Celiac disease

diagnostic criteria of celiac disease

1. Diagnostic Criteria of celiac disease Dr. Virendra Kumar Gupta MD Pediatrics,MIAP Fellowship In pediatric Gastroentero-Hepatology & Liver Transplantation Assistant Professor Institute of Paediatric Gastroenterology Nims University Jaipu r  

2. DEFINITION An immune-mediated systemic disorder Elicited by gluten and related prolamines In genetically (mainly HLA) susceptible individuals Characterized by a combination of: gluten dependent clinical manifestations anti-tissue transglutaminase (TG2) antibodies enteropathy Husby et al. JPGN 2012

3. CLINICAL SPECTRUM Symptomatic CD Frank clinical features Silent CD No symptoms but + ve serology and HPE. In most cases identified by serologic screening in at-risk groups Latent CD Normal HPE but before or after have shown Gluten dependent enteropathy Potential CD Normal HPE but Positive serology . It might or might not be symptomatic ESPGHAN Guidelines for Diagnosis of Coeliac Disease

4. PREVALENCE IN CHILDREN BETWEEN 2.5 AND 15 YEARS OF AGE: 3 to 13 per 1000 children or approximately 1 in 300 to 1 in 80 children CDHNF/NASPGHAN guidelines on the Diagnosis and Treatment of Celiac Disease in Children JPGN ©2005; Volume 40, Number 1 (Jan): pages1-19.

5. Increased prevalence of CD in children with • Type 1 diabetes 2–12 % • Autoimmune liver disease 12-13 % • Autoimmune thyroid disease up to 7 % • IgA deficiency 2-8 % • Down’s syndrome 5-12 % • Turner syndrome 2-5 % • Williams’ syndrome up to 9 % • First degree relatives with CD 10-20 % Garampazzi A, Rapa A, Mura S, et al. Clinical pattern of celiac diseaseis still changing. J Pediatr Gastroenterol Nutr 2007;45:611–4.

6. Prevalent, But Under Diagnosed Those not diagnosed have a higher death rate Raise awareness IMPROVE SCREENING

7. Celiac disease as a multiorgan autoimmune disease General: Puberty & growth delay Malignancies Anemia GI system: Diarrhea, vomiting Distension, pain Malnutrition, weight loss Hepatitis, cholangitis Bone: Osteoporosis, fractures Arthritis Dental anomalies Skin & mucosa: Dermatitis herpetiformis Aphtous stomatitis Hair loss Heart: Carditis CNS: Ataxia, seizures Depression Reproductive system: Miscarriage Infertility

8. EVIDENCE-BASED GUIDELINES FOR CD DIAGNOSIS AHRQ (USA, 2004) Adults and children Rostom A, et al.. Celiac Disease. EvidenceReport / Technology Assessment No. 104. AHRQ Publication No. 04-E029-2, 2004 NICE guidelines (UK, 2009) Adults and children For GP’s and general paediatricians NICE Clinical Guidelines 86. Coeliac Disease: Recognition and assessment of coeliac disease. UK, May 2009

9. Guidelines: AHRQ (USA, 2004) Main issues 1. Sensitivity/specificity of serological tests 2. Prevalence / incidence of CD 3. CD associated lymphoma 4. Consequences of testing for CD 5. Interventions for adherence to a gluten free diet Conclusions 1. Sensitivity and specificity of EMA and TG2 are quite high 2. CD common, prevalence in the general population likely close to 1:100 3. Education/participation in coeliac societies improves compliance with a GFD Rostom A, et al.. Celiac Disease. Evidence Report/Technology Assessment No . 104.AHRQ Publication No. 04‐E029‐2, 2004

10. Who Should Be Tested for CD? Group 1: unexplained symptoms and signs chronic or intermittent diarrhoea , failure to thrive, weight loss, stunted growth, delayed puberty, amenorrhoea , iron-deficiency anaemia , nausea or vomiting, chronic abdominal pain, cramping or distension, chronic constipation, chronic fatigue, recurrent aphthous stomatitis (mouth ulcers), dermatitis herpetiformis –like rash, fracture With inadequate traumas/ osteopenia / osteoporosi , and abnormal liver biochemistry. Group 2: Asymptomatic increased risk for CD Type 1 diabetes mellitus (T1DM) Autoimmune thyroid disease Autoimmune liver disease IgA deficiency Down syndrome Turner syndrome Williams syndrome First-degree relatives

11. DIAGNOSTIC TOOLS CD-specific Antibody Tests Histological Analysis of Duodenal Biopsies HLA Testing for HLA-DQ2 and HLA-DQ8

12. ANTIBODIES Anti- tTG /TG2 (tissue transglutaminase ) Anti-EMA ( Endomysial antibody) Anti- DGP ( deamidated Gliadin Peptides) IgA level should be done with EMA/ tTG Anti- Gliadin /Anti- Reticulin

13. SENSITIVITY/SPECIFICITY Test % Sensitivity %   Specificity Age tTG-IgA 90-100 94-100 Children 84-100 91-100 Combined EMA- IgA 87-95 95-100 Adults   88-100 90-100 Children   91-98 99-100 Combined DGP 91 98 Combined Am J Gastroenterol. 2009 Jan;104(1):154-63. 

14. False Positive tTG / Serology Other autoimmune conditions Infections Tumors Tissue damage

15. FALSE NEGATIVE SEROLOGY ( tTG ) Children younger than 2 yr Restricted gluten consumption Severe symptoms On immunosuppressive medications Technical problems

16. HISTOPATHOLOGY Crypt Hyperplasia Crypt to villous ratio is increased Intra-Epithelial Lymphocytosis Abnormal surface epithelium Subtotal to total villous atrophy

17. ENDOSCOPY & BIOPSY Biopsies should be taken preferably during upper endoscopy bulb (at least 1 biopsy) second or third portion of duodenum (at least 4 biopsies)

18. 19 Normal small bowel Celiac disease Gluten Gluten-free diet

19. MARSH Staging

20. Causes of Flat Mucosa (Villous Atrophy) Celiac Disease Giardiasis HIV Enteropathy PEM CMPI Bacterial Overgrowth Primary immunodeficiency Tropical sprue Chemotherapy & irradiation Eosinophilic Gastroenteritis

21. Multiple genes involved The most consistent genetic component depends on the presence of HLA-DQ (DQ2 and/or DQ8) genes One or both of these genes are found in 95% of celiac patients Having one or more of these genes doesn’t mean you will develop celiac, but if you have the disease you likely have the gene. HLA ? ? ? ? Gluten Celiac Disease + Genes Genetics 22

22. HLA TYPING HLA DQ2 and DQ8 Strong negative predictive value Present in > 95 % patients of CD Present in > 30% normal population Weak positive predictive value

23. Diagnosis without biopsy is still not recommended in India & Developing countries Reliable HLA testing and EMA estimation is not widely available Secondly tTG is being done by various labs with different kits and their standardization is doubtful, so >10 times criteria is also difficult to implement.

24. Anti‐TG2 & total IgA * Anti‐TG2 positive Anti‐TG2 negative Paed . GI discusses with family the 2 diagnostic pathways and consequences considering patient’s history & anti‐TG2 titers Consider further diagnostic testing if: IgA deficient Age: < 2 years History: ‐ low gluten intake ‐ drug pretreatment -severe symptoms -associated diseases Positive Anti‐TG2 > 10 x normal EMA & HLA testing for DQ2/DQ8 Positive Anti‐TG2 <10 xnormal OEGD & biopsies Not available Not CD EMA+vHLA +v EMA+v HLA -v EMA-v HLA -v EMA-v HLA +v Marsh 0‐1 Marsh 2 or 3 CD+ GFD & F/u Consider false neg. HLA test Consider biopsies Consider false pos. Anti‐TG2 Unclear case Consider: false pos. serology false neg. biopsy or potential CD Extended evaluation of HLA/serology/biopsies GFD & F/u CD+ Child / Adolescent with Symptoms suggestive of CD *or specific IgG based tests

25. HLA DQ testing (+/‐Anti‐TG2) Consider retesting in intervals or if symptomatic HLA positive for DQ2 and/or DQ8 Anti‐TG2 & total IgA * EMA Not CD, no risk Positive Anti‐TG2 > 3x normal Marsh 2 or 3 CD+ GFD & F/u Consider: Transient / false pos. anti‐TG2 F/u on normal diet with further serological testing Consider: age, false neg. results, exclude IgA deficiency and history of low gluten intake or drugs Asymptomatic Person at Genetic Risk for CD Explain implication of positive test result(s) and get consent for testing HLA negative for DQ2 and/or DQ8 Anti‐TG2 negative Positive Anti‐TG2 < 3x normal Not CD EMA negative EMA positive OEGD & biopsies: 1 x bulbus & 4 x pars descendens , proper histological work up Unclear case F/u on normal diet Consider: false pos. serology, false neg. biopsy or potential CD Marsh 0-‐1 *or specific IgG based tests

26. CELIAC DISEASE Gluten Free Diet Nutritional Education Dietician Periodic assessment of Symptoms, Diet & Serology Serology Abnormal ? Reinforce adherence Symptoms Present ? Evaluate for other causes of symptoms Consider Re- Biopsy FOLLOW UP Yes No Yes No

27. GLUTEN CHALLENGE- When and How ? Performed under special circumstances- Doubt exists about the initial Gluten challenge should be discouraged Before a child is 5 years old During the pubertal growth spurt Gluten challenge always should be performed Under strict medical supervision Preferably by a paediatric gastroenterologist Preceded by HLA testing /assessment of duodenal histology Ensuring that a normal amount of gluten in the diet is ingested IgA anti- tTg antibody should be measured during the challenge period Challenge for practical purposes is considered-Complete after 2 years Follow-up should be continued -relapse may occur at a later time.

28. Why different algorithms for symptomatic and asymptomatic (at risk) patients? 1. False positive or transient TG2 antibody levels more frequent in genetically at risk persons than symptomatic cases 2. TG2 titres with normal histology (Marsh 0) are often of low titre (<3 x upper limit of normal) 3. In asymptomatic patients with low antibody levels there no urgency to perform biopsies compared to symptomatic patients with the same low levels.

29. Treatment GLUTEN FREE DIET (dietician consult) Identification and treatment of nutritional deficiencies Pneumococcal vaccine

30. “A New Hope For CD Sufferers?” New study, no conclusions yet Pills that break down gluten Immunotherapy: training the immune system to tolerate gluten through injections + ?

31. CONCLUSION CD is common IgA tTG -good screening test for CD. ( exceptions < 2 years) A gluten-free diet (GFD) should be introduced only after the completion of the diagnostic process, when a conclusive diagnosis has been made ( expensive and lifelong diet ) .

32. THANKS