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Celiac Disease: What You Need to Know Douglas Zabrowski, MD Pediatric Gastroenterology 9/19/2017

Topics NOT Discussed Gluten Sensitivity In-depth discussion of possible neurological symptoms linked to gluten

Definition A Chronic small-intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals First described in 1888 by Samuel Gee, but not linked with gluten protein from wheat/rye until the 1950s

Background Gluten is comprised of polymeric glutenins and monomeric gliadins w/ gliadins being the toxic element Glutenins can be immunogenic as well Wheat, rye, barley all contain gliadins Oats have close taxonomic relation to wheat and have shown no microscopic or serologic effect on disease, but many patients are sensitive to it (?contamination?) Rice & corn are okay & often used as substitutes

Epidemiology Prevalence of 1:1000, and women>men, but overall underdiagnosed Sweden 1:250, Denmark 1:4000 up to 1% of the population in some parts of the world Many new diagnoses are through screening of asymptomatic at-risk individuals Incidence however is increasing beyond anticipated change of improved detection High concordance rates in monozygotic twins (75%) & siblings Risk of CD in 1st degree relatives is 10% 30% if HLA-identical (Chromosome #6) Recent evidence does NOT support strong link between breastfeeding or time of gluten introduction and Celiac disease

Genetics HLA-DQ2 + in ~95% of CD patients, but + in 20-40% of healthy controls HLA-DQ8 + in ~4-5% of CD patients, but can be in healthy controls as well Originally thought <1-2% of CD (-) for both, but experts believe that it is unlikely that CD can be present without these markers due to pathogenesis HLA on CELIAC1 locus seem to be necessary for CD may be responsible for gliadin antigen presentation to T-cells changes in other gene loci also needed (CELIAC2-4 on cr5/2/19 respectively) Association w/ DM-1 and other autoimmune diseases that share the HLA loci

Pathology T-cell mediated disease that affects superficial mucosa down to lamina propria Gliadin is resistant to digestion and is able to activate both innate & adaptive immunity Gliadin is cleaved by tTG-2 into fragments more immunogenic to T-cells triggering anti-gliadin responses tTG-2 is inactive in normal conditions and the mechanism of its activation is unclear Speculative evidence that rotavirus may increase risk of CD one of its proteins shares homology with tTG there is correlation with the seasonality of birth month Activation pattern is TH-1 predominant with interferon-gamma includes pro-inflammatory cytokines IL-6/18/21 Downstream activation of metalloproteinases and factors of angiogenesis lead to prototypical histology findings

Pathology There is migration of lymphocytes to the epithelium which lead to apoptosis signaling and villous atrophy Anti-tTG antibodies produced by gut mucosa reduce tTG-2 activity interfere w/ epithelial cell differentiation promote proliferation speculated that circulation of these Abs leads to systemic manifestations This process upregulates tTG-2 and further gliadin cleaving exposes the antigenic sites, thus increasing presentation to T-cells and auto-antibody production (theoretical) Auto-antibodies to actin, calreticulin, enolase, and ATP Synthase have been found in CD, but with unclear significance

Endoscopy Visible changes: scalloping, atrophic patches, mosaic appearance, fissuring Histology: changes alone are not specific to CD CMSPA, intractable diarrhea of infancy, Giardia, HPylori, Crohn’s, Peptic disease, immunodeficiency, tropical sprue, lymphoma, CVID, and SBBO have to be considered Requires establishing a gluten-dependent link to the lesions

Presentation Toddlers: most commonly FTT, chronic diarrhea/steatorrhea, vomiting, abdominal distention, anorexia, irritability Classic symptoms: vomiting, GERD Sx, diarrhea, constipation, erratic BMs, bloating, steatorrhea Older children may present with solely extra-intestinal manifestations or be clinically silent EIMs due to either circulating auto-ABs (theory) or to malnutrition

Extraintestinal Manifestations Iron-Deficiency anemia (8.5% of adults w/ anemia resistant to Iron Tx have CD) Difficult-to-treat Fe-deficiency anemia should be screened Elevated transaminases: 9% of cases of cryptogenic transaminitis Short stature (up to 10% of children with this have CD) Vitamin deficiencies: D, B12, B6, zinc (macrocytosis often masked by Fe-Deficiency) Dermatitis Herpetiformis subepidermal IgA deposits, symmetric blistering rash, Tx w/ GFD + Dapsone Osteopenia (higher chance of normalizing if GFD adopted in youth) Arthritis/Arthralgias Headaches

Less Common Manifestations Epilepsy Infertility, difficult/premature pregnancy, delayed puberty Early Atherosclerosis Recurrent aphthous stomatitis Hyposplenism Enamel Hypoplasia Fatigue Alopecia areata

Associations CD pts have higher childhood rates of Learning disorder, ADHD, Dev Delays, Psychiatric illness Not responsive to GFD, effect of GFD closer to onset of Sx unclear No clear mechanism Associated diseases: AI Thyroid disease, Addison’s, pernicious anemia, AIT, sarcoidosis, DM-1, alopecia, AIH, PBC 10% of pts w/ DM-1 have CD, CD pts have 2.4xrisk of DM-1 7% of pts w/ AI thyroid disease have CD, CD patients have 4xrisk of AI thyroid disease WHY? There are some shared HLA haplotypes, but some evidence of increased risk of AI disease with longer duration of gluten exposure Patients with Downs, Turner’s, Williams, and IgA Deficiency all have increased incidence of CD

Diagnosis - Serology Anti-endomysial (EMA), anti-deaminated gliadin (DGP), and Anti-tTG antibody ELISAs have high specificity and sensitivity for CD IgA endomysial ABs – sensitivity 85-98% (88-100); specificity 97-100% (91-100) IgA tTG-2 ABs – sensitivity 90-98% (92-100); specificity 95-97% (91-100) IgA deamidated gliadin peptide – sensitivity 94% (66-72); specificity 99% (92-97) IgG deamidated gliadin peptide – sensitivity 92%; specificity 100% Anti-tTG IgA is firstline screen and EMA can be used for equivocal results EMA may be more sensitive in patients with known AI disease Anti-endomysial Abs against monkey esophagus or human umbilical cord Reacts to tTG and is a very specific marker of mucosal damage in untreated patients Very operator-dependent Positive tTG IgA or EMA with negative biopsies is still a risk for future development of CD (Potential Celiac)

Diagnosis – Serology IgA deficiency must be ruled out concurrently IgA deficiency present in up to 2% of CD patients, rare in general population If known to be IgA deficient, anti-tTG & anti-endomysial IgG levels are recommended DGP ABs are more specific in children <4yo than tTG Abs (not true in adults) As all these antibodies are produced in gut mucosa, negative results may still miss mild disease without spillover into serum 2-3% of CD patients have serologies that are (-), low +, or fluctuate Rapid/Point of Care tTG IgA testing screens are being developed

Disease Prediction by Antibodies   Positive Likelihood Ratio Negative Likelihood Ratio Odds Ratio EMA/IgA 31.8 (18.6-54.3) 0.067 (0.038-0.118) 553 (218-1402) Anti-TG2/IgA 21.8 (12.9-36.8) 0.060 (0.040-0.090) 469 (250-880) Anti-DGP/IgG 13.6 (8.1-22.8) 0.061 (0.017-0.221) 234 (100-546) Anti-DGP/IgA 9.4 (6.8-13.1) 0.121 (0.072-0.203) 86.1 (56-132) AGA/IGA 7.3 (4.5-11.8) 0.186 (0.095-0.362) 40.6 (14-117) 95% confidence intervals in parentheses Giersiepen, Evidence report, JPGN 2012

Diagnosis – next level EGD with biopsy is the gold standard to confirm diagnosis Diagnosis requires histological evidence and clinical remission on GFD Biopsy to prove efficacy of GFD on mucosal healing is standard (6-12months) Otherwise, only repeat EGD when symptoms relapse or if serologies increase Important to consider screening at risk individuals, those w/ + 1st degree relative or other AI diseases HLA-typing: Strong negative predictive value, low PPV Often difficult to get insurance coverage Limited utility May be useful for screening asymptomatic at-risk individuals (if results are negative)

Gluten Challenge Many patients trial GFD prior to coming to PCP office Testing may be falsely negative if following GFD Due to long-term complications, establishing diagnosis is necessary Challenge requires (at least 3g per day) for at least 2-3wks If asymptomatic/negative screens, but high suspicion, challenge only recommended after 7yo, not during adolescent growth spurt

Treatment Gluten free diet: no wheat, barley, rye, +/- oats. Maximum of <50g/day, though some patients require stricter restrictions as they can have symptoms on 50mg/day (food w/ <20ppm) Difficult due to intensive, expensive diet, and requires education Can lead to symptomatic nutritional deficiencies, constipation, and weight gain due to altered diet Mucosal healing is better in children than adults, but no clear explanation

Treatment Nondietary Tx is not currently available, but 2 drugs in Phase II trials ALV003 (recombinant gluten-specific protease) – reduces the amt of mucosal injury on 6wk gluten challenge Larazotide acetate (modulates intestinal tight junctions) – reduced symptoms in patients on gluten challenge These are being targeted to help with chronic low-grade or intermittent gluten exposures

Treat All CD Patients GFD recommended for CD even if asymptomatic to avert increased risk of intestinal adenocarcinoma (80x baseline risk) enteropathy-associated T-cell lymphoma (EATL) malnutrition sequellae

Nonresponsive Celiac Disease (NRCD) NRCD: symptoms and findings of CD despite 12-18mth on GFD 7-30% of CD patients Most common cause: inadvertent or intentional gluten exposure Normal serologies do not rule out gluten exposure Other food intolerances such as FODMaPs may contribute GI and Nutrition re-evaluation is most important to rule out Gluten exposure

Prognosis of CD Increased malignancy risks, but these reduce to population baseline after 5yrs on GFD for responders 2-3x Increase in risk of Non-Hodgkin’s Lymphoma 10x risk of Small intestinal adenocarcinoma Future research areas: Non-immunogenic wheat strains Pharmological targets: HLA-binding drugs that don’t activate T-cell receptors, Anti-IL10 agents, inhibition of gliadin antigen presentation, TG2 inhibitors Inducing immune-tolerance to gluten

Takeaways Have a high suspicion for Celiac in Autoimmune patients, Down’s, primary relatives and in those with short stature 1st degree relatives can be screened starting at 3yo and 1yr after 1st gluten exposure Early detection and referral improves health outcomes

Takeaways Screen patients 1-3yo with tTG IgA/IgG, DeAmidated Gliadin IgA/IgG, and Total IgA Screen patients >4yo with tTG IgA and total IgA EMA as an initial screen should be reserved for patients with known AI disease

References Hadithi M, et al. Accuracy of Serologic Tests and HLA-DQ Typing for Diagnosing Celiac Disease. Annals of Internal Medicine. 2007. Vol 147, No 5. UpToDate.com Kelly C, Bai J, Liu E, Leffler D. Celiac Disease: Clinical Spectrum and Management, Advances in Diagnosis and Management of Celiac Disease. Gastroenterology. 2015;148:1175-1186 Guideline for Diagnosis and Treatment of Celiac Disease in Children: Recommendations of NASPGHAN. 2005. JPGN 40:1-19. ESPGHAN Guidelines for the Diagnosis of Coeliac Disease. 2012. JPGN 54:1:136-160. Hill ID, Fasano A, Guandalini S, et al. NASPGHAN Clinical Report on the Diagnosis and Treatment of Gluten-related Disorders. 2016. JPGN 63:156-165

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