Hello, and thank you for taking time out of your busy schedule to join us today. My name is Dr. David Blyweiss, Chief Medical Officer for Cell Science Systems. The purpose of this webinar series is to broaden your understanding of the immunological differences between innate and specific immunity, and how those differences manifest, in disorders ranging from gluten and other food sensitivities, to more severe manifestations such as celiac disease.
The next lecturer is clinician Tania Dempsey, and she’ll be talking about “Gluten and Beyond…The Role of Food Sensitivities in Chronic Disease.” Be sure to stick around at the end of the lecture, as I’ll be giving you information on some of Cell Science Systems’ innovative laboratory testing.
I’m so happy to be here, and I’m so excited to share with you my experience. Specifically, we’re going to be talking about the role of food sensitivities, in the development of chronic disease and inflammation. All of us who are healthcare professionals, our mission has been to heal patients. But as functional medicine or integrative physicians or practitioners, our mission is to prevent disease. And that’s becoming harder and harder with the epidemic of chronic disease that we have in this country.
What I want to today, though, is to focus on one area that may make a big impact in preventing chronic disease. And that is the area of food sensitivities. Including gluten, which we’ve obviously talked about and we’ll continue to talk about during the course of this conference. But I’ll focus in on it in a different way, and hopefully give you tools that you can use in treating your own patients.
My objective then will be to review the obesity epidemic and the factors involved in the development of chronic disease. We’ll review food allergy and sensitivity, and the development of inflammation and subsequently, chronic disease. And I think it’s very important that we talk about allergy and not just food sensitivity, because they are clearly linked, and we need to understand that link.
I will discuss testing options for evaluating obese and chronically ill patients for food sensitivities and how to interpret the results. And I’ll review treatment options in the setting of a case study. Or a few case studies if we have time.
Clearly, there’s an epidemic of chronic disease. This is Dr. Dean Ornish, who was quoted as saying, “75% of the $2.7 trillion in healthcare costs, which are really ‘sick care’ costs, are from chronic diseases that can be largely prevented, or even reversed, through simply changing diet and lifestyle.” We all know that, but how do we do it?
24/7 Wall St. is a financial website that reviewed the ten leading causes of death, as was described by the CDC to determine how much they cost, and how they reflect on the efficiency that they’re being treated. Heart disease, $190 billion being spent in treating heart disease, cancer, $227 billion, diabetes, $112 billion. These numbers are staggering and obviously concerning. And obesity is a contributing factor in five out of the ten leading causes of death. Heart disease, cancer, stroke, diabetes, and kidney disease.
And if we look at the statistics on obesity, one-third of all adults are obese, one-third are overweight, bringing the number to 68.8% of US adults being overweight or obese. And the numbers are getting worse. Look at the numbers for children, 31.8% of children and adolescents are obese or overweight.
What causes obesity and chronic disease? Now, I’ll focus on one area today, but I think it’s important that we review all the different things that contribute. When we think about functional medicine and integrative medicine, we’re looking at all the pieces. And you have to think about these things when you’re evaluating your patients. You have to think about the costs…we’re going to talk a lot about inflammation, but inflammation can be caused by a variety of different factors. Lifestyle is a big part. Stress…and I cannot overemphasize stress as a cause of chronic disease and obesity, lack of exercise, and diet. And diet plays a role from various perspectives. It could be, sure, fast food or whatever, but it’s the toxins in the food, it’s the estrogens in food, it’s the heavy metals in food. And so, that’s a real problem.
I think genetics and epigenetics needs to be understood as well. Aberrant DNA methylation, histone acetylation, deacetylation may mediate the development of chronic inflammation by modulating the expression of pro-inflammatory cytokine TNF-alpha, interleukins, tumor suppressor genes, oncogenes, and activation of transcription factor NF-Kappa B. Epigenetics is important.
Inflammation is also caused by or also is contributed to by metabolic syndrome. Metabolic syndrome is a constellation of signs and symptoms that increases the risk of developing diabetes and cardiovascular disease, as well as cancer. And it’s not clear which came first, the chicken or the egg here. Metabolic syndrome causing inflammation, inflammation developing into metabolic syndrome. And clearly, food allergies and sensitivities and intolerances, and that’s what we’re going to focus on today, and changes in the gut microbiota, which we’re talking a lot about in the next two days.
What are we going to blame obesity on today? Is it the pasta, the soda? Who knows? But let’s talk about the reactions to food, because I think that’s where the money is. We’re going to look at all the different reactions to food. Whether it’s allergy, which is an IgE-mediated immediate Type 1 hypersensitivity reaction. We’re going to look at autoimmunity, which would be like celiac. We’re going to look at intolerances, and intolerance comes in various forms. Inborn or acquired errors of metabolism of certain nutrients. So they could be enzyme deficiencies like lactase, fructose, etc. It could be chemical reactions due to low molecular weight compounds either found in nature or manufactured, and those are things like histones, salicylates, sulfites, and food dyes and additives.
Then there’s the sensitivity/hypersensitivity reactions that we’re seeing. They could be IgG-mediated hypersensitivity reactions, or they could be chronic activation of the innate immune system. And specifically, we’ll look at gluten sensitivity, the innate immune system responds to gluten and induces an inflammatory response, and again, we’re going to be covering that throughout the day, not just through me. And the chronic activation of the innate immune system may be the predominant factor in the development of food sensitivities.
What are the symptoms of food sensitivities? We all know them, right? It’s about everything. Gastrointestinal symptoms, obviously. Bloating, diarrhea, constipation, irritable bowel. Respiratory symptoms like asthma, cough, sinusitis. Dermatologic like eczema, psoriasis, keratosis pilaris. Neurologic, migraines, behavioral issues, ADHD. Musculoskeletal, arthritis, stiff joints, tendonitis; the list goes on. How many patients do you know who have stiff joints, and that you take them off of food, you take them off gluten, and they start moving again? We all hear those stories. Endocrine, obviously, is a big factor. And definitely is affected by food intolerances, including weight gain or weight loss, thyroid disease, and the immune system, obviously.
When we look at the immune system, I want to divide it into two parts, and I want to talk about the adaptive or acquired immune system, and I want to talk about the innate immune system. Because I think it’s very clear that the sensitivities that we’re seeing to food really come from various aspects of the immune system, not just one. And traditionally, allergists, for instance, were very involved with looking at…and they still are, involved in looking at IgE, the one reactivity, one reaction to food or the environment or whatever. But clearly, it’s a bigger story, and we can’t ignore that part, but we need to see how it all fits together.
When we look at the adaptive acquired immunity, this is an antigen-specific defense mechanism. It takes several days to become protective. And it’s designed to remove a specific antigen. This is immunity that develops through the course of the lifetime, and this is something that continues to evolve with exposure.
You can divide the adaptive immune system into two parts: The humoral part or the cell-mediated immunity. When we think about humoral immunity, that’s really involved in the production of antibody molecules. And this is in response to an antigen, and is mediated by B-lymphocytes. It could be also called an immediate hypersensitivity reaction, and there’s various types; I, II, III, and IV. And then we have the delayed hypersensitivity reaction, and that is a cell-mediated response. And it really involves the production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigen. And this is mediated by the T-lymphocytes.
Just to review basically what’s happening with an antibody-antigen response, an antibody reacts to the antigen which is foreign. And in this case, this is an antigen, a foreign body that is sitting on the red blood cell. And the antibody is developed, produced in response, and it binds it. And that leads to a whole host of inflammatory responses that we’ll review.
Once an antibody is produced against a specific antigen, the next time the antigen enters the body, the immune system remembers it and produces the antibody. You can check IgE, you can check IgG for things like this to get a better idea.
Just to review the five classes of antibodies. This will make it clearer when we talk about the various parts of the immune system. IgA is found in high concentrations in the mucous membranes, respiratory, gastrointestinal tract. Immunoglobulin G is the most abundant in our body. It protects against both bacterial and viral infections. But it’s also involved in Type II and Type III hypersensitivity reactions.
Immunoglobulin M is probably the first in line in our line of defense. It’s produced initially, and it’s found in the lymph. Then we have IgE, which is associated with allergic reactions, as I mentioned. It’s found in the lungs, the skin, and the mucous membranes, and it’s involved in the Type I reaction. D is only found in minute amounts.
The food allergy statistics are also staggering and increasing; 15 million people in this country have a food allergy. This is just looking at the IgE, mind you. We didn’t even get to the other part. The number of kids with food allergies went up 8% in a period of ten years from 1997 to 2007. And about 6 million children younger than 18 have a food allergy.
What happens with this Type 1 hypersensitivity reaction? Again, following exposure to an antigen, the mast cells and basophils degranulate. They release substances and they induce inflammation. And the process begins with an antigen interacting with an IgE molecule that’s bound to a high-affinity receptor on the surface of mast cells, called fragment crystallizable receptors. And this induces degranulation. Let me show you a picture of this.
Here you have a mast cell. You have the IgE receptor here, the IgE antibody sits in that receptor. The food antigen cross-links these, and it causes degranulation. Mast cell degranualation, again, leads to the release of inflammatory mediators. These include histamines, proteoglycans, serine proteases, and leukotrienes. And obviously, the immediate release of these inflammatory mediators produce hives, redness, angioedema, etc. The classic allergic reaction.
But it seems…the IgG has obviously been focused the most in the immediate hypersensitivity reaction, but we now understand that IgG can also be involved in the immediate hypersensitivity reaction. And it turns out that high-affinity receptors for IgG on mast cells or basophils are activated in the immediate hypersensitivity reaction through IgG binding. And this results in degranulation and release of histamine also. So it seems that, again, IgE is not the only one that’s involved. IgG may be as well.
When you have those patients who get that skin prick test, and they have allergic-like symptoms, you know they have a lot of histamines, and they react negatively to the skin test, or they have negative IgE in the blood, it may be that it’s IgG that’s involved.
The other problem with IgG is that…and I’m going to talk about it in various ways. But in the immediate hypersensitivity role, it might play several roles. One is it’s been shown in studies to cause anaphylaxis, and we think it’s due to the sub-type IgG4. There also seems to be a correlation between IgE and IgG4 levels in atopic patients. And it may be that this is IgG4 hampers the antigen binding to the cell-bound IgE, and that might blunt the IgE reaction.
It’s also thought that maybe IgG is not the problem not causing the symptom, especially in those of us who used to test IgG in the blood. Maybe it’s that the IgG is actually doing something in those patients who are allergic and have IgE. So it’s confusing, but definitely, there are multiple layers.
This was a study that looked at the clinical significance of food-specific IgG4 antibodies, and actually, they looked at milk protein and they looked at egg protein. And what they found that although milk-specific IgG4 is frequently detectable in sera of apparently healthy individuals, the presence of alpha-casein, that particular milk protein, appears to be diagnostic of milk intolerance, causing eczema in adults. But the same did not hold true for eggs. It’s complicated.
But why are we seeing more food allergies? We’re going to discuss this in the context of food intolerance, and I think it’s all the same. I think it’s changes in our diet, changes in our gut flora, changes in our environment, and changes to our exposure to childhood infections.
And I love this. “When I was your age, there were no food allergies.” He grows up, “When I was your age, there were food allergies.” Many of us remember as kids not seeing as many allergies, nut allergies, etc. in school as we’re seeing now. Eight foods account for 90% of all food-allergic reactions, and I think this holds true also for food-intolerant reactions. We’re looking at milk, egg, peanut, tree nuts, fish, shellfish, wheat, and soy.
Again, there are two types of allergy testing, skin prick or blood work. But clearly, they’re not that accurate all the time, because if there’s another type of reaction, if there’s a food sensitivity reaction, if there’s an IgG reaction, if there’s a reaction from the innate immune system, you’re not going to pick it up in an allergist’s office.
Then there’s a Type II hypersensitivity reaction that involves IgG. This is an antibody-dependent cytotoxicity. And so basically, what happens is that IgG is produced against normal self antigens that resemble food antigens. This goes back to what Dr. Brady mentioned this morning about mimicry. This leads to opsonization of host cells. Basically, what it leads to is apoptosis and cell death with an attack of the cytotoxic system. One example would be cow’s milk-induced thrombocytopenia, where the platelets are destroyed due to this phenomenon.
There’s a Type III hypersensitivity reaction also involving IgG. This appears to be immune complex-mediated, where the antigen and the antibody, like I showed you earlier, that picture of the cell, the red blood cell with an antigen and antibody. If you develop enough complexes, which should be normally removed through the macrophages by macrophages in the spleen, they form in large amounts and they overwhelm the body. And these small complexes can become trapped in the basement membrane and they can lead things to like vasculitis and glomerular disease.
In Type III reactions, if we’re looking specifically at food, what we think is going on is that the IgG1 antibody is the initial IgG class responder to a new food allergen. Upon continued exposure, it is proposed that IgG1 antibody production will class switch to IgG4. But IgG4 actually, that, in itself will not activate complement cascade. It acts as a blocking agent against the actions of IgE, which I mentioned earlier.
What eventually happens is that IgG4, food immune complexes, they have a long half life. And they’re subject to alterations. And they present, actually, as new antigen. And now, you get IgG1 attacking this complex and it begins a new cycle of IgG1 to IgG4 conversion. And now, the complex is getting larger and larger and larger, and they basically destroy the body and the tissue.
Some studies suggest that these complexes do not cause damage, but rather help the body eliminate them. Again, this is how complex this is. Are these IgG molecules, immunoglobulins the problem, or are they helping us? What’s really going on? It does seem clear that high IgG titers correlate with exposure, but not necessarily with sensitivity. And as I suggested earlier, the IgG and IgG4 production may just be a normal immunological response, maybe because of the IgE issue.
The innate immune system may be able to give us a little bit more information. And they help us figure out what the food sensitivity is. And to describe the innate immune system, it’s really an antigen non-specific defense mechanism. It’s the first line of defense. Innate immunity can be divided into an immediate response and an early-induced innate immunity.
Now, the immediate immunity begins 0 to 4 hours after exposure, and it involves a host of different mechanisms, including antimicrobial enzymes, peptides, complement system proteins, anatomical barriers, mechanical removal of microbes, etc. And early-induced immunity begins 4 to 96 hours after exposure to an infectious agent or food, and it involves the recruitment of defense cells, and these defense cells are phagocytic cells. These cells release inflammatory mediators, and they’re natural killer cells.
The innate immune system does not rely on repeated exposure. And so, full-term babies can mount a normal innate immune response. Antigen-specific adaptive immune responses, as I mentioned before, the IgE, the IgG, those immune responses are slow to develop. They take time. They develop over the course of a lifetime. But the innate immune system is there, it’s present at birth.
Now, what happens is you have T cells. In newborns, they are naive T cells. They require potent co-stimulatory signaling for activation, and they require more potent co-stimulatory signaling for activation than memory T cells. And adults have more memory T cells because they’ve had time to develop it.
By adulthood, half of the circulating T cells become memory T cells. And during the first few months of life, then, you get a rapid expansion of antigen-specific T and B cells. And so, there are these subtle changes that continue to evolve in the immune system, and we think that molecules in breast milk may suppress some of these changes.
Again, why are we seeing more sensitivities, intolerances, allergies? Well, susceptibility is definitely dependent on many factors. Genetics is certainly a factor, and we see that a lot. There are certainly links between families who have atopy versus non. The integrity of the natural barrier of the gut wall or leaky gut is, I think, probably a major factor in the development of food intolerances and sensitivities. And really, it’s the cellular damage at the level of the intestines that allows undigested and partially-digested proteins, carbohydrates, and fats, as well as fragments from microorganisms to pollute the blood and lymph of the intestinal tract. These compounds then circulate throughout the body. They put strain on the immune system, and virtually any other organ in the body.
This is the vicious cycle of chronic toxic overload. And toxic overload, I include, is food, for sure. Here’s alcohol, cigarette smoke, rich foods. But you can talk about gluten, you can put everything else on the list here, leading to intestinal permeability. You have drugs that we’re using; antibiotics, etc. causing intestinal permeability. And then it’s just circling back; candida, dysbiosis, etc. causing liver overload, etc., etc., leading back to these health problems.
Now, the other issue to think about is when you’re thinking about food intolerances and sensitivity is it may be that the amount of food people are eating is the problem. The amount of the ingested food. If eaten in a small quantity, will not produce a reaction. If eaten in a large quantity, will. The combination of foods. Maybe if the gluten is eaten with the dairy, it makes a difference, versus dairy alone. And stress, again, I’m going to mention is definitely a factor in food intolerance because of the increased cortisol levels that lead to a decrease in protective secretory IgA.
The viability of the phase I and phase II detoxification pathway is also important in the development of food intolerances. And as Dr. Davis mentioned this morning, advances in food technology, including methods of processing, preserving, fertilizers, pesticides, etc., have altered the food to the point that it disrupts the immune system. And genetically modified food is a problem.
And then you further complicate things by adding antibiotics for bacterial infections, and you couple that with the increased consumption of simple sugars and flours. And this causes, obviously, the dysbiosis, the imbalance in the flora of the intestinal tract, an overgrowth of yeast. Yeast may affect the mucosal lining, contributing to leaky gut syndrome. And then again, you get those macro-molecules entering the bloodstream, overwhelming the immune system, leading to food intolerance.
I want to now talk about the role of food intolerance in the development of obesity and chronic disease. What’s the link? And this is one link. We’re going to talk about the role of serotonin in the development of obesity. And what we think happens is that when you eat a food that you may be sensitive to, and let’s just say it’s gluten, the blood level of the neurotransmitter serotonin goes down. And in order to compensate for that low serotonin level, you need to eat something to raise your serotonin up. And so, you’re going to eat carbohydrates, but you’re going to temporarily raise the serotonin up until it falls again, and you repeat the vicious cycle. And this ultimately, obviously, if you’re eating like that, it will lead to weight gain.
This was a study…they took pre-fat cells, pre-adipocytes. It was done in the lab, but I think it’s an interesting study because they looked at these pre-adipocytes and they exposed them to different concentrations of serotonin. And what they found was that the serotonin promoted triglyceride accumulation, the emergence of adipogenesis markers, and induced expression of PPAR Gamma.
Serotonin may play a role in weight gain through a variety of mechanisms, and maybe through that mechanism I mentioned in the last slide. And we think that it may be related to why patients gain weight when you give them SSRI antidepressants.
Now, inflammation is a big factor here, and pro-inflammatory cytokines, interleukin-6, and tumor necrosis factor-A are present in large amounts in adipocytes. And these cytokines block insulin receptors on muscles, brain, and liver cells. And they decrease adiponectin levels and low levels of adiponectin lead to obesity and insulin resistance. So you see this is a vicious cycle. All of these things contribute, and it goes round and round.
Again, we’re going to talk about leaky gut again because when we talk about inflammation, certainly, leaky gut plays a role leading to systemic-wide immune response. Inflammation causes more insulin resistance and more fat storage. Interestingly, gut flora in itself can induce insulin resistance apart from the immune response. And the changes in the gut flora can increase the rate of absorption of fatty acids and carbohydrates, and increase the storage of calories as fat. One of these particular type of flora implicated here is Firmicutes, which includes Bacilli and Clostridia, and obese patients have been shown to have higher proportions of Firmicutes, which may contribute to the obesity.
This was a review article in the Journal of Obesity titled “Is the Gut Microbiota a New Factor Contributing to Obesity and Its Metabolic Disorders?” And they outlined everything that had to do with gut microbiota and obesity, and they showed that there probably is a link.
This is a very interesting study, and this looks at…this is going to look at IgG, so just take for a moment…that we’re not sure about the IgG, specifically, but IgG antibodies against antigens were correlated with inflammation. What they did was they took 30 obese children, and they compared them to 30 normal weight children. The obese children had higher C-reactive protein, which is a marker for inflammation, increased intima media thickness of the carotid arteries, and let me show you what that looks like.
This is a normal intima media. This is one that has thickened and has blocked. You see that the lumen here is decreased. They were seeing this in children already who had high C-reactive protein, they’re obese. They had increased thickness of the carotid artery. But they also had high levels of IgG to food. And what they concluded was there seemed to be a tight correlation between high IgG levels and C-reactive protein levels, suggesting that maybe food IgG might be involved in the development of atherosclerosis and obesity.
What does gluten have to do with it? Obviously, Dr. Davis spent a lot of time this morning talking about wheat. I want to go over the role of gluten on insulin resistance, and talk a little bit about zonulin and intestinal permeability, but we have an expert here who will talk a lot about that, and gluten and food addiction, and go over the mechanism.
I won’t bore you with a lot of this because we talked about it this morning, but certainly, humans have not been exposed to gluten except for the last 10,000 or so years. That may be part of the issue. Just to explain again what gluten is, gluten is a storage protein. It’s difficult to digest. It’s favorable for the growing of that grass. And it’s found in wheat, rye, and barley.
If you fractionate the gluten, you can divide it into two components; gliadin and glutenin, and it’s based on their solubility in aqueous alcohol. Gliadin is the fraction of wheat protein that’s soluble in alcohol, and it’s considered the prolamin category of protein. This is believed to inflict the damage on the intestines that we see in celiac. Glutenin is the faction of wheat proteins that’s insoluble in alcohol, and it’s associated with asthma and autoimmune skin disease.
Now, some peptides in gluten act like morphine, and I think this was mentioned earlier. Let me show you the studies. Gluten contains five opioids, A4, A5, B4, B5, and C. Now, if you take A5 which is the one that’s most studied…if you take one glutenin protein, there are 15 sites of A5 on it, and it equals one nanomole of morphine. And they did a study in mice that showed that A5 had both peripheral and central nervous effects.
This study actually looked just to prove that this glutenin protein could be broken down into those various components. And what we think also is that gluten may trigger increased insulin production and release through the pancreas. This was done in rats, but they looked at postprandial plasma insulin levels, and what they found was that when they gave these rats either oral or IV A5 at a certain dose, they potentiated the postprandial plasma insulin level, and the effect was reversed by naloxone, which is an opioid receptor antagonist.
This was a study looking at whether a gluten-free diet could reduce adiposity and inflammation, and insulin resistance. And what they showed…this was done in mice, unfortunately, not humans, but when the mice were fed either a high-fat diet containing 4.5% gluten or a gluten-free diet, they looked at certain markers of inflammation and adiposity. And what they found was that the gluten-free animals showed a reduction in body weight gain and adiposity, without changes in food intake or lipid excretion. And it’s thought that it may be through this PPAR Gamma receptor.
I’m going to skip over celiac a little bit because I think there are a number of speakers who are going to be talking about it. But I do want to mention that celiac disease is obviously associated with other autoimmune diseases, and it obviously has a role in our immune system. And my issue with gluten-free diets in patients who have gluten intolerance or sensitivity is that there are grains that may have a cross-reaction with patients who are gluten-sensitive. I also am concerned about gluten-free foods, which may contain up to 0.3% protein from gluten-containing grains. That’s allowed…the FDA allows that.
I’m sure that Dr. Sana is going to speak quite a bit on the role of zonulin. But I’ll mention zonulin in the context of inflammation, and the development of obesity and autoimmune disease. And here, human protein zonulin regulates the permeability of intestines for those of you who are not aware of that. And they think that zonulin may be a contributing factor to other autoimmune diseases.
But this study looked at circulating zonulin as a marker of intestinal permeability, and an increased risk in association with obesity-associated insulin resistance. This was showing that patients who had increased zonulin levels were at higher risk for obesity and insulin resistance. This, again, the same thing. Looking at gliadin, zonulin, and gut permeability, and looking at the impact on autoimmune disease. Here’s my slide, sorry about that.
My concern is their cross-reactivity with gluten has been shown with a number of other grains and other foods. It’s thought that the maize prolamin zein might contain amino acid sequences that resemble the wheat gluten peptides, that might bind even better to the HLA-DQ2/DQ8 molecules.
I want to spend a little bit of time before I go into the cases…I want to talk about histamines a little bit, because the histamine reactions…there are a lot of different reactions that patients can have to chemicals in food and in our body. I think histamines are important for a variety of reasons because histamines also act as neurotransmitters. I think that this is something that needs to be explored further. But just so you know, a histamine, really, is a regulator of inflammation, gastric acid secretion, neuromodulation, and regulation of the immune system. And it’s produced in special storage granula inside the cell. And as I mentioned before, in the mast cell or a basophil, if it’s activated, it will release these histamines. But histamine may also be produced in neurons, as well as the enterochromaffin-like cells in the gastric mucosa.
Histamine may be found in foods, particularly fermented foods. Histamines may be converted from certain foods that have histadine as the amino acid. Intestinal bacteria convert histadine to histamine. Histamine does not cross the blood-brain barrier. The histamine that is found in the brain is produced in the brain, and the highest amounts are found in the hypothalamus.
When histamine is released from mast cells, or histamine is ingested through the diet, it may cause tight junctions in the intestinal wall to degrade. And foods that are high in histamine tend to be foods like tomatoes, chocolate, aged cheeses, fermented vegetables, even tuna. There are foods that induce the release of histamines. And there are foods that are competitive amines, and they saturate the enzyme that breaks down histamine in the gut, and that’s the DAO enzyme. There are certain medications that inhibit it as well, and so we get a high histamine response. These are the foods…I’ll just go through that.
N- acetylcysteine, that many of us use in our practice, does degrade or prevent DAO from working, which could lead to higher histamine levels. If you have a patient who has histamine-like symptoms…they could be varied, they could include anything on that food intolerance list. But you know those histamine patients? They look allergic, right? But you’ve done the skin test and it’s negative, and you’ve done some of the other testing and you’re not sure, but they still seem like they have a lot of histamines. You need to figure out why, you need to figure out how to lower it. And so, certainly anti-histamine drugs may be helpful. But making sure they’re not taking something that could be contributing as well, and looking at the diet and eliminating foods that could be raising histamine levels is important.
Histamine does a variety of things. And when we talk about the allergy response, it’s through the H1 receptor, which is found, really, mostly in the mucosa, in the skin, and it causes vasodilation and a variety of other things. The H2 receptor is found in the gut, and it is mediated by gastrin. The H3 receptor is found in the nervous system, and may regulate the release of other neurotransmitters, and that’s why I think this is very important.
And just to review histamine metabolism. Histadine is an amino acid. It gets decarboxylated, so a CO2 group gets removed through an enzyme and made into histamine. And the histamine can be degraded in two ways. It could be broken down through DAO, and this is only found in the intestine, or it could be methylated. And the methylation process leads down this path.
And I think why this is important is that if you’re going to treat patients who have food intolerances, you need to understand that maybe the way you need to address this is by addressing this histamine issue, maybe giving them DAO enzymes, or preventing the histamines from being produced in the first place. This was an article actually looking at the histamine intolerance, and looking at DAO and the various symptoms that were associated with histamine. It’s worth reading.
Diamine oxidase, by the way, was a good measure of mucosal maturation and integrity. And so, again, here we go going back to this leaky gut premise. Maybe it’s diamine oxidase and histamines that are affecting our gut lining, our intestinal lining.
Okay, so now that you know about the various reactions patients can have, how are you going to figure out what their problem is? I always think about it, the easiest thing to do…we do this with a lot of our patients, is we put them on elimination diets. It’s easy in some ways because we tell them to avoid the foods that are most likely to cause a problem and hope they feel better. But patients, not crazy about that all the time, they want to know what they’re really sensitive to.
You can certainly do different types of testing, such as IgG and IgE, and of course, celiac. And the issue with testing, again, as I mentioned, it’s inconclusive. We’re not sure what to make of blood testing for IgG right now. And for those of us who live in New York, we can’t even test it anymore.
But then we can measure the innate immune system, which was mentioned earlier by Dr. Brady. And it’s an antigen leukocyte cellular antibody test. And it reproducibly measures the final common pathway of all pathogenic mechanisms, whether it’s immune, non-immune, or cytotoxic.
Again, when you’re evaluating the patient, you want to identify not just what the food problem is, sensitivity, but you want to know why they’re sensitive to that food. And of course, we’re going to think about leaky gut and intestinal permeability. We need to think about auto-immunity and immunity, stress, of course, and genetics.
And in terms of trying to make a diagnosis, I’m thinking about food sensitivity testing. I can consider doing a histamine level or a diamine oxidase level to see whether that may be contributing. I think stool studies are very, very helpful. Looking at secretory IgA, parasites, yeast, and opportunistic infections. Mannitol/lactulose tests to looking for SIBO or intestinal permeability. And nutrient analysis looking for malabsorption, because these patients who are reacting to food are not absorbing their nutrients.
You want to remove food allergens when you find out what they are. You want to remove the offending pathogens, you want to increase DAO, and you want to decrease intestinal permeability. And that’s obviously the focus of the conference, right?
You have to eliminate gluten almost always. I hate to say it. Even in testing when it comes back negative, in my experience, if they’re chronically ill, they’re reacting to the wheat and the gluten. These are some things that I do in my practice to produce more DAO. B6 is a co-factor, so obviously, you want to get B6. You want to treat the underlying stress and adrenal hypofunction. And there are a couple of products on the market now that it is DAO and can be given when the patient eats.
You want to reestablish the normal gut flora with probiotics, which should be broad spectrum. Saccharomyces boulardii can be very helpful because it decreases zonulin. It competes with candida and prevents adhesion, and reduces cytokine mediated host response. You want to decrease intestinal permeability at all costs.
I want to spend the last part of the talk reviewing some of the cases. These are patients of mine who allowed me to discuss their case today, and I think you’ll see how interesting it is when you start really focusing on the underlying problem, how they start to get better.
This was a 70-year-old female with a lot of problems. This is a typical patient. In my former practice where I was really just doing primary care, she had hypertension, hyperlipidemia, metabolic syndrome, thyroid disease, migraines. But the concern was that she had this diagnosis of multiple sclerosis, and had been treated for a number of years with Copaxone. And she was not getting better, she was very frustrated, and she really didn’t know what else to do. She complained of headaches, fatigue, insomnia, depression, and diffuse joint pains. She was on a lot of medication and nothing was working. And the insomnia, she was treating with Ambien and a lot of other meds.
And when we started really looking, when she really wanted to get help, we looked at her blood work, which she continued to have Vitamin D deficiency despite adequate supplementation, so we thought. She had elevated hemoglobin A1C, which is a marker for pre-diabetes, low HDL levels, elevated homocysteine.
We did a heavy metal test which showed cadmium toxicity which was not really a surprise. And we did some organic acid testing, which showed some insufficiencies in adenosylcobalamin, tetrahydrofolate, renal ammonia overload, deficiency in ATP production, bacterial and yeast overgrowth. She was a mess. And when we initially started the process, she really didn’t want to go anywhere near thinking about food sensitivity. It just was not someplace her brain could go. And so, she agreed to the other testing, and we started doing…obviously, I wanted to do the obvious things. I wanted to take her off processed food, sugar. But her diet was very low in protein and she was really a binge eater, so she could not control it.
She finally…after many attempts, we did the food sensitivity test. And what we found was that in her severe intolerant column, she had corn and rice, which was not a surprise. She definitely had gluten sensitivity in all the grains that she had. She had casein sensitivity as well. She had quinoa, sunflower, and olive oil…I’m showing a lot of them, but the ones that I highlighted are the ones that she was…I don’t know, eating a lot of. And I don’t think that necessarily means anything here, but it does mean that she was focusing on the wrong foods.
From mild intolerance, again, she had a number of different things. Coffee, yeast…she was eating bread. And so, she was very committed to doing it. And when we gave her the rotation diet and she was able to really stick to it, she saw immediate results. Number one, the binge eating went away almost immediately within the first week. She was able to control what she was eating. She had one migraine for the entire month, and she was usually getting two to three per week. And when she cheated, she knew right away she’d get a migraine. It was becoming very obvious to her, and I think that was helping her stay on the program.
She definitely felt groggy, less foggy, and had more energy. And the original diagnosis of MS was looked at again, because when we reviewed her prior work-up, her CSF…her spinal fluid was really negative. She had some white matter changes on her brain that a neurologist had decided to treat her as migraine, and I would argue that…her MS symptoms went away when we took her off the food. What I would argue that this may be a gluten-induced issue or something that we don’t know, but clearly, she was better even if the MRI didn’t change. She felt better.
If I have time, I’m going to go over another case. Because this was a young girl…there was this 25-year-old girl who presented with a history of anaphylaxis to all fish and seafood. Every single fish and seafood, which was very, very interesting. She suspected a dairy intolerance. She had irritable bowel, eczema, seasonal allergies, and polycystic ovarian syndrome. And she was somebody who was very compliant with diet and exercise, she was very committed to it, but she thought she was eating really well. She was eating whole grains because the nutritionists always tell us to eat a lot of whole grains, and she was avoiding the fish and the seafood because she really thought that that’s all she needed to do.
When we worked her up initially, we saw that her IgE definitely showed the sensitivity as we suspected. The IgE also showed positive to milk and casein, some nuts and peanuts, and many other foods. And she had IgG reactivity to the same foods, which goes back to what I mentioned earlier, that the IgG may somehow be protective against the IgE.
We treated her with an elimination diet based on those results, and she definitely saw improvement. Her IBS was better. But she was still symptomatic. She was not 100%. She was very frustrated and she was very committed to going the next step.
The other problem was that the eczema got worse on this diet which didn’t make sense to us. She just was feeling more tired. And the eczema did not respond to topical steroids that were prescribed by her dermatologist.
So she agreed to further testing and we did the test for the innate immune system. And what it showed was that she definitely had a gluten sensitivity, but it also showed the oat sensitivity. And this is concerning because there are a lot of patients who are gluten-sensitive or intolerant, they’re eating gluten-free oats, but they may be sensitive to that as well, and this was the case here. Definitely confirmed the casein and whey sensitivity, and a variety of other…what I call “healthy” foods were also confirmed that she was sensitive to, including broccoli and kale.
These were the rest of her test results. A lot. What was interesting is we tested the rest of the family, and the mother, brother, and father…basically, they all did it, and the father and the brother had very similar sensitivities, but not the mother. Clearly, there’s some genetic link.
And what we did is within two weeks on the rotation diet, her symptoms resolved. She had more energy, that was apparent immediately. She lost five pounds, even though she really didn’t need to. But the eczema remained, and we couldn’t figure out what was going on with the eczema. And what we did was I made her bring in all her cosmetic products.
And what we found was that in a lot of these natural products, they were all organic. She was very much aware of avoiding parabens and whatnot. But what we found was that she had been using products that had wheat germ, soy, oats. There were parabens hidden in some of the things that she was using, even though she thought they were natural. And immediately, when we changed her cosmetic products, her eczema resolved completely.
I think that does illustrate the importance…when you’re thinking about patients and what they’re eating, you also have to think about what they’re putting on their skin, what they’re washing their hair in, what they’re using in their house to clean. I do this all the time. I sit down with my patients, and we go over their cleaning supplies and their cosmetics. Because if I don’t do that, even if I look at their food, I may not get the whole problem. How much time do I have left? Almost done? I’ll do one more case.
This was another typical patient that I do see in my practice who had a lot of issues. Again, she’s 65, she had migraines also, pre-diabetes. She had a peripheral neuropathy. She had suspected food intolerances to milk and dairy, but really thought it was just a lactose intolerance issue. She had anaphylaxis to scallops only, seasonal allergies, and asthma. But she recently developed alopecia and weight gain, and she had a history of osteoporosis. She was treated with a lot of different medications including Metformin, topiramate for prevention of migraines, proton pump inhibitors.
And when she came in, she had already tried the gluten-free diet, because several family members were found to be sensitive, although there was no family history of celiac. She noticed improved symptoms on the gluten-free diet, but very shortly, the symptoms returned. Then she tried the dairy-free diet, and she did this on all her own. She figured, “Well, she’s lactose-intolerant. Maybe she should just cut out dairy.” And again, some improvement in some of her symptoms, but not complete.
We did initial testing and she was somebody who really didn’t have the funds to do further testing for food sensitivity, so we concentrated on the things that we can do through her insurance, and we tested her thyroid, and her hemoglobin A1C and her vitamin levels. And what we found was that despite being on Metformin, her hemoglobin A1C was still in the pre-diabetic range. And this is also somebody who was working out five days a week, who was exercising, and thought she was eating well. And we were still seeing this persistence of the pre-diabetes.
Her TSH was elevated as well, and her free T3 was low. She had normal thyroid antibodies. She had a high cholesterol with a high LDL, very low ferritin levels, so she was very anemic, and a low B12 level. But she was on Vitamin D, so her Vitamin D levels were normal.
We treated her initially with what I would call a paleo-type diet; low-carb, high protein and fat. We treated her with some desiccated thyroid hormone, activated B vitamins. I couldn’t give her iron because she couldn’t tolerate it, but we did give her probiotics, and alpha lipoic acid. And really, her hair stopped falling out which was nice. She felt better, she lost a few pounds. Her TSH levels improved, her lipids improved a little bit. But her IBS was still there, and her migraines, although better, were not completely resolved.
At that point, she agrees to the food sensitivity testing because she sees we’re making progress, but we’ve not gotten there yet. We did the testing, and she had a mild reaction to gluten and gliadin, which was not surprising, she had a mild reaction to whey. She had severe reactions to quinoa and garlic, and quinoa was a big part of her diet after having gone gluten-free. She had moderate reactions to other foods that she happened to be eating a lot of.
And when we eliminated all of the reactive foods, she followed a four-day rotation diet. And within one week, her bowel symptoms started to subside. Within one month, they were resolved. And this was somebody who had actually had IBS-like symptoms all her life. But they resolved very quickly when we eliminated these foods.
When we tried to add back some of the mild reactive foods, she did react, so I knew that we still had work to do. She lost 10 pounds on that diet. Her migraines improved and only came back when she cheated. So three months her thyroid function was markedly better.
What I see is that you have to look at the patient from so many different views. You have to look at their gut, you have to look at their toxicities, you have to look at their lifestyle, you have to look at their food. And food clearly plays a significant role in our health and the development of obesity and chronic disease. And I hate to sound cliché here, but we are what we eat, and that’s become very clear. And we’re being exposed to foods that we’ve not been exposed to in the history of mankind, and inflammation is known to the root of all chronic conditions including obesity, and the major cause of inflammation, I believe, is food sensitivity.
What can you do for your patients? You can test them, you can put them on elimination diets. I strongly recommend going gluten-free, eating organic and avoiding genetically-modified foods. And you have to take care of the gut. Thank you.
You’ve just listened to Dr. Tania Dempsey and her lecture on the role of food sensitivities on chronic disease and inflammation, and especially the tools we have available to treat patients.
Cell Science Systems has several assays relevant to this lecture series. The first being markers which determine genetic predisposition for celiac disease. This includes the HLA DQ2 and DQ8 genes. Also available are various antibody markers such as tissue transglutaminase, TTG, and deamidated gliadin peptide, DGP. As well, ASCA Anti-Saccharomyces cerevisiae antibody, found primarily in inflammatory bowel disease patients with Crohn’s disease. Additionally, cellular analysis for gluten and other food sensitivities using the Alcat methodology is available.
These assays are available to providers in various single and multiple assay configurations. To inquire for additional literature or research, you can contact the lab at firstname.lastname@example.org.