Celiac Disease & Non-Celiac Gluten Sensitivity

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1 Disclosures Celiac Disease & Non-Celiac Gluten Sensitivity Pentax Research Grant (ergonomics) Amandeep Shergill, M.D., M.S. Associate Clinical Professor of Medicine University of California, San Francisco Director of Endoscopy, San Francisco VA Medical Center Celiac Disease & Non-Celiac Gluten Sensitivity Case Scenario Celiac Disease Pathophysiology Prevalence Presentation Diagnosis Mortality & Morbidity Treatment Non-celiac Gluten Sensitivity 28 yo female 6 year h/o IBS : abd gas, bloating, diarrhea alternating with constipation Tried on multiple medications without relief Friend told her she might have Celiac Disease and should get herself tested Case Scenario Celiac Disease Doc what is celiac disease? What is celiac disease? Chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals Ludvigsson, BMJ

2 Pathogenesis of Celiac Disease: Gluten Wheat Rye Barley Pathogenesis of Celiac Disease: Gluten Wheat Rye Barley Shan Science 2002 Pathogenesis of Celiac Disease: Gluten bio.davidson.edu; Figure from glutenpost.com Genetic Factors: HLA-DQ2/HLA-DQ8 Pathogenesis of Celiac Disease Host -HLA:DQ2/DQ8 -Non HLA genes Triggers -Wheat -Barley -Rye % Caucasian population DQ2/8 positive - 4% of DQ2/8 positive individuals exposed to gluten develop CD Cofactors -Intestinal Infections -Infant feeding practices -Socioeconomic factors Kagnoff, Gastro 2005;128:S10-18.; Di Sabatino, Lancet

3 Riddle AJG 2012 Incidence of Celiac Disease: active duty US military Incidence of CD diagnosis in a healthy US adult population is increasing and appears higher than other population-based estimates Increasing prevalence over time: serological studies, 2-4x higher prevalence Two large Finnish population-based studies 20y apart ttg and EMA antibodies doubling in CD prevalence from to American study compared sera collected between 1948 and 1954 with two matched cohorts collected between and between respectively Prevalence of CD was 4x higher in the recent cohorts Retrospective analysis of matched serum samples taken from US community volunteers in 1974 and 1989 showed a doubling in prevalence Khang et al; Aliment Pharmacol Ther 2013; 38: ; Rubio-Tapia Gastro 2009 Incidence of Celiac Disease: Pediatrics Almallouhi JPGN 2017 Lebwhol BMJ 2015 Environmental Risk Factors: Environmental Risk Factors Infection: Rotavirus infection an independent risk factor for celiac disease in pediatric onset CD Changes the permeability of and the cytokine balance in the intestinal mucosa Suggested risk of CD after Campylobacter, but not other foodborne infection etiologies. Infant feeding practices Breastfeeding Gluten introduction Swedish epidemic: 3x higher CD prevalence with change in national recommendations Tack et al, NatRevGastroHep 2010; Riddle DDS 2013; Riddle AJG 2012; Nadal J Med Micorbiol 2007 Ivarsson, Acta Ped 2000; Silano WJG

4 Potential mechanisms: Immunomodulatory activity breast milk: ábifidobacteria âinfection Amount of gluten introduced Environmental Risk Factors: Infant feeding PreventCD TRIAL: early introduction of gluten Multicenter, randomized, double-blind, placebo-controlled dietary intervention study 944 children: positive for HLA-DQ2 or HLADQ8, at least one firstdegree relative with celiac disease weeks of age: 475 participants received 100 mg of immunologically active gluten daily 469 received placebo. Primary outcome: frequency of biopsy-confirmed celiac disease at 3 years of age Nadal, J Med Microbio 2007; Silano WJG Vriezinga SL et al. N Engl J Med 2014;371: PreventCD TRIAL: early introduction of gluten (16 weeks) CELIPREV TRIALS: gluten at 6 vs 12 m 832 newborns: first-degree relative with celiac disease Randomized to the introduction of dietary gluten: at 6 months (group A) or 12 months (group B). HLA genotype: was determined at 15 months of age Serologic screening for celiac disease: evaluated at 15, 24, and 36 months and at 5, 8, and 10 years Patients with positive serologic findings underwent intestinal biopsies. Primary outcome was the prevalence of celiac disease autoimmunity and of overt celiac disease among the children at 5 years of age. Vriezinga SL et al. N Engl J Med 2014;371: Lionetti NEJM 2014 CELIPREV TRIALS: gluten at 6 vs 12 m Breastfeeding during Gluten Introduction 2 years of age: Group A vs Group B Celiac disease autoimmunity significantly greater (16% vs. 7%, P = 0.002) Overt celiac disease significant greater (12% vs. 5%, P = 0.01) 5 years of age: between-group differences were no longer significant for autoimmunity (21% in group A and 20% in group B, P = 0.59) or overt disease (16% and 16%, P = 0.78 by the log-rank test) 10 years: risk of celiac correlated with high-risk HLA Other variables, including breast-feeding, were not associated with the development of celiac disease. Lionetti NEJM 2014 Chmielewska Ann Nutr Metab

5 GLUTEN INTRODUCTION AND THE RISK OF COELIAC DISEASE: A POSITION PAPER BY THE EUROPEAN SOCIETY FOR PAEDIATRIC GASTROENTEROLOGY, HEPATOLOGY & NUTRITION Although breastfeeding should be promoted for its other well-established health benefits, neither any breastfeeding nor breastfeeding during gluten introduction has been shown to reduce the risk of CD. Gluten may be introduced into the infant s diet anytime between 4-12 completed months of age. In children at high risk for CD, earlier introduction of gluten (4 vs. 6 mo or 6 vs. 12 mo) is associated with earlier development of CD autoimmunity (defined as positive serology) and CD, but the cumulative incidence of each in later childhood is similar. Based on observational data pointing to the association between the amount of gluten intake and risk of CD, consumption of large quantities of gluten should be avoided during the first weeks after gluten introduction and during infancy. However, the optimal amounts of gluten to be introduced at weaning have not been established. Szajewska JPGN 2016 Environmental Risk Factors: Microbiome Mouse model expressing HLA-DQ8: microbiome can enhance or attenuate gluten-induced inflammation Higher incidence of Gram-negative and potentially proinflammatory bacteria in the duodenal microbiota of CD children Fecal concentration of Bifidobacterium bifidum were found to be significantly higher in untreated patients with celiac disease than in healthy adults Nadal J Med Micorbiol 2007; Galipeau Am J Pathol 2015; Nistal Biochimie 2012; Lebwhol Lancet 2018 Environmental Risk Factors: Socioeconomic Factors Russian Karelia vs. Finland TTG ab: 0.6% versus 1.4% (P=.005) Biopsy proven CD: Prevalence of 1 in 496 Karelian children compared to 1 in 107 Finnish children Remote territory of Russia They live like Finns 50 years ago. Environmental Risk Factors: Microbiome Worse conditions might protect against CD Variations in gut flora Infections hygiene hypothesis Analysis of house dust and potable water: Russian Karelians encountered a greater variety and quantity of microbes, including many that were absent in Finland. Tack et al, NatRevGastroHep 2010; Kondrashova Ann Med 2008; Velasquez-Manoff, NYT Velasquez-Manoff, NYT 2013 Environmental Risk Factors: Microbiome Inflammation process and possible routes of probiotic action in the maintenance of CD. In CD patients, increased epithelial tight junction permeability ( leaky gut ) favors the entrance of nonwell-digested gluten peptides from the lumen to the lamina propria. Children who were born via elective Caesarian section are at increased risk of developing celiac disease, while those born via emergent Caesarian section (and may have had contact with the birth canal) are not Inverse relationship between Helicobacter pylori colonization and celiac disease Population-based studies from Sweden have shown that prescription of antibiotics and proton pump inhibitors are each associated with an increased risk of the subsequent development of celiac disease. Lebwohl CGH 2014; Marild Gastroenterology 2012; Lebwohl Am J Epidemiol 2013; Marild BMC Gastroenterol 2013; Dig Liver Dis Luís Fernando de Sousa Moraes et al. Clin. Microbiol. Rev. 2014;27:

6 Pathogenesis of Celiac Disease Case Scenario Host -HLA:DQ2/DQ8 -Non HLA genes Triggers -Wheat -Barley -Rye How common is it? Di Sabatino, Lancet 2009 Cofactors -Intestinal Infections -Infant feeding practices -Socioeconomic factors -Microbiome Celiac Disease Prevalence Celiac Disease Prevalence How common is it? US: 1:100 (range 1:80 to 1:140) Estimated that less than 5% of those with CD in the US are currently diagnosed Green AJG 2007 Country Adults Children Europe % % Germany Great Britain Finland Italy Russia 0.2 NA North and South America % Mexico 2.6 NA USA Asia India NA 1.0 Syria 1.6 NA Africa Algeria NA 5.6 Tunisia Tack, Nature Review Gastro Hep 2012; Mustalahti, Annals Med 2010 Celiac Disease Prevalence Country Adults Children Europe % % Germany Great Britain Finland Italy Russia 0.2 NA North and South America % Mexico 2.6 NA USA Asia India NA 1.0 Syria 1.6 NA Africa Algeria NA 5.6 Tunisia Tack, Nature Review Gastro Hep 2012; Mustalahti, Annals Med 2010 Worldwide Seroprevalence of Celiac Disease Singh CGH

7 Worldwide Biopsy Proven Prevalence CD Celiac Disease Prevalence: New Epidemiology : Saharawi children Highest known prevalence of CD Genetic factors: high frequency of HLA DQ2 Arabic and Berber ancestry Environmental factors: live as refugees in Algeria rates and duration of breast feeding reduced large amount of wheat consumption in early life humanitarian aids from western countries Singh CGH 2017 Cataldo, WJG 2007 Celiac Disease Prevalence: New Epidemiology : Punjab Genetic predisposition Aryan descent with HLApredisposing genes Environmental factors summer diarrhea wheat typical staple food (chapattis, roti) winter maize (makhi roti) 2016 study: >450,000 duodenal biopsy samples taken from people throughout the USA prevalence of villous atrophy calculated for ethnicities using a previously published name based algorithm highest prevalence of villous atrophy: descendants of Punjab area of northern India (3.08% vs 1.80% for other Americans) Cataldo, WJG 2007; Krigel Clin Gastroenterol Hepatol Celiac Disease Prevalence: New Epidemiology Worldwide public health problem Involves all ethnic groups in all the areas of the world where there is great consumption of wheat westernization diet humanitarian interventions Celiac Iceberg The ratio of diagnosed to undiagnosed cases of CD is thought to be highly variable 1 : 2 in Finland 1 : 20 in Argentina, US Most cases undetected US: National Health and Nutrition Examination Survey (considered representative of the US population):, showed that more than >80% of people with coeliac disease were undiagnosed in 2009 decreased to <50% in Cataldo, WJG 2007 WGO Celiac Guidelines 2012; Choung Mayo Clin Proc 2016 Grossman Pract Neurol 2008; 8:

8 Screening for Celiac Disease US Preventive Services Task Force Recommendation Celiac Disease: a systemic disease The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for celiac disease in asymptomatic persons. (I statement) General Growth delay GI Diarrhea, malabsorption Constipation hepatitis Skin: Dermatitis herpetiformis USPSTF JAMA 2017 Rewers, Gastro 2005;128:S Dermatitis Herpetiformis Celiac Disease: a systemic disease Cutaneous manifestation of gluten sensitivity extensor surfaces of the elbows, knees, buttocks, and back pruritic General Growth delay GI Diarrhea, malabsorption Constipation hepatitis Skin: Dermatitis herpetiformis Metabolic bone disease Neurologic Depression, epilepsy, migraine Gluten ataxia Endocrine Type I DM, thyroid disease Cardiovascular Infertility Emedicine.medscape.com Rewers, Gastro 2005;128:S High Risk Populations Relatives: 10% Fe def anemia Asymptomatic: 5% serology, 8.7% biopsy Symptomatic: % Should be considered in any adult with unexplained IDA, including menstruating women Liver Disease: 1.5-9% LFT abnormalities of unknown cause Osteopenia/Osteoporosis 1% and 3.4%. Should be considered in any patient with premature-onset osteoporosis Infertility The pooled relative risk of celiac disease in infertile women compared with controls was 3.7 (95% CI, ). Detection of CD in Primary Care: A multicenter case-finding study in North America Multicenter, prospective study Questionnaire to individuals over 18yo soliciting: Symptoms Diarrhea Abdominal pain, constipation Chronic fatigue Infertility Epilepsy or ataxia Abnormal lab values Anemia LFTs Associated diseases IBS Autoimmune Down s syndrome Turner s syndrome Family h/o celiac disease AGA Technical Review, Gastro 2006 Catassi et al, AJG

9 Detection of CD in Primary Care: A multicenter case-finding study in North America CD: Trends in presentation 38% (976/2568) responded affirmatively 1+ items CD diagnosed in 2.25% (22/2568) Most frequent reason: bloating (12), thyroid disease (11), IBS (7), unexplained chronic diarrhea (6), chronic fatigue (5), constipation (4) Following implementation of active screening fold increase in diagnosis of CD Catassi, AJG 2007 Rampertab AJM 2006 Celiac Disease and IBS: Systematic Review and Meta-analysis Almallouhi JPGN 2017 Irvine et al, AJG 2016 Diagnosis in Elderly Case Scenario Approximately a quarter of all diagnoses are now made at the age of 60 years or more A fifth are made at 65 years or over 4% are diagnosed at 80 years or above. Around 60% remain undetected symptoms subtle: tiredness, indigestion, reduced appetite. Compliance with gluten free diet, resolution of symptoms and improvement in laboratory indices can be achieved in over 90% of patient How do we diagnose it? Collin APT

10 5/1/18 Serology Serology IgA ttg: preferred single test IgA EMA: more time consuming, operator dependent IgA deficiency: 2-3% patients with CD Rashid Can Fam Physician 2016;62:38-43 AGA Technical Review, Gastro 2006; ACG Celiac Guidelines Endoscopy with Biopsy for Diagnosis: Pathological Diagnosis Villous atrophy Crypt hyperplasia Increased intraepithelial lymphocytes: >30-40 per 100 surface enterocytes Endoscopic sings: Decrease in duodenal folds Scalloping of folds Mucosal fissures Nodularity 4-6 biopsies Including duodenal bulb Green et al, Gastro 2005;128:S74-8. Kragnoff, Gastro 2005;128:S10-8. Case Scenario Will I get cancer? Am I going to die from it? Samir at en.wikipedia Dewar et al, Gastro 2005;128:S Kagnoff, Gastro 2005;128:S _Intestine_Mucosa_% %29.jpghttps://commons.wikimedi a.org/wiki/file:celiac_disease_-_high_mag.jpg Mortality in Undiagnosed Celiac Disease Study results variable Ab screen on stored serum samples, matched to mortality data Four studies: no increased mortality (UK, Finland, US elderly) Two studies: SMR (Germany, USA) Biagi, Nat Rev Gastro Hep

11 Mortality Increased risk for all-cause mortality in celiac patients: OR 1.24; 95% CI Mortality Increased risk for NHL in celiac patients: OR 2.61; 95% CI ). Tio APT 2012 Tio APT 2012 Mortality Increased risk for enteropathy associated T cell lymphoma in celiac patients: OR 15.84; 95% CI Mortality No increased risk for any malignancy in celiac patient: OR 1.07; 95% CI ) Tio APT 2012 Tio APT 2012 Mortality in Celiac Disease Dominant cause of death: cardiovascular death: 20% increased risk increased risk of ischemic heart disease, stroke, atrial fibrillation and potentially also autoimmune heart disease malignancy GFD appears protective Adherence: no excess mortality Unlikely to comply: SMR 2x higher Definitely noncompliant: SMR 6x higher SMR correlated to severity of presentation Risk of mortality decreased over time Mortality in Undiagnosed Celiac Disease 9133 healthy young adults at Warren Airforce Base TTG, anti-endomysial ab testing During 45 years of follow-up, undiagnosed CD was associated with a nearly 4- fold increased risk of death. Biagi, Nat Rev Gastro Hep 2010; Ludvigssson Gastrointest Endoscopy Clin N AM Rubio-Tapia et al, Gastro

12 Morbidity in Undiagnosed Celiac Disease Undiagnosed maternal celiac disease á risk of infertility, spontaneous abortions á preterm birth and ceasarean section rates negative effect on intrauterine growth/ birth weight Associated with increased fracture risk Associated with increased risk of lymphoma and small bowel cancer although overall rates are low Case Scenario Oh, I already feel so much better after starting on the diet NICE Celiac Guidelines 2009; ACG Celiac Guidelines Common Pitfalls in Diagnosis of CD Gluten reduced diet may reduce sensitivity of serological screening and the severity of lesion on pathology Negative test in the setting of GFD not conclusive 4-6 week challenge with sufficient gluten ACG: 3g gluten challenge for 2 and then 6 weeks Case Scenario No way am I going back on a gluten diet AGA Technical Review, Gastro 2006; NICE Celiac Guidelines 2009; ACG Celiac Guideline 2013 HLA-DQ2 and DQ8 Sensitivity 100% Absence of these alleles provides a NPV close to 100% Poor specificity Approximately 25% 40% of the general population in the United States carry the HLA class II heterodimer HLA-DQ2 or HLA-DQ8 Necessary but not sufficient for diagnosis of CD AGA Technical Review, Gastro 2006 ACG Guideline Celiac Disease

13 Gluten Free Diet (GFD) GFD Only effective treatment for CD Avoidance of wheat, rye, barley Found in bread, biscuits, cakes, pastries, breakfast cereals, pasta, beer and most soups, sauces (including soy sauce), and puddings Supplements, medications Registered Dietician Green, NEJM 2007; ACG Celiac Guidelines Monitoring Celiac Disease Patients with celiac disease should be evaluated at regular intervals by a health care team including a physician and a dietician. Repeat serologic testing after 3-6 months on a GFD the serologic test results tend to become negative as the histologic findings improve 80% at one year; 99% at 5 years sensitivity for minor dietary indiscretion can be LOW Followed at least annually ACG Guideline Celiac Disease AGA Technical Review, Gastro 2006; ACG Celiac Guidelines Management of Celiac Disease Cardiovascular prevention: Cessation of smoking Treatment of hypertension Treatment of hyperlipidemia Encouraging physical activity Avoiding obesity: Dickey AJG % dx Metabolic bone disease: DEXA Thyroid disease: TSH Hyposlenism: prophylactic pneumococcal vaccination Kelly Gastro 2015 Ludvigsson Gastointest Endoscopy Clin N AM 2012; Lewis ExpRev Gastro Hep

14 Celiac Disease Case 2 Pathophysiology gaps in knowledge Prevalent disease with associated morbidity and mortality Diverse populations Diverse presentations Screening: sensitive and specific serology Treatment is effective, low risk/ high benefit 64yo male with extensive work up for abdominal pain, gas/bloating, negative for celiac disease (negative serology, negative biopsy), but insistent that he cannot tolerate gluten. Non-Celiac Gluten Sensitivity Gluten Goodbye: One-Third Of Americans Say They're Trying To Shun It "Right now 29 percent of the adult population says, 'I'd like to cut back or avoid gluten completely NPR, March by Nancy Shute IBS- like symptoms occurring after the ingestion of gluten Abdominal pain, bloating, diarrhea, flatulence Negative celiac serology, normal histology Ruled out wheat allergy (skin prick, serum IgE) Symptoms disappear after gluten is withdrawn from the diet Symptoms re-present after double blind placebo controlled gluten rechallenge Di Sabatino, J Clin Gastro 2013; Sapone BMC 2012 Non-Celiac Wheat Sensitivity Diagnosed by Double-Blind Placebo-Controlled Challenge: Exploring a New Clinical Entity Non-Celiac Wheat Sensitivity Diagnosed by Double-Blind Placebo-Controlled Challenge: Exploring a New Clinical Entity OBJECTIVES: Non-celiac wheat sensitivity (WS) is considered a new clinical entity. An increasing percentage of the general population avoids gluten ingestion. However, the real existence of this condition is debated and specific markers are lacking. Our aim was thus to demonstrate the existence of WS and define its clinical, serologic, and histological markers. 1/3 Carroccio AJG 2012 Carroccio AJG

15 Double blind placebo controlled trial Non-celiac Wheat Sensitivity 1/3 of IBS patients who underwent DBPC wheat challenge were really suffering from WS. Two groups of patients: 70/920 (7.6%): suffering from WS alone - characterized by clinical features similar to those found in CD patients 206/920 (22.3%): suffering from multiple food sensitivity - characterized by clinical features similar to those found in allergic patients. Corroccio AJG Corroccio AJG 2012 Double blind placebo controlled crossover challenge: 59 subjects Double blind placebo controlled crossover challenge: 59 subjects Wheat: Gluten Fructans Soluble proteins Skodje Gastro 2018 Skodje Gastro 2018 FODMAPs FODMAPs Gastroenterological Society of Australia, Digestive Health Foundation 2013 Staudacher Gut

16 Gluten Free Diet Gluten Free Diet: Deficiencies Difficult: Food availability Food contamination Expensive Canadian study: gluten-free products 242% more expensive Potential nutritional deficiencies fiber iron folate B complex vitamins calcium magnesium vitamin A zinc riboflavin Stevens Can J Diet Pract Res 2008; Cureton Practical Gastro 2007 Shepherd, J H Nutrition & Dietetics 2012 Gluten Free Diet: Deficiencies GFD: Weight Gain fiber iron folate B complex vitamins calcium magnesium vitamin A zinc riboflavin At diagnosis: 90% of the study population were at normal weight or with a body mass index (BMI) > 20 81% of the population gained weight when on the gluten-free diet. Of the study population that was obese, 82% gained more weight *Oats improves the nutrient content of GFD Shepherd, J H Nutrition & Dietetics 2012; ACG Celiac Guidelines Dickey AJG 2006 Heavy Metal Accumulation: National Health and Nutrition Examination Survey 2009 through GFD Blood Avoidance of gluten -> heavy reliance on rice as a staple grain Mercury levels (1.37 mcg/l) compared with persons not on a GFD (0.93 mcg/l) (P =.008) Lead (1.42 vs 1.13 mcg/l; P=.007) Cadmium (0.42 vs 0.34 mcg/l; P=.03) Urine Arsenic (15.15 mcg/l) than urine samples from subjects not on a GFD (8.38 mcg/l) P=.002 Non Celiac Gluten Sensitivity Likely related to fructans in diet non celiac wheat sensitivity GFD is not without harm: weight gain, vitamin/ mineral deficiencies, heavy metal accumulation Diet -> Microbiome Dietician referral for guidance Raehsler CGH

17 5/1/18 Photo courtesy of Dr. Quinny Cheng 17