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  • Expert Q&A with Dr. Rob Loblay – Misconceptions about food intolerance

    Expert Q&A with Dr. Rob Loblay – Misconceptions about food intolerance

    The Allergy Unit at the Royal Prince Alfred Hospital in Australia has been a pioneer in food intolerance research. The unit is directed by Dr. Robert Loblay, a clinical immunologist who has spent the better part of his career helping patients suffering from food allergy, food intolerance, and celiac disease. Working with Head Dietitian Anne Swain (whose doctoral thesis documents the research behind the well-known RPAH Elimination Diet) and a team of doctors and dietitians, Dr. Loblay has laid out the basic ideas of food intolerance, namely that reactions are dose dependent, not limited to one type of food, and most easily diagnosed after a suitably restrictive elimination diet.

    Today we’ll ask Dr. Loblay some questions that address common misconceptions about food intolerance.

    Q: Thank you, Dr. Loblay, for spending time with us. Let’s start with a few quick questions. First off, does food intolerance cause weight gain?

    A: No.

    Q: Can you become intolerant to a food if you eat it too often?

    A: No. But reactions are dose-dependent, so if you have a tendency to intolerances, eating them more often might provoke symptoms and bring them to attention.

    For foods eaten at subthreshold levels, we generally advise: “Not too much…Not too often…”

    Q: Is there a cure for food intolerance? Are there any supplements or enzymes that people can take to prevent food intolerance reactions?

    A: No, and No.

    Q: As both an immunologist and a food intolerance expert, what is your opinion on the ‘delayed allergies’ (sometimes referred to as food intolerance) that are supposed to be picked up by IgG blood tests? Do these tests provide any meaningful results?

    A: We have not found any correlation between challenge results and IgG blood tests, so we don’t think they’re helpful. IgG antibodies to food are simply a marker of exposure, and IgG4 subclass levels correlate with the development of clinical tolerance in people who have outgrown their IgE mediated food allergies. This has nothing to do with intolerances, in my opinion.

    Q: In the time since the RPAH Allergy Clinic began looking at food intolerance, histamine intolerance has become a hot topic. Do you test for histamine intolerance specifically? In real-life meal planning, does the distinction between histamine and other biogenic amines make a difference?

    A: ‘Histamine intolerance’ is a misnomer, popularized in Europe, used to describe people who get certain symptoms in response to foods containing biogenic amines. They fail to recognize that (1) such people are usually also sensitive to one of more other substances, and (2) that their skin responses to a standard prick test with histamine (the positive control used in allergy skin tests) are perfectly normal.

    We find that our standard challenge tests with tyramine and phenyl ethylamine (done with purified chemicals and/or selected foods) are sufficient for identifying people with intolerance to biogenic amines and to guide real-life meal planning.

    Q: In your experience, do people with food intolerance usually have some inkling that their symptoms are related to food? How many are truly surprised to find that they have food intolerance?

    A: About half the people we see have an ‘inkling’ that food is involved. The rest are unaware and many are ‘truly surprised’. There are 2 likely reasons: (1) natural chemical intake accumulates from many different food sources which vary from day-to-day, so individual foods do not stand out; (2) reactions can be delayed by many hours or a day or more, so the cause-effect relationship is often not obvious. When people on the elimination diet are tested with carefully selected foods (grouped according to chemical content), some only begin reacting after 4-5 days – for that reason our open food challenge protocol goes for up to 7 days for each group.

    And in those who do suspect foods or ingredients, they often incriminate the wrong ones.

    Q: A lot of Internet advice tells people that they can check for food intolerance by avoiding a food for a week or two – most often, the ‘food’ in question is gluten. Are there any problems with doing this?

    A: People who eliminate gluten usually also unknowingly cut back on their intake of other things in their diet which are high in natural chemicals, e.g. ham, cheese, tomato and spreads on sandwiches, burgers, etc; tomato-based sauces and spices with pasta; and all the things that go on top of a pizza base. As a result they can mistakenly attribute any clinical improvement to the elimination of gluten, overlooking all the other changes they’ve made. Proof of the pudding is always in the eating – systematic challenges – but it needs to be done on a suitable low-chemical baseline diet to get reliable answers.

    People can be misled in much the same way when they go on other diets such as ‘sugar-free’, ‘dairy-free’, ‘yeast-free’ etc. Hence the popularity of any number of other diet approaches, as well as various dodgy testing methods. Any major change in one aspect of a person’s diet inevitably alters their intake of various food chemicals to which they may be sensitive, so a degree of clinical improvement is common. In other words, some people can get the right answer for the wrong reasons. For people with mild intolerances, such changes may be sufficient to get their symptoms under control. However for the more severe/persistent intolerances, improvement is usually temporary, and more rigorous investigation is needed to get to the bottom of their problem.

    Q: Many adults claim to be soy intolerant, and there is some talk on the Internet that people with gluten sensitivity will also be sensitive to soy. Is there anything behind this?

    A: Some people with celiac disease and persistent symptoms despite sticking to their gluten free diet don’t tolerate soy. [These findings were published by Dr. Loblay and colleagues in 1999.].

    Q: But outside of celiac disease and perhaps gluten intolerance, do you find that soy intolerance is something common in adults?

    A: In people with irritable bowel symptoms, we eliminate wheat, soy, and milk in addition to natural and added chemicals initially; then we challenge with each in turn. People vary in their pattern of sensitivities, so at the end of the process each is prescribed an individualized diet based on their challenge responses. There is no single diet that suits everybody.

    Soy is not really an issue in people with non-GI symptoms.

    Thank you, Dr. Loblay.

    If that you suspect that you have food intolerance, first see your doctor to rule out food allergies and other potential causes for your symptoms. Food intolerance is diagnosed through an elimination diet and food challenges, and it is best done with the help of a registered dietitian. Contact the professional dietitics association in your country to find a dietitian who is familiar with food intolerance or visit the directory of member dietitians on their website.
     
  • Lies, damned lies, and gluten sensitivity – a story of statistics

    Lies, damned lies, and gluten sensitivity – a story of statistics

    Author’s note: I have not been keeping up with the latest research on gluten sensitivity. This article was written in 2015, and while it still serves as a good example of how to evaluate scientific research, I cannot say whether it represents the current thinking on gluten sensitivity.

    You’ve heard the Mark Twain quote, “There are three kinds of lies: lies, damned lies, and statistics” [1] – it refers to the way that numbers can be used to win arguments. Statistics can be used deliberately to deceive, but it can also lead us quite innocently to conclusions that overreach the data. Here I’m thinking about the most recent publication on non-celiac gluten sensitivity from Di Sabatino et al. [2], “Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: a Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial.”

    At first glance, this study seems to say that gluten sensitivity is real. The abstract tells us:

    “In a cross-over trial of subjects with suspected NCGS, the severity of overall symptoms increased significantly during 1 week of intake of small amounts of gluten, compared with placebo.”

    This is the only conclusion that we see there. Later in the paper, though, we get some clarification:

    “However, when we examined the individual patients’ overall scores we found that only a minority of the participants experienced a real worsening of symptoms under gluten.”

    and

    “If we look at the distribution of delta overall scores (gluten minus placebo), it is not surprising to note that a fair number of patients are victims of the nocebo effect…”

    This sounds more like what we have been hearing from other gluten trials [3], and it certainly tempers the enthusiasm of the abstract. It even makes you wonder how the conclusion in the abstract could be so strong in light of the nocebo effect and negative gluten challenges. But there is no deliberate deception here, and, in fact, the authors caution that these results do not provide “crucial evidence in favor of the existence of this new syndrome.” It simply turns out that 3 of 59 participants – that’s 3 out of 59 people who had all originally believed that they were sensitive to low doses of gluten – reacted strongly enough during their gluten challenges to skew the group results in favor of gluten sensitivity. And how much stock can we place in these three individuals? Pretty much none. Let’s take a look at this in more detail.

    Learning from the past

    The gluten sensitivity debate has remained unsettled because of flaws in the previous studies. I have already discussed these problems in an article on Science-Based Medicine – essentially, either the baseline diets failed to exclude foods high in fermentable carbohydrates (FODMAPs), which are a source of considerable gastrointestinal discomfort, or the challenge capsules contained wheat instead of gluten. The Di Sabatino work seems to have taken this into account, and there are many good things about the way their study was carried out:

    • It was a randomized double blind placebo-controlled food challenge.
    • With its crossover design, data was obtained from 59 participants, which is a large group considering this type of study. A large group was needed because researchers were looking for a relatively small change (15 points) in symptom ratings relative to placebo over a collection of 15 intestinal and 13 extra-intestinal symptoms.
    • Unlike previous trials, this study did not focus on IBS sufferers, who may not be the best candidates for gluten sensitivity. Participants were recruited from patients who were referred to two celiac clinics for suspected gluten intolerance.
    • Patients were excluded if they showed signs of lactose intolerance or sensitivity to FODMAPs foods. Unfortunately, though, we don’t have any details on the criteria that was used to discover these sensitivities.
    • The placebo (rice starch) was selected to minimize fermentable carbohydrates in the intestine.
    • It seems that sufficient time was allowed for each of the challenges and the washout period in between (one week each).
    • Participants complied well with the baseline gluten-free diet, as evaluated using a standard questionnaire.
    • The study followed established statistical protocols.

    I do have some misgivings about the baseline or ‘elimination’ diet, though. The elimination diet levels the playing field so that no effects from a participant’s regular diet are carried over into the study; it also serves as the baseline diet against which the effects of the placebo and gluten challenges should be measured. Ideally, the elimination diet would contain minimal food intolerance triggers, even going above and beyond the elimination of gluten. For example, histamine and other dietary amines can induce gastrointestinal symptoms and headaches (one of the extra-intestinal symptoms in this study) in some people [4], and either these people should be excluded from the trial or high-amine foods should be excluded from the baseline diet. Unfortunately, the Di Sabatino article gives us no details on the gluten-free diet that spanned the study, so I assume that the participants were allowed to select their own foods.

    The plot thickens

    Despite my misgivings, the effects of an uncontrolled elimination diet, as well as other random factors, can be accounted for by analyzing the challenge data on a group, not an individual, basis. Indeed, this study’s enthusiastic conclusion comes from the overall symptom scores for the group, which were greater for the gluten challenge than for the placebo (P = 0.034). Furthermore, the group symptom scores for many individual symptoms were also significantly higher for the gluten challenge than the placebo. However, the group data – although properly treated – does not give us the entire picture. As I mentioned earlier, it seems that the group response was skewed by three individuals who had an exceptionally high response to gluten compared with the placebo.

    How can we know this? The article doesn’t offer that much in the way of details on individual patients, except for a very interesting scatter plot of the ‘delta weekly overall score’ for each person. (The delta score is overall weekly gluten score minus the placebo score.) In this plot we see what looks to my ruler and laser-beam eyes like a Gaussian distribution of points centered around an average delta score of 12.2. On both extremes – at a distance of more than two standard deviations beyond the average – we see a few lonely points, including three on the positive end and two on the negative. The authors identify the three points in the positive tail as the only “true gluten sensitive” participants in the study. I’ll repeat – only three participants were deemed gluten-sensitive.

    Don’t worry if you can’t visualize what I just described – here are the two main ideas that we get from this graph. First, it seems that the placebo response rate in this study is somewhere around 50%, which isn’t surprising for gluten sensitivity, but which is higher than the 35% that is seen when double blind placebo-controlled food challenges are used to detect allergies [5]. This idea will come into play in a moment. Second, the three points being located more than two standard deviations (2 x 50.4) away from the average delta score means that there is only a 5% likelihood that these high scores would occur by chance. In other words, the math says that these three results probably aren’t a fluke – they’re a definite reaction. Again, everything is on the statistical up-and-up.

    But the big question is, while being statistically correct, do these results really make a strong case for gluten sensitivity? I don’t think so. There are little things that don’t feel right, like the two people who reacted to the placebo to a similar degree as the “true gluten sensitive” (I prefer to call them ‘reactors’). On top of this, the reactors made up only 5% of a group of 59 people who believed that they suffered from gluten sensitivity. Could the 3 reactors be outliers in the sense that we have two distributions here – one random (meaning, gluten isn’t causing any real effect) and one related to some other type of food intolerance? My doubts about the uncontrolled elimination diet are coming back.

    The preceding paragraph is just speculation, though. Here’s the real clincher. In this study, each participant took one gluten challenge and one placebo challenge. This is a fine thing to do when you are going to look at the group averages, which the researchers did. However, once you start to place more weight on the three gluten reactors, you are looking at things on an individual basis, and to diagnose food sensitivity in an individual, you need more than one set of challenges. (Think of it this way – in the group case, you do one test on multiple people, but in the individual case, you do multiple tests on one person.) Assuming a typical placebo response rate, an individual must go through three gluten and three placebo challenges in order for us to be 95% certain that they didn’t happen upon the three gluten challenges by luck [6]. Since the placebo response rate in this study is higher than normal, the three reactors really should have repeated the challenges even more than three times, but, unfortunately, we only have one set of results from them each. In a funky bit of irony, statistics tells us that we cannot conclude that these individuals have gluten sensitivity based on the limited data.

    What’s next?

    Life is full of compromises. Researchers look at things like group averages because double blind placebo-controlled food challenges are time consuming and difficult on the participants. To properly evaluate individual responses, participants would need to be on an extremely restrictive elimination diet (above and beyond excluding gluten) for months – just imagine the compliance problems and drop-out rates! Alternatively, the initial screening could be beefed up to identify likely placebo responders and to rule out more food intolerances, but imagine the costs! The current study addressed these issues in a reasonable way, and future researchers would do well to copy much of what Di Sabatino and colleagues have done…HOWEVER, we all must remember that gluten sensitivity cannot be identified in any individual without multiple gluten and placebo challenges.

    © 2015 Anna (Laurie) Laforest. All rights reserved.
    Photo © Can Stock Photo Inc.
    FoodConnections.org – The skeptic’s guide to food intolerance

    References

    1. Lies, damned lies, and statistics [Internet]. Wikipedia, the free encyclopedia. 2015 [cited 2015 Mar 3]. Available from: http://en.wikipedia.org/w/index.php?title=Lies,_damned_lies,_and_statistics&oldid=645997091

    2. Di Sabatino A., Chiara Salvatore, Paolo Biancheri, Giacomo Caio, Roberto De Giorgio, Michele Di Stefano & Gino R. Corazza (2015). Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: a Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial, Clinical Gastroenterology and Hepatology, DOI: http://dx.doi.org/10.1016/j.cgh.2015.01.029

    3. Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. No Effects of Gluten in Patients With Self-Reported Non-Celiac Gluten Sensitivity After Dietary Reduction of Fermentable, Poorly Absorbed, Short-Chain Carbohydrates. Gastroenterology. 2013 Aug;145(2):320–328.e3. http://dx.doi.org/10.1053/j.gastro.2013.04.051

    4. Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007 May 1;85(5):1185–96.

    5. Gellerstedt M, Bengtsson U, Niggemann B. Methodological issues in the diagnostic work-up of food allergy: a real challenge. Journal of Investigational Allergology and Clinical Immunology. 2007;17(6):350.

    6. Bindslev-Jensen C. Standardization of double-blind, placebo-controlled food challenges. Allergy. 2001;56(s67):75–7.

  • Beware of elimination diet instructions (Part 2) – Which foods cause intolerances?

    Beware of elimination diet instructions (Part 2) – Which foods cause intolerances?

    Let’s talk some more about whether it’s a good idea to try an elimination diet on your own to check for sensitivities to milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat and soybean. As I explained in an earlier post, these foods are known as the Big 8 food allergens in the US, and anyone who suspects that they have ever had an allergic reaction to one of these foods should talk with their doctor. As we saw, food allergies often diminish over time, but they will never cross over into a food sensitivity or intolerance.

    With that established, we can move on to another issue: Can the Big 8 allergenic foods also cause intolerances? Well, it is true that wheat, milk, soy, and eggs can trigger flare-ups in people with irritable bowel syndrome (IBS), but to date, no one has established that this is related to allergy or to pharmacological food intolerance. We also know that lactose intolerance is real, and egg whites, soy sauce, and spoiling fish have the potential to cause adverse reactions by way of biogenic amines (including histamine). But, for the most part, the answer to my question is “No.”

    This is not to say that people cannot have other problems with these foods. In fact, outside food allergies and the limited examples of food intolerance I just mentioned, doctors have identified several disorders in adults where the immune system unnecessarily reacts to certain food proteins – these are listed in the table below under ‘Other immune system reactions.’ These problems can be quite serious, so they are not something you should try to diagnose on your own.

    Table 1. Possible reactions to the Big 8 food allergens in adults. When dealing with these foods, there are a lot of reasons to see a doctor and not many reasons to do an elimination diet on your own.
    Foods Allergic reactions Other immune system reactions Food intolerances
    Milk Cow’s milk protein allergy Cow’s milk protein intolerance
    (unknown mechanism)    		 Lactose intolerance
    Wheat Wheat allergy
    Wheat-Dependent Exercise-Induced Anaphylaxis    		 Celiac disease
    Dermatitis herpetiformis
    Gluten sensitivity (?)    		 –
    Soy Soy allergy Soy protein intolerance
    (only in children)
    Possible aggravation in celiac disease (?)    		 Possible amine intolerance to soy sauce (?)
    Eggs Egg allergy
    (to whites, yolk, or both)    		 – Egg white intolerance
    (histamine)
    Crustacean shellfish Shellfish allergy Food protein induced entercolitis syndrome – FPIES
    (rare but serious)    		 –
    Fish Fish allergy – Scombroid poisoning
    (histamine)
    Peanuts Peanut allergy – –
    Tree nuts Tree nut allergy – –
    Any food protein
    (varies by person)    		 – Eosinophilic esophagitis
    (usually males)    		 –
     

    One more thing: In the table above, I have classified reactions to the Big 8 foods as food allergy, food intolerance, and other immune system reactions; however, you might also run into the term ‘food sensitivity’ on the Internet. It’s important to be clear about what this phrase implies. In many contexts, ‘food sensitivity’ can be used as a generic term to describe any type of adverse reaction to food. I’m often guilty of using it this way. However, when someone recommends that you try an elimination diet or take a blood test to see whether you have ‘food sensitivities’ to the Big 8 foods, they are probably referring to something very specific – and very incorrect – namely, the idea that you may have some kind of chronic, low-level allergic reaction to food that is undermining your health. These IgG-based ‘food sensitivities’ don’t actually exist and so are not listed in my table of possible reactions.

    To summarize, most reactions to the Big 8 foods are serious problems that require proper medical care; light-weight allergic ‘food sensitivities’ do not exist, so there is no need to test for them on your own. Even in the case of gluten sensitivity, you need to be checked for possible celiac disease before you go gluten free. And you certainly shouldn’t try to test yourself for egg white or fish/histamine intolerance without having properly ruled out allergies to eggs or fish. If you do feel that you are experiencing symptoms related to food, the best thing to do (after seeing your doctor) is talk to a registered dietitian about other foods that can cause food intolerance.

    Last updated March 29, 2015

    © 2014 Anna (Laurie) Laforest. All rights reserved.
    Photo © Can Stock Photo Inc.
    FoodConnections.org – Food intolerance resource with a scientific twist

  • Beware of elimination diet instructions (Part 1) – Don’t mess with the Big 8!

    Beware of elimination diet instructions (Part 1) – Don’t mess with the Big 8!

    I have mixed emotions whenever I see an article on the Internet that instructs people on using an elimination diet to discover their food sensitivities. Of course, it’s not the idea of an elimination diet that bothers me – I have said many times that a properly done elimination diet and food challenges are the only way to diagnose food intolerance. These articles worry me when they suggest testing for sensitivities to foods that are on the list of Big 8 allergens. Simply put, don’t mess with these foods without consulting your doctor.

    The Big 8 foods account for 90% of the food allergies in the US. (Interestingly, the most common food allergens vary by country.) The Big 8 foods are milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat and soybean. Other notable allergens include buckwheat, sesame, celery, mustard, and even corn. Fruits can also cause allergic reactions, and, quite frankly, it is possible to be allergic to any food, even if it isn’t commonly thought of as an allergen. Deadly anaphylactic reactions in adults are most often caused by peanuts, but any allergen can lead to a life-threatening reaction, even when your previous reactions were mild.

    Adult-onset allergies

    Did you know that it is possible for adults to develop food allergies after a lifetime of being able to eat anything? Allergies can start at any age, and adult-onset food allergies come with an increased risk for severe reactions.

    Recently, doctors from Northwestern University [1] wanted to learn more about adult-onset food allergies, so they looked at the medical records of 1,111 patients from their allergy clinics. Fifteen percent of these patients were newly diagnosed as adults. In this group, the average age of onset was 31 years old, and 64% of patients were women. Shellfish and fish were the most common allergens, but all of the major allergens were represented.

    If you think that you may have experienced an allergic reaction to a food in the past – even something as small as tingling in the mouth or a delayed reaction – ask your doctor for help in ruling out food allergies. For each person, the minimum amount of allergen required to produce a reaction is different. While the minimum amount for some foods is generally small (think peanuts), others often require larger amounts. When you ‘challenge’ yourself with a food to see whether you have a reaction, you don’t want to get into trouble by eating a large amount of something you wouldn’t normally eat. Even if your doctor allows you to do the food challenges on your own, it’s better to have asked than to be sorry later.

    You might wonder why certain Internet MDs and nutritionists are giving out bad advice on testing for sensitivities to these allergenic foods. Unfortunately, they are basing their advice on misinformation from the alternative medicine community. Alternative medicine will have you believe that there is a lower grade of allergic reaction – originally referred to as food intolerance but now most often called a ‘sensitivity’ – that occurs when your IgG antibodies try to protect you from harmful foods. (A different antibody, IgE, is responsible for true allergic reactions.) As the story goes, IgG-based symptoms are delayed but never deadly. The truth is, these reactions don’t exist, and IgG antibodies are present in all of us as a sign that we can tolerate the foods that we commonly eat, like wheat, milk, eggs, soy, etc. Don’t mistake your mild but true allergic reactions for one of these ‘sensitivities.’ Even though food allergies often diminish over time, they will never cross over into a food sensitivity.

    For more information on the common foods that produce allergic reactions (and for some interesting reading, too), check out these websites:

    Stay tuned for a second article on this topic, where I will discuss the other conditions associated with these food allergens that you should talk to your doctor about.

    Last updated September 25, 2015

    © 2014 Anna (Laurie) Laforest. All rights reserved.
    Photo © Can Stock Photo Inc.
    FoodConnections.org – The skeptic’s guide to food intolerance

    References

    1. Kamdar TA, Peterson S, Lau CH, Saltoun CA, Gupta RS, Bryce PJ. Prevalence and characteristics of adult-onset food allergy. The Journal of Allergy and Clinical Immunology: In Practice. 2015 Jan;3(1):114–115.e1.

  • The prevalence of food intolerance

    The prevalence of food intolerance

    How common is pharmacological food intolerance? Several million people are currently suffering from this problem in the West, and more – perhaps 5-10% – will have experienced it in their lifetime. You might see figures out there, however, that vary widely, from less than a percent to 20% and upwards, but this isn’t so surprising considering that it has also been difficult to get good prevalence estimates for food allergies (1,2). In this article we will sort through the available data and see why 5-10% is a fair estimate for the lifetime prevalence of food intolerance.

    What is prevalence?

    Prevalence tells us how many people are suffering from a disorder at a single point in time, given as a percentage of the total population. Since it is impossible to ask every person whether they have a certain condition, researchers work instead with a sample of people who will represent the entire population. The size of this sample will dictate the reliability of the results. The best studies also verify a person’s response by having them go through a medical examination or some other diagnostic procedure.

    What data is out there on food intolerance?

    For conditions like food intolerance, where the prevalence is expected to be only a few percent (or less than a percent), the most reliable data will come from studies where the sample size is in the hundreds (or thousands). From among these studies, we only want to consider the ones that use a double blind placebo-controlled food challenge (DBPCFC) to check whether a person really suffers from food intolerance. It turns out that just a handful of investigations meet our requirements (see Table 1), and four out of five of these focus only on the effects of food additives like artificial colors and sodium benzoate.

    Table 1. Large-scale prevalence studies for food intolerance
    Country Study type Population Prevalence
    Denmark (4)
    N = 4274    		 Additives
    DBPCFC    		 All children 1-2%
    Denmark (5)
    N = 379    		 Additives
    OC, DBPCFC    		 Atopic children 2-7%
    Denmark (6)
    N = 1094    		 Additives
    DBPCFC    		 22 year olds 0.5%
    UK (7)
    N = 18,582    		 Additives
    DBPCFC    		 Adults 0.01%-0.23%
    Germany (8)
    N = 4093    		 Foods,
    additives
    & salicylate
    DBPCFC    		 Adults 0.78-1.1%
    • N is the sample size
    • DBPCFC is double-blind placebo-controlled food challenge, an elimination diet and food challenge where the researchers and participants are unaware of who is receiving a real food challenge or a placebo
    • OC is open challenge, where the challenge food is known to all involved

    Overall, it appears that food additive intolerance occurs in a few percent of children and a fraction of a percent of adults; when more foods are included, as in the German study, the prevalence increases to about one percent. The studies given in Table 1 also verify what has been observed elsewhere, namely that:

    1. Food intolerance is more common in women than in men.
    2. Children are more likely to suffer from food additive intolerance than adults.
    3. Atopic individuals (people with allergies and often asthma) are more likely to see adverse reactions to food, which often exacerbate flare-ups of their existing conditions.

    Unfortunately, the data that we have falls short in several ways, most notably in scope. As mentioned, the studies in Table 1 focused on food additives, not naturally-occurring trigger chemicals in food. Even in terms of additives, each study differed in the number and amounts of additives that were tested, and common preservatives, such as sulphites, were absent in many cases. Madsen (3) pointed out that these studies also differed in their inclusion criteria, that is, the symptoms that people could have and still participate in a study. Furthermore, many symptoms, including migraine, gastrointestinal symptoms, and hyperactivity in children, were not considered. Thus, the reported prevalence rates are slightly lower than what should be expected for pharmacological food intolerance when it is more completely defined.

    Towards a more inclusive prevalence rate

    Is there any other data that we can use to improve our estimate? Numerous smaller studies have been done on food intolerance in specific groups – like sufferers of chronic skin reactions, respiratory symptoms, and gastrointestinal problems – and it is tempting to extend the numbers found there to the rest of the population. Unfortunately, we cannot rely on studies that were not originally designed to establish prevalence rates because the results may be biased. For example, specialized clinics are likely to have reputations that attract specific types of patients, and these may or may not be representative of all patients with those conditions. This is called spectrum bias, a well-known cause of variation in clinical studies.

    Alternatively, we could look at prevalence estimates for sensitivities to individual food chemicals, or at the co-occurrence of food intolerance and certain illnesses, and add it all up. For example, histamine intolerance, defined as two or more non-allergic symptoms that improve through antihistamine use and a low histamine diet, is thought to have a prevalence rate of at least 1% and perhaps higher (9). In the US alone, about 12% of the population suffers from migraines, and food triggers are involved in about half the cases (10). Indirect evidence (11) suggests that irritable bowel syndrome is aggravated by foods that contain or cause the release of histamine in the body – this could affect as much as 5-10% of the population, but this has not been clinically verified. The picture is even less clear for other food triggers and conditions, and we are missing information on sensitivities to naturally-derived salicylate and benzoate, other biogenic amines, etc.

    Looking at the numbers that we do have, it seems reasonable, if not conservative, that the overall prevalence of food intolerance would be at least several percent. This consistent with the lifetime prevalence estimate of 5-10% from Loblay and Swain of the RPAH Allergy Clinic in Australia (12); they based this estimate on their experience with thousands of patients, although experience does not carry the same scientific weight as epidemiological studies. Still, we can double check if these numbers make sense by considering lifetime prevalence and self-reported prevalence rates.

    Lifetime prevalence

    When scientists give prevalence rates, they are actually talking about point prevalence, which is how I defined prevalence at the beginning of this article: the fraction of people suffering from a disorder at a single point in time. Lifetime prevalence is the fraction of people who will suffer from a disorder at some point in their lifetime. For life-long illnesses, the point prevalence and the lifetime prevalence will be equal; for disorders that last for relatively brief periods, the lifetime prevalence can be several or even many tens of times higher than the point prevalence, depending on exactly what it is that predisposes a person to developing a disorder. We can expect that the lifetime prevalence of food intolerance will be higher than the point prevalence values we have been discussing, but we don’t know by how much.

    If we have some idea of how long food intolerance lasts, we can put some limits on how many times higher lifetime prevalence could be. Food intolerance is thought of as a transient and individualized problem (13, 14). Different people will experience food intolerance for different lengths of time, and, after undergoing a period of avoiding their personal triggers, will have varying success in reintroducing these food chemicals to their diet. There are limited follow-up reports on individuals who have undergone food intolerance testing. Swain (15) found that 81% of respondents to a follow-up questionnaire still experienced a recurrence of symptoms as much as five years after having identified their trigger chemicals. We can make some assumptions and use a probability calculation to estimate that for this group, food intolerance lasts for 14 years – this means that the lifetime prevalence for adults would be about three times higher than the point prevalence. (16) This keeps us in line with our lifetime prevalence estimate of 5-10%.

    Self-reported rates

    Doctors and researchers often note that people perceive more adverse reactions to foods than can be verified through double-blind placebo-controlled food challenges. Self-reported prevalence rates from surveys of the general population are as much as 10 times higher than the rates determined through controlled testing – this goes for all types of food reactions, even allergies. For example, in the German study included in Table 1, which also looked at food allergy, the self-reported lifetime prevalence for all food hypersensitivities was 34.9%, while the point prevalence was found to be 3.6% based on food challenges. (8) Surveys conducted in different countries give different self-reported rates (17), which can be explained by different diets, different genetic make-ups, and cultural differences.

    The discrepancy between clinical and self-reported rates causes some medical professionals to be suspicious about the existence of food intolerance. But does this discrepancy really mean that food intolerance is, for the most part, ‘all in the mind?’ Let’s consider some possible reasons for the higher self-reported rates:

    1. Depending on the survey questions, the self-reported rates could be representing the lifetime prevalence instead of the point prevalence – we need to be careful not to compare apples and oranges.
    2. The respondents could simply be wrong about what caused their symptoms. Most of the self-reported rates were recorded before the current media focus on food allergies and food intolerance, but, today, heightened awareness is increasing the perception that food is the source of symptoms that are otherwise unexplained.
    3. Food aversion is a real phenomenon – you begin to associate a food with an illness and then any exposure to that food makes you feel ill – and this could be mistaken for food intolerance.
    4. Some people may experience a food sensitivity reaction once or twice in their lives, never to be repeated. Large-scale diagnostic studies like the ones listed in Table 1 do have procedures for screening out such events (for example, see reference 7) and only inviting individuals who have a history of reproducible food-related symptoms to participate in the food challenge phase. Studies that present only self-reported rates may or may not use such procedures, so we need to look carefully at each figure to see exactly what it includes.

    Another possibility is that there is something about how food intolerance is verified in clinical studies that leads to an underestimation of the true prevalence. Next we will look at the difficulties involved in diagnosing food intolerance to see if this has any effect on point prevalence.

    Diagnostic challenges

    While it is possible to diagnose food intolerance by elimination diets alone and by open food challenges, only the double-blind placebo-controlled food challenge (DBPCFC) is viewed by researchers as providing a definitive result. This makes it the ‘gold standard’ among test procedures, but, unlike many other gold standard tests, the accuracy of the DBPCFC is not known. (18) In other words, since the process has not been standardized, the accuracy will vary from study to study depending on how the test was conducted.

    The DBPCFC was developed with food allergies in mind, where a single food is expected to produce a fairly rapid reaction. These reactions are often easy to see – an asthmatic patient experiences a decrease in breathing ability or a patient develops hives. However, even with food allergies, the results are not always clear cut. (19-21) Take chronic eczema that has not cleared before the test – how much of a change in skin irritation is needed for a positive result? How long should you wait for a response? How do you grade subjective symptoms like headache? How many times should you repeat the test if the patient responds to the placebo? Should you stop medications during the test? Etc.

    The diagnosis of food intolerance shares these uncertainties and more, and it can be difficult to reproduce positive food challenge results even in people with good evidence of food intolerance. (7) Several things come into play here:

    1. It is not uncommon for someone to need to be exposed to a combination of food chemicals before they see symptoms. For example, Di Lorenzo et al. (22) found that few patients with chronic urticaria (hives) reacted to challenges with a single food additive but that many reacted to mixtures. Something like this could result from a true sensitivity to each of the triggers (12, 15) (even ones that are not chemically related) or from the unique effects that mixtures have on the processes that rid the body of foreign chemical substances.
    2. Food intolerance reactions are dose-dependent, so a person will only see symptoms if the accumulated amount of food chemical in their body exceeds their threshold dose. Each person has a different threshold dose and this threshold can change over time. Researchers have trouble addressing these issues in food intolerance studies. For example, high challenge doses do not necessarily guarantee more positive reactions and, in any case, might not be representative of normal consumption. Incremental challenges might seem to mimic real life, but they could also lead a person to become more tolerant of a food chemical.
    3. Similarly, some sufferers will be more sensitive to food triggers when they are also under stress, suffering from an illness, or exposed to certain chemicals (cleaning chemicals, fragrances, etc.) in their environment. (23) These additional factors may not be present at the time of the food challenge. Hormonal changes can also play a role in food sensitivity, but I have yet to see a study account for menstrual cycle, even though more women suffer from food intolerance than men.
    4. Patients with chronic or allergic conditions need to be experiencing symptoms at the time of the food challenge in order for any worsening effect to be observed.
    5. Researchers could simply be testing for sensitivity to the wrong chemicals. While salicylate or histamine intolerance is most often associated with fruit, German researchers reported that patients who failed to react to those substances still reacted to tomato extract, pointing to other unknown trigger chemicals. (24, 25). In another example, Lessof (26) pointed out years ago that a reaction to pesticide residue on unwashed fruit can also mimic food intolerance.
    6. Trying to prove an association between food intolerance and a specific condition is like a shot in the dark if the condition that you are looking at is not uniform. As an example, consider the association between attention deficit hyperactivity disorder (ADHD) in children and food additives. For decades, scientists and the public have gone back and forth over whether behavior in these children is influenced by food chemicals. In 2010, one group of researchers found that food additives affected ADHD-like symptoms in children who possessed a gene that decreased their ability to break down histamine. (27) This result has yet to be replicated, but, if verified, it would go a long way to explaining why different studies had been finding different results – only a subgroup of children with ADHD (those with a certain gene) are sensitive to food chemicals. If a study did not happen to include any of these children, then it would have found no connection between behavior and food.

    Right now we do not know the extent to which these diagnostic challenges might impact clinically-determined prevalence rates for food intolerance, but we can say that there is more uncertainty in these rates than is currently understood. From the examples that I have given, you might conclude that point prevalences could only go up if researchers addressed these issues; however, it all depends on how you define food intolerance and its impact on health. Increasing the specificity of the DBPCFC would certainly benefit individuals with hard-to-diagnose food sensitivities; at the same time, large-scale prevalence studies might also find more people who experience occasional reactions that do not lead to significant impairment. In the latter case, better diagnostics would not give us any more useful information on food intolerance as a public health problem.

    Since self-reported prevalence rates vary more between countries than clinically-verified rates do (see ref 16 for examples), the inflation seen in self-reported rates is probably related more to cultural effects than to limitations of the DBPCFC. Based on self-reported rates, the real lifetime prevalence of food intolerance should never be more than 20-30%, which still supports our estimate of 5-10%. If we knew more about the mechanisms behind food intolerance, we could set upper limits on the prevalence rates for sensitivities to individual trigger chemicals; however, this will not necessarily be an easy task, because for each chemical sensitivity, there are still likely to be different mechanisms at work in different people.

    Conclusions

    A lifetime prevalence estimate of 5-10%, as given by Loblay and Swain, is probably a good, and perhaps conservative, estimate of the true prevalence of food intolerance. Better prevalence rates will not be available until researchers standardize the double blind placebo-controlled food challenge, define food intolerance consistently in terms of trigger chemicals and recognized symptoms, and make progress uncovering the mechanisms behind food intolerance.

    Last updated March 29, 2015

    © 2014 Anna (Laurie) Laforest. All rights reserved.
    Photo © Can Stock Photo Inc.
    FoodConnections.org – Food intolerance resource with a scientific twist

    References

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    2. Kuznar W. Food Allergies May Not Be as Common as Reported. American Journal of Nursing. 2010 Aug;110(8):18.

    3. Madsen C. Prevalence of Food Additive intolerance. Human & Experimental Toxicology. 1994 Jan 1;13(6):393–9. PubMed

    4. Fuglsang G, Madsen C, Saval P, Østerballe O. Prevalence of intolerance to food additives among Danish school children. Pediatric Allergy and Immunology. 1993;4(3):123–9. PubMed

    5. Fuglsang G, Madsen C, Halken S, Jørgensen M, Østergaard PA, Østerballe O. Adverse reactions to food additives in children with atopic symptoms. Allergy. 1994;49(1):31–7. PubMed

    6. Osterballe M, Mortz CG, Hansen TK, Andersen KE, Bindslev-Jensen C. The Prevalence of food hypersensitivity in young adults. Pediatric Allergy and Immunology. 2009;20(7):686–92. PubMed

    7. Young E, Patel S, Stoneham M, Rona R, Wilkinson JD. The prevalence of reaction to food additives in a survey population. J R Coll Physicians Lond. 1987 Oct;21(4):241–7. PubMed

    8. Zuberbier T, Edenharter G, Worm M, Ehlers I, Reimann S, Hantke T, et al. Prevalence of adverse reactions to food in Germany–a population study. Allergy. 2004;59(3):338–45. PubMed

    9. Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007 May 1;85(5):1185–96. PubMed

    10. Headache: Hope Through Research: National Institute of Neurological Disorders and Stroke (NINDS) [Internet]. [cited 2013 Dec 1]. Available from: http://www.ninds.nih.gov/disorders/headache/detail_headache.htm (Archived by WebCite® at http://www.webcitation.org/6Ojafedcl).

    11. Smolinska S, Jutel M, Crameri R, O’Mahony L. Histamine and gut mucosal immune regulation. Allergy. 2013 Nov 29; PubMed

    12. Loblay R, Swain AR. Food Intolerance. In: Wahlqvist ML, Truswell AS, editors. Recent Advances in Clinical Nutrition. London: Libbey; 1986. p. 169–77.

    13. Pollock I, Warner JO. A follow-up study of childhood food additive intolerance. J R Coll Physicians Lond. 1987 Oct;21(4):248–50. PubMed

    14. Hayder H, Mueller U, Bartholomaeus A. Review of Intolerance Reactions to Food and Food Additives. International Food Risk Analysis Journal. 2011;1.

    15. Swain A. The role of natural salicylates in food intolerance [Internet] [PhD Dissertation]. University of Sydney; 1988.

    16. Assumptions: The disappearance of symptoms follows a fixed probability and can be modelled by an exponential distribution; 81% still experience symptoms after 3 years. The rate of decline would be 0.07 events/year, which would lead to an expectation of 1/0.07 ≈ 14 years/event. For adults, assume a lifetime period of 40 years: 40/14 ≈ 3.

    17. Skypala I. Other Causes of Food Hypersensitivity. In: Skypala I, Venter C, editors. Food Hypersensitivity: Diagnosing and Managing Food Allergies and Intolerance. John Wiley & Sons; 2009. p. 210–42.

    18. Gellerstedt M, Bengtsson U, Niggemann B. Methodological issues in the diagnostic work-up of food allergy: a real challenge. Journal of Investigational Allergology and Clinical Immunology. 2007;17(6):350. PubMed

    19. Niggemann B, Beyer K. Pitfalls in double-blind, placebo-controlled oral food challenges. Allergy. 2007 Jun 15;62(7):729–32. PubMed

    20. Bindslev-Jensen C. Standardization of double-blind, placebo-controlled food challenges. Allergy. 2001;56(s67):75–7. PubMed

    21. Niggemann B. When is an oral food challenge positive? Allergy. 2010 Jan;65(1):2–6. PubMed

    22. Di Lorenzo G, Pacor ML, Mansueto P, Martinelli N, Esposito-Pellitteri M, Lo Bianco C, et al. Food-additive-induced urticaria: a survey of 838 patients with recurrent chronic idiopathic urticaria. Int Arch Allergy Immunol. 2005 Nov;138(3):235–42. PubMed

    23. Allen DH, Van Nunen S, Loblay R, Clarke L, Swain A. Adverse reactions to foods. Med J Aust. 1984 Sep 1;141(5 Suppl):S37–42. PubMed

    24. Henz BM, Zuberbier T. Most chronic urticaria is food-dependent, and not idiopathic. Exp Dermatol. 1998 Aug;7(4):139–42. PubMed

    25. Zuberbier T, Pfrommer C, Specht K, Vieths S, Bastl-Borrmann R, Worm M, et al. Aromatic components of food as novel eliciting factors of pseudoallergic reactions in chronic urticaria. J Allergy Clin Immunol. 2002 Feb;109(2):343–8. PubMed

    26. Lessof MH. Food intolerance. Proc Nutr Soc. 1985 Feb;44(1):121–5. PubMed

    27. Stevenson J, Sonuga-Barke E, McCann D, Grimshaw K, Parker KM, Rose-Zerilli MJ, et al. The role of histamine degradation gene polymorphisms in moderating the effects of food additives on children’s ADHD symptoms. Am J Psychiatry. 2010 Sep;167(9):1108–15. PubMed

  • Reactions to fruit: Food intolerance or allergy?

    Reactions to fruit: Food intolerance or allergy?

    With so many Internet resources available on salicylate sensitivity and histamine intolerance – where fruits are a big culprit – it is easy to get the impression that adverse reactions to fruit are signs of food intolerance and not food allergy. But even though fruit are not included in the Big 8 list of allergenic foods (except for nuts, which technically are fruit), it is still possible to develop fruit allergies and even suffer anaphylaxis from fruit. In fact, since most allergy symptoms overlap with food intolerance symptoms and both types of reactions can be delayed, you should not try to distinguish between the two conditions on your own.

    Fruits, vegetables & allergy

    The following fruits and vegetables are most often implicated in allergy. This list is not exhaustive – other fruits are possible.

    Primary allergy

    Cherry, pepper, kiwi, grape, apple, peach, celery, carrot

    Oral allergy syndrome

    Birch pollen – Apple, pear, cherry, peach, nectarine, apricot, plum, kiwi, hazelnut, other nuts, almond, celery, carrot, potato

    Birch/mugwort pollen – Celery, carrot, spices, sunflower seed, honey

    Grass pollen – Melon, watermelon, orange, tomato, potato, peanut, Swiss chard

    Ragweed pollen – Watermelon and other melon, banana, zucchini, cucumber

    Plane tree pollen – Hazelnut, peach, apple, melon, kiwi, peanuts, corn, chickpea, lettuce, green beans

    Latex – Avocado, chestnut, banana, passion fruit, kiwi fruit, papaya, mango, tomato, pepper, potato, celery

    Source: Skypala, p. 154

    There are two types of fruit allergies:

    1. Primary fruit allergy is just like any other food allergy: specific proteins unique to fruits (lipid transfer proteins) bind to IgE antibodies and trigger the release of histamine and other chemicals. Symptoms are the same as classic allergy symptoms and develop along similar time frames.
    2. Oral allergy syndrome (OAS), also known as pollen-food syndrome, is most common food allergy in adults. In order to suffer from OAS, you must have an existing allergy to pollen or latex. OAS occurs because certain proteins in fruit are similar enough to plant proteins that they can also bind to pollen-specific IgE antibodies and trigger symptoms. Symptoms arise rapidly – between 15 minutes to 1 hour after eating fruit – and typically include itching or hives in the mouth and throat. However, gastrointestinal and systemic symptoms are also possible, and foods related to birch pollen can also cause or aggravate chronic eczema in children and adults.

    The worldwide prevalences for primary fruit allergy and for OAS are both around 5%. The prevalence rates and predominant types of fruits and vegetables involved vary from country to country. OAS is often regarded as a mild condition, but about 2% of people with OAS could experience anaphylactic shock. Taking ACE inhibitors for hypertension or congestive heart failure amplifies OAS symptoms, and this could lead to facial swelling that stops you from being able to breathe.

    If you do have a fruit allergy or OAS, a doctor can answer your questions about managing your condition: Should you completely avoid your trigger foods? How much could you safely eat? Should it be cooked or peeled? Which varieties of troublesome fruits should you shop for?

    If your doctor tells you that you do not suffer from a fruit allergy or OAS, then you can probably pursue a diet investigation for food intolerance with a registered dietitian – get your doctor’s OK. Remember, if you are a person who experiences laryngeal edema (swelling of the throat or upper airways), food challenges for food intolerance should be done only in a clinical (inpatient or outpatient) setting.

    © 2014 Anna (Laurie) Laforest. All rights reserved.
    Photo © Can Stock Photo Inc.
    FoodConnections.org – Food intolerance resource with a scientific twist

    Bibliography

    American College of Allergy, Asthma and Immunology (ACAAI). Oral allergy syndrome, high blood pressure medications can create lethal cocktail. [Internet] ScienceDaily; 2013 November 13. Available from: http://www.sciencedaily.com/releases/2013/11/131108090135.htm [Accessed 2014 January 18] (Archived by WebCite® at http://www.webcitation.org/6Oja4p5cB).

    Breuer K, Wulf A, Constien A, Tetau D, Kapp A, Werfel T. Birch pollen-related food as a provocation factor of allergic symptoms in children with atopic eczema/dermatitis syndrome. Allergy. 2004;59(9):988–94. PubMed

    Osterweil N. Foods That May Worsen Pollen Allergies. [Internet] WebMD. Available from: http://www.webmd.com/allergies/features/oral-allergy-syndrome-foods [Accessed 2014 January 18] (Archived by WebCite® at http://www.webcitation.org/6Oja92gwn).

    Skypala I. Fruits and Vegetables. In: Skypala I, Venter C, editors. Food Hypersensitivity: Diagnosing and Managing Food Allergies and Intolerance. John Wiley & Sons; 2009. p. 147–65.