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How are mast cell issues treated?

In many cases, an over-the-counter antihistamine may be all that is needed.  But different types of antihistamines are available, and in order to make the right choice, it's necessary to have a basic understanding of how the different types work, and which symptoms they are most useful for suppressing.

Remember that histamine is not just involved with causing allergy symptoms.  Histamine is also responsible for providing numerous vital chemical and neuronal functions, in order to keep various systems operating smoothly, and it accomplishes these various tasks by attaching to histamine receptors at various locations in the body.  When histamine attaches to a histamine receptor, this bonding triggers the subsequent events that either provide a beneficial action, (such as increasing the acidity of the stomach, in preparation for digesting a meal), or cause an undesirable response, (such as an allergy symptom).  There are basically 4 different types of histamine receptors in various organs of the body, specified as H1, H2, H3, and H4.

The most common is the H1 receptor, which is found throughout the body in smooth muscles (including the heart), blood vessels, and in the central nervous system.  When histamine attaches to these receptors, the bonding typically results in smooth muscle contractions (which can cause constriction of broncial tubes and contractions in both the small and large intestines, for example), dilation of blood vessels, itching, watery eyes, runny nose, sneezing, and in the case of insect stings, pain.  In severe cases, the response can include anaphylaxis, which can result in life-threatening symptoms.

H2 receptors also cause blood vessels to dialate, but their primary purpose is to stimulate the production of gastric acid, when they are activated.  And their activation can result in the relaxation of smoooth muscle tissue (primarily in the digestive system).1  This is in direct contrast with the function of H1 receptors, which induce smooth muscle contractions (rather than relaxation).  Note that activated H2 receptors are also capable of inhibiting the production of antibodies, T cells, and cytokines.  This appears to explain why the use of H2 type antihistamines can trigger inflammation and microscopic colitis symptoms in some cases (because they limit or eliminate the natural tendency of histamine activated H2 receptors to suppress the proliferation of
antibodies, T cells, and cytokines).  H2 antihistamines are used primarily to suppress the production of gastric acid, in order to treat conditions such as peptic ulcers and gastroesophageal reflux disease (GERD), but they are clearly not without risk, especially for certain individuals who have microscopic colitis.

H3 receptors are found primarily in the brain and in the central nervous system, and to a lesser degree, in the peripheral nervous system.   When H3 receptors are activated, they tend to suppress the release of neurotransmitters, such as histamine, acetylcholine, norepinephrine, and serotonin.  Since the suppression of those items is generally a desired effect, (for someone who has microscopic colitis), using an H3 antagonist would appear to be generally counterproductive.  Therefore, H3 receptors and H3 antagonists are not of interest to us in this discussion.

H4 receptors are found in leukocytes (white blood cells) known as basophils, bone marrow, the thymus, spleen, small intestine, and colon.  H4 receptors are associated with chemotaxis.  Since chemotaxis is a chemical phenomenon primarily associated with the navigation of bacteria and certain similar processes, it's outside the range of interest for this article, so H4 receptors are also irrelevant to this discussion about mast cell issues.


Note the differences between H1 and H2 receptors:

1. When activated, H1 receptors cause smooth muscle contraction, while H2 receptors can cause smooth muscle relaxation (particularly in the intestines).  In addition, activated H2 receptors can suppress the production of antibodies, T cells, and cytokines, all of which are inflamatory.  

2. This implies that the use of H1 antihistamines should reduce the dilation of blood vessels, and suppress most or all of the common allergy symptoms.  H1 antihistamines should also relax smooth muscle contractions that are induced by histamine-based reactions.

3. By comparison, the use of H2 antihistamines should suppress the production of acid in the stomach, reduce the dilation of blood vessels, and may induce contractions in smooth muscle tissue, under certain conditions.  It may also cause an increase in the production of antibodies, T cells and cytokines, resulting in a proinflammatory condition.  Smooth muscle contractions in the intestines can lead to a reduction in motility (which might be helpful for reducing diarrhea), and excessive amounts might possibly lead to cramps and even constipation.  This attribute can be helpful for controlling diarrhea associated with microscopic colitis, but in some cases, the increase in proinflammatory agents due to the use of H2 antihistamines apparently trumps any advantage that might otherwise be gained by reduced motility.

In general, H1 type antihistamines are used as anti-allergic drugs (since they are primarily associated with IgE-based reactions).  It's tempting to view antihistamines as receptor antagonists, but both H1 and H2 type antihistamines are not actually true H1 antagonists — they are inverse agonists.  A receptor antagonist works by bonding to a receptor in order to block any subsequent attachment of an antigen to that receptor — in this case it would prevent histamine from attaching to a receptor.  An inverse agonist goes farther than that.  An inverse agonist actually induces a pharmacological response that is the direct opposite of the response normally produced by an agonist (in this case, the agonist would be histamine).  In other words, not only do inverse agonists prevent histamine from bonding with a receptor, but they also suppress the active functional level of the receptor to below it's normal state.  This is the reason why taking antihistamines when they are not needed, can constrict blood vessels (to increase blood pressure), cause dry eye, dry out nasal passages, and cause similar effects that are opposite to the symptoms caused by histamines.

I'd like to make an observation here.  In view of the fact that one of the symptoms of histamine is smooth muscle contraction, and bearing in mind that both H1 and H2  antihistamines  are inverse agonists, that implies that an H1 antihistamine should be capable of relaxing smooth muscle contractions in the intestines, resulting in reduced motility.  Perhaps this is why some patients who have microscopic colitis have found that certain antihistamines seem to control their diarrhea issues as well as a corticosteroid, for all practical purposes.

In cases where H1 antihistamines show no benefits, or inadequate control, sometimes an H2 antihistamine, either alone, or in combination with one or more H1 antihistamines, can be helpful.  Typically, H1 antihistamines either help, or show no benefits.  Unless an actual allergy to the antihistamine itself, or to one of the inactive ingredients exists, H1 antihistamines virtually never make symptoms significantly worse.  On the other hand, while H2 antihistamines may be beneficial in certain cases (either alone or in combination with an H1 antihistamine), in some situations, they can cause significant adverse effects, such as increased inflammation.  Therefore a decision to try an H2 antihistamine should be weighed carefully, since they carry risks that are not associated with H1 antihistamines, especially for individuals who have microscopic colitis.

The bottom line is, some individuals find that one or more antihistamines can control their symptoms as well or better than a treatment regimen based on the use of a corticosteroid, and the risk of significant side effects (at least with H1 antihistamines), appears to be rather miniscule when compared with the risk of side effects associated with treatment programs using corticosteroids.  

H1 antihistamines come in two basic types, short-acting and long-acting.  Short-acting antihistamines are typically older medications that have been available for many years, and they tend to cause drowsiness, significant enough to interfere with work and other daily routines.  An example of this is Benadryl (diphenhydramine), which works very well for many people, but the sleepiness that it causes can definitely be troublesome in many situations.  Another example is Chlor-Trimeton (
chlorpheniramine), and a long-acting version is available by prescription.

Long-acting antihistamines are usually newer medications, and most of them are less likely to cause drowsiness.  Claritin (loratidine), Zyrtec (cetirizine), and Allegra (fexofenadine) are all long-acting antihistamines, and they are available without a prescription.  Prescription long-acting antihistamines are also available, including Atarax (hydroxyzine) and Periactin (cyproheptadine).  Unfortunately, both of these drugs tend to cause drowsiness.  A presctiption H1 anthistamine that is less likely to cause drowsiness is Xyzal (levocetirizine).

Examples of type H2 antihistamines include Zantac (ranitidine), Tagamet (cimetidine), and Pepcid (famotidine).  These drugs were originally developed to treat ulcers, and they are frequently prescribed to treat indigestion, acid reflux, and gastroesophageal reflux disease (GERD), but many doctors also recommend their use for treating certain allergy symptoms, such as rash or hives.


Examples of H1 and H2 antihistamines can be readily found on the internet.2
 Specialists who are familiar with the treatment of mast cell issues frequently prescribe dosage rates of antihistamines up to 4 times the maximum recommended dosages specified on the labels, especially in cases where symptoms include a persistent rash.3

Other treatments are also sometimes helpful for controlling mast cell problems.4  For example, avoiding foods that are high in histamine content, and/or foods that promote the degranulation of mast cells, is an effective, and safe way to reduce mast cell problems.5, 6

For anyone who is sensitive to NSAIDs (as many of us are), limiting foods in the diet that are high in salicylates can be helpful, because for those individuals who have an IBD and who are sensitive to salicylates (NSAIDs are derived from salicylic acid), salicylates stimulate the production of proinflammatory leukotrienes.7  It's impossible to avoid salicylates complete, because virtually all foods contain some amount.  The trick is to limit the total amount in the diet, to keep it below a certain threshold that our immune system can handle.8, 9

Taking a mast cell stabilizer, such as cromolyn sodium can help to prevent mast cells from degranulating.  Other drugs of this type include lodoxamide, nedocromil sodium, olopatadine hydrochloride, and pemirolast potassium.  These medications
work by stabilizing the membranes of mast cells.

Research shows that people who have an inflammatory bowel disease, or food allergies, often have a deficiency of diamine oxidase (DAO) enzyme.10, 11, 12  DAO serves to remove surplus histamine from circulation in the body.  If DAO is deficient, then residual histamine levels can build up to levels where histamine becomes a problem.  Therefore, in some cases, a DAO supplement may be helpful.

Corticosteroids are known to suppress inflammation, and it appears that the mechanism by which they accomplish that purpose, involves the reduction of mast cell numbers.13

Some drugs are known to interfere with the production or function of DAO, and other drugs promote the release of histamine by other means.  Examples of such drugs can be found in research articles on the internet.14

With so many ways that mast cells can be triggered to inappropriately degranulate, and other ways for histamine to build up to excessive levels in the body, it's no wonder that mast cells are a major problem for anyone who has an inflammatory bowel disease, or food sensitivities.  And for many of us, appropriately treating mast cell issues may hold the key to our remission.

1. Effects of histamine H1-, H2- and H3-receptor selective drugs on the mechanical activity of guinea-pig small and large intestine

2. Hives and Angioedema

3. Urticaria Medication

4. Mast Cells in Gastrointestinal Disease

5. Foods That Contain Histamine Or Cause The Body To Release Histamine, Including Fermented Foods

6. Histamine-Restricted Diet

7. Diarrhea Associated with Mesalamine in a Patient with Chronic Nongranulomatous Enterocolitis

8. Foods High in Salicylic Acid

9. Salicylate Sensitivity Food Guide

10. Human intestinal diamine oxidase (DAO) activity in Crohn's disease: a new marker for disease assessment?

11. Diamine oxidase activities in the large bowel mucosa of ulcerative colitis patients

12. Analysis and topographical distribution of gut diamine oxidase activity in patients with food allergy

13. Corticosteroid treatment reduces mast cell numbers in inflammatory bowel disease

14. Histamine and histamine intolerance1,2,3


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