Against the grain: An overview of celiac disease

PRACTICE Against the grain: An overview of celiac disease Suzanne Martin, RN, FNP-C (Clinical Instructor) College of Nursing and Student Health Center, University of Utah, Salt Lake City, Utah Keywords Celiac disease; diarrhea; malabsorption syndrome; gluten-free diet. Correspondence Suzanne Martin, RN, FNP-C, College of Nursing and Student Health Center, University of Utah, 555 Foothills Boulevard, Salt Lake City, UT 84112. Tel: 801-581-6546; Fax: 801-585-5294; E-mail: suzanne.martin@shs.utah.edu Received: December 2006; accepted: July 2007 doi:10.1111/j.1745-7599.2008.00314.x Abstract Purpose: To review the epidemiology, pathophysiology, clinical presentation, diagnosis, and management of celiac disease (CD). Data sources: Review of literature using Pub Med and Access Medicine. The following search terms were used: celiac disease, malabsorption syndromes, diarrhea, and gluten-free diet (GFD). There was no limitation placed on publication year. Only articles written in English were included. Conclusions: CD is a chronic systemic autoimmune disorder triggered in genetically susceptible individuals by the ingestion of gluten proteins (wheat, barley, and rye). CD often presents atypically, and diagnosis delays are common. Currently, the only effective treatment for CD is strict adherence to a GFD. This is a difficult diet to comprehend and follow. Adherence to a GFD requires ongoing education and support from a multidisciplinary healthcare team, support groups, family, and friends. Implications for practice: Once considered a rare disease of childhood, CD is now recognized as a common disorder that can occur at any age. Clinicians need to be cognizant of risk factors, clinical manifestations, conditions, and complications associated with CD in order to make a timely diagnosis, ameliorate symptoms, and minimize disease complications. Introduction Celiac disease (CD) is a chronic systemic autoimmune disorder triggered in genetically susceptible individuals by gluten proteins (wheat, barley, and rye). It can affect the gut, skin, joints, uterus, brain, heart, and other organs (Rewers, 2005). The emergence of new serologic tests has enabled large-scale screening studies across the globe. Fasano et al. (2003) conducted a large multicenter study to determine the prevalence of CD in at-risk and not-atrisk populations in the United States between 1996 and 2001. Among the at-risk populations, they found the prevalence of CD to be 4.5% (1/22) in first-degree relatives, 3.3% (1/30) in second-degree relatives, and 1.8% (1/56) in symptomatic individuals. Among the not-at-risk populations, they found a prevalence of 0.95% (1/105) in adults and 0.31% (1/320) in children. The increase of prevalence in not-at-risk adults compared to not-at-risk children suggests the development of an immune response to gluten over time. The overall prevalence in the not-atrisk population was 0.75% (1/133). Many cases of CD go undiagnosed because the condition presents in a variety of ways and can even be clinically silent, as depicted in Figure 1. Green et al. (2001) found that the average time between the onset of symptoms and the diagnosis of CD in adults is 11 years. Primary care clinicians (PCPs) need to have a working understanding of CD in order to make a timely diagnosis, lessen symptoms, and reduce the risk of disease-related complications. Pathogenesis CD is characterized by chronic inflammation of the small intestinal mucosa, which may result in atrophy of intestinal villi, malabsorption, and a variety of clinical manifestations (National Institutes of Health, 2004). A biopsy of the luminal surface of the normal small intestinal mucosa Journal of the American Academy of Nurse Practitioners 20 (2008) 243 250 ª 2008 The Author(s) Journal compilation ª 2008 American Academy of Nurse Practitioners 243

An overview of CD S. Martin Figure 1 The celiac iceberg. Note. Reproduced with permission from The Children s Digestive Health and Nutrition Foundation, September 2006 (http://www.celiachealth.org). will show abundant villi, a smattering of intraepithelial lymphocytes, and a normal complement of lymphocytes and plasma cells in the lamina propria consistent with normal physiologic inflammation. In contrast, a biopsy of the luminal surface of the small intestinal mucosa in patients with CD will show loss of villi, a flat mucosal surface marked by ridges and numerous crypt openings onto the laminal surface, increased intraepithelial lymphocytes, chronic lymphocyte and plasma cell infiltration of the lamina propria, and marked crypt hyperplasia (see Figure 2). The severity of these changes varies among CD patients (Kagnoff, 2005). The pathogenesis of CD is only partly understood but involves a clear interaction between environmental, genetic, and immunologic factors. The environmental factors are disease-activating proteins collectively referred to as gluten found in wheat, barley, and rye. Gluten contains two protein fractions, glutamine and proline, that are particularly resistant to proteolytic digestion and play a key role in the pathogenesis of CD. Genetics also play a critical role in the pathogenesis of CD. Ninety to ninety-five percent of CD patients exhibit the HLA-DQ2 genotype, while the remaining 5% 10% of CD patients exhibit the HLA-DQ8 genotype (Kagnoff, 2005). Autoantibodies specific to tissue transglutaminase develop in patients with CD. These autoantibodies facilitate the binding of proline-rich peptides to DQ2 and DQ8 molecules. The DQ gluten peptide complex then activates CD4 T cells in the lamina propria of the intestinal mucosa. These CD4 T cells trigger the production of cytokines that contribute to the chronic inflammation seen in CD. Finally, the increased intraepithelial lymphocyte count seen in CD has been recognized for many years. The role of this increase is still unclear, but it may play a role in epithelial cell damage, Figure 2 Normal versus CD small bowel biopsy. Top: Normal small bowel biopsy with finger-like villi. Bottom: CD small bowel biopsy with villous atrophy and hypertrophy of crypt. Note. Reprinted with permission from Endocrine Reviews [Collin, P., Kamkinen, K., & Välimǎki, M. (2002). Endocrinological disorder and celiac disease. Endocrine Reviews, 23(4), 464 483]. refractory CD, and CD-associated T-cell lymphoma (Kagnoff). Risk factors, associated conditions, and complications Risk factors associated with CD include a positive family history of CD and white race (Fasano et al., 2003). CD is associated with dermatitis herpetiformis (DH), an intensely pruritic papulovesicular rash over buttocks, scalp, face, elbows, and knees (Wolff, Johnson, & Suurmond, 2005). CD is also associated with other autoimmune disorders (e.g., type 1 diabetes, thyroiditis, hepatitis, and cardiomyopathy), selective IgA deficiency, and genetic disorders (e.g., Down, Williams, and Turner syndromes). The most concerning complication of CD is cancer. Adults with CD have a threefold increased risk of non- Hodgkin lymphoma. They also have an increased risk of other gastrointestinal cancers, including small bowel 244

S. Martin An overview of CD adenocarcinoma, esophageal and pharyngeal carcinoma, and primary liver cancer. Early intervention and strict adherence to a gluten-free diet (GFD) have been shown to reduce the risk of these rare but aggressive cancers (Catassi, Bearzi, & Holmes, 2005). Interestingly, two studies have demonstrated a significantly reduced risk of pre- and postmenopausal breast cancer. This may be because of lower body weights and smoking rates associated with CD (Card, West, & Holmes, 2004; Swinson, Slavin, Coles, & Booth, 1983). Another complication of CD is iron deficiency anemia because of malabsorption. More than 10% of patients with iron deficiency anemia not because of gastrointestinal blood loss may have CD (McPhee, Papadakis, & Tierney, 2007). More extensive CD will result in a megaloblastic anemia because of deficient folate or vitamin B12 deficiency. Decreased serum calcium and elevated serum alkaline phosphatase reflect reduced calcium and vitamin D absorption and osteomalacia or osteopenia. Elevation of prothrombin time reflects malabsorption of fat-soluble vitamins, including vitamins A and K. Reduced serum albumin suggests small intestine protein loss or poor nutrition (McPhee et al.). Additional complications of CD include lactose intolerance, amenorrhea, infertility, repeated miscarriage, peripheral neuropathy, ataxia, depression anxiety, and elevated liver enzymes (Green, 2005). Patient presentation/patient history The onset of CD can occur at any age. Infants and toddlers begin to express classic CD symptoms when gluten is introduced to their diet between 6 and 24 months. Classic symptoms include diarrhea, abdominal distention, impaired growth, muscle wasting, decreased appetite, weight loss, lethargy, and irritability. Atypical presentations are less likely to occur in this population (Fasano, 2005). Older children between the ages of 5 and 7 years tend to present with unusual intestinal symptoms, including recurrent abdominal pain, abdominal bloating, nausea, vomiting, and constipation. They may also present with atypical extraintestinal symptoms, such as short stature, delayed puberty, dental enamel defects, liver function abnormalities, and/or iron-deficient anemia (Fasano, 2005). The majority of adults will present with atypical or silent CD. The term silent is a misnomer as many patients in this category have mild or nonspecific symptoms, such as fatigue or depression. Adults frequently present with complications of CD, such as lactose intolerance, unexplained iron deficiency anemia, or decreased bone mineral density. Atypical CD may be diagnosed in patients undergoing endoscopy for symptoms not usually associated with CD, such as gastroesophageal reflux or dyspepsia. Finally, silent CD may be truly asymptomatic when diagnosed through screening of family members and other high-risk patients. Adults who present with classic symptoms will report diarrhea, steatorrhea, flatulence, abdominal pain, abdominal distention, vomiting, anorexia, and weight loss (Green, 2005). Physical examination The physical exam in pediatric patients may reveal failure to thrive, weight loss, dental enamel defects, abdominal distention, muscle wasting, and lethargy. The physical exam in adults may be normal or may demonstrate pallor, aphthous ulcers, hypotension, edema, bruising, diminished sensation, diminished deep tendon reflexes, ataxia, muscle spasm, bone pain, and rash consistent with DH. Laboratory workup and diagnosis All tests for CD must be performed on a gluten-containing diet. Either the IgA endomysium (IgA EMA) or IgA tissue tranglutaminase (IgA ttg) is recommended to screen for CD (Hill, 2005). The sensitivity and specificity of these tests exceed 90% and 95%, respectively, in research settings in patients with more extensive disease. In this setting, a negative test dependably excludes the diagnosis of CD (McPhee et al., 2007). The sensitivity and specificity of these tests may not be as high in patients with less extensive disease. Therefore, negative serology results should not preclude small bowel biopsy in patients with symptoms that are suggestive of CD (Dewar, 2005). When selective IgA deficiency is present, it may be best to proceed directly to small bowel biopsy (Hill). Patients with positive serologic tests require small bowel biopsy to confirm or refute CD (Dewar, 2005). Patients with biopsy-proven DH, a dermatologic manifestation of CD, do not need small bowel biopsy as they are presumed to have CD and a GFD will often relieve symptoms of both DH and CD (Zone, 2005). Small bowel biopsy must reveal some degree of inflammation and villous atrophy to support the diagnosis of CD. The Marsh and Oberhuber classifications are designed to describe the progression of abnormalities seen in CD as shown in Table 1 (Chand & Mihas, 2006). If the biopsy is normal in the setting of positive serology, the diagnosis of latent CD is appropriate. The natural history of latent CD is largely unknown, but anecdotal reports suggest that some individuals with latent CD eventually develop clinical CD. If the biopsy is suggestive of CD, a presumptive diagnosis of CD is appropriate (Dewar). 245

An overview of CD S. Martin Table 1 Pathologic classification of celiac disease Marsh classification Type 0 (preinfiltrative) Type 1 (infiltrative) Type 2 (hyperplastic) Type 2 (destructive) Oberhuber classification Type 0 Type 1 Type 2 Type 3 No detectable changes in inflammation No detectable changes in crypt/villous height ratio Increase in the number of intraepithelial lymphocytes (IELs) Inflammation, villous blunting, and increase crypt/villous height ratio Severe inflammation, flat villi, and hyperplastic crypts Normal mucosa with <40 IEL/EC Increased IEL/EC, normal villous architecture, and normal height of crypts Normal villous architecture, increased IEL, and crypt hyperplasia Destructive type with varying degrees of villous atrophy; in all subtypes, there is increased crypt height and influx of inflammatory cells Type 3a Partial villous atrophy; villi blunt/shortened with villous/crypt ratio <1:1 Type 3b Subtotal villous atrophy; villi atrophic but still separate and recognizable Type 3c Total villous atrophy; villi rudimentary or absent; mucosa resembles colonic mucosa Type 4 Atrophic hypoplastic lesion; flat mucosa with normal crypt height and no significant inflammation with normal IEL counts Note. Adapted with permission from Chand and Mihas (2006). EC, epithelial cell. Treatment/management Currently, the only known treatment for CD is strict adherence to the GFD. The GFD eliminates all foods that contain wheat, rye, and barley as depicted in Table 2. A subset of CD patients who have concurrent lactose intolerance will also have to restrict lactose-containing foods, at least until the intestine recovers (Murray, 1999). This diet is extremely complicated and demanding; therefore, all patients diagnosed with CD require prompt referral to a qualified registered dietician (RD) for comprehensive patient and family education. Periodic follow-up visits are often needed to support long-term adherence to the GFD. The GFD can become monotonous and nutrient deficient unless care is taken to diversify food choices. A qualified RD can help patients meet their nutrient needs and expand meal options despite dietary constraints. Dietary supplements such as iron, vitamins A, D, and B, calcium, zinc, and magnesium are commonly used to prevent and/or correct nutrient deficiencies (Kupper, 2005). Local and national CD support groups also play a critical role for patients and families by providing emotional support along with practical resources, such as gluten-free friendly supermarkets, manufacturers, literature, and restaurants (Case, 2005). There is controversy over what constitutes an acceptable GFD. These issues often lead to inconsistent recommendations, consumer confusion, and unnecessary dietary restrictions (Thomas, 2000). For example, the inclusion of oats in the GFD is not widely recommended in the United States because of concerns over cross-contamination of commercial oats (Kupper, 2005). However, results of several studies suggest that most adults with CD can safely consume a moderate amount (approximately onehalf cup of dry whole-grain rolled oats per day) of uncontaminated oats. To avoid contaminated oats, patients should purchase oats that are milled and processed in oat-dedicated facilities (Thomson, 2003). Adherence rates to a GFD range from 17% to 83% (Case, 2005). Adhering to a strict GFD is a daunting task because of the ubiquitous presence of wheat and wheat-based products in the North American diet, along with the hidden sources of gluten found in many products, such as food additives, lipstick, envelope glue, and medications. Even small amounts of gluten can trigger symptoms in some patients, so vigilant label reading is critical. Hectic U.S. households may have difficulty finding affordable gluten-free convenience/packaged foods (Case). Moreover, the GFD can easily become a social liability by restricting food choices when visiting friends, dining out, and traveling (Case). Symptomatic patients are more likely to adhere to a GFD than asymptomatic patients, despite findings that asymptomatic patients report a higher quality of life after initiating a GFD (Pietzak, 2005). Young adults diagnosed with CD prior to age 4 were much more likely to adhere to the GFD than young adults diagnosed after age 4, suggesting that an earlier diagnosis may predict greater adherence to the GFD (Hogberg, Grodzinsky, & Stenhammar, 2003). Patient education PCPs will often be the first source of patient education and must approach the patient and his or her family in a positive and reassuring manner. Patients need to have a basic understanding of the pathogenesis of CD. They also need to be aware of the typical and atypical symptoms, associated conditions, and possible complications of CD. As mentioned above, all patients with CD need prompt referral to a qualified RD and local support groups in order to 246

S. Martin An overview of CD Table 2 GFD guidelines Food Milk products Breads Cereals Pastas Miscellaneous Meat/meat alternatives Eggs Other Fruits/vegetables Milk, cream, buttermilk, plain yogurt, cheese, cream cheese, processed cheese and processed cheese foods, and cottage cheese Milk drinks, flavored yogurt, frozen yogurt, and sour cream Malted milk Products made from corn, rice, soy, arrowroot, pea flour, corn, starch, potato starch, potato flour, whole-bean flour, tapioca, sago, rice bran, cornmeal, buckwheat, millet, flax, teff, sorghum, quinoa, and amaranth Products containing wheat, rye, triticale, barley, oats, wheat germ, wheat bran, graham flour, gluten flour, durum flour, wheat starch, oat bran, bulgur, farina, wheat-based semolina, spelt, kamut, and imported foods labeled gluten free (may contain wheat starch) Hot cream of rice, soy cereal, hominy, hominy grits, brown/white rice, buckwheat groats, millet, cornmeal, and quinoa flakes Cold puffed corn, puffed rice, puffed millet, and rice flakes Rice and soy pablum Products make from wheat, rye, triticale, barley, and oats; products with added malt extract and malt flavoring Products from rice, corn, soy, quinoa, beans, potato, pea, or other allowed flours Products from wheat, wheat starch, and other ingredients not allowed Corn tacos and corn tortillas Rice crackers, rice cakes, and popped corn cake Wheat tacos and wheat tortillas Fresh, frozen, canned, salted, and smoked Prepared/preserved meats, for example, luncheon meat, ham, bacon, meat and sandwich spreads, meat loaf, frozen meat patties, sausages, pate, wieners, bologna, salami, imitation meats or fish products, and meat product extenders Fish canned in vegetable broth containing hydrolyzed vegetable protein (HVP) or hydrolyzed plant protein (HPP) from ingredients not allowed; turkey basted or injected with HVP/HPP Eggs Egg substitutes, dried eggs, and egg whites Lentils, chickpeas, peas, beans, nuts, seeds, and tofu Baked beans, dry roasted nuts, and peanut butter Fruits fresh, frozen, and canned fruit juices Vegetables fresh, frozen, and canned Fruits pie filling and dried fruits Vegetables fried potatoes (especially in restaurants) 247

An overview of CD S. Martin Table 2 Continued Soups Fats Desserts Beverages Snack foods Condiments Other Fruits scalloped potatoes (containing wheat flour) Vegetables battered dipped vegetables Homemade broth, gluten-free bouillon cubes, cream soups, and broths made from ingredients allowed Canned soups, dried soup mixes, soup bases, and bouillon cubes Products containing ingredients not allowed and HVP/HPP Butter, margarine, lard, vegetable oil, cream, shortening, homemade salad dressing with allowed ingredients Salad dressings and some mayonnaise Packaged suet Ice cream, sherbet, water, ice, whipped toppings, egg custards, gelatin desserts, cakes, cookies, pastries made with allowed ingredients Milk puddings, custard powder, and pudding mixes Ice cream, cakes, cookies, muffins, pies with ingredients not allowed; ice cream cones, wafers, and waffles Tea, instant and ground coffee (regular/decaffeinated), cocoa, soft drinks, cider, distilled alcoholic beverages such as rum, gin, whiskey, and vodka; wines and pure liqueurs Instant tea, coffee substitutes, fruit-flavored drinks, chocolate drinks, chocolate mixes, and flavored and herbal teas Beer, ale, and lager; cereal and malted beverages Plain popcorn and nuts Dry roasted nuts, flavored potato chips, and tortilla chips Pizza, unless made with ingredients allowed Plain pickles, relish, olives, ketchup, mustard, tomato paste, pure herbs/spices, pure black pepper, all vinegars, and gluten-free soy sauce Worcestershire sauce and mixed spices/seasoning (e.g., chili or curry powders) Soy sauce (made from wheat), mustard pickles (made from wheat), and imitation pepper (small packets found in some restaurants and airline meals) Sauces/gravies made with ingredients allowed, pure cocoa, pure baking chocolate, chocolate chips, carob chips and powder, monosodium glutamate, cream of tartar, baking soda, yeast, brewer s yeast, coconut, and aspartame Baking powder Sauces/gravies made from ingredients not allowed, for example, HVP/HPP if source is from wheat protein or plant source is unknown, oat gum, and communion wafers Note. Adapted with permission from American Dietetic Association and Dieticians of Canada (2000). 248

S. Martin An overview of CD Figure 3 An approach in the management of a patient with CD. Note. Reprinted from Pietzak (2005) with permission from the American Gastroenterological Association. 249

An overview of CD S. Martin acquire detailed information about the GFD along with practical suggestions and ongoing emotional support. After initiating the GFD, symptoms typically decrease over the course of several weeks. Serologic tests and biopsy changes may require several months to return to normal. Negative serology is often more suggestive of adherence to the GFD and does not guarantee intestinal mucosal recovery. Serology test results may not return to normal in patients with concurrent autoimmune disorders and, therefore, may not be useful in this group. The American Gastroenterological Association recommends a small bowel biopsy 4 6 months after initiating the GFD to assess improvement (Pietzak, 2005). The main goals of follow-up in CD are monitoring for adherence to therapy and screening for recognized complications of CD. Newly diagnosed patients should be checked for nutritional deficiencies such as iron-deficiency anemia and fat-soluble vitamin deficiencies. In addition, they need to be screened for osteoporosis, neurological symptoms, and autoimmune thyroid and liver disease. Children need to be monitored for growth problems and delayed puberty. First- and second-degree relatives should be screened for CD. After 3 6 months of gluten restriction, patients should follow up with either the PCP or the gastroenterologist to discuss symptoms and to reinforce the importance of adhering to therapy. If adherence to the treatment regimen is acceptable and no complications are detected, the patient may follow up with either the PCP or the gastroenterologist annually. Annual visits should include a detailed review of dietary adherence, follow-up IgA EMA or IgA ttg, and screening for nutrient deficiencies and complications (see Figure 3; Pietzak, 2005). Conclusion CD is an important diagnosis to understand and consider when seeing patients with risk factors, symptoms, associated conditions, or complications of CD. 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