Troy E Gibbons MD 2 nd Annual Barnstable Brown Diabetes Center Symposium Lexington Ky September 2018 CONFLICT OF INTEREST NOTHING TO DECLARE Objectives Upon completion of this activity participants will be able to ID: 1042273
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1. CELIAC DISEASE:What is this and what is the relation to DiabetesTroy E. Gibbons, M.D.2nd Annual Barnstable Brown Diabetes Center SymposiumLexington, Ky.September 2018
2. CONFLICT OF INTERESTNOTHING TO DECLARE
3. ObjectivesUpon completion of this activity, participants will be able to: Select appropriate diagnostic testing for the evaluation of Celiac Disease in patients with diabetes.
4. WHEAT INDUCED IMMUNE RELATED DISORDERSIN THE U.S APPROX 1:105 IN POPULATION WITHOUT RISK FACTORS MAY HAVE GLUTEN-RELATED DISORDERS*50% OF CALORIES IN INDUSTRAILIZED AND DEVELOPING COUNTRIES COME FROM WHEAT2013 PER CAPITA WHEAT FLOUR CONSUMPTION 132.5 lb. IN THE U.S** LOSS OF WHEAT/GLUTEN TOLERANCE MAY OCCUR AT ANY POINT DUE TO UNKNOWN ENVIRONMENTAL TRIGGERS*****www.ers.usda.gov/topics/crops/wheat/wheats-role-in-the-us-diet.aspx#*Lohi S et al Aliment Pharmacol Ther. 2007;26(9): 1217–1225. ***Catassi C, Kryszak D, et al. Natural history of celiac disease autoimmunity in a USA cohort followed since 1974. Ann Med. 2010; 42(7):530–538.
5. IMMUNOLOGICAL DISEASES RELATED TO WHEAT INGESTIONCELIAC DISEASEWHEAT ALLERGY NON CELIAC GLUTEN SENSITIVITY
6. WHEAT ALLERGY (WA)One of the 8 most common IgE mediated food allergies0.3%-.5% among children*Results in an immediate or delayed type reactionSkin, gut, respiratory typical targetsFood dependent exercise induced anaphylaxis, baker’s asthma*Venter C et al.Prevalence of sensitization reported and objectively assessed food hypersensitivityamongst six-year-old children: a population-basedstudy. Pediatr Allergy Immunol 2006: 17: 356–63.
7. NON CELIAC GLUTEN(WHEAT) SENSITIVITY (NCG(W)S)Most difficult to diagnosis as there are no diagnostic test, defined by clinical symptoms when CD and WA are ruled out by negative testingPrevalence between 3%-6%?No confirmatory tests implies there is a lot of self-diagnosingImmune mediated innate immune responseIntestinal permeability is intact unlike CDVolta U. et al New understanding of gluten sensitivity. Nat Rev Gastroenterol Hepatol 2012; 9: 295–299.Sapone A. et al Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med 2012; 10: 13.
8. CELIAC DISEASE
9. DEFINITIONAn immune mediated disorder of the small intestine that is triggered by gluten exposure in genetically susceptible host. The pathogenesis usually involves increased small intestinal permeability.
10. PREVALANCE OF CDChanged in the last half centuryVaries world wide but averages 1%in the U.S. prevalence is about 1 in 133 (.75%)Average age of diagnosis 45 yrs.Average time to diagnosis 10 to 12 yrs.N.I.H estimates 3 million with CD in U.S. most are undiagnosed
11. WHAT IS GLUTENComplex group of proteins in wheat endosperm (gliadins and glutenins.Related proteins in rye (Secalin) and barley (Hordeins) will trigger inflammation in people with CD.
12. WHAT IS GLUTENThese proteins have repetitive sequences rich in the amino acids proline and glutamine which resist digestion.Undigested peptides Translocate intestine barrier.
13. WHAT IS GLUTENTissues transaminase 2 (TG2) converts glutamine on Peptides with the sequence Gln X X Pro to glutamate.This sequence has high affinity binding to the cell surface proteins of HLA-DQ2 or DQ8This leads to a gluten specific T-cell response
14. GLUTEN RELATED PEPTIDES DE AMIDATED GLUTENTG2HLA-DQ2/8HLA/DEAMINATEDGLUTEN COMPLEXCD4+ T-CELL RESPONSECYTOKINE INDUCED INFLAMMATORY CASCADEVILLOUS ATROPHYINFILTRATION OF INFLAMMATORY CELLSCRYPT HYPERPLASIAGLUTEN RELATED PEPTIDESLUMEN CELL
15. PRESENTAION OF CD
16. PRESENTAION OF CD
17. COMPLICATIONS OF CDMalnutritionGrowth failureExtra intestinal diseaseOsteoporosisInfertility Gastrointestinal malignancy
18. DIAGNOSTIC TOOLS FOR CDCD SPECIFIC ANTIBODY TESTING: IgA ANTIBODIES AGAINST TISSUE TRANGLUTAMINASE (TG2)IgA ANTIBODIES AGAINST ENDOMYSIUM * (AMA) ANTIBODIES AGAINST DEAMIDATED GLIDEN PEPTIDE (DGP)HLA TESTING FOR HLA-DQ2 AND HLA-DQ8ENDOSCOPY/HISTOLOGY Husby S. J.European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. . 2012 Jan;54(1):136-60Endomycium is the reticulin-like connective tissue around the smooth muscle fibers of monkey esophagus
19. DIAGNOSTIC TOOLS FOR CDSEROLOGY TESTING FOR CD:IgA levels should be done.Patient should have recent exposure to gluten.Presence/absence of immunosupressors.IgG results used only when IgA is low. Husby S. J.European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. . 2012 Jan;54(1):136-60Endomycium is the reticulin-like connective tissue around the smooth muscle fibers of monkey esophagus
20. DIAGNOSTIC TOOLS FOR CDHLA TESTING FOR HLA-DQ2 AND HLA-DQ8:90 - 95% of population with CD has this HLA allele 10 – 5% DO NOT!HLA-DQ2 AND HLA-DQ8 are very common in North America and EuropeOnly about 3-4% of population with HAL-DQ2 AND HLA-DQ8 will develop CD. Husby S. J.European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. . 2012 Jan;54(1):136-60
21. PRESENTATIONGROSS APPEARANCENORMAL DOUDENAL MUCOSADOUDENAL MUCOSA WITH CD
22. PESENTATION HISTOLOGYNORMAL DOUDENUMMUCOSA IN CD
23. WHO SHOULD BE TESTED FOR CDGROUP 1: CHILDREN WITH UNEXPLANINED SYMPTOMS/SIGNSGROUP 2: ASYMPTOMINC CHILD WITH INCREASED RISK OF CD Episodic diarrhea FTT Wt. lossGrowth stunting Delayed puberty Iron deficient anemia Chronic abd. pain Cramping or distensionAtypical rashes Fractures with minimal traumaAbnormal LFT Type 1 IDDM Trisomy 21 Turners syn. Autoimmune thyroid disease First degree relative with CD Husby S. J.European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. . 2012 Jan;54(1):136-60
24. THERAPYGluten free dietImproves GI symptoms in weeksHistological responseSerological responseProblemRequires life long adherence
25. ADHERANCE: PROBLEMSGluten is everywhereSome may be sensitive to very small amountsGluten free products may be contaminated unknowinglyIt may be expensive
26. TYPE 1 DIABETES (T1D) AND CELIAC DISEASE (CD)
27. RELATION BETWEEN CD AND T1DNATURE OF ASSOCIATION BETWEEN CD AND TID?PREVALENCE OF CD IN PATIENTS WITH T1D?PREVALENCE OF T1D IN PATIENTS WITH CD?HOW TO MONITOR CD IN T1D?DOES MANAGING CD IMPROVE T1D OUTCOME?
28. WHY THE RELATION BETWEEN T1D AND CD?
29. GENETIC RELATIONSHIPOverlap of susceptibility genes in the HLA class 11 region [ HLA-DRB1, HLA-DQA1, HLA-DQB1] contribute to the coexistence of T1D and CD.HLA-DQ2 [alleles DQA1805 and DQB1*02] and HLA-DQ8 [alleles DQA1*03:01-DQB1*03:02 and HLA-DR4-DQ8] have the strongest genetic risk factors for T1D and CD (MHC class 11 genes**)** Class 1 genes variations on MHC also associated T1D and CD
30. MECHANISMThe trans-membrane glycoproteins may bind peptides from insulin secreting cells or gluten –derived protein. Presentation to the CD4+ T lymphocytes may be atypical and result in a subsequent inflammatory cascade in the islet cells and intestinal epithelial cells.
31. WHAT IS THE ROLE OF ENVIROMENTAL FACTORS?
32. ARE THERE KNOWN TRIGGERS IN THE ENVIRONMENT?Prevalence of T1D and CD has risen significantly in the last half century.Suggest that genetic risk factors are not the primary cause for the increased prevalence
33. ARE THERE KNOWN TRIGGERS IN THE ENVIRONMENT?Understanding/identifying risk factors has the potential to reduce the prevalence of T1D/CD.Large number of studies are ongoing to address relation between environmental factors, CD and T1D
34. Adapted from Verdu EF, Danska JS . Nature Immunologyvolume 19, pages685–695 (2018)
35. ENVIRONMENT : DietFeeding practices or gluten introduction have no influence on T1D risk (BABYDIET 2015).Delayed gluten introduction (12 months or greater) has no effect on the risk of islet autoantibodies [AABs] (BABYDIET).Infection at the time of gluten introduction is not a major risk factor.Delayed introduction of bovine milk did not effect prevalence of TID or increase risk of development of islet cell antibodies or antibodies to TG2. (TRIGR).
36. ENVIRONMENT : Intestinal microbiome/productsC/S delivery did not increase risk of infants developing IABs born to diabetic parents but when T1D does develop it progresses more rapidly (BABYDIAB).There may an association between TID and low gut microbial diversity
37. ENVIRONMENT : InfectionStudies suggests that viral exposure can induce islet autoimmunity.Enteroviral infections may be a risk factor based on epidemiological evidence and observation of enterovirus proteins and RNA in the islet of people with T1D*Op de Beeck et al. Nat. Rev. Endocrinol. 12, 263-273 (2016)
38. IS CD PHENOTYPICALLY THE SAME AS CD/T1D?CD in T1D/CD may be phenotypically less severe than CD alone (Touska a et. al.) T1D/CD may have increase prevalence of other autoimmune diseases (especially Thyroid) compared to CD alone. Tsouka A et. al . JPGN 2015;61: 297-302
39. RELATION BETWEEN CD AND T1DNATURE OF ASSOCIATION BETWEEN CD AND TID?PREVALENCE OF CD IN PATIENTS WITH T1D?PREVALENCE OF T1D IN PATIENTS WITH CD?HOW TO MONITOR CD IN T1D?DOES MANAGING CD IMPROVE T1D OUTCOME?
40. PREVALENCE BETWEEN TID AND CD IN THE GENERAL POPULATION> 26,ooo patients with type T1DBx. confirmed CD 6% world wide (4.8% North America)Heterogeneity was large (1.6% to 12.3%)Prevalence lower in adults with T1D and higher in children with T1DThe underlying prevalence in the general population had no relationship to the prevalence of CD in individuals with T1D in that country. Elfstrom et al. aliment Pharmacol Ther 2014;40: 1123-1132
41. PREVALENCE BETWEEN TID AND CD IN THE GENERAL POPULATIONConclusion: 1 in 20 patients with T1D have biopsy proven CD.
42. PREVALENCE BETWEEN TID AND CD: SCREENING IN CHILDRENPediatric study, 300 participants followed for 5 years.Low prevalence of symptomatic CD at diagnosis (0.7%)Increasing prevalence of silent CD during 5 year follow up to a prevalence of 10%Larsson et al. Ped Diabetes 2008 :9 (part 11): 354-359
43. PREVALENCE BETWEEN TID AND CD: SCREENINGLarsson et al. Ped Diabetes 2008 9 (part 11): 354-359Time between TID and CD (yrs.)
44. PREVALENCE BETWEEN TID AND CD: SCREENINGCONCLUSION:PEDIATRIC PATIENT WITH T1D SHOULD BE SCREENED FOR CD:At the onset of diagnosis.Annually for the first 2 years.Patients with clinical symptoms should be screen regardless.
45. RELATION BETWEEN CD AND T1DNATURE OF ASSOCIATION BETWEEN CD AND TID?PREVALENCE OF CD IN PATIENTS WITH T1D?PREVALENCE OF T1D IN PATIENTS WITH CD?HOW TO MONITOR CD IN T1D?DOES MANAGING CD IMPROVE T1D OUTCOME?
46.
47. Longitudinal retrospective study from 1989 to 20111215 CD cases and 6075 matched referencesLooked at TID and thyroid diseaseNoted:Increased risk of subsequent TID but this was not statistically significant (HR 2.5 [95% CI 0.94-6.66])Canova et al. J Pediatr 2016;174:146-52.
48. CONCLULSIONBe aware of an association of patients with CD who may develop T1D but screening is not necessary
49. RELATION BETWEEN CD AND T1DNATURE OF ASSOCIATION BETWEEN CD AND TID?PREVALENCE BETWEEN T1D AND CD?PREVALENCE BETWEEN CD AND T1D?HOW TO MONITOR CD IN T1D?DOES MANAGING CD IMPROVE T1D OUTCOME?
50. MONITORING RESPONSE TO GLUTEN FREE DIETSEROLOGYDIET EVALUATIONENDOSCOPY WITH BIOPSY
51. MONITORING RESPONSE: SEROLOGY TESTING AND TREATMENT RESPONSE; IS IT GOOD?In adult studies we know:Poor correlation between serology normalization and dietary transgressionsAnti-endomysial markers are poor markers of ongoing mucosal injurySerum IgA TTG class antibodies also poorly correlated with mucosal healing in adultsThe recommendation in adults is assessing mucosal recovery is best done by histological evaluation.* *Haines et al. Aliment. Pharmacol. Ther. 2008;28:1042-66
52. MONITORING RESPONSE: SEROLOGY TESTING AND TREATMENT RESPONSE IN THE CHILD; IS IT GOOD?CD in children however may be phenotypically different. On a gluten free diet most children have mucosal healing in 1 year compared to adults (2 years).Children with autoimmune disease (T1D) more likely to have elevated TTG IgA in the presence of normal mucosa.** Sardy et al. Clin Chim Acta 2007 ; 376 : 126 – 35
53. MONITORING RESPONSE: SEROLOGY TESTING AND TREATMENT RESPONSE; IS IT GOOD?Bannister et al (Australia). Prospective longitudinal study on 150 children (all inclusive). Compared endoscopic mucosal healing at 12 months with TTG IgA and anti-deamidated gliadin peptide [IgG] (DGP) serology. Bannister et al.Am J Gastroenterol 2014; 109:1478–1483;.
54. SEROLOGY TESTING AND TREATMENT RESPONSE; IS IT GOODCONCLUSION:Many positive antibody test in the presence of healed intestinal mucosa suggest weak positive predictive value.Especially so with TTG IgA.Combined negative serology of TTG IgA and DGP very high negative predictive value (98%).
55. MONITORING RESPONSE: VALIDATED DIETARY QUESTIONNAIREDietary evaluation by a highly skilled nutritionist remains the standard to monitor for a gluten free diet. Offering alternatives to gluten containing food that are :PalatableMicronutrient appropriate.
56. MONITORING RESPONSE: VALIDATED DIETARY QUESTIONNAIREIntentional and unintentional gluten exposure is problematic particular in the patient without symptoms of CD. Dietary evaluation will involve:Review of a 3 day diet diaryFood ingredient reviewClinical review
57. RELATION BETWEEN CD AND T1DNATURE OF ASSOCIATION BETWEEN CD AND TID?PREVALENCE OF CD IN PATIENTS WITH T1D?PREVALENCE OF T1D IN PATIENTS WITH CD?HOW TO MONITOR CD IN T1D?DOES MANAGING CD IMPROVE T1D OUTCOME?
58. HOW IMPORTANT IS MANAGING CD IN PATIENTS WITH T1DBoth diseases have long-term serious sequel on their own.Quality of Life (QAL) issues are important. QAL of life studies in adults and pediatrics show reduced QAL if on a GFD and patient was asymptomatic for CDQAL improves if patient was symptomatic for CD.
59. HOW IMPORTANT IS MANAGING CD IN PATIENTS WITH T1DMetabolic controlBone mineralization Microvascular complications
60. HOW IMPORTANT IS MANAGING CD IN PATIENTS WITH T1DMetabolic control:Adults; no difference in HbA1c on GFDPediatrics; equivocal with no change, decrease and even increase* in HbA1C on GFDImpaired bone mineralization:Pediatric and adults may have reduced bone mineral density (BMD) with CD and T1D compared to T1D alone***Sun et al Diabet Med 2009;26 1250-4 ** Diniz-Santos DR et al. Dig Dis Sci 2008;53:1240–5 **Lunt H et al, Diabetes Care 2001;24:791-2
61. HOW IMPORTANT IS MANAGING CD IN PATIENTS WITH T1DMicrovascular complications:Adult; Increased prevalence of renal disease and retinopathy in adults with CD and T1D compared to T1D*Pediatrics; lower protective high density lipoprotein (HDL) in children with CD and T1D compared to T1D***Leeds et al. Diabetic Care . 2011: 34,(2158-2163)** Warncke K et al Pediatric Diabetes 2016: 17:191-198
62. RELATION BETWEEN CD AND T1DNATURE OF ASSOCIATION BETWEEN CD AND TID?PREVALENCE OF CD IN PATIENTS WITH T1D?PREVALENCE OF T1D IN PATIENTS WITH CD?HOW TO MONITOR CD IN T1D?DOES MANAGING CD IMPROVE T1D OUTCOME?
63. ENDEND