{{:celiac_intro.jpg|}}

====== Introduction ======
<style justify>
Celiac disease (gluten-sensitive enteropathy), which is also referred to as spruce or coeliac is a digestive and autoimmune disease that leads to the destruction of the lining of the small intestine when foods containing gluten are consumed.<sup>[1]</sup> The immune system of individuals with celiac disease forms antibodies to gluten which attacks the intestinal lining causing inflammation and damage to the villi of the intestine.<sup>[2]</sup> The damage done to the intestinal lining leads to the inability of the body to absorb nutrients including proteins, fats, carbohydrates vitamins and minerals which are vital for good human health.<sup>[1]</sup>
</style>


<style center>
{{:norm-celiac.jpg|}}



**Figure 1**: Image comparing the intestinal villi of a healthy individual to someone with Celiac Disease
</style>


<style justify>
Gluten is a protein that can be found in wheat, rye, triticale, barley. Gluten is the ingredient in wheat that assists in holding bread and other baked goods together and keeps them from crumbling.<sup>[2]</sup> Oats that are made in plants that process other grain products can also be found to contain gluten. Lipsticks, medicines, and vitamins can also contain gluten.<sup>[3]</sup> 
</style>


<style center>
{{:breadbun.jpg|}}


**Figure 2**: Various product that contain gluten 
</style>


<style justify>
Some long-term health problems that can accompany celiac disease include<sup>[1]</sup>:
  * Osteoporosis- caused by the inability to absorb calcium and vitamin D
  * Miscarriage or infertility
  * Birth defects (e.g., growth problems)- caused by poor absorption of nutrients including folic acid
  * Seizures
  * Cancer of the intestine
 
Individuals with celiac disease may also be more prone to other autoimmune diseases including - Thyroid Disease, type 1 Diabetes, Lupus, Rheumatoid arthritis
 
It has been estimated that 1 in 133 people in Canada are affected by celiac disease.<sup>[2]</sup> It is an inherited condition where people have a 1 in 22 chance of developing the disease if their parent or sibling has the condition.<sup>[3]</sup> Not all individuals that carry the gene for celiac disease will develop the disease.<sup>[4]</sup> Environmental factors including stress, pregnancy, surgery of an infection can sometimes lead to the onset of the disease.<sup>[5]</sup> When treated early with a gluten free diet, the damaged tissues are about to heal and help decrease the risk of developing other long-term complications association with celiac disease.<sup>[4]</sup>
</style>


====== Mechanism of Celiac Disease ======
There are many mechanisms involved in Celiac Disease. Some are listed below.

===== Factors Involved in Disease Pathogenesis  =====
<style justify>
Celiac disease pathogenesis involves interactions among: environmental factors, genetic factors, and immunological factors. Firstly, in terms of the environmental factors, the specific proteins  found in grain products such as wheat, rye, and barley are what contribute to celiac disease. Secondly, the MHC class II HLA-DQ alleles are the key genetic factors that interact with the environmental factors to produce the negative consequences of CVD. Finally, tissue TGase is a critical compound that leads to the cascade of events that lead to the symptoms of celiac disease.<sup>[6]</sup> 
</style>

===== Environmental Factors: Gluten =====
<style center>
{{:treedia.jpg|}}


**Figure 3**: Taxonomy of dietary grains. It is shown that grains like wheat, rye, and barley which are most commonly associated with celiac disease are also very closely related. Whereas, grains like oats and rice which are rarely contribute to celiac disease are more distantly related to wheat.
</style>



<style justify>


As shown in figure 3 celiac disease is activated by proteins in wheat, rye, and barley. These proteins are popularly referred to as “gluten”, however, it is important to note that gluten only represents the specific proteins found in wheat. There are two major types of gluten which are known as gliadins and glutenins. These have a high proline and glutamine content. A high proline content causes these proteins to be resistant to complete proteolytic digestion by enzymes in the human intestine. This leads to the accumulation of large peptide fragments with a high proline and glutamine content in the intestines.  In individuals with celiac disease this accumulation leads to epithelial cell brush border injury and pancreatic dysfunction.<sup>[6]</sup>


</style>

===== Genetic Factors: MHC class II HLA-DQ alleles =====
<style float-right>
{{:blahblah.jpg|}}







**Figure 4:** This venn diagram shows that almost all individuals with celiac disease will also express the alleles HLA-DQ2 or HLA-DQ8
</style>

<style justify>




Pathogenesis of celiac disease is rooted by host genetic factors and this evident in monozygotic twins  who have a concordance rate of about 75%. Celiac disease is related to specific MHC class II alleles mapping the HLA-DQ locus. The presence of HLA-DQ is necessary for the phenotypic expression of celiac disease, in all individuals affected by celiac disease, regardless of where they are from, they express HLA-DQ alleles which encode HLA-DQ2 or HLA-DQ8 heterodimers which leads to the susceptibility of celiac disease. The HLA-DQ2 allele can be inherited in cis (on 1 parental chromosome) or trans (on 1 chromosome from each parent). Usually, the prevalence of CD is higher in individuals where 50 or 100% of heterodimers of HLA-DQ are HLA-DQ2 than those with only 25% of HLA-DQ heterodimers being HLA-DQ2. HLA-DQ2 on APCs (antigen presenting cells) can bind and present “gluten” peptides to populations of CD4+T cells in the lamina propria of the small intestine. The binding of HLA-DQ2 on APCs to CD4+ T cells usually occurs with the help of the tissue TGase.<sup>[6]</sup> 


</style>

===== Immunological Factors: Tissue TGase =====
<style center>
{{:diagramofcells.jpg|}}


**Figure 5:** Tissue TGase helps mediate the binding of HLA-DQ2 to APCs (antigen presenting cells) which eventually lead to the cascade of events in which the end result is intestinal inflammation.
</style>

<style justify>
Tissue TGase is primarily released in the intestinal mucosa usually during tissue injury. It plays a role in tissue repair and cross-links proteins by forming isopeptide bonds between glutamine and lysine residues. During conditions of low pH it can deamidate glutamine and convert it into neutral glutamine into a negatively charged glutamic acid which then increases the binding affinity of HLA-DQ2 molecules which favour binding negatively charged residues. Once the HLA-DQ2 molecules bind, they form the gluten-peptide-HLA-DQ complex which then meet a population of CD4+ T cells that are HLA-DQ2 restricted. Upon meeting, these T cells which recognize the complex become activated in the small intestine. These T cells lead to the production of IFN-γ which plays a major role in the downstream initiation of mucosal damage. This was found by neutralizing IFN-γ in mucosa that was affected by celiac disease which resulted in the prevention of mucosal damage.<sup>[6]</sup> 
</style>

===== Pathogenesis of Celiac Disease =====
<style center>
{{:diagramofprocesssssss.jpg|}}


**Figure 6:** This image represents the three major events that eventually lead to intestinal tissue damage, specifically targeting the villi in the small intestine. The three events include: luminal and early mucosal events, activation of pathogenic CD4+ T cells and tissue damage.
</style>

<style justify>
There are three major events that eventually lead to the symptoms that represent celiac disease. These include: luminal and early mucosal events, activation of pathogenic CD4+T cells, and subsequent events that lead to tissue damage. The start of luminal and mucosal events occurs when an individual that is genetically susceptible to celiac disease ingests gluten. Gluten can’t be digested by this individual due to high levels of proline. This leads to a large amount of undigested gluten peptides. These peptides then cross the epithelial barriers and enter the lamina propria where they encounter tissue TGase and APCs. These APCs express HLA-DQ2 heterodimers that bind to proline-rich peptides that contain negatively glutamic acid residues; this conversion was done by tissue TGase which caused the glutamine in the peptides to undergo deamidation. Once this occur APCs present the peptides to HLA-DQ2 restricted populations of CD4+ T cells which are then activated. This activations leads to the release of mediators which are what eventually cause tissue damage.<sup>[6]</sup>
</style>

===== Unknowns of Pathogenesis =====

<style justify>
The mechanism of celiac disease is very complex as it involves various different compounds and processes that eventually lead to the primary characteristic of celiac disease, mucosal damage. As a results there are multiple unknowns such as: how gluten crosses the epithelial cell barrier, role of immunity, role of IFNs in pathogenesis of celiac disease, how tissue TGase leads to deamidation, and sequence of CD4+T cell responses.<sup>[6]</sup>
</style>


====== Treatment of Celiac Disease with a Gluten-Free Diet ======
<style justify>
As we already know celiac disease is a condition in which the absorptive surface of the small intestines is damaged by certain substances we intake, primarily gluten. Celiac disease cannot be cured but can be effectively treated and controlled. One treatment is a strict adherence to a gluten-free diet (for life).  
</style>

<style center>
{{:glutentable.jpg|}}


**Figure 7:** Shows what products have gluten and what products do not
</style>
<style justify>
With the complete removal of a gluten from the diet, the patient will result in symptomatic, serologic, and histologic remission.<sup>[7]</sup> For children, the growth and development returns to normal following the gluten-free diet. While in adults, many complications are often avoided following this. It usually takes around two weeks for improvement in symptoms after starting the gluten free diet. Additionally, many reported that with a strict dietary control the antibody levels may revert to normal during 6-12 months after initiating the diet.<sup>[7]</sup>
</style>
===== Problems =====
<style float-right>
{{:fissruessss.jpg|}}



**Figure 8:** Shows the problems that have been found in the duodenum
</style>

<style justify>
In a study conducted it was seen that small intestinal recovery and resolution of the symptoms is incomplete. This maybe on account that the form of celiac disease is more complicated like refractory celiac disease. In cases like this it was found some patients may not fully respond to the gluten free diet.<sup>[7]</sup>


Nutrition is an important thing to look at if a patient has celiac disease. The nutritional status of a person diagnosed will depend on the length of time the person lived with an active but undiagnosed disease, as well as the damage to the GI tract, and degree of malabsorption. The most common things noted in patients who start the gluten free diet is that there is substantial weight loss, anemia, and vitamin/mineral deficiencies.<sup>[7]</sup> The malabsorption of iron, folate, and calcium is common with patients having celiac disease as these nutrients are absorbed in the proximal small bowel. If the malabsorption is further along the intestine then it will affect the absorption of carbohydrates, fat, and vitamins (fat-soluble) like A, D, E, and K.<sup>[7]</sup> Anemia can be treated by intaking iron, folate, or vitamin B-12 supplements but it depends on the origin of the anemia. Nonetheless, studies have shown 78% to 94% have recovered from anemia due to being on a gluten free diet.<sup>[7]</sup>
</style>
===== Case Studies =====

<style justify>
One treatment that is often used for patients having celiac disease is going on a gluten-free diet for life. This is because people who have celiac disease are ‘gluten sensitive’ thus avoiding it can often be a treatment. As discussed gluten is a protein that is found in wheat, barley, rye, and other products. An individual who consumes gluten who has celiac disease would have symptoms such as dermatitis hepetiformis (an itchy skin rash), fatigue, gastrointestinal distress (e.g. diarrhea, constipation, gas, bloating, etc.), and many more.<sup>[7]</sup> Most of this can be avoided by sticking with a gluten free diet.<sup>[7]</sup>


While Gluten Free Diet is a treatment for celiac disease there are some potential setbacks. A study conducted with patients having celiac disease and the effects of what a gluten-free diet would do. Malnutrition is something often under looked, and a huge problem for individuals who undertake this diet. In a study that had two groups one that followed strict dietetic prescriptions and another group having gluten-containing food. It was noted that the dietary levels of calcium, fiber, were low. This is further exacerbated within females, with iron being low as well.<sup>[7]</sup>


Another study conducted on individuals who were on a gluten-free diet examined the endoscopic and histopathologic appearance of the duodenum. With over 39 adult patients in the study, with an average age of 52, who had been on a gluten-free diet (average person was on for about 8.5 years). The results showed that only 9 patients had their endoscopic appearance as normal. The other patients had at least one abnormality, while 18 had multiple abnormalities. The two most common abnormality was reduced folds and mucosal fissures which were in 46% and 44% of patients. This was then followed by scalloping of folds and nodularity of the mucosa in 33%. The study concludes that despite adherence to a gluten-free diet, there still is endoscopic and histopathologic abnormalities found in the duodenum in most patients.<sup>[8]</sup>
</style>

====== Signs and Symptoms ======
<style justify>
Celiac disease has over 200 symptoms making it difficult to diagnose,as it affects people differently.<sup>[9]</sup> some people with celiac disease have no symptoms at all, but still test positive on the celiac disease blood test.  A few others may have a negative blood test, but have a positive intestinal biopsy. There are 3 classifications of celiac disease: 

**Classical celiac disease**, which is rare, patients have signs and symptoms of malabsorption, including diarrhea, steatorrhea (pale, foul-smelling, fatty stools), and weight loss or growth failure in children.<sup>[10]</sup>

**Non-classical celiac disease**, patients may unclear signs of malabsorption and mild gastrointestinal symptoms. Some symptoms include abdominal distension and pain, and/or other symptoms such as: iron-deficiency anemia, chronic fatigue, chronic migraine, tingling, numbness or pain in hands or feet, reduced bone mass and bone fractures, and vitamin deficiency (folic acid and B12), late menarche/early menopause and unexplained infertility, dental enamel defects, depression and anxiety.<sup>[9]</sup>

**Silent celiac disease** is also known as asymptomatic celiac disease.<sup>[9]</sup> Patients do not complain of any symptoms, but still experience villous atrophy damage to their small intestine. Studies show that even though patients thought they had no symptoms, after going on a strict gluten-free diet they report better health and a reduction in acid relux, abdominal bloating and distention and flatulence.<sup>[10]</sup>
</style>

====== Gluten Free-Diets in the General Population ======
===== Popularity and Prevalence =====
<style jusify>
Within the last 5 years, the popularity of gluten-free diets has increased substantially in the general population. In fact, researchers estimate that 2.7 million people in the US have eliminated or reduced their consumption of gluten despite never having been diagnosed with a wheat allergy or celiac disease.<sup>[11]</sup>
 
In 2016, Kim et al. analyzed data from the National Health and Nutrition Examination Survey (NHANES) to describe trends over time in both prevalence of people with celiac disease and the percentage of people following a gluten-free diet without medical need to do so. Figure 9 showed that prevalence of celiac disease among Americans have declined since 2009 whereas the number of people who did not have celiac disease but were avoiding gluten has more than tripled.<sup>[11]</sup>
</style>

<style center>
{{:prevalance_of_celiac.jpg|}}


**Figure 9:** Prevalence of people in the US with celiac disease compared to prevalence of people who did not have celiac disease but were avoiding gluten.<sup>[11]</sup>
</style>

<style justify>
Reasons for popularity increase may be attributed to endorsement by popular celebrities and figures. For example, actress Gwyneth Paltrow has adopted a gluten-free diet and has dedicated a book, It’s All Good, regarding tips that will make you “look good and feel great”. Popular recording artist, Miley Cyrus has also been known to advocate a gluten-free diet in her tweets stating that it will give amazing “change[s] in your skin, physical and mental health”.
</style>


<style center>
{{:celebrities_are_dumb.jpg|}}


**Figure 10:** Celebrities endorsing gluten-free diets
</style>




<style justify>
The market for gluten-free foods have also grown substantially because of increased popularity. Sales of gluten-free foods have grown 34% to nearly one billion dollars in revenue over the last five years.<sup>[12]</sup> In a recent US survey by Packaged Facts in Fall 2010, only 8-12% of gluten-free consumers said they bought gluten-free products because they or a family member of their household has celiac disease or an intolerance to gluten.<sup>[12]</sup> Furthermore, the top reasons for buying gluten free foods were because consumers believe they were ‘generally healthier’ (46%) and that they would help in managing weight (30%).<sup>[12]</sup> Going gluten-free was especially popular among three groups who did not have a medical need for the diet: younger adults ages 20 to 39, females, and non-hispanic whites.<sup>[11]</sup>
</style>

===== Weight Loss Claims =====
<style justify
Despite nearly one third of consumers adopting a gluten-free diet to lose weight, there is no scientific evidence supporting the alleged benefit that a gluten-free diet will promote weight loss. In fact, it may be associated with weight gain.
 
In April 2006, the American Journal of Gastroenterology released a study following CD patients on a gluten-free diet for 2 years. At the end of the trial, 81% gained weight, and 82% of patients that were already overweight gained additional weight.<sup>[13]</sup> In 2010, similar results were found. Twenty one of eighty-eight (27%) of initially overweight CD patients had gained more weight while strictly adhering to a GFD. However, this may be due to improved intestinal function and more efficient nutrient absorption for those with celiac disease.<sup>[14]</sup> Another reason for weight gain may be due to the decreased consumption of fiber that often accompanies gluten-free diets. Fiber allows for increases in satiety (fullness). Consequently, a decrease in fiber may lead an individual to consume more food to feel satisfied.
</style>

===== Gluten-Free Products – Are they healthier? =====
<style center>
{{:cost_of_gluten.jpg|}}

**Figure 11:** Cost in euros/kg between-gluten free and gluten-containing foods across seven different food categories.<sup>[16]</sup>
</style>
<style justify>
Gluten-free (GF) products were evaluated by two studies done in Australia and Austria respectively. In comparison to the gluten-containing counterparts, gluten-free products were not found to offer any superior health effects. In fact, the studies have found that it was generally unhealthier than normal food products. Firstly, protein content was found to be around 31.9% lower in GF foods whereas saturated fats and sodium content were often higher.<sup>[15]</sup> Additionally, vitamins and minerals were also found to be significantly lower than gluten-containing products. For example, zinc content was lower by 82.1% on average (Missbach et al., 2015). Lastly, GF products generally costed a lot more – often 2-3 times as expensive (Figure 11).<sup>[16]</sup> Ultimately, GF products are often unhealthier than gluten-free products and rumored health benefits from GF foods is not only false, but the opposite from the truth.
</style>

===== Negative Health Implications of Gluten-Free Diets =====
<style center>
{{:grains_picture.jpg|}}
</style>


<style justify>
There are quite a few disadvantages to consuming a gluten free diet. The big one being is that you miss out on consuming whole grains (since most of them contain gluten). A meta-analysis of 45 cohort studies and 21 randomized control trials found that whole grain consumption was associated with lower risks of type 2 diabetes, cardiovascular disease and obesity.<sup>[17]</sup> Furthermore, whole-grain interventions were shown to have favorable effects on glycemic control, immune function and blood lipids (ie. triglyceride levels). <sup>[18]</sup> Research has shown that adherence to the gluten-free dietary pattern may actually result in a diet that is low in carbohydrates, iron, folate, niacin, zinc, and fiber.<sup>[14]</sup>
 
It has also been shown that gluten free diets can adversely affect your gut flora (or bacterial intestinal health) if you don’t have celiac disease.<sup>[19]</sup> A month on a gluten free diet can drastically decrease numbers of healthy gut bacteria and increase numbers of unhealthy bacteria in your intestines. This imbalance of gut flora can lead to chronic constipation, bloating, diarrhea, irritable bowel disease, and anemia.<sup>[19]</sup>
</style>

====== Conclusion ======
<style justify>
Celiac disease is a very rare disease with no cure and with several symptoms and negative long term implications. The only management for these individuals are gluten-free diets and unfortunately, the media has exploited the use of these diets to make a large market and profit.
 
Ultimately, unless someone has celiac disease or a wheat allergy, there’s no reason to really adopt this diet. It has been shown that to the general population, adopting gluten-free diets may be detrimental to one’s health. Gluten is widely misunderstood, naturally occurring wheat protein, but fad diets exploit peoples’ imaginative tendencies to demonize what they don’t understand.
</style>

====== References ======
[1] WebMD. (n.d.). Celiac Disease Causes, Symptoms, Treatments, Tests, & More. Retrieved from http://www.webmd.com/digestive-disorders/celiac-disease/celiac-disease#


[2] Celiac Disease Association. (n.d.). About Celiac Disease. Retrieved from http://www.celiac.ca/?page_id=882


[3] Lights, V., & Boskey, E. (2016, February 19). Celiac Disease (Gluten Intolerance). Retrieved from http://www.healthline.com/health/celiac-disease-sprue


[4] Health Canada. (2016, January 11). Celiac Disease. Retrieved from http://www.hc-sc.gc.ca/fn-an/securit/allerg/cel-coe/index-eng.php


[5] Celiac Disease Canada. (n.d.). Celiac Disease. Retrieved from http://www.diabetes.ca/diabetes-and-you/complications/celiac-disease


[6] Kagnoff, M. F. (2007). Celiac disease: pathogenesis of a model immunogenetic disease. Journal of Clinical Investigation, 117(1), 41–49. http://doi.org/10.1172/JCI30253


[7] Niewinski, M. M. (2008). Advances in Celiac Disease and Gluten-Free Diet. Journal of the American Dietetic Association, 108(4), 661-672. doi:10.1016/j.jada.2008.01.011


[8] Lee, S. K., Lo, W., Memeo, L., Rotterdam, H., & Green, P. H. (2003). Duodenal histology in patients with celiac disease after treatment with a gluten-free diet. Gastrointestinal Endoscopy, 57(2), 187-191. doi:10.1067/mge.2003.54


[9] Celiac Disease Foundation. (n.d.). Celiac Disease Symptoms - Celiac Disease Foundation. Retrieved from https://celiac.org/celiac-disease/understanding-celiac-disease-2/celiacdiseasesymptoms/


[10] Mooney, P. D., Hadjivassiliou, M., & Sanders, D. S. (2014). Coeliac disease. Bmj, 348(Mar03 6). doi:10.1136/bmj.g1561


[11] Kim, H.-S., Patel, K. G., Orosz, E., Kothari, N., Demyen, M. F., Pyrsopoulos, N., & Ahlawat, S. K. (2016). Time Trends in the Prevalence of Celiac Disease and Gluten-Free Diet in the US Population: Results From the National Health and Nutrition Examination Surveys 2009-2014. JAMA Internal Medicine, 176(11), 1716–1717. https://doi.org/10.1001/jamainternmed.2016.5254


[12] Daniel Granderson. (2016). Gluten-Free Foods in the U.S., 6th Edition (No. LA15012937). Packaged Facts. Retrieved from https://www.packagedfacts.com/Gluten-Free-Foods-10378213/


[13] Dickey, W., & Kearney, N. (2006). Overweight in celiac disease: prevalence, clinical characteristics, and effect of a gluten-free diet. The American Journal of Gastroenterology, 101(10), 2356–2359. https://doi.org/10.1111/j.1572-0241.2006.00750.x


[14] Gaesser, G. A., & Angadi, S. S. (2012). Gluten-free diet: imprudent dietary advice for the general population? Journal of the Academy of Nutrition and Dietetics, 112(9), 1330–1333. https://doi.org/10.1016/j.jand.2012.06.009


[15] Wu, J. H. Y., Neal, B., Trevena, H., Crino, M., Stuart-Smith, W., Faulkner-Hogg, K., … Dunford, E. (2015). Are gluten-free foods healthier than non-gluten-free foods? An evaluation of supermarket products in Australia. The British Journal of Nutrition, 114(3), 448–454. https://doi.org/10.1017/S0007114515002056


[16] Missbach, B., Schwingshackl, L., Billmann, A., Mystek, A., Hickelsberger, M., Bauer, G., & König, J. (2015). Gluten-free food database: the nutritional quality and cost of packaged gluten-free foods. PeerJ, 3. https://doi.org/10.7717/peerj.1337


[17] Ye, E. Q., Chacko, S. A., Chou, E. L., Kugizaki, M., & Liu, S. (2012). Greater whole-grain intake is associated with lower risk of type 2 diabetes, cardiovascular disease, and weight gain. The Journal of Nutrition, 142(7), 1304–1313. https://doi.org/10.3945/jn.111.155325


[18] Slavin, J. (2004). Whole grains and human health. Nutrition Research Reviews, 17(1), 99–110. https://doi.org/10.1079/NRR200374


[19] Sanz, Y. (2010). Effects of a gluten-free diet on gut microbiota and immune function in healthy adult humans. Gut Microbes, 1(3), 135–137. https://doi.org/10.4161/gmic.1.3.11868