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 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.
Source: 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.
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.
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.
- 12/01/2015 • Drug Tolerance Testing and Why You Should Not Use Online Report Readers
- 07/21/2015 • A Bio-Individual List of Histamine Inhibitors
- 07/02/2015 • Glutathione: A List of the Most Potent Inhibiting and Inducing Anti-oxidant Foods and Bioactives
- 06/25/2015 • CYP450 Enzymes: A Complete List of the Most Potent Inhibiting and Inducing Foods and Bioactives