Gastroenterology: Celiac Disease Courses in Therapeutics and Disease State Management

Learning Objectives Discuss the etiology and pathophysiology of celiac disease Describe the gastrointestinal and extraintestinal symptoms of celiac disease Differentiate between screening for and diagnosis of celiac disease Explain who should be screened for celiac disease Discuss treatment of celiac disease including nonpharmacologic and lifestyle measures

Required Reading Patel PN, Mangione RA. Celiac Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; 2017 .

What is Celiac Disease? Celiac disease is a small intestinal immune-mediated enteropathy caused by intolerance to ingested gluten Gluten is a generic term for a variety of proteins found in grains such as wheat, barley, and rye Link: Table on grains and other foods that do and do not contain gluten Chronic inflammation caused by exposure to gluten leads to GI discomfort, nutrient malabsorption, and systemic complications Celiac patients experience both GI and extraintestinal symptoms

Epidemiology Celiac disease is common in North America and Europe It affects approximately 1% of Americans The prevalence of celiac disease is higher in women than men at rates ranging from 2:1 to 3:1 It is estimated that only 10% - 15% of those with celiac disease in the U.S. have been diagnosed

Etiology (Slide 1 of 3) Celiac disease occurs when a genetically predisposed person ingests gluten Wheat gluten proteins exist in 2 fractions: gliadins and glutenins Barley contains proteins called hordeins and rye contains proteins called secalins both of which are similar to glutenins Ingestion of any of these proteins will lead to an autoimmune response in celiac disease patients

Etiology (Slide 2 of 3) Genetic factors likely play a role in the development of celiac disease A concordance rate of 85% in monozygotic twins has been reported 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

Etiology (Slide 3 of 3) Certain infectious agents and other compounds may contribute to the development of celiac disease Adenovirus and hepatitis C viruses are thought to act as triggers Campylobacter jejuni, Giardia lamblia, rotavirus, and enterovirus infections have been described in case reports as associated with celiac disease Interferon-α has also been suggested to play a role in celiac disease development

Pathophysiology (Slide 1 of 2) Sensitive individual eats gluten  inappropriate T-lymphocyte response against the antigen in the small intestine  release of antibodies and activation of the inflammatory cascade (interferons, interleukins, TNF, etc.)  injury characterized by changes in the structure and loss of intestinal villi  malabsorption of vitamins, minerals, and essential nutrients

Pathophysiology (Slide 2 of 2) Link: Table on Proposed Pathophysiology of Celiac Disease Link: Figure showing small-intestinal mucosal biopsies

Signs and Symptoms (Slide 1 of 3) The recognition of celiac disease may be quite challenging due to the wide range of presenting symptoms, which includes patients who are asymptomatic Clinical manifestations of celiac disease also vary between age groups Link: Table on Selected Signs and Symptoms of Celiac Disease

Signs and Symptoms (Slide 2 of 3) Infants and young children GI: Diarrhea, abdominal distention, vomiting, anorexia, and sometimes constipation Extraintestinal: Failure to thrive, irritability Older children and adolescents Extraintestinal: Short stature, delayed puberty, anemia, neurologic findings (peripheral neuropathy, ataxia, seizure, migraine, dementia)

Signs and Symptoms (Slide 3 of 3) Adults GI: Classic presenting sign is diarrhea accompanied by abdominal pain or discomfort Other GI: Weight loss, constipation Extraintestinal: iron-deficiency anemia, osteoporosis, neurologic symptoms, dermatitis herpetiformis, hypoproteinemia, hypocalcemia, elevated liver enzymes

Dermatitis Herpetiformis (Slide 1 of 2) Dermatitis herpetiformis is a skin manifestation of small intestinal immune-mediated enteropathy caused by the ingestion of gluten It is characterized by an extremely pruritic, bullous skin rash generally found on the elbows, knees, buttocks, and scalp but can occur anywhere on the body It occurs in approximately 15% to 25% of those with celiac disease Can occur in patients of any age but most commonly is found in celiac disease patients between the ages of 30 to 40 years

Dermatitis Herpetiformis (Slide 2 of 2) Every patient with celiac disease does not develop dermatitis herpetiformis, but every person with dermatitis herpetiformis also has celiac disease Link: Photograph of dermatitis herpetiformis of the face Link: Photograph of bullous dermatitis herpetiformis

Screening for Celiac Disease (Slide 1 of 3) Who should be screened for celiac disease? Children older than 3 and adults experiencing symptoms of celiac disease First-degree relatives of people with celiac disease Parents, siblings, and children have a 1 in 10 risk compared to 1 in 100 in the general population Any individual with an associated autoimmune disorder or other associated condition Examples of these conditions include type 1 diabetes, autoimmune thyroid disease, rheumatoid arthritis, scleroderma, autoimmune liver disease, primary biliary cirrhosis, Down syndrome, Turner syndrome, Williams syndrome, Sjogren’s syndrome First-degree relatives are parents, siblings, and children. People with any of these associated autoimmune conditions are at increased risk of also having celiac disease.

Screening for Celiac Disease (Slide 2 of 3) Serologic tests screen for celiac disease antibodies Serum IgA antibodies to tissue transglutaminase (tTG) are increased in most cases of active celiac disease This test is referred to as a tTG-IgA test < 4.0 u/ml – Negative 4 – 10 u/ml – Weak positive > 10 u/ml – Positive This test can be used to determine which patients should undergo a endoscopic small intestine biopsy

Screening for Celiac Disease (Slide 3 of 3) Genetic testing can be done to determine if a person may ever develop celiac disease Patients with celiac disease carry one of both of the HLA DQ2 and DQ8 genes. 30% - 40% of the population carries one or both of these genes as well. So, carrying either or both of these genes does not mean a patient will develop celiac disease. If a person does carry one or both of these genes, then he/she is at increased risk of developing celiac disease

Diagnosing Celiac Disease Diagnosis is based on clinical suspicion and confirmation with laboratory tests and duodenal biopsy Endoscopic duodenal biopsy is the gold standard for diagnosis Positive findings on biopsy include increased intraepithelial lymphocytes, 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

Goals of Treatment Relieving symptoms Healing the intestine Reversing the consequences of malabsorption Correcting deficiencies in iron; folic acid vitamins D, E, A, and K; minerals such as magnesium, copper, zinc, and selenium Enabling adherence to a healthy, interesting, gluten-free diet

Nonpharmacologic Therapy (Slide 1 of 4) Strict, lifelong adherence to a gluten-free diet is the only proven treatment for celiac disease Even very small amounts of ingested gluten can cause intestinal injury Wheat, barley, and rye must be avoided Oats have also been problematic and should not be eaten unless they are certified pure gluten-free oats and the consumption of oats if approved by the patient’s healthcare provider Encourage the consumption of naturally gluten-free foods of high nutritional value Patients should be alerted to and avoid ingestion of gluten in nonfood products such as toothpaste, lip balm, and medications

Nonpharmacologic Therapy (Slide 2 of 4) Implementing a gluten-free diet is often very challenging A dietician is particularly helpful in educating about a gluten-free diet and assisting patients with adherence C Consultation with a skilled dietician E Education about the disease L Lifelong adherence to a gluten-free diet I Identifying and treating nutritional deficiencies A Access to an advocacy group Continuous long-term followup by a multidisciplinary team Table 41-15. Mnemonic for Celiac Disease. From: Patel, Priti N., and Robert A. Mangione.. "Celiac Disease." Pharmacotherapy: A Pathophysiologic Approach, 10e Eds. Joseph T. DiPiro, et al. New York, NY: McGraw-Hill, , http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146060170.

Nonpharmacologic Therapy (Slide 3 of 4) Oral prescription medications, nonprescription medications, vitamin and mineral supplements, health and beauty aids, and cosmetics that have oral ingestion potential should not be overlooked as sources of gluten Pharmacists should be actively involved in helping patient identify medications and supplements that contain gluten (so they can be avoided) and do not contain gluten

Nonpharmacologic Therapy (Slide 4 of 4) Newly diagnosed patients should be evaluated for nutritional deficiencies associated with vitamin and mineral malabsorption Common deficiencies include folic acid, vitamin B12, iron, calcium, fat soluble vitamins (e.g. vitamins D, E, A, and K) and some minerals Vitamin and mineral supplementation is typically recommended

Osteopenia and Osteoporosis Most adults with celiac disease are found to have some degree of bone loss All patients should be screened for osteoporosis or osteopenia via dual-energy x-ray absorptiometry (DEXA) scan Supplementing a calcium-rich gluten-free diet with calcium, magnesium, and vitamin D may arrest or reverse celiac-related bone loss In some patients, medications used to treat bone loss (e.g. bisphosphonates, selective estrogen receptor modulators, etc.) may be necessary

Pharmacologic Therapy Dietary avoidance of gluten in the mainstay of celiac disease treatment Novel pharmacologic treatments are under investigation Most instances of the use of pharmacotherapeutic agents is in response to refractory disease Agents with immunosuppressant effects such as corticosteroids, azathioprine, cyclosporine ,tacrolimus, infliximab, and alemtuzumab has been used in refractory celiac disease and reported in case reports

Evaluation of Outcomes Dietary modification as described will usually result in rapid remission of symptoms with clinical improvement observed within days to weeks

References (Slide 1 of 2) Mangione RA and Patel PN. Chapter 27. Celiac Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. Patel PN, Mangione RA. Celiac Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; 2017 . Crowe SE. Celiac disease. Ann Intern Med. 2011; 154(9): ITC5-1.

References (Slide 2 of 2) Binder HJ. Disorders of Absorption. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e New York, NY: McGraw-Hill; 2014. Celiac Disease Foundation.  www.celiac.org. Accessed February 24, 2017.