In-Depth Insight

Alpha-gal Syndrome: Origin and Mechanics

Understand the alpha-gal sugar molecule, the role of tick bites, and the unique delayed reaction that characterizes this syndrome.

The Biology Behind Alpha-Gal

What is alpha-gal syndrome?

Alpha-gal (α-Gal) is a sugar molecule that occurs naturally in the cells of most mammals. In people with alpha-gal syndrome, the immune system reacts to alpha-gal as if it were a foreign substance. This is a unique form of allergy because the reaction is often delayed and is not noticeable immediately after exposure.

After previous exposure, the immune system can produce IgE antibodies against alpha-gal. When someone with these antibodies is exposed to alpha-gal again, mast cells and basophilic granulocytes, among others, can become activated. Substances such as histamine are then released. These substances cause the various symptoms of an allergic reaction.

An important characteristic of alpha-gal syndrome is the delayed reaction. Unlike many other food allergies, symptoms often do not occur until several hours after exposure. This can make it difficult to establish a link between the symptoms and the food or product that caused the reaction.

Symptoms can vary greatly from person to person and can range from mild to severe. Possible symptoms include:

Skin: itching, redness, hives (urticaria) and swelling, for example of the face, lips or eyelids.
Stomach and intestines: abdominal pain, abdominal cramps, nausea, vomiting and diarrhea.
Respiratory tract: coughing, wheezing, a tight feeling in the chest or shortness of breath.
Heart and circulation: dizziness, a weak or rapid heartbeat, a drop in blood pressure or a feeling of fainting.
General: sudden fatigue, weakness or a strong feeling of being unwell.

In severe cases, an anaphylactic reaction may occur. This is a serious, potentially life-threatening allergic reaction in which multiple organs and body systems may be involved. In the event of severe or rapidly worsening symptoms, immediate medical attention is necessary.

The mechanism

How come the reaction may be delayed?

There is not yet a general consensus on why the reaction to alpha-gal is delayed. The following is generally speculated:

The reaction is delayed because the immune system only responds once the relevant form of alpha-gal, after digestion and absorption into the body, can reach mast cells and other immune cells. Alpha-gal can occur in foods, among other things, attached to fat molecules (glycolipids). These fats are processed differently from proteins during digestion and are, among other things, packaged into chylomicrons, which are transported through the lymphatic system and subsequently into the bloodstream. As a result, it can take several hours for the relevant form of alpha-gal to reach the immune cells and trigger an allergic reaction.

How does one develop alpha-gal syndrome?

Not everyone who is bitten by a tick develops alpha-gal syndrome. The presence of IgE antibodies against alpha-gal also does not automatically mean that someone will actually develop symptoms. The development of the syndrome and the severity of reactions can vary from person to person.

Once sensitization has developed, products derived from mammals can trigger a reaction because they may contain alpha-gal. This includes certain types of mammalian meat, such as beef, pork and lamb. Other mammal-derived products may also cause a reaction in some people.

The severity of a reaction is not determined solely by exposure to alpha-gal, but can also be influenced by individual sensitivity and the circumstances surrounding the exposure. Factors such as physical activity and alcohol consumption can, in some people, intensify or trigger a reaction. This partly explains why a person may not necessarily experience the same symptoms every time they are exposed to the same product.

The alpha-gal syndrome usually develops after a tick bite. Certain tick species can transfer substances containing alpha-gal during a bite. In some people, this causes the immune system to produce IgE antibodies against alpha-gal. The person has thereby become sensitized to alpha-gal.

Although a tick bite forms the theoretical basis, in practice there are also people who develop alpha-gal syndrome without having been bitten by a tick.

Upon subsequent exposure to alpha-gal, these IgE antibodies can bind to mast cells and other immune cells. This activates these cells, causing histamine and other inflammatory substances to be released. This can subsequently lead to the typical symptoms of alpha-gal syndrome.

The syndrome therefore does not develop because alpha-gal itself is harmful, but because the immune system has developed an allergic reaction to alpha-gal.

What products contain Alpha-gal?

Alpha-gal (α-Gal) occurs naturally in the cells of most non-human mammals. As a result, alpha-gal may be present in foods and other products derived from mammals. For people with alpha-gal syndrome (AGS), it is particularly important to note that the amount of alpha-gal and the way in which it is present in a product can vary greatly from one product to another.

Mammalian meat

The main foods that may contain alpha-gal are types of meat derived from mammals. These include:

Beef
Pork
Lamb
Goat meat
Venison and other game meat
Rabbit
Other types of meat derived from mammals

Products containing these types of meat may also be relevant. Examples include sausages, ground meat products, cold cuts, broth, gravy, stews and ready-made meals containing mammalian products.

The amount of alpha-gal is not the same in every part of an animal. The method of preparation and composition of a product may also affect exposure. Therefore, the reaction to a particular food can vary from person to person.

Organs and high-fat products

Organs and other animal tissues from mammals may also contain alpha-gal. Examples include liver, kidneys and other organ meats. In addition, high-fat products derived from mammals may be particularly relevant for some people with AGS.

This is partly related to the fact that alpha-gal can also be present on glycolipids, in which alpha-gal is attached to fat molecules. This may help explain the characteristic delayed onset of a reaction after eating mammalian products.

Gelatin and collagen

Gelatin is made from animal collagen and may be derived from, for example, cattle or pigs. Gelatin can therefore be relevant for people with AGS. It may be found in, among other things:

sweets and marshmallows;
desserts and gelatin-based products;
some dairy and food products;
capsules of medications and dietary supplements;
some other processed foods.

Collagen and ingredients derived from it may also come from mammals. Whether a specific product poses a risk depends, among other things, on the animal source and the individual's sensitivity.

Dairy products

Milk from mammals, such as cow's milk and goat's milk, naturally contains alpha-gal. However, this does not mean that everyone with AGS needs to avoid dairy products. Most people with AGS tolerate some or many dairy products, while others may experience symptoms.

The reaction may also vary depending on the type of product. High-fat dairy products may be more relevant for some people than low-fat varieties. Examples of dairy products include milk, cream, butter, cheese and ice cream.

Therefore, it is not advisable to automatically avoid all dairy products based solely on the presence of alpha-gal. Individual tolerance is an important consideration.

Other ingredients of animal origin

Alpha-gal may also be relevant in various ingredients and excipients of animal origin. These may be present in small amounts in foods, medications, cosmetics or other products.

Examples include certain forms of:

Gelatin
Collagen
Animal fats
Some animal proteins
Some medications
Ingredients derived from organs or other animal tissues

However, not every ingredient of animal origin necessarily contains alpha-gal, and not every product containing such an ingredient causes a reaction. The source and processing of the ingredient are important factors.

Carrageenan (E407)

Carrageenan (E407) is a thickening and stabilizing agent derived from red algae (seaweed). Carrageenan is therefore not derived from mammals and does not contain alpha-gal.

The chemical structure of carrageenan may show certain similarities to structures that contain alpha-gal. Therefore, a possible cross-reaction is sometimes discussed, but carrageenan should not automatically be considered a source of alpha-gal or a proven trigger in AGS. It is important to distinguish between a structural similarity and an actual documented allergic reaction.

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Important to know

Not every person with alpha-gal syndrome reacts to every product derived from a mammal. Individual sensitivity varies greatly, and the amount and form of alpha-gal present in a product may also play a role.

In practice, we sometimes see people who do not have an allergic reaction to alpha-gal and therefore do not have alpha-gal syndrome, but instead have an allergy to specific types of meat. Clinical experience also shows that SAAT can be used effectively in these cases.

It is therefore not always necessary or desirable to eliminate all mammalian products from the diet without medical guidance. An overly restrictive elimination diet may also lead to unnecessary dietary restrictions.

If AGS is suspected or if there are questions about specific foods, medications or ingredients, it is advisable to discuss this with a doctor or allergist.

Alpha-gal in Europe

Alpha-gal syndrome is not exclusively an American problem

Although alpha-gal has received considerable attention in the United States, the syndrome has also been described in several European countries.

Research has documented cases in, among other countries, Sweden, Denmark, and France. The situation in Europe differs from that in the United States, and the relevant tick species may vary by region.

Ixodes ricinus is widely distributed throughout Europe, from Portugal to Scandinavia and from Western Europe to Eastern Europe. Online sources often state that there is a clear link between a tick bite and the development of AGS, although in practice we sometimes see patients who have not been directly bitten by a tick themselves.

The SAAT method

In our practice, we treat reactivity to alpha-galactose using the SAAT method. The primary aim is to switch off the reaction and thereby achieve remission.

SAAT