What is Histamine Intolerance? Diagnosis and Treatment

Ever heard of histamine intolerance (HIT)? In recent years, this health condition has gained increased attention. From pesky headaches to puzzling digestive pain or runny nose, the symptoms associated with HIT can be diverse and challenging to pinpoint.

But what is histamine intolerance? In this blog post, we’ll delve into the basics behind HIT and factors that predispose you to it. We’ll also explore how HIT is connected to the gut microbiome and how it’s diagnosed.

What is histamine?

We tend to think of histamine as bad because we associate it with allergic reactions like runny nose and sneezes. But histamine is essential for maintaining good health and is actually important for many different physiological processes. Among other things, histamine has a role in:

• Mediating inflammatory and allergic responses
• Promoting gastric acid production
• Influencing temperature regulation, alertness, and cognitive and behavioral functions [1]

In the human body, histamine is produced by immune cells, like when your body reacts to an allergen and produces histamine at the site. It’s also produced by cells in your stomach and even neurons [2]–[4]. What’s more, certain microbes in your gut are capable of producing histamine [5], [6], and you can also get histamine from certain foods [1], [7], [8]. But more on that later. Then there are histamine receptors, which ‘react’ to histamine, present all over the body [9]. Through these, histamine acts as a chemical messenger, promoting, for example, the recruitment of immune cells to sites of inflammation.

Histamine levels in your body are kept under control by two different enzymes that break histamine down. One of these is diamine oxidase, or DAO, which is mainly produced in your intestines [10]. Among other things, this is important to prevent an exacerbated immune response or too much gastric acid production due to excess histamine.

What is histamine intolerance?

Histamine intolerance (HIT) is described as a type of food intolerance that doesn’t involve an immune response. It’s different from immune-mediated food allergy, in which immune cells react to an allergen by releasing histamine and other inflammatory compounds. There is no such immune response in HIT. Instead, HIT is thought to result from an imbalance between eating food high in histamine and your body’s ability to break it down [1]. Scientists think this occurs when your body doesn’t produce enough DAO enzyme (also known as DAO deficiency). 

DAO deficiency may occur due to genetic factors, that is, mutations in the DAO gene that lead to limited production of the enzyme or reduced activity [11]. And certain medications such as ambroxol, metoclopramide, amitriptyline, and ibuprofen may reduce DAO activity, although evidence of this only comes from laboratory studies [12].

Having increased levels of histamine-producing bacteria in your gut is another factor that seems to predispose you to HIT [6], [13].

HIT is different from an allergic reaction in which even the smallest amount of allergen can cause severe symptoms. In HIT, the severity of symptoms depends on how much food with histamine you eat.

Since histamine receptors are present all over the body, symptoms vary a lot among people. Most common symptoms include:

• Bloating
• Headache
• Gassiness
• Diarrhea
• Heartburn
• Intermittent vomiting
• Abdominal, muscular, and articular pain [6], [14]

For some people, HIT can also manifest with skin symptoms (skin rash, erythema, itchiness, hives, edema) or respiratory symptoms (runny nose, shortness of breath) [1], [6], [14].

Chronic allergic diseases (eczema, allergic rhinitis, asthma) and intestinal diseases (celiac disease, food allergy, inflammatory bowel disease) have been associated with HIT [15]–[18].

Histamine intolerance diagnosis

A practitioner will usually diagnose HIT based on symptoms, clinical history, presence of chronic diseases, and possible relationships with food. But given that symptoms vary so much among people, it may be difficult to reach a diagnosis. Besides, HIT is sometimes confused with other allergic diseases, which should be ruled out appropriately.

The most recommended approach to properly diagnose HIT is to follow a low histamine diet plan for 4 to 8 weeks [19]. This plan considers 3 different phases:

Phase 1: elimination of all foods containing histamine. Foods most often recommended to be avoided include:

• Canned or fermented fish products like sardines in oil and canned tuna
• Fatty fish like salmon, mackerel, and herring
• Hard and semi-hard mature cheese like Parmesan, Cheddar, and Camembert
• Cured, air-dried sausages, hams, and smoked meats
• Certain vegetables like tomato, sauerkraut, and spinach
• Citruses like lemon, orange, and grapefruit
• Strawberries
• Wine and beer

Phase 2: Some of the excluded foods are slowly reintroduced to evaluate if symptoms reappear.

Phase 3: Trial of a long-term diet.

It’s important to follow this low histamine diet plan with the guidance of a healthcare provider.

Additional tests that are sometimes used as histamine intolerance tests to support HIT diagnosis include:

• Determination of DAO concentration in blood serum. This is the most used approach to diagnose HIT, but it’s also controversial because serum levels don’t entirely correspond to intestinal levels, which is where DAO is most active [20]–[22].
• Histamine 50 skin prick test (SPT). This is similar to a standard SPT to diagnose allergy, except that the size of the histamine wheal is assessed after 50 minutes. The problem with this test is that it may be difficult to differentiate between HIT and other allergic disorders and that it may give a positive result to people without HIT [23].
• Intestinal biopsy. Highly sensitive and specific, but invasive and of high cost, so not often used [24].
• Oral histamine challenge test. It involves taking a solution containing histamine and observing clinical symptoms. It’s not recommended because it can also trigger a positive response in people without HIT [25], [26].
• Genetic test. A non-invasive test that looks for mutations in histamine-degrading enzymes, using a sample of blood or from the oral mucosa. This is not used in routine diagnosis [11].

Determination of histamine levels in blood serum. This is of high cost, low availability, and not good to differentiate people with and without HIT [27].

Histamine intolerance treatment

If your provider confirms HIT, treatment will be a long-term diet that limits the amounts of foods that contain histamine. This diet should be personalized for you, as a diet that completely eliminates all foods with histamine is not feasible.

You may also be prescribed a supplement of DAO enzyme. Take into account that there are only a few studies evaluating the effectiveness of these supplements. Some are of low quality, some were supported by the supplement manufacturer, and results regarding effectiveness of the supplements are mixed [25], [28]–[30]. More studies are needed to clearly demonstrate if DAO supplements are a good treatment choice for HIT.

Histamine intolerance and the gut microbiome

Some gut bacteria (e.g. Klebsiella aerogenes, Clostridium perfringens, and Citrobacter youngae) are capable of producing histamine [5] and thus may contribute to your overall levels of histamine. In certain people, having too much of these bacteria could increase sensitivity to ingested histamine, because total levels of histamine circulating in your body will be higher.

Compared to healthy people, those with asthma or inflammatory bowel disease seem to have higher levels of histamine-producing species in the gut [5], [31].

If you have taken a Tiny Health Gut Test, you’ll see a section that reports the levels of histamine-producing species.

It’s important to interpret this section correctly:

• If you have high levels of histamine-producing species but don’t experience any symptoms when eating foods that contain histamine, it’s likely you don’t have HIT. It’s still a good idea to focus on improving your gut microbiome in any areas that need support. This will likely decrease the levels of these unfriendly species.
• If you have low or absent levels of histamine-producing species but experience symptoms or have been diagnosed with HIT, you should take into account that the gut microbiome is only one part of the picture. Genetics and food choices are important factors that may contribute to HIT.
• If you have high levels of histamine-producing species and you’re experiencing symptoms when eating foods with histamine, it’s possible you have HIT. We recommend trying a low histamine diet with the guidance of a healthcare provider to get a proper diagnosis.