Histamine Intolerance Causes, Symptoms and Diagnosis

This article is the first of a two part article. It covers histamine intolerance causes, the symptoms, and diagnosis. The second part of this article is called Histamine Intolerance Solutions.

What You Will Learn About Histamine Intolerance

• What histamine Intolerance is
• How histamine is used by the body
• Where histamine comes from
• Other biogenic amines
• Genetic & more permanent causes of high histamine vs acquired causes
• Histamine poisoning from super doses of histamine
• How cooking affects histamine content in food
• How to diagnose histamine intolerance

In the second part of this article called Histamine Intolerance Solutions  we cover

• How to lessen histamine from forming in food
• Foods likely to be high in histamine
• The use of specific probiotics to compete with commensal bacteria overgrowth that make histamine
• Treating health conditions that induce histamine release by mast cells
• How to remove histamine from the body by the use of supplemental enzymes
• How to decrease histamine release by stabilizing mast cells

 

For a shortened article on  this subject where we examine different types of food allergies in relation to histamine intolerance and take a quicker look at this whole subject, check out the article called " When Food Allergy Is Really Histamine Intolerance ".

The Basics On Histamine Intolerance

Histamine intolerance is also called food histaminosis or histamine sensitivity. It is a condition where there is either excess histamine in the diet, or an individual produces excess histamine, or bacteria in the intestines produce histamine or there is a lack of adequate enzymes to remove the histamine from the body. There is a difference in histamine intolerance  and IgE-mediated allergy that also involves extremely high histamine or histamine intoxication or poisoning. In contrast to histamine intolerance, histamine poisoning is when an extreme amount of histamine in food is consumed to create an acutely toxic situation. Sometimes people who think their issue is histamine intolerance may be actually eating foods with really high histamine that would bother many people, however most individuals who are labeled as having a histamine intolerance actually have a deficiency of the enzyme needed to remove histamine from the body and those people are bothered by lower levels of histamine in the digestive tract.  The cause of the low enzymes might be genetics or it might be acquired due to inflammatory bowel disease or other causes of intestinal inflammation or damage that blocks secretion of the enzyme called diamine oxidase (DAO) from the intestinal wall. There are also drugs which inhibit DAO. In addition, the presence of other biogenic amines, largely putrescine and cadaverine can compromise the intestinal removal of histamine by enzymatic competition. Lastly monoamine oxidase (MAO) is also involved in degradation of histamine and the use of MAO inhibitors might interfere with histamine removal.

A condition called mastocytosis is also related to high histamine levels, but is another condition entirely and we won't discuss it here.

What Is Histamine

Histamine is a biogenic (made by a life form) amine and it is made from the amino acid histadine through a process called decarboxylation. Histadine is an essential amino acid and is required from our diet. It is found in meats, soy and other legumes as well as nuts and seeds. Histadine is enzymatically changed by our bodies using the the enzyme histadine decarboxylase along with the cofactor B6 to make histamine. Histamine has important roles to play in the body when it is in normal amounts.

Our Bodies Make Histamine

Histamine can be synthesized by:

• Immune system cells
  • mast cells
  • basophils
  • platelets
• Nervous system
  • histaminergic neurons
• Gastroentestinal system
  • enterochromaffin cells

These cells can be triggered to release histamine by a variety of causative factors not related to food and digestion and this is discussed to some degree in this article.

Histamine Is Involved In Necessary Bodily Processes

Histamine is normally found in our body and is vital for our health. Symptoms of histamine intolerance arise only when histamine levels are beyond the normal amount the body can use and remove. Histamine is always removed quickly by enzymes. If this process breaks down and there is more histamine than what can be used and removed, histamine causes symptoms.

We need histamine for the following bodily processes:

• Stimulates the release of gastric acid in the stomach, which is involved in the digestion of protein, absorption of minerals and other nutrients, and protects us from pathogens.
• Stimulates motility of your intestines (stool movement)
• Histamine is a vasodilator
• Acts as a neurotransmitter in the brain and central nervous system. Histamine conveys messages between nerve cells.
• Necessary for part of immune response. It protects the body from infection and helps with healing in trauma, where it is an essential component of inflammation, which is a necessary part of the immune systems response to infection and trauma.
• Allergies are an immune reaction also and histamine is involved here.  Allergies are an over-reaction, but the excess histamine release during an allergic reaction is the immune system trying to protect the individual.

Where All That Extra Histamine Is Coming From

• Food contains high histamine from bacterial alteration of histadine to histamine
• Some Foods stimulate the body to make histamine
• Bacteria in the gut convert amino acid histadine into histamine
• Bacteria in the gut cause release of histamine by the body (mast cells usually) in response to gut irritation and damage
• Toxins in the gut can cause release of histamine by the body in response to gut irritation and damage
• Other physical stress or mental/emotional stress can cause mast cell release of histamine adding to the histamine load.
• Low diamine oxidase can cause increased histamine
• Besides gut related histamine, histamine can be released from mast cells due to mast cell triggers from temperature changes, medications, supplements, herbs, air borne allergens, and air borne chemicals/toxins and any true allergen that the individual is known to have an IgE-mediated reaction from.
• Drugs or supplements can decrease the amount of enzymes needed to degrade histamine.
• High histamine is most commonly due to lack of adequate enzymes. Both diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT) can be affected but since we are examining diet and gut related histamine we are focusing on DAO. We also have more solutions for low DAO.
• Histamine Can be made in reaction to physical or mental/emotional stress -  this can be caused by pathogens (viral, bacterial, parasitic), medications, chemicals, heavy metals, and biotoxins such as venom or mycotoxins and other toxins in general.
• Hay fever will add a layer of extra histamine  to the body and makes the body burden of inflammation worse.

 

The Signs And Symptoms Seen In Histamine Intolerance

These are the most common signs and symptoms seen with histamine intolerance that is diet and gut related. For additional signs and symptoms check out the article called Mast Cell Activation and Histamine Intolerance.

• Digestive Tract: food intolerance, nausea, vomiting, abdominal pain, diarrhea, bloating
• Respiratory Tract: Asthma like wheezing, shortness of breath, runny or congested nose
• Heart: lowered blood pressure but could be raised, fast pulse, palpitations
• Head, Brain, CNS: headache, migraine, anxiety, feelings of panic, confusion, depression, trouble with temperature regulation
• Skin: itchy skin, hives, flushing, rashes

Genetic Causes Verses Acquired Histamine Intolerance

Genetic Intolerance: The genetic causes of histamine intolerance have to do with an individual having genetic variants that make it harder for them to make adequate enzymes to remove histamine from the body. This is discussed further below. I have clients with high histamine reactions ask me if this is a permanent condition for them since they have genes that predispose them to this issue.  Although, we can't say for sure, it helps to ask when the person first remembers the histamine reactions starting. Are the symptoms life-long or did they start at some defined moment perhaps after a traumatic stress or illness?  Those that have had life-long issues, will often continue having  issues but can decrease the symptoms tremendously by attending to diet and enzyme support as well as keeping their gut bacteria balanced for the rest of their life. The people who did not have this issue their whole life, may be able to resolve the excess histamine issue as long as another life stressor does not present itself.

Acquired Intolerance: For those with an acquired histamine intolerance the issue has arisen from a causative factor that can often be remedied. For instance a common reason for high histamine is from either gut pathogens or dysbiosis where excess histamine is either 1)  being produced by the pathogen or overgrowth of a commensal bacteria (these bacteria are considered normal and friendly when not in excess  and abnormal if they are in excess) or 2) the pathogen or overgrowth of commensal is causing damage to the gut wall which stimulates release of histamine from mast cells. These pathogens or overgrowth of commensals can often be identified on PCR testing. This can be remedied. Another cause is the blocking of diamine oxidase (DAO)enzyme due to drugs, or supplements. This also can be remedied. Any time there is a cause other than genetics, it is often something that can be removed, altered, or at least improved upon. Once the person has removed sources of excess histamine and adequate DAO production is supported, the histamine intolerance is a thing of the past.

Genetic Variants In Histamine Degradation

The number one factor for histamine intolerance has been found to be impaired enzymatic degradation of histamine. There are two types of enzymes that are known to degrade histamine and the type that is mostly responsible for removing histamine in the digestive tract is called diamine oxidase or DAO. There are specific genetic single nucleotide polymorphisms that decrease the availability of this enzyme. Different polymorphisms of a single nucleotide in the gene that encodes this enzyme (AOC1 on chromosome 7) have been associated with lower DAO activity. You can't change the genes you are borne with, but you can support DAO enzymatic action with nutrients and you can use DAO enzyme replacement when needed.

Diagnosis

Although there are tests to look for histamine, it is usually not around for long as enzymes remove it. Therefore unless you induce histamine in a lab setting it is hard to measure. This can be done  such as in testing for IgE-mediated allergic responses to foods that cause big histamine releases from mast cells. However this only measures for mast cell release. If the issue is not primarily a mast cell release of histamine but a lack of DAO, the tests will be negative. In fact if someone thinks they have an allergy to foods and does these tests and finds out they are negative, but the symptoms appear to be related to histamine, the next thing to consider is histamine intolerance.  If an individual is reacting to food with histamine in it, a trial test with DAO can be used to determine if this is the issue. Details will be in part two of this article.

Genetic variants that decrease the amount of DAO (diamine oxidase) can be tested for. The gene associated with DAO is AOC1. Some of the common DNA variants are 47 C>T (rs10156191), 995 C>T (rs1049742), 1990 C>G (rs1049793).

In research serum DAO values less than 10 U/mL have indicated histamine intolerance and people with histamine intolerance symptoms with levels <0 U/mL have shown significant improvement in symptoms when they use DAO replacement with meals. I expect to see this test offered in the near future at labs. Currently, it is not.

Testing Issues And How To Diagnose

There are a variety of testing methods for histamine but testing for histamine intolerance is often inaccurate and an individual's reaction to high histamine foods changes day to day. Diamine oxidase testing would be useful if it was available. Ultimately, if a person notices that histamine foods bother them, that is the most important factor.

There are other ways to diagnose histamine intolerance:

• Look for symptoms of histamine intolerance
• Are the symptoms triggered by high histamine food?
• Do they have allergies that might support a general high histamine state otherwise?
• Are they using any drugs that increase histamine or that inhibit production of DAO or HNMT?
• Do they have any illness associate with  high histamine such as excess commensul or pathogenic gut bacteria known to make histamine, any inflammatory or degenerative bowel disease that could cause temporary DAO deficiency? Anything that disrupts the intestinal epithelium may lead to DAO deficiency as 90% of DAO is produced from intestinal epithelium. So any inflammation of the gut wall could create a temporary absence of the DAO enzyme and create histamine intolerance until the gut is healed.
• Does the person have a DAO genetic variant making them more prone to histamine intolerance. You can check HNMT variants, but remember low DAO is the main issue here in studies.

If it appears a patient may be reacting to histamine foods, have them keep a diet diary that includes responses to foods. Look for changes in blood pressure or palpitations after meals, itchy skin or other skin changes,  changes in breathing, and changes in digestion are the most common. These will usually not be as noticeable as in outright IgE-mediated allergies. If they keep the diary, a pattern will usually become noticeable.

If the diet diary confirms this, have them try a low-histamine diet, use mast cell stabilizers and DAO. Consider the use of low histamine gut flora replacement if they have dysbiosis that includes bacteria known to make histamine. Many people try just the low-histamine diet at first and find it makes a big difference, this tells you what you need to know. Adding DAO and mast cell stabilizers will help even more if high histamine and low DAO are the issue.

Enzymatic Degradation Of Histamine

No matter the cause of high histamine, the number one issue that is found in people with histamine intolerance is lack of adequate diamine oxidase (DAO).

Diamine Oxidase or DAO is an enzyme that is made in the cells of the small intestine and the upper large intestine. Diamine oxidase is created in the intestinal wall cells and released into the the gastrointestinal tract to rapidly remove  histamine in the intestine.  Diamine oxidase is the enzyme that scavenges histamine that is outside of cells while the enzyme histamine-N-methyltransferase (HNMT) is the enzyme that removes histamine inside of cells in conjunction with S-adenosylmethionine (SAM-e) forming N-methylhistamine. If histamine makes it past the DAO, and gets into the intestinal wall cells, HNMT  inside the cells is there to degrade histamine. This prevents excess histamine from getting into the blood stream. However, when it is high or one or both of these enzymes are not in high enough concentration, histamine does get by them and into the blood stream where it can roam around the body. Since the histamine in the gut is outside of cells,  DAO is the main enzyme responsible for metabolising histamine in the intestinal tract. Anyone with low DAO is at risk of  intolerance or if the histamine is high enough outright toxicity from histamine.

For individuals who are not having IgE-mediated allergy responses, but think they are reacting to histamine in food, they often try taking diamine oxidase (DAO) at the beginning of their meals to test out their theory. This is the enzyme that metabolizes histamine and it is available as a supplement. When taken with food that has histamine it will break the histamine down and lower the histamine level in the digestive tract. If this does not work and the person took enough DAO to deal with the histamine in the food, something other than histamine is bothering  the person. If the person actually gets worse, it means there is another enzyme that is not working up to par called aldehyde dehydrogenase and I will deal with this more in my book on histamine intolerance that is currently being written. There are also other reasons beyond histamine that cause us to react to foods. Usually, a trained practitioner can figure out which food constituents or types of foods are bothering an individual through diet diaries, testing and a good history intake.

For Chemistry Nerds

Histamine-N-Methyltrasferase is the enzyme that starts the process to break down histamine intracellularly, while Diamine Oxidase is the enzyme that starts the process extracellularly to break down histamine.

Histamine-N-Methyltrasferase Metabolism of histamine

The enzyme Histamine-N-Methyltrasferase adds a methyl group to histamine to become N-Methyl-histamine. The methyl group comes from S-adenosyl-methionine (SAM or SAMe). N-Methyl-histamine can be acted on by diamine oxidase to become 1-Methylimidazole-4-Acetaldehyde.

In the brain the enzyme MAO-B (rather than the diamine oxidase) can also process N-Methyl-histamine to become 1-Methylimidazole-4-Acetaldehyde.

Once we have 1-Methylimidazole-4-Acetaldehyde, it is acted upon by the enzyme Aldehyde Dehydrogenase to become 1-Methylimidazole-4-Acetic Acid. This enzyme needs NAD+ (think niacin) as a cofactor. Imidazole-4-Acetic Acid can be excreted in the urine.

Diamine Oxidase Metabolism of Histamine

Histamine can also be broken down by Diamine Oxidase (also called histamininase) to form Imidazole-4-Acetaldehyde. Diamine oxidase can be released by eosinophils into the circulation to help decrease histamine in circulation. The enzyme Aldehyde Dehydrogenase acts on Imidazole-4-Acetaldehyde to break it down to Imidazole-4-Acetic Acid. The Aldehyde Dehydrogenase enzyme needs NAD+ (think niacin) as a cofactor. At this point the Imidazole-4-Acetic Acid is broken down by the enzyme Imidazole-Acetic-Acid Phosphoriboxyl Transferase (this enzyme  can be inhibited by salicylic acid) into 1-Riboxyl-Imidazole-4-Acetic Acid.

You can see a diagram of this process on YouTube.

Other Biogenic Amines

Histamine is usually not in these foods by itself. The same foods high in histamine are usually high in other biogenic amines such as putrescine, tyramine, spermidine, cadaverine and others.  In fact, because multiple amines are often high in a food at the same time, a histamine reaction might be better termed a biogenic amine reaction. However, histamine is considered the most common amine and one of the more toxic  ones when high in food.

Our digestive tract is a thoroughfare for the receipt of histamine in food, but additionally some bacteria in our intestines are associated with  producing histamine themselves from the amino acid histadine. Gut bacteria can produce other amines also, it is not just histamine they make.  It has also been noted in research that other biogenic amines, such as putrescine, may be involved in displacing histamine from its mucosal mucine linkage, which results in an increase of free absorbable histamine in circulation.

 

Examining  High Histamine And The Digestive Tract

Histamine In Food

Some folks are inflammatory due to excess histamine and other biogenic amines in food. I specify excess as much of our food has some level of histamine or other amines in the food, this includes meat, fish, milk and fruits as well as some vegetables. Histamine in food becomes high due to bacterial growth in the food making histamine from histadine.

All foods that contain the amino acid histadine (meat - especially dark muscle meat) that are not refrigerated or left at room temperature after cooking for too long will have increased amounts of histamine in them due to bacteria in the meat changing histadine to histamine through carboxylation. All biogenic amines will increase as a function of time and temperature. Usually if one biogenic amine such as histamine has increased, others have also.

Histadine  is an essential amino acid in mammals, fish and poultry. Histadine is abundant in red meat and dark meat of fish compared to the lighter colored fish muscle. This might be  the same for dark meat of chicken and turkey although I have not seen studies on them.

Bacterial action is also why fermented meats and other fermented foods such as soy sauce, and aged cheese can contain more histamine in them. Any food that is fermented with bacteria is suspect as to carrying high histamine. Anyone with a  histamine reaction should try removing fermented foods from the diet and later they can try adding them back in small amounts at a time.

Since bacterial growth will increase histamine, taking care to refrigerate, freeze or otherwise preserve food prior to cooking and eating, as well as refrigerating/freezing food after cooking is necessary to lower histamine in your meals.

We often don't know how meat was handled when we get it at the grocer. I have noticed that fish is often old in the stores. The head use to be left on a fish so you could look at it's eyes to see if it was fresh or not when purchasing it. I believe they purposely remove them so no one knows how old they are now. A fishes eyes should be clear, not cloudy.  I smell everything and often notice off smells in fish. I don't eat red meat, but I sometimes smell my friends or families meat and notice off smells in them too. it is my belief that our meat and fish are simply not as fresh as they once were and people don't know the difference. Poultry is better attended to, but it too can have issues.

Recognizing Histamine In Food

The bad news is that histamine does not have a scent. Ugh! The good news is that if another biogenic amine is high in the food, many of the other types of amines do have unpleasant odors. If that fish smells fishy, it is old. I have done a lot of fishing in my life and fresh fish do not smell bad. They also have clear eyes, not opaque eyes.

Histamine And Wine

Wine may contain biogenic amines that were already present in the grapes such as  isoamylamine, methylamine, and putrescine. However, they can also be produced by a process called malolactic fermentation.

Foods That Are Considered High Histamine (or other amines)

• Any  meat, fish, chicken or other high animal protein that is not completely and totally fresh and refrigerated appropriately
• Cured meat such as salami, prosciutto etc.
• Aged beef
• Some smoked meats
• Aged cheese
• Fermented vegetables such as kimchi, sauerkraut, sour pickles
• Fish sauce
• Shrimp paste
• Fish paste
• Fermented anchovies
• Kefir
• Soy sauce
• Red pepper paste
• Soybean paste
• Tamari
• Champagne is sometimes quite high

Any food that has been fermented or cultured is suspect as having high histamine.

 

Bacteria Continue To Produce Histamine In the Gut

Bacteria growing in food can continue to produce histamine in the gut. So, if an individual eats a food that contains bacteria that are producing histamine or other biogenic amines from the amino acids in the food, some of the bacteria may be killed by the acid in the stomach but depending on how many bacteria there are and if the person makes enough acid, will depend on how many of them continue on into the intestine.  Here in the intestine the decarboxylase enzymes made by these bacteria could easily continue to break down the amino acids into amines including histamine.

 

Pathogens And Overgrowth Of Commensal Bacteria May Stimulate Histamine Production

Both commensal bacteria and pathogenic bacteria found in the intestine are included in the group of gut bacteria known to make histamine. Some gut bacteria are known for making histamine while others do not make histamine, however many have not yet been studied as to their histamine making capabilities.

We know cells in the body can degrade the amino acid histadine (from protein) to histamine using histadine decarboxylase enzyme (HDC). This process takes place in the cells as the body  needs some histamine to function. Some of the normal intestinal flora also make HDC and are able to use it to make histamine out of the amino acid histadine.  If we have bacteria out of balance (dysbiosis) this can in some situations add to a higher histamine state if those bacteria are ones that make HDC.

People who have histamine intolerance were shown in one study to have increased levels of Proteobacteria and Bifidobacteriaceae, reduced alpha-diversity as well as elevated stool zonulin levels suggesting a dysbiosis and intestinal barrier dysfunction in histamine intolerant patients.

There is also another situation called small intestinal bacterial overgrowth (SIBO), where bacteria are thought to move upward in the small intestine where they are usually not commonly found. This is a situation where the increased bacteria can often have histamine producers in their midst and be the cause of excess histamine production. So, you will see people with SIBO having problems with excess histamine and overhelmed DAO.

Any pathogen in the gut that puts out toxins will end up setting off the mast cells in the gut lining which will be a source of additional histamine as well as other inflammatory mediators.

Bacteria Produce Histamine In Two Ways

Some microbes have been found in research to erode the protective mucus lining on the gut wall. When the gut wall is irritated mast cells become active and release inflammatory mediators including histamine. This is meant to take care of pathogens, but it also adds to the inflammatory state to some degree. It is important to get the bacterial balance back and heal the gut wall.  If the out-of-control commensal bacteria is one that is a big histamine maker, it will be producing histamine both from its own metabolism as well as from its  bad behavior at the gut wall.

Probiotics - The Good, The Bad And The Ugly

We know probiotics help many people, but they are not always appropriate. We need to be weary that probiotics are not one size fits all. Be careful about suggesting probiotics if someone has histamine intolerance. People with histamine intolerance can react negatively to probiotic mixes unless they are low histamine producing flora. Don't give your patients with histamine intolerance probiotics that contain bacteria that are high histamine producing. Histamine intolerant folks will also react to most fermented products for the same reason. Some of these bacteria used as probiotics or in fermenting food will produce histamine decarboxylase and change the essential amino acid histadine (histadine is found in the gut as a metabolite of protein based foods) into histamine. This is not an issue if the person has enough DAO enzyme, but if they are low in DAO, the person is going to react as if you gave them an allergen. The research examining bacteria that does and does not make histamine is spotty and not at its best. Eventually, we will get this all sorted out.

Decrease The Bacteria Making Histamine  Through Competition With Low Histamine Flora

We know that both pathogenic as well as commensal bacteria can make  L-histidine decarboxylase (HDC) which is what the bacteria in food as well as in our gut use to turn histadine into histamine. Additionally, pathogenic bacteria and excessive growth of some commensal bacteria can irritate and damage the gut causing histamine release. If testing shows there are pathogenic bacteria in an individuals gut, they need to be attended to. The same with out of control commensal bacteria (these bacteria are considered normal and friendly when not in excess  and abnormal if they are in excess). When commensal bacteria are out of control and they are known to make HDC, I suggest my clients use non HDC making bacteria replacement to help to control them before using antimicrobial herbs and supplements.

Some Foods May Cause The Bodies Mast Cells to Release Histamine

All of the foods below are thought to stimulate the mast cells in the intestinal wall to release the histamine, however research is needed. Some of the foods below are also known to contain histamine and sometimes be high in histamine besides possibly causing histamine release by the body. Some of these probably due actually induce mast cell production of histamine, perhaps in certain people or all people to some degree, but we don't have the studies needed. Some of these may only have high histamine rather than actually inducing histamine release. There is some confusion in this category for sure. Here are the foods that are thought might induce histamine release.

• Citrus
• Tomatoes
• Alcohol
• Shellfish
• Pork
• Egg white
• Papaya
• Strawberries
• Nuts
• Peanuts
• Spinach
• Pineapples
• Chocolate
• Chemicals in the diet
  • monosodium glutamate
  • food dyes
  • food flavorings
  • food preservatives

How Cooking Alters Histamine

Researchers looked at how cooking food altered histamine. They found frying and grilling vegetables increased histamine levels in foods while boiling it had little influence or reduced it slightly. All biogenic amines are fairly heat stable and won't be decreased by cooking. Basically, if there is histamine in the food, you are not going to get rid of it by cooking it and if you fry or grill the food, the studies show an increase in histamine.

Severe Histamine Poisoning From Food

Some foods are so high in histamine that they cause Scombroid poisoning. This poisoning can occur when consuming fish, fish products or other possible foods with histamine levels that total more than 1000 ppm. One study found histamine concentrations in tuna fillet in oil, tuna and fresh yellow fin tuna loin are 4398, 3110, and 1774 mg/Kg, respectively. The foods most commonly known to do this are canned or smoked fish such as tuna, mackerel, sardines and anchovies. However, all dark fish that are improperly processed or stored are suspect for Scombroid poisoning which is due to the high histamine levels caused by the improper handling. The histamine is created by decarboxylation of the amino acid histadine in the muscle of the fish. The enzymes that cause the decarboylation are made primarily by gram-negative bacteria growing due to inadequate refrigeration prior to processing or sitting at room temperature after cooking. The bacteria often found in association with this process are Morganella morganii, Escherichia coli, Klebsiella species and Pseudomonas aeruginosa.

This illness usually is seen in allergenic individuals, however it can be seen in anyone. The symptoms are those typical of excess histamine and can include: flushing, rash, urticaria (generally widespread erythema, usually lacking wheals), heart palpitations, headache, dizziness, sweating, and burning of the mouth and throat. Digestive symptoms can include abdominal cramps, nausea, vomiting and diarrhea. Bronchospasm, respiratory distress and vasodilatory shock have also been described. Symptoms begin within 10 to 90 minutes after eating the fish. The rash lasts 2–5 hours, and the other symptoms usually disappear within 3–36 hours. The diagnosis is often clinical and can be confirmed by measurement of histamine in incriminated spoiled food. If measured immediately during the reaction, there will be an elevated histamine level in plasma or the elevated level of histamine metabolites (e.g., n-methylhistamine) in the urine.

This reaction has been linked to what is called "Chinese restaurant syndrome". A study revealed that histamine content in a Chinese restaurant consumed in a regular meal could approach toxic levels of histamine.

There is a variety of foods that are high in histamine. This includes fermented foods, spoiled food, salami, any meat that is old should be suspect. This again relates to bacteria that ferments the food or spoils the food. Therefore making sure food is fresh and well taken care of prior to eating is important.

Pointers To Remember Regarding Food, Bacteria, Mast Cell Release and Histamine

• Research reports some foods in their raw state have a low level of histamine to start with even though the food appears fresh. This includes meat, fish and fruits and even some vegetables. A review of studies showed the only plant foods with significant levels of histamine were eggplant, spinach, tomato and avocado. However, each of these showed high variability of content. I noted in the various studies that some studies showed these vegetables to have relatively low amounts of histamine also. I have to wonder if they were looking at fresh food in some studies and too ripe or damaged food in others since there was such variance in histamine. There was no mention of the condition of the food or how it was grown.  Another amine called putrescine has been found in almost all plant foods. Putrescine competes with histamine for enzymatic degradation. Spermidine is another amine that uses DAO for degradation, although it has a lower affinity for DAO than histamine does.
• Any high protein food that is not super fresh will contain histamine and the less fresh it is the more histamine it will contain. The simple reason for this is bacterial growth that starts soon after death of plant or animal if the food is not properly chilled and or preserved.
• Any food that has been fermented with lactic acid bacteria is suspect as having high histamine and other amines. This is because some of the lactic acid producing bacteria produce decarboxylase enzymes that can produce biogenic amines from amino acids. Some of the bacterial fermented foods known to have high histamine and other amines would include:
  • Kefir
  • Fermented vegetables such as sauerkraut, kimchi, sour pickles etc.
  • Soy sauce
  • Tamari
  • Aged cheeses
  • Cured meats
• Overgrowth of some commensal bacteria or pathogens may be decarboxylase enzyme producing bacteria and make biogenic amines including histamine
• Toxins that end up in the gastrointestinal tract from eating them or from inhalation can add to the histamine load by causing mast cell release of histamine.
• Toxins and anything the body reacts to as a toxin such as pollen that are creating histamine in other areas of the body can add to the general inflammatory load of the body caused by histamines.

• Anything that lowers DAO will increase histamine.
  • Inflammatory or degenerative bowel diseases are a cause of temporary DAO deficiency.
  • Anything that disrupts the intestinal epithelium may lead to DAO deficiency as 90% of DAO is produced from intestinal epithelium.
  • Some drugs will inhibit DAO.
  • Genetic variants can lower ability to produce DAO
• Alcohol can cause histamine reactions for a variety of reasons.
  • First I want to state that alcohol can contain a variety of inflammatory triggers including sulfites, phenolic compounds, aldehydes, histamine, tyramine, inflammatory prostaglandins and various other compounds that give flavor, but also toxicity.
  • Alcohol can  cause a mast cell reaction, liberating histamine due to sulfites or other allergenic and/or toxic components of the wine.
  • Alcohol can contain histamine in the product, stemming from the fermentation process if bacteria is used during the process or if bacteria contaminates the process.
  • Alcohol  is changed into acetaldehyde by the liver and it can liberate histamine from mast cells as well as depress histamine elimination by inhibiting diamine oxidase. In research with Asians, the histamine release helped decrease gastric, lung, and intestinal damage as well as flushing.

 

The Key To Lower Histamine In The Digestive Tract Is DAO

Diamine oxidase or DAO is an enzyme that rapidly removes dietary histamine as well as bacterial made histamine and even helps with that made by the mast cells lining the gut. It will help remove any histamine in the digestive tract.  It has also been shown to remove the amines called putrescine and cadaverine. It is considered the major enzyme for removal of histamine. Anyone with low DAO is at risk of  intolerance or outright toxicity. DAO is the main enzyme responsible for metabolising histamine in the intestinal tract. The number one factor for histamine intolerance has been found to be impaired enzymatic degradation of histamine caused by either genetic or acquired impairment in the enzyme production. Both the DAO enzyme and enzyme histamine-N-methyltransferase (HNMT) can be affected by genetic variants, but since we are examining diet and gut related histamine we are focusing on DAO. Some people are low in DAO due to polymorphisms of a single nucleotide in the gene that encodes this enzyme (AOC1 on chromosome 7). Other people have what is usually a temporary lack of DAO due to inflammatory or degenerative bowel diseases that can have temporary DAO deficiency while the illness is active. Anything that may alter the enterocytes (intestinal cells) may decrease DAO production. This means anything that causes intestinal inflammation or damage is a possible factor in histamine intolerance.

Some  Drugs Are known to block or inhibit  DAO production

• Alcohol
• Nicotine
• Acetylcysteine (not a drug, a supplement)
• Cimetidine
• Dihydralazine
• Clavulanic acid
• Metoclopramide
• Verapamil
• Pimagedine (AKA aminoguanidine)
• Chloroquine
• Pentamidine
• Cycloserine
• Dobutamine
• Pancuronium
• Radiologic contrast media
• Morphine
• Metamizole
• Verapomil
• Propfenon
• Cefuroxime
• Calvulanic acid
• Cimetidine
• Thiopental
• Metoclopramide
• Amiloride
• Ambroxl aminophyline
• Ibuprofen
• Aspirin
• Prozac
• Zoloft
• Humira
• Enbrel
• Plaquenil
• Propanolol
• Metrapolol
• Cardizem
• Norvasc
• Allegra
• Zyrtec
• Benadryl
• Tagamet
• Pepcid
• Zantac
• Some food additives

The drug diphenhydramine has been shown to increase DAO activity.

Other things researchers have found lower DAO activity

• Excessive intake of probiotics
• Chemotherapy
• Excessive intake of tyramine or putrescine
• Gastrointestinal inflammatory diseases
• Gastrointestinal cancers

Drugs Are known to block HNMT

If an individual is taking one of these drugs, they may be adding to the excess histamine level in their body.

• Chloroquine (Amodiaquin, an antimalarial))
• Chloroguanil
• Folate antagonists such as metoprine (HNMT requires folate for activity)
• Hydroxychloroquine
• Pyrimethamine
• Promethazine
• Metoprine
• Diphenhydramine
• Tacrine (anticholinesterase, early Alzheimer’s drug)

 

What We Learned About Histamine Intolerance

• We learned that histamine is made from the amino acid histadine and is created by bacteria in food that is not fresh. Some small amount of histamine can normally be found in food, but when high it is due to bacterial activation in old or mishandled food OR it might be a cultured or fermented food where bacteria were used to alter the food into an aged cheese, a preserved meat, or soured vegetable.
• Eating a low histamine diet can lower reactions to food. However the main issue is how food is handled and preserved rather than certain foods always having high histamine.
• Histamine can also be made in the body by bacteria that live in our gut. They can make histamine from histadine in the food eaten or if the bacteria is not completely friendly they or their toxins might irritate the gut wall and cause release of histamine from mast cells.
• Some people have genetic variants that keep them from making enough DAO while some people have acquired histamine intolerance that may be transient.
• Acquired histamine intolerance may be due to using DAO blocking drugs, HTNM blocking drugs, gut dysbiosis or pathogens or may be due to intestinal inflammation and damage from toxins or disease.
• The most common reason for histamine intolerance is a lack of adequate DAO and it can be replaced.
• Histamine in the gut is taken up into the bloodstream and increased plasma concentrations of histamine can cause symptoms elsewhere. Additionally, metabolites of histamine may also inhibit HNMT which is the intracellular enzyme that breaks down histamine.

 

In the second part of this article called Histamine Intolerance Solutions we cover

• How to lessen histamine from forming in food
• Foods likely to be high in histamine
• The use of specific probiotics to compete with commensal bacteria overgrowth that make histamine
• Treating health conditions that induce histamine release by mast cells
• How to remove histamine from the body by the use of supplemental enzymes
• How to decrease histamine release by stabilizing mast cells

See part two of this article called Histamine Intolerance Solutions.

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