September 2014: Post summaries and take home points

Effects of estrogen and progesterone and the role of mast cells in pregnancy

  • Estrogen and progesterone have many functions in the reproductive system and outside of the reproductive system.
  • The activity of progesterone is amplified by estrogen.
  • Estrogen levels can make cells more responsive to progesterone.
  • Mast cells express receptors for both estrogen and progesterone.
  • Estrogen and progesterone both induce mast cell degranulation individually.
  • Estrogen and progesterone together induce more mast cell degranulation.
  • During pregnancy, secretion of histamine by uterine mast cells is induced.
  • Mast cell degranulation increases uterine contractility.
  • Allergic reactions can induce uterine contractions.
  • Severe allergic reactions may be responsible for pre-term labor.
  • Asthmatic pregnant women are at higher risk of pre-eclampsia.
  • 30-40% asthmatic women have more symptoms during premenstrual period.
  • Women taking hormone replacement have higher risk of new onset asthma.
  • Many women with mast cell disease report more degranulation when menstruating.
  • A 2011 study found that only 6.7% of women with SM delivered prematurely, compared to 7.4% in the general population.

Mastocytic enterocolitis

  • First named in 2006.
  • Refers to having increased mast cells in the GI tract mucosa.
  • Usually causes chronic diarrhea and abdominal pain.
  • Increase in mast cells not associated with SM or CM.
  • The original paper defined mastocytic enterocolitis as more than 20 mast cells/hpf.
  • However, there is not a consensus on what is a “normal” amount of mast cells in the GI mucosa.
  • Some healthy controls have more than 20 mast cells/hpf.
  • Some MCAS patients have mast cell counts in GI tract of 17-23/hpf.

Gastrointestinal manifestations of SM: Part 1

  • 80% of SM patients experience GI symptoms.
  • 11% have GI bleeding.
  • Abdominal pain in SM is usually either upper abdominal pain or lower abdominal cramping.
  • 23% of SM patients have peptic ulcer disease.
  • 85-100% of SM patients have elevated histamine production.
  • Some SM patients produce too much acid, some too little, and some normal amount.
  • In those who overproduce, the levels can be extremely high.
  • 28% of SM patients have esophageal abnormalities.

Gastrointestinal manifestations of SM: Part 2

  • Thought that at least 30% SM patients have abnormalities in small bowel.
  • Many types of abnormalities in GI biopsies of SM patients.
  • 5-25% of SM patients have malabsorption due to small intestine defects.
  • One study found 67% of SM patients have elevated fat excretion in feces.
  • SM patients may have malabsorption of fat soluble vitamins.
  • 20% of SM patients have colon abnormalities.
  • 19% of SM patients have had diverticulitis.
  • Elevated PGD2 may cause diarrhea.

MCAD, MCAS and the hierarchy of mast cell disease classifications

  • MCAD (mast cell activation disease) is a catch-all term for mast cell disease.
  • MCAS (mast cell activation syndrome) is the diagnosis you get if you have evidence of elevated mediator release but don’t meet the criteria for other mast cell diseases.
  • If you have UP: you have UP, you have CM, you have MCAD.
  • If you have TMEP: you have TMEP, you have CM, you have MCAD.
  • If you have SM: you have SM, you have MCAD.
  • If you have SM with UP: you have SM with skin involvement, you have UP, you have MCAD.
  • If you have SM with TMEP: you have SM with skin involvement, you have TMEP, you have MCAD.
  • If you have SM-AHNMD: you have SM-AHNMD, you have MCAD.
  • If you have ASM: you have ASM, you have MCAD.
  • If you have MCL: you have MCL, you have MCAD.
  • If you have MCAS: you have MCAS, you have MCAD.

Neurologic symptoms of mast cell disease

  • Syncope (fainting) affects 14.3% of mastocytosis patients.
  • 6% had back pain.
  • Compression fracture is a common cause of back pain.
  • 35% had headaches.
  • Some mastocytosis patients have migraines.
  • Trigeminal neuralgia has been reported in some patients.
  • 3% of mastocytosis patients develop multiple sclerosis, compared to 0.1% of the general population.

Mast cell disease and chronic constipation

  • Diarrhea or constipation can affect mast cell patients.
  • In one study, 57% of SM patients reported at least two pseudoobstructions a year.
  • Bowel retraining is a good option for managing chronic constipation.
  • People with chronic constipation may have pelvic floor dysfunction.
  • Pelvic floor PT may help.
  • Anorectal manometry and bowel transit time tests are helpful for identifying a cause for constipation.
  • Straining to stool causes long term nerve damage, hemorrhoids, bleeding and fissures.
  • Bowel obstructions can cause rupture and are serious.
  • Many mast cell medications slow GI motility, complicating the constipation issue.

Mast cell look alikes

  • A number of conditions present similarly to mast cell disease.
  • Carcinoid tumors are slow-growing neuroendocrine tumors that may release excessive serotonin.
  • Carcinoid syndrome is diagnosed with a 24-hour urine test for 5-HIAA, a metabolite of serotonin.
  • Pheochromocytomas are neuroendocrine tumors of the adrenal gland that secrete a lot of norepinephrine.
  • Pheochromocytoma is diagnosed with 24-hour urine test for catecholamines and metanephrines.
  • Medullary thyroid cancer produces excessive calcitonin.
  • Medullary thyroid cancer is diagnosed by serum calcitonin.
  • Dysautonomia is an inherent dysfunction of the autonomic nervous system, which can cause wide ranging symptoms.
  • Dysautonomia can be secondary to another condition, like mast cell disease, or a primary condition.
  • Primary asthma can cause airway symptoms.
  • Vocal cord dysfunction can cause airway obstruction.
  • Angioedema causes swelling of any part of the body. It can be hereditary or not.
  • Irritable bowel syndrome is a diagnosis of exclusion.
  • Mast cell disease is often mistaken for anxiety or panic attacks.

Hemolytic anemia

  • A type of anemia that causes abnormal destruction of red blood cells.
  • This causes the body to break down more hemoglobin than usual.
  • Can cause high concentration of reticulocytes (immature red cells) in the blood.
  • Can have many causes, including genetic issues, certain infections, and autoimmune disease.
  • Diagnosed with blood smears. Further testing can reveal specific type.
  • Transfusions can be required in severe cases.
  • If autoimmune, long term steroids or spleen removal are sometimes necessary.

 

2 Responses

  1. kim webster July 13, 2015 / 7:51 pm

    1. A patient of mine just made me aware of MCAD so I’m slowly coming up to speed. Thus I don’t know what a lot of the acronyms are.
    up
    cm
    tmep
    sm-ahnmd
    asm
    2. Thanks for all the info. Greatly appreciate as I try to learn as much as I can
    3. I’m assuming that the impact of ” estrogen ” on mast cells is complex. There are a bunch of different estrogens in our body. The studies I looked at used Estradiol. Estriol could have a significantly different impact as I see big differences in how women react with regards to their non-mast cell mediated symptoms ( at least I think that they’re not related to mast cells ) with Estradiol vs Estriol.
    4. Is tetrabiopterin one of the things used in MCAD?
    thanks

    • Lisa Klimas July 14, 2015 / 11:59 am

      Hi, Kim,

      Sorry for the jargon. I have been working on a glossary for quick reference but it is far from complete at this time.

      CM: cutaneous mastocytosis; abnormal proliferation of mast cells in the skin, resulting in characteristic lesions
      UP: urticaria pigmentosa; a brown macular rash that may urticate when touched (Darier’s sign); the most common form of cutaneous mastocytosis
      TMEP: telangiectasia macularis eruptiva perstans: a form of cutaneous mastocytosis present almost exclusively in adults
      SM-AHNMD: systemic mastocytosis with associated hematologic non-mast cell lineage disease; a sub-category of systemic mastocytosis in which the patient also has another clonal disease of the blood, such as essential thrombocythemia, polycythemia vera, myelodysplastic syndrome, chronic myelogenous leukemia, etc
      ASM: aggressive systemic mastocytosis; a rare form of SM (affects about 3% of SM patients) marked by aggressive infiltration of organs by mast cells that can cause organ damage and ultimately failure

      Yes, that post refers to estradiol. I walk a fine line between making things simple and straightforward so that patients can understand while also providing enough detail to be meaningful to providers. I don’t always get it right.

      Mast cells cause a number of symptoms and are involved in many inflammatory and autoimmune disease processes on top of their more well known functions as allergic effector cells and immune defense, particularly against parasites. Mast cell activation can have far reaching consequences affecting virtually every system of the body. Mast cells are also heavily involved in menstruation and reproduction, and are thought to be responsible for PMS and “period” symptoms.

      MCAD (which as a classification includes both mast cell activation syndrome and systemic mastocytosis) is usually treated as follows: a second H1 antihistamine like zyrtec; an H2 antihistamine like famotidine; a mast cell stabilizer like cromolyn; and a leukotriene inhibitor like montelukast. It is important to note that it is not unusual for mast cell patients to take larger doses than the general public does, particular with antihistamines. A first generation H1 like diphenhydramine is often used for “rescue” (sudden symptoms that could progress to an episode involving degranulation symptoms affecting multiple systems). Doxepin is often used for its H1 properties. Ketotifen, which is not FDA approved for oral consumption, but can be procured through compounding pharmacies, is both a mast cell stabilizer and an H1 antihistamine. Other treatments for refractory symptoms or recurrent anaphylaxis include IM/IV benadryl, IV hydration, corticosteroids, and anti-IgE.

      However, in addition to these treatments, which are largely rendered by MDs, there is a significant presence of holistic treatments in the mast cell community. As with many holistic therapies, there have been no studies determining the efficacy of these treatments in MCAD or conditions from which we may be able to derive useful information (allergic asthma, inflammatory bowel disease, etc). Some of these treatments focus on the belief that chronic illness stems from dysregulation of epigenetic methylation, which partially determines the level of expression of many genes. Self testing for MTHFR and taking specific types of folic acid/folate based upon the results is also quite common.

      Tetrabiopterin is one of these unproven but frequently mentioned treatments. A study investigated the effects of tetrabiopterin on autism spectrum disorders and found that it ameliorated a number of troubling symptoms. There is a growing body of evidence that implicates mast cells in some aspects of the autistic phenotype, though it still requires significant study, so some patients feel that if BH4 works in autism spectrum disorders, that may be mediated by attenuating mast cell response.

      Despite a number of web sites stating the opposite, there is NO indication that improper methylation or folate metabolism causes MCAD. None. While treatment with nutraceuticals and substances like BH4 is not uncommon in the mast cell community, it is my feeling that it should not replace more conventional methods such as antihistamines and mast cell stabilizers.

      Lastly, all MCAD patients should carry two epinephrine autoinjectors at all times. The risk of anaphylaxis (well studied in SM but not yet in MCAS) is not insignificant and anaphylaxis often evolves into biphasic or protracted episodes in this population. Delay in administration of epinephrine is the single unifying factor when comparing death by anaphylaxis across groups, so carrying and knowing how to administer epinephrine is crucial.

      i hope this clarifies things for you and helps your patient. If you have any further questions, please feel free to comment back or email me directly at Lisa.Klimas@gmail.com.

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