Robert A. Mangione and Priti N. Patel
Celiac disease is a chronic, small intestinal immune-mediated enteropathy caused by intolerance to gluten found in wheat, barley, rye, and other foods when a genetically predisposed person is exposed to the environmental trigger, gluten.
Celiac disease affects 1 in 100 to 120 adults and 1 in 80 to 300 children in the North American population and appears to be increasing in prevalence.
The integrity of the tissue junctions of the intestinal epithelium is compromised in patients with celiac disease; this enables gluten to reach the lamina propria. The presence of gluten in the lamina propria and an inherited combination of genes contribute to the heightened immune sensitivity to gluten that is found in patients with celiac disease.
The classic presenting symptom in adults is diarrhea, which may be accompanied by abdominal pain or discomfort; however, it is noteworthy that during the past decade diarrhea has been reported as the main presenting symptom of celiac disease in less than 50% of cases.
Dermatitis herpetiformis is a skin manifestation of small intestinal immune-mediated enteropathy caused by exposure to dietary gluten. All patients with celiac disease will not develop dermatitis herpetiformis; however, it is generally agreed that all patients with dermatitis herpetiformis also have celiac disease.
The frequency of diagnosis of patients with celiac disease has increased; however, the majority of patients with this condition remain undiagnosed.
A confirmed diagnosis of celiac disease requires both positive findings on duodenal biopsy and a positive response to a gluten-free diet. The most common serologic markers that are used for screening patients are serum anti–tissue transglutaminase antibodies and serum immunoglobulin A (IgA) endomysial antibodies.
Strict, lifelong adherence to a gluten-free diet is the only treatment for celiac disease that is currently available.
Clinicians must evaluate the patient with celiac disease for nutritional deficiencies (including folic acid, vitamin B12, fat-soluble vitamins, iron, and calcium) due to malabsorption. Iron-deficiency anemia may be the only presenting sign of disease in patients without diarrhea.
Celiac disease is a small intestinal immune-mediated enteropathy caused by intolerance to ingested gluten, a storage protein found in wheat, barley, and rye. Genetic, environmental, and immune factors all play a role in the development of celiac disease. The mainstay of treatment of the disease is strict, lifelong adherence to a gluten-free diet.1,2
A disease resembling celiac disease was first described by a Greek physician in the second century AD.3 In the mid-1900s, the connection between the ingestion of cereals and celiac disease was made. For many years, celiac disease was considered a disease of childhood with primarily GI symptoms. It is now recognized as a disease of all ages with varied presentation.
Celiac disease has also been known as celiac sprue, nontropical sprue, and gluten-sensitive enteropathy; however, these terms are currently not recommended. The disease is characterized by both GI and extraintestinal symptoms. Chronic inflammation caused by exposure to gluten leads to GI discomfort, nutrient malabsorption, and systemic complications. GI symptoms, including diarrhea, cramping, bloating, and flatulence, are the “classic” symptoms; however, a patient with celiac disease may initially present with a variety of extraintestinal symptoms. Patients with subclinical celiac disease have no or minimal symptoms but manifest mucosal damage on biopsy and have positive serologic testing. Patients with celiac disease classified as potential are asymptomatic patients who may show positive serology and have the human leukocyte antigen (HLA)-DQ2 and/or DQ8 haplotype, but have normal mucosa on biopsy.1,4
Adherence to a gluten-free diet is essential because it improves symptoms and prevents long-term complications of celiac disease, which include T-cell lymphomas, small bowel adenocarcinoma, and esophageal and oropharyngeal carcinomas.5
Originally thought to be a pediatric disease, celiac disease is now being diagnosed in increasing numbers of adult and pediatric patients due to increased awareness and improved diagnostic techniques.5Celiac disease is common in Europe and North America. The prevalence of the disease is 1 in 100 to 120 adults in Western nations.5,6 In children in the United States, the prevalence of the disease is 1 in 80 to 300 children.7 Similar to other autoimmune diseases, the prevalence of celiac disease is higher in females than in males at rates ranging from 2:1 to 3:1.8 In Finland and the United States, the prevalence of celiac disease has increased fourfold during the past 50 years. This finding has resulted from a true increase in the prevalence of the disease rather than simply an increase in the number of individuals who are diagnosed. While the reason for this increase is not known, it may be due to environmental factors such as the changing nature of gluten or other factors associated with diet.9
Celiac disease has been less well studied in other parts of the world. Previously believed to rarely occur in nonwhite populations, improved screening and diagnostic techniques now provide evidence that the prevalence of celiac disease in many non-Western nations is similar to that in Europe and North America.10,11 In addition, in Asian countries where rice has traditionally been a staple, meals with rice are increasingly being replaced by a Western-style wheat-based diet. This transition in dietary preferences may lead to an increased prevalence of the disease in those populations.12
Celiac disease is known to occur when a genetically predisposed person ingests gluten. Wheat gluten proteins exist in two fractions: gliadins and glutenins. Storage proteins similar to glutenins, called hordeins and secalins, are found in barley and rye, respectively. Table 27-1 refers to grains and other foods that do and do not contain gluten and related proteins. Ingestion of any of these proteins will lead to an autoimmune response in celiac disease patients.
TABLE 27-1 Grains and Other Foods that Do and Do Not Contain Gluten
It is still a matter of controversy whether or not oats are safe for consumption by patients with celiac disease. Wheat, barley, and rye, which contain the disease-activating proteins gliadin, hordein, and secalin, respectively, are all derived from the Triticeae tribe of the grass (Gramineae) family. Oats, from the Aveneae tribe, are distantly related and therefore only contain few disease-activating proteins.13 Another concern with oats is that they may be contaminated with gluten during the manufacturing process.14 Gluten-free uncontaminated oats are now commercially available. Although a small number of individuals with celiac disease may not tolerate even pure, uncontaminated oats, clinical evidence has confirmed that the consumption of 50 to 70 g (1/2 to 3/4 cup [120 to 180 mL] dry certified gluten-free oats) is safe in adults with celiac disease.14 It has raised concern that some celiac disease patients are found to have avenin-reactive T cells that can cause mucosal inflammation.15 Investigators examined nine different cultivars of oats and found some to be more toxic than others regardless of their purity, leading them to conclude that some oats may trigger a greater immunologic response than others.16 Although the consumption of limited quantities of oats is generally considered to be acceptable, clinical followup of celiac disease patients who consume oats is advisable even if these patients are maintaining a strict gluten-free diet.14,15
Genetic factors, in combination with exposure to gluten, are necessary for the development of celiac disease. A concordance rate of 85% in monozygotic twins has been reported, indicating that genetics play a large role in the disease, but other factors are likely also involved.17,18
Virtually all patients with celiac disease have variants of HLA-DQ2 or HLA-DQ8 molecules that are expressed on the surface of antigen-presenting cells.19 Other non-HLA genes may also play a role in enhancing genetic susceptibility to celiac disease.18
Certain infectious agents and other compounds may contribute to the development of celiac disease. Both adenovirus and hepatitis C viruses are thought to act as triggers, whereas other agents, including Campylobacter jejuni, Giardia lamblia, rotavirus, and enterovirus infections, have been described in case reports as associated with celiac disease.20 The biologic agent interferon-α has also been suggested to play a role in celiac disease development.21
In Sweden, increased rates of diagnosis of celiac disease in the mid-1980s corresponded to a change in infant feeding practices where mothers reduced breast-feeding and introduced cereal into babies’ diets earlier than had been previously in practice. Based on this finding, prolonged breast-feeding with introduction of gluten-containing grains during breast-feeding may help avoid the development of celiac disease.22
During normal digestion, peptides that remain from gastric or pancreatic digestion are broken down into amino acids, dipeptides, or tripeptides by the small intestinal brush-border membrane enzymes.23These GI proteases that are found in the intestinal lumen are one of the body’s first defenses against potentially toxic dietary proteins.6 The intestinal epithelium, with its intact intercellular tight junctions, functions as the primary barrier to the passage of macromolecules into the lamina propria. Gluten is unusually rich in the amino acids glutamine and proline, which enable part of the molecule to withstand the digestive processes. These peptides are kept within the GI tract and are primarily excreted before they can illicit an immune reaction. Small fractions of gluten do cross this important defense barrier in patients without celiac disease; however, the quantity of gluten that passes across the GI lining is generally insufficient to illicit a significant response from a normally functioning immune system.24,25
Events likely associated with the pathophysiology of celiac disease have been characterized as an interaction between gluten and immune, genetic, and environmental factors.26 In celiac disease, the integrity of the tissue junctions of the intestinal epithelium is compromised, enabling gluten to reach the lamina propria through different routes. The presence of gluten in the lamina propria and an inherited combination of genes contribute to the heightened immune sensitivity to gluten found in patients with celiac disease (Table 27-2).24,25 The notable immune response to gluten consists of both adaptive and innate immune responses that occur only in individuals who carry the HLA type DQ2 or in some populations DQ8.27 The precise mechanism by which the immune system leads to damage of the intestinal lining of patients with celiac disease continues to be studied.
TABLE 27-2 Proposed Pathophysiology of Celiac Disease
The primary toxic components of wheat gluten are a family of closely related proteins called gliadins.23 The gliadin peptides induce changes in the epithelium through innate immunity and in the lamina propria through adaptive immunity.18 Researchers have concluded that protected transport of gliadin peptides occurs in patients with celiac disease via a CD71-mediated transcytosis of immunoglobulin A (IgA)/gliadin peptides immune complexes from the lumen of the intestine to the lamina propria. In patients without celiac disease, the gliadin peptides are entirely degraded by lysosomal acid proteases during intestinal transcytosis. The abnormal expression of the IgA receptor CD71 at the apical side of the enterocytes that is found in celiac disease patients allows a protected retrotransport of serum immunoglobulin A (SIgA) gliadin immune complexes that could play an important role in triggering the immune activation that is characteristic of celiac disease. These researchers note that the normal function of SIgA (i.e., the containment of harmful antigens in the intestinal lumen) is deficient in celiac disease. They further state that the fate of the immune complexes once absorbed is unknown; however, the complexes may bind to IgA receptors that are present on local antigen-presenting cells and trigger the activation of local memory CD4+ T cells, which will perpetuate the inflammation.28
Tissue transglutaminase (tTG), a ubiquitous enzyme that catalyzes posttranslational modification of proteins and is released during inflammation, may play at least two crucial roles in celiac disease by serving as the main target autoantigen for antiendomysial enzymes and as a deaminating enzyme that raises the immunostimulatory effect of gluten. Expression and activity of tTG are raised in the mucosa of patients with celiac disease.6 This enzyme, by deaminating glutamine to glutamic acid, makes the gliadin peptides become negatively charged and therefore more capable of fitting into pockets of the HLA-DQ2 (or HLA-DQ8) antigen-binding groove on the antigen-presenting cells.6,26 Gliadin is presented to gliadin-reactive CD4+ T cells through a T-cell receptor, which then results in the production of cytokines that cause tissue damage. This then leads to villous atrophy, crypt hyperplasia, and the expansion of antibody-producing B cells found in celiac disease.26
The recognition of celiac disease may be quite challenging due to the wide range of presenting symptoms, which includes patients who are asymptomatic.6 Clinical manifestations of celiac disease also significantly vary according to age group (Table 27-3). Infants and young children generally experience diarrhea, abdominal distention, and failure to thrive. Vomiting, irritability, anorexia, and even constipation are also common in these young patients. Extraintestinal manifestations such as short stature, neurologic findings (e.g., peripheral neuropathy, ataxia, seizure, migraine, and dementia30), or anemia are often found in older children and adolescents. The classic presenting symptom in adults is diarrhea, which may be accompanied by abdominal pain or discomfort; however, it is noteworthy that during the past decade diarrhea has been reported as the main presenting symptom of celiac disease in less than 50% of cases. Adults may exhibit what are sometimes characterized as silent manifestations of this disease such as iron-deficiency anemia or osteoporosis. Less common but important presentations of celiac disease in adults include abdominal pain, constipation, weight loss, neurologic symptoms, dermatitis herpetiformis, hypoproteinemia, hypocalcemia, and elevated liver enzymes. Some adults may be diagnosed as a result of having an endoscopy performed in response to their complaints of symptoms associated with gastroesophageal reflux.26 Prior to age 65 years, the disease is two to three times more common in adult women than in adult men.6 Regrettably, patients with celiac disease often experience symptoms for a long period of time and may experience multiple hospitalizations and undergo surgical procedures before celiac disease is diagnosed.26
TABLE 27-3 Selected Signs and Symptoms of Celiac Disease
Dermatitis herpetiformis is a skin manifestation of small intestinal immune-mediated enteropathy caused by the ingestion of gluten (Figs. 27-1 and 27-2).1 It occurs in approximately 15% to 25% of patients with celiac disease.31This extremely pruritic, bullous skin rash is generally found on the elbows, knees, buttocks, and scalp but can occur anywhere on the body.30,31 Although dermatitis herpetiformis is most frequently observed in patients who are 30 to 40 years of age, it can also be found in children and elderly patients.32 Patients with dermatitis herpetiformis often do not have the typical GI symptoms that are associated with celiac disease; however, they are at risk for developing intestinal damage.33 Although dermatitis herpetiformis was once considered to be a skin disease that was often found in patients with celiac disease, researchers have also suggested that it is actually a cutaneous manifestation of the disease.34 Although every patient with celiac disease does not develop dermatitis herpetiformis, it is generally agreed that every individual with dermatitis herpetiformis also has celiac disease.33
FIGURE 27-1 Photograph of dermatitis herpetiformis of the face (Copyright © American Pharmacists Association [APhA]. Reprinted by permission of APhA. Photographs provided by Peter H.R. Green, MD, Professor of Clinical Medicine, College of Physicians & Surgeons, Columbia University, New York.)
FIGURE 27-2 Photograph of dermatitis herpetiformis of the face (Copyright © American Pharmacists Association [APhA]. Reprinted by permission of APhA. Photographs provided by Peter H.R. Green, MD, Professor of Clinical Medicine, College of Physicians & Surgeons, Columbia University, New York.)
The diagnosis of celiac disease is based on clinical suspicion and confirmation with laboratory tests and duodenal biopsy.35 When suspected, the diagnosis of celiac disease is easily established.26Although the frequency of diagnosis of patients with celiac disease has increased, the majority of patients (an estimated 97%) with this condition remain undiagnosed.30 This is particularly concerning as undiagnosed celiac disease has been associated with a nearly fourfold increased risk of death compared with subjects without serologic evidence of disease.36
Perhaps the most important initial step in making this diagnosis is for healthcare providers to recognize its many and diverse possible symptoms.37 Only 11% of celiac disease cases are diagnosed in a timely manner, with an average reported period of 5.8 to 11.7 years from the onset of symptoms to the diagnosis.38 Clinicians can help reduce the time from the onset of symptoms to the diagnosis of celiac disease by being aware of the common diseases with which many celiac patients are misdiagnosed (Table 27-4). Although these disorders may be mistakenly diagnosed instead of celiac disease, they may also coexist with celiac disease.38
TABLE 27-4 Selected Common Misdiagnoses
Clinicians should also note that individuals with certain disorders are more likely to have celiac disease than the general population. Examples include other autoimmune diseases, such as thyroid disease, diabetes mellitus (type 1), multiple sclerosis, myasthenia gravis, Raynaud’s disease, rheumatoid arthritis, Addison’s disease, chronic active hepatitis, cystic fibrosis, scleroderma, and Sjögren’s syndrome; Down’s syndrome; neurologic conditions such as ataxia, epilepsy, and cerebral calcifications; and primary biliary cirrhosis. Although patients with these disorders are more frequently found to have celiac disease than the general population, these associated conditions are not believed to cause celiac disease.33
Diagnostic testing for celiac disease must be performed while the patient continues to consume gluten.39 A confirmed diagnosis of celiac disease requires both a positive finding on duodenal biopsy and a positive response to a gluten-free diet.26 The identification of villous atrophy with small bowel endoscopy and biopsy is generally regarded as the diagnostic gold standard (although guidelines from the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition suggest that a small intestinal biopsy may not be required in children with typical symptoms, titers of anti-tTG greater than 10 times the upper normal limit and predisposing HLA genotype).2,40 Although villous atrophy is associated with celiac disease, clinicians must consider that this may also be found in other diseases, including giardiasis, autoimmune enteropathy, tuberculosis, Crohn’s disease, intolerance to food other than gluten, intestinal lymphoma, and Zollinger-Ellison syndrome.5,26
Positive findings on biopsy include increased intraepithelial lymphocytes (i.e., >30/100 enterocytes), loss of nuclear polarity, change from columnar to cuboid cells, lamina propria cellular infiltration, crypt elongation and hyperplasia, increased crypt mitotic index, and progressive villous flattening or blunting.40 The Marsh classification system is a standardized approach used by pathologists to describe the histologic changes seen in celiac disease. This classification includes ratings of Marsh I to IV with Marsh III being further subdivided into Marsh IIIa (partial villous atrophy), IIIb (subtotal villous atrophy), and IIIc (total villous atrophy). Most celiac disease patients (50% to 60%) are placed in one of the Marsh III categories.41 Histologic findings lead to a presumptive diagnosis that is followed by placing the patient on a gluten-free diet. A definitive diagnosis can only be made after the patient’s symptoms clearly improve while maintaining the special diet. A second biopsy to confirm histologic improvement is not required except in cases when the clinical symptoms of celiac disease were absent.40 Some clinicians have suggested that a repeat biopsy after dietary intervention may have merit to demonstrate histologic improvement that will support the diagnosis, assess the patient’s dietary compliance, and reassure the patient. A second biopsy can be useful for patients whose initial biopsy demonstrated ambiguous histologic changes, whose serology was negative or discrepant, or who continue to have symptoms after initiating the gluten-free diet.6 Dermatitis herpetiformis is diagnosed by taking a small skin biopsy from normal skin that is next to the blister site.33 The characteristic skin biopsy finding in this disorder is the deposition of IgA granules at the dermal–epidermal junction.31 The 2004 National Institutes of Health (NIH) Consensus Development Conference on Celiac Disease reported that patients with skin biopsy–proven dermatitis herpetiformis generally are not required to have small bowel biopsies.37
Serologic test results provide clinicians with a useful noninvasive tool that helps to determine if symptomatic patients, or patients who are at risk for celiac disease, require a biopsy.4,24,42 Available tests include those for antigliadin antibodies, connective tissue antibodies (antireticulum and antiendomysial antibodies), and antibodies against tTG.26 The most common serologic markers that are used for screening patients are serum IgA endomysial antibodies and IgA tTG antibodies.39 Both of these tests have over 90% sensitivity; therefore, a test for either marker is considered to be the best means of screening for celiac disease.26 Antiendomysial antibody testing is operator dependent, rather time consuming, and more expensive than the test for IgA tTG antibodies, which is operator independent.4 A rapid test for anti-tTG antibodies that only requires a sample of fingertip blood may be a convenient point-of-care test to aid with diagnosis and dietary monitoring.26 Testing for gliadin antibodies is no longer utilized because of its low sensitivity and specificity for celiac disease.35,39 Although serology is a good method to identify patients who will benefit from endoscopy and biopsy, negative serology should not preclude a biopsy examination in individuals for whom disease is suspected on clinical grounds.5,6
Genetic testing can be performed as a means of confirming the diagnosis of celiac disease or to determine which family members of a diagnosed patient may develop the disease (the prevalence of celiac disease has been reported to be 10% to 12% in first-degree relatives and is also higher than that found in the general population in second-degree relatives).30 Patients and their family members can be tested for HLA-DQ2 and HLA-DQ8 as the HLA-DQ2 is found in up to 95% of celiac disease patients, with most other patients being HLA-DQ8 positive.4,35 Although nearly all celiac disease patients carry one of these alleles, they are also found in 30% to 40% of the general population. Therefore, when these alleles are absent, it is extremely unlikely that the individual has celiac disease (i.e., the test has a high negative predictive value [NPV]).37 A patient-administered saliva-based test for HLA-DQ2/DQ8 was released for direct sale to consumers.43 It will be interesting to observe how the availability of this test will impact on the already rather strong interest of those patients who seek self-diagnostic methods.44
More accurate diagnostic measures will assist with the management and hopeful reduction of comorbid conditions (correcting deficiencies of iron, folic acid, vitamin B12, fat-soluble vitamins; diagnosing and treating osteoporosis; etc.) and complications (a gluten-free diet may reduce the increased mortality related to risk of malignancy) that are associated with celiac disease.39 Preventing additional comorbid conditions and/or celiac disease complications not only will improve the patient’s quality of life but may also avoid the costs that are associated with treating these other disorders.
Overall goals of treatment include relieving symptoms, healing the intestine, and reversing the consequences of malabsorption while enabling the patient to adhere to a healthy, interesting, and practical gluten-free diet.27,45
Table 27-5 presents a mnemonic that summarizes the major principles of the treatment of celiac disease. Strict lifelong adherence to a gluten-free diet is the only proven treatment for celiac disease.6Patients must recognize that adhering to a gluten-free diet includes not ingesting anything that contains gluten or has been contaminated with gluten. Wheat, barley, and rye must be avoided.27 Although oats are in a different plant family, they have also been regarded to be problematic; however, the ingestion of certified pure gluten-free oats appears to be safe.6 Due to the continued difference of opinion regarding the safety of oats, patients are generally advised to discuss the risks and benefits associated with consuming oats with their healthcare provider before they include oats in their diet. Patients must also commit to avoiding the ingestion of gluten found in nonfood items such as toothpaste, lip balm, lipstick, etc. A list of gluten-free grains can be found in Table 27-1.
TABLE 27-5 Mnemonic for Celiac Disease
Oral prescription drugs, nonprescription drugs, vitamin and mineral supplements, and health and beauty aids and cosmetics that have oral ingestion potential must not be overlooked as sources of gluten due to its presence in their formulation or due to contamination or contact.46,47 Although clinicians have concluded that as little as 10 to 50 mg/day of gluten is the minimum dose required to produce measurable damage to the small intestinal mucosa, it is difficult to set a universal threshold given the individual variability among patients.2,30,34,42
The FDA’s Office of Food Safety Center of Food Safety and Applied Nutrition determined, after an evaluation of all low-dose–response data available on the adverse health effects of gluten in celiac disease patients, the tolerable daily intake level for gluten in individuals with celiac disease to be 0.4 mg gluten/day for adverse morphologic effects and 0.015 mg gluten/day for adverse clinical effects.48 These concerns regarding low-level exposure emphasize why healthcare providers must check to determine whether prescription drugs contain gluten in their formulation or have been contaminated with gluten before these drugs are provided to the patient with celiac disease. Patients should also be assisted with determining whether nonprescription drugs and health and beauty aids are safe for their use.49 Lack of reliable information may lead individuals with celiac disease to mistakenly assume that their prescription or nonprescription drugs contain gluten and therefore refuse to take newly recommended or prescribed medications, or stop taking previously prescribed and needed medications without conferring with their healthcare provider.50 Although there are published lists of gluten-free drugs, it is often difficult to obtain information about the gluten content of medications.51–53
It is extremely important that patients become thoroughly knowledgeable about celiac disease. Although there are an increasing number of articles, reference materials, and other sources of information readily available to patients and their families, patients should still be advised to obtain advice and guidance from their healthcare providers. Consultations with a knowledgeable dietician will assist the patient to understand and effectively adhere to the gluten-free diet.54
Newly diagnosed patients should be evaluated for nutritional deficiencies associated with vitamin and mineral malabsorption. This assessment should include assuring that the patient does not have deficiencies of folic acid, vitamin B12, fat-soluble vitamins, iron, and calcium.26 Iron-deficiency anemia may be the only presenting sign of disease in patients without diarrhea.55 Monitoring for potential nutritional deficiencies should also continue during subsequent followup visits.
Most adults with celiac disease are found to have some degree of bone loss; therefore, all patients must be screened for osteoporosis or osteopenia. A dual-energy x-ray absorptiometry (DEXA) scan is often performed to assist with this evaluation.30,45 Supplementing a calcium-rich gluten-free diet with calcium, magnesium, and vitamin D may arrest or reverse celiac decrease–related bone loss. Although their use has not been extensively studied in patients with celiac disease, bisphosphonates, selective estrogen receptor modulators, anabolic agents, and other drugs have been prescribed for patients with bone disease.27Antiresorptive drugs have been utilized in some instances when patients do not adequately improve after at least 1 year of observing an appropriate diet and taking calcium supplements. These drugs have also been used sooner in patients with low bone mineral density and little or no intestinal malabsorptive problems. Clinicians must note that these drugs can cause serious adverse effects if they are administered before the intestine properly heals. Excessive dangerous drops in blood calcium can lead to cardiac dysrhythmias, muscle weakness, and seizures.30
Implementing a gluten-free diet presents some challenges. A dietician will be helpful, particularly when the patient is newly diagnosed. Patients are advised to initiate a complete gluten-free lifestyle immediately after diagnosis. Partial adherence to this diet is not adequate. In order to accomplish this objective, patients must be aware of what foods are gluten-free and when in doubt must know how to confirm whether a food contains gluten. Reading labels is extremely important; however, it may be difficult to identify hidden sources of gluten listed among the ingredients. Patients with celiac disease must also determine whether products were processed on equipment shared with wheat, barley, or rye. It may be necessary to call the manufacturers or check their website to obtain the needed information.33
Individuals with celiac disease must also be advised to maintain a gluten-free kitchen. A dedicated toaster, bread maker, waffle iron, and other appliances should be obtained for use in preparing gluten-free meals. Utensils and dishes must be carefully cleaned to avoid gluten contamination. Care must also be taken when dining in restaurants and homes of family and friends. The individuals who prepare and serve the food must be knowledgeable about gluten-free foods and food preparation.30 Patients with celiac disease will often eat before leaving home and will bring gluten-free food with them when dining out.33
The economic burden associated with maintaining a gluten-free diet may present some challenges.45,56,57 The relatively low availability and high cost of these foods contributes to the challenges associated with adhering to the required strict diet and may lead to varying degrees of noncompliance.56,57 Patients also find that the extra cost associated with the special diet is not reimbursed by healthcare plans, and most policies do not pay for consultations with a dietician.58 These challenges with compliance are particularly concerning as noncompliance with the gluten-free diet is associated with an increased mortality rate and compromised quality of life.57 Patients are also encouraged to investigate their personal circumstances as to whether some of the costs of maintaining a gluten-free diet are eligible for approval as a tax deduction.58
Dietary avoidance of gluten remains the mainstay of treatment of celiac disease. Novel pharmacologic treatment modalities are under investigation. Most reports related to pharmacotherapy for celiac disease focus on the treatment of refractory disease.
In case reports, corticosteroids, azathioprine, cyclosporine, tacrolimus, infliximab, and alemtuzumab have been reported as effective treatments for refractory celiac disease.59–62 Patients characterized to have refractory celiac disease have persistent or recurrent malabsorptive symptoms and signs with villous atrophy despite maintaining a gluten-free diet for more than 12 months.1 Less than 5% of adult patients are found to have refractory celiac disease.63
Based on the pathophysiology of celiac disease, two categories of novel targets for the treatment of the disease have been identified: decreasing the antigenic load and modulation of the immune response.
Methods of decreasing the antigenic load include blocking the activity of tTG, GI destruction of proline peptides via enzyme therapy, blocking the binding of deaminated proteins to HLA-DQ2 and HLA-DQ8, detoxification of gluten peptides, and decreasing intestinal permeability in patients with celiac disease, in particular through inhibition of zonulin.64–66 Investigational tTG inhibitors have been developed; however, their safety is questioned due to the presence of the enzyme throughout the body and its role in many functions necessary for homeostasis.67 In the area of gluten detoxification, gluten proteins were developed in which the proline residues were replaced by azidoprolines; these azidoproline residues bound to HLA-DQ2 but did not stimulate an autoimmune response.68 A zonulin inhibitor was shown to be well tolerated and effective in a small study and is currently being studied in larger populations.67
Means of modulating the immune response include the neutralization of inflammatory cytokines and regulation of T cells.65 All of these methods are currently investigational but may offer hope in the future.
Changes in intestinal microflora have been linked with celiac disease.69 One theory behind this link suggests that changes in the glycosylation in the mucous layer in the intestines can promote adhesion of harmful bacteria, leading to celiac disease. A second theory behind this link suggests that harmful bacteria are responsible for the changes in mucous layer glycosylation, which in turn promotes celiac disease. Among the strains of probiotics studied in in vitro and in animal studies for improving the bacterial flora in patients with celiac disease are Bifidobacterium longum, B. bifidum, Lactobacillus paracasei, L. fermentun, and L. casei. As of this writing, none have been proven to be beneficial in either preventing or treating celiac disease.
Evaluation of Therapeutic Outcomes
Clinical improvement will often be observed within days or weeks of instituting the required diet.26 Although dermatitis herpetiformis is also treated with the prescribed diet, these cutaneous lesions may not completely resolve for 1 to 2 years after initiating strict dietary measures.55
Healthcare providers must also be mindful of conditions that are related to celiac disease and that are potential complications of the disease, including certain forms of cancer, neurologic manifestations, osteoporosis, depression, diabetes, infertility, as well as other autoimmune and related illnesses. Cancers that are of particular concern include thyroid cancer, adenocarcinoma of the small intestine, lymphoma (predominantly non-Hodgkin’s lymphoma of any type), esophageal cancer, melanoma, and malignancies found in childhood.31 Patients with celiac disease have also been found to have an increased risk of developing certain infectious diseases that include pneumococcal or staphylococcal sepsis and tuberculosis.70 The immune system of celiac patients is not compromised as it is actually overactive. The risk of infections due to encapsulated organisms (pneumococcal pneumonia, meningococcal infections) arises from hyposplenism, which is common in active celiac disease. Therefore, patients over 50 years of age are advised to receive pneumococcal vaccine.30 Annual influenza vaccine is advisable as this will reduce the incidence of secondary bacterial infections.70
Increased hazard ratios (HRs) for death were found in individuals with biopsy-verified celiac disease, inflammation, and potential celiac disease (the absolute risks were small). Individuals undergoing small-intestinal biopsy in childhood had increased HRs for death. These researchers concluded that the main causes of death in patients they studied were cardiovascular disease and malignancy.71
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