there are several effective treatments available for mast cell conditions. However, a mast cell problem needs to be suspected before it can be confirmed.

What are mast cells?

Mast cells are unique immune cells that have granules containing various chemical mediators that have many important bodily functions. We have mast cells distributed all throughout our body. These unique cells control many bodily functions and are important immune, allergy and infection fighting or defensive cells. They commonly reside at our body's various borders where we are exposed or vulnerable to attack. However, if we have too many of these covert immune cells in an area or they misbehave, severe symptoms and serious disorders can result.

Why do I care so much about mast cells?

My interest in these cells over the past year had been primarily because they have been suspected for years as a cause of IBS or the symptoms attributed to IBS. In the past year or so special stains have become available to look for these cells in intestinal biopsies. In just the past few months numerous new research findings have strengthened the link of mast cells to stress, leaky gut and various digestive conditions, especially IBS. However, my interest is not only more intense but is now not just professional. It is personal. I recently confirmed that my wife, who has celiac disease but has continued to have some unexplained or poorly controlled symptoms despite a strict gluten free diet, has exces mast cells in intestinal biopsies done by one of my partners on her about a year ago. This was found after having her previous biopsies evaluated further with special stains for mast cells. I think these excess cells are probably to blame for her apparent refractory celiac disease symptoms and ongoing non-digestive symptoms.

What has been my professional experience with mast cells as a stomach and intestine specialist?

In just over a year I have found over 60 patients who have excess mast cells in their intestinal lining that could only be detected when MCT stains were specifically requested. Almost all of these people would otherwise been told their biopsies were “normal” or non-diagnostic. This includes several of my celiac disease patients on a strict gluten free diet (GFD), usually with “normal biopsies” and blood tests who have continued to have problems. Though most celiac disease patients dramatically respond to a gluten free diet, some continue to have problems. What I have found is that some of these people have increased mast cells in their biopsies. They meet diagnostic criteria for new condition known as mastocytic enterocolitis or what I prefer to call mastocytic inflammatory bowel disease (MIBD).

Why are they called mast cells and what is so unusual about them?

Mast cells have been known about since at least 1878. A German scientist Paul Ehrlich first described them but he mistakenly thought that since they contained granules that their function was to nourish tissues. This mistake is understandable since mast cells are commonly found near blood vessels and nerves. His name for them was derived from “Mastzellen”, a German term for “feeding-cells”. It is now known that these granules contain various chemical mediators important for the role of mast cells in immune and nerve regulating functions.

Why are mast cells granules and chemical mediator release so important?

Full of chemical mediators that are released when their abundant granules “degranulate”, mast cells have a great many effects on the tissue were they reside. Mast cells can be triggered to degranulate, thereby releasing their chemical mediators, in response to mechanical stimulation, stress, and other immune or nerve signals. Mast cells originate in the bone marrow. They then travel via the blood stream and lymph to tissues where they specialize. Their tissue specific specialties depend on their location and functions needed at that tissue location.

Where are mast cells and can they be missed?

Being widely distributed throughout the body, tissue specific mast cells are typically found near blood vessels and nerves though they are hard to see under the microscope without special stains. They are covert. Giemsa, Toludine Blue and special immunohistochemistry stains for tryptase are stains that are used to help see mast cells. However, they are not routinely used. Mast cell tryptase (MCT) stains take of advantage of the large amounts of tryptase in the granules. Giemsa and Toludine Blue stains don't allow mast cells to be seen well if they have released their chemicals from their granules. Mast cell tryptase is specific for these cells and allow them to be seen even if they have degranulated. It may also stain tryptase that has been released into the tissues.

Since, these stains are not routinely ordered or done on tissue biopsies, increased mast cells is frequently missed. This is a particularly important point in the intestine. Only recently has it been recognized that increased mast cells may be present in intestinal biopsies of people with IBS, especially when abdominal pain is severe and diarrhea is present. However, constipation can occur with increased mast cells. An example of increased mast cells in a biopsy of intestinal tissue is shown below. The mast cells are easily seen with the tryptase stain as brownish cells mixed within the tissue.



In this example of mastocytic enterocolitis in one of my patients and kindly provided as courtesy to me from GI Pathology PLLC, it is clear that there are increased mast cells. You can easily count more than 20 per high power field of view under the microscope and make the diagnosis. However, if the special stain had not been used this finding would be completely missed.

Have you had intestinal biopsies that you were told were normal? If so, you should discuss with your doctor having those biopsies stained with mast cell tryptase immunohistochemical special stains to look for excess mast cells. This usually can be done on biopsy tissue that is still available at the pathology laboratory where your samples sent to be reviewed by a pathologist. Most laboratories retain samples for up to five years, some even longer. If the laboratory cannot do the special stains you can request that samples be sent ot GI Pathology in Memphis TN (www.gipath.com). Lets explore more about mast cells in the next post and I will take up my review of leaky gut again in future posts as well.


Copyright © 2008, The Food Doc, LLC, All Rights Reserved.
www.thefooddoc.com

Scot M. Lewey, D.O., FACP, FAAP, FACOP
Gastroenterology Associates of Colorado Springs
1699 Medical Center Point
Colorado Springs CO 80907
719 387 2110 Fax: 719 302 6000

Author Bio

Dr. Scot Lewey is a digestive disease specialist doctor (board certified gastroenterologist) whose medical practice focuses on digestive and food related illness. Also, known as Dr. Celiac, the Food Doc, Dr. Lewey shares his experiential knowledge for a healthy gut, healthy life on-line. Start learning today from his extensive personal and professional experience. Dr. Lewey is uniquely qualified as an expert and one of the few GI doctors who is also gluten sensitive and dairy sensitive. He has nearly a quarter of century of experience in the diagnosis and treatment of food allergy & intolerance, colitis, Crohn's disease and IBS. He is married to someone who has Celiac disease. He and his family live gluten free in Colorado.

GACS Clinic Website (Dr. Lewey’s Office)
The Food Doc Journal (Blog)
The Food Doc Website (under construction)
“Experiential Knowledge for a “Healthy Gut, Healthy Life”
Secure on-line consultation (fees apply)

Gluten free food report
Dr. Lewey’s expert author bio & articles

info@thefooddoc.com

New changes in Prometheus celiac disease DQ genetic reporting help determine your risk of severe autoimmune gluten related disease

Prometheus Therapeutics and Diagnostics has modified their celiac genetics testing and reporting. They are now including the number of copies of DQ2 and DQ8. Along with the DQ results they also include a table that summarizes the risk of celiac disease over the general population. Previously Prometheus only reported the presence or absence of DQ2 or DQ8. If you happened to be positive for both DQ2 and DQ8 then we knew your entire DQ pattern. However, if you only had one copy of either or two copies of one the results had less value for determining your risk of celiac disease, its severity and the possible risk of your parents and children for having at least one copy of the at risk genes predisposing to celiac disease.

Now Prometheus provides a very detailed report of the DQ2 and DQ8 genes detected along with an estimate of your risk of celiac disease. They also include a table that summarizes the various at risk DQ patterns and their relative risk compared to the general population.

An example of the new Prometheus reporting method is shown below (may require zoom to see well).




As you see they report the detailed DQA1 subunit and DQB1 subunits as well as number of copies of DQ at risk genes. The two risk patterns for celiac disease are DQ2 and DQ8. The table is shown below but will likely require you to zoom on the page to be able to read it.


However, the current testing still does not include other DQ types, DQ types that are reported to carry risk of gluten sensitivity. Other DQ patterns have also been associated with specific types of gluten sensitivity and gluten related illness such as neurological problems such as balance difficulties (ataxia), skin problems and microscopic colitis.

To understand the table and the risk estimates you must also understand the terms homozygous and heterozygous. Homozygous is when you have two copies of the same gene, one from each parent. DQ patterns reside on chromosome 6. Each of us has 46 chromosomes, 23 pairs, and therefore we all have two copies of chromosome 6, one from each parent. We all have two DQ patterns, one from each of parents, such that we are all DQx/DQx, where x is a number between 1 and 9. I am DQ2/DQ7 and my wife is DQ2/DQ5. We are both therefore heterozygous for DQ2 that is we have only one copy of DQ2. Scott Adams, the founder of celiac.com is DQ8/DQ8, he is homozygous for DQ8.

Homozygous means you have two copies e.g. DQ2/DQ2 whereas heterozygous means you have one copy of DQ2 or DQ8. Some people have one copy of DQ2 and one of DQ8 (DQ2/DQ8) and they are higher risk for celiac disease than someone with only one copy of either DQ2 or DQ8 but not as high as someone with two copies of DQ2 (DQ2/DQ2). Since DQ2 carries greater celiac disease risk than DQ8 then one copy of DQ2 plus a DQ8 (DQ2/DQ8) is higher risk than having two copies of DQ8 (DQ8/DQ8).

Other laboratories besides Prometheus providing DQ testing are Kimball Genetics, LabCorp, Bonfils, Quest and Enterolab. However, Bonfils actually does the testing for Quest and Enterolab. Also, Bonfils, and therefore Quest and Enterolab, only do a portion of DQ2 and DQ8 testing. Bonfils only tests for the beta subunit portions of the DQ molecules. This means that they can miss a minor alpha subunit component of DQ2 that does carry an increase risk of celiac disease though the test may report you are DQ2 and DQ8 negative when you may or may not be.

I will be reviewing this in more detail but I wanted to provide this new information about the changes in Prometheus celiac DQ genetic testing. If you are still confused by your test results or want more personalized review of your results, symptoms or diagnostic tests I recommend you see a physician who is an expert in celiac disease and understands these tests. I also offer on-line consultation for a reasonable fee through a secure consultation site medem.com. You simply register (registration is free) for secure on-line communication and request a consultation. The fee is $50. Some insurance companies will cover on-line communication. For those in Colorado or willing to travel you can contact my office at the number or website below. I see many people from outside of Colorado Springs for consultation though my office staff inform me that my new consult office visits are booked out 6-8 weeks. A more detailed review of the celiac and non-celiac gluten sensitivity has been forwarded to my colleagues Dr. Rodney Ford (www.doctorgluten.com), Dr. Ron Hoggan (author of Dangerous Grains) and Scott Adams, editors of ScottFree newsletter. Ron is working on a book proposal that he, Rodney and I are working on for a book about the broader problem of gluten sensitivity or as Rodney has named it, "the gluten syndrome".


Copyright © 2008, The Food Doc, LLC, All Rights Reserved.
www.thefooddoc.com

Scot M. Lewey, D.O., FACP, FAAP, FACOP
Gastroenterology Associates of Colorado Springs
1699 Medical Center Point
Colorado Springs CO 80907
719 387 2110 Fax: 719 302 6000

Author Bio

Dr. Scot Lewey is a digestive disease specialist doctor (board certified gastroenterologist) whose medical practice focuses on digestive and food related illness. Also, known as Dr. Celiac, the Food Doc, Dr. Lewey shares his experiential knowledge for a healthy gut, healthy life on-line. Start learning today from his extensive personal and professional experience. Dr. Lewey is uniquely qualified as an expert and one of the few GI doctors who is also gluten sensitive and dairy sensitive. He has nearly a quarter of century of experience in the diagnosis and treatment of food allergy & intolerance, colitis, Crohn's disease and IBS. He is married to someone who has Celiac disease. He and his family live gluten free in Colorado.

GACS Clinic Website (Dr. Lewey’s Office
The Food Doc Journal (Blog)
The Food Doc Website (under construction)
“Experiential Knowledge for a “Healthy Gut, Healthy Life”
Secure on-line consultation (fees apply)

Gluten free food report
Dr. Lewey’s expert author bio & articles

info@thefooddoc.com

Questions and Answers About the Diagnosis and Treatment of Mastocytic Enterocolitis or Mastocytic Inflammatory Bowel Disease (MIBD)

WHAT IS MASTOCYTIC ENTEROCOLITIS?

Mastocytic enterocolitis (entero-small intestine, colitis- colon+ -itis or inflammation) is a relatively new condition inflammatory bowel disease to be recognized. It is characterized by increased number of mast cells in the intestine surface lining, also known as the mucosa. Mast cells are a type of blood cell. They are involved in various immune and infection fighting processes in the body. In the gastrointestinal tract typically around 12 mast cells can be seen per high power field (40X magnification) under the microscope. In mastocytic enterocolitis is now defined by the presence of 20 or more mast cells per HPF in the small intestine and/or colon.

WHAT ARE MAST CELLS AND WHY ARE INCREASED NUMBERS PRESENT IN MASTOCYTIC ENTEROCOLITIS?

Mast cells are present in the blood, bone marrow and various tissues throughout the body. They originally arise from the bone marrow and migrate to other areas as needed. Rat studies have previously confirmed that stress increases mast cells in the intestine and causes leaky gut. Mast cells seem to have several important functions in the gut including not only immune function but also gut nerve function. Mast cell activation can result in increase gut contractions or decrease gut contractions. A recent study confirms that the stress hormone corticotropin-releasing hormone (CRH) stimulates mast cells in the human colon through receptors present on the mast cells and can trigger their release of chemicals from granules. Increase mast cells are found in association with other inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease as well as in celiac disease, “allergic esophagus” or eosinophilic esophagitis, and in post-infectious irritable bowel syndrome (IBS). Mast cells are increasingly being mentioned in the predisposition, subsequent development or progression of these other conditions as well as many cases of IBS.

WHAT ARE THE SYMPTOMS?

The classic symptoms of mastocytic enterocolitis are cramping quality abdominal pain and urgency with diarrhea. However, constipation, nausea, vomiting and non-GI symptoms are also commonly reported or associated such as flushing or feeling hot, poor appetite, and headaches. Since mast cells release mediators that can affect the nerves of the gut resulting in increase contraction or reduced contractions, it makes sense that either diarrhea or constipation can occur. In fact, a recent study confirmed that mast cell release of their various chemical mediators is the cause of intestinal paralysis or delayed function after abdominal or intestinal surgery known as postoperative ileus. The mechanical stimulation of the surgeon handling the intestines during traditional open abdominal surgery has been shown to trigger the release histamine and other chemicals present in mast cell granules. This is what is believed to cause the gut fail to normally contract initially after surgery.

WHAT CAUSES MASTOCYTIC ENTEROCOLITIS?

It appears that infections and stress are causes. Food allergy and sensitivity are also suspected. There may be a genetic risk, in particular DQ genetic risk common to celiac disease. Leaky gut or increased gut permeability is a risk factor and the presence of increase mast cells in the gut. This predisposes or increases leaky gut so that a vicious cycle may result. Altered gut microbes likely also play a role. Either having a gastrointestinal infection or receiving antibiotics for an infection appears to be a risk factor. Mast cell levels tend to vary in the gut. They are increased the most during active symptoms, especially periods of stress and altered gut permeability.

HOW IS MASTOCYTIC ENTEROCOLITIS DIAGNOSED?

The diagnosis is made by determining that there are 20 or more mast cells per high power field in the superficial intestinal lining or mucosa. However, in order to see these mast cells, which are otherwise “covert” or hidden behind other cells, special stains are required. Until recently these stains were either expensive or not readily available. Mast cells in mucosa contain an enzyme tryptase that stains with a special immunohistochemical making the mast cells easy to see and count. However, these stains typically must be requested by the doctor obtaining intestinal biopsies at the time of endoscopic procedure is performed or by alerting the pathologist that the condition is suspected. The stains can also be performed on tissue previously obtained by special request as long as the tissue is available and the pathology department has the stain.

HOW IS MASTOCYTIC ENTEROCOLITIS TREATED?

The usual treatment is combinations of antihistamines and mast cell stabilizers along with a search for food allergies and intolerances. Since one of the main chemical mediators released from the granules in mast cells is histamine antihistamine medications are often helpful in reducing symptoms. Histamine receptors come in two types, type 1 and type II. Type I histamine receptors are typically found in respiratory and skin tissues and type I antihistamines are commonly used to treat allergic reactions. Common type I antihistamine or H1 blockers are Benadryl, Zirtec, Allegra, and Claritin, etc. There are type II histamine receptors found in the digestive tract, especially the stomach where their stimulation results in increase acid production and competitive inhibition by type II antihistamines suppresses or reduces stomach acid production. The common type II antihistamine or H2 blocker medications are Zantac, Tagamet, and Pepcid. Typically, both type I and type II antihistamines are used and help reduce abdominal pain and diarrhea in mastocytic enterocolitis.

Mast cell stabilizing medications also exist but the only commonly commercially available one is sodium Cromalyn. It is used in eye drops, nasal sprays and for inhalation for eye and nasal allergies and asthma. For the treatment of systemic mastocytosis related GI symptoms and mastocytic enterocolitis, sodium Cromalyn is commercially available in the brand name preparation Gastrocrom. Gastrocrom comes in a dosage form of 100 mg per 5 ml concentration packaged in a box of 96 5 ml ampules. The usual dose is 200 mg orally four times a day for 4-6 weeks.

Since food allergies and food intolerances may be a trigger, testing for both is recommended. Also, because stress is related, stress reduction or treatment is recommended. Avoidance of things that increase gut permeability or leaky gut and promotion of increase tight junctions by use of probiotics also makes sense though these treatments have not been formally tested specifically in mastocytic enterocolitis.

WHAT IS THE LONGTERM PROGNOSIS OF MASTOCYTIC ENTEROCOLITIS?

This is not known. However, mast cells are dynamic and appear to regress from the gut. Treatment with antihistamines and mast cell stabilizers do reduce symptoms in most patients. Avoidance of foods determined to cause allergic reactions or chemical mediator release seems to help also. It is no known whether mastocytic enterocolitis is a precursor or transition to other inflammatory bowel diseases such as ulcerative colitis, Crohn’s disease, Celiac disease or eosinophilic gastrointestinal disorders. Genetics, immune status, intestinal microbe make up, and degree of gut inflammation or injury with resultant leaky gut are all likely important factors regarding risk of development of other inflammatory conditions, recovery or improvement.

Selected References:

The FO et al. “Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus.” Gut 2008; 57:33-40

Wallon, C et al. “Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro.” Gut 2008; 57:50-58.

Jakate, S. “Mastocytic Enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.” Arch Pathol Lab Med 2006; 130:362-367.

Helpful Websites:

NIH website overview of mastocytosis

The Mastocytic Society

Copyright © 2008, The Food Doc, LLC, All Rights Reserved.
www.thefooddoc.com

Dr. Scot Michael Lewey
“Dr. Celiac, the food doc”
www.thefooddoc.com
info@thefooddoc.com
1699 Medical Center Point
Colorado Springs CO 80907

Mastocytic enterocolitis: A new epidemic, mastocytic inflammatory bowel disease (MIBD), may mimic IBS and be related to stress

Mastocytic enterocolitis is a new entity that has been described more recently as a condition characterized by increase mast cells of 20 or more per high-powered field in the duodenum or colon. Jakate et al. described 47 patients with intractable diarrhea and abdominal pain without other cause who had elevated mast cell numbers in intestinal biopsies and responded to therapy directed at mast cells. The patients generally met criteria for diarrhea predominant irritable bowel syndrome (IBS). Normal subjects had much lower levels of mast cells of an average of 12 per HPF.

Until recently this condition was missed due to lack of ability to see mast cells on biopsies in the background of normal cells. However, commercially available special stains utilizing immunohistochemistry for the enzyme tryptase allows the mucosal mast cells to be seen and counted in intestinal tissue obtained from routine random intestinal biopsies.

Over the past year I have been asking the pathologists to perform mast cell stains on intestinal biopsies in my GI patients with diarrhea and abdominal pain. Recently, I began expanding this to include as many patients as possible as well as requesting these stains be done on biopsies performed previously in patients who I suspected might have this condition.

I have now accumulated fifty patients meeting criteria for mastocytic enterocolitis or mastocytic enteritis. These patients are in various stages of evaluation and treatment. I am collecting and analyzing the clinical information with the intent to submit the data for publication. What I have observed on initial review is that appears to be a higher than expected prevalence of the celiac disease risk genes DQ2 and DQ8. In particular, DQ8 appears to be overrepresented compared with the incidence in the general population. There also appears to be an association with celiac disease, non-celiac gluten sensitivity and multiple food intolerance.

The latter finding of multiple food intolerance determined by mediator release testing abnormalities (MRT, Signet Diagnostic Corporation www.nowleap.com; Alcat www.alcat.com) makes sense. The principle of these tests is the detection of changes in cell volumes that occur due to chemical mediator release from cells present in the blood. The tests are not specific for the mediator or mediators released but is assumed that the greater the reaction the greater the number of mediators released and more likely a particular food, chemical or food additive can cause an adverse reaction.

The laboratories that provide mediator release testing report great success in treating a variety of symptoms commonly attributed to food intolerance or chemical/additive sensitivity. It is my belief that mast cells are heavily involved in this process. This would make sense since success with conditions now being associated with mast cells are reported to respond favorably to dietary elimination of foods or substances with abnormal MRT reactions. Classic examples include IBS, headaches, and interstitial cystitis that have been linked to mast cells as well as stress that is now linked to increase mast cells and mast cell degranulation releasing mediators.

Mediator release tests are criticized by some U.S. doctors, in particular www.quackwatch.com as being unproven or not proven for "food allergy” evaluation. However, they are not food allergy tests. Food allergy is an IgE mediated type I immediate immune response known as allergy. MRT tests for non-immune delayed type reactions resulting from mediator release from immune cells. The point is that MRT is not food allergy testing it is a form of non-immune food intolerance or sensitivity reaction.

New articles published in the January 2008 issue of the journal Gut reveal exciting new associations of mast cell degranulation with postoperative ileus and a link to a stress hormone. The first study may be the first to show that mast cells in human bowel release mediators when the bowel is handled during surgery resulting in temporary bowel paralysis known as postoperative ileus. The minimally invasive surgery technique of laparoscopy results in less mechanical stimuli to the bowel and has a lower incidence of postoperative ileus.

Stress association with IBS and inflammatory bowel diseases (Ulcerative colitis, Crohn's disease) has been long known but a mechanism had not been determined definitely. In the same issue of Gut investigators showed that the stress hormone corticotropin-releasing hormone (CRH) regulates intestinal permeability (leaky gut) through mast cells. The investigators even identified specific receptors on mast cells. This new information sheds new light on the possible link of leaky gut and mast cells with IBS, IBD and celiac disease.

So, how do I believe this new information may help us? Since stress can increase mast cells in the bowel and these cells can release mediators that cause gut injury and symptoms, stress reduction important. These cells can cause abdominal pain, diarrhea, and constipation as well as other symptoms outside the gut so they are important. Yet, the significance of these cells is generally not recognized because most doctors, including gastroenterologists and pathologists are unaware of their presence and importance.

These cells cannot be seen in the intestine without special stains done on intestinal tissue obtained during upper endoscopy or colonoscopy. Those stains are not routinely done but generally require the doctor performing the biopsy to request them. If no biopsy is performed then obviously these cells cannot be found. There may be a genetic predisposition for what I think may be better termed mastocytic inflammatory bowel disease (MIBD) rather than mastocytic enterocolitis. There also may be the same genetically determined white blood cell protein patterns that are associated with Celiac disease playing an important role in MIBD.

As note above, stress reduction and probiotic therapy may be helpful to reduce mast cells and leaky gut but what about once the mast cells are increased in the gut. Once elevated mast cells are present, treatment may include medications and dietary interventions. Antihistamines, both type I (e.g. Claritin, Allegra, Zirtec) and type II (e.g. Zantac, Tagamet, Pepcid) to block histamine effects have been used successful in reducing abdominal pain and diarrhea in people with mastocytic enterocolitis. A very specific mast cell stabilizer, sodium Cromalyn (Gastrocrom), also has reduced symptoms. It is an accepted therapy for the more severe condition of generalized mastocytosis.

Searching for food allergies and food intolerance (by mediator release testing) followed by dietary elimination of problem foods until leaky gut resolves and mast cell numbers in the bowel reduce is also helpful in my experience. Food allergy testing consists of skin testing and IgE RAST antibody tests. These tests do not exclude non-allergic food intolerance and sensitivity. Antibody tests for IgG in blood or IgA in stool or saliva have been used for food sensitivity. In my experience MRT tests are much more helpful as they look for any abnormal mediator release to a variety foods, chemicals, or additives, regardless of the nature.

Stay tuned for new developments about the role of mast cells and look for more interest in mastocytic enterocolitis in the future. I propose that the GI community should adopt the broader term mastocytic inflammatory bowel disease since there is information indicating mast cells have an important role in allergic esophagus and stomach problems.

Selected References:

The FO et al. “Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus.” Gut 2008; 57:33-40

Wallon, C et al. “Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro.” Gut 2008; 57:50-58.

Jakate, S. “Mastocytic Enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.” Arch Pathol Lab Med 2006; 130:362-367.

Helpful Websites:

NIH Mastocytosis information

The Mastocytosis Society

Copyright © 2008, The Food Doc, LLC, All Rights Reserved.
www.thefooddoc.com

Dr. Scot Michael Lewey
“Dr. Celiac, the food doc”
www.thefooddoc.com
info@thefooddoc.com
1699 Medical Center Point
Colorado Springs CO 80907

Update on genetics of celiac disease

Genetic tests exist for Celiac disease and are highly accurate for determining the risk of the disease. When a complete genetic panel is performed the possibility that someone having or ever getting Celiac disease can be determined to an extremely high degree of certainty. Unfortunately, some tests are misleading because they do not include a portion of the genetic pattern that may be present that can predispose to the disease yet the report may imply absence of increased risk.

Some tests can be done without a doctor’s order. Insurance coverage for the tests is highly variable. A couple of laboratories can run the tests on samples obtained from a mouth swab that is painless and well accepted by children. Genetic testing can be done at any age whereas blood tests for Celiac disease are not recommended before a year of age. Celiac disease genetic tests are not influenced by whether one is eating or not eating gluten.

If you do not have the commonly recognized genetic patterns associated with Celiac disease you are generally excluded from the risk of ever getting the full autoimmune disease and don’t need to be periodically retested though you can be intolerant or sensitive to gluten. This can be very helpful for those who have a family member with Celiac disease or other autoimmune diseases associated with at risk Celiac disease genetics.

HLA DQ2 and DQ8 are the simplified white blood cell patterns or types that are known to be associated with an increase risk of Celiac disease and one the necessary requirements to develop the disease. The HLA term stands for human leukocyte antigen. Leukocytes are white blood cells. Antigens are proteins that serve or elicit an immune response by the body. So, the HLA system is a complex set of proteins on the surface of white blood cells.

These protein patterns are inherited just like the red blood cell proteins that constitute what is commonly known your “blood type”. I, for example, am A positive blood type. This means I have a pattern of proteins designated A and Rh+ on the surface of my red blood cells. On the other hand I have a white blood cell type pattern DQ2/DQ7 inherited from my parents. My Dad gave me a DQ2 and my Mom the DQ7. You have two DQ patterns on your white blood cells that you received from your parents and you give one of your DQ types to each of your children.

Since only a single copy of either DQ2 or DQ8 can be associated with an increase risk of developing Celiac disease, most laboratories test for the presence of either and simply report their presence or absence. However, knowing if you have one or two copies not only provides additional information about degree of your risk and possible severity of Celiac disease but also information about your parents and your children’s risk of inheriting an at risk gene. If you have DQ2 and DQ8 we know your complete DQ pattern as well that both your parents and all of your children have or will get at least one at risk gene.

Other non-HLA genetic factors are involved in the risk of Celiac disease. These are still being worked out. However, one poorly understood and little known fact to most doctors and almost all patients is that HLA DQ2 and DQ8 testing done by some laboratories does not include the full spectrum of at risk components of these patterns. DQ2 and DQ8 are a summary blood type designations or serotypes for the presence of several protein subunits. There are alpha and beta subunits to these protein patterns. The beta subunit is the most influential and important component. Most laboratories only test for and report the beta subunit. However, the alpha subunit does carry risk on its own, albeit much less than the presence of the beta subunit or the presence of both alpha and beta subunit.

The most commonly used laboratories for Celiac disease genetic testing in the U.S. are Kimball Genetics, LabCorp, Quest, Prometheus, and Enterolab. The Laboratory at Bonfils in Denver not only provides testing directly but also does the testing for several hospitals, Quest and Enterolab. Bonfils only does beta subunit testing. They report results of DQ2 and DQ8 negative based on the absence of the beta subunits associated with DQ2 and DQ8 however this is misleading since someone could have only the alpha subunit and be “partially” DQ2 or DQ8 positive.

Though the risk of being “half” DQ2 positive from only having the alpha subunit is low overall it is still there. Furthermore, there are people who may believe that they are DQ2 or DQ8 negative based on testing from Bonfils, Quest or Enterolab, therefore they and/or their doctor may exclude the possibility that they have or are at risk for ever getting Celiac disease when in fact this may not be true.

The existence of DQ2 and DQ8 negative Celiac disease has been debated and is clouded to some degree by this confusion. Most Celiac experts assert that the presence of DQ2 or DQ8 is a requirement to develop the disease and their absence excludes the possibility. However, reports of DQ2 and DQ8 negative Celiac disease persist.

I have a couple of patients who have the specific blood tests for CD, endomysial and tissue transglutaminase antibody, and the classic biopsy features that were reported DQ2 and DQ8 negative by laboratories who only test for the beta subunit. Re-testing for alpha unit positive “half” DQ2 or DQ8 is being requested on these patients. However, I am deeply concerned that many patients and doctors may have been lulled into a false sense of security or diagnoses of Celiac disease may have been withdrawn on some individuals based on incomplete genetic results.

The issue of DQ2 and DQ8 testing is further complicated by reviews on the subject that are incomplete or vague. The best reviews I have found are by Ludvig Sollid and Benedicte Lie of Oslo, Norway “Celiac Genetics: Current Concepts and Practical Applications” Clinical Gastroenterology and Hepatology 2005 and Bourgey’s 2007 review. In a recent update article by Victorien, there is a general review the genetics of celiac disease including the association of myosin IXB gene (MYO9B). However, it doesn’t explain the DQ2 or DQ8 typing well. They conclude that “To date, only HLA-DQ2 or HLA-DQ8 typing is clinically relevant…” but fail to point out that HLA DQ2 and DQ8 typing should include both alpha and beta subunits.

It is clear that both HLA and non-HLA genetic factors are important in the risk of celiac disease. However, the absence of the celiac disease high-risk genes does not preclude adverse reactions to gluten including leaky gut, skin, digestive and neurological symptoms. When genetic testing is used to try to assess the risk or exclude celiac disease then I recommend that full testing including both alpha and beta subunit typing. Hopefully more research will better define the genetics of both celiac disease as well as non-celiac gluten sensitivity or gluten syndrome.


Selected References:

Bourgey, M et al. HLA related genetic risk for coeliac disease. Gut 2007; 56:1054-1059.

Johnson, TC et al. Relationship of HLA-DQ8 and severity of celiac disease: Comparison of New York and Parisian cohorts. Clin Gastroenterol Hep 2004; 2:888-894.

Kaukinen K. et al. HLA-DQ typing in the diagnosis of celiac disease. Am J Gastroenterol 2002; 97(3): 695-699.

Lundin, KE. HLA-DQ8 as an Ir gene in coeliac disease. Gut 2003; 52:7-8

Mazzarella G. et al. An immunodominant DQ8 restricted gliadin peptide activates small intestine immune response in in vitro cultured mucosa from HLA-DQ8 positive but not HLA-DQ8 negative coeliac patients. Gut 2003; 52:57-62.

Sollid, LM and Lie, BA. Celiac disease genetics: Current concepts and practical applications. Clin Gastro Hep 2005; 3:843-851.

Wolters,VM and Wijenga C. Genetic background of celiac disease and its clinical applications. Am J Gastroenterol 2008; 103:190-195.

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Dr. Scot Michael Lewey
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