Gluten Intolerance-What Your Doctor May Not Tell You

By Ralph Sanchez, L.Ac.,CNS,D.Hom.


The associated health issues related to gluten intolerance (GI), have a wide range, with Celiac Disease being the defining and best known aspect of that problem. However, GI can often go undiagnosed, because it does not always present with the more obvious symptoms seen in Celiac Disease (CD). GI and even CD can be cryptic, or a hidden problem, in many individuals. Gastrointestinal symptoms, such as diarrhea, abdominal pain, bloating, fatty stools, nausea or vomiting, and distention are at times part of the clinical presentation of GI and CD, however these symptoms may be mild or absent altogether. Cryptic or hidden GI, is commonly referred to as sub-clinical gluten intolerance or sensitivity, and bears distinguishing it’s clinical features from CD.


Sub-clinical gluten intolerance is often confused with celiac disease, also referred to as celiac sprue or non-tropical sprue, or gluten enteropathy. In essence, CD is a diagnosis that is confirmed by biopsy of intestinal tissue. If the damage is apparent upon biopsy and there is other supportive evidence, such as elevated antibodies, then the diagnosis of CD is given.

The reaction to gluten in sub-clinical gluten intolerance, commonly referred to as “gluten sensitivity”, may be similar to the gluten intolerance in celiac disease, except for the actual degree of presenting symptoms and the damage to the small intestine-if any exists. Typically, gastrointestinal symptoms are absent. However, there are a host of health issues related to gluten sensitivity, such as anemia, fatigue due to malabsorption of nutrients, mood disorders, elevated thyroid antibodies, rheumatic pains or other related autoimmune diseases.

Other medical references to forms of CD, include “silent” CD, which does not present with any symptoms that normally characterizes a GI, but upon a biopsy, there will be damage to the tissues of the small intestine. Silent CD, may present as one of many other celiac disease related disorders. “Latent CD”, refers to a finding of positive blood antibody tests, but there are is minimal or no appearance of damage to the intestinal tissues upon examination (biopsy). It is thought that these latent cases reflect gluten sensitive individuals, or perhaps a relatively gluten free diet, albeit also having a high probability for eventual damage to the intestinal tract with any significant exposure to gluten. These references to GI and classifications of CD are at times used interchangeably. However, they represent distinct medical categorizations of atypical CD.

Gluten Intolerance-Celiac Disease

The exact mechanisms in Celiac disease (CD), are complex and not completely known. What is generally accepted to be the primary course of CD, involves the effects of gluten on the intestinal structures and immune system. There is perhaps no other such complex biological disease that has such a simple answer-the avoidance of gluten. Nevertheless, the understanding of the inter-related processes of gluten intolerance and CD, gifts us with insights into the dynamics of the intestinal milieu and subsequently a better grasp as to the workings of an amazing universe within-our digestive tracts.

The gluten/celiac disease theory proposes that CD is caused by an exaggerated (hyper) immune response to the gluten found in wheat, and wheat related and hybrid grains-spelt, kamut, and triticale, as well as barley, and rye. There are many other wheat strains, such as couscous and bulghur that are in the family of prime gluten offenders as well. Other grains like oats are considered by some to potentially have negative health effects related to gluten Intolerance (GI), albeit in most studies, they do not promote the same immune/gluten intolerance reactions. The issue of oats is somewhat confounding. Oats have the similar toxic peptide sequences (avenin) as gliadin in wheat, yet in studies, there are conflicting results indicating that oats are very harmful to some individuals with CD, while not very harmful to others. It may be that the load of the gluten in oats is such that it may take more long term exposure, or greater amounts of oats ingested, to elicit the gut immune responses typical of gluten sensitivity or celiac disease. The issue of oats in some individuals, may also be one of cross contamination by wheat, in processing facilities that handles both grains. In any case, oats and other grains may contribute to inflammatory reactions (allergies) in sensitive individuals and contribute to, or converge with the cascade of immune responses and leaky gut issues that occurs in CD, regardless of their gluten profile. A distinction to note here is that intolerances to foods, is not an allergy response. There are several food intolerances, such as lactose intolerance, that are primarily due to a lack of specific enzymes that break down either sugars or proteins. Gluten intolerance is the only intolerance that involves an immune system reaction, albeit not the same as in a true allergy or delayed food sensitivity.

The predominant theory with respect to GI, is that there is an inherent lack in ability to break down gluten, a generic term for a type of protein in grains. More specifically, gliadin (i.e. alpha-gliadin), a polypeptide in wheat gluten, and other prolamins in grains are the offending protein. Prolamins (a group of proteins-prolamines, with similar protein structures), namely gliadin from wheat, hordeins from barley and secalins from rye, have been identified as the trigger for celiac disease. These polypeptides (strings of amino acids) are the residual from incompletely broken down pieces of protein from gluten that are potentially toxic to the intestinal tissues. Gluten and prolamins, are in other grains like rice and corn, but these do not contain the toxic peptide(s) sequence that can provoke an immune response and that are toxic to, and damage the intestinal tissues in gluten intolerant or sensitive individuals. Nevertheless, as noted above, some grains like corn and soy, are common allergens that can problematic in people with food sensitivites and intolerances and should be carefully assessed as to any possible role they may be playing in ramping up inflammation in the gut. The toxic peptides from select prolamins eventually trigger a specific immune response that is part of the immune cascade associated with CD. However, a proinflammatory condition in the digestive tract may be a requisite intestinal environment before gluten can exert it’s influence.(1,2) Food allergies and sensitivities as well as some common gut infections, can potentially contribute to “breaking tolerance” (see below), and opening the gate to immune/inflammatory reactions characteristic of CD.

In GI and CD, chronic exposure to these gliadin containing grains, leads to an inflammatory condition of the small intestine. The repeated immune reactivity to gluten/gliadin, in some individuals, eventually manifests in an “autoimmune” condition, in which immune system antibodies attack the intestine and cause severe damage over time. The immune/inflammatory reaction in the small intestine, damages the villi of the small intestine, and causes changes to the structure (hyperplasia) of the tissues deep between and at the base of the villi, the crypts. The villi are finger-like projections on the intestinal wall where nutrient absorption occurs. This damage impairs the absorption of nutrients from digested food. With repeated exposure to gliadin in gluten, these villi can become shortened or completely flattened, with the subsequent loss of nutrient absorptive surface area. The immune reaction and intestinal intolerance to gluten, can cause diarrhea, abdominal pain, bloating, nausea, malabsorption of nutrients (iron, calcium, zinc, folate, fat soluble vitamins), and other gastrointestinal problems. However, the typical symptom picture of sub-clinical or silent CD, may not have much or any of the digestive distress symptoms that characterizes CD. Often GI and CD may be written off as an irritable bowel syndrome problem, or a spastic colon. More severe intestinal/bowel disorders related to gluten intolerance reactions are inflammatory bowel diseases such as Crohn’s disease. Other symptoms that may indicate an intolerance to gluten include, bone pain, muscle cramps, migraine headaches, tingling, numbness and nerve pain of the extremities (neuropathy), miscarriage and infertility problems, menstrual irregularities, depression, gall bladder disease, vitiligo (discoloration of skin), and developmental and growth problems in children


Healthy Villi…..Damaged Villi….. Destroyed Villi

villi_healthy3 villi_damaged5 villi_destroyed2

Enzyme Therapy

Enyzyme deficiency (peptidase) in gluten intolerance was once theorized to play a role in the development of CD. Peptidases, are protein digesting enzymes secreted by the intestinal tissues (brush border), and are distinguishable from pancreatic enzymes that also break down proteins for absorption. More recent research in enzyme therapy and CD, reveals that enzyme therapy with newer enzyme products demonstrate a promising role, in at the very least, ameliorating gluten intolerance (GI) reactions and perhaps buffering the margin of error in a gluten free diet. In numerous studies, pancreatic insufficiency (enzyme production) has been noted in a considerable percentage of celiac patients, and could in part explain why a population of celiac patients do not do as well despite eliminating gluten from the diet.(3) Enzyme therapy in part protects patients with CD with amelioration of symptoms related to gluten intake.(4) Enzyme therapy can provide important digestive support, and offer some protection for all CD patients where the gluten status of the meal is uncertain, as when eating out, or for those who are especially sensitive to gluten. Specific enzyme derivatives, demonstrate enhanced gluten digest, and shows promise in management of GI. Enzyme products that contain Aspergillus niger (fungal) derived enzymes, survive stomach acid and pepsin degradation, and effectively break down gluten proteins.(5) However, to date Aspergillus niger derivatives specific for gluten digest are not commercially available.

Several peptidase enzymes also have demonstrated resistance to stomach acid, effective break down of gliadin peptides, and thus promise in the treatment and management of celiac disease.(6) An additional benefit to enzyme therapy is the enhanced digest of other proteins, particularly those in dairy products, as well as the sugar lactose. A secondary feature of GI is lactose intolerance, that is a consequence of the damage to the intestinal tissues and the enzyme secreting cells. Lactose intolerance and bacterial overgrowth of the small intestine, the latter a common condition that follows the inadequate digest of foods, are suspected as underlying factors that contributes to the unresponsiveness to a gluten free diet in some individuals.(7,8) The autoimmune profile of CD may also result in hydrochloric acid deficiency (HCL). HCL deficiency has been associated with dermatitis herpetiformis (9), a skin disorder that is linked to CD. I consider enzyme and HCL supplementation a must for the management and support of GI and CD.

The Lectin Connection

According to another theory, a component in wheat gluten, wheat germ agglutinin (WGA), may act as a lectin with toxic properties to the intestinal cells. Lectins, are specialized proteins that bind specifically to sugars or other carbohydrates, usually on other proteins, which are located on the membranes of cells. They are thus often referred to as carbohydrate-binding proteins. Lectins causes cells to agglutinate, or stick to each other, compromising their function. In the digestive tract, lectins bind to specialized intestinal cells (crypt cells).(10) If they enter the blood stream, they also bind to red blood cells causing agglutination or clumping. High levels of lectins may be found in grains, the legume family (beans, peanuts), dairy and plants in the nightshade family. While lectins are present in most foods, their higher levels in some, are problematic for many individulas that are genetically vulnerable to their potentially toxic effects. “Lectins are (a) toxic, inflammatory, or both; (b) resistant to cooking and digestive enzymes; and (c) present in much of our food.”(11) Among the effects observed in the small intestine of lectin fed rodents is stripping away of the mucous coat lining the intestinal tract, increased intestinal permeability (leaky gut), and the overgrowth of toxic bacteria and.(12,13,14). The characteristic damage from gluten intolerance (crypt hyperplasia), to the intestinal tissue, is also caused by WGA.(15)

Breaking Tolerance

In examining the details of a food intolerance like gluten, it is a logical course to look at the known pathways of the immune reactions, intestinal anatomy and function, the genetic characteristics of predisposed individuals, and the unique construct of gluten containing grains. Nevertheless, all of that examination does not entirely reveal why some genetically gluten intolerant individuals never develop celiac disease (CD), why some celiac disease patients do not recover even after eliminating gluten from the diet, or why a few (rare) without the genetic blueprint, manage to become “intolerant”. The answers to these questions, may come from a deeper examination as to the factors that may “break” a gluten tolerant individual, into an intolerant pattern - it is the proverbial straw that broke the camel’s back.

Normally, the intake of food does not elicit an immune reaction as the body is able to modify the immune response to proteins in the diet. As we ingest proteins growing up, our immune system adapts, and suppresses immune reactions to many of the more allergenic foods we are exposed to. This phenomenon is known as “oral tolerance”. Oral tolerance of foods that potentially can provoke an immune response is acquired as our digestive tracts are exposed to foods, and our immune systems accomodate during childhood. That is familiar to many families as they slowly introduce a variety of foods, particularly proteins, to a growing and developing child.
In a large study, the second by the same investigators, of 1560 children with a genetic predisposition (diabetes type 1 genotypes-HLA-DR3 or DR4 gene variations)* for celiac disease, those exposed to gluten before month 3, had a 5-fold increased risk in developing CD, compared with children exposed to gluten-containing foods at 4 to 6 months.(17) An interesting timing aspect of this study, was that children exposed to gluten after 7 months, had a significantly increased risk of CD compared with exposure at 4 to 6 months. While the age times of exposure raises some questions that hopefully will be answered by other studies, the real takeaway, is that exposing genetically susceptible children to gluten at a young age increases their risk for CD. I would not recommend exposing at-risk infants to gluten at age 4 to 6 months to hopefully lessen the probability of incurring CD. Why raise the probability of breaking tolerance! Especially if there is a family history of type 1 diabetes or CD.

The immune system of the digestive tract is constantly in a state of tolerance to it’s own population of microorganisms (bacteria) and to food allergens as it attempts to maintain a steady immune response-one that is not reacting to just any potential insult, and subsequently moderating inflammatory responses. So what is it that skews an immune response in one individual that results in an allergy response or perhaps a gluten intolerance response, and yet in another individual there is a tolerance to that allergen? The answers are complex and specific to types of foods or proteins. Gluten intolerance (GI) is predicated on a number of factors. Yes genetics plays a role, but it may be more limited than is currently accepted, or there are a number of other genes that are yet not understood as to their specific influences. As detailed below, some interesting research is percolating, that implicates leaky gut genes as part of the holism of gluten intolerance.

It is largely accepted that genetics plays a primary role in various food intolerances. This certainly could fully explain the intolerance to gluten as we well know that gliadin and other prolamins stimulate immune-inflammatory reactions in susceptible individuals. Nevertheless, we also have evidence that in tolerant individuals, regardless of genetics, certain triggers will turn that tolerance into an intolerant profile. Viruses (rotavirus), gut infections (bacteria & candida) and even pregnancy may act as triggers in a apparently gluten tolerant individual, and stimulate inflammatory responses that promotes the cascade of events that results in intolerance. The preganacy link indicates that hormones may exert some influence as well.

There may be degrees of intolerance as evidenced by cases that manifest into full blown celiac disease, down to the less “sensitive” individual that seems to have a tolerance predicated on the amount of gluten ingested, the timeline involved or “triggers” that may push one over the edge. Two recent scientific publications have now shown that a rotavirus (common gut viral infection) protein may be linked to celiac disease through a “molecular mimicry” mechanism. “Molecular Mimicry” describes a phenomena whereby some pathogens like viruses, yeast or bacteria, can evoke an immune response because they have enough similarity to the body’s own proteins to cause an autoimmune reaction. This is evident in a number of autoimmune disorders associated with certain HLA genotypes (susceptibilty genes) such as in rheumatoid arthritis (RA) or Ankylosing Spondylitis (AS). In some cases of AS or RA, gut bacteria that passes through the gut barrier and is recognized by the immune system as “similar” to joint tissues. As the immune system reacts to the bacteria to eliminate it, it actually attacks the joint isssue. In the case of a rotavirus infection, a common cause of gastrointestinal infection and inflammation (gastroenteritis), it is seen as a similar to the gialdin molecule and the body is triggered into the same intolerance, or immune reaction as stimulated by gliadin in susceptible individuals. Antibodies to this celiac peptide also recognize and bind to the rotavirus protein (VP-7) and cause the same leaky gut/intestinal permeability that is a key step in the immune activation associated with CD.(19) Thus, viral infection and/or tissue damage in the intestine may cause inflammation and immune reactivity, leading to loss of tolerance for gluten. These recent studies on the link of a viral trigger in CD, provide the first indication that a high frequency of rotavirus infections may increase the risk of celiac disease autoimmunity in childhood in genetically predisposed individuals.(18) “Our findings show that in active celiac disease, a subset of anti-transglutaminase IgA antibodies recognize the viral protein VP-7, suggesting a possible involvement of rotavirus infection in the pathogenesis of the disease, through a mechanism of molecular mimicry.”(19)

Bacterial (dysbiosis) and yeast (i.e. candida albicans) overgrowth are common patterns in digestive disorders-either as a primary infection causing digestive or systemic health problems, a concommitant or byproduct of various intestinal disease processes, or as a residual of other causative factors like antibiotics. In the case of Candida albicans, a fascinating dynamic occurs between Candida and the reactive antibody tTG (tissue Transglutaminase) IgA. Apparently Candida contains proteins-peptide sequences, that are identical and very similar to those found in gluten, including gliadin. Candida infections or overgrowth, in individuals that are genetically inclined to be GI, can trigger the same tissue transglutaminase and endomysial enzyme antibodies involved in celiac disease.(20) This study and several others illustrate that Candida albicans can “mimic” gliadin, and that under certain conditions, may result in the reactive immune response typical of GI. There is not enough research yet, to unequivocally establish the candida link to CD as a trigger. However, the lack of sufficient evidence, to draw firm conclusions does not rule it out either. Based on my own clinical observations, gluten sensitive individuals that address “overgrowth” of unhealthy gut bacteria and yeast, wind up with better tolerance and reduced titers of gut SIgA gliadin. Bacterial overgrowth of the small intestine may also inhibit the success of a gluten free diet and recovery from CD.(21)

Gluten Intolerance-Related Conditions

The prevalence of CD in general Western populations is close to 1% and is somewhat higher in certain Western European populations.(21) Estimates will vary depending on the populations studied as evidenced by the following numbers:

PREVALENCE OF CELIAC DISEASE IN THE UNITED STATES (22)

  • In average healthy people: 1 in 133
  • In people with related symptoms: 1 in 56
  • In people with first-degree relatives (parent, child, sibling) who are celiac:1 in 22
  • In people with second-degree relatives (aunt, uncle, cousin) who are celiac: 1 in 39
  • Estimated prevalence for African-, Hispanic- and Asian-Americans: 1 in 236

Many experienced practitioners think that the rate of gluten intolerance (GI) is much higher, particularly since many individuals are diagnosed as having primarily other related disorders, and so many others are probably never diagnosed with an intolerance or a sensitivity. More often, the intolerance to gluten causes sub-clinical celiac disease (CD), or CD that is not more readily apparent by it’s classical clinical symptom presentation, leads to a variety of chronic health conditions including osteoporosis, anemia, type 1 diabetes and depression. Researchers are also beginning to see a connection between gluten GI, and neurological disorders. Gluten sensitivity can be primarily and at times, exclusively a neurological disease, without the presence of intestinal damage.(24) Unexplained neurological dysfunction may comprise up to 10% of of GI cases.(24) Autism,(25) Down’s Syndrome,(26) and epileptic disorders,(27) to one extent or another, are associated with GI. In children, “softer” neurological problems associated with celiac disease (CD), include ADHD, developmental delay, chronic headache, and abnormally low muscle tone (hypotonia).(28) In Autistic Spectrum Disorders and ADHD, morphine-like exorphins (substances having opiate-narcotic like activity), derived from the incomplete breakdown of grains and dairy, alter mood and behavior by depressing serotonin, dopamine and norpinephrine levels. The type of gluten intolerance associated with these conditions is considered to originate from the body’s inability to break down the gluten and casein proteins without the typical autoimmune response, as seen in CD.

Gluten and dairy elimination benefits a population of schizophrenic patients. Dr. F.C.Dohan, who in some 40 years ago noticed that the rate of schizophrenia was substantially higher than in places where gluten consumption was absent, has since advocated a gluten-schizophrenia link in several research studies. “Considerable evidence indicates that the major cause of schizophrenia is the inborn inability to process certain digestion products of some food proteins, especially cereal grain glutens…”(29)

Cerebellar Ataxia, a neurological disorder (describes a lack of coordination while performing voluntary movements), in many cases is representative of chronic ingestion and intolerance to gluten. There is evidence that links the same gene influences in Sporadic Cerebellar Ataxia (Gluten Ataxia)to gluten intolerance.(30) “Gluten ataxia is a common neurological manifestation of gluten sensitivity,” according to M. Hadjivassiliou, M.D., of the Royal Hallamshire Hospital, Sheffield, UK. Hadjivassiliou reported complete resolution of symptoms on a gluten-free diet in patients with prompt diagnosis.(31)

It is my feeling that an undiagnosed silent GI over the years can contribute to the brain inflammation associated with Alzheimer’s Disease, in genetically predisposed (ApoE4) individuals. While there is not any significant studies to that, it is a logical theory that our second brain, the gut, can drive neuorological degeneration through the inflammatory processes that originate in the digestive tract, and are carried to immunologically vulnerable tissues like the brain. Memory loss is associated with gluten driven neurological disease. Just las year (2006), researchers at the Mayo Clinic examined medical records for the years 1970 through 2005 to identify eight male and five female patients, aged 45-79, showing cognitive decline within two years of onset or a severe exacerbation of symptoms of biopsy-proven celiac disease.(32) While the Mayo study confirmed CD through a biopsy, similar neurological disorders may be present and develop over time in the absence of clear and obvious gastrointestinal symptoms. While numerous studies make reference to CD and a possible connection to atypical dementia, presently, there is a dearth of similar studies demonstrating a clear link between CD and cognitive disorders and dementia. More are needed.

There is sufficient evidence to implicate Gluten intolerance in diseases that are characterized by “hyper” or autoimmune disorders, yet are not gastrointestinal diseases. Autoimmune disease associated with GI include, Addison’s disease, autoimmune chronic active hepatitis, Alopecia Areata, Graves’ disease, type 1 diabetes, Autoimmune hepatitis, myasthenia gravis, scleroderma, Sjogren’s syndrome, lupus, and Hashimoto’s thyroiditis. Tissues and organs affected outside the gastrointestinal tract are potential “immunological target organs” that are vulnerable to immune driven inflammation arising from other areas of the body, like the gut and liver, and triggers like gluten.

Many cases of Chronic Fatigue Syndrome (CFS), and Fibromyalgia (FM) are known to in part be caused by GI as well. Abdominal pain and irregular bowel movements that are written off as an “Irritable Bowel Syndrome” in patients with CFS, are very likely due to a GI condition.(33) Dr. Paul Cheney, a leading CFS researcher who first characterized CFS as a disorder in the ’70s, recommends diet modifications, including gluten restriction for CFS and FM. (34) In a nationwide study that surveyed patients with CD that presented as other disorders, 9% were fibromyalgia cases. Other studies indicate the prevalence of positive CD antibody assessments in patients with CFS and suggest that it would be prudent medical procedure to screen for CD in CFS cases.(35) I personally have found that in CFS and FM, that it is essential to screen for food allergies and intolerances and the inevitable bacterial (dysbiosis), yeast, parasite infections, and leaky gut problems that are to one degree or another, consistent underlying elements of any chronic gut disorder.

Skin conditions such as Dermatitis herpetiformis, a chronic, extremely itchy rash consisting of bumps and blisters, is a common problem seen in GI, and is considered to have similar genetic components.(36) Psoriasis and eczema are accepted by many practitioners to have a gluten-related component. I have seen this connection with eczema countless times in practice. However, whether it is a gluten related reaction or simply a wheat allergy, is at times difficult to separate.

Last but not least, people with celiac disease who don’t maintain a gluten-free diet also have a greater chance of getting one of several forms of cancer, especially intestinal lymphoma and bowel cancer.

Genes

Gluten intolerance (GI) is an inherited disorder. However, you need gluten from the grains mentioned above to trigger the health issues related to GI. And not all individuals that carry genes associated with GI, develop celiac disease (CD) or the sub-clinical forms. “HLA gene typing” (genotype) is used for determining the susceptibilty a person may have to developing CD or celiac related disorders. HLA stands for Human Leukocyte Antigen* which are certain molecules found on the surface of cells. More than 100,000 HLA molecules can be expressed on the surface of a single cell. There are four primary HLA gene types implicated in gluten intolerance/sensitivity-DQ1,2,3,& 4. Four variants or subtypes of DQ1 (DQ5 &6) and DQ3 (DQ7,8 & 9) comprise the rest of the gene pool associated gluten intolerance/sensitivity and CD. Classic CD is associated with HLA-DQ2 (DQA1*0501, DQB1*0201) and, to a lesser extent, HLA-DQ8 (DQA1*0301, DQB1*0302). The HLA-DQ2 (DQB1*0201) variant is associated with increased risk for celiac disease. Approximately 90-95 percent of CD patients carry HLA-DQ2 molecules, and 5-10 percent carry HLA-DQ8.(37) Celiac related disorders, gluten ataxia and microscopic colitis, have a significant association with DQ1,2 and DQ3. A stronger gene influence is exerted when several of the DQ genes are present together-i.e DQ2/DQ2, DQ8/DQ8, DQ2/DQ8, DQ1/DQ1. This is called a “gene-dosage effect”. The gluten/immune reactions are more significant when there are specific combinations of genes. It amounts to a more gluten intolerance picture in one individual with these gene factors, as opposed to another individual that may have more of a gluten sensitivity. While genetics in CD and celiac related disorders is significant, only a small relative percent of these individuals develop CD. 20-50 percent of humans express the DQ2 genotype,(38) yet there is low causal link between a positive HLA-DQ2 and development of CD, unless one is a first degree relative diagnosed with CD or type 1 diabetes. HLA genes contribute only about 40% of the total genetic predisposition to celiac disease.(39) The researchers suggest that several genes work collectively to cause celiac disease, and a single missing or altered gene is probably not its cause.

Once all the risk factors are weighed, it becomes apparent that it is the combined influence of HLA and non-HLA genes, together with gluten exposure, and a host of additional factors that are the involved in disease development.

There is a genetic link (referred to as linkage genes), between susceptibilty genes in CD and type 1 diabetes. The CD gene variations also are associated with increased risk for type 1 diabetes. Individuals with type 1 diabetes and their first-degree relatives have increased risk of celiac disease.(40)

Leaky Gut Genes

Celiac disease is also known to cause increased permeability of the intestine through the inflammatory processes that occur in gluten intolerance. Commonly referred to as “leaky gut”, Leaky Gut Syndrome is a disorder in which the intestinal lining is more permeable or porous than normal. Apart from factors like inflammation, there are genetic factors that predispose individuals with CD to having a more permeable intestine. Zonulin, a protein that influences the integrity of the intestinal wall through a regulatory function, has recently been identified as playing a key role in CD and other autoimmune disorders.(41) Individuals with celiac disease have higher levels of zonulin, leading to a higher degree of leaky gut, and allowing gliadin to permeate between the normally tight junctions of the intestinal cellls. A component of the immune reactivity associated with CD, is dependent on the passage of gliadin peptides through the intestinal barrier where a component of gliadin/immune cell cross reactivity occurs. So, you have gliadin slipping through a more permeable membrane, in part by the influence of increased zonulin release, which is integral to the eventual disease process typical of CD.(42) Another genetic link, is the discovery of another genetic variant involved in the maintaining the tight junctions of the intestinal barrier (myosin IXB variant) which further empasizes the connection of a leaky gut mecahnism as a primary process in celiac disease.(43) The leaky gut pivot to GI and CD is undoubdetly a factor not only in CD, but also in the neurological, rheumatological and other autoimmune disoders that are comorbid (coexisting) conditions in CD. After one weighs the various gene influences in GI and CD, it is hardly a stretch to conclude that perhaps a series of genetic factors combine together to influence the gamut of gluten intolerance related disorders and CD.

Traditional Testing

There is currently no test for diagnosing celiac disease with 100% certainty. Most doctors base their recommendation for the avoidance of gluten on positive test results for CD. Serology (blood) tests for CD are used as an indicator of gluten stimulated immune reactions, and a predictor of damage to the mucosal barrier-the intestinal wall. They include:

  • total IgA,
  • anti-gliadin antibodies (AGA) - IgG and IgA,
  • anti-endomysial antibody (EMA) IgA, and
  • tissue transglutaminase (tTG) IgA antibody tests.

Of the latter two antibody assessments, indicators of immune mediated inflammation and damage to intestinal tissue, the tTG antibody IgA test is now considered by many practitioners, the preferred marker for diagnosis, although the research literature is rife with elder references to the superior value of the anti- endomysial antibody marker. There is evidence to support using the tTG antibody test as an accurate alternative to the anti-endomysial antibody test.(44) A new convenient option for the clinician looking to evaluate a possible GI or CD condition, are blood testing kits that can be done in the office. There is now available “in office” test kits, with proven efficacy, for tTG/IgA antibodies.(45)

A test commonly used in the past, the anti-reticulin antibodies (ARA) IgA, IgA Anti-ARA is not usually ordered as it once was, because it is less sensitive and not as precise than the other tests. The first serum marker reported to be of use in the diagnosis of celiac disease was the IgG antigliadin antibody (IgG-AGA). Though a sensitive marker of gliadin/immune reactions, this antibody is also found in other diseases and is therefore not specific for celiac disease. IgA-AGA is a more sensitive marker than IgG-AGA for CD and celiac related disorders, with a combined positive IgA-AGA and IgG-AGA, increasing sensitivity. Total IgA, which can be low due to a genetic propensity to underproduce, can skew any value to IgA antibody results. It is estimated that 2% of celiacs have IgA deficiency. The total IgA assessment is critical for gaining insight into a possible GI and CD case. Although any of these tests are commonly used as potential screening or diagnostic tools, a negative result for any one of these antibodies, does not rule out CD. Dr. Peter Green, a Gastroenterologist and director of the Celiac Disease Center Unit of Columbia-Presbyterian Medical Center in New York, feels that “about 30% of Celiacs have negative antibodies at diagnosis. Therefore, the absence of positive antibodies does not rule out celiac disease.”(46) A positive antibody test is not a diagnosis in and of itself, but it is a valuable tool for correlating an individual’s clinical presentation or symptoms, to the probability and risk for having CD. An intestinal biopsy is needed for confirming CD, but biopsies can be mishandled and findings of any intestinal damage could indicate other disease processes (Whipple’s Disease,Tropical Sprue,Parasitic Infections). It is now recognized that negative celiac biopsies do not rule out celiac related disorders that are driven by gluten intolerance. The digestive tract may be undamaged in the presence of chronic gluten mediated inflammation and the numerous health disorders related to gluten sensitivity and intolerance. Clearly, the diagnosis of GI or gluten sensitivity, is not always predicated on lab results or even biopsies, especially if the individual has eliminated suspect gluten grains from their diet. Many individuals that I have determined to have some degree of GI, did not have positive indicators (antibodies) from traditional lab testing. However, a marker I have found useful, in context of clinical presentation, diet and personal and family history, is a gut sIgA antibody test for gliadin.

The intestinal mucosa is a major site for antigliadin antibody production.(47,48) Stool analysis for antibodies against gluten-related antigens may be a more sensitive assessment to gluten/immune reactions than serum antibody assessments. Positive fecal anti-gliadin and anti-tissue transglutaminase IgA (produced in situ by the intestinal mucosal) result from a specific immune reaction to gluten in the digestive tract, and may be present in the absence of similar antibodies in serum , especially in the absence of the typical celiac disease-related damage to the intestinal tract (i.e., villous atrophy). This again represents the immune/inflammatory response to gluten that may be ongoing without any apparent damage to the gut or without any elevated serum antibody titers. The takeaway? Intestinal gluten antibody assessments may be a more accurate method of detecting gluten intolerance reactions, and may reflect such immune reaction before,or in the absence of any traditional serum evaluations. Dr. Kenneth Fine, a gatroenterologist, founder, and medical director of EnteroLab.com, has advocated and refined the methodology of stool antibody tests for gluten intolerance and sensitivity. His research, over the past 18 years supports the utilization of specific stool antibody assessments-tTG-IgA and AGA-IGA, as a viable window into gluten intolerance and sensitivity reactions where they occur-in the digestive tract. These assessments may indeed be a more reliable indicator of immune responses over and above serum evaluations commonly used.

However, any positive antibody test for GI may be predicated on the exposure to gluten and other triggers and genetic propensities for IgA production. I personally have observed stress and parasite infections as layers to positive gut antibody titers. In the literature, there is one documented case of giardiasis (giardia infection) treatment reversing “active” coeliac disease to “latent” coeliac disease.(49) Usually, if one is sensitive or intolerant to gluten, elimination of gluten will result in a “cure” and revert any tissue damage if not to severe, as well as normalize any titers of antibodies that may be elevated. However, as in the case of giardiasis and other gut infections detailed above, or any proinflammatory factors, it may take a more comprehensive gut and antigen evaluation to effectively return recalcitrant cases back to normal.

A test that has proved to be a sensitive predictor of CD, is the rectal gluten challenge. In studies with children, rectal gluten challenges, with an exposure to gliadin, identified 100% of patients with CD, independent of gene type. (50,51) In the latter referenced study , the 100% accuracy was predicated on biopsies taken after a 4 hour challenge. A post 2 hour challenge biopsy was not as accurate.

Genetic Testing

The genes that are screened for in genetic testing for GI and CD were previously mentioned above-HLA genes-HLA-DQ2 (DQA1*0501/DQB1*0201) and HLA-DQ8 (DQA1*0301/DQB1*0302). The HLA-DQ2/ DQB1*0201 incurs increased risk. The logic for genetic testing for CD has a couple of rationales. The first is to rule out a genetic predisposition to CD. This is a useful strategy when an individual is exhibiting some of the problems associated with GI and any of the various forms of CD, but the blood antibody tests are negative and a biopsy is not possible or desired. The antibody and gene markers are often ordered as a comprehensive panel of tests to weigh all the possible indicators. Without these core gene influences, it is considered rare that the individual with a negative gene test will develop celiac disease in the future. People who test negative for the gene would essentially rule out any possible link to GI and CD and could eliminate regular testing and screening for the remainder of their lives. A negative gene test in context of a suspected celiac, or celiac related case, would then rule out the probability of CD, and the various celiac related diseases, and shift the investigation to another diagnosis. Another advantage in gene testing, is the screening of children of parents with a history of GI or CD. A gene test for children of an adult with such a history would provide invaluable dietary guidelines. Positive results would allow the parents to know which children need close monitoring. A convenient and viable screening for celiac genes that is ideal for testing children and adults, is a cheek cell specimen (buccal swab) test that is offered by Enterolab. The buccal swab gene test can be done at home and bypasses the needle trauma that very young children fear and abhor. In all cases, a positive gene test is not specific to, nor does it diagnose CD. Nevertheless, it does increase the likelihood, if positive, that either GI is potentially a health threat, or that indeed, CD may be present if there is supporting clinical indications, and positive antibody assessments. It places an individual into an “at-risk” group for celiac disease, and provides leverage for prudent dietary choices as well as the need for future screening. Only 3% of individuals that carry the HLA celiac markers, HLA-DQ2 or HLA-DQ8 develop celiac disease, which infers that HLA gene testing, even if positive, is not a perfect predictor of risk for CD and that there are multiple gene influences, including the “leaky gut” genes detailed earlier.

Finally, each person has a different level, influenced by a number of factors, at which an autoimmune response associated with CD will be activated. Most will be more likely fall into the gluten sensitive group that will never be diagnosed with CD, but will present with a wide spectrum of low grade health disorders, and in some cases more severe diseases, that may never be connected to gluten intolerance or sensitivity. For some the avoidance of any of the typical gluten suspects will bring relief and healing. For others, looking at similar food sensitivities and intolerances, as well as gut infections and leaky gut promoters, will be an important piece for full recovery. Early diagnosis and evaluation for gluten intolerance and related disorders is key. Individuals who suspect that they are gluten sensitive or intolerant, and may be affected to one degree or another, should seek the careful analysis, management and guidance by an experienced practitioner to determine their risk, and to optimize their health.

* Having this combination of HLA type genes, predisposes an individual to a higher risk of developing type 1 diabetes. Inheriting the HLA-DR3 gene from one parent and the HLA-DR4 from the other parent, he/she will have an HLA type described as DR3/DR4.
http://www.genetics.com.au/factsheet/49.htm
When looking at genotypes such as HLA-DR3 or DR4 gene variations that are primarily associated with type 1 diabetes, but also linked to celiac, they are commonly referred to as linkage genes.

** The immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person’s HLA type belongs to that person (and therefore is not an invader). Any cell displaying some other HLA type is “not-self” and is an invader. HLA types are inherited, and some of them are connected with autoimmune disorders and other diseases. People with certain HLA antigens are more likely to develop certain autoimmune diseases, such as Ankylosing spondylitis, Celiac Disease, SLE (Lupus erythematosus), Myasthenia Gravis, and Sjogren’s Syndrome.

References

1. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease.
Hue, S., J. J. Mention, R. C. Monteiro, S. Zhang, C. Cellier, J. Schmitz, V. Verkarre, N. Fodil, S. Bahram, N. Cerf-Bensussan, and S. Caillat-Zucman.

Immunity 21: 367-377. 2004

2. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.
Meresse, B., Z. Chen, C. Ciszewski, M. Tretiakova, G. Bhagat, T. N. Krausz, D. H. Raulet, L. L. Lanier, V. Groh, T. Spies, E. C. Ebert, P. H. Green, and B. Jabri.

Immunity 21: 357-366. 2004

3. Is exocrine pancreatic insufficiency in adult coeliac disease a cause of persisting symptoms?
Leeds JS, Hopper AD, Hurlstone DP, Edwards SJ, McAlindon ME, et al.

Aliment Pharmacol Ther. 2007 Feb 1;25(3):265-71.

4. Enzyme therapy for management of coeliac disease
Hugh J. Cornell, Finlay A. MacRae, Joy Melny, Catherine J. Pizzey, Fiona Cook, Sandra Mason, Prithi S. Bhathal, Teodor Stelmasiak

Scandinavian Journal of Gastroenterology; Volume 40, Number 11/November 2005

5. Highly efficient gluten degradation with a newly identified prolyl endoprotease: implications for celiac disease.
Stepniak D, Spaenij-Dekking, Mitea C, Moester M, de Ru A, Baak-Pablo R,
van Veelen P, Edens L, Koning F.

Am J Physiol Gastrointest Liver Physiol. 2006 Oct;291(4):G621-9. Epub 2006 May 11.

6. Comparative biochemical analysis of three bacterial prolyl endopeptidases: implications for coeliac sprue
Lu Shan, Thomas Marti, Ludvig M. Sollid, Gary M. Gray, and Chaitan Khosla

Biochem J. 2004 October 15; 383(Pt 2): 311-318.

7. Partially responsive celiac disease resulting from small intestinal bacterial overgrowth and lactose intolerance.
Ghoshal UC, Ghoshal U, Misra A, Choudhuri G.

BMC Gastroenterol. 2004 May 22;4:10.

8. High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal.
Tursi A, Brandimarte G, Giorgetti G.

Am J Gastroenterol. 2003 Apr;98(4):839-43.

9. Auto-immune atrophic gastritis in patient with dermatitis herpetiformis.
Stockbrugger R, Andersson H, Gillberg R, et al.

Acta Derm Venereol 1976;56:111-113.

10. The lectin properties of gluten as the basis of the pathomechanism of gluten-sensitive enteropathy
E. Kottgen, F. Kluge, B. Volk and W. Gerok1

Journal of Molecular Medicine; Volume 61, Number 2 / January, 1983

11. Handbook of plant lectins: properties and biomedical applications.
Van Damme EJM, Peumans WJ, Pusztai A, Bardocz S.

London: Wiley, 1998:31-50.

12. The effect of concanavalin A and wheat germ agglutinin on the ultrastructure and permeability of rat intestine. A possible model for an intestinal allergic reaction.
Sjolander A, Magnusson KE, Latkovic S.

Cell Struct Funct. Sep 1986;11(3):285-293.

13. Intestinal microbial flora after feeding phytohemagglutinin lectins (Phaseolus vulgaris) to rats.
Banwell JG, Howard R, Cooper D, Costerton JW.

Appl Environ Microbiol. 1985 Jul;50(1):68-80.

14. Morphological changes of rat small intestine after short-time exposure to concanavalin A or wheat germ agglutinin.
Sjolander A, Magnusson KE, Latkovic S.

Cell Struct Funct. 1986 Sep;11(3):285-93.

15. Elevated levels of serum antibodies to the lectin wheat germ agglutinin in celiac children lend support to the gluten-lectin theory of celiac disease.
Falth-Magnusson K, Magnusson KE.

Pediatr Allergy Immunol. 1995 May;6(2):98-102.

16. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease.
Norris JM, Barriga K, Hoffenberg EJ, Taki I, Miao D, Haas JE, Emery LM,
Sokol RJ, Erlich HA, Eisenbarth GS, Rewers M.

JAMA. 2005 May 18;293(19):2343-51.

17. Rotavirus infection frequency and risk of celiac disease autoimmunity in early childhood: a longitudinal study.
Stene LC, Honeyman MC, Hoffenberg EJ, Haas JE, Sokol RJ, Emery L,
Taki I, Norris JM, Erlich HA, Eisenbarth GS, Rewers M.

Am J Gastroenterol. 2006 Oct;101(10):2333-40

18. In Celiac Disease, a Subset of Autoantibodies against Transglutaminase Binds Toll-Like Receptor 4 and Induces Activation of Monocytes
Giovanna Zanoni, Riccardo Navone, Claudio Lunardi, Giuseppe Tridente, Caterina Bason, Simona Sivori, Ruggero Beri, Marzia Dolcino, Enrico Valletta, Roberto Corrocher, Antonio Puccetti

PLoS Medicine Volume 3, Issue 9, SEPTEMBER 2006

19. Is Candida albicans a trigger in the onset of coeliac disease?
Nieuwenhuizen WF, Pieters RH, Knippels LM, Jansen MC, Koppelman SJ.

Lancet. 2003 Jun 21;361(9375):2152-4.

20. High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal.
Tursi A, Brandimarte G, Giorgetti G

Am J Gastroenterol. 2003 Apr;98(4):839-43.

21. The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review.
Dube C, Rostom A, Sy R, et al.

Gastroenterology 2005; 128:S57-S67.

22. UNIVERSITY OF CHICAGO CELIAC DISEASE PROGRAM
Fact Sheets about Celiac Disease

Celiac Disease Information Line: 773-702- 7593

23. Gluten sensitivity as a neurological illness

M Hadjivassiliou, R A Grunewald and G A B Davies-Jones

Journal of Neurology Neurosurgery and Psychiatry 2002;72:560-563

24. NEUROLOGICAL MANIFESTATIONS OF CELIAC DISEASE
Siqueira Neto, Ana Carolina Leite Vieira Costa,
Francisco George Magalhaes, Gisele Sampaio Silva

Arq Neuropsiquiatr 2004;62(4):969-972

25. Heat shock protein and gliadin peptide promote development of peptidase antibodies in children with autism and patients with autoimmune disease.
Vojdani A, Bazargan M, Vojdani E, Samadi J, Nourian AA, Eghbalieh N,
Cooper EL.

Clin Diagn Lab Immunol. 2004 May;11(3):515-24.

26. Prevalence of celiac disease in Down syndrome in the United States
Zachor DA, Mroczek-Musulman E, Brown P

J Pediatr Gastroenterol Nutr 2000 Sep;31(3):275-9

27. Epilepsy, cerebral calcifications and coeliac disease. The importance of an early diagnosis
Diaz RM, Gonzalez-Rabelino G, Delfino A.

Rev Neurol. 2005 Apr 1-15;40(7):417-20.

28. Range of neurologic disorders in patients with celiac disease.
Zelnik N, Pacht A, Obeid R, Lerner A.

Pediatrics. 2004 Jun;113(6):1672-6.

29. Cereals and schizophrenia data and hypothesis.
Dohan FC.

Acta Psychiatr Scand. 1966;42(2):125-52.

30. Sporadic cerebellar ataxia associated with gluten sensitivity
K. Burk, S. Bosch, C. A. Muller, A. Melms, C. Zühlke, M. Stern, I. Besenthal, M. Skalej, P. Ruck, S. Ferber, T. Klockgether and J. Dichgans

Brain, Vol. 124, No. 5, 1013-1019, May 2001

31. Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia.
Hadjivassiliou M, Grunewald RA, Chattopadhyay AK, Davies-Jones GA, Gibson A, Jarratt JA, et al.

Lancet. 1998 Nov 14;352(9140):1582-5.

32.Cognitive Impairment and Celiac Disease

William T. Hu, MD, PhD; Joseph A. Murray, MD; Melanie C. Greenaway, PhD; Joseph E. Parisi, MD; Keith A. Josephs, MST, MD

Arch Neurol. 2006;63(10):1440-1446.

33. Food intolerance exists as a co-morbidity in Chronic Fatigue
Syndrome

TM Emms, TK Roberts, HL Butt, I Buttfield, NR
McGregor, RH Dunstan

Program and abstracts of the Fifth International Research, Clinical and Patient Conference; American Association for Chronic Fatigue Syndrome; January 26-29, 2001; Seattle, Washington. [Abstract No. 15].

34. The Third International Clinical and Scientific Meeting
Abstracts Sydney Conf. (25/35)

35. High prevalence of serum markers of coeliac disease in patients with chronic fatigue syndrome
A Skowera, M Peakman, A Cleare, E Davies, A Deale and S Wessely

Journal of Clinical Pathology Vol. 54, pp: 335-336, April 2001

36. Molecular analysis of HLA DP and DQ genes associated with dermatitis herpetiformis.
Fronek Z, Cheung MM, Hanbury AM, Kagnoff MF.

J Invest Dermatol. 1991 Nov;97(5):799-802.

37. Overview and pathogenesis of celiac disease.
Kagnoff ME

Gastroenterology 2005; 128:S 10-S18.

38. Where is celiac disease coming from and why?
Catassi C.

J Pediatr Gastroenterol Nutr 2005;40:279-282.

39. Poly (ADP-ribose) polymerase-1 haplotypes are associated with coeliac disease.
Rueda B, Koeleman BP, Lopez-Nevot MA, et al.

Int J Immunogenet 2005; 32:245-248.

40. Cryptic gluten intolerance in type 1 diabetes: identifying suitable candidates for a gluten free diet
D Sblattero, A Ventura, A Tommasini, L Cattin, S Martelossi, F Florian,
R Marzari, A Bradbury and T Not

Gut 2006;55:133-134; doi:10.1136/gut.2005.077511

41. Intestinal zonulin: open sesame!
Fasano A.

Gut. 2001 Aug;49(2):159-62.

42. Rapid disruption of intestinal barrier function by gliadin involves altered expression of apical junctional proteins.
Sander GR, Cummins AG, Henshall T, Powell BC.

FEBS Lett 2005; 579:4851-4855.

43. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defect.
Monsuur AJ, de Bakker PI, Alizadeh BZ, et al.

Nat Genet 2005; 37:1341-1344.

44. Diagnostic accuracy of coeliac serological tests: a prospective study.
Reeves GE, Squance ML, Duggan AE, Murugasu RR, Wilson RJ, Wong RC,
Gibson RA, Steele RH, Pollock WK.

Eur J Gastroenterol Hepatol. 2006 May;18(5):493-501.

45. Looking for celiac disease: diagnostic accuracy of two rapid commercial assays.
Nemec G, Ventura A, Stefano M, Di Leo G, Baldas V, Tommasini A,
Ferrara F, Taddio A, Citta A, Sblattero D, Marzari R, Not T.

Am J Gastroenterol. 2006 Jul;101(7):1597-600.

46. Presentation to Westchester Celiac Sprue Support Group, Phelps Memorial Hospital, North Tarrytown, NY, September 29, 1996.

47. Production of antibodies to gliadin in intestinal mucosa of patients with coeliac disease: a study at the single cell level.
Lycke N, Kilander A, Nilsson LA, Tarkowski A, Werner N.

Gut. 1989 Jan;30(1):72-7.

48. Class and subclass-associated specificity differences of anti-gliadin antibodies from mucosa and serum.
P E Engstrom, U Sundin, B Lavo, G Norhagen, R Hallgren, C I Smith, and L Hammarstrom

Immunology. 1992 December; 77(4): 604-608.

49. Treatment of giardiasis reverses “active” coeliac disease to “latent” coeliac disease
Carroccio A, Cavataio F, Montalto G, Paparo F, Troncone R, Iacono G.

Eur J Gastroenterol Hepatol. 2001 Sep;13(9):1101-5.

50. In siblings of celiac children, rectal gluten challenge reveals gluten sensitization not restricted to celiac HLA.
Troncone R., Greco L., Mayer M., Mazzarella G, Maiuri L, Congia M, Frau F, Do Virgiliis S, Auricchio S.

Gastroenterology 1996 Aug;111(2):318-324

51. Diagnosing coeliac disease by rectal gluten challenge: a prospective study based on immunopathology, computerized image analysis and logistic regression analysis.
Ensari A, Marsh MN, Morgan S, Lobley R, Unsworth DJ, Kounali D,
Crowe PT, Paisley J, Moriarty KJ, Lowry J.

Clin Sci (Lond). 2001 Aug;101(2):199-207.

1 comment to Gluten Intolerance-What Your Doctor May Not Tell You