A. Case study
A 41-year-old man experienced 2 episodes of adverse effects (red rash, headache, sweating and nausea) after eating at restaurants: once at a Chinese restaurant and once at a bistro. He had never experienced these symptoms on any other occasion and had no previous history of allergy. This is what he ate on these occasions:
Chinese restaurant: tuna steak on egg noodles with 500ml red wine
Bistro: a small bread roll with butter, salmon sushi starter, half chicken with a tomato-based sauce, and 3 beers.

The symptoms appeared within 30 minutes after ingestion and spontaneously disappeared within 4 hours after the meal. He had eaten at these restaurants before without experiencing any adverse reactions, but had, however, never eaten these specific dishes at these restaurants. He had had similar dishes at home, but not in the same amounts or combinations; e.g., he hadn't had sushi followed by chicken and accompanied by beer. He confessed to having had larger amounts of the food and alcoholic beverages on these occasions than he would normally have at home.

THOUGHT PROCESS:
What type of reaction could this be?
a. Food poisoning
b. Food allergy
c. Food or food additive intolerance

DISCUSSION:
a. Shortly after the onset of symptoms of the first reaction, the patient visited a general practitioner. The doctor excluded food poisoning as a cause, on consideration of the quick resolution of symptoms and the absence of diarrhea, which is usually a main feature of food poisoning. He suspected a food allergy and asked for a total IgE test to be done. The results were within the normal range.

b and c. The fact that the total IgE test was normal excluded immediate IgE hypersensitivity, but did not exclude non-IgE hypersensitivity. The type of red rash could give a clue about the type of reaction. If it were hives/urticaria, allergy would be a more likely cause, but erythema is usually more characteristic of an intolerance. The GP the patient visited described the rash as erythema.

The type of symptoms experienced, and their onset and duration, pointed to an intolerance rather than an allergy. If it were an intolerance, this could explain why the patient had eaten these dishes before without developing symptoms. Intolerances usually show a dose-response. Even though the patient has eaten these foods before, on the later occasions he could have eaten a higher dose, which elicited the reaction. The history and results therefore suggested that an intolerance was the more likely cause.

THOUGHT PROCESS:
What, in each of the foods he ate, could have caused the reaction? The following are constituents present in each food that could result in an intolerance-type reaction:
Chinese restaurant:
Tuna: histamine
Egg noodles: gluten
Red wine: alcohol, histamine, yeast

Bistro:
Bread roll: yeast, gluten
Butter: nothing at significant levels
Salmon sushi: histamine
Chicken: nothing at significant levels
Tomato-based sauce: histamine, MSG, serotonin, tyramine and salicylates
Beer: alcohol, bromelin, histamine, nitrates, sulphites, sulphur dioxide, tartrazine, tyramine and yeast
Also, several of the dishes besides the tomato-based sauce could have contained MSG, as many restaurants add large amounts to their food.

Constituents such as gluten, alcohol, yeast, serotonin and tartrazine would most likely not have been the cause of the adverse reactions, as they are present in many other foods that the patient had eaten before without experiencing adverse reactions.

The following should therefore be considered as possible causes:
a. MSG intolerance (also known as Chinese Restaurant Syndrome)
b. Histamine intolerance
c. Tyramine intolerance

DISCUSSION:
a. MSG: Although it is difficult to determine the exact level of MSG of each meal, none of the foods eaten (except tomato) were significant sources of MSG. The seasoning, however, would probably contain MSG. Note that the association between Chinese restaurant syndrome and MSG intake has not been proven beyond doubt. What we do know about MSG sensitivity is the following:
i. Adverse reactions are more likely to occur when MSG-containing food is eaten on an empty stomach. This patient had a bread roll before his main meal at the bistro and thus did not have an empty stomach.
ii. The reported duration of symptoms is about 2 hours, but longer periods have been recorded.
iii. Because alcohol was taken with the food, it could have increased the severity and onset of the symptoms.
When questioned about his MSG intake, the patient said that his family did use significant amounts of MSG-containing seasonings and processed foods. MSG would therefore be an unlikely cause of the adverse reactions, as he had never experienced these symptoms when eating larger quantities of MSG at home.

b. Histamine: Most of the foods the patient had at both restaurants are significant sources of histamine. On both occasions he had fish, which can contain large amounts of histamine when it has not been stored properly. (The reactions are also known as scromboid poisoning.) Fish could therefore result in adverse reactions on one occasion but not another (when the histamine levels are lower). This could explain why he had never experienced a reaction before. On both occasions, the histamine level of the meals was high enough to elicit a reaction.

c. Tyramine: Only some of the foods the patient had were significant sources of tyramine. However, it cannot be ruled out as a possible cause yet.

Based on the clinical history, the reactions were most likely due to histamine and/or tyramine rather than to MSG. There is no easy test to diagnose sensitivity to histamine or tyramine. For prevention of future reactions, the patient was given a list of foods that contain high levels of these substances. He was advised to be careful not to eat high levels of them at one meal and to always make sure that the fish that he ate was fresh.

TIP for Allergy Advisor users: To find out which constituents are present in each of the foods, as was done with this case study, enter the specific food into the search function, "Items, substances & allergens". The "Possible additional constituents" can be found on the right of the screen. This can help to determine what constituent the person is reacting to in a specific food or product. The risk of a person reacting to a specific constituent is indicated next to each constituent with a number ranging from 0 to 5 (0 indicating no risk and 5 indicating a high risk).

B. More information:
Monosodium glutamate (MSG) is one of the glutamate salts of glutamic acid (or L-glutamic acid), an amino acid. It consists of glutamate, salt and water. In the food industry, MSG is used for developing and enhancing the flavor of, predominantly, savory products.¹

Glutamic acid is naturally present in most foods in either the free form or bound to peptides and proteins.² In its free form, it is present in mushrooms, tomatoes, soy sauce and other fermented soy products. It is a major constituent of food proteins (in some foods comprising 20% of the total amino acid content) such as meat, fish, milk and some vegetables. Regardless of dietary source (protein, protein hydrolysates or salts of free glutamic acid, including MSG), all glutamate molecules that are absorbed are structurally identical and are metabolized in the same way. Once glutamate is ingested, our bodies make no distinction among the origins.³

Umami
MSG does not have a distinct taste of its own, but adds flavor to other foods. Its taste is different from the four basic tastes (sweet, sour, salty, bitter), and has been named "umami" by the Japanese.¹ Umami describes the savoriness, deliciousness or succulence of a food and has been proposed as a fifth taste sensation.⁴ MSG is also known to enhance the perception of sweetness and saltiness, and to diminish that of sourness and bitterness.² The distinctive taste of MSG has a self-limiting characteristic: once the correct amount has been used in a product, any additional amount added contributes little or no additional taste to the product. Excessive consumption of MSG can result in a decrease in taste sensitivity.

Protein-bound glutamic acid, which occurs in virtually all proteins, has no umami effect; only the free form has this property.⁴ Besides MSG, other salts of free glutamate have a taste-enhancing effect: examples are monopotassium glutamate and monoammonium glutamate.⁵ MSG is commonly used to enhance the natural flavors of meats, poultry, seafood, soups and stews, but has no flavor-improving effect on some foods such as confectionery and dairy products, soft drinks, fruit drinks, and desserts. MSG will not improve the flavor of poor-quality food.

MSG in the food industry

What adverse reactions to MSG have been reported?
There is an ongoing debate concerning whether MSG does cause any of the alleged adverse reactions.³ There is little evidence that MSG causes adverse effects at normal levels of consumption. The following symptoms and conditions have been associated with the consumption of MSG:

1. Chinese Restaurant Syndrome/MSG symptom complex/Kwok's syndrome: These names refer to a syndrome caused by the ingestion of MSG-rich food, typically at Chinese restaurants. Symptoms experienced usually include one or more of the following: headache/migraine, facial flushing, numbness and pain in the back of the neck, feeling of pressure or pain in the face, feeling of pressure in the upper chest muscles, pins and needles in upper limbs, blurred vision, dizziness, problems with balance, sweating, nausea and vomiting, diarrhoea, changes in mood, abdominal pain and cramps, weakness, thirst, heart palpitations, chills and shaking.3,7 The symptoms usually occur within 15-30 minutes of eating a meal high in MSG and continue for about 2 hours.3,7 There is evidence that reactions occur only after ingestion of MSG on an empty stomach, as in a soup at the beginning of a meal.

However, many studies have failed to show a relationship between this syndrome and MSG intake. But some clinicians have estimated that the prevalence of "Chinese Restaurant Syndrome" may be as high as 1.8% of the adult population.⁵

Although this syndrome has been associated with eating at Chinese restaurants, it should be noted that foods from French or even Australian restaurants might contain more MSG than Chinese food. However, in line with the suggestion that adverse reactions occur only if MSG is ingested on an empty stomach, one should bear in mind that the hors d'oeuvres that are served before an MSG-rich meal in some countries and cultures may protect the consumer from the effects of the MSG.

2. Neurotoxicity: The evidence is clear that MSG can be neurotoxic at high doses in several animal species. But there is substantial disagreement about the significance of this observation for humans. The dose of MSG ingested to induce this effect in animals is many times higher (10- to 40 times) than those occurring in humans under normal conditions of MSG use, and far exceeds maximum palatable doses. To be effective as a neurotoxin in animals, MSG must be administered in relatively high concentrations in a very short time. In humans, MSG is ingested as a food flavoring at low concentrations over a relatively long period, the duration of a meal.^2,5,8,9

3. Asthma: Studies have suggested that MSG induces or -exacerbates asthma (with especially bad effects in patients with severe, poorly controlled asthma). Asthmatics have been found to react 6-12 hours after consuming MSG in doses of 0.5-2.5g, but subsequent studies have failed to confirm these findings.^{3,5,6,7,8,10,11,12}

4. Skin manifestations: Although many studies have investigated the association between additives and skin reactions, most of these studies have been poorly designed. There have been some reports that MSG induces or exacerbates urticaria, angioedema and atopic dermatitis.^5,13,14,15

5. There has been a report of 4 women diagnosed with fibromyalgia syndrome, which they had manifested for 2 to 17 years. After undergoing multiple treatment modalities with limited success, MSG or MSG plus aspartame was excluded from their diets. All had complete, or nearly complete, resolution of their symptoms within months and had recurrence of symptoms whenever MSG was ingested.¹⁶

6. Migraine/headache has been associated with MSG ingestion, but there has also been a great deal of criticism of these studies.^5,17,18,19

7. Taken orally, MSG has been found to stimulate gastric secretion. It is therefore sometimes recommended as an adjuvant in combined therapy of atrophic gastritis.²⁰

8. Depression, irritability, and other mood changes have also been reported.⁷

The mechanism of action has not been established, but reactions appear to be due to intolerance. The effects of MSG may therefore be dose-related, and responses may vary between individuals.

How safe is MSG?
MSG has been safely used as a food ingredient for more than 60 years.⁵ It is one of the most thoroughly researched food ingredients, as has been confirmed by regulatory and scientific agencies around the world. MSG is safe for the majority of the population, although it may be responsible for adverse reactions in a small number of individuals. Nevertheless, an ongoing debate exists concerning whether MSG causes any of the alleged reactions.³

In 1958 the United States Food and Drug Administration (FDA) classified L-glutamic acid and hydrolyzed protein products containing L-glutamic acid (including monosodium glutamate and hydrolyzed vegetable proteins) as generally recognized as safe (GRAS). This status was reaffirmed when the FDA Hypersensitivity Committee in 1986 and the FDA Health Hazards Evaluation Board in 1990 concluded that dietary intake of glutamates does not present a hazard to human health and requires no additional regulatory action. Glutamates were declared safe at current consumption levels for the general population, including children and pregnant and lactating women.³ Glutamate was found not to readily pass through the placental barrier, so that it would not affect the fetus. The ingestion of MSG has also not been associated with elevated levels of the substance in breast milk. Infants were found to metabolize MSG similarly to adults and therefore not to be at a higher risk of adverse effects.^2,9

The Joint FAO/WHO Expert Committee on Food Additives (JECFA) allocated an "acceptable daily intake (ADI) not specified" to glutamic acid and its salts in1988, which indicates that there were no toxicological concerns associated with their use as food additives in accordance with good manufacturing practice (GMP). The Scientific Committee for Food (SCF) of the European Commission made a similar evaluation in 1991, placing MSG in the safest category for food additives.8,9 MSG is permitted worldwide, although in some countries and for some types of foods, maximum concentration limits apply. Other salts of glutamic acids that are occasionally used are potassium, calcium and ammonium glutamic acids. These salts are not permitted worldwide. Most countries' legislation requires that the presence of MSG be indicated on the label of any product.

Management of MSG Sensitivity
For a confirmed MSG sensitivity, the following should be kept in mind:

2. Which of the following statements regarding the umami taste sensation is false?
(a.) It is claimed to be the fifth taste sensation.
(b.) It describes the savoriness, deliciousness or succulence of a food.
(c.) The more MSG is added, the better the taste.
(d.) The protein-bound glutamic acid has no umami effect.

3. Which of the following foods' flavor will be enhanced the most (if at all) by MSG?
(a.) Soup
(b.) Confectionery
(c.) Soft drinks
(d.) Desserts

4. By what percentage can the addition of sodium chloride be reduced, while maintaining the same perception of saltiness, by adding the appropriate amount of MSG to a product?
(a.) 0.1-0.8%
(b.) 5-15%
(c.) 30-40%
(d.) 100%

5. Which of the following is not true concerning what we know about "Chinese Restaurant Syndrome"?
(a.) Symptoms that are typically experienced include headache, numbness and pain in the back of the neck, sensation of facial pressure, sweating, nausea and vomiting.
(b.) The onset of symptoms is usually delayed by 6-8 hours.
(c.) Symptoms appear to occur only after ingestion of MSG on an empty stomach.
(d.) The estimated prevalence is as high as 1.8% of the adult population.

6. Studies have indicated (although not yet conclusively proven) that MSG can cause which of the following symptoms?
(a.) Asthma
(b.) Urticaria
(c.) Migraine
(d.) All of the above

7. True or false: MSG has been found to be neurotoxic in humans when ingested in relatively high concentrations in a very short time.
(a.) True
(b.) False

8. True or false: MSG is safe at current consumption levels for the general population, including children and pregnant and lactating women.
(a.) True
(b.) False