Histamine and Mast Cell Activation Disorder - Your weird symptoms finally answered

I like to think of Mast Cell Activation Disorder (MCAD) as the “weird” and “strange” symptoms disorder. Since MCAD can affect nearly any organ in the body, the symptomology is incredibly vast, diverse, and unique to the individual. If you or your doctor are not aware of this illness, then your symptoms may appear seemingly unrelated, as did mine.

Full Disclosure: I was diagnosed with Mast Cell Activation Syndrome. You can read a little bit about it here. *Some of the information isn’t referenced, and that is because I got a lot of the information directly from my addendum written by Dr. Afrin, who is a pioneer in MCAD.

 

What is Mast Cell Activation Disorder (MCAD)?

MCAD is the broad term used to describe a number of disorders related to mast cells functioning improperly. Just like there are different forms of Inflammatory Bowel Disease (Crohn’s and ulcerative colitis), there are different forms of MCAD, including the following: systemic mastocytosis (SM), mast cell activation syndrome (MCAS), and mast cell leukemia (MCL). Systemic Mastocytosis tends to show up in middle age or early adulthood, while MCAS tends to present symptoms in childhood or adolescence. MCAS symptoms usually shows up early in life, and then after a stressful event, symptoms may begin to get worse.

To understand what MCAD is, it’s best to understand what mast cells are.  Mast cells are a type of immune cell that play central roles in adaptive and innate immune responses. Mature mast cells can be found all over the body, including but not limited to vascularized tissue, skin, airways, bone marrow, and the gastrointestinal tract. When activated, they have the ability to release over 200 mediators, which can cause a variety of responses in the body. One of the most well-known responses is the activation of mast cells role in allergic reactions.

Tryptase is the most abundant mediator and secretory granule released from mast cells, which is why it is the gold standard for diagnosing mast cell activation disorder. Tryptase itself has the ability to stimulate mast cell degranulation and histamine release, which could be a vicious cycle. (1)

Tryptase plays a major role in allergic and inflammatory conditions like rhinitis, conjunctivitis, and asthma. It’s also likely a factor in gastrointestinal, dermatological, and cardiovascular disorders. (2)

Mast cells also have the ability to produce and release histamine, prostaglandins, leukotrienes, and other inflammatory cytokines. The complexity of the mediators released from mast cells and the location in which they act leads to diverse symptoms.

This is not a complete list, but here are some clinical signs and symptoms of MCAD:

Abdominal pain, cramping, bloating, diarrhea, nausea, chest pain, gastritis, malabsorption, cough, asthma-like symptoms, rhinitis, sinusitis, conjunctivitis, difficulty focusing vision, splenomegaly, elevated liver enzymes, hypercholesterolemia, blood pressure irregularity, headache, neuropathic pain, difficulty concentrating, forgetfulness, brain fog, lightheadedness, tinnitus, hives, urticarial pigmentosa, pruritus, flushing, muscle pain, osteoporosis, osteopenia, bone pain, arthritis, fatigue, fever, environmental sensitivities. (3)

 

Histamine and Histamine Intolerance

I believe that histamine and histamine intolerance is what people first learn about when they are feeling sick and trying to figure out why certain foods or environmental triggers cause reactions.  From there, they may try a low-histamine diet and feel better. However, symptoms may continue to progress, and then later on, possibly months or years later, they learn that the real culprit to their illness is MCAD. Since histamine plays such a huge role in the symptomology of MCAD, it’s important to discuss it here.

Histamine is synthesized by the B6 dependent enzyme L-histidine decarboxylase (HDC) from the amino acid histidine. Histamine is synthesize by not only mast cells, but also basophils, platelets, and other cells, and it’s well known for triggering mast cell degranulation.

Histamine elicits effects by binding to 4 different histamine receptors (H1, H2, H3, H4) located on cells of various tissues. Histamine causes many physical changes, including muscle cell contraction, vasodilation, increased vascular permeability, mucus secretion, tachycardia, arrhythmias, gastric acid secretion, and plays various roles in biological processes such as wound healing and circadian rhythm. 

Short summary on each of the histamine receptors:

H1: found in smooth muscle and endothelial cells. Some functions include allergic responses, vasodilation, and circadian rhythm.

H2: found in gastric parietal cells. Major function in stimulating the secretion of gastric acid.

H3: found in the central nervous system. Major function includes neurotransmitter release.

H4: found on mast cells, eosinophils, T cells, dendritic cells. Major function includes regulating immune responses.

It’s really important to understand that while H1 and H2 antihistamines are a standard treatment for MCAD, you can see that histamine will still be able to bind to H3 and H4 receptors and create havoc. It’s even more important to understand that mast cells themselves have H4 receptors, and when histamine binds to an H4 receptor on a mast cell, it can cause them to release more mediators.  We currently don’t have a suitable H4 blocker drug yet, at least that I’m aware of.

Headaches can be induced by giving both healthy and susceptible patients certain doses of histamine. Histamine headaches are vascular headaches, and caused by the binding of histamine to H1 receptors. Increased numbers of mast cells in the brain is associated with migraine, cluster headaches, and multiple sclerosis. Low histamine diets and antihistamines reduce or alleviate headaches. (4)

Histamine intolerance “might” be different than MCAD, since histamine intolerance has more to do with the ability to breakdown and metabolize histamine. If the body can’t break down histamine effectively and efficiently, then histamine levels can increase and lead to symptoms.

Common symptoms of histamine intolerance include:

diarrhea, headache, nasal congestion, hypotension, arrhythmia, urticarial, pruritis, flushing, urticarial pruritus, flushing. These symptoms are also synonymous with MCAD for obvious reasons. It’s estimated that about 1% of the population has histamine intolerance.

 

Metabolizing Histamine (DAO and HNMT)

Diamine oxidase (DAO) is the main enzyme that degrades ingested histamine. Histamine N-methyltransferase is the enzyme that helps to degrade histamine inside of cells. Reduced DAO activity can lead to higher levels of histamine in the body. Eating foods that are high in histamine can stimulate mast cell activation, or eating foods that block DAO may lead to increased symptoms in those that are susceptible. Following a low-histamine diet and/or taking antihistamines can reduce or eliminate some symptoms.

Histamine intolerance is generally caused by genetic mutations or some other impairment of the enzymes that help metabolize histamine. Genetic mutations in DAO or HNMT may lead to increased histamine levels. Certain single-nucleotide polymorphisms (SNPs) in the gene that codes for DAO is associated with inflammatory diseases, such as food allergies, gluten-sensitivity, Crohn’s disease, ulcerative colitis, and colon adenoma. Histamine intolerance mostly seems to present itself through inhibited DAO activity, and not so much HNMT. (4)

Gastrointestinal diseases that are characterized by altered and damaged enterocytes may cause a decrease in the production and availability of DAO to degrade histamine. So, while you may not have any genetic mutations for the genes that code for DAO or HNMT, you may still have lower levels of DAO if your gut is damaged.

 

Criteria for Diagnosing MCAD

The criteria for diagnosing which form of MCAD (i.e. Systemic Mastocytosis vs. MCAS) a patient has is slightly different from one another. Without going in to too much detail here, I will briefly discuss what doctors will mostly be looking for.

The first thing that needs to be carefully and diligently reviewed, is a complete patient medical history starting from birth. Doctors and patients need to discuss every single symptom a person has had through their entire life, but mostly focusing on what seems unusual, such as lots of ear infections, nasal congestion, stomach issues, headaches, hives, itchiness, etc; things that stick out when comparing to other people of the same age. Usually with MCAS, inflammatory symptoms start during early childhood and adolescence, and progress through age. If a patient has Systemic Mastocytosis, it’s more likely that symptoms came on rather suddenly, and usually somewhere around middle age or a little sooner. However, this is just generally speaking, so this thinking isn’t set in stone.

After going through a complete and thorough health history, the next step is testing, and lots of it. During a physical examination, the doctor will likely do a scratch test to look for dermatographism. 

By JAguayo18 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=48386362

By JAguayo18 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=48386362

The blood and urine testing is detailed and specific. One of the hallmarks of MCAD is a persistent elevated serum total tryptase greater than 20 ng/ml. Other elevated mediators include histamine, prostaglandins, heparin, chromogranin A, and leukotrienes.

The other tests are a bit more complicated and more invasive. One test is looking at biopsies taken from different tissues. In my case, I’ve had a few colonoscopies with biopsies and they were able to get samples taken from 6 years ago, restain them, and check for abnormalities in the quantity and/or quality of mast cells. If there are dense aggregates of mast cells or irregularities seen, this would be another indication of MCAD.

If it looks like your MCAD is leaning towards Systemic Mastocytosis, the doctor may order a bone marrow biopsy and aspiration. It’s not fun, it hurts (I had to do it). However, it’s pretty quick and over in about 10 minutes. The pain comes in short bursts every 15 seconds or so and lasts a few seconds at a time, so it’s manageable. You’ll likely need bone marrow biopsies from each side of the hip (iliac crest), and then in my case, I had 4 bone marrow aspirations from each side. Again, they are looking for abnormalities in mast cells, but also checking for different genetic mutations such as the Kit codon 816 mutation.

In order to be diagnosed with MCAD, 2 or 3 of the tests need to be positive (abnormal), as well as a medical history that points towards the illness. Also, it’s common for testing to come back negative, which is why retesting is usually a good idea. Even if all of your tests come back negative for MCAD, it doesn’t necessarily mean you don’t have the condition. It’s a pretty detailed a long process, but it’s worth it.

Mast cell leukemia (MCL) is rare and is characterized by higher levels of mast cells in the bone marrow and in circulation (≥20%). MCL has a poor prognosis, and most patients who are diagnosed with MCL have less than 1 year to live. While both Systemic Mastocytosis and MCL are rare disorders, MCAS may actually be relatively common.

 

Treatment for MCAD

*You need to talk to a doctor before starting any of the mentioned supplements or drugs, whether they are OTC or not. MCAD is a complicated illness, and you don’t want to be making things worse.

 

Unfortunately, MCAD is not curable. Some patients are lucky to find therapies that work within the first few months of trying them, while other take years to figure out what medications and treatments work for them. Avoiding triggers, antihistamines, and mast cell stabilizers are the main treatments. It takes about 4 weeks to see results once a therapeutic dosage tailored to the individual is reached. (3)

Mast cells produce and release over 200 mediators, and currently, only a few of these mediators are being targeted by drug or herbal therapy. This makes it difficult because if lab test results show elevated prostaglandins, then logically, one would believe that non-steroidal anti-inflammatory drugs (NSAIDS, i.e. ibuprofen) would greatly improve symptoms. However, this isn’t the case, because of the complexity and nature of MCAD. This is why I believe mast cell stabilizers are so important. 

Due to the nature of MCAD, patients can react to just about anything, which is why it can be difficult to find exactly which medications and treatments work for them.  As an example, one person may have reactions to all of the brands selling loratidine (generic Claritin), except for the children’s version of loratidine sold at CVS. The antihistamines and active ingredients in medications generally aren’t the cause of reactions, the fillers, binders, dyes, etc. are what cause reactions. It’s important to try out different brands of the same drug, because they all tend to use different inactive ingredients, which can be helpful for those with MCAD.

Treatment: Avoid Triggers

The first line of treatment is to identify all of the triggers (chemical, food, environment, physical, etc.), and avoid them as much as humanly possible. This can take a long time. It requires you to know you’re body very well, and be mindful of how you feel each day. I recommend keeping a health journal for quite some time (6 months, 1+ year), until you have a good grasp of what causes reactions or makes symptoms flare up. You’ll need to pay attention to exactly what you eat, the quantities, how much sleep you’ve gotten, the smells you’ve encountered, physical activity, pretty much anything and everything. Over time you’ll know what you can and can’t do. At some point after “successful” treatment, it’s likely that you’ll be able to tolerate more of the things that trigger reactions.

Treatment: Diet

Pretty much what you see here is a big no-no if you've got MCAD.

Pretty much what you see here is a big no-no if you've got MCAD.

Diets should be treated as an intervention, and it’s important to avoid extreme dieting if possible. If a diet, (i.e. low-histamine diet) does not seem to be helpful after a month or so, then it should be discontinued. With MCAD, low-histamine diets generally help, but people can react to other things besides high histamine foods, like gluten or whole grains. Sometimes it’s not even the food itself, it might actually be the pesticides and herbicides; even if it’s organic pesticides.  Also, if the diet does not seem reasonable and attainable, in which it completely interferes with life, then it may be a good idea to not follow it or not follow it 100% of the time. In most cases, I believe that a lower histamine diet will help, but if possible, be sure that you are getting all of the nutrients (vitamins, minerals, calories) you need in order to live. Extreme diets and elimination diets are just that, eliminating foods, which means that’s less options of getting the nutrients you need. Some patients can’t tolerate any foods, and sometimes medications don’t help with it. In those cases, some patients can’t eat and need enteral tube feeding, and rarely, parenteral nutrition is needed.

I recommend trying a low histamine diet for a month or so to see if you have any improvements. If you are unsure if you have issues with histamine or mast cell activation, then a low histamine diet can actually be a tool to help diagnose MCAD.

Although there are a few different lists and guides for eating low histamine, I like the one created by the Mastocytosis Society Canada. Click here to download the pdf.

Treatment: Supplements

There are a variety of supplements that have been shown to stabilize mast cells and help prevent them from releasing mediators so easily, inhibit histamine by some mechanism, and/or decrease inflammation.

*As always, consult your doctor before trying any of these supplements. Also, be careful. With MCAD you can react to just about anything.

Quercetin and other Flavonoids

Flavonoids are known for their antioxidant and anti-inflammatory roles.  Some flavonoids have been found to inhibit histamine release from mast cells. Quercetin and rutin have been found to inhibit histamine release and prevent elevated intracellular calcium, and decrease the production of proinflammatory cytokines. (5)

Quercetin is also a mast cell stabilizer. In human cultured mast cells, luteolin inhibits the release of histamine, leukotrienes, and prostaglandins from mast cells, and decreases the production of TNF-α and other proinflammatory cytokines in bone marrow cultured murine mast cells. (6)

Vitamin C

Vitamin C inhibits mast cell production, increases the breakdown and degradation of histamine, and decreases histamine synthesis by inhibiting histidine decarboxylase (the enzyme that forms histamine)

Started at 750-1000 mg once a day, slow-releasing or an extended release form is best, some patients find it better and tolerable to take this dose twice daily.

Vitamin D

Vitamin D; mast cells contain vitamin D receptors, and activation of the vitamin D receptor has been shown to decrease inflammation.  Some patients see improvement in taking vitamin D, and 1,000 IU per day seems to be a reasonable dose that should be safe. Also, changes in bone density is common in those with MCAD, such as osteopenia, osteoporosis, and/or osteosclerosis.

Diamine Oxidase (DAO)

DAO supplements have helped some patients.  The supplements are dosed in terms of histamine-degrading units (HDU). HistDAO can be taken at 20,000-40,000 HDUs (1-2 caps) 15 minutes before a meal.

Curcumin

Curcumin is found in turmeric, and probably one of the most (if not the most) recognized natural anti-inflammatory.  The USDA has approved curcumin as GRAS (generally recognized as safe) status, so that’s always nice to hear.

A study on mouse bone marrow derived mast cells found that curcumin inhibits cyclooxygenase-2 (COX-2) dependent prostaglandin D2 (PGD2) and 5-lipoxygenase (5-LO) dependent leukotriene C4 (LTC4) in mouse mast cells. Curcumin also inhibits intracellular calcium influx and nuclear factor- κB (NF-κB). PGD2 plays an important role in inflammation and allergic diseases. Studies have shown that curcumin inhibits mast secretion of histamine, tumor necrosis factor-α (TNF- α) and interleukin-4 (IL-4). It also inhibits other IgE-induced reactions. (7) In rat models, curcumin improves rhinitis, and lowers histamine. (7) Curcumin also inhibits the production of interleukin (IL) -1, IL-2, IL-6, IL-8, and IL-12, and it’s good for ulcerative colitis and arthritis. (8)

Curcumin can help with wound healing and has antimicrobial activities. As you can tell, it is likely and has been shown to be beneficial for a wide variety of conditions, including cancer and autoimmune conditions. Piperine increases the bioavailability of curcumin by 2,000%. Meriva is a patented version of curcumin mixed with soy phosphatidylcholine that is 29 times more bioavailable than curcumin alone. This means that you need to take a lot less Meriva compared to regular curcumin in order to reach the same effect. Interestingly, curcumin becomes more bioavailable when it’s mixed back with some of the other components of turmeric, which means turmeric might be suitable or more suitable than curcumin. Either way, I recommend trying curcumin without added ingredients first, since those with MCAD can react to just about anything.

*PLEAE NOTE:  Curcumin was found to decrease DAO levels, so it may worsen things. (9)

As with all supplements and drugs, there’s the possibility of adverse effects. Some people who’ve taken curcumin experience nausea, diarrhea, abdominal pain, and increased serum alkaline phosphatase and lactate dehydrogenase. (10)

Alpha Lipoic Acid

Alpha lipoic acid decreases histamine and lowers mediator release from rat mast cells. (11)

Epigallocatechin gallete (EGCG)

EGCG is found in green tea, and it decreases the level of mast cells and their activity, as well as decrease TNF-α and NF–κB in rats with colitis. (13)

Probiotics

A probiotic containing Bifidobacterium longum and Bifidobacterium infantis reduces histamine-mediated symptoms in rats. (14)

 

Treatment: Drugs

H1 and H2 Antihistamines

H1 and H2 blockers are used for baseline treatment.  Your doctor will likely have you start with these.

By Phn003 at English Wikibooks [Public domain], via Wikimedia Commons

By Phn003 at English Wikibooks [Public domain], via Wikimedia Commons

H1 antihistamines – block the activation of mast cells and histamine mediated symptoms by antagonizing (blocking) H1-histamine receptors. Examples include: Claritin (loratidine), Benadryl (diphenhydramine), Zyrtec (cetirizine), Allegra (fexofenadine). Zyrtec (cetirizine) also possesses some mast cell stabilizing activity. (15)

H2 antihistamine – block the activation of mast cells and histamine mediated symptoms by antagonizing (blocking) H2-histamine receptors. Examples include: Zantac (ranitidine), Pepcid AC (famotidine), Tagamet (cimetidine)

Epinephrine

In patients who experience anaphylaxis, epinephrine is advised to be carried with at all times (i.e. Epi-Pen), and readily and quickly absorbable forms of H1 and H2 blockers.

Cromolyn (Disodium cromoglycate)

Cromolyn is a very common drug used to stabilize mast cells, and can inhibit histamine, leukotrienes, and prostaglandins from mast cells. (16)

However, it isn’t absorbed well. Cromolyn can be purchased over the counter in a nasal spray (Nasalcrom) and in eyedrops (Opticrom). It can also be taken orally or inhaled. Interestingly, a Cromolyn cream can be made by mixing Nasalcrom and a skin cream like (Eucerin). *Talk to a doctor before trying these even though you can purchase different versions over the counter.

Glucocorticoids (steroids)

Glucocorticoids and other immunosuppressive drugs can be an effective treatment for cooling down the immune system and decreasing mast cell activation. (17)

Acetylsalicylic acid (ASA) (aspirin)

Acetylsalicylic acid (ASA) (aspirin) is sometimes used to inhibit cyclooxygenases and decrease levels of prostaglandins.  However, ASA can stimulate mast cells to degranulate. (17)

 

 

In summary, MCAD diagnosis is likely to increase over the coming years, as are the treatment options available. It’s pretty complex and diverse, and treatment requires patients, time, and diligence in taking one step at a time. If you think you’ve got MCAD, I recommend finding and seeing a doctor who either specializes in MCAD, or at least knows what it is to get formally diagnosed.