Celiac Disease: A Holistic Review

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Celiac Disease: A Holistic Review Ryan Seals B.S. (Bachelor of Science) Celiac disease is a condition characterized by an abnormality of the small intestine caused by the consumption of gluten in the diet.

1 Celiac Disease: A Holistic Review Ryan Seals B.S. (Bachelor of Science) Celiac disease is a condition characterized by an abnormality of the small intestine caused by the consumption of gluten in the diet. Celiac disease classically has the following three features: small intestinal villous atrophy; symptoms of malabsorption (e.g. steatorrhea, weight loss, nutrient deficiencies); and resolution of symptoms upon withdrawal of gluten containing foods within weeks to months.[1] It was first described during the second World War by a Dutch pediatrician who observed diarrhea that seemed to correlate with the consumption of grain products in the diet; symptoms disappeared when these grains were unavailable due to shortages during the War. Then in 1954 the histological changes of the proximal small intestine were observed and documented. Those with the condition have an abnormal immune response to gluten, which causes destruction of the villi in the small intestine. Because of this damage to the villi the absorptive ability of the small intestine becomes compromised and nutrient deficiencies can develop.[1] Celiac disease occurs primarily in those of northern European descent and was originally thought to have a prevalence of 1:8000 to 1:4000. However with more sensitive blood tests some estimates state that as many as 1:250 to 1:100 of those with northern European descent may have some form of celiac.[2] Section A Wide Range of Celiac With the availability of different serologic measurements, patients are being identified as having celiac disease even though they may lack the classic symptoms mentioned above. These patients may have mild and unspecific symptoms such as fatigue, borderline iron deficiency, or unexplained elevation of aminotransferases; some patients may not have any noticeable symptoms at all. Celiac can be behind delayed puberty in adolescents, sterility in some women, or small stature in children.[1] Celiac disease or gluten sensitivity may be behind other non-gastrointestinal symptoms such as ataxia, depression, anxiety, epilepsy, headache, developmental delay, and learning disorders. Arthritis is also more prevalent among those with celiac, and it is nearly twice as prevalent among celiac patients on a diet containing gluten when compared to those on a gluten-free diet according to one study.[1] Bone loss is common among these patients because of secondary hyperparathyroidism caused by vitamin D deficiency. Other nutrient deficiencies include calcium, folic acid, B 12, and iron. [1,2] There also appears to be an overall increased in mortality from gastrointestinal malignancies in adults with celiac disease compared to the general population. Therefore, it is important to identify these subclinical cases of celiac disease to address any nutritional deficiency, possible chances of malignancy, and associated autoimmune conditions.[1] Section B Associated Clinical Conditions Several other clinical conditions are often associated with celiac disease. Dermatitis herpetiformis is characterized by pruritic papulovesicles on the extremities and trunk. The primary symptom of these vesicles is itching and burning that is ameliorated when the blister bursts.[2] Diagnosis is confirmed by identifying granular IgA deposits in the subepidermal basement membrane. Anti-transglutaminase antibodies are elevated in patients with dermatitis herpetiformis as they are in those with celiac disease. Studies have found that 24 percent of patients with celiac disease showed signs of the skin condition, while 85 percent of patients with dermatitis herpetiformis were found to have celiac disease.[1] Relief from dermatitis herpetiformis is usually delayed 6-12 months after the removal of gluten from the diet; therefore, dapsone or other medical treatments are often used in conjunction with dietary change.[2] Celiac disease also has a close association with type 1 diabetes mellitus. It has been shown that between 2.6 and 7.8 percent of adults with type 1 diabetes had IgA autoantibodies to endomysium or to tissue transglutaminase; most of these patients were proven to have celiac disease with small bowel biopsy.[1] However, celiac disease does not appear to trigger diabetes (despite some allegations) because the

2 antibodies are usually found after the onset of the type 1 diabetes. There appear to be genetic connections between celiac and diabetes as noted below, but it remains unclear if a gluten-free diet would help diabetics and it is unknown exactly how the two diseases interact.[1] Downs syndrome patients have a much higher incidence of celiac disease than the normal populaion. Some reports estimate a prevalence of 16 percent; that is 100 times the frequency seen in the normal population. Autoimmune thyroid disease (more often hypothyroid) is seen more often in patients with celiac; other associated conditions include primary biliary cirrhosis and IgA deficiency.1 With all of these associated diseases it may be worth investigating the interrelationship between the causes of these conditions. Could many of these conditions be just different symptoms of an identifiable cause? More research needs to be done to help explain how gluten Section C What is Gluten? It is first important to understand what gluten is and how it affects the body. The term "gluten" is used to describe the ethanol soluble part of the plant proteins (known as prolamins) that cause the autoimmune reaction. Because of genetic similarities in plants, glutens include the corresponding plant proteins in barley, wheat, rye, and oats. Oats, however, are less genetically related than the others and this could be the reason why recent studies have put into question just how reactive oats are in patients with celiac. These studies have shown that among a group of adults with celiac disease that those that consumed oats, but otherwise a gluten-free diet, had no significant differences from control groups in quality of life scores or small intestine histology. It is worth noting, however, that another study found that those consuming oats had more gastrointestinal complaints than the gluten-free group. A study in children showed no significant difference in those consuming oats versus the control group. These studies lead to the current recommendations to limit oat consumption to 50 or 60g (about 2 oz.) a day because more than this may result in disease recurrence.[3] In addition, some patients are very sensitive to oat prolamins and oats should also be avoided in these sensitive patients along with those with more severe forms of celiac disease.[3] This discrepancy can be partially explained by examining the molecular structure of oats versus that of other gluten containing grains. Oats appear to have a smaller portion of the toxic prolamin sequence, and this could explain the dose related response to oats. Some alternative practitioners and nutritionists carry this same logic to apply to other grains besides those classically considered gluten containing. Due to similarities in structure called "molecular mimicry" many different grains can have somewhat of the same effect; almost all grains except for buckwheat (which is a grass) and rice.[4] Therefore, these practitioners may advocate more extensive food allergy tests, such as the LEAP test discussed below, to better identify an individual's sensitivity to various grains and other foods. Section D What Causes Celiac Disease? Nobody knows exactly why some people become sensitive to gluten. One theory that tries to explain why the initial cross reactivity occurs contends that there are protein similarities between glutens and the protein coat of adenovirus.[3] Therefore, in susceptible people, viral exposure could be involved in the pathogenesis. Other theories show genetic implications for the development of celiac disease. Correlations seem to occur between HLA DQ2 and/or DQ8, but correlation among siblings is only 36% so other sites must also be involved. Even among identical twins concordance is only 70%. This suggests that there must be variable penetrance genetically, or environmental factors that account for this less than 100% relationship.[6] Other possible gene locations include 15q26 (which seems to be present in those with susceptibility to type I diabetes), 5q, and 11q.[1] It is worthwhile to investigate the environmental influences involved in the development of celiac disease. For example, babies who are breast fed less than 30 days are four times more likely to get celiac than those breast fed longer than 30 days.[5] Another study showed that breast feeding was a protective factor against developing celiac disease in infancy.6 Additionally breast feeding seemed to be protective if gluten was introduced in the infant's diet while still being breast fed.[7] A possible explanation for this is the development of the gut in newborns. The protective barrier of the gut may not entirely close off until around nine months of age.4 Therefore, if an infant is exposed to gluten too early, protein particles may slip through the blood-gut barrier and be attacked by the immune system. This is consistent with the fact that those with celiac disease have increased permeability of macromolecules in the gut.[6] From an evolutionary perspective, grains are a relatively new addition to the human food supply. Agriculture was introduced approximately 10,000 years ago, and this may not be long enough time for the human genome to have evolved.[8] Even more changes in food processing came about after the industrial revolution, not to mention the continued changes that are occurring every day with genetically modified foods [4]. 72.1% of the foods eaten in the United States were not available prior to this agricultural revolution. This includes cereals, refined sugars, dairy products, refined vegetable oils, and alcohols.[9] It is also interesting to note that lactose intolerance is also present in many patients with celiac disease.[3] Just imagine how many of the foods we eat every day are composed of the above listed ingredients and we

3 may begin to understand why our bodies don't handle certain foods well. So those groups of people that have been exposed to grains for the shortest period of time in history may be those most likely to get the disease [4] (i.e. northern Europeans). Section E Signs and Symptoms The symptoms of celiac disease or gluten sensitivity can be very nonspecific, however the following guidelines may help practitioners decide who should be considered for testing. Any patients with gastrointestinal complaints such as chronic diarrhea, irritable bowel, abdominal distenion, weight loss, or malabsorption should be tested. Also consider testing those patients with consistent elevation of serum aminotransferases, short stature, delayed puberty, iron-deficiency anemia, recurrent fetal loss, and infertility. Those patients with high risk for celiac include first or second degree relatives of those with celiac, type 1 diabetics, other autoimmune conditions, and those with Turners, Downs, or Williams syndromes.[2,6] At this time screening of those with osteoporosis seems to be controversial, but it would be encouraged if other gastrointestinal symptoms were present. Experts do not currently recommend screening of the general population.[1,2] Section F Testing for Celiac Disease Currently, the most sensitive and specific tests are IgA anti tissue transglutiminase and IgA endomysial antibody. These two tests have equal diagnostic accuracy, while antigliadin antibody tests are no longer routinely used due to low sensitivity and specificity.[2,6] It is also worth noting that serologic tests may not be as accurate in children under the age of five. All serologic tests should be performed while the patient is on a gluten-containing diet. Antibody titers generally stay elevated for one to six months, so technically tests could be performed during this time frame of being gluten-free, but being on a gluten-containing diet is preferred for testing. If the patient is on a gluten-free diet, then it is recommended that he or she resume a gluten-containing diet for a period of 2-4 weeks before being tested. This recommendation is based on a study of children that showed that 75 percent of subjects will have abnormal antibody tests within that timeframe. This strategy may not be as effective in adults based on at least one study. It was shown that 3 weeks a gluten-containing diet for those with proven celiac disease who had been on a gluten-free diet did not produce positive antibody titers, but did produce symptoms along with carbohydrate and fat malabsorption. These patients might be better tested by performing malabsorption tests after a period of eating a gluten-containing diet. The gold standard remains a gluten challenge followed by a small bowel biopsy. A gluten challenge would involve the ingestion of 10g of gluten (about 4 slices of bread) for four to six weeks before being tested.[2] Patients that have a positive endomysial or transglutiminase antibody tests should then undergo a small bowel biopsy. The only exception to this should be if a patient also has a biopsy proven case of dermatitis herpetiformis, where diagnosis can be made without a small bowel biopsy. Multiple biopsies should be obtained from the second and third portion of the duodenum. Many experts recommend at least four, but the exact minimum remains uncertain.2 The diagnosis is made with positive serologic tests and biopsy finding, and is then confirmed when symptoms resolve on a gluten-free diet.2,6 Demonstration of histological normalization is not currently required, but some recommend a repeat biopsy after three to four months to check for histological improvements. Some authors also advocate a gluten rechallenge which requires the ingestion of 10g of gluten (about 4 slices of bread) for four to six weeks to further confirm the diagnosis. This approach can help differentiate celiac disease from allergy to cow's milk and infectious diarrhea. Still others oppose the rechallenge if biopsy, antibodies, and clinical signs all show improvement due to the rare chance of fulminant diarrhea with resultant "gliadin shock" (consisting of acidosis, dehydration, and metabolic disturbances).[2] Section G Treatment Current treatment involves a strict adherence to a gluten-free diet. This currently includes the following grains or their derivatives: wheat, barley, rye, oats, spelt, kamut, and triticale.[6] According to most medical literature soybean or tapioca flours, rice, corn, buckwheat and potatoes are considered safe.[3] However, this is contested by those that promote the "molecular mimicry" hypothesis mentioned above. These practitioners believe that all grains except rice and buckwheat can potentially cause similar reactions with gluten and similar proteins.[4] Because of the radical dietary alterations that are necessary to eliminate gluten, it is very helpful to have written information or dietary counseling to provide for the patient. Dairy products should also initially be avoided because of the high correlation of lactose intolerance among patients with celiac disease. In addition, patients must learn to read food labels to look for food stabilizers or emulsifiers that may

4 contain gluten.[3] Some patients may be resistant to such dramatic dietary alterations and need to know the importance of staying on a gluten-free diet. This can be especially difficult for those patients with particularly mild symptoms who may not think the sacrifice is worth it. These patients still need to be encouraged to be strict with their diet for several reasons. Nutrient deficiencies of any of the previously mentioned micronutrients can result such as bone loss due to vitamin D deficiency. There is also evidence of increased gastrointestinal malignancy in celiac patients that can potentially be reduced if the inflammation of the gut is controlled. Mothers with celiac are at increased risk for low birth weight babies. The development of associated autoimmune disorders (e.g. type 1 diabetes, Hashimoto's thyroiditis, Graves) appears to related to the duration of gluten exposure.[1-3,6] The next step in treatment would be to identify and correct any nutrient deficiencies. Specific nutritional supplementation may be used to correct deficiency states. The most common are supplementation with iron, folate, calcium, and fat-soluble vitamins. Bone density should be measured in adults at or shortly after the time of diagnosis because osteopenic bone disease is common and may be profound in patients with newly diagnosed celiac disease. Patients with decreased axial bone density should be advised to obtain 1200 mg Ca and 100% of the recommended dietary allowance of vitamin D daily.[6] Because celiac disease is associated with hyposplenism, it is recommended that a pneumococcal vaccine be given to children with celiac.[3] Section H Non-Responders to Gluten Removal The majority of patients with celiac disease respond well to a gluten-free diet. Poor dietary compliance or inadvertent gluten consumption is the most common reason for the persistence of symptoms and clinical markers; therefore a meticulous dietary history is necessary to examine these non-responders. These patients are then examined for ulcerative jeujunitis or intestinal lymphoma as causes of their complaints. There is also a group of non-responders that are considered to have refractory sprue. Refractory sprue can present in either a complete nonresponse to gluten, or one can initially respond to a gluten-free diet and then become symptomatic again despite dietary adherence.[3,6] The cause of refractory sprue is unknown. This could be a sign of other dietary sensitivities besides gluten. One case report documented normalization of refractory sprue after eliminating eggs, chicken, and tuna from the diet.[3] Certain food tests are available that may be able to help identify other food sensitivities besides gluten that may be causing symptoms. One such test is the LEAP test. This type of test measures the body's sensitivity to 150 foods and chemicals by individually reacting them with a sample of the patient's blood. The sensitivity is then based on the quantity of chemical mediators released in response to these foods. This is one tool that may lead practitioners toward eliminating foods that may be causing inflammatory reactions in the body.[4] Most physicians attempt to control inflammation of refractory sprue with corticosteroids. Other steroid-sparing immunosuppressants include 6-mercaptopurine, azathioprine, and cyclosporine. Alternative treatments involve using newer food allergy tests to attempt to identify the irritating agents coupled with L-glutamine, licorice root, and aloe supplementation. Glutamine is the primary amino acid used by the gut, and aloe and licorice are thought to increase mucous production by the gut. These are thought to help the gut heal from the damage of chronic inflammation.[4] Section I An Osteopathic Perspective Viewing celiac disease from an osteopathic perspective can provide several different insights to the astute physician. First of all by viewing a patient as a whole person we may be able to see the connection between several nonspecific symptoms (e.g. a patient with iron deficiency, headaches, and signs of osteoporosis) and look for a unifying underlying cause. If no other typical diagnosis seems to be forthcoming, it may be worth a celiac workup. This would be more prudent than sending the patient to the hematologist and neurologist. Secondly, a good osteopathic examination may reveal clues of celiac in the form of viscerosomatic reflexes. Tissue texture changes in the area of T9-T11 would be consistent with small intestine irritation.[10] In addition, Chapman's reflex points at the interspaces of ribs 9-12 could also lead the osteopathic physician to search for small intestine pathology.[11] Osteopathic treatment can also provide benefit to celiac patients. In the interim between diagnosis and alleviation of symptoms via diet, osteopathic treatment may be able to help the patients symptoms. Chapman's reflexes may be worth trying in order to calm down the sympathetic reflex caused by the celiac disease. Vertebral manipulation can also correct somatic dysfunction caused by viscerosomatic reflexes. Good osteopathic treatment helps normalize autonomic tone and improves overall body function which may help an individual have less severe symptoms.

5 Section J Conclusion There are still many things that are unclear about celiac disease. More research is needed to examine all the complex dietary causes of celiac and refractory sprue. It is the author's contention that celiac may provide a glimpse into the complex interplay between the foods we eat and the myriad of effects that they have on the body. Celiac disease seems to show how common irritants cause complex biochemical and immunologic responses in people that can lead to various forms of disease. Why are some more sensitive to gluten, and how does this immunologic response lead to associated autoimmune conditions? These are questions that can hopefully someday be definitively answered with continued research. Due to the limited scope of current medical treatment (eliminate gluten from the diet) it may be worth examining alternative treatment to determine if other food insensitivities may be contributing to the patient's symptoms. Celiac disease is a good reminder to practitioners of the complex interactions that can occur in the body. We must always remember to continue to search for the underlying cause to effectively treat our patients. References 1. Schuppan, D, Dieterich, W, Lifschitz, C. Pathogenesis, epidemiology, and clinical manifestation of celiac disease in children. Retrieved from UpToDate October 5, Kelly, C. Diagnosis of celiac disease. Retrieved from UpTo Date October 5, Ciclitira, P, Lifschitz, H. Management of celiac disease in children. Retrieved from UpToDate October 5, Margiotta, N D.N. Personal interview conducted on October 10, Auricchio S, Follo D, de Ritis G, et al. Does breast feeding protect against the development of clinical symptoms of celiac disease in children? J Pediatr Gastroenterol Nutr 1983;2:428Ð Murray, Joseph. The widening spectrum of celiac disease. Am J Clin Nutr, Vol. 69, No. 3, , March Anneli Ivarsson, Olle Hernell, Hans Stenlund, breast feeding protects against celiac disease. Am J Clin Nutr, Vol. 75, No. 5, , May Cordain, Loren et al. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr, Vol. 81, No. 2, , February Cordain L, Brand Miller J, Eaton SB, Mann N, Holt SHA, Speth JD. Plant to animal subsistence ratios and macronutrient energy estimations in world wide hunter-gatherer diets. Am J Clin Nutr 2000;71: Loeser, John. Bonica's Management of Pain 3rd ed. P Patriquin, David. Chapman's reflexes. Foundations for Osteopathic Medicine 2nd ed. Ch 66. Pg Page modified on 5/15/2011

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