Gluten is the major storage protein found mainly in wheat. It is sticky, elastic, traps air and gives baked goods their sponginess. It is also used in countless processed foods as a stabilizer or thickener. The gluten-free food industry is a significant trend. More people buy gluten-free food than those diagnosed with celiac disease or gluten-related disorder (non-celiac gluten sensitivity or gluten allergy). Celiac disease, gluten sensitivity, and gluten allergy are described. Atypical celiac disease and difficulties in diagnosis are described. The need for research on gluten sensitivity is highlighted; it is poorly defined and there is not a validated biomarker for diagnosis; still, it is a recognized medical condition with symptoms overlapping many of that of celiac disease.
Gluten-free nutrition is among the most engaging and debated topics in dietetics. Awareness on gluten and the gluten-free lifestyle is highly important to dietitians and other health practitioners in integrative and functional medicine. Celiac disease and gluten-related disorders are grossly misunderstood, even among highly-educated health practitioners. Those familiar with the gluten-free lifestyle are likely to encounter the Paleo diet, which is a call for return to eating the way humans did before the agricultural revolution 10,000 years ago. The Paleo diet reinforces the gluten-free lifestyle by placing restrictions on grains, among other things. The science on gluten, celiac disease and gluten-related disorders is briefly reviewed here. A gluten-free pizza recipe is provided.
What is Gluten?
Gluten (Latin for “glue”) is the major storage protein in wheat and is also found in barley and rye. Its sticky and elastic properties trap air when leavened, which gives baked goods their sponginess and cohesion. Gluten is also used as a binding or thickening agent in countless processed foods (eg, salad dressing and deli meats). Gluten and its close relatives secalin and hordein, from barley and rye, are:
- only partially broken down in the human digestive tract and yield protein fragments called gliadins, which trigger unfavorable immune responses in susceptible individuals1.
- theorized to be mistakenly interpreted by the gut-associated immune cells as a part of a dangerous microbe, which triggers an immune response in everyone, like that triggered by harmful bacteria. This is not exclusive to those with gluten-related disorders2.
- body’s fight against gluten is like its fight against bacteria: Everyone’s immune system fights potentially harmful bacteria every day; only rarely do we lose the fight against bacteria or gluten3.
- present in higher amounts in and comprised of new antigens due to modern agriculture hybridization, which creates a greater chance for a susceptible individual’s immune system to mount a maladaptive immune response4.
- relatively new to the human diet, being introduced about 10,000 years ago at the birth of agriculture1.
Gluten Freedom by Alessio Fasano, MD
Alessio Fasano, MD and author of Gluten Freedom1, is an international expert on celiac disease and gluten-related disorders. He is the founder of the Center for Celiac Research, located in Boston at Mass General Hospital for Children. He and his team discovered zonulin, a protein produced by the small intestine cells, which regulates intercellular permeability by regulating tight junctions (gated channels between cells)5. Its evolutionary, homeostatic purpose may be to enable the immune system to mount attacks on potentially harmful microbes or substances6. In individuals with genetic susceptibility to gluten-related disorders, zonulin is produced in excess and leads to impaired intestinal barrier function6. The constant flux of undigested proteins and antigens from the intestine into the bloodstream can increases the work load of the immune system and may increase risk for autoimmunity: conditions in which the immune system loses the ability to distinguish potential threat from self-cells, resulting in damage to self-cells in effort to destroy perceived threats7.
Celiac disease (CD) is a “genetic disorder affecting children and adults. People with celiac disease are unable to eat foods that contain gluten…. In people with celiac disease, gluten sets off an autoimmune reaction that can eventually lead to complete destruction for the villi, the tiny fingerlike projections lining the small intestine”8. Healthy villi increase the surface area of the small intestine and allow nutrient absorption. In CD, production of antibodies and cytokines (inflammatory chemicals) lead to the destruction and flattening of villi, which causes nutrient malabsorption and impaired intestinal barrier function. Celiac disease affects one in 133 people in the United States9. Common symptoms are malabsorption, including diarrhea, bloating, enamel loss, nausea, vomiting, anemia, osteoporosis, and tooth enamel defects8. Celiac disease is not food allergy; an individual may outgrow a food allergy; celiac disease is an autoimmune disease that requires a gluten-free diet for life8. CD is now known as a clinical chameleon, which means that it is difficult to diagnose and often manifests in various and atypical signs and symptoms, as reported in the following excerpt from Sheila Dean, RD, in The Integrative RDN newsletter10:
In a 2005 paper by Sanders and colleagues in the British Medical Journal, the authors state, “CD used to be perceived as involving gastrointestinal symptoms suggestive of malabsorption, but this manner of presentation is now described as the classic (typical) form.” 5Furthermore, the authors suggest that patients with CD may have the “silent” or atypical form – that is, without gastrointestinal symptoms — where the condition affects organs other than the small intestine, with manifestations such as altered thyroid function, skin abnormalities, bone disease, iron-deficiency anemia, and even neurological disorders, including depression, mood changes, migraines and inability to focus.5 As a result, one could potentially have CD but be free of the classic GI symptoms for years. More recently, the term “potential” or “latent” CD has been used to describe patients with sub-clinical pathology and other subtle immunological abnormalities, such as celiac-like mucosal immunoglobulin pattern and increased density of intra-epithelial T cells, suggesting a significant risk of developing CD later in life.
Researchers have found that undiagnosed CD (often associated with atypical CD) seems to have increased greatly in the US in the last 50 years, and that it is associated with a nearly 4-fold increased risk of death11.
Diagnosing Celiac Disease
Fasano says that “blood test panels can screen for presence of specific antibodies; a biopsy of the intestine (before beginning a gluten-free diet) is usually needed to make a final diagnosis8.
According to NIH12:
Genetic tests may be used to detect the genes that turn on the body’s immune response to gluten. Such tests can help rule out celiac disease, but they can’t be used for diagnoses; many people who have the genes never develop celiac disease. Your doctor can use a blood test to look for signs of celiac disease. Before the test, continue eating foods with gluten. Otherwise, the results may be negative for celiac disease even if you have it. Eating a regular diet can also help your doctor determine if you have a form of gluten sensitivity that is not celiac disease. Gluten sensitivity is something you may grow out of over time, Fasano explains, whereas celiac disease is a lifelong condition.
Genetic predisposition markers HLA DQ2/8 are positive in about 97% of cases of CD13. Many of the symptoms of gluten sensitivity are like celiac disease. They include tiredness, stomachaches, muscle cramps, and leg numbness14.
Non-Celiac Gluten Sensitivity and Non-Celiac Wheat Sensitivity:
Gluten sensitivity, the new kid on the block in gluten-related disorders, is15:
- as the word sensitivity suggests, a reaction to ingesting gluten-containing grains.
- a condition producing a myriad of symptoms like celiac disease, though less severe.
- a cause for many gastrointestinal and non-specific symptoms like “foggy mind” and joint pain.
- not linked to the intestinal inflammation and flattening villi characteristic of celiac disease.
- not linked to the presence of tissue transglutaminae (tTG) autoantibodies, which are used in celiac disease diagnosis.
- linked to an innate immune response; whereas, celiac disease is linked to an adaptive immune response.
There is new research stating that those with non-celiac gluten sensitivity or non-celiac wheat sensitivity are more numerous than those with celiac disease. Sufferers experience a systemic immune response and intestinal cell damage to the level of compromising intestinal barrier function, which is often referred to as “leaky gut.”18 Measurement of certain antibodies may be used to diagnose NCGS. Sufferers may experience up to 200 symptoms shared with celiac disease including “foggy mind’, depression, ADHD-like behavior, abdominal pain, bloating, diarrhea, constipation, headaches, bone or joint pain, and chronic fatigue when they have gluten in their diet, yet do not test positive for celiac disease.”
Experts are “not quite sure what genetic or immune mechanisms trigger this condition. [They] do know that the number of individuals with gluten sensitivity is exploding.”19 Concerning gluten-related disorders, Fasano says that the real experts are those who have navigated their way back to health with the gluten-free lifestyle. Diagnosis is made by an elimination diet followed by a challenge, which is the monitored re-introduction of gluten-containing foods to evaluate whether health improves with the decrease or exclusion of gluten from the diet1.
Non-celiac gluten sensitivity (NCGS) was “originally described in the 1980s and [is a] recently ‘re-discovered’ disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA)”.20
The discussion on gluten gets more complex with the identification of “other plant proteins contained in wheat, such as lectins, agglutinins and amylase-trypsin inhibitors, [which] may have a role in the development of symptoms after the ingestion of cereals by triggering the innate immune response[72-74]. For these reasons, and given the scattered data regarding the pathogenesis of NCGS, it has been suggested that the “non-celiac wheat sensitivity” definition may be more appropriate[75,76]”21.
Even from a conventional AND viewpoint, gluten sensitivity has been identified as a real health condition that requires sufferers to identify what agrees with their own body’s, and to diligently seek solutions22:
Because we don't know if there are long-term health consequences to continuous exposure [to gluten in NCGS], individuals with gluten sensitivity make their own decisions about what kind of gluten-free diet they wish to follow. Some choose to completely avoid gluten, while others may be more lenient in their efforts to avoid risk of cross-contact.
Linking Gluten-Related Disorders and Other Health Conditions
The prescription of a gluten-free diet (at least a temporary one) for health complaints typically not associated with gluten-related disorders is very popular in integrative and functional medicine. With consideration of the importance of maintaining gut barrier function for overall health, the premise that humans cannot digest gluten completely and that it may temporarily increases intestinal permeability in everyone, a gluten-free diet is a common intervention point for any health complaint in integrative and functional medicine. More specifically, adverse reactions to gluten are considered a contributing factor to Hashimoto’s (autoimmune thyroiditis). Support for this idea follows23:·
- People with Hashimoto’s often present with food sensitivities (including that for wheat or gluten), which are revealed in elevated levels of certain IgG antibodies (food sensitivity testing).
- By decreasing intake of IgG-reactive foods, IgG levels may decrease; IgG antibodies are thought to be the same types of antibodies that attack the thyroid gland in autoimmune disease.
- The incidence of Hashimoto’s is higher in those with CD.
- Surveys suggest that many with Hashimoto’s experience improvement in symptoms on a gluten-free diet.
- Autoimmune disease is grossly underdiagnosed and misunderstood: 72 million people in the US have an autoimmune disease—only 24 million are diagnosed.
- Celiac disease is now recognized as a common autoimmune condition that may develop at any age and affect many organ systems.
- The prevalence of CD in people with T1DM is 10-30 times that found in the general population.
- Hashimoto’s disease and T1DM are the most frequently reported CD-associated conditions.
- Early detection of atypical CD is important in prevention of T1DM due to their common genetic base, which is human leukocyte antigen (HLA).
- Screening for atypical CD includes salivary tests for anti-gliadin antibodies (AGA) and tTG-Abs, and antibody serological assays including anti-emdomysial and anti-tissue transglutaminase tests.
Wheat allergy is different from celiac disease and non-celiac gluten sensitivity in that24:
- It triggers a different and usually more immediate immune response.
- It is linked to overproduction of IgE antibodies; whereas, celiac disease is linked mainly to IgA autoantibodies; there is no increase in IgE antibodies or autoantibodies with food sensitivity.
- It is 10 times less common than CD, occurring in only 0.1 to 0.3% of the US general population; it’s prevalence rate is more frequent in children at 3 to 5 percent.
- Its reactions can include baker’s asthma, GI distress, itchy skin and hives, and fatal anaphylaxis
- Diagnostic tests include skin prick tests, blood tests for specific antibodies, and elimination diets (with a food diary) and food challenges to reintroduce the food being tested.
- People with life threatening food allergy must carry an emergency kit with injectable epinephrine.
Paleo (“Caveman”) Nutrition
The Paleo diet (aka the Caveman or Stone Age diet) is centered on the idea that humans evolved on a hunter-gatherer lifestyle that includes fruits, vegetables, nuts, seeds, and meat-- excluding grains (especially gluten-containing grains), legumes, and milk25. These exclusions are of the purist persuasions of “Paleoism”. There are modified Paleo diets that include moderate amounts of gluten-free grains, legumes, and milk. A proponent of Paleo may emphasize traditional preparation of grains and legumes (soaking, sprouting, and fermenting) to increase digestibility, and to lower gluten and anti-nutritional factors like lectins and phytates26. A2 milk is popular in modified Paleo, which is milk from cows (Guernsey or Jersey breeds), goats, and sheep, which produce A2 casein, which some consider in line with ancestral nutrition and more compatible with human physiology than A1 casein-containing milk produced by Holstein cows27. Validating the practices of Paleo nutrition is beyond the scope of this article. The purpose here is to highlight significant ideas in the health food industry, those that are promoted by the Paleo and gluten-free lifestyle community, and those that are accepted by many in integrative and functional dietetics. Many integrative and functional dietetics practices are based on the “n of 1” concept, or self-based research, which is relies heavily on elimination diets, food challenges, and subjective reports on signs and symptoms. This is popular due to the expenses and limitations of diagnostic testing, especially with poorly understood conditions like gluten sensitivity. This may also be in line with patient-centered care and empowering people to take initiative and responsibility for their own health.
There is sufficient research to state that the number of people who may benefit from a gluten-free diet is greater than that diagnosed with celiac disease. Gluten sensitivity is poorly understood and has recently become a recognized medical condition that may require strict exclusion of gluten-containing foods like CD. Recent research has linked gluten-related disorders to other health conditions and diseases including T1DM, autoimmune thyroiditis, and a variety of non-specific symptoms like joint pain, fatigue, and “foggy mind.” Gluten is a peculiar protein that humans cannot digest completely, and one that my increase intestinal permeability (“leaky gut”) in healthy, non-celiac individuals. According to Alessio Fasano, however, gluten is like bacteria we encounter everyday: The immune system fights it and most do not lose the fight to gluten. Citing his book, Gluten Freedom, is appropriate here due to his status as the leader in celiac research. RDs and doctors in integrative and functional medicine continue to prescribe gluten-free diets as having potential to reduce symptoms of nearly any disease. A gluten-free diet poses financial and food preparation challenges. That said, it is not necessary to use gluten in making a highly palatable pizza, as shown in the recipe below.
Yield: 12 3.75’’x 3.33’’ square pieces Oven: 400˚F (375˚F in convection)
- Almond flour- ½ cup
- Garbanzo bean flour- ½ cup
- Arrowroot flour- ½ cup
- Ground flax seed- 2 Tbsp.
- Baking powder- ½ tsp.
- Olive oil- 1 Tbsp. + 1 tsp.
- Eggs - 2 large
- Shredded mozzarella- 1 cup, packed (5 oz.); dairy-free cheese may be used.
- Water- ¼ cup
- Pizza sauce- ½ cup
- Parchment paper
1) Preheat oven to 400˚F.
2) Mix all dry ingredients: flours, flax seed, and baking powder). Add 1 ounce or ¼ cup shredded mozzarella. Mix well.
3) Whisk eggs briefly. Add eggs, water and 1 Tbsp. olive oil to flour mixture. Mix well with whisk.
4) Spread dough on parchment paper. Make a 14’’x10’’ rectangle. Moisten hands to keep it from sticking to hands. Dough will be approx. ¼’’ thick.
5) Spread pizza sauce evenly on dough.
6) Bake for 12 minutes. Remove from oven and sprinkle remainder of mozzarella on pizza. Optional: add oregano to taste. Bake for additional 5 minutes to melt cheese.
7) Cut pizza 3x4 for 12 pieces.
Note: Reduce baking times in convection oven, even at 375˚F (try 8 minutes plus 3 minutes).
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3. Wagner O. Grains, brains and bellies review. The Integrative RDN. 2015; 17(3): 57.
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12. NIH. Going gluten free: necessary for some, optional for others. News In Health. 2016. https://newsinhealth.nih.gov/2016/05/going-gluten-free. Accessed 12/7/17.
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17. Celiac Disease Foundation. Non-celiac wheat sensitivity. https://celiac.org/celiac-disease/understanding-celiac-disease-2/non-celiac-gluten-sensitivity-2/. Accessed 12/10/17.
18. Uhde M, Ajamian M, Caio G, et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016 ;65(12):1930-1937. https://www.ncbi.nlm.nih.gov/pubmed/?term=Intestinal+cell+damage+and+systemic+immune+activation+in+individuals+reporting+sensitivity+to+wheat+in+the+absence+of+coeliac+disease. Accessed 12/10/17.
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21. Elli L, Branchi F, Tomba C, et al. Diagnosis of gluten related disorders: Celiac disease, wheat allergy and non-celiac gluten sensitivity. World Journal of Gastroenterology: WJG. 2015;21(23):7110-7119. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476872/. Accesses 12/10/17.
22. Begus R. Food allergies, celiac disease and gluten sensitivity. http://www.eatright.org/resource/homefoodsafety/four-steps/separate/food-allergies-celiac-disease-and-gluten-sensitivity. Accessed 12/9/17.
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