Diagnosis and Treatment of Celiac Disease in Children Dr.Fawaz ALRefaee, MBBS FAAP FRCPC Pediatric Gastroenterologist,Al-Adan Hospital KMA Conferance March 18,2016

Outline -Case presentation -Definition -Epidemiology -Clinical features -Pathogenesis -Diagnosis -Treatment

Case presentation 14 month old F with FTT Watery diarrhea x 2 months; 3-10 episodes per day; stool infectious work-up by PCP negative No nausea, vomiting, abdominal pain, abdominal distention, hematochezia, melena No improvement in symptoms with change to soy milk No significant PMH or FH PE: Pale skin, abdomen distended but soft and nontender, normal bowel sounds, no organomegaly

Growth Chart

Labs WBC 14.1, Hb 9.7, Plt 392; normal MCV and iron studies AST 30, ALT 23, albumin 28 Hemoccult negative, stool WBC negative, spot fecal fat test positive Celiac Panel IgA level was normal Endomysial AB Positive Tissue Transglutaminase IgA AB >100* Negative = < 15

What is Celiac Disease? Auto-immune condition Occurs in genetically susceptible individuals A unique autoimmune disorder because… Environmental trigger (gluten) and the autoantigen (tissue-transglutaminase) are known Elimination of the environmental trigger leads to a complete resolution of the disease Permanent sensitivity to gluten

Why is it Important? If untreated it poses long-term adverse health consequences including: Malabsorption Anemia Poor growth Osteopenia Intestinal lymphoma Nutritional Deficiencies Iron, zinc, calcium, Vitamin A, D, E, and K

Relatives 1:133 1st degree relatives: 1:18 to 1:22 • Healthy population: 1:133 • 1st degree relatives: 1:18 to 1:22 • 2nd degree relatives: 1:24 to 1:39 Fasano, et al, Arch of Intern Med, Volume 163: 286-292, 2003 25

Prevalence of Celiac Disease is Higher in Other Autoimmune Conditions Type 1 Diabetes Mellitus: Thyroiditis: 3.5 - 10% 4 - 8% Arthritis: 1.5 - 7.5% Autoimmune liver diseases: Sjögren’s syndrome: 6 - 8% 2 - 15% Idiopathic dilated cardiomyopathy: IgA nephropathy: 5.7% 3.6% 24

Genetic Disorders • Down Syndrome: 4-19% • Turner Syndrome: 4-8% • Williams Syndrome: 8.2% • IgA Deficiency: 2-3% • Can complicate serologic screening 23

The Celiac Iceberg Symptomatic Celiac Disease Manifest mucosal lesion Silent Celiac Disease Latent Celiac Disease Normal mucosa Genetic susceptibility: - DQ2, DQ8 Positive serology

Risk Factors for Celiac Disease The Grains The Genes

Pathogenesis

Genetics Strong HLA association 90-95% of patients HLA DQ2 –also found in 20-30% of controls Concordance in MZ twins is 70% HLA-DQ2 and /or DQ8 genes are necessary (No DQ2/8,no celiac disease!) but not sufficient for the development of the disease

Clinical Manifestations Gastrointestinal Symptoms (“Classic”) Chronic or recurrent diarrhea Abdominal distention Abdominal pain Vomiting Anorexia Failure to thrive or weight loss Constipation Irritability -- 25% of patients present with “classic” symptoms

“Classic” Celiac Disease

Asymptomatic Silent Latent Silent: No or minimal symptoms, “damaged” mucosa and positive serology Identified by screening asymptomatic individuals from groups at risk such: First degree relatives Down syndrome patients Type 1 diabetes patients, etc.

Asymptomatic Silent Latent Latent: No symptoms, normal mucosa May show positive serology. Identified by following in time asymptomatic individuals previously identified at screening from groups at risk. These individuals, given the “right” circumstances, will develop at some point in time mucosal changes (± symptoms)

Abnormal Laboratory Findings in CD

Dermatitis Herpetiformis Erythromatous papule> urticarial papule> tense vesicles Symmetrical with severe pruritis 90% no GI symptoms Gluten sensitive 75% villous atrophy

Recurrent Aphtous Stomatitis By permission of C. Mulder, Amsterdam (Netherlands) 33

Short Stature/Delayed Puberty Short stature in children/teens: About 10% of short children and teens have evidence of celiac disease Delayed menarche Higher prevalence in teens with untreated celiac disease

Dental Enamel Defect Involve the secondary dentition Could be the only presenting sign of celiac disease

Osteoporosis

Celiac Disease Complicated by Enteropathy-Associated T-cell Lymphoma (EATL) By permission of G. Holmes, Derby (UK)

Neurological and Behavioral Problems Zelnick et al. Pediatrics. 2004.

Serological Tests Role of serological tests: Identify symptomatic individuals who need a biopsy Screening of asymptomatic “at risk” individuals Supportive evidence for the diagnosis Monitoring dietary compliance -- Recommendation to screen all first-degree relatives of patients with CD with serologic testing

Tissue Transglutaminase - TTG IgA based antibody against tissue transglutaminase (Celiac Disease autoantigen) Advantages high sensitivity and specificity (human TTG) non operator dependent (ELISA/RIA) relatively cheap Disadvantages false negative in young children false negative in IgA deficiency possibly less specific than EMA The tissue transglutaminase test is IgA based and performed by means of either an ELISA or RIA technique. The major advantages of the test are that it is highly sensitive and specific, is non operator dependent and is relatively cheap to perform. The disadvantages are that it is unable to detect celiac disease in IgA deficient individuals and it may be less specific than the endomysial antibody.

Endomysial Antibody - EMA NEGATIVE POSITIVE Antibodies against the outer layer of the smooth muscle of monkey esophagus This slide illustrates the microscopic appearance of a positive of endomysial antibody test.

Serum IgA Level Individuals with IgA deficiency are at increased risk for Celiac Disease IgA deficient individuals will have negative EMA-IgA & TTG-IgA Check IgA levels with Celiac Disease serology in all symptomatic individuals Consider IgG based tests (EMA-IgG & TTG-IgG) in IgA deficiency It is known that individuals with selective IgA deficiency are at increased risk for celiac disease. This presents a problem when using serological tests for screening purposes as most tests are based upon an IgA antibody and hence will give a negative result. In order to better interpret the relevance of a negative endomysial or transglutaminase test in a symptomatic individual, determination of a serum IgA level is helpful. In the event the individual has a low serum IgA level indicative of IgA deficiency, the IgA based endomysial and transglutaminase tests will fail to identify those who have celiac disease. In such cases additional strategies are needed. One such strategy is to use IgG based anti-endomysial and anti-tissue transglutaminase tests that are offered by some commercial laboratories. Studies suggest these are not as sensitive or specific as the IgA based tests but are superior to the IgG based anti-gliadin tests. If the clinical suspicion for celiac disease is strong, it may be necessary to proceed to an intestinal biopsy even if all serological tests for celiac disease are negative.

Serological Test Comparison

Endoscopic Findings

Intestinal Histopathology Histologic abnormalities associated with CD are characteristic, but not completely specific. Classically, small intestinal mucosal surface is flattened with absence or marked blunting of intestinal villi Total absorptive surface area is greatly reduced There are typically an increased number of inflammatory cells present in the lamina propria (plasma cells, CD4 cells)

HLA Tests Potential role for DQ2/DQ8 Asymptomatic relatives Trisomy 21, Turner & Williams syndrome Type 1 diabetes Diagnostic dilemmas TTG +, EMA -, Bx -, Symptoms +

Treatment Only treatment for Celiac Disease is a gluten-free diet (GFD) Strict, lifelong diet Avoid: Wheat Rye Barley Oats? -- Follow serology to confirm adherence to gluten-free diet. If serology does not normalize, continued exposure is likely. Involvement of an experienced dietician is critical – often able to identify hidden exposures.

Why is Adherence Important? Good evidence to suggest that when children with symptomatic celiac disease adhere to a GFD it results in resolution of GI symptoms, improved growth in height and weight, and normalization of hematological and biochemical parameters. Celiac disease is associated with an overall increased risk of mortality in adults which is primarily the result of GI malignancies. When CD is diagnosed in childhood and GFD is initiated, there appears to be no increased cancer risk and reduced risk of other autoimmune diseases.

Diagnostic Approach in symptomatic child

Summary Celiac Disease is a common, subtle enteropathy with variable presentation. Active, appropriate screening is needed to avoid long-term complications of untreated CD. Life long adherence to the diet is important

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