If you think you may suffer from histamine intolerance or mast cell activation syndrome (MCAS) and are looking for answers, then this post is for you.
Before I begin, you need to know that mast cell degranulation and histamine intolerance are completely separate issues to a condition called undermethylation, which is determined via an elevated whole blood histamine test, and this, I believe, is where people are getting confused.
Keep in mind there is still much to learn about histamine intolerance, as there are many different variants of this disorder. Research shows different blockages or plugs in the system are leading to different disorders. Methylation is one part of that, and our current understanding of histamine as it relates to epigenetics is helping pave the way.
Special thanks to Dr. William Walsh of the Walsh Research Institute for his contribution to this post.
- Protects against infection and inflammation allowing white blood cells to engage pathogens in infected tissues.
- Regulates physiological functions in the gut, especially the release of gastric acid as part of the breakdown of proteins in the digestion of food.
- Acts as a neurotransmitter affecting sleep cycles and cognitive function.
- Naturally occurring in food and continues to rise the longer food sits, and during the process of fermentation.
- Through bacteria using histidine decarboxylase enzymes unrelated to those found in animals.
Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-N-methyltransferase or diamine oxidase (DAO). In a healthy individual, if everything is functioning properly, the right amount of DAO will reside in the GI tract where nearly all histamine from food is metabolized (destroyed/eliminated by DAO).
DAO is responsible for controlling histamine levels in blood fluids, not basophils and mast cells. Blood fluids are supposed to be very low in histamine. Mast cells are where most of the histamine in the body should reside.
An individual with DAO weakness may have normal whole blood histamine with very elevated plasma histamine and depressed DAO levels. Antihistamines and certain antidepressant medications can cripple DAO function and make symptoms worse.
Systems That Control Histamine
Mast cell disorders and methylation imbalances are epigenetic in nature and both are connected to histamine, but there are separate systems that control histamine. They are (a) blood basophils and tissue mast cells and (b) blood plasma.
Histamine elevations in plasma cause crippling skin and intestinal problems, while the histamine in basophils and mast cells correlate with mental problems (methylation imbalances).
Very elevated histamine in the blood signals blood basophil cells where additional methylation of histamine is needed (this is how we check methylation status). Keep in mind you can be over, under, or normally methylated, and still have an intolerance to histamine. Individuals with low DAO activity also tend to have high levels of histamine in serum and plasma, which affects the histamine/mast cell relationships.
A classic symptom of histamine intolerance in women is that they feel uncomfortable and miserable throughout life, but during pregnancy feel fabulous. This is because DAO can be at 500 times higher concentration during pregnancy.
The interesting tie that binds the mast cell/methylation relationship together is the undercurrent of severe oxidative stress, which is an imbalance between antioxidants and free radicals in the body. I see a couple of things that contribute to a significant amount of oxidative stress in people with histamine intolerance: bacterial overgrowth in the GI tract and copper/zinc imbalances.
This also explains why mast cell disorders most commonly affect women, with the onset of serious symptoms beginning between the ages of 35 and 50 (but can occur much younger than that). I believe the reason women are hit so hard is because of the estrogen copper relationship, which in turn impacts gut microbiota.
Estrogen, Copper/Zinc, Gut Relationship
When estrogen rises, so too does copper. The onslaught of hormonal events such as puberty, pregnancy, and menopause, as well as exogenous sources are also triggers for women. These sources include birth control, hormone replacement therapy (synthetic and natural sources), IUDs, vitamin and mineral supplements, food, and drinking water.
Copper lowers dopamine and increases norepinephrine in the brain leading to anxiety, depression, and in some cases, psychosis. With copper overload depression, 95% are female. Postpartum depression is especially interesting because, with each successive pregnancy, copper levels continue to rise rather than go back to normal after baby is born.
Copper and zinc work in tandem to control the overgrowth of fungal, yeast, bacteria, and parasitic infections. Without the proper ratio of copper and zinc, these types of infections can become chronic and difficult to eliminate. Copper/zinc imbalance also contributes to high levels of other toxic metals such as mercury, lead, cadmium, and arsenic.
An overgrowth of bacteria in the GI tract secretes histamine which also stimulates the immune system to release histamine as an immune response. This damages villi in the small intestine that are responsible for secreting DAO and absorbing nutrients from the foods you eat. As I shared previously when the DAO mechanism is impaired, histamine enters the bloodstream increasing its plasma concentration (where it should be low) and once located in the blood it spreads throughout the body.
This can lead to all kinds of nasty side effects such as migraines, digestive and skin problems, dizziness, irregular heartbeat, as well as a very high sensitivity to food, supplemental therapies, and environmental toxicants.
Many people turn to a low histamine diet along with DAO and other supplementation, such as quercetin, which can be helpful, but these remedies don’t get to the root cause of the issue, which is an overgrowth of bacteria in the GI tract along with nutrient imbalances and overloads.
Copper Metabolism and Regulation
The GI tract contains one of the most powerful antioxidants: metallothionein (MT), a family of cysteine-rich proteins.
If a person has an excess of copper in the GI tract, more MT is automatically expressed, which then binds to copper and prevents the amount of copper that can make it into the liver and bloodstream. That’s the primary way copper is regulated or to put it another way, copper elevation is prevented.
When a person has chronic, elevated copper, it means there is a genetic weakness to MT function. When copper gets into the bloodstream, it gets there by binding to proteins such as albumen as it leaves the intestinal membrane, then goes into the liver where most of the copper becomes bound to ceruloplasmin (a copper-binding protein that acts like a chaperone carrying copper throughout the body and delivering it where it’s needed). What’s also interesting is ceruloplasmin’s ability to destroy histamines (along with the copper-containing enzyme histaminase).
In a normal, healthy individual, copper is regulated throughout the bloodstream and bound to ceruloplasmin. If you wind up with too much copper in the liver, the excess is supposed to bind with ceruloplasmin and MT and go out through the bile duct.
A small percentage of free copper is normal, but if a person has a much higher level – higher than 30% – this is a definite indicator of high oxidative stress.
- Detoxification of mercury and other toxic heavy metals
- Development and functioning of the immune system
- Delivery of zinc to cells throughout the body
- Prevention of yeast overgrowth
- Regulation of stomach acid pH
- Taste discrimination by the tongue
- Protection of enzymes that break down casein and gluten
- Enhanced efficiency of the intestinal and blood-brain barriers
- Reduction of inflammation after injury or illness
So the effect of these disorders is that people become intolerant to things like casein, gluten, and high histamine foods. This does not mean that these foods are the cause of the disorder. Intolerance is an effect of massive oxidative stress and a lack of MT function, which in turn impacts gut microbiota.
More research and intense study are needed, and Dr. Walsh is currently looking at the factors that enhance genetic expression and utilization of DAO once it’s present in the body, which is the same line of research he did with MT.
If you know of someone who struggles with histamine intolerance or a mast cell disorder, please share this post. If you are struggling, please share your experience in the comments below. It is through sharing your story that we create community, eliminate guilt and shame, and bring about healing.
Oxford Journal. Effects of Histamine and Diamine Oxidase Activities on Pregnancy: A Critical Review.
Walsh, William J. (2012). Nutrient Power: Heal Your Biochemistry and Heal Your Brain. (190). New York, NY: Skyhorse.
Experimental Biology and Medicine. The Histaminase Activity of Ceruloplasmin.
American Journal of Clinical Nutrition. Histamine and Histamine Intolerance.
Pfeiffer, Carl C. (1975). Mental And Elemental Nutrients. New Canaan, CT: Keats Publishing.
Lontie, Rene. (1984). Copper Proteins and Copper Enzymes. Boca Raton, FL: CRC Press.
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