What if this was about the liver?

What if this was about the liver?

At the moment it is very trendy to see leaky gut as the cause of all evils. Don’t get me wrong the gut is extremely important, and gut dysbiosis is a significant source of histamines, but histamine intolerance is a symptom with many causes.

Personally, supporting the gut only got me so far. Supporting the liver has got me close to the end-game.

I have dramatically improved my histamine tolerance, and put my mast-cell activation type symptoms into remission, and dropped by 2/3rds my inflammation markers, by supporting my liver.

And it makes sense that the liver plays a role in histamine intolerance.

Histamine is not just disassembled in the gut by diamine oxidase (DAO). It is also disassembled in the liver by histamine N-methyltransferase (HNMT or HMT) where it is in high concentrations.

Why would HNMT be in the liver? The liver disassembles ALL inflammatory material including histamine released from mast-cells, along with a long list of chemicals manufactured by the body and those ingested.

The Role of the Liver

The liver is an amazing organ. It filters the blood to remove fat-soluble toxins, then disassembles those toxins into water soluble toxins, ready for excretion. This filtering process occurs in two equally important steps; phase I, and phase II.

Phase 1

Phase 1 predominantly uses cytochrome P450 (CYP450) enzymes with each gene designed to detoxify specific types of natural substances. The main CYP450 enzymes involved in the liver are shown below.

Liver CYP450 GenesSource: Stingl JC, Brockmöller J, Viviani R, Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function. Molecular Psychiatry. 2013 Mar;18(3):273-87.

23andMe tests for mutations of the CYP450 enzymes.

My 23andMe results showed that I had significant mutations of the CYP2E1, CYP2C19, and CYP2D6 enzymes. Separate testing via DNA Dose established the degree of mutation and precisely explained the drugs, supplements, and hormone replacement therapy, that caused severe adverse reactions.

When a CYP450 enzyme metabolises a toxin it does one of three things. It either immediately transforms it into a water-soluble form where it is excreted, it temporarily converts it to an even more toxic form ready for phase II, or if it cannot metabolise the toxin it stores it in fat cells, where it is excreted for reprocessing when stressed, fasting, or with weight loss.

The intermediate toxins that are produced ready for Phase II are regulated with glutathione (the master anti-oxidant which works synergistically with antioxidants) which prevents the toxins from causing free radical or oxidative damage.

If glutathione levels remain depleted then Phase 1 will remain compromised. This can lead to a vicious circle where oxidative stress, results in mast-cells releasing inflammatory chemicals, which in turn needs to be processed by Phase 1 of the liver, which if it remains glutathione challenged, will be unable to process it, and result in further oxidative stress.

The answer is simple. Reducing or eliminating toxins and raising glutathione levels is the key.

Phase 2

Some toxins are passed from Phase 1 to Phase 2 for further processing.

The type of process that is undertaken in Phase 2 depends upon the composition of the toxin. It is passed through one or more of seven pathways including; glutathione, methylation, amino acid, sulfation, glucuronidation, acetylation, and sulfoxidation.

Of these pathways, glutathione is the most important pathway, and thought to process around 60% of all toxins. Depending on the toxin the other pathways may be important.

Once again a deficiency in glutathione creates a vicious circle. Glutathione is needed for phase 1. If it is depleted by Phase 1, there may be a deficiency in Phase 2.

To complicate matters even further, methylation and glutathione, are co-dependent. There is a critical turn in the liver’s methylation cycle, at homocysteine, where cysteine for glutathione or methionine for methylation, is made.

The end result? If glutathione is deficient it cannot protect against oxidative stress. If the methylation donors are deficient, genes will not be properly regulated.

This has lead Dr Bill Walsh, and Dr Ben Lynch, both leading experts on methylation, to conclude that no progress can be made on methylation issues until glutathione levels are restored. Restoring glutathione levels may also resolve methylation issues.

Liver Detoxification I


Identifying the Cause

The cause of my histamine intolerance is a DAO mutation, but the cause of my mast-cell activation symptoms, was oxidative stress triggered by medication. I do not have HNMT mutations.

Yes I have had histamine intolerance all my life. But those symptoms were merely inconvenient until my mid 40s when I was put on medication. Then what was merely inconvenient became catastrophic consistent with mast-cell activation disorder.

The key uniting symptom was a severe hypersensitivity to a broad range of toxins (Ct contrast, medication, supplements, hormone replacement therapy, perfumes, MSG, preservatives, pesticides, exercise, and so on) that commenced when I was prescribed medication.

Genetic tests (23andMe and DNA Dose) eventually confirmed that I was effectively being poisoned and precisely explained my adverse drug and supplement reactions. I had severe  CYP450 (Phase 1) mutations and could not metabolise them.

During this time I also put on 40 kilos in 6 weeks (yes you read that right – this was all an inflammatory response to medication), had chronically high insulin paradoxically with glucose tolerance, chronically high cholesterol other than from my diet, out of range liver markers, low glutathione levels, and chronic inflammation markers (CRP). Oddly, on testing my gut was not really one of my many problems.

What do all of these things have in common? Its the liver!

How Have I Put Myself Into Remission? 

So how have I walked myself out of this? The answer is very slowly one step at a time.

Step 1 – Address Any Gut Dysbiosis

The gut is still the first line of defence, and should be addressed first before detoxifying the liver, but the liver is the second line of defence, and should be addressed next, before addressing methylation.

Step 2 – Reduce Toxin Exposure

I removed all medication and used food as my medicine.

First and foremost, the liver is designed to process foods, not drugs or supplements, and even when I could not tolerate a supplement, I have been able to tolerate foods.

It is also a common misconception that supplements are safer than medications, as many supplements appear to be metabolised by the same CYP450 genes, which means they are only safe to the extent that your genes can metabolise them, and that some supplements, as with medications, will become pro-inflammatory at the point at which the liver can no longer metabolise that dose.

Curcurmin is worth touching on briefly. Importantly, Curcurmin is metabolised by CYP450 genes and if Phase 1 is compromised curcurmin becomes toxic and should not be taken. I tolerate turmeric in its food version but not curcurmin supplementation. Paradoxically, curcurmin up-regulates Phase 2 and so is recommended when Phase 2 alone is compromised.

Step 3 – High Protein, Nutrient Rich, Anti-Inflammatory Diet

It is simply not necessary to do a “detox.” What is necessary is a nutritious diet. A poor diet will compromise the liver, whilst a high protein, nutrient rich diet, will give the liver all the ingredients it needs to detoxify itself.

Simplistically, any toxins need to be avoided. Phase 1 needs anti-oxidant and glutathione rich nutrition. Phase 2 need protein, glutathione, and a sulfur rich diet.

Step 4 – Rebuilding Phase 1

I developed a bio-individual diet where my body stopped hyper-responding. Essentially it was organic, low in histamines, and paleo-ish.

Once my body had stopped hyper-responding I started to work on manipulating my diet to include more phase 1 supportive foods.

This has included in particular un-denatured whey protein, herbs and micro-sprouts (particularly broccoli sprouts), cruciferous vegetables, and citrus (other than grapefruit) which I tolerate.

Step 5 – Liver Protective and Regenerative Supplements

Once I was tolerating the phase 1 supportive foods, I have introduced supplements as a temporary measure, aimed at boosting my glutathione and supporting liver detoxification.

In a previous versions of this post I had my supplement routine however I became concerned that people were taking these without obtaining testing or the advice of a health practitioner to so what was right for them and have removed them from the blog post.

Has It Worked?

I continue to be a work in progress. This protocol has however dropped:

– All my liver panel back to normal

– Insulin by 75% to normal

– CRP by 75% (although it is still slightly raised)

– Cholesterol by 25% (although it is still slightly raised)

– Eliminated ALL chemical hypersensitivity

– Enabled me to eat a much broader diet

– Allowed me to steadily lose weight.

It is my hope that my glutathione levels will continue to build, my liver will regenerate, and that I will eventually be able to reduce or eliminate my supplementation. In the meantime, I continue to focus on new ways, to reverse oxidative stress, and am currently experimenting with a ketogenic diet.


Is this approach right for you? It depends on whether you have a history of adverse drug reactions and sensitivity to chemicals. Was there a defining moment where your symptoms got worse? Was that a toxin exposure? Do you have CYP450 mutations?

It is my hypothesis that mast-cell activation is caused by oxidative stress. There are many causes of oxidative stress. Mine is just one of them. Yours may be different. However, if medication triggered your symptoms, then I believe it is possible to significantly improve your symptoms, and put your condition into remission through supporting your liver. At least that has been my experience.

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  • John Zimmerman

    please find a better font

  • LeeAnn

    On the diagram one of the pictures says “liver expression” and the other “brain expression”. Can you clarify what that means?

    • The drug metabolising genes concerned are not only expressed in the liver. Whilst they know what the genes in the liver do, they are not yet clear as to the role of those genes in the brain. The diagram is from the article cited.

      • Kelly

        That’s why they’re not really genetic ‘mutations’, but rather, polymorphisms, at least according to Dr. Lynch.

        • CYP450 genes are a life time mutation unlike other genes according to Professor Les Sheffield whom is a geneticist. Dr Ben Lynch to my knowledge has never said the same regarding CYP450 mutations. Can you provide a source; as that is wrong, and I would like to contact him.

          • Kelly

            Oh, okay — I thought you were talking about methylation genetics. That’s good to know. I wish I had done the 23&me years ago, but did “Yasko” instead, and then a few months later 23&me came out, and a much, much lower price. But am on disability now and can’t afford a thing…

          • Oh no! sorry to hear that. Methylation is different so do you have a CYP mutation; because if you have done 23andMe then it would be reliable. Further testing merely shows the degree of function which is useful for determining avoidance or reduced dose.

          • Kelly

            I don’t know if I have a CYP mutation — that isn’t tested for in the Yasko testing, unfortunately. But Dr. Lynch has said:

            “High histamine = low methylator = greater need for methylation support such as methylfolate and methylcobalamin.”


          • Hi Kelly that is just one form of histamine imbalance. There are many faces of histamine intolerance. That is just one.

  • Philip Clax

    I agree, the liver can often be the root cause. For me it was taking antidepressants for too long, that caused my chemical sensitivities afterwards, on top of the other damaging effects. I find myself fasting often to achieve more mental clarity. Hopefully this places less off a burden on my liver.

    • Phillip I want to assure you that you l get better, your experience is (sadly) not unique, and that food has the capacity to heal us.

      • Philip Clax

        Thankyou 🙂 On top of all this I have dental fillings I need removed…*sigh* getting healthy can be such a puzzle, but worth it.

  • Bronwen Beith

    Wow Alison, what a fantastic article, I’ve just found you and I’m so glad I have! Do you have a view on IV glutathione to break the vicious cycle?

    • Hi Bronwen; yes IV glutathione is an option, however, it is an expensive one. There is also a new Glutathione product on the market which is very cheap and I will write about it shortly.

      • Bronwen Beith

        Would be great to hear about that Alison as IV Glutathione is indeed expensive to say the least. I was wondering about it because my mast cell activation symptoms are very recent following an impressive histamine reaction due to scombroid fish poisoning. My logic was that if I can majorly boost my glutathione levels I may be able to break the vicious cycle. I know I have methylation issues from blood testing, including low SAM-e and gluathione (homozygous for MTHFR C677T).

      • Bronwen Beith

        Hi Alison, I’d love to have a session with you and note your first one is free, the ‘contact me’ link on your ‘Meet Alison’ page isn’t working unfortunately though. How can I best get in touch? Many thanks 🙂

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  • Andrea Adinolfi

    Hi Alison, this article have litteraly surprise and amazing me! i?ve problem with methilation, but i want ask you what test did you do for know that you have or not dao and hnmt mutation? because 23andme don’t have this indication

    • HI Andrea I will have a blog post up next week on this! It is already written. The simple answer is that you need a blood test for DAO immediately prior and immediately after a 7 day low histamine diet. WIth HNMT it is a urine test. It is a common misconception that 23andMe provides results (it does have DAO and HNMT mutations) but only tells you whether it is possible not whether it is active.

  • Shelley

    Which SNP can I look at to check my CYP450 status? I have all the data, and would like to see. Thank you!

    • Hi shelley
      It is all the enzymes with CYP in front of them.

      if you run the data through http://www.mthfrsupport.com you will get a report. That report will show some of them. It is phase 1 liver and on the report.

      Not all CYP enzymes process medications. Some process other things like fats etc.

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  • Lee

    What brand of chromium do you use?

    • I have used a variety of brands so cannot recommend a specific one. Most brands are relatively clean (just check the listing).

  • Human Kind

    i wonder why nobody says that milk thistle has a big amount of HISTAMINE naturally present!! i’ve read million of histamine and HIT related articles, webs etc, and nobody talks about it.
    since its a nice help for glutathione, im taking anyway, and sincerelly dont felt any issue about histamine intolerance condition… but…the fact is the fact… it have a lot of tiramine and histamine,.

    • Thanks human kind. Wondering what the scientific reference is of your information so that I can check the research. I use The Handbook of Medicinal Herbs which is a textbook that lists all the activities, indications, dosages and contra-indications, and all the research references. It has not histamine action listed and that has not been my experience. I rarely share my own experiences on my blog but I did so here because this was a game changer for me and I wanted to move the conversation from food to underlying causes. Increasingly I am finding results within my practice by restoring the underlying function. It is important that people get advice about their own situation and dont just take supplements randomly. Milk thistle (as with any supplement has contra-indications). I would very much like to see that research so if you could please email it to me at hello@alisonvickery.com.au

      • Human Kind

        sure Alison!! check your email, its easy to find that info, ive seen on pubmed but i cant find now, anyway please see the attached doc.
        again, tnx for your amazing work!

        • thanks Human Kind; responded. Happy to discuss further.

  • Human Kind

    Constituents of Milk Thistle.

    Milk Thistle contains a bitter principle, antioxidant properties, essential oil, polyacetylenes, tyramine, histamine, and flavolignans collectively referring to Silymarin. These are silybin, silychristin, and silydianin.

  • kristie kaye

    milk thistle is wonderful. However, my biggest challenge w/ milk thistle is the side effects. I am blaming it on my terrible ragweed allergy…all part of the same family. It has been quite the challenge to find any liver support supplements that do not contain milk thistle. but now that i was recently diagnosed w/ MCAS, maybe that is root cause?

    • Hi Kristie, yes milk thistle is not suitable for people with ragweed allergies. There are many other good liver herbs out there too so do persist.

      • kristie kaye

        thank you, alison. i have been searching for a milk thistle free liver support supplement for quite some time and will continue to do so. i still firmly believe that my liver has been stressed for a long time and that in turn has caused it to be quite sluggish. before i start any MCAS treatment, i need to get the phase 1 and phase ii liver detoxification process stabilized. i don’t want to “add fuel to the fire”, so to speak. i agree w/ my mcas specialist that i likely had MCAS since childhood. however, i also think it has become more pronounced as i get older and i think my sluggish liver has a lot to do with it! 🙁

        • Yes; it did for me. It was the source of my body’s oxidative stress that triggered MCAS. Consider speaking to a naturopath; there are options.

  • Mike Robins

    Hi Alison – i developed geographic tongue and have th1 dominant autoimmunity. are the supplements you suggested safe for me? does milk thistle contain histamine? thanks 🙂

    • Hi Mike I am not able to recommend supplements to you as I do not have your medical history and/or tests. You are welcome to make an appointment. with thanks Alison

      • Mike Robins

        thanks Alison. Just needed to know if milk thistle contains histamine. also you said you were sensitive to vitamin C. what do you think is the best form to take? ive been using magnesium ascorbate but think i may be sensitive to it 🙂

  • Mike Robins

    Hi Alison just following up on my question 🙂 many thanks

    • thanks Mike I am not able to provide personal advice as previously stated.

      • Mike Robins

        Thanks Alison. I didnt need personal info. just wanted to know if milk thistle is histamine free and which vitamin C you take. Appreciate your help! 🙂

        • see response on histamine below ( I actively use it with clients without issue). In relation to Vitamin C it depends on lab test results.

  • Brian Edward

    Spot on

    Can you tel.more where to get glycine

  • Dan Lanier

    Thank you for a nicely thought out and instructive article. I will certainly go back through it together with my wife. We can both benefit from your wisdom. The histamine factor appears to be the next hurdle on our journey. 🙂

    • Thanks Dan; supporting the liver has been very important to me (and is for many clients also with gut issues). Enjoy!

      • Dan Lanier

        Inspired by your article and also one by Dr. Axe (9 Ways to boost), We decided to add NAC and ?-Lipoic Acid as a start. Since the bioavailability of GSH is questionable (we will look at sublingual glutathione options later), we thought it would be a great start

  • sp Sacher

    Hi Alison. I too have had histamine issues all my life and have always eaten well and been otherwise in good health. I have however never been able to tolerate supplements and medications…When I turned 50 and hit menopause things started to change. After taking an antibiotic for a brief illness and then Valtrex for shingles I started to experience odd symptons which i now know to be MCAD. Once i added in Methyl B Vitamins I pushed into a full blown MCAD situation. I still experience histamine episodes however it is the medications and supplements that always tip me to the MCAD. My liver tests and inflammation are all normal and always were and my glutathione levels are very good. For me it is strictly supplements and medications (including those found in any dairy or meat) as well as preservatives, dyes and colorings which tip me in a bad direction. Perhaps this is due to my MTHFR. I am compound heterozygous. My question for you is…..if my liver tests are fine but I always have problems with medications what am I supposed to do if god forbid i need to take something? Have you been able to reintroduce medications when needed and been okay?

    • Given the nature of your question to receive personal attention from Alison, specific to your individual needs, it would be best to book a comprehensive health review here http://alisonvickery.com.au/work-with-me/. Alison cannot give personal advice as you are not her client.

  • This testing, as it impacts on drug prescribing, is not all part of the raw data. Also, it needs to be properly interpreted. 23andMe was prohibited from collecting data on CYP2d6 perhaps one of the most important, for example is not collected (only a few of the insignificant snps. So a separate test needs to be done. In Australia i recommend https://www.mydna.life/

  • Hannah Wykes

    I came across this post searching for an explanation for liver-area pain. I have histamine intolerance, pyroluria, adrenal fatigue, undermethylation. Interesting read, sounds like it could all be linked. Unfortunately still feeling so lost as to what to focus on and how.

  • Anna Bennett

    Gosh this sounds EXACTLY like my story…moderate histamine issues most of my adult life, but then I go on high hormone therapy, then prescribed thyroid medicine and BOOM all hell breaks loose. The worst anxiety I’ve ever experienced, weight gain, etc.

    What is the connection with histamine and weight gain? Why is it so darned difficult to lose and easy to gain?
    Also…curious if thyroid medicine also tripped your horrible symptoms into overdrive like it did me. Is a thyroid connection to this specifically known?

  • Bodhi B Wayne

    How did you address you gut dysbiosis?

    • See a functional health specialists and get labs run. Test dont guess.