Mast Cell Activation Syndrome (MCAS): When Histamine Goes Haywire...

Mast Cell Activation Syndrome (MCAS): When Histamine Goes Haywire...

Mast cells are present in most tissues throughout the human body, especially connective tissue, skin, intestinal lining cardiovascular system, nervous system, and reproductive organs. They are part of the allergic response designed to protect us from threat and injury.  When the body is exposed to a perceived threat, the mast cells secrete chemical mediators, such as histamine, interleukins, prostaglandins, cytokines, chemokine and various other chemicals stored in the cytoplasm of the cell.  These chemical messengers produce both local and systemic effects, such as increased permeability of blood vessels (inflammation and swelling), contraction of smooth muscle (stomach cramps and heart palpitations), and increase mucous production (congestion, sneezing, etc).   Historically, we thought of mast cells only in relation to an allergic or anaphylactic response.  We now know they play a profound role in immune activation, development of autoimmunity and many other disorders, such as POTS (postural orthostatic tachycardia syndrome).  Sadly we are seeing a large increase in patients presenting with mast cell disorders and MCAS.  I believe it is in part do to the onslaught of more pervasive environmental toxins, molds and chemicals.

Withouts mast cells, we would not be able to heal from a wound.  They protect us from injury and help the body to heal.  Unforunately, overactive mast cells can cause a variety of serious symptoms.

Symptoms of overactive mast cells may include:

• skin rashes/hives
• swelling/edema
• flushing
• itching
• abdominal pain
• nausea/vomiting
• diarrhea
• wheezing
• shortness of breath
• heart palpitations
• anxiety, difficulty concentrating
• headaches
• brain fog
• low blood pressure
• fatigue

Mast cell activation syndrome (MCAS) is a condition symptoms involving the skin, gastrointestinal, cardiovascular, respiratory, and neurologic systems. It can be classified into primary (clonal proliferation or mastocytosis), secondary (due to a specific stimulus), and idiopathic (no identifiable cause). Proposed criteria for the diagnosis of MCAS included episodic symptoms consistent with mast cell mediator release affecting two or more organ systems with hives, swelling, flushing, nausea, vomiting, diarrhea, abdominal pain, low blood pressure, fainting, heart palpitations, wheezing, red eyes, itching, and/or nasal congestion.  For a diagram of all of the varied symptoms histamine can cause, click here.

Triggers may be medications, foods, supplements, hormones, opioids, stressors (physical or emotional), cold temperature, heat, pressure, noxious odors, chemicals, insect bites, trauma or environmental toxins.

We commonly see mast cell activation syndromes associated with CIRS (chronic inflammatory response syndrome) in response to biotoxins, such as mold, inflammagens, and lyme-related toxins.

 

Low MSH and Mast Cell Disorders?

As mentioned above, we frequently see histamine intolerance and MCAS in patients with mold-related CIRS (chronic inflammatory response syndrome).  It is interesting to note that a common finding in CIRS is low MSH.  According to this study in the Journal of Investigative Dermatology, alpha-MSH plays an immunomodulatory role during inflammatory and allergic reactions of the skin.  In addition, there is evidence that MSH induces mast-cell apoptosis (cell death).

 

Definition of Mast Cell Activation Syndrome (MCAS)

1. Typical clinical symptoms as listed above
2. Increase in serum tryptase level or an increase in other mast cell derived mediators, such as histamine or prostaglandins (PGD2), or their urinary metabolites,
3. Response of symptoms to treatment

Mast cells can be activated by both direct and indirect mechanisms as a result of exposure of the host to pathogens.

Diseases Associated with Mast Cell Activation Syndrome (MCAS)

• Allergies and Asthma
• Autism
• Autoimmune diseases (Hashimoto's thyroiditis,  systemic lupus, multiple sclerosis, bullous pemphigoid, rheumatoid arthritis and others.Eczema
• Celiac Disease
• Chronic Fatigue Syndrome
• CIRS (chronic inflammatory response syndrome)
• Eosinophilic Esophagitis
• Fibromyalgia
• Food Allergy and Intolerances
• Gastroesophageal reflux (GERD)
• Infertility (mast cells in endometrium may contribute to endometriosis)
• Interstitial Cystitis
• Irritable Bowel Syndrome (IBS)
• Migraine Headaches
• Mood disorders - anxiety, depression, and insomnia
• Multiple Chemical Sensitivities
• POTS (postural orthostatic hypotension)

Mast cells are known to be the primary responders in allergic reactions, orchestrating strong responses to minute amounts of allergens. Several recent observations indicate that they may also have a key role in coordinating the early phases of autoimmune diseases, particularly those involving auto-antibodies.

Lab Tests for Mast Cell Activation Syndrome (MCAS)

• Lab tests specific to mast cell activation for suspected MCAS may include:
  • Serum tryptase (most famous mast cell mediator)
  • Serum chromogranin A
  • Plasma histamine
  • Plasma PGD2 (chilled)
  • Plasma heparin (chilled)
  • Urine for PGD2 (chilled)
  • PGF2a
  • N-methylhistamine
• Tryptase is the most famous mast cell mediator. Serum tryptase value is usually normal in MCAS patients, but sometimes it is elevated.  Tryptase values that show an increase of 20% + 2 ng/ml above the baseline level are considered diagnostic for MCAS.
• Chromogranin A is a heat-stable mast cell mediator.  High levels can suggest MCAS, but other sources must first be ruled out, such as heart failure, renal insufficiency, neuroendocrine tumors and proton pump inhibitor (PPI) use.
• Heparin is a very sensitive and specific marker of mast cell activation.  However, due to its quick metabolism in the body, it is very difficult to measure reliably.
• N-methylhistamine is usually measured in a 24 hour urine test to account for the variability in release over the course of the day.
• Prostaglandin D2 is produced by several other cell types, but mast cell release is responsible for the dominant amount found in the body.  PGD2 is less stable than histamine and metabolized completely in 30 minutes.
• Other less specific mast cell mediators that are sometimes abnormal in MCAS patients include Factor VIII, plasma free norepinephrine, tumor necrosis factor alpha, and interleukin-6.

 

Treatments to reduce MCAS symptoms and lower histamine

• H1 Blockers
  1. hydroxyzine, doxepine, diphenhydramine, cetirizine, loratadine, fexofenadine
• H2 Blockers
  1. Famotidine (Pepcid, Pepcid AC)
  2. Cimetidine (Tagamet, Tagamet HB)
  3. Ranitidine (Zantac)
• Leukotriene inhibitors
  1. Montelukast (Singulair)
  2. Zafirlukast (Accolate)
• Mast cell stabilizers -
  1. Cromolyn
  2. Ketotifen
  3. Hyroxyurea
• Tyrosine kinase inhibitors - imatinib
• Natural anti-histamines and mast-cell stabilizers
  • Ascorbic Acid
  • Quercetin
  • Vitamin B6 (pyridoxal-5-phosphate)
  • Omega-3 fatty acids (fish oil, krill oil)
  • Alpha Lipoic Acid
  • N-acetylcysteine (NAC)
  • Methylation donors (SAMe, B12, methyl-folate, riboflavin)
• Certain probiotics decrease histamine production
  • Lactobacillus rhamnosus and bifidobacter species 
• DAO Enzymes with meals - Xymogen HistDAO or Histamine
• Decrease consumption of high histamine foods (more on histamine-restricted diet)
  • Avoid alcoholic beverages
  • Avoid raw and cured sausage products such as salami.
  • Avoid processed or smoked fish products. Use freshly caught seafood instead.
  • Avoid pickles
  • Avoid citrus fruits.
  • Avoid chocolate
  • Avoid nuts
  • Avoid products made with yeast and yeast extracts
  • Avoid soy sauce and fermented soy products
  • Avoid black tea and instant coffee
  • Avoid aged cheese
  • Avoid spinach in large quantities
  • Avoid tomatoes, ketchup and tomato sauces
  • Avoid artificial food colorings & preservatives
  • Avoid certain spices: cinnamon, chili powder, cloves, anise, nutmeg, curry powder, cayenne pepper

Specific Symptom Treatment in MCAS

(Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options)

• Headache⇒ paracetamol; metamizole; flupirtine
• Diarrhea⇒ colestyramine; nystatin; montelukast; ondansetron
• Colicky abdominal pain ⇒ metamizole; butylscopolamine
• Nausea⇒ metoclopramide; dimenhydrinate; 5-HT3 receptor inhibitors; icatibant
• Respiratory symptoms (mainly increased production of viscous mucus and obstruction with compulsive throat clearing) ⇒ montelukast; acute: short-acting albuterol
• Gastric complaints⇒ proton pump inhibitors
• Osteoporosis, bone pain⇒ biphosphonates, Vitamin D plus calcium
• Non-cardiac chest pain⇒  H2-histamine receptor antagonist; proton pump inhibitors
• Tachycardia⇒ verapamil; AT1-receptor antagonists; ivabradin
• Neuropathies ⇒ a-lipoic acid
• Interstitial cystitis⇒ pentosan, amphetamines
• Sleep-onset insomnia/sleep-maintenance insomnia⇒ triazolam/oxazepam
• Conjunctivitis⇒ preservative-free eye drops with glucocorticoids for brief course
• Elevated prostaglandin levels, persistant flushing⇒ incremental doses of acetylsalicylic acid (50-350 mg/day; extreme caution because of the possibility to induce mast cell degranulation)

References

1. Mast Cell Activation Syndrome, A Review
2. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options
3. Presentation, Diagnosis and Management of Mast Cell Activation Syndrome by Dr. Afrin
4. Histamine and Gut Immune Mucosal Regulation
5. Dr. Theoharides presents “Mast Cell Disorders”
6. Diagram of Histamine Symptoms
7. Mast Cell Aware
8. A Tale of Two Syndromes
9. Mold Histamine Connection

How to Heal a Leaky Gut, Part II

Did you miss my first Leaky Gut Article?! Read more here

So now you may be wondering if you have leaky gut...

Food allergies, toxins, sugar, antibiotics, parasites and stress can wreak havoc with your gastrointestinal system, upsetting the balance in your intestine as well as allowing harmful substances to enter the system. Gas, bloating, diarrhea, constipation or abdominal discomfort may be the first clue that something is wrong with the digestive tract, but did you know allergies
or even lack of energy and fatigue can often be traced to digestive problems as well?

Normally the gastrointestinal epithelium provides a semi-permeable barrier with allows nutrients to be absorbed while preventing larger molecules from crossing into the bloodstream. When this lining becomes inflamed or damaged, then the barrier becomes "leaky". The fallout results in larger, undigested food molecules and other “bad stuff” (yeast, toxins, and all other forms of waste) that your body normally doesn’t allow through, to flow freely into your bloodstream.

Causes of increased intestinal hyperpermeability or "leaky gut":

• Medications (NSAIDS) like ibuprofen and motrin
• Microbial overgrowth or infection
• Parasite infections
• Fungal overgrowth (Candida)
• Ingestion of allergenic foods
• Maldigestion/malabsorption (pancreatic insufficieny or low HCl)
• Radiation therapy or chemotherapy
• Stress
• Aging
• IgA deficiency
• Chronic alcohol intake
• Excessive or strenuous exercise
• Inflammatory bowel disease - Crohn's or Ulcerative colitis

The small and large intestines contains numerous dietary and bacterial products with toxic properties. These include bacteria, bacterial cell wall (LPS), peptides, and bacterial antigens capable of inducing antibodies which may cross-react with human tissues.... when these antibodies react, they may form systemic immune complexes which can circulate and deposit in tissues far away from the gut.

Abnormalities of the gut lining barrier lead to increased uptake of inflammatory molecules and pathogenic bacteria. With inflammation & injury to the gut lininng, mucosal absorption of normally-excluded substances increases dramatically. Intestinal inflammation enhances the uptake and distribution of potentially injurious bacteria and proteins .

Leaky Gut is seen in disorders such as:

• Inflammatory bowel disease (Crohn's & Colitis)
• Inflammatory joint disease
• Food allergy
• Celiac disease
• Rheumatoid arthritis
• Ankylosing spondylitis
• Reiter’s syndrome
• Eczema & psoriasis
• Bipolar, depression and schizophrenia
• Allergies and asthma
• Autoimmune thyroiditis
• Multiple sclerosis
• Autoimmune liver & gallbladder disease

So how do we test for "Leaky Gut"?

Small molecules (glucose or mannitol) readily penetrate cells and passively diffuse through them. Larger molecules such as lactulose are normally are normally not able to diffuse through the cell. If the tight junctions between the cells are functioning properly, they will prevent the lactulose from leaking through. The Intestinal Permeability Test directly measures the ability these two sugar molecules—mannitol and lactulose—to permeate the intestinal mucosa.

Mannitol is readily absorbed and serves as a marker of transcellular uptake. Lactulose is only slightly absorbed and serves as a marker for mucosal integrity (ability of those "tight junctions" to keep out the bad stuff) The test is a 6 hour urine test that compares ratios of the two substances.

For more info:

Genova Diagnostics Intestinal Permeability Assessment
You will need to contact your functional medicine physician in order to order the test.
Now for some treatment options for this leaky gut!

Nutritional Support

1. Glutamine, an amino acid, has been shown to reverse intestinal mucosal damage from various insults. Glutamine is the principle fuel used by the upper intestinal tract to repair and heal.
2. Agents that stimulate protective mucus secretion may also help with the healing. Some common ones I use are marshmallow root extract and deglycyrrhizinated licorice (DGL) extract.
3. Probiotics are essential! Lactobacillus casei, bifidobacter species, and saccromyces boulardii, a beneficial type of yeast are all important to restore gut health.
4. Fish oil can be very helpful in the treatment of intestinal inflammation by decreasing inflammatory prostaglandins. EPA and DHA should be used in the range of 2-4gm daily
5. Quercetin functions as a natural mast cell stabilizer and decrease release of histmine which contributes to inflammation & injury. To be effective, quercetin should be used in powder form and taken 3-6gm daily.
6. Vitamins A and D are critical to supporting secretory IgA function and restoring the mucosal immune system. Ask your doctor for specific doses...

To Decrease Toxic Load:

• Eliminate all known foods that you are sensitive to. This can be determined through a comprehensive elimination diet or IgG/IgE food tests on the blood.
• Avoid alcohol, NSAIDS (ibuprofen, motrin, alleve), and minimize other medications.
• Bentonite clay is a well-known intestinal adsorbent which absorbs numerous toxins, endotoxins and bacteria. Its value in permeability alterations may result from lowering the toxin load in the lumen, thus facilitating repair. I also frequently recommend Upgraded charcoal tabs for the same purpose.
• HCI and digestive enzymes such as plant enzymes, pepsin and pancreatin might help to lessen the antigenic load or toxic molecules being presented on the intestinal lining.

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Photo courtesy of www.freedigitalphotos.net

FODMAPs?! The Diet That May Eliminate Your IBS Symptoms!

Are you looking for relief from your IBS symptoms?

Symptoms of Irritable Bowel Syndrome include abdominal bloating and distension, excess wind (flatulence), abdominal pain, nausea, changes in bowel habits (diarrhea, constipation, or a combination of both), and other gastrointestinal symptoms.

What are the FODMAPs?

FODMAPs are found in the foods we eat. FODMAPs is an acronym for:

• Fermentable
• Oligosaccharides (eg. Fructans and Galactans)
• Disaccharides (eg. Lactose)Monosaccharides (eg. excess Fructose)
• Polyols (eg. Sorbitol, Mannitol, Maltitol, Xylitol and Isomalt)

This is a collection of molecules found in food, that can be poorly absorbed by some people. When the molecules are poorly absorbed in the small intestine of the digestive tract, these molecules then continue along their journey along the digestive tract, arriving at the large intestine, where they act as a food source to the bacteria that live there normally. The bacteria then digest/ferment these foods and can cause symptoms of Irritable Bowel Syndrome.

Where are FODMAPs found?

• Excess Fructose: Honey, Apples, Mango, Pear, Watermelon, High Fructose Corn Syrup, Corn Syrup Solids
• Fructans: Artichokes (Globe), Artichokes(Jerusalem), Asparagus, Beetroot, Chicory, Dandelion leaves, Garlic (in large amounts), Leek, Onion (brown, white, Spanish, onion powder), Raddicio lettuce, Spring Onion (white part), Wheat (in large amounts), Rye (in large amounts), Inulin, Fructo-oligosaccharides.
• Lactose: Milk, icecream, custard, dairy desserts, condensed and evaporated milk, milk powder, yoghurt, margarine, soft unripened cheeses (eg. ricotta, cottage, cream, marscarpone).
• Galacto-Oligosaccharides (GOS): Legume beans (eg. baked beans, kidney beans, bortolotti beans), Lentils, Chickpeas
• Polyols: Apples, Apricots, Avocado, Cherries, Longon, Lychee, Nectarines, Pears , Plums, Prunes, Mushrooms, Sorbitol (420), mannitol (421), xylitol (967), maltitol (965) and Isomalt (953).

The most common FODMAP is fructose!

What is fructose?

Fructose is a monosaccharide, or single sugar. It is found in three main forms in the diet as:

• fructose in fruits, honey and some root vegetables
• part of the disaccharide, or double sugar, sucrose. Sucrose is made up of glucose and fructose.
• Sucrose is also known as table sugar.
• fructans in some vegetables and wheat. Fructans are short chains of fructose. They are also called inulins and fructo-oligosaccharides.

Fructose is the sweetest of all naturally occurring carbohydrates. For this reason it is often added as a sweetening ingredient in prepared foods. Since it is sweeter than table sugar, smaller amounts of fructose are needed to get the same sweetness.


How do I go on the FODMAPs diet?

During your elimination trial, it is recommended that you eliminate all FODMAPs either significantly or entirely. Most patients will begin to feel significantly better within a few hours and a few days, but will take up to two weeks to feel fully healthy. A minority of patients have reported that it took up to three months to fully recover. After recovery, you can begin to gradually reintroduce foods using the steps outlined at the end of this article.

Many IBS sufferers with generally mild symptoms will find that a general reduction of fructose intake alone significantly relieves them of their symptoms. Other individuals will find that they must significantly reduce their intake of all FODMAPs to experience relief. You may find over time that eating certain FODMAPs does not bother you.

Finally, it should be noted that fructose – the ubiquitous simple sugar – is often allowed in “safe foods” if the food also contains a glucose-to-fructose ratio greater than one. This is because research shows that ingesting glucose at the same time as fructose (and in the same quantities as fructose) eases fructose absorption.

Is it dangerous to limit fructose intake?

In short: no. While carbohydrates are an essential source of energy, refined sugars are anything but and current research shows that fructose may be best ingested in strict moderation.

Further, some sources report that a modern diet contains upwards of ten times the amount of sugar humans ingested for much of evolution. This may help to explain why fructose malabsorption is found in up to 40% of inhabitants of western countries. You will still be ingesting a significant level of glucose and other carbohydrates. Overall, limiting your fructose intake will likely be beneficial to your health. But when in doubt, listen to your body (and, of course, doctor). It is also not inherently dangerous to limit other FODMAPs, but missing out on whole food groups could easily lead to a diet missing in nutrients and lacking in vitamins.

Which foods contain FODMAPs?

The best way to determine the fructose content of a given food is to use publicly available USDA data.

To save you some time, and to bring your attention to foods which contain non-fructose FODMAPs, the list below names some foods that you will definitely want to avoid at least initially. .

Fruits

Most fruits which are excluded are excluded due to excessive fructose content, or greater than a 1:1 Fructose:Glucose ratio. Also, some contain Polyols.

• Apples
• Apricots
• Cherries
• Mango
• Pears
• Nectarines
• Peaches
• Pears
• Plums and prunes
• Watermelon
• High concentration of fructose from canned fruit, dried fruit or fruit juice

Grains

• Rye
• Wheat

Lactose-Containing Foods

• Custard
• Ice cream
• Margarine
• Milk (cow, goat, sheep)
• Evaporated milk
• Condensed milk
• Milk powder
• Soft cheese, including cottage cheese and ricotta
• Yogurt
• Greek yogurt

Legumes

• Many legumes contain Galacto-Oligosaccharides (GOS).
• Baked beans
• Chickpeas
• Lentils
• Kidney beans

Sweeteners

• Sweeteners which end in -ol are excluded because they are fermentable polyols.
• Fructose
• High fructose corn syrup
• It should be noted that HFCS actually only contains marginally more fructose than glucose as compared to refined sucrose. It is included in this list only because it was found on another list (better safe than sorry), and because it still has a F:G ratio greater than 1. The accuracy of this entry will be checked soon for validity.
• Corn syrup solids
• See above
• Palm sugar
• Honey
• Agave nectar
• Isomalt
• Maltitol
• Mannitol
• Sorbitol
• Xylitol

Vegetables

• Vegetables may be on this list for containing fructans.
• Artichokes
• Asparagus
• Avocado
• Beets
• Broccoli
• Brussel sprouts
• Cabbage
• Cauliflower
• Garlic
• Garlic is possibly okay to consume, but should not be ingested in large quantities.
• Fennel
• Leeks
• Mushrooms
• Okra
• Onions
• Onions have recently been reported to be especially troublesome. It is best to completely avoid them.
• Peas
• Radiccio lettuce
• Scallions (white parts)
• Shallots
• Sugar snap peas
• Snow peas

So, what’s safe to eat?
It’s best to obtain your calories principally from a source that is indisputably fodmap-friendly (such as rice or meat). In moderation, however, the following foods are safe to eat on a low-FODMAP diet.

Fruits

• Banana
• Blueberry
• Grapefruit
• Grapes
• Honeydew melon
• Kiwi
• Lemon
• Lime
• Mandarine oranges
• Orange
• Raspberry
• Strawberry

Sweeteners

• Artificial sweeteners that do not end in -ol
• Glucose
• Maple syrup
• Sugar (sucrose)

Lactose Alternatives 

• Butter
• Hard cheeses
• Brie (exceptional cheese)
• Camembert (exceptional cheese)
• Lactose-free products, such as lactose-free ice cream and yogurt
• Gelato
• Rice milk
• Sorbet

Vegetables

• Bok choy
• Carrots
• Celery
• Corn
• Eggplant
• Green beans
• Lettuce
• Parsnip
• Scallions (green parts only)
• Tomato
• Reintroducing foods/Moving beyond the elimination phase

Once you are symptom-free, you may attempt to reintroduce foods in order to determine exactly what was causing your symptoms. There are really no established guidelines on how to best do this – it varies from individual to individual. Key concepts, however, follow:

1. Write it down! Be scientific. Keep a food diary. Your future self will thank you.
2. Only reintroduce one food at a time.
3. Wait ~72 hours for symptoms to reappear before moving on to the next food