GLU1: Diamine Oxidase & Histamines

In my first post – Celiac Disease and My Story – I outlined the main tenets of the disease, my story in relation to it, and a lot of the symptoms that I both experienced and are commonly experienced. This post is more solution-focused, and while I would not use the word ‘treatment,’ it certainly appears that solutions exist in a future context depending on the framing of the disease itself.

NONE OF THIS SHOULD BE CONSTRUED AS ADVICE, AS WITH ANY POST OF THIS NATURE, TALK TO YOUR LOCAL MEDICAL PROFESSIONAL IF IT APPLIES TO YOU.

In this post, I will explore this statement in depth.

There are no pharmaceutical treatments or cures for celiac disease. A 100% gluten-free diet is the only existing treatment for celiac disease or non-celiac gluten sensitivity today.

Celiac Disease Society

There is an open and difficult-to-resolve contradiction in Celiac that very few seem to question in my experience: that a gluten-free diet (GFD), while absolutely necessary for Celiacs, generally does not resolve the actual disease for most people over the long-term.

Several research groups have observed that in a considerable portion of patients complying to a presumed strict GFD, complete mucosal recovery and/or resolution of symptom do not occur

Nutrients

Clinical symptoms will improve on a gluten-free diet for the majority, but if they re-introduce gluten into their diet in any meaningful way they will return. ‘Refractory Celiac’ which constitutes about 30% of cases officially (and probably more in reality) does not improve at all on a gluten-free diet at the intestinal/auto-immune level.

While most individuals will display improvement in symptoms and signs of coeliac disease following institution of the GFD, up to 30% will continue to experience symptoms and/or have persisting intestinal inflammation. These individuals can be classified as having non-responsive coeliac disease (NRCD), which may be associated with dietary indiscretion, slow healing, refractory coeliac disease, and/or an alternative condition.

Nutrients

As someone who has a science mind, and who studied Biochemistry in university, this simple fact would suggest that gluten is not itself the lone causative element of Celiac. It is a paradoxical medical problem that requires non-linear thinking.

Diagnostics & Early-Stage Outlook

It was a stroke of good fortune that I ended up in London, UK in in 2014 when my ‘immunological state’ hit rock bottom, as I ended up going from the ER > Private GP > Nutritionist who had the intuition and experience to zone in how gluten was effecting my body.

As I explained in my first post – Celiac Disease and My Story – on the subject, I did not officially test “+” for Celiac in a clinical sense. The original blood test I did in Canada in the summer of 2013 was “-” and without follow-up. As I mentioned, I didn’t even really understand what gluten was at that point, let alone Celiac. While I initially felt relieved about the negative blood test, my symptoms and state ended-up getting dramatically worse into the spring of 2014 when I had moved to London, UK.

Through a series of referrals via a GP (Doctor) there to a Nutritionist, I ended up getting a series of very advanced (and expensive) Cyrex Lab serum tests ordered, which you cannot actually get in Canada (or couldn’t as of 2019 anyways). These tests we ordered ended up showing three things:

  • extremely high sensitivity to gluten (measured across multiple different dimensions)
  • cross-reactivity to gluten-free grains such as sorghum, teff, buckwheat, and amaranth
  • a surprise positive test for a rare parasite

My gluten sensitivity had devolved to molecular-level sensitivity by mid 2014. This was one of my first observations, was that there was a variance to my sensitivity.

Late 2012 on 1st trip to London(left), spring 2014 right after massive immune-system problems

I was also having problems with pollution (outdoors) and cleaning chemicals (indoors), which to me was an obvious liver problem. For this reason alone, I had to move (unexpectedly) back to the clean air of Canada in mid 2014.

In the interest of brevity, I will share that I realized that there were three huge problems I was having in late 2014 that I had to put my Biochemisty hat on to remedy:

  • I was having histamine outbreaks (hives mainly) and I started to solve them by cutting back back on caffeine and taking L-Methionine (methylating histamines)
  • I had to figure out how to kill the parasite, which was not easy and created a huge die-off, using (food-grade) diatomaceous earth and raw honey (has to be raw)
  • I also was having big energy lulls (rare for me), which I solved with a quality B multi-vitamin (more on this later)

I will come back to the above later on, but they are all extremely important factors. The early-stage outlook was horrendous until I started making breakthroughs in 2016.

One clarification I will make is that at no point did I take OTC anti-histamines. Even though I had had hives, etc. it wasn’t like a typical IgE reaction like one would have to bees, or pollen, or peanut butter. L-Methionine is a somewhat obscure supplement, but it worked very effectively for me.

Resveratrol & Iterative Remedies

This could be another section I write 10 pages on because it has been an extensive and exhaustive 7+ years of testing everything under the sun, so I am bulle-pointing most of this section for brevity.

  • There was an order of operations for me, and since I did study Biochemistry for 3 years in university prior to going into Business, I was comfortable testing OTC supplements
  • Early-stage (2014), I was on an array of supplements that were pretty general for the digestive tract, controlling gut flora, etc. We tried some enzymes like DPP-IV for incidental gluten ingestion, but it didn’t work. By this time I had started tracking every single ingredient I was eating in a spreadsheet because I was having awful reactions every other day. As it turns out, many sauces and common ingredients have gluten in them and this problem is getting worse. An example of this is Worcestershire Sauce.
  • If there is any question about whether or not I was ‘sneaking’ gluten into my diet at this point, I literally couldn’t. I was sensitive to molecular levels of gluten by late 2014, I could barely even go to a restaurant.
  • I started challenging the orthodoxy and conventional thinking in early 2015 and that’s when I started getting some results.
  • My very first breakthrough happened when I added a digestive supplement to my repertoire that included papain (enzyme from papaya), which I would pre-load before all meals
  • I became very focused in late 2015 on the ‘pre-load innovation’ so that I could get back to eating meals in restaurants
  • My process was legitimately researching and ordering $100s sometimes of $1,000s of dollars of supplements per month – there was no other way
My suitcase when traveling – more supplements than clothes!
  • I had detailed notes of every meal and supplements combination for about 2 – 3 years
  • My first breakthrough came with Resveratrol in mid 2016 when the waiter in a restaurant in Waterloo, Ontario accidentally put tempura (deep-fried wheat) on my sushi – PS: these types of events have happened to me multiple times over the years, sometimes with full pizzas, and I don’t blame the waiter(s) in these cases .
  • I had pre-loaded with Mint + Resveratrol prior to the meal and after my initial panic when I heard the “whoops, we accidentally …” after half the sushi roll, I was pleasantly surprised by the lack of reaction an hour or so later
  • As it would turn out, I ended up learning that Resveratrol could mitigate the worst of the reaction, both pre and post exposure, but it could not relieve the tension in the small intestine nor ‘unlock’ it. I only found one remotely plausible explanation out of Canada actually comparing Resveratrol’s effects to Tranilast, an allergy medication

Resveratrol inhibited mast cell function at the level of degranulation, and cytokine and cysLT production, and was comparable, and in some cases, more potent than the anti-allergy drug tranilast. Thus resveratrol may be an effective therapeutic agent for the treatment of allergic disease.

Allergy, Asthma and Clinical Immunology
  • Resveratrol was my big BOOM in those years, it very much freed me up to get back to traveling and eating out, but I would say it was the equivalent of finding an aspirin for a daily headache – it could only do so much
  • I made another breakthrough in early 2017 around high-dose Vitamin C, which I believe relates to it being an anti-histamine. The negative counter-effect one has to be very careful of with high-dose Vit C is Oxalates which have a very negative effect on the kidneys
  • Through an extensive tracking and tracing process of my diet, I saw a positive correlation to olives and added Olive Leaf Extract to my pre-load routine (before eating out) and used Resveratrol only when I as having a gluten reaction. I have no working theory why this worked (works), but the common theme to almost everything I figured out in this era is related to histamines
  • By mid 2018 I had gotten to the point where I actually went for it and proved to myself that I could eat gluten. Once I ate a piece of sourdough bread, and another time some pita bread in a restaurant. And while I could do it, it was not seamless and I had to dedicate all my energy to doing an exact set of steps of what I took as supplements before, during and after. As an example, one thing I ABSOLUTELY AVOID if I have any gluten in my system is chocolate. Why? I don’t know, but it causes big problems. Whereas wine, for example, is fine because of the Resveratrol content
  • In 2019 – 2021, I no longer had any fear of being ‘glutened.’ I basically lived my life as I would have otherwise, but my no means was I completely “healthy” in a holistic sense

The pattern I noticed with my continued tracking on it was a progressive targeting – and effectiveness – of the liver. For the record, I don’t have ‘liver problems.’ I also have a healthy lifestyle and diet, not to mention multiple possible supplements to boost the liver.

But related to L-Methionine, N-Acetyl Cysteine, Alpha-Lipoic Acid, Triphala (detox), Quercetin (as an anti-histamine) and others, I started to see an a new pattern emerge around the liver.

Targeting the Liver & Methylation

Symptoms are hell if you are the sufferer but they can also be clues if you are the researcher. I learned how to reduce the symptoms and focus on the clues, which led me to the liver.

Based on what I posted in Celiac Disease and My Story, the connection to the liver is clearly a major factor in the disease, but one you rarely hear about.

I mentioned L-methionine and how it helped me deal with early-stage outbreaks such as hives, etc. Histamine methylation – or lack there of – directly impacts the liver.

This image is titled ‘Your Liver on Histamine‘ on the blog Healing Histamines.

Researchers found that patients with liver disease have chronically elevated histamine levels as a result of mast cell activation. Those in the study had itchy, rashy skin. And as with everything histamine related, it’s a case of chicken and egg, because excess blood histamine has been found to cause liver enzyme fluctuations

Healing Histamine

The next question you may ask is ‘what evidence is there to correlate Celiac diease to histamine levels?’

The results demonstrate that 18 of the 20 refractory, non-responsive celiac disease patients presented various, additional food intolerance/malabsorption and/or H.p. infection. Seven NRCD patients demonstrated lactose intolerance, 7 showed fructose malabsorption, 11 had additional histamine intolerance and 6 had signs of H.p. infection or combinations thereof. If present, then eradication of H.p. was performed. Histamine intolerance, was found in more than 50% of patients, and it seems to play an important role in non-responsive celiac disease.

Med Hypotheses – 2021

A recent (2021) , small study among those with the worst of Celiac disease (“refractory Celiac” where ~30% do not have clinical symptoms resolve on a gluten-free diet) showed > 50% testing “+” for histamine intolerance.

Deficit DAO

Nevertheless, histamine location within the body is not specific, as there are four types of histamine receptors (H1, H2, H3 and H4) in different areas.

Histamine receptors are found throughout the body (including the liver) and are also linked to Mast Cells, which play an important role in the disease as well.

Mast cells are a part of the white blood cells that make up the immune system. They contain histamine and other inflammatory agents that they release to begin the healing process when we’re injured or sick. Histamine is the first responder. 

Healing Histamine

As you start to join the dots between Histamines – The Liver – Mast Cells – White Blood Cells – Immune System you can see how a blueprint starts to emerge of what is happening in the body metabolically and why the liver is negatively effected.

Methylation is the process of adding a methyl group (1 carbon + 3 hydrogens) to a compound in your body, resulting in a specific action. Genetic variants, otherwise known as Single Nucleotide Polymorphisms, or SNPs (pronounced “snips”) can cause the MTHFR (methyltetrahydrofolate reductase) gene, the one that is responsible for methylation, to not work as well. This can cause a person to not be able to detoxify as well or to not repair as well. It also makes a person have a hard time breaking down folate from foods and converting it to the active (useful) form.

Healing Histamines

I could write an entire post on this pathway, but for the moment I am just highlighting the area of Histamine Methylation, as I very rarely see it mentioned in relation to Celiac. Suffice to say, to view the liver symptoms in relation to Celiac as “random” is a big mistake.

Nature

Diamine Oxidase (DAO) & Histamines

Reminder: none of this is to be construed as recommendations or advice. The part below is presented as an open thesis based on the simple facts that a) recent biomedical research aligns with it in some ways b) in my own experience, it works on gluten at the small-intestine level

Deficit DAO

At the end of the path is DAO (Diamine Oxidase), and I have both the research and experience to share.

First off, the research.

If this was the first section you read, and you compared this data to the Celiac Disease and My Story section ‘Symptoms and Other Complications’ you would see a near perfect correlation to the seemingly random symptom map associated with DAO deficiency.

Deficit DAO

DAO Deficiency is an alteration in the metabolism of food histamine that appears when Diamine Oxidase (DAO) enzyme activity is low. In other words, when for some reason there is a significant deficiency in the functional activity of the main enzyme in the metabolism of histamine. The imbalance between ingested histamine and the histamine released from the histamine storage cells, and the capacity for histamine degradation, leads to histamine accumulation in plasma. It triggers the occurrence of adverse effects on health.

Deficit DAO

DAO is synthesized in the kidney, intestinal lining, thymus – and normally – released into the gut where it degrades dietary histamines and prevents them from circulating into the blood plasma. As we saw above in relation to the liver, this is an extremely important point.

Postheparin diamine oxidase levels were significantly lower in untreated celiac patients (mean 1.53 units/ml) than in healthy controls (mean 5.85), treated celiac patients (mean 4.82), and abnormal controls (mean 2.62).

Digestive Disease Sciences – 1988

The fact that this research is from 1988 shows that this is not a ‘new’ correlation. What certainly appears to be new is research into DAO as a treatment. It is available OTC in supplemental form as a synthesis from ‘porcine kidney.’

A small, and inconclusive study was done in 2020 trying to link those with DAO (Diamine Oxidase) deficiency linked to symptom of Migraines, Non-Celiac Gluten Sensitivity (NCGS), and Celiac.

We argue, that migraine, celiac disease and NCGS may benefit from treatment with a multidisciplinary approach, involving neurologists, gastroenterologists and dietitians.

Medical Hypotheses – 2020

I would argue that this area should be much further explored with the additional layer of Histamine Methylation (L-Methionine, etc.) and the surrounding B-vitamin co-factors (B6, B9, B12), along with TMG (Trimethylglycine).

As for my own experience, DAO does the trick on gluten exposure, either incidental or direct. It works almost instantly and to a certain extent ‘unlocks’ the small intestine. The extent to which it works will be something I continue to investigate in relation to histamine levels and other related factors. It is not, in my opinion, a panacea but a VERY IMPORTANT OPTION for a disease that is allegedly untreatable.

Supplements I Currently Take & Future Exploration

Reminder: none of this is to be construed as recommendations or advice.

Methyl Guard (Active Ingredients): Methyl-Guard contains betaine (Trimethylglycine), 5-MTHF (B9), methyl-B12, and P5P (B6)

Histamine Block Plus: The DAO enzyme and copper in this formula support normal histamine breakdown in the digestive tract. Vitamin C, SAMe, riboflavin, Thiamine (B1) and others help the histamine imbalance

Methyl Guard is a daily supplement for me, Histamine Block Plus is more situational around gluten at this moment. Neither have any real known negative side effects, but my experience in taking these types of supplements over an extended time period can cause changes to your metabolism and biochemistry, so one needs to be careful regardless.

The area I believe merits further investigation is the B6, B9, B12 pathways and their synthesis. Normally, we can get these vitamins in our diet, but if the absorption is messed up in the intestine then this can feed a vicious negative cycle. The question for me is, can this cycle be overcome? If DAO is indeed deficient, can it be replenished so to speak?

Diamine Oxide is dependent on Vitamin B6 synthesis, which is derived from P5P. (Vitamin B6 Fact Sheet)

Overall, this is Part 2 of a two-part series about Celiac (Part 1). There will be a day when we solve Celiac and help the millions of people who suffer around them. My goal in writing about my experience is to try and catalyze the solutions pathway, not dig deeper into the problems pathway. Feel free to let me know any thoughts.

GLU 1 (Part 1): Celiac Disease and My Story

GLU1 (Part 3): Pterostilbene and the Liver

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