Histamine Intolerance: Everything You Need to Know

February 5, 2021 Seeking Health

Do you get a runny nose or headaches after eating certain foods?

Do you have chronic itchy or flushing skin?

You might be struggling with histamine intolerance, which can cause adverse symptoms when consuming certain foods and drinks that are high in something called histamine.

Is Histamine Intolerance Real?

This intolerance is relatively new in the medical field. Though often referred to as a single “condition,” it represents many different dysfunctions relating to a natural compound in our bodies called histamine.

Histamine has become an enormous topic for health bloggers, in clinics, and most of all, with our customers here at Seeking Health.

Why?

Histamine intolerance is controversial and something that many health professionals don’t yet understand. It is reminiscent of when celiac disease first arose: people knew there was a sensitivity appearing with grains and breads, but science could not yet explain it. Along the same lines, histamine intolerance is difficult to diagnose because you can’t accurately test for histamine in your body and the symptoms overlap with many other conditions, such as food allergies and mast cell activation syndrome (MCAS).

And this is where it gets tricky — histamine intolerance can also be a cause of something simple, such as medications you're taking. This makes it difficult for medical professionals and scientists to label it as a “condition” or “disease.”

Most people have not heard of histamine intolerance unless they’ve had symptoms themselves! It’s these multifactorial, undefinable properties that make this condition so difficult to treat. Before we dive into histamine intolerance, let's first look at why histamine matters.

What is Histamine?

If you have heard of histamine before, you probably know it as something that causes allergic symptoms — swelling, itchy, watery eyes, and anaphylaxis.

Histamine is a signaling compound that acts as a neurotransmitter. One of its primary responsibilities is telling the rest of the body when something is wrong so that it can be fixed. It operates a bit like an alarm system that goes off in your house when a burglar is detected. (1, 2, 3) When your body has an injury or infection, histamine is released to signal immune cells to help fight microbes and other invaders. This also signals swelling to occur in the area of injury to localize the immune cells for healing. You might recognize the effects of histamine if you have a runny nose and itchy eyes when you walk through a field or have any food allergy. (1,2,3) But histamine is much more than allergies.You can have zero food allergies and still struggle with histamine intolerance.

Histamine is profound in that it is a necessary part of our immune system. For example, have you ever had motion sickness and taken the popular anti-nausea medication Dramamine? The main ingredient is an antihistamine called Dimenhydrinate. (6) Histamine and sitting a boat in choppy waters may not seem to have a connection — but they do.

Histamine is found in nearly all tissues, such as stomach mucosa lining, neurons, mast cells, and basophils (a type of white blood cell.) It plays extensive roles in smooth muscle contraction, brain excitation (yes, this is why you can get tired after taking antihistamines, like Benedryll!), widening of blood vessels, and sensory system signaling in the brain. (1, 3,4,7) This role in sensory signaling — specifically overactivation of the H1 histamine receptor — can lead to a feeling of nausea when you are in a moving boat or car, known as motion sickness. (6,7)

Prolonged high histamine levels or an overactive histamine response can contribute to things like motion sickness, specific food sensitivities, spontaneous skin rashes, ulcerative colitis, or even migraines. (13, 20, 21, 28, 29)

So yes, histamine is more than allergies. Histamine is crucial to your health!

What is Histamine Intolerance?

Histamine is a natural, necessary compound in the body, but in high amounts, it can lead to histamine overload symptoms. Histamine intolerance is a condition where you get side effects from exposure to histamine, such as the consumption of high histamine foods (like fermented foods). (1, 2)

Histamine intolerance occurs when there is an abnormally high amount of histamine in the body. Our body is usually quite efficient at regulating histamine levels. As our body produces histamine, we have enzymes that break it down to assure that there is not too much floating around at one time. When we consume foods high in histamine, our intestinal cells produce an enzyme called diamine oxidase (DAO) to help us break it down. Histamine intolerance can occur when these enzymes are not doing their jobs. With this dysregulation of histamine, there becomes a histamine overload, in which the body is sensitive to any added histamines. Where might we get exposed to extra histamine? From foods, drinks, and the intestinal microbiome. (1, 2) Our gut can increase the burden when it is inhabited by organisms that are notorious for producing histamine. In fact, some organisms are quite skilled at producing histamine in both our intestines and our foods.

For example, foods that contain the highest amounts of histamine tend to be those that are produced via microbial fermentation, such as alcohol, pickled items, processed meats, and aged cheeses. (2, 15) (So a charcuterie board may be your worst enemy, especially because it is always accompanied by wine!)

If you are a person that responds to these foods with headaches, rapid heartbeat, flushed skin, and runny nose, you may benefit from examining histamine intolerance. (1)

Histamine Intolerance vs. Food Allergies

You might be wondering: what is the difference between food allergies and histamine intolerance?

Histamine intolerance is not a food allergy. It's an entirely different concept.

Food allergies are an incorrect response by your immune system. Due to either genetics, a poorly trained immune system, a lack of healthy bacterial exposure at birth, nutrient deficiencies, exposures to harmful food antigens via a permeable gut, or a combination of these things, the immune system mistakes a food protein as a foreign invader and launches an attack against it. As part of that response, IgE antibodies are put into the blood circulation that bind to mast cells, where they wait to be bound to fragments (antigens) from the allergic food. When that food is eaten, and the mast cells have fragments of this food attached to them, they release histamine and create classic allergic symptoms. (2, 18)

On the other hand, histamine intolerance is the overload of histamine in the body, leading to negative symptoms such as skin flushing and rapid heartbeat when histamine-containing foods are consumed. Ingested histamine does not trigger IgE or antibody responses. But it's the similarities in symptoms that can confuse the diagnosis. (2)

What is Mast Cell Activation Syndrome?

To confuse matters even more, researchers have discovered another condition that releases histamine into the body called Mast Cell Activation Syndrome or MCAS. MCAS occurs when the mast cells release histamine into the body at an accelerated rate. Usually, the mast cell will contain histamine until it receives a strong signal to release it. Science is now showing that mast cells can be more susceptible to releasing histamine due to chemical exposures, genetic abnormalities, and even nutrient deficiencies. (8, 16, 40) Not to complicate things further, but it's entirely possible to have food allergies, MCAS, and histamine intolerance by the above definitions.

So, if you still think histamine intolerance is a culprit of yours, let’s look at the common symptoms to see if they match yours.

Symptoms of Histamine Intolerance

The thing about histamine intolerance is that the symptoms overlap very closely with allergies and sensitivities, such as Mast Cell Activation Syndrome. As such, histamine intolerance is very difficult to diagnose. (2)

It is essential to work with a qualified healthcare practitioner who is familiar with treating histamine intolerance. For example, dietitians, nutritionists, Functional Medicine practitioners, naturopathic doctors, and allergists are a great place to start. In a bit, we’ll discuss how your practitioner can help to test for and diagnose histamine intolerance. Keep in mind that it’s important to work closely with your healthcare professional to track your symptoms, especially after eating foods high in histamine.

Common Symptoms of Histamine Intolerance (1)

Headaches
Dizziness
Rapid heartbeat
Weak muscle tone
Sudden low blood pressure/cardiac collapse
Itchy skin
Flushing skin
Hives
Eczema
Swelling
Runny nose
Nasal congestion and irritation
Sneezing
Shortness of breath
Bloating and gas
A feeling of ‘fullness’
Diarrhea
Abdominal pain
Constipation
Nausea
Vomiting

The above symptoms are the main symptoms of histamine intolerance. But there are many more symptoms in which histamine intolerance can be the direct or indirect cause. If you think you have histamine intolerance based on the above symptoms, you will want to manage it effectively and address the root cause.

Why is it important to diagnose and address histamine intolerance if you have symptoms? Research has associated altered levels of histamine and histamine response with major diseases, including neurodegenerative disorders and brain diseases. (5, 11, 13, 14)

What Causes Histamine Intolerance?

The causes of histamine intolerance are not specific, but multifaceted. It may start because of genetic polymorphisms in enzymes that produce, degrade, or trigger histamine release. However, it can also be due to a combination of other conditions. Be patient: it may take several avenues of support before seeing a decrease in your symptoms.

Now, let’s explore how histamine production and degradation can lead to intolerance.

Histamine is produced from the amino acid histidine via an enzyme called histidine decarboxylase (HDC). It is then stored in mast cells (in the gut, lungs, and skin), basophils (found throughout the body), platelets (found circulating in the bloodstream), neurons (nerves in the brain and spinal column), and GI mucosal cells (of the stomach and intestines). Once it is released from storage, histamine can be activated via four histamine receptors: H1, H2, H3, or H4. These receptors are located in various areas around the body and activate histamine in different ways.

In healthy individuals, histamine is then metabolized and excreted properly to prevent damage to the body. Your histamine is broken down using two enzymes:

Histamine-N-methyltransferase (HNMT)
Diamine oxidase (DAO)

HNMT metabolizes about 50 to 80 percent of histamine inside your cells by placing a carbon onto it and changing its shape. This carbon is called a methyl group. As you likely know, this group relies on sufficient levels of active folate and B12 to work. If there are problems with these B vitamins or other aspects of your methylation cycle, HNMT has a hard time doing its job, and histamine levels may build up.

DAO metabolizes about 15 to 30 percent of your histamine outside of your cells. This includes histamine from food, drinks, and microbiome production. (4) In histamine intolerance, much of the research is directed towards improving DAO levels to lower symptoms. Therefore, improving DAO activity on histamine is a logical first step on your journey of normalizing histamine associated symptoms.

A “Slow” DAO

DAO deficiency is the most well-known cause of histamine intolerance. (2) For this reason, we will focus on improving DAO production in the body for the management of histamine intolerance. Normally, when you consume histamine from food, it gets metabolized in your gut by the enzyme DAO. Too little of this enzyme can lead to unmetabolized histamine.

The DAO gene writes the code for the DAO enzyme. This means that if there is a variation in this gene, it may affect the DAO enzyme activity. DAO variations, called single nucleotide polymorphisms (SNPs), can cause a slower DAO enzyme, and therefore a slowed ability to metabolize histamine. (2, 12, 21) You can take a DNA test that evaluates potential variations in your histamine pathway, called StrateGene^® The detailed report you receive will show you whether you have roadblocks in your ability to break down histamines, such as your DAO enzyme.

Keep in mind that genetic testing is NOT diagnostic for histamine intolerance. It will only show you genetically how your histamine pathway works. Many factors in your environment can improve how your genes are functioning. For example, the DAO enzyme can be slowed by environmental factors such as excessive alcohol intake, small intestinal bacterial overgrowth, ‘leaky’ gut, and NSAIDs’ overuse. (2)

The Strategene^® DNA test can inform you about the genes you have and the lifestyle factors that can assist them in normal functions. In combination with looking at symptoms, a skilled healthcare practitioner can refer to StrateGene^® to help you to determine your histamine load and even the underlying causes of your histamine intolerance symptoms. (10, 12, 13, 21, 24)

Sluggish Histamine Pathway

Addressing DAO alone may not solve all your histamine intolerance issues. Why? There are many environmental causes of histamine intolerance. The process by which multiple enzymes help to break down histamine and histamine byproducts is called the histamine pathway. You may want to look at other enzymes in your histamine pathway with a qualified healthcare practitioner to see what else (other than, or in addition to DAO deficiency) might be contributing to histamine intolerance.

Let's take a look at the histamine pathway.

Histamine is created from the amino acid histidine.

Histamine exerts its effects through four histamine receptors (HR) when it's needed (i.e., stomach acid secretion before you eat). These receptors each have their own role in activating histamine response in a certain area in the body. Therefore, if there is a genetic variation in the gene that causes these receptors to increase their activity, you may experience an increased histamine response. These receptors and associated SNPs are involved in many conditions, including motion sickness, allergies, autoimmune disease, and heart failure. (10, 21, 23, 22)

Histamine is metabolized in two major ways: via the Histamine N-Methyltransferase (HNMT) enzyme or Diamine Oxidase (DAO) enzyme. Most of your histamine is metabolized via HNMT (50 to 80 percent), which is intracellular histamine. However, DAO metabolizes extracellular histamine, including that which you consume from foods and drinks. Normally, DAO is of special focus because it's the main cause of histamine intolerance. It can be genetically varied and have weakened levels in your body due to excessive alcohol intake, overuse of NSAIDs, leaky gut, and small intestinal bacterial overgrowth. This means that the low presence of this enzyme can result in higher sensitivity to histamine from dietary sources. A polymorphism in the DAO or HNMT gene that reduces these enzymes’ activity can be a major contributor to histamine intolerance. (2, 1, 10, 11, 13, 21)

Knowing your genetic variations by taking a genetic test like StrateGene^® can empower you to make the right choices for your body. DNA testing can often help people understand the “why” behind their histamine intolerance and drive them to focus on the areas of need.

Gut Imbalances

Though gut inflammation does not cause histamine intolerance, it is associated with higher histamine levels by lowering DAO activity. Addressing your gut conditions could be a major step in managing histamine intolerance. On top of that, certain bacteria in your gut produce extra histamine. Too much pathogenic bacteria in your gut from things like antibiotic use, IBS, ‘leaky gut,’ or poor diet can cause an overproduction of bad bacteria and an underproduction of beneficial bacteria and gut inflammation. Research shows that those with Irritable Bowel Syndrome (IBS) and Irritable Bowel Disease (IBD) have higher histamine release from mast cells due to inflammation. (17, 19) Research also shows that ulcerative colitis and Crohn's disease are associated with DAO alterations or high histamine. (20, 24, 25)

It's important to note that while there are many causes of histamine intolerance, the most common is related to the DAO enzyme. Deficiency in DAO (which breaks down extracellular histamine) can lead to an overload of histamine, and therefore histamine intolerance.

How to Diagnose Histamine Intolerance

Approximately 1 percent of the population has histamine intolerance. Yet, this emerging condition may be more prevalent than we are able to record, as we are continually finding more symptoms associated with high histamine levels. Because of this condition’s multifaceted symptoms and the often delayed response to histamine ingestion, histamine intolerance is extremely difficult to test for. (2)

Due to the short life of histamine in the body, histamine itself is challenging to measure accurately. Measuring histamine or DAO levels alone is not the best diagnostic tool. Even genetic testing is not diagnostic. For the most part, determining histamine intolerance involves evaluating and tracking symptoms along with diet and other tests. (1)

Always work with a qualified healthcare professional, as they will best be able to diagnose histamine intolerance. Below is a science-backed way to define histamine intolerance with your dedicated health professional.

How to Know If You Have Histamine Intolerance: (1)

1. Medical History Checklist:

1. Have two or more symptoms of histamine intolerance
2. Rule out food allergies and mastocytosis: skin prick test (36)
3. Rule out other gastrointestinal diseases
4. Rule out DAO-inhibiting medications

2. Histamine Exclusion/Elimination

1. Follow a low-histamine diet (4-8 weeks)
2. Thorough 24-hour record of food consumption and symptomatology
3. Remission or improvement of symptoms

3. Complementary Testing

1. Determination of DAO enzymatic activity in plasma or intestinal biopsy
2. Histamine challenge test
3. Histamine 50-skin-prick
4. Identify genetic variations (SNPs) in Histamine Pathway, such as with StrateGene®
5. Stool and urine testing for histamine biomarkers

How to Treat Histamine Intolerance

Below are different approaches to managing histamine intolerance naturally, depending on your health professional’s recommendations and the causes for high histamine.

Antihistamines

Taking antihistamines is a common and immediate approach for those who get reactions to high histamine foods. (2, 6) Antihistamines act on histamine receptors by modulating their response to histamine, but do not help metabolize excess histamine. Benadryl, a common antihistamine used for seasonal allergies, is also a standard option for those experiencing histamine intolerance symptoms. The popular medication for motion sickness, called Dramamine, contains an antihistamine, as motion sickness is related to the histamine response. (6) Because histamine functions as a neurotransmitter that can excite the brain, antihistamines are known to cause drowsiness. (1, 6)

Keep in mind that antihistamines act on histamine receptors. They do not reduce histamine levels. Therefore, they are not effective in addressing the root cause of histamine intolerance.

Low-Histamine Diet

A histamine-free diet may be the best option for histamine intolerance, especially if your symptoms are more systemic, such as intense itching. (27) However, DAO activity does not change for histamine-free diets, which is why it may be essential to consider supplements that enhance DAO activity. A histamine-free diet may involve removing or minimizing all foods that are high in histamine.

Foods High in Histamine (2, 15)

Fish (frozen, smoked, salted, canned), including:
- Tuna
- Mackerel
- Herring
- Sardine
Cheese, including:
- Parmesan
- Swiss
- Cheddar
- Gouda

Other high histamine foods include:

Salami
Sauerkraut
Spinach
Eggplant
Tomato Ketchup
Red wine vinegar
Wine
Beer
Champagne

In addition to the above-mentioned histamine-containing foods, there are also foods known to promote histamine release from mast cells, even if some of them do not contain histamine. A histamine-free diet may also include removing these foods, depending on your individual reaction to them.

Foods Known to Promote Histamine Release (2)

Citrus Fruit
Fish
Crustaceans
Papaya
Strawberries
Pineapple
Nuts
Peanuts
Tomatoes
Spinach
Chocolate
Food additives
Licorice
Spices
Egg white
Pork

DAO (diamine oxidase)

Supplementing with DAO is one of the quickest and most effective ways to reduce histamine from ingestion of high histamine foods. This is because if you have histamine intolerance, you most likely have inefficient DAO levels. (32)

Consuming DAO orally has been shown to help support symptoms of itching and headaches due to histamine intolerance. (28, 29) DAO supplementation has also been shown to improve histamine response by lowering histamine levels. (26)

Amazing.

But keep one thing in mind: providing your body with DAO does not cure histamine intolerance.

It just gives you enough DAO for that meal — and then it's gone. It can be an excellent tool for meals with friends, holidays, and times when you simply want to eat foods that contain histamines. But you still need to do something about your body’s own production of DAO and support your own histamine metabolism.

Histamine-Free Probiotics

As discussed earlier, gut inflammation can trigger histamine and also can contribute to lower DAO activity. (17, 19, 20, 24, 25) Treating any gut conditions or imbalances by working with a qualified healthcare practitioner may be the best choice for your histamine intolerance.

Probiotics are a fantastic way to support a healthy balance of gut bacteria for optimal health. However, many probiotics produce histamine naturally. So this means, taking a probiotic may actually make your histamine intolerance symptoms worse! Thus, it is best to choose a probiotic strain formulated not to include any histamine-producing species.

Vitamin C

Vitamin C is a popular supplement for immune support. One of its supportive mechanisms may be its role in histamine breakdown. When taken orally, vitamin C is known to help reduce histamine levels, possibly due to its role in DAO production and histamine breakdown, as well as slowing the release of histamine from storage in immune cells. When given in an IV, it reduces histamine in people with high histamine conditions of all types. (31, 33) It is also known to support sea/motion sickness. (30) As you can see, don’t go without your vitamin C! Adding vitamin C into your regime is a fantastic and straightforward way to support healthy histamine breakdown.

Histamine Enzyme Cofactors

Cofactors are nutrients that are needed for an enzyme to function, such as DAO and HNMT. Without adequate cofactors, enzyme activity can be slowed down. For DAO to function, sufficient levels of copper, calcium, and vitamin B6 are needed. (2, 34, 35) It’s important to understand that supplementing with certain nutrients, such as calcium and copper, can be dangerous in high amounts. Always work with your qualified healthcare practitioner to test your levels of these nutrients and to work towards ensuring adequate body stores.

For HNMT to function, it needs something called methyl groups. These methyl groups are provided by S-adenosyl-methionine (SAMe), our body’s primary “methyl donor.” This compound may be helpful if you need to support the function of your HNMT, such as having a genetic variant in the HNMT gene. (2)

Flavonoids

Flavonoids support a healthy response to inflammation and are mostly found in citrus fruits. They have anti-inflammatory and antioxidant properties in nature and have been studied in their effects on human health. In particular, a flavonoid compound found in many fruits and plants, known as quercetin, can help to support a healthy response to histamine and healthy inflammation. It has also been shown to have a positive effect on skin issues related to inflammation and histamine. Another flavonoid, called luteolin, supports healthy anti-inflammatory activity. (37,39, 38)

The Bottom Line

Histamine is a substance released by the immune system and has a host of responses in the human body, many of which could be problematic. As a result, the body has tight regulatory mechanisms, including the enzymes HNMT and DAO. When these enzymes are not operating well due to genetic or epigenetic factors, we build up too much histamine and “lose tolerance” for any additional histamine coming from the diet or intestinal microbes. The solution appears to be supporting the enzyme functions, reducing the amount of histamine ingested, and balancing the gut microbial ecosystem with organisms that are less likely to hyper-produce histamine. Once these actions are taken, and a state of balance is reached, histamine from the diet and gut microbes will likely be better tolerated.

Histamine intolerance is extremely multifactorial — many other conditions and lifestyle choices can cause high histamine and poor degradation. However, the most common reason for histamine intolerance is low DAO enzyme activity compared to histamine levels. This is most likely due to a DAO gene variation or another lifestyle factor.

It can be difficult to accurately test for histamine intolerance, and it is essential to work with a skilled healthcare professional. Tracking symptoms is the most critical component of diagnosing histamine intolerance. Many people follow an elimination diet that removes high histamine and histamine-trigger foods for a few weeks or months. Re-introducing these foods one at a time can give insights as to whether they are playing a role in symptoms.

When it comes to managing histamine intolerance, the first step is removing any barriers to histamine metabolism and following a low-histamine diet. Some people discover a medication is what’s disrupting their DAO enzyme. If there are other existing conditions, such as food allergies, you will want to address them first to not confuse your histamine intolerance symptoms with them.

No matter what, know that you are not alone in your search for answers and solutions. If you’re looking for a place to start, consider taking the StrateGene® DNA Test to gain insights into your DAO gene and other histamine pathway genes and enzymes. Most importantly, be sure to work with a qualified healthcare practitioner who can test and evaluate you for histamine intolerance and guide you through a histamine elimination diet.

References

Topics: Diet, Histamine, Histamine Intolerance, Low Histamine, Nutrition, StrateGene

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