Histamine Intolerance: Morbus Gouda

4. March 2013

It is often questioned whether histamine intolerance exists as a singular  freestanding disease. An argument: The body cannot react incompatibly to a biogenic transmitter. Since 2012, the HIT has had its own guidelines.

Histamine intolerance is not a real allergy in the classical sense. No antigen-antibody reaction occurs, rather the body cannot sufficiently break down exogenously absorbed histamine. In red wine, aged cheese, raw sausage, tomatoes and sauerkraut there are sometimes significant amounts of histamine present. Tuna is the leader in this respect. After enjoying these foods, an enteral histaminosis occurs with patients.

Pathogenesis is unclear

The activity of the histamine-degrading enzyme diaminoxidase (DAO) is restricted in the intestine and thus this activity is reduced. Another histamine breakdown pathway is by methylation via histamine-N-methyltransferase (HNMT). The consequences are headache, circulatory disturbances, gastrointestinal disorders and rash. In addition to histamine, serotonin is also counted among the biogenic amines. It occurs at high levels in walnuts, bananas and pineapple, among other sources. The assumed pathogenesis thus far.

Particularly histamine-containing food
Fish (such as tuna, mackerel, anchovies, canned fish)
Cheese (such as hard cheese, Swiss cheese, Camembert, Roquefort, Brie)
Smallgood sausage (such as sausage, salami, ham)
Vegetables (such as cabbage, spinach, tomatoes)
Alcohol (e.g. red wine, champagne, white wine, beer)
These foods also contain biogenic amines: chocolate, nuts, eggs, milk, pineapple, papaya, strawberries.

HIT-test is not a hit

So far, no objective parameters for the detection of histamine intolerance exists. It is true that the plasma histamine levels, methylhistamine in the urine and DAO activity in serum can be measured, but the values do not allow solid conclusions. In addition challenge tests using 0.75 mg /kg histamine hydrochloride are not valid, since even some healthy volunteers respond to it. As part of medical efforts to solve the puzzle, differential diagnosis of inflammatory bowel disease, celiac disease, carbohydrate utilisation disorders, or “real” food allergies should be worked out.


Prof. Dr. Reinhart Jarisch, an allergist from Vienna, denounces the following foods as HIT triggers:

  1. Alcoholic beverages
  2. Cheese (especially hard cheeses such as Emmental)
  3. Chocolate
  4. Salami sausages and other preserved smallgood sausages
  5. Nuts
  6. Tomatoes (= ketchup = pizza with tomato paste)
  7. Strawberries, citrus fruits (not vitamin C)
  8. Sauerkraut
  9. Spinach
  10. Fish

The histamine content of food can vary widely, depending on its maturity, duration of storage and processing. Thus for example one finds with Emmentaler a histamine content from < 0.1 to 2000 mg/kg. With alcoholic beverages it is not just the alcohol, but the impurities which are histamine liberators. Barrel-stored red wine or champagne is more suspect in regard to HIT than white wine from a steel tank. Upon request growers reveal the specific histamine content of their wine.

Chinese restaurant syndrome is almost as famous as Nessie from Loch Ness. The real existence of both can be debated. For a long time an allergy to glutamate had been seen as responsible for flush reactions after visiting a Chinese restaurant. Presumably it is not a true allergy, but rather that glutamate acts as inhibitor to degradation of DAO. Another theory holds that fish sauce or soy sauce could act as a trigger. Typically the histamine content gets reduced by the heating of food. Soy sauce is an exception: the already high histamine content increases even further. Dark sauces in particular show high histamine values. And in the preparation of some sauces such as shoyu, during fermentation flavones arise which inhibit histidine-decarboxylase. The result is that the liberated histamine is no longer degraded.

Taking the S1 to Knowledge Square?

In the 2012 S1 guideline published by the German Society for Allergology and Clinical Immunology Association (DGAKI), HIT is indeed recognised as a disease, the pathogenesis, however, is viewed as being unclear. “The scientific evidence for the postulated relationship is limited, a reliable determination of the definitive laboratory diagnosis is not present”, runs one sobering statement. Based on current information in humans – as opposed to the animal model – the concentrations of DAO in the blood nevertheless does not permit any conclusion to be made on the enzyme activity of DAO in the small intestine. The term “histamine intolerance” was coined by following the concept presented by lactose intolerance. So far, however, prospective controlled studies are lacking which indicate with certainty an enzyme and/or enzyme activity deficiency as a cause of intolerance of orally ingested histamine.

Therapy in three stages

A symptom diary of about six to eight weeks duration and a three-stage diet is recommended n the guidelines. A 10 to 14 day abstinence period serves in the substantial reduction of symptoms.

  • For the abstinence period it states: only low-histamine foods. Alcohol, smoked meat products, certain types of fish (tuna, mackerel and sardines) and cheese are cut from the diet.
  • In the subsequent test period histamine-rich foods are successively introduced into the diet, and as such the individual compatibilities determined. In the instance of dietary errors H1 or H2 blockers are worth a therapeutic trial. “A pragmatic and conceivable approach is to tread patients with suspected histamine intolerance for a defined period with H1/H2-receptor blockers to check whether the clinical picture changes” is one recommendation in the guideline.
  • For Phase III, the duration diet, there exist individual, demanding comprehensive dietary recommendations. Only then should the personal threshold be determined via titration with histamine hydrochloride (at two-hour intervals, 0.5, 0.75 and 1.0 mg /kg).

Cough medicines inhibit DAO

Numerous medications inhibit histamine-degrading enzymes. In the SPC, the clauses “can cause asthma attacks” or “may lead to flush reactions” are well hidden. It’s a contentious matter that many drugs which are used by asthmatics inhibit DAO and other enzymes.

DAO-inhibiting drugs
Acetylcysteine Haloperidol
Ambroxol Metamizol
Aminophylline Metoclopramide
Amitriptyline Naproxen
Ciprofloxacin Noscapine
Docein X-ray contrast agents
Diazepam Verapamil

Diet? Advice!

The guidelines authors advise physicians to provide the patients with a professionally competent dietary consultation. Thus it can be avoided that patients end up not following scientifically supported diets, “leading to unnecessary constraints in the quality of life”. The extent to which diet actually achieves biological changes or how much the psychological component through expert advice comes into play should be ascertained by further studies. The inconsistent data available on biogenic amines in foods makes safe recommendations for diagnosis and determining therapeutic measures difficult.

Alternative or adjuvant therapies are sought in the guidelines in vain. Many orthomolecular agents and dietary supplements promise improvement. In observational studies, vitamins C, B6 and the minerals zinc, calcium, copper, magnesium and manganese have proven potential DAO promoters. One up-to-market product contains diamine oxidase plus a few vitamins as a fixed combination. Unfortunately, valid study data is lacking here.

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