Histamine Intolerance

Do you have health issues when you consume foods such as alcohol, bananas, chocolate, milk, nuts, papayas, pineapples, or shellfish? Does consumption of these foods lead to headaches, rashes, high blood pressure or heart rate, anxiety, increased body temperature, dizziness, or swelling?

If so, histamine intolerance might be an issue for you to consider.

What does histamine do?

Histamine is best known as being a response to an allergic agent. It sounds the alarm for the immune system to respond to the perceived threat while it dilates the blood vessels to allow white blood cells to do their thing. Once the histamines have finished their job, enzymes break histamine down so it doesn’t continue to affect us.

According to Bob Miller, histamine helps to regulate a variety of functions. 

  • Immune response
  • Digestion
  • Inflammation
  • Sexual function
  • Blood pressure/vasodilation
  • Muscle contraction
  • Thermoregulation
  • Wakefulness
  • Neuromodulation

It is important to point out that depending on cell and the receptor histamine binds to it can be inflammatory or anti-inflammatory. 

Histamine receptors

Histamine receptors are proteins situated in various parts of the body and bind with histamine to produce a specific effect. There are four known receptors, designated H1 – H4.

H1R

This receptor can be found throughout the body and is associated with allergies and inflammation. It stimulates smooth muscle contraction in the respiratory tract, vascular permeability, vasodilation, and platelet activating factor–much like an “allergic” respond we expect.

H1R may also have an important role in regulating the Th1 /Th2 whose imbalance balance has been linked to autoimmune condition. 

H2R

This receptor is known for its role in gastric secretions. Similar to H1R, H2R is found in white blood cells, mast cells, hepatocytes, and endothelial, epithelial, cardiac, and nerve cells, among others.

H2 receptors have an important role in stimulating the relaxation of airways, uterus, and smooth muscle cells in our blood vessels.

H3R 

It is exclusively to  neurons and has an important role in the regulation of the blood-brain barrier, energy levels, sleep-wake cycle, cognition, and inflammation. It regulates and inhibit histamine synthesis in neurons playing a critical role in suppressing neuroinflammation. H3R helps regulating the release of neurotransmitters,

Due to various nerve endings in nasal passages, H3R may also have an important role in sinus-related allergic reactions.

H4R

The H4 receptor is primarily found in immune cells, and has an important role in regulating inflammation. It is expressed in mast cells, monocytes, eosinophils, dendritic cells, T  cells, NK cells, and well as our neurons.

H4R have been shown to have a greater affinity for histamine than H1R.  Despite low expression in lung tissues, H4R may also have a role in regulating lung inflammation, and the migration of mast cells in airways.

How is a histamine response different than an allergy?

There is a difference between an allergic response and a histamine reaction.

Allergens can initiate an allergic reaction–called IgE or immediate immune response–which involves the release of histamine. A histamine reaction is the body’s reaction to histamine released due to exposure to specific  foods, infection or inflammation. It is not an allergic reaction to the trigger.

A histamine load is cumulative based on issues in histamine degradation and removal, unlike food sensitivities or allergies which are based on exposure to the irritant.

What causes a histamine release?

The amount of histamine in the blood fluctuates depending on…

  • The types of food consumed (high in histamine and/or histamine liberating)
  • Environmental factors that trigger histamine or block enzyme activity

Sources may include:

  • Consumption of high-histamine and fermented foods
  • Increased ingestion of histidine (which converts to histamine) 
  • Oxidized fats
  • Fermented alcohol
  • Bacterial overgrowth such as SIBO, mold, Lyme, yeast, mycotoxins, parasites, etc…
  • Genetics 
  • Gastrointestinal damage (leaky gut, inflammation, infection)
  • Mast cell degranulation
  • Environmental triggers

What foods cause a histamine response?

We need to consider both histamine containing and releasing foods. Foods that alter the removal of histamine may also lead to symptoms. Dr. Amy Myers, MD, recommends those with histamine issues avoid the following foods:

Histamine containing foods

  • Fermented alcoholic beverages, especially wine, champagne, and beer
  • Fermented foods: sauerkraut, vinegar, soy sauce, kefir, yogurt, kombucha, etc.
  • Vinegar-containing foods: pickles, mayonnaise, olives
  • Cured meats: bacon, salami, pepperoni, luncheon meats, hot dogs
  • Soured foods: sour cream, sour milk, buttermilk, sourdough bread, etc.
  • Dried fruit: apricots, prunes, dates, figs, raisins
  • Most citrus fruits
  • Aged cheeses, including goat cheeses
  • Nuts: walnuts, cashews, peanuts
  • Vegetables: avocados, eggplant, spinach, tomatoes
  • Smoked fish and certain species of fish: mackerel, mahi-mahi, tuna, anchovies, sardines

 Histamine releasing foods

  • Alcohol
  • Bananas
  • Chocolate
  • Cow’s milk
  • Nuts
  • Papaya
  • Pineapple
  • Shellfish
  • Strawberries
  • Tomatoes
  • Wheat germ
  • Many artificial preservatives and dyes

DAO inhibitor and histamine clearance associated foods

  • Alcohol
  • Energy drinks
  • Black tea
  • Green tea
  • Mate tea
  • Many medications including  Analgesics, antidepressants, antirheumatics, antiarrhythmics, antihistamines, mucolytics, and others

Leftover foods

The longer a food sits, the higher the histamines it develops due to microorganisms on the food. Cooking will not degrade the histamines. Freezing may help slow the process.

What is Histamine Intolerance?

Histamine intolerance occurs when there is more circulating histamine (from the sources above) than can be effectively broken down and cleared by the body.

Histamine is broken down with DAO and HNMT enzymes. If there are issues with low enzyme levels, enzyme performance, or lack of required cofactors, etc., histamine deactivation is inhibited. This leads to resorption of histamine in the intestines and negative health affects throughout the body.

What are symptoms of high histamines?

Symptoms occur when the level of histamine in the body exceeds what the body can clear and is often indistinguishable from an allergic reaction. They may include: 

  • Headaches or migraines
  • Nasal congestion or sinus issues
  • Fatigue
  • Hives/eczema
  • Digestive issues
  • Irregular menstrual cycle
  • Nausea
  • Vomiting
  • Heart palpitations
  • Fever
  • Depression
  • Swelling and soft-tissue pains usually diagnosed as fibromyalgia
  • In childhood and adolescence, DAO deficiency has been linked to attention deficit and hyperactivity disorder (ADHD). 
  • Hormone issues
  • Arrhythmias
  • Arthritis
  • Certain neurologic conditions such as MS. depression or anxiety
  • Etc.

Why do I have an issue with high histamines?

Histamine breakdown  issues

After its release, histamine is naturally degraded by two enzymes DAO and HNMT. Issues with inflammation, infection, genetics, certain medications, gluten or high-histamine foods may affect these enzymes

HNMT (Histamine-N-methyltransferase)

HNMT provides a methyl molecule to histamine so that it can then metabolized by DAO or MAO. BHNMT is found in human tissues with the highest amounts in the intestine, stomach, liver, lung, kidney, spleen, and brain. 

Additionally, to much mast cell activation blocks this enzyme.

DAO (Diamine oxidase)

DAO breaks down histamine produced in the body as well as food sources to prevent its uptake into the blood. The International Society of DAO Deficiency states that high histamine concentrations in the blood are related to DAO deficiencies, not HNMT.

Recent research indicates that in tissues where both DAO an HNMT enzymes are present, DAO tends to exhibit a histamine-degrading capacity ten times higher than that of HNMT (Huertz, 2003).

Diamine oxidase is primarily found in the villi of cells of the small intestine, colon, placenta, and kidney. Since DAO activity decreases as intestinal mucosa is damaged, DAO might be a good indicator of small intestinal damage. Folks suffering from diseases like hives, SIBO, Crohn’s or Celiac disease are reported to show low DAO activity in serum or plasma. 

Note: Olive oil has been touted to help naturally raise DAO levels. It does stimulate the release of DAO, but it does so via the intermediate production of histamine. So for those folks with DAO deficiency, the net result may be an increase in histamine levels.

For those interested in genetics, ABP1 gene produces DAO, not the DAO gene. 

Histamine clearance issues

Enzymes responsible for clearing issues have been found to be susceptible to genetic weakness.

  • MAOA –Monoamine oxidase-A
  • UGT1A4 – Histamine clearance through detoxication called Glucoranidation
  • ALDH – Histamine clearing by Aldehyde dehydrogenases.

Methylation issues

As we mentioned earlier, the HNMT enzyme provides a methyl to histamine so it can be broken down. The process of methylation is to provide methyl donors for various reactions throughout the body. Methylation has been found to be highly susceptible to genetic defects or SNPS so makes it unable to effectively act as a universal methyl donor.

As an interesting side note, according to Bob Miller, whole blood histamine can be used  “marker” for methylation status. “High blood histamine indicates undermethylation, low serotonin levels, etc….. low blood histamine the opposite. If histamine is “undermethylated”, it can begin to build up in the system. When blood contains high levels of histamine, the excess histamine is stored in the blood basophils (a type of white blood cell involved with inflammatory reactions in your body) and brain neurons.”

Adrenal issues

Cortisol is a powerful anti-inflammatory. If the body is not able to clear histamine, it may require cortisol.

The adrenals mediate histamine release and inflammatory reactions. When the adrenals are fatigued, cortisol release is compromised. The harder the adrenals have to work to support high histamine, the more fatigued they may become and the less cortisol they produce. This vicious cycle can lead to deepening adrenal fatigue as well as continued histamine intolerance.

Since cortisol is made from progesterone, issues with hormone levels or conversion issues due to a CYP2A1 SNPs , may further reduce cortisol levels.

Zonulin

High histamine levels may also contribute to gut issues by creating zonulin whose job it is to regulate the permeability of tight junctions in our intestines. Tight junctions controls what passes through the small intestine into the blood. 

High zonulin levels create gaps between our intestinal cell walls which may lead to leaky gut. This can lead to additional secondary immune response causing body pain and swelling, IBS like symptoms,  brain issues, etc, and the creation of more histamines.

What about amines?

According to the Clinical and Translational Allergy Journal, amines  are produced by bacteria during fermentation, storage, or decay of food.

Just like histamines, there are additional amine containing foods that may negatively affect our health. These include:

  • Tyramine (e.g., in cheese)
  • Phenyl ethylamine (e.g., in chocolate)
  • Agmatine, putrescine, cadaverine, spermidine (e.g., in decomposing fish)
  • Tryptamine from tryptophan

As with histamine, enzymes are used to break down amines. In this case, the body requires an enzyme called MAO, which—as I have seen in my clinical practice—is prone to genetic SNPs or defects.

Where are amines found?

  • All cured meats, especially pork products: ham, salami, pepperoni, wild boar, bacon, sausages, fresh pork
  • Fresh or canned tuna, canned sardines, anchovies, mackerel, salmon, herring, processed fish products (fish pastes, smoked fish, dried fish, or pickled fish, fish sauce)
  • Blue cheese, Parmesan, Brie, Camembert, Emmental, Gouda, Cheddar, and hard cheeses in general
  • Oranges, bananas, tangerines, pineapple, grapes, strawberries
  • Tomatoes, pickled cabbage, eggplant, spinach, broad beans, peanuts, tree nuts
  • Fermented soy products, including miso and tempeh
  • Green tea, champagne, coffee, cocoa, chocolate, wine, beer, fresh fruit juices, smoothies

In addition to food, amines can be found in over-the-counter cold medicines, decongestants, nasal drops or sprays, some pain relievers, anesthetics, and antidepressants.

Can amine levels vary?

The amine content of foods can vary based on its method of processing, age, ripeness, handling, storage, variety, cooking method, and other factors.

According to the article  “Are Consumers Aware of the Risks Related to Biogenic Amines in Food?”, amine formation is often prevented by chilling and freezing methods.

When these methods aren’t possible, the use of “hydrostatic pressure, irradiation, controlled irradiation, controlled atmosphere packaging, or the use of food additives” are employed.

How can I minimize a histamine or amine response?

There are 4 ways histamine affects our health.

  • Reduce triggers such as histamine containing foods and pathogenic overgrowth in our gut. For example, 58% of adult patients with irritable bowel syndrome (IBS) have found that amines were the cause of their symptoms, while 73% of patients have found that low-amine diets helped alleviate their migraine symptoms. Over 61% of folks found that amines and salicylates were responsible for their hives.
  • Support histamine clearance–both the DAO enzyme as well as methyl factors that support HNMT and MAO. 
  • Reduce immune tolerance issues that cause histamine amplification response activities — such as adrenals issues, microbiome, leaky gut, pathogens, chemicals, foods, etc..
  • Reduce prostaglandins, an inflammatory responses caused by poor diet choices, infection, etc. 
  • Support oral tolerance with supplementation such as vitamin A and butyrate

How can I test for histamine issues?

Food allergy tests that measure IgE reactions to specific foods will be negative because reactions to histamine are not caused by an IgE food allergy. Immune markers such as white blond cells, eosinophils, and basophils are standard blond tests that can provide indications of immune function.

Serum histamine tests may indicate histamine activity.

Zonulin levels can be measured with Gi Map Stool testing. 

What about Mast Cell Activation or MCAS?

Mast Cell Activation Syndrome (MCAS) is an ongoing aggressive histamine response. It is a serious disorder and according to Dr. Datis Kharrazian PhD is not as common as the internet may lead you to believe. He states the following  criteria for MCAS: 

  1. Severe histamine response that affects 2 or  more organs: skin, lung. gut, etc.
  2. Laboratory test results indicating a 20% increase response in serum Tryptase from baseline upon provocation
  3. Normally caused by genetics or underlying infection
  4. Requires treatment from a licensed MD.
  5. Require histamine leukotriene blockers

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