Histamine Intolerance

Histamine intolerance (HIT) is one of the frequently cited issues that are difficult to diagnose and treat.
Every individual is sensitive to a different amount of histamine, manifesting through a range of different symptoms. Additionally, many other diseases are associated with HIT, which can lead to symptoms being initially attributed to a different illness. HIT can occur in anyone, at any age, and can also disappear at any time during one’s life. It is not a condition that people suffering from HIT must adhere to a low-histamine elimination diet for the rest of their lives.
Histamine is a substance that is formed from the amino acid histidine. When dealing with HIT, it is important to know that histamine is produced:

- In the human body.
Inside mast cells and basophilic granulocytes (mast cells are most commonly found in the skin and digestive system, basophilic granulocytes in the blood, capable of releasing histamine into their surroundings and causing allergic reactions).
Histamine is also produced by the activity of intestinal bacteria.

- In foods.
During their storage or processing, primarily through the fermentation activities of certain microorganisms (e.g., Enterococcus, Staphylococcus, Lactobacillus, Streptococcus, Escherichia, etc.), which multiply on foods during improper storage. Generally, as the storage time increases (i.e., as the freshness of the food decreases), the amount of histamine in the food increases.

Histamine is a substance that the organism necessarily needs and plays several functions in the body:
- A hormone causing cell growth and division,
- A neurotransmitter in the central nervous system,
- Acts as a wakefulness hormone in the brain and stimulates us for performance,
- In the digestive tract, it supports gastric acid secretion, aiding in food digestion.
In larger quantities, it causes allergic and inflammatory reactions, vasodilation, and other pathological states.

In healthy individuals, the rapid breakdown of histamine in the gut is ensured by the enzyme diamine oxidase (DAO). In addition to DAO, the body also produces histamine N-methyltransferase (HNMT), which can also degrade histamine (if histamine is not broken down by DAO in the gut, it is absorbed through the intestinal mucosa and carried by the blood to the liver, where it is broken down by HNMT). Both enzymes are important because:
1. DAO can only degrade extracellular histamine taken from foods,
2. HNMT breaks down only endogenous histamine produced by mast cells, basophilic granulocytes, or intestinal bacteria.

At first glance, it might seem that avoiding foods with high histamine content is sufficient when managing HIT. The situation, however, is more complex because its toxic effects can be exacerbated by the presence of other substances. Chemically, histamine belongs to the group of substances known as biogenic amines. These are substances formed from amino acids, and the following biogenic amines have a direct relationship with histamine metabolism (and thus the development and course of HIT):

Tyramine.
Formed from the amino acid tyrosine. Cheese, meat, cured meat products, and soy products are rich sources. Symptoms of tyramine poisoning include migraines, and due to blood vessel constriction, also an increase in blood pressure.

Cadaverine and putrescine.
Cadaverine is formed from the amino acid lysine, and putrescine from ornithine during meat decomposition, revealing a characteristic “fishy” odor. They are most commonly found in smoked and pickled meat products (during the thermal processing of these foods, nitrosamines are formed, which have carcinogenic effects). Both together increase histamine toxicity.

Serotonin.
Formed from tryptophan. It acts as a neurotransmitter in the nervous system, supports vasoconstriction, helps regulate sleep, thirst, hunger, mood, and sexual activity.

These biogenic amines are found in varying concentrations in many foods (meat, cheese, fish, vegetables, alcoholic beverages, etc.) and play an important role as indicators of food quality. Their formation is influenced by:
- The quality of raw materials (composition, pH, salt concentration),
- The presence of certain microorganisms (Enterococcus, Pseudomonas, Micrococcus, Lactobacillus, etc.),
- Conditions of storage and processing of foods (fresh, pickled, fermented, chilled, frozen, modified atmosphere, irradiated).
Their formation is also determined by the temperature of storage – low temperatures reduce microbial activity, thereby decreasing the production of biogenic amines. Higher temperatures, on the other hand, promote microbial growth in foods, which leads to the formation of large quantities. All these factors work together and determine their total amount in foods. Important for dietary planning is knowing that these substances are thermostable – once formed, it is difficult to subsequently destroy them (e.g., by cooking).

Histamine intolerance is defined as a compromised ability to degrade histamine, leading to its accumulation in the body. Impaired histamine degradation can be caused by:
1. Reduced activity of DAO or HNMT,
2. Increased concentration of endogenous and exogenous (dietary, alcohol) histamine.

These problems are caused genetically, or can be acquired through an impaired function of the DAO or HNMT enzymes. To make matters more complicated, reduced DAO activity can be caused by:

- Certain intestinal or gastric diseases.
Most often, celiac disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, where intestinal cells (enterocytes) are damaged.

- Use of medications that act as DAO blockers.
The most common are antidepressants.

- Use of medications affecting histamine metabolism in other ways.
These include mainly analgesics, antirheumatics, diuretics, antibiotics.

Additionally, HIT is closely associated with other allergies and food intolerances (to lactose, fructose, gluten), making its diagnosis and the implementation of an elimination diet complex and time-consuming.

Typical symptoms of HIT are:
- Migraines,
- Dizziness,
- Digestive issues (diarrhea, vomiting),
- Respiratory issues (shortness of breath, cough, asthma, rhinitis),
- Atopic eczema,
- Itchy rashes,
- Increased heart rate,
- Low blood pressure.

In practice, the diagnosis of HIT most often focuses on examining the level of DAO in the blood. The problem is that the concentration of the enzyme may not correspond to its activity on the intestinal mucosa. This means that higher levels of DAO in the blood are not necessarily an indicator of HIT status. Much more reliable are histological examinations of the intestinal mucosa, where the DAO activity on the intestinal mucosa itself is determined; however, this procedure is costly and demanding.
Another complication in correctly diagnosing HIT is determining HNMT – this enzyme is only present in cells, and it cannot be measured in the blood.
Another challenge in diagnosing HIT is that the reason for the body's reactions may not be direct intolerance to histamine or biogenic amines, but disrupted intestinal microbiota or FODMAP carbohydrates, which for various reasons the digestive tract cannot process.

The Influence of Diet on Histamine Intolerance

The most effective for the treatment of HIT is following a low-histamine elimination diet, whereby histamine intake is limited and symptom alleviation occurs. The fundamental and logical principle of this diet is to avoid foods with higher histamine content. However, the elimination diet has a few minor flaws, as manifestations of HIT:

1. Are not dependent solely on the quantity of histamine intake from the diet. Thus, the elimination diet will have varying effects on each individual. It cannot be generalized.

2. Are intensified by the presence of certain diseases or administered medications.

3. Are intensified by the presence of additional biogenic amines.

In practice, the elimination diet for HIT is managed as follows:

1. Focus absolutely on the freshest possible foods (as the storage time increases, so does the histamine content, even in foods commonly presented as low-histamine).

2. Because this is an elimination diet, in which a whole range of foods are excluded, there is an increased (and very real) risk of nutritional deficiency and subsequently the development of various metabolic disorders (including weakening of the immune system). Therefore, it is necessary to monitor nutritional parameters of the diet and try to balance all deficiencies.

3. Since an elevated amount of histamine in the body is a factor that lays the foundation for the development of inflammatory processes (or HIT occurs together with inflammatory diseases), it is beneficial in the diet to prefer foods (and their combinations) that exhibit anti-inflammatory characteristics (in this sense, it is possible to refer to substances or foods with anti-inflammatory effects as natural antihistamines).
This includes increasing the intake of antioxidants and monitoring acid-base characteristics of foods. Practice shows that simply avoiding histamine sources while leading to nutritional deficiency does not simply work for the population affected by HIT.

4. Histamine produced in the large intestine can be influenced by modifying the activity of the intestinal microbiota. Generally speaking, this involves respecting basic rules:
- A lower number of meals during the day (ideally 3),
- Increased intake of fiber,
- Intake of selected probiotics.

5. The activity of the enzymes DAO and HNMT can be supported by a sufficient intake of certain substances – these include vitamins B6, B9, B12, magnesium, iron, and zinc. Higher doses of vitamin C help (together with a higher intake of fluids) to break down histamine and excrete it from the body in urine. During the elimination diet, it is not always easy to ensure their adequacy through diet, so it pays off to include appropriate dietary supplements.

6. A 4-6 week elimination diet is typically recommended in the first phase. During this period, it is necessary to avoid:
- Foods with a high content of not only histamine itself but of biogenic amines as a whole.
- Foods that lead to increased release of histamine – the so-called histamine liberators.
- Sources of gluten – a gluten-free diet is practically an advantageous and sensible addition to the elimination diet.

7. After this dietary phase, a new food is included in the diet every other day.
Reactions of the body must be monitored as histamine release can occur up to 48 hours after food consumption (contrary to an allergy, whose manifestations are very quick). If such a food does not cause any reactions, it is fine and can be incorporated into the diet.

One must always account for the fact that this process is lengthy; it is necessary to be patient and not seek shortcuts that do not exist in this area. Apart from dietary modifications, the standard treatment for HIT includes the use of antihistamines (medicines that block the binding of histamine to its receptors, thereby preventing the manifestations of histamine effects). Antihistamines are drugs; however, they do not cure nor prevent the accumulation of histamine in the body, they only prevent unwanted manifestations of HIT. If you are in the process of elimination diet, i.e., mapping foods that are (not) tolerated, using antihistamines will substantially complicate the entire effort.
There are also dietary supplements containing DAO, whose use helps break down histamine in the body. The problem with them is that the enzyme consumed in this way functions only in the intestine, meaning it influences only the histamine ingested with food. Unfortunately, it does not affect histamine released into the blood with other situations. Practice shows that such supplementation does not have the expected impact.