CELIAC DISEASE NO PAIN NO GRAIN MICHAEL BARNA

CELIAC DISEASE “NO PAIN? NO GRAIN!” MICHAEL BARNA, MD, MPH, CPE, FAAFP

PRIMARY CARE ENDOSCOPY • MY STORY – TRAINING, STAFF ENDOSCOPY, & FACULTY • PRIMARY CARE ENDOSCOPY – UTILITY TO FELLOW PRIMARY CARE PRACTITIONERS • COLORECTAL CANCER SCREENING & DIAGNOSTIC COLONOSCOPY • GERD/BARRETT’S ESOPHAGUS • UNDIFFERENTIATED DYSPEPSIA • DYSPHAGIA, EOE, STRICTURE • CELIAC DISEASE & NCGS • STRONGER PART OF THE MULTI-DISCIPLINARY TEAM

OVERVIEW • DEFINITIONS AND SCOPE OF GASTROINTESTINAL DISORDERS • CASE PRESENTATION • CELIAC DISEASE DEFINED & STATISTICS • SCREENING/TESTING CONSIDERATIONS • COMPARISON OF SEROLOGIC TESTING • ADULT VERSUS PEDIATRIC TESTING • EGD & HISTOPATHOLOGIC CLASSIFICATION • NOTES ON GLUTEN-FREE DIETS • FOLLOW-UP AND SURVEILLANCE CONSIDERATIONS • NON-RESPONDERS AND REFRACTORY CELIAC DISEASE • SUMMARY AND RECOMMENDATIONS

FOOD INTOLERANCE VS FOOD ALLERGY FOOD INTOLERANCE FOOD ALLERGY “NON-IMMUNOLOGIC REACTION THAT CAUSES AN ADVERSE HEALTH OUTCOME UPON EXPOSURE“ “IMMUNE RESPONSE THAT OCCURS ON EXPOSURE TO A CERTAIN FOOD” • METABOLIC (E. G. , LACTASEDEFICIENCY ) • PHARMACOLOGIC (E. G. , CAFFEINE) • PRIMARILY IGE-MEDIATED (E. G. , PEANUT EXPOSURE IN A PREVIOUSLY SENSITIZED INDIVIDUAL) • TOXIC (E. G. , SCOMBROID POISONING/HISTAMINE TOXICITY) • NON-IGE-MEDICATED IN THE CASES OF FOOD PROTEIN-INDUCED ENTEROPATHIES • UNDEFINED MECHANISMS (E. G. , SULFITE PRESERVATIVES) • EXACERBATION OF EOSINOPHILIC GI DISORDERS INTESTINAL RESPONSE ONLY INTESTINAL AND EXTRA-INTESTINAL RESPONSES IN THESE INDIVIDUALS • FOOD-INDUCED ALLERGIC CONTACT DERMATITIS. US National Institute of Allergy and Infectious Diseases (NIAID)

CASE PRESENTATION • • • ), ”GI ISSUES” (MOTHER), HTN (MOTHER/FATHER)

CASE PRESENTATION • PERTINENT EXAM FINDINGS: • VITAL SIGNS – WNL; WEIGHT DOWN 5 KG SINCE LAST NOTED VISIT 2 YEARS AGO • ABDOMINAL EXAM – MILD, DIFFUSE TENDERNESS TO PALPATION W/O GUARDING/REBOUND TENDERNESS; NABSX 4; NOH SM • SKIN – NO ACTIVE SKIN LESIONS • RECTAL EXAM – NORMAL TONE, NO GROSS BLOOD

CASE PRESENTATION • LABORATORY EVALUATION: • COMPLETE BLOOD COUNT IS REMARKABLE FOR A MILD HYPOCHROMIC, MICROCYTIC ANEMIA • LIVER ENZYMES DEMONSTRATE A MILD ELEVATION (2 TIMES THE UPPER LIMIT OF NORMAL) IN ASPARTATE AND ALANINE AMINOTRANSFERASES (AST/ALT) BUT ARE OTHERWISE NORMAL • CHEMISTRY, THYROID STIMULATING HORMONE, LIPASE, AND OCCULT BLOOD ARE NORMAL/NEGATIVE

IBS WHEAT ALLERGY FODMAP/OTHER FOOD INTOLERANCE SIBO NCGS/WHEAT SENSITIVITY CELIAC DISEASE

CELIAC DISEASE • CHRONIC, SMALL BOWEL ENTEROPATHY • ~1% PREVALENCE (HIGHLY VARIABLE GEOGRAPHICALLY) • GROUPS WITH INCREASED PREVALENCE* • STARTS WITH INITIAL EXPOSURE TO DIETARY GLUTEN IN PREDISPOSED INDIVIDUALS • AUTOANTIBODIES • TISSUE TRANSGLUTAMINASE 2 (ANTI-T TG 2) • ENDOMYSIUM (EMA) • DEAMIDATED GLIADIN PEPTIDE (ANTI-DGP)

INCREASED-RISK GROUP PREVALENCE • TYPE 1 DIABETES – 3 -12% • AUTOIMMUNE THYROID DISEASE – 3% • AUTOIMMUNE LIVER DISEASE – 13. 5% • DOWN SYNDROME – 5. 5% • TURNER SYNDROME – 6. 5% • IGA DEFICIENCY– 3% Adapted from Husby et al.

CELIAC DISEASE - PATHOPHYSIOLOGY • GLUTEN (GLIADIN AND GLUTENINS) ARE INGESTED BY GENETICALLY-SUSCEPTIBLE INDIVIDUALS • GLIADIN/GLUTENIN POORLY DIGESTED, LEAVING PEPTIDES THAT CAN TRIGGER HOST IMMUNITY • TRANSLOCATION OCCURS OF THESE PEPTIDES IN THE SMALL BOWEL (PASSIVE AND ACTIVE) • INNATE IMMUNE SYSTEM PRODUCES CYTOKINES (IL-15 AND INF ALFA) – ACTIVATES DENDRITIC CELLS AND INTRAEPITHELIAL LYMPHOCYTES • CD 4+ CELLS ACTIVATE THE ADAPTIVE IMMUNE RESPONSE LEADING TO CRYPTAL HYPERPLASIA AND VILLOUS BLUNTING

• • • IN THE CORRECT CLINICAL SETTING CORRELATES WITH THE PRESENCE OF THE DISEASE AND • NEGATIVE TESTING FOR BOTH HAPLOTYPES INFERS A NEGATIVE PREDICTIVE VALUE OF >99%

INTESTINAL AND EXTRAINTESTINAL MANIFESTATIONS OF CELIAC DISEASE INTESTINAL EXTRAINTESTINAL • ABDOMINAL PAIN • ANEMIA (INCLUDING IRON-DEF) • NAUSEA/VOMITING • ARTHRALGIA/ARTHRITIS • BLOATING • DERMATITIS HERPETAFORMIS • CONSTIPATION/DIARRHEA OR BOTH • ELEVATED LIVER ENZYMES • ANOREXIA/WEIGHT LOSS • FATIGUE • GI REFLUX • OSTEOPOROSIS

WHO TO TEST? 1. 2. 3. 4. 5. 6.

SCREEN FOR CELIAC DISEASE? JAMA. 2017; 317(12): 1252 -1257. doi: 10. 1001/jama. 2017. 1462

CASE PRESENTATION 32 Y/O F PRESENTS WITH ONGOING SYMPTOMS OF ABDOMINAL PAIN, BLOATING, FREQUENT PASSAGE OF GAS, AND DAILY BOUTS OF FOUL-SMELLING STOOL X 1 YEAR ROS: ? WEIGHT LOSS IN LAST 4 -6 MONTHS, OCCASIONAL RASH ON HANDS (SELF-RESOLVES IN A FEW WEEKS), 1 -2 EPISODES OF DIZZINESS WITH STANDING IN PAST 3 MONTHS PMHX/PSHX – UNREMARKABLE SHX – NO TOBACCO, 1 GLASS WINE/WEEK, MANAGER LOCAL RESTAURANT FHX – T 1 DM (MOTHER), ”GI ISSUES” (MOTHER), HTN (MOTHER/FATHER) EXAM: 5 KG WEIGHT LOSS • • VITAL SIGNS – WNL; WEIGHT DOWN 5 KG SINCE LAST NOTED VISIT 2 YEARS AGO ABDOMINAL EXAM – MILD, DIFFUSE TENDERNESS TO PALPATION W/O GUARDING/REBOUND TENDERNESS NABS; X 4; NO HSM SKIN – NO ACTIVE SKIN LESIONS RECTAL EXAM – NORMAL TONE, NO GROSS BLOOD LABS: COMPLETE BLOOD COUNT IS REMARKABLE FOR A MILD HYPOCHROMIC, MICROCYTIC ANEMIA LIVER ENZYMES DEMONSTRATE A MILD ELEVATION (2 TIMES THE UPPER LIMIT OF NORMAL) IN ASPARTATE AND ALANINE AMINOTRANSFERASES (AST/ALT) BUT ARE OTHERWISE NORMAL CHEMISTRY, THYROID STIMULATING HORMONE, LIPASE, AND OCCULT BLOOD ARE NORMAL/NEGATIVE

SEROLOGIC TESTING FOR CELIAC DISEASE Antibody Sensitivity (%) Specificity (%) Notes on use Ig. A t. TG 74 -100 78 -100 Best screening test Ig. G DGP 80 -97 86 -97 Screening in individuals with Ig. A deficiency Ig. A EMA 83 -100 95 -100 Confirmatory testing Ig. G t. TG 13 -99 86 -100 Not recommended Ig. A DGP 81 -95 86 -93 Not recommended 2013 ACG - Test children < 2 for Ig. A t. TG and Ig. A/Ig. G DGP 2017 JAMA Review – Test all patients w/o Ig. A deficiency with Ig. A t. TG; w/ Ig. A def – Ig. G DGP Adapted from Leonard, Maureen M. , et al.

PROPOSED WORKUP OF CELIAC DISEASE (ADULTS) Rubio-Tapia A et al. 2013 ACG Guidelines

PROPOSED WORKUP OF CELIAC DISEASE (CHILDREN < 2 Y/O) Avoiding duodenal biopsy (ESPGHAN criteria): 1. Signs/symptoms 2. + Ig. A t. TG (>10 ULN) 3. + Ig. A/G EMA (separate) 4. + HLA DQ 2/DQ 8 Add Ig. A/Ig. G DGP during initial screening Rubio-Tapia A et al. 2013 ACG Guidelines

PROPOSED WORKUP OF CELIAC DISEASE FOR PATIENTS ALREADY ON A GLUTEN-FREE DIET Rubio-Tapia A et al. 2013 ACG Guidelines

EGD – KEY FINDINGS/WHERE TO BIOPSY? ASGE 4 -6 biopsies in the distal duodenum and bulb ACG ≥ 4 biopsies in distal duodenum Duodenal bulb biopsy Correct Answer? Unknown http: //medicaldetectivemd. com/product-categories/gastrointestinal-support-

RELATIONSHIP WITH DYSPEPSIA – 2013 ACG THE COMPLEXITY OF DECIDING WHO TO TEST ISEXEMPLIFIED BY PATIENTS WITH DYSPEPSIA. THE PREVALENCE OF BIOPSY-PROVEN CD IN PATIENTS WITH DYSPEPSIA IS 1% , SIMILAR TO THAT OF THE GENERAL POPULATION, AND THEREFORE SYSTEMATIC SCREENING FORC D IS NOT RECOMMENDED BASED ON DISEASE PREVALENCE ALONE. HOWEVER, TREATMENT FOR DYSPEPSIA CAN BE A CLINICAL CHALLENGEA ND DYSPEPSIA AS A SYMPTOM OF CD WILL READILY RESPOND TO THE GLUTEN-FREE DIET (GFD). THUS, MUCOSAL BIOPSIES OFTHE DUODENUM SHOULD BE CONSIDERED IN PATIENTS WITH DYSPEPSIAWHO UNDERGO INVESTIGATION WITH UPPER ENDOSCOPY BECAUSE OFP ERSISTENT SYMPTOMS DESPITE INITIAL THERAPY, ARE AGED > 55 YEARS OLD, ANDOR / PRESENT ALARM SYMPTOMS (E. G. , WEIGHT LOSS OR CLINICAL EVIDENCEO F ANEMIA). Rubio-Tapia A et al. 2013 ACG Guidelines

MARSH PATHOLOGIC CLASSIFICATION Adapted from Leonard, Maureen M. , et al.

MARSH PATHOLOGIC CLASSIFICATION http: //virchowseye. blogspot. com/2010/04/marsh-classification-celiac-disease. html

ADDITIONAL PATHOLOGIC CLASSIFICATION SYSTEMS Adapted from Leonard, Maureen M. , et al.

GLUTEN-FREE DIET (GFD) • CURRENTLY, ONLY TREATMENT FOR CELIAC DISEASE • AUG 2013 – FDA REQUIRES “GLUTEN-FREE” LABELED FOODS <20 PPM • SEVERAL LARGE EUROPEAN STUDIES ~50% NON-COMPLIANCE • MANY BARRIERS TO LIFE-LONG GFD • INCONVENIENCE • UNINTENTIONAL INGESTION • LOW PALATABILITY OF GLUTEN-FREE FOODS • SOCIAL PRESSURE • HIGHER RISK FOR NON-COMPLIANCE – ADOLESCENT AND YOUNG ADULTS • ACG RECOMMENDS REFERRING NEWLY-DIAGNOSED CD PATIENTS TO A GFDKNOWLEDGEABLE REGISTERED DIETITIAN

ISSUES WITH GFD ADHERENCE AND MONITORING • CURRENTLY, NO VALIDATED BIOMARKERS FOR MONITORING ADHERENCE • SEROLOGIC MARKERS HAVE LONG HALF-LIVES AND LEVELS DO NOT CORRELATE WELL WITH HISTOLOGIC FINDINGS • SYMPTOM-BASED ASSESSMENTS OFTEN USED HOWEVER • PERSISTENT GLUTEN EXPOSURE OFTEN RESULT OF UNINTENTIONAL INGESTION • SYMPTOM-BASED ASSESSMENTS CAN MISS DISEASE PRESENCE • ASYMPTOMATIC • MINIMALLY-SYMPTOMATIC

FOLLOW-ON TESTING AND COMPLIANCE Rubio-Tapia A et al. 2013 ACG Guidelines

NON-RESPONDERS VS. RESISTANT CD Rubio-Tapia A et al. 2013 ACG Guidelines

SUMMARY AND RECOMMENDATIONS • MYRIAD OF IBS-LIKE GASTROINTESTINAL DISEASES BE DIFFICULT TO SORT OUT – MAY • MAY BE USEFUL TO THINK IN TERMS OF FOOD ALLERGY VERSUS FOOD INTOLERANCE • LOOK FOR INTESTINAL AND EXTRAINTESTINAL SIGNS AND SYMPTOMS, PMHX, FHX • OPTIMAL TESTING FOR CD – GLUTEN-CONTAINING DIET • IGA TTG – BEST TEST FOR SCREENING TISSUE ; BIOPSY – DISEASE CONFIRMATION • SLIGHT DIFFERENCES FOR WORKING UP ADULTS VS PEDIATRICS (<2 Y/O) • GFD ONLY CURRENT THERAPY COMPLIANCE ISSUES – MANY • USE A MULTIDISCIPLINARY TEAM FOR FOLLOW-ON CARE • FOR NON-RESPONDERS, CONSIDER COMPLIANCE FIRST THEN ALTERNATIVES • REFRACTORY CELIAC DISEASE SHOULD BE MANAGED BY A MULTIDISCIPLINARY TEAM FAMILIAR WITH RFD

SELECTED REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. RUBIO-TAPIA A, HILL ID, KELLY CP, ET AL. ACG CLINICAL GUIDELINES: DIAGNOSIS AND MANAGEMENT OF CELIAC DISEASE AM. J GASTROENTEROL. 2013; 108: 656 -676. LEONARD, MAUREEN M. , ET AL. “CELIAC DISEASE AND NONCELIAC GLUTEN SENSITIVITY. ” JAMA, VOL. 318, NO. 7, 2017, P. 647. , DOI: 10. 1001/JAMA. 2017. 9730. ACCESSED 13 OCT. 2017.