Managing Patients With Celiac Disease: Guidelines for the Community Pharmacist

Transcription

1 CONTINUING EDUCATION Managing Patients With Celiac Disease: Guidelines for the Community Pharmacist by Nicole Marcotullio, PharmD; Natalie Bari; 2015 PharmD candidate; Esther Okorie, 2015 PharmD candidate Nov. 3, 2014 (expires Nov. 3, 2017) Activity Type: Knowledge-based To earn continuing education credit: ACPE Program H01-P; H01-T Upon successful completion of this article, the pharmacist should be able to: 1. Explain the etiology and diagnosis of celiac disease. 2. Identify the signs and symptoms of celiac disease and associated conditions. 3. List potential food and medications sources of gluten and write counseling points for community pharmacists. 4. Discuss non-pharmacologic and pharmacologic treatments as they related to celiac disease. 5. Identify factors that would influence product selection in the community pharmacy setting. Upon successful completion of this article, the pharmacy technician should be able to: 1. Explain the etiology and diagnosis of celiac disease. 2. Identify the signs and symptoms of celiac disease and associated conditions. 3. List potential food and medications sources of gluten. 4. Discuss non-pharmacologic and pharmacologic treatments as they related to celiac disease. NCPA is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCPA has assigned 1.5 contact hours (0.15 CEU) of continuing education credit to this article. Eligibility to receive continuing education credit for this article expires three years from the month published. FREE ONLINE CE. To take advantage of free continuing pharmacy education (CPE) for this program, pharmacists and pharmacy technicians must achieve a passing score of 70% on the online continuing education quiz for the program. If a passing score is not achieved, one free reexamination is permitted. To take this test, go to and click on the CE tab. Click on the CE Center, which will take you to the online activities that are available. If you have not registered with Pharmacist elink, you must do so before being able to access the CE Center. You will receive immediate online test results and credits will be posted to CPE Monitor within six weeks. To obtain your CPE Monitor e-profile ID, please go to to register. 41

2 ETIOLOGY AND PATHOPHYSIOLOGY Celiac disease (CD) was first described in the second century as a malabsorptive diarrhea, but its pathophysiology was not fully understood until the 20th century. Other associated references include celiac sprue, non-tropical sprue, and gluten-sensitive enteropathy. CD is an inherited disease that affects approximately 1 percent of the population in the United States, according to the University of Chicago Celiac Disease Center. The number of newly diagnosed cases is increasing annually, and research suggests that there has been a fourfold increase in the disease over the past 50 years. The disease occurs throughout the United States, as well as in Europe, the Middle East, Asia, South America, and North Africa. Caucasians of Northern European descent tend to have the highest prevalence, with reports of CD affecting as many as 1: Europeans and 1:250 Americans. With an estimated 3 million people affected by the disease, a staggering 97 percent are thought to currently be undiagnosed, according to the University of Chicago Celiac Disease Center. Celiac disease is an autoimmune disorder that affects villi of the small intestine. The small intestine s main function is to complete the process of digestion while absorbing nutrients and passing on any residue to the large intestine. Villi are tiny, fingerlike protrusions that line the small intestine and normally allow nutrients from food to be absorbed into the bloodstream. In the case of CD patients, the autoimmune response causes an IgA-mediated attack on the villi, resulting in villous inflammation, injury, and atrophy. The damage prevents absorption of nutrients, which can often lead to malnutrition. The immune response is an adverse reaction to gluten, a protein found in grains such as wheat, barley, rye, and, to a lesser extent, oats. Gluten contains particular amino acid sequences that are harmful to persons with CD. The alcohol-soluble fraction of gluten proteins stimulates the activation of T-cells causing the inflammatory response and the damage to the intestinal villi. The genetic predisposition to CD appears to be linked to genetically transmitted histocompatibility cell antigens, specifically the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish between the body s own proteins and proteins made by foreign invaders like viruses and bacteria. The HLA genes specifically linked to celiac disease are DQ2 and DQ8, and the majority of people with CD (90-95 percent) express the DQ2 allele. Many CD patients express both HLA genetic markers, but some patients with one or both of these markers do not go on to develop CD, which implies that other factors contribute to disease development. CD is rare in those that do not have the HLA typing. It is also noteworthy that celiac disease shares a common genetic risk region with other autoimmune conditions, including type 1 diabetes, thyroid disease, and rheumatoid arthritis. Women are two to three times more likely to develop CD than men. This gender predisposition does tend to level out after the age of 65. Ultimately, the onset of the disease can occur at any age, from infancy to adulthood, and affect both men and women. If an infant develops CD, symptoms are typically seen within four to 24 months of age. This age range is likely associated with the introduction of gluten-containing cereal to the infant diet. One reported strategy to decrease the risk of infant CD development has been to gradually introduce gluten-containing foods while infants are still breast-feeding. However, there is limited evidence that the risk of CD, in those genetically susceptible, is reduced by breastfeeding for a longer duration or is increased by introducing gluten-containing cereals before four months of age. Other factors that are speculated to play a role in the timing of disease onset include the age a person started eating gluten-containing foods, and the amount of gluten-containing foods ingested. Not all genetically-susceptible people will go on to develop symptoms of celiac disease. Most research suggests that an environmental trigger causes the onset of symptoms in those who are genetically susceptible. These triggers are not fully identified or understood, and they are thought to be precipitated by a myriad of events including extreme emotions, stress, surgery, viral or bacterial infection, pregnancy, childbirth, and puberty. CD is generally considered to be a benign condition. However, if it goes undiagnosed and/or is not treated, patients have an increased risk of developing other autoimmune diseases, osteoporosis, hepatic disease, and reproductive disorders. There have also been reports of a small increase in the risk of developing malignancies including esophageal cancer, non-hodgkin lymphoma, and small intestine adenocarcinoma. DIAGNOSTIC TESTING It is not currently recommended to routinely screen people for CD, especially if they are asymptomatic. Unfortunately, a large portion of people with CD go undiagnosed. A largescale screening study was conducted in Italy and examined 17,201 children ages 6 to 15 to identify the prevalence of CD in this population. The prevalence was 1:184, and the ratio of undiagnosed to diagnosed was significant at 7:1. There have also been studies that describe an increase in prevalence of CD with age. Another survey conducted in Italy identified that approximately 15 percent of newly diagnosed celiac patients were over the age of 65, and often suffered from symptoms 11 years or more prior to diagnosis. This may be due to nondescript symptoms that appear similar to, and are often misdiagnosed as, other conditions such as inflammatory bowel disease, irritable bowel syndrome, GERD, and chronic fatigue syndrome. 42 America s PHARMACIST November 2014

3 It may also be that patients simply do not seek medical attention for their symptoms. Fortunately, with advances in screening and awareness of the disease, more people are being appropriately identified and diagnosed. Various testing methods are recommended to confirm the diagnosis including serologic studies, a trial of a gluten-free diet, and confirmation through endoscopy with a small bowel biopsy. When counseling patients, it is important to instruct them not to go on a gluten-free diet prior to antibody testing or a biopsy, as this may cause the antibody levels to appear normal and improve the intestinal villi, resulting in a false negative result. Serologic studies consist of autoantibody testing for anti-tissue transglutaminase (IgA ttg), total serum IgA and anti-endomysial antibody (IgA EMA). The antibody testing will determine the level of response a person is having to the gluten protein with positive results indicated by high antibody levels. Initially IgA ttg should be analyzed. Tissue transglutaminase, the target auto-antigen contained within the endomysium, demonstrates specificity of greater than 95 percent and a sensitivity in the range of percent, especially in cases of moderate to severe CD. IgA ttg testing is often performed over the gliadin antibody test due to its accuracy, reliability and low cost. It is considered the preferred method of serologic detection. IgA EMA analysis may also be performed. It has a slightly lower and variable sensitivity but excellent specificity (99.6 percent). Although the IgA EMA testing method is accurate, it has greater error potential, is operator-dependent, time-consuming and also more expensive so it is typically reserved for difficult to diagnose patients. Finally, IgG ttg analysis may also be useful in patients with a known IgA deficiency, although the prevalence of this in CD patients is low. Testing of IgA EMA or IgA ttg should be the first step in the process of diagnosis, as the presence of these antibodies is useful to identify patients likely to have CD. To confirm the diagnosis, however, further workup through a small intestine biopsy is required. The small bowel biopsy through an upper endoscopy is the gold standard for the diagnosis of celiac disease. During the endoscopy, the patient swallows a small flexible instrument with a camera. This camera allows the physician to examine the upper part of the gastrointestinal system and to painlessly remove a small piece (biopsy) of the small intestine. The intestinal mucosal lining normally has distinct fingerlike villi, but in patients with CD the villi are atrophic and appear flattened with elongated intestinal crypts. There is also an increased presence of intraepithelial lymphocytes. This damage is not permanent; the villi will eventually resume a normal growth pattern once patients stop eating gluten. Approximately 70 percent of people experience improvement of symptoms within two weeks of going on a gluten-free diet. The villi may take anywhere from six months to two years to fully recover and return to a normal functional capacity. As there is a genetic component to the disease, it is often recommended that patients with first-degree and sometimes with second-degree relatives that have a confirmed CD diagnosis be screened, especially if they exhibit signs or symptoms of the disease. These patients have a greater chance of also being diagnosed, with a prevalence of about 10 percent in first-degree relatives, and percent in second-degree relatives. An additional diagnostic tool is testing for the HLA DQ2 and/or DQ8 genetic markers. This is typically an exclusionary test, which can help rule out CD for patients with similar symptoms and discrepant serologies. Genetic testing is also useful in screening asymptomatic family members. It is virtually impossible to have CD if you do not have these genes, but it is also possible to have these genes and never develop the disease. Therefore, it is important to emphasize that these patients are at an increased risk, and that they should have additional testing if they begin to exhibit clinical signs and symptoms of the disease. For follow-up testing, serologies may be used to determine if the gluten-free diet is working. If the levels of antibodies in the blood decline on a gluten-free diet, this indicates efficacy. Due to the malabsorptive nature of the condition, additional testing is often performed to identify and evaluate iron, folate, calcium, and vitamin D deficiencies. SIGNS AND SYMPTOMS There are hundreds of symptoms of celiac disease. Many of them may be subtle and seem unrelated. Presentation of symptoms is most often tied to age with children exhibiting more classic gastrointestinal symptoms and adults having a more varied symptomology. In children, CD most often presents with the following: chronic diarrhea/ constipation, recurrent abdominal bloating and pain, and signs of malabsorption including weight loss, muscle wasting and growth deficiencies. Adults may have symptoms that are atypical and not gastrointestinal in nature. Diarrhea and weight loss are not always present. The most common sign of CD in adults is iron-deficiency anemia that does not respond to oral iron therapy. Unfortunately, the wide variety of atypical symptoms can present a challenge in identifying adult CD patients, especially those that should go on for further testing. Refer to Table 1 for a more comprehensive list of classic and atypical signs and symptoms. ASSOCIATED CONDITIONS Patients with chromosomal abnormalities such as Down syndrome (10 percent) and Turner syndrome (6.4 percent) are generally more susceptible to autoimmune conditions and thus have a higher likelihood of developing CD. All CD patients also have a greater likelihood of developing other 43

4 Table 1: Signs and Symptoms of Celiac Disease Classic Gastrointestinal Signs & Symptoms Abdominal pain and bloating Diarrhea Steatorrhea (floating, fatty stool) Flatulence Weight loss* Fatigue* Constipation Vomiting Esophageal reflux Anorexia* Failure to thrive* Irritability* * These symptoms are typically the results of gastrointestinal symptoms; they are most commonly found in children. Atypical Signs & Symptoms Iron-deficiency anemia (very common in adults) Osteopenia/osteoporosis Bone or joint pain Arthritis Peripheral neuropathy Folate-deficiency anemia Neurological deficits (Vitamin B deficiency) Bleeding gums and bruising (Vitamin K deficiency) Aphthous mouth ulcers Dental enamel defects Dermatitis herpetiformis (DH) Anxiety or depression Liver abnormalities Seizures or migraines Infertility Thrombocytosis **Patients with CD often exhibit one or more of the above signs and symptoms. autoimmune disorders such as Type 1 diabetes mellitus (3-10 percent), ulcerative colitis, autoimmune thyroiditis ( percent) and rheumatoid arthritis. Other manifestations and comorbidities of CD include infertility (male and female), miscarriages, menstrual irregularity, rheumatic disorders, liver disease, thyroid disease (hypothyroid more than hyperthyroid), pancreatitis, osteopenia (40-45 percent), osteoporosis (10-30 percent), depression, epilepsy, migraine headaches, anxiety, suicidal tendency, carpal tunnel syndrome, and myopathy. Lactose intolerance is common in celiac disease patients, especially those who are undiagnosed and untreated. Cancers, particularly non-hodgkin s lymphoma, may also occur as a complication of the disease. It is important to note that although people with celiac disease may not experience any symptoms, damage is still occurring in the intestinal tract, which can ultimately lead to malnutrition and comorbidities. Dermatitis herpetiformis (DH) is an autoimmune skin condition associated with percent of celiac disease patients. Interestingly, 90 percent of patients who present with DH have some form of CD and should be screened accordingly. DH is a skin rash that is most likely found on the elbows, knees, buttocks, lower back, face, neck, trunk, and occasionally within the mouth. The blisters appear round and red with a raised, fluid-filled center and are extremely itchy. The itchiness usually resolves when the blister is ruptured. The diagnosis of DH is made through a skin biopsy which shows IgA deposits along the sub-epidermal basement membrane. Celiac disease in patients with DH may be asymptomatic, and most patients with DH tend to report less severe digestive symptoms. DH is often misdiagnosed as eczema, psoriasis, or other forms of dermatitis due to its presentation and symptoms. DH skin lesions will most likely resolve through patient adherence to a gluten-free diet. The most significant improvement is typically seen within several weeks. DH can also be treated with antibiotics (commonly dapsone) which will help alleviate the itching and rash. NONPHARMACOLOGIC AND PHARMACOLOGIC TREATMENT OPTIONS The 2013 American College of Gastroenterologists (ACG) guidelines state that a strict gluten-free diet is the only effective treatment for CD. Currently, there are no medications that can safely and reliably prevent the mucosal damage caused by exposure to gluten. The National Institute of Health Consensus Development Conference on Celiac Disease developed six components of treatment which are best illustrated by the CELIAC mnemonic 44 America s PHARMACIST November 2014

5 Table 2: National Institutes of Health-Defined Components of Celiac Disease Management C E L I A C Consultation with a skilled dietitian Education about the disease Lifelong adherence to a gluten-free diet Identifying and treating nutritional deficiencies Access to a support or advocacy group Continuous long-term follow-up by a multidisciplinary team outlined in Table 2. Symptomatic medication therapy for CD is not necessary in most cases due to the dramatic improvement of symptoms (days to weeks) seen as a result of a gluten-free diet. However, complete healing of the small intestine will take longer. It might be seen in as little as three to six months for children, but it can take years for adults who may have gone undiagnosed and accumulated damage for more than a decade. Some patients may experience refractory disease (1-2 percent), which is defined as persistent or recurrent malabsorptive symptoms and villous atrophy despite strict adherence to a gluten-free diet (GFD) for at least 6 12 months. A smaller subset of adult patients may experience the rare, life-threatening celiac crisis which presents as severe diarrhea, dehydration, weight loss, acidosis, hypocalcemia, and hypoproteinemia. In both of these cases, patients may be treated with corticosteroids such as prednisone and enteric-coated budesonide, or immunosuppressants including azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and anti-tnf antibodies (such as infliximab). They are also treated with vitamin and mineral supplements to correct serious deficiencies from malabsorption. The latest ACG guidelines also recommend that most patients, who are newly diagnosed with CD, undergo testing and treatment for micronutrient deficiencies. Calcium, vitamins A, B12, B6, D and E, folate, and iron should be recommended to ensure adequate nutrition for these patients. Some patients with refractory CD require symptomatic treatment to reduce diarrhea as well. Treatment strategies currently under investigation involve the use of recombinant enzymes that digest gliadin, the gluten protein found in wheat, in the stomach or small intestine. Other possible treatment options being explored include therapies that interfere with the immune response and vaccines that desensitize patients to gluten proteins through the use of immune response-causing peptides. Stage I and II clinical trials have been completed for a few of these therapies, but they are still years away from the marketplace. GLUTEN-FREE DIET Gluten is actually a general term for storage proteins found in grains. Each grain has its own protein: gliadin in wheat, secalin in rye, hordein in barley, avenin in oats, zein in corn and oryzenin in rice. The proteins found in wheat, barley and rye have been shown to cause the inflammation and symptoms of CD, and thus, gluten has become a generic term used to identify these grain proteins, even though glutens found in rice and corn do not cause the same inflammatory process. The first line and only effective treatment for CD is strict adherence to a gluten-free diet, and this undoubtedly represents a significant challenge for celiac patients. For most patients this requires a dramatic change in their eating habits and product selection. Furthermore, it affects not only the patient but his/her family and friends who may be involved in grocery shopping and meal preparation. The 2013 ACG guidelines suggest that all newly diagnosed CD patients be referred to a registered dietitian who is knowledgeable about the disease and can help them face the challenge and succeed. During their first encounter, patients receive a thorough nutritional assessment and education on beginning a gluten-free diet. Dietitians continually teach patients which foods to avoid while maintaining a balanced diet and help patients devise learning strategies for shopping, preparing food and identifying lifestyle resources. Nutritional education is critical for patients diagnosed at an older age and/or for children who must have proper dietary intake for growth and development as well as for the prevention of malabsorption. Other excellent resources for patients are celiac medical centers, organizations, advocacy and support groups. Refer to Tables 5 and 6 for a list of resources. SOURCES OF GLUTEN Adhering to a gluten-free diet may seem difficult due to the extensive list of foods containing gluten. See Table 3 for a list of sources of gluten, including processed foods that may contain wheat, barley or rye. Fortunately, maintaining a gluten-free diet has become easier over the years, due in part to the increasing availability of gluten-free foods in local grocery stores, farmers markets, specialty grocers, and organic food stores. Many of these stores have sections devoted to gluten-free products. If a store does not have a gluten-free section, these products may be available in the organic or specialty food aisle. See Table 4 for a list of gluten-free foods. One complication CD patients often encounter when converting to a gluten-free diet is that gluten is often hidden in prepared foods, supplements, cosmetics and medications as additives, binders and flavorings. Gluten is in products such as lipsticks, Play-Doh, and starch binders for oral medications. Gluten is typically responsible for the doughy, spongy and elastic texture of foods. CD patients must ingest or swallow gluten to be exposed to the harmful effects on the intestinal lining. It is not believed to be absorbed through the skin, and therefore, gluten-containing items such as sham- 45

6 Table 3: Sources of Gluten including Processed Foods That May Contain Wheat, Barley, or Rye Gluten-Containing Flours, Cereals and Starches Barley Malt, malt flavoring, malt vinegar (generally made from barley) Wheat (einkorn, emmer, durum, farina, faro, graham, kamut, semolina, spelt) Bulgur Matzo Wheat (starch, bran, germ, cracked wheat, hydrolyzed wheat protein) Rye Triticale (cross between wheat and rye) Flour (bromated, durum, enriched, graham, phosphate, plain, self-rising, white) Breading and coating mixes Couscous (granules of semolina made from durum wheat) Processed Foods or Products That May Contain Wheat, Barley, or Rye* Seasoned potato and tortilla chips Cold cuts, hot dogs, salami, sausage Rice pilaf Self-basting turkey/chicken Seasoned nuts Croutons Marinades Energy bars Drink mixes Beers/lagers Dairy substitutes Flavored teas Chocolate milk Pastas Imitation seafood Imitation bacon Salad dressings Stuffing Bouillon cubes Sauces, gravies Soup bases (i.e. chicken/beef stock) Soy sauce Seasonings, spice blends Thickeners French fries Oats Icing or frostings (from wheat flour) Dried fruit (dusted with flour) Baked beans Candy (i.e. candy coating, licorice) Cheese spreads Communion wafers Medications, vitamins, supplements Toothpaste lip balm, lipstick, lip gloss Putty, play dough, glues * Most of these foods can be found gluten-free. Carefully read all food labels, and when in doubt, check with the food manufacturer. (List is not inclusive.) Table 4: Gluten-free foods Arrowroot Flax Rice (white, brown and wild) Almond meal flour Guar gum Rice bran, rice flour Amaranth Indian rice grass Seed flours (i.e. sesame) Buckwheat Legumes Beans, bean flours (garfava, romano) Millet Sago Sorghum flour Coconut flour Nuts, nut flours (i.e. almond, hazelnut, pecan) Soy, soy flour (NOT soy sauce unless specified as gluten-free) Cassava Pea flour Tapioca, tapioca starch Potatos, potato starch, potato flour Corn Teff Distilled alcohols (unless flavoring is added after) Quinoa Yucca 46 America s PHARMACIST November 2014

7 poos and lotions are considered safe for celiac patients. However, exposure to gluten may occur when gluten-containing topical products (such as lipstick) are ingested (through licking or biting of the lips). There is also a risk for unintentional ingestion when children who regularly play with putty or Play-Doh stick their fingers into their mouths. Dining out was once quite difficult for CD patients, but as of September 2014, there are more than 5 million Internet search results that tell people how to dine out gluten-free. Restaurants are moving forward to provide gluten-free menus, naturally gluten-free items, or items that can easily be made without gluten. Cross-contamination can be a concern, so it is important for patients to be proactive by notifying restaurant staff. This allows the chef to keep the meal from coming into contact with gluten, or to modify the ingredients used in preparation of the meal. One dining-out example of requesting gluten-free preparation is beef prepared at a steakhouse. Many restaurants will dust the beef in flour before cooking. This would not be evident from simply reading the menu, but alerting restaurant staff would enable changes in the preparation procedure. Another dietary and health concern with maintaining a gluten-free diet is that most gluten-free cereals, pastas and breads are not fortified with essential vitamins and minerals such as A, B12, B6, zinc and iron. Thus, CD patients often benefit from taking supplements. Some patients may also gain weight due to a combination of factors such as a tendency to rely excessively on high protein and/or fatty foods to supplement their diet while avoiding gluten. Furthermore, the avoidance of most grains and the resulting low fiber diet associated with some gluten-free foods can result in patients developing constipation or an exacerbation of irritable bowel symptoms. Coexistence of other food intolerance is also common. The most common concomitant food intolerance is lactose, but soy and fructose intolerances are notable as well. Many patients ask their health care providers if there is a threshold for the amount of gluten they can safely ingest without causing mucosal damage. This is of concern because cross contamination can be difficult to detect, and in some cases, unavoidable. There are differing reports of what is exactly considered the maximum tolerable amount of gluten that would avoid symptoms and mucosal damage in celiac patients. Some research states that complete avoidance is the only acceptable approach, but a study by Catassi and colleagues reported that the ingestion 10 mg of gluten/day appeared safe for most of the CD study subjects. Based on these findings, they concluded that 20 ppm (20 parts per million) would be the safest and most conservative threshold to recommend for gluten-free products. However, Catassi et al. did note that individual CD patients have varying responses to small amounts of gluten, which leads some to believe that patients should managed on a case by case basis based on their individual response. To put this into perspective, the Center for Celiac Research website states that 10 milligrams of gluten is roughly the equivalent of one-eighth of a teaspoon of flour, a crumb from a slice of wheat bread, or 18 slices of gluten-free bread with each slice containing 20 ppm of gluten. The Center s website goes on to state that 20 ppm is an accepted standard in many parts of the world for products that are labeled gluten-free. In fact, this is the standard set forth by the Food and Drug Administration s 2013 Final Rule on Gluten-Free Food Labeling which went into effect on Aug. 5, Other good news for CD patients is that most food manufacturers are now required by law to directly list allergy information (such as wheat) in the ingredients section or on the front of the package. The reason for improved labeling is due to the Food Allergen Labeling and Consumer Protection Act (FALCPA), a bill passed in FALCPA has determined that eight major foods or food groups account for 90 percent of food allergies: milk, eggs, fish, crustacean shellfish, tree nuts, peanuts, wheat, and soybeans. FALCPA requires food manufactures to clearly label if a food product contains protein derived from any of listed food allergens. The law applies to packaged foods imported and domestically manufactured that are subject to FDA regulation. FALCPA does not include meat, poultry, and egg products. Under FALCPA, a food product may be subject to recall if it contains one of the major food allergen as an ingredient that is not properly identified on the food label. As of January 2006, FALCPA requires presentation of allergen information to be in one of the two following formats: 1. In the ingredient list, the name of the food source of the allergen is in parenthesis after the common name and may be in bold, for example: Ingredients: Chicken stock, enriched pasta (wheat flour, egg whites, niacin, ferrous sulfate, thiamine mononitrate, riboflavin, folic acid) carrots, modified food starch, flavoring (milk, soy) celery, salt, corn starch, sugar, water 2. Near the ingredient list or immediately following the list of ingredients the word, Contains followed by the allergens, for example: Ingredients: whole corn, vegetable oil (contains one or more of the following: corn, and/or sunflower oil), calcium, guar gum, wheat flour, cinnamon, caramel color, chocolate chips (sugar, chocolate liquor, milk, vanilla), eggs, garlic powder, red and green bell pepper powder. Contains: Milk, egg, and wheat ingredients FALCPA also requires some manufacturers to list disclaimers for foods that may be unintentionally cross-contaminated with major food allergens during manufacturing and processing. These disclaimers may be printed anywhere 47

8 Table 5: Celiac Centers & Celiac Experts The Children s Hospital Los Angeles Wm K. Warren Medical Research Center for Celiac Disease Celiac Disease Program, University of Chicago The Celiac Disease Clinic, Rady Children's Hospital Celiac Disease Clinic, Celiac Disease & Inflammatory Bowel Disease Center Center for Celiac Research, University of Maryland School of Medicine Celiac Disease Center, Columbia University The Kogan Celiac Center, St. Barnabas Ambulatory Care Center Celiac Disease Clinic, Mayo Clinic Center for Celiac Disease, Beth Israel Deaconess Medical Center Celiac Center, University of Tennessee Medical Center Bonnie Mechanic Celiac Disease Clinic, Children s Hospital of Wisconsin Table 6: Celiac Disease Resources American Celiac Disease Alliance The Celiac Disease Foundation National Foundation for Celiac Awareness(NFCA) American Dietetic Association Food Allergy Network Gluten Intolerance Group of North America Celiac Disease and Gluten-Free Diet Support Center Gluten Free Drugs (As of 9/2014 the latest update was 5/2014) on the product label but most often are found on the front of the package or under the ingredient list. Clarifications of ingredients may also be listed in the allergen section at the end of the ingredient list. Examples of these include: May contain traces of nuts, soy and wheat Packed in a facility that handles peanuts, milk, soy, wheat and egg products Contains: milk and soy, may contain traces of wheat Other labels on food products that are not required but may help identify gluten-free products include: Gluten-Free Manufactured or produced in a gluten-free facility The FDA was required by FALCPA to issue a final report on the labeling of gluten-free products for manufacturers in order to define gluten-free and state the requirements of a product under that claim. This report was completed and published in The FDA requirements state that products may NOT be labeled as gluten-free if they contain any of the following: A prohibited grain, including wheat (genus: Triticum), rye (genus: Secale), barley (genus: Hordeum) and cross breed wheat hybrids (triticale) A prohibited grain (or derivative) that has not been processed to remove gluten A prohibited grain (or derivative) that has been processed to remove gluten, but still contains 20 parts per million (ppm) gluten 20 ppm gluten (based on reliable detection technology) IS COMPLETE AVOIDANCE OF OATS NECESSARY? In the past celiac patients have been advised to avoid oats in addition to wheat, barley and rye; however, oats are not considered one of the prohibited grains by the FDA, and they have not been identified as a definitive cause of celiac symptoms. Research is contradictory as to whether or not oat protein causes an immune reaction in CD patients. Current research suggests that patients diagnosed with CD can tolerate gluten-free oats (not contaminated by 48 America s PHARMACIST November 2014

9 wheat gluten during processing) in amounts as much as 60 grams/day (about 2 oz. or ¼ cup dry steel oats). Avoidance of oats is recommended in patients with CD if they are among the small percentage of patients who react to oats and experience GI symptoms like bloating and diarrhea. For patients who are considering adding oats to their diet, it is recommended they introduce them after eating a strict, oatless gluten-free diet for a trial period. This way, patients can clearly see what effects (if any) the oats are having on their health. Patients choosing to eat oats should only purchase oats labeled as gluten-free which are also manufactured in a gluten-free facility. GLUTEN IN PRESCRIPTION AND OTC MEDICATIONS A surprising number of medications contain gluten in their excipient ingredients. Excipients are inactive ingredients, designed to bind tablets together, provide bulk, serve as lubricants and aid in the dissolution of tablets. Excipients obtained from whole grains, grain flour or grain starches are the most common sources of gluten. The FDA has strict regulations for active ingredients but provides only a list of approved inactive ingredients that does not specify the source and type. Therefore, identifying these products can be difficult. Unlike trends in food-labeling, there has not been an increased push to seek gluten-free status for drug products (prescription or OTC). A survey published in 2001 reported that only five pharmaceutical companies have a policy of producing gluten-free products and would guarantee their products as gluten-free. Other companies often believed their products were gluten-free but could not guarantee their status. Most of the time pharmaceutical companies reported that they did not test their final products for the presence of gluten, and so, they could not verify their products as gluten-free. Most pharmaceutical manufacturers are producing multiple products at the same time using various suppliers of raw materials. This means risk of cross contamination is high. Furthermore, suppliers of raw materials and ingredients can change frequently, so although a product is determined to be gluten-free today, it may not be gluten-free tomorrow. All of these issues make it challenging for pharmacists to help CD patients maintain their strict gluten-free diet. Pharmacists with celiac patients must learn to err on the side of caution regularly consulting ingredient lists, reviewing gluten-free drug references, and even turning to the manufacturer for clarification. Helpful resources for patients and pharmacists include websites that list medications which may or may not include gluten. Table 6 contains a list of these resources. While these resources are helpful in determining gluten content, verification with the manufacturer is still preferred. When gluten-free status cannot be determined, pharmacists should turn to the provider and request a therapeutic alternative that can be verified as gluten-free. Compounding pharmacists provide a valuable service to CD patients by compounding medications that are gluten-free and not subject to cross-contamination. Table 7 includes the gluten status of different ingredients. IMPORTANT PATIENT COUNSELING POINTS FOR THE COMMUNITY PHARMACIST Community pharmacists have the ability to help patients living with celiac disease through counseling of the disease state. Education is needed for patients to understand the Table 7: Gluten-Free and Gluten-Containing Ingredients (often used in prescription and OTC medications) Gluten-Free Ingredients Starches, specifically from corn (most common) or potato Sweeteners (uncontaminated) from sucrose, honey, dextrose, fructose, corn syrup Uncontaminated: Acacia Agar Alginates Carrageenan Tapioca Gellan Guar gum Xanthan gum Cellulose and cellulose derivatives Other polymers Gluten-Containing Ingredients Any ingredient derived from barley, barley malt, rye, or wheat Whole grains Grain flour Unspecified: Starch Starch grain Pregelatinized starch Modified food starch Botanical sources of starches Dextrates Dextrin Dextrimaltose Malt Caramel coloring Other possible sources: vegetable gum 49

10 progression of the disease state including its short and long-term complications. Another way pharmacists can provide assistance is by encouraging patients with lifestyle modifications. Adhering to a gluten-free diet is the key component to halting or slowing the progression of the disease. Pharmacists should inform patients that although they may not be currently experiencing symptoms there may be underlying intestinal damage from eating gluten. Also, as the adoption of a strict gluten-free diet is a major lifestyle modification, many patients may need more consistent encouragement as they adjust to the change. When counseling and encouraging patients with CD it is important to understand the multiple challenges and potential barriers of maintain living a gluten-free lifestyle, such as: Hidden gluten/cross-contamination Psychological well-being (stress of maintaining the diet) Co-morbid or associated conditions Cost of the food (estimated to be two times more expensive) Avoidance of activities (restaurants, traveling) Education (available resources, diet, medications) Access to gluten-free foods Label reading (visual impairment, knowledge, time) Ongoing support and education is critical to promote success in achieving and maintaining a gluten-free diet. To assist with the psycho-social aspects of celiac disease, encourage patients to join an advocacy or support group. Community pharmacists can also help their celiac patients with product recommendations. Before making recommendations, pharmacists should consider any interactions with the patient s current medication profile. Pharmacists should also review the medication profiles of CD patients to determine if the patient is taking any medication that could have pharmacokinetic changes (such as decreased efficacy or increased side effects) due to alterations in gastrointestinal absorption. Since CD patients are susceptible to vitamin and mineral deficiencies, pharmacist should provide guidance on proper supplementation. Patients with classic malabsorption diseases are deficient of fat-soluble vitamins (A, D, E, K). As a counseling point, patients should be advised to take their vitamins with food to avoid stomach discomfort. Iron deficiency anemia is another common issue with celiac diease patients, thus, supplementation with iron is recommended and it may be a good idea to stock a gluten-free formulation and tell patients it is always on hand. Counseling points for iron supplements include taking the tablet with meals and not taking the tablet within two hours of other medications. The most common adverse effects with iron are upset stomach and constipation. Patients should be also instructed to take the iron product while sitting upright and with at least 100 ml of water to avoid esophagitis. Patients with celiac disease are also at risk for osteoporosis, with up to 40 percent of patients displaying evidence of osteoporosis or osteopenia Decreased bone mineral density leads to an increased risk for bone loss, fractures and falls. Although significant improvement is seen within the first year of adhering to a gluten-free diet, celiac patients who have signs and symptoms of osteoporosis should have a dual-energy X-ray absorptiometry (DEXA) scan and their calcium and Vitamin D levels checked at the time of diagnosis. Follow-up labs should be conducted after 6-12 months on a gluten-free diet. The 2014 National Osteoporosis Foundation guidelines (NOF) recommend daily intake of 1,200 mg calcium and 800-1,000 IU vitamin D3 per day, either through dietary or supplement sources. Additionally, those with malabsorptive or gastrointestinal disorders should have their serum 25-hydroxy vitamin D [25(OH)D] levels measured to ensure it is within normal limits ( 30 ng/ml or 75 nmol/l) for optimal calcium absorption. The guidelines also note that these patients may need higher doses of vitamin D3 to achieve this level due to their underlying malabsorption. Patients should only take a maximum of 500 mg of elemental calcium per dose for optimal absorption. Calcium carbonate should be taken with meals as an acidic environment is needed for proper absorption. Calcium citrate, on the other hand, may be taken with or without food and is ideal for patients who also take proton pump inhibitors, H2 antagonists, or who are achlorhydric. Pharmacists can help CD patients estimate their dietary intake of calcium using the formula below. Estimating Daily Dietary Calcium Intake (NOF) Step 1: Estimate calcium intake from calcium-rich foods* Product Servings x Estimated calcium = Calcium servings(mg) Milk (8 oz.) x 300 = Yogurt (6 oz.) x 300 = Cheese (1 oz. or 1 cubic in.) x 200 = Fortified foods or juices x 80 to 1,000** = Step 2: Total from above mg for nondairy sources = total dietary calcium Calcium, in mg * About 75 to 80 percent of the calcium consumed in American diets is from dairy products. ** Calcium content of fortified foods varies. Community pharmacists should also discuss vitamin B and folic acid supplements with CD patients. Patients should be educated on how to optimize their gluten-free diet by including vitamin-enriched, non-grain food sources of folic acid and B vitamins. If dietary sources are insufficient, supplements 50 America s PHARMACIST November 2014

11 should be recommended. When recommending vitamin and mineral supplements, pharmacists should select only verifiable gluten-free products. Finally, due to the low fiber content of gluten-free products, pharmacists may need to recommend fiber supplements for patients experiencing constipation. Recommendations include dietary rice bran, psyllium fiber and/or methylcellulose supplements, all of which are gluten-free. BUSINESS OPPORTUNITIES FOR COMMUNITY PHARMACISTS Due to the increase in supply of gluten-free foods on the market, there are numerous opportunities for community pharmacists to reach out to patients with celiac disease. The research firm Mintel projects that the growth of the gluten-free market will reach more than $15 million by Drug manufacturers have also noted the growth trend and are strategizing for ways to promote their gluten-free medications. Compounding pharmacists should also look at this niche, since they have the skills and resources to compound medications guaranteed to be gluten-free. Pharmacists can also perform a service reviewing medications for their gluten status and recommending gluten-free alternatives if necessary. The following are additional business strategies to promote the role of pharmacists in the management of celiac disease. 1. Be a source of medication information. Your patients are often unaware which medications are gluten-free. You should have this knowledge, and go one step further by confirming the gluten-free status of medications with manufacturers. Calling manufacturers may be time consuming, but it can also be an advertised service unique for your CD patients. Gluten-free medication knowledge will also benefit other health care providers when selecting alternative medications. 2. Provide gluten-free OTC products. Designating a gluten-free section among OTC products can reassure celiac patients feel that your pharmacy shares their concerns about their health. Gluten-free OTC products can be identified through the online resources listed in Table Provide gluten-free food products. Gluten-free foods and snacks may help you stand out among your competition. Stocking these items gives patients an opportunity to check off their gluten-free shopping lists while filling their prescriptions. Utilize the demographics of your patient population to provide you with a key for selecting the right products. Advertise gluten-free products and place them near the front of the store. Consider offering samples of products to taste. 4. Offer pamphlets and flyers at your pharmacy. Provide health literature resources so that your patients and their families can learn more about celiac disease. Contact CD organizations directly or through their websites to send free educational materials to your patients. Refer to Table 6 for a list of resources. 5. Host education sessions or provide educational newsletters. This is a great opportunity for you to connect with your CD patients. Invite speakers (doctors, nurses, dietitians, chefs, fellow celiac patients, etc.) from the area who are able to provide insight as well as practical tips for your patients. Consider partnering with other health care providers to offer screening services at such events. Newsletters can provide additional information on CD and can also be used to promote upcoming events on the topic. 6. Stay current with updated guidelines. All health care professionals need to have up-to-date information. Participate in educational activities, such as conferences, online training, CE sessions, and meetings with experts in the field in order to stay abreast of current guidelines and ongoing research. CONCLUSION Celiac patients face many challenges in managing their disease, and the effects of poor disease state management can have long-lasting health consequences. Fortunately, pharmacists possess unique knowledge and skills about medication safety which can greatly benefit this patient population. Opportunities are rapidly expanding for community pharmacists to provide innovative care for patients with celiac disease. Initiatives aimed at newly diagnosed CD patients can help with the many changes these patients will need to make to manage their disease. These initiatives should include strategies for follow-up and maintenance emphasizing patient-centered care. Nicole Marcotullio, PharmD, is an assistant professor of pharmacy practice at the Duquesne University Mylan School of Pharmacy. This article, originally published in 2011, was updated in September 2014 by two APPE interns. Natalie Bari is a 2015 PharmD candidate at the University of Arkansas for Medical Sciences College of Pharmacy, and Esther Okorie is a 2015 PharmD candidate at Notre Dame of Maryland University School of Pharmacy. Editor s Note: For the list of references used in this article, please contact America s Pharmacist Managing Editor Chris Linville at , or at chris.linville@ncpanet.org. 51

12 CE QUIZ Continuing Education Quiz Select the correct answer. 1. Celiac disease is described as: a. An inflammatory bowel disease that causes chronic inflammation of the digestive tract, usually affecting only the innermost lining of the large intestine (colon) and rectum b. A noninflammatory disorder that affects the large intestine (colon) and causes signs and symptoms of cramping, abdominal pain, bloating, gas, diarrhea and constipation, but does not cause permanent damage or changes to the colon and bowel tissue c. An autoimmune inflammatory gastrointestinal disorder that is IgA-mediated and causes damage to the mucosal lining or villi of the small intestine resulting in inflammation, injury, and villous atrophy d. An inflammatory condition of the lining of the digestive tract which often spreads deep into the layers of affected bowel tissue and can be both painful and debilitating e. None of the above 2. The human leukocyte antigen (HLA) DQ2 is found in what percent of patients with celiac disease? a percent b percent c percent d. 100 percent 3. Which of the following is true regarding the diagnosis of celiac disease? a. Recommended serologic studies consist of autoantibody testing for anti-tissue transglutaminase(iga ttg) and anti-endomysial antibody (IgA EMA). b. Prior to serologic testing you should recommend a patient follow a gluten-free diet to prevent false negative results. c. Routine screening of the general population is recommended due to the large number of people with undiagnosed CD. d. Positive serologic results confirm a diagnosis of CD and further workup is not necessary. 4. S.M. comes into your pharmacy and states that she has celiac disease and was wondering if she needs to take an iron supplement. Which of the following would be the best response? a. Iron supplementation is not necessary as iron deficiency is not associated with celiac disease. b. Celiac disease patients may become iron deficient; however, iron supplements all contain gluten and are not recommended. c. Celiac disease patients may become iron deficient and supplementation would be recommended if clinically indicated. d. Celiac disease patients may become iron deficient; however, due to the intolerable side effects of iron supplements they are not recommended. 5. Which of the following is a common sign or symptom of celiac disease? a. Peptic ulcer b. Diarrhea c. Hirsutism d. Renal failure 6. Symptomatic individuals with all of the following concomitant conditions have a higher prevalence of celiac disease EXCEPT those with: a. Type I diabetes b. Asthma c. Ulcerative colitis d. Rheumatoid arthritis 7. Which of the following is true regarding dermatitis herpetiformis (DH)? a. It is a skin rash that affects about half of all celiac patients. b. It is a form of contact dermatitis and will resolve with use of topical corticosteroids. c. DH is most likely found on the elbows, knees, buttocks, lower back, face, neck, and trunk. d. No treatment is necessary for DH as the skin lesions are transient and will resolve on their own over time. 8. What is the most effective way for patients to treat celiac disease? a. Calcium and vitamin D supplementation b. Adherence to a strict gluten-free (GF) diet c. Avoidance of wheat and rye only d. Infliximab 52 America s PHARMACIST November 2014