Celiac Disease. Samuel Gee (1888) first described Celiac disease in On the Coeliac Affection Gluten sensitive entropathy Non-tropical sprue

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1 Celiac disease Mohammad Rostami Nejad, PhD Head of Celiac disease department Gastroenterology and Liver Diseases Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 Celiac Disease Samuel Gee (1888) first described Celiac disease in On the Coeliac Affection Gluten sensitive entropathy Non-tropical sprue Aretaeus from Cappadocia (now Turkey) described similar malabsorption disorder in second century AD

3 What is Celiac Disease? Chronic autoimmune disease of the small intestine triggered by the ingestion of gluten Causes intestinal inflammation Inflammation leads to damage and atrophy of intestinal villous Impairs absorption of nutrients Contributes to systemic complications Milito T, Muri M, Oakes J, et al. Celiac disease: Early diagnosis leads to the best possible outcome. Journal of the American Academy of Physician Assistants. 2012;25(11):43-47.

4 Cause of celiac disease Willem K Diche recognized association between consumption of bread & relapsing diarrhoea *unconventional, non-cereal foods: Fruits, potatoes, banana, milk or meat After stop, symptoms reappeared

5 Deamidated Gliadin

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8 World Wide Prevalence Europe Prevalence Asia Prevalence Italy 1:106 Iran 1:104 Czech 1:218 Israel 1: 157 Norway 1:262 Syria 1.5:100 Portugal 1:134 Turkey 1:87 Sweden 1:190 Anatolian adults 1:100 Netherlands 1:198 Kuwait (Chronic diarrhea ) 1:18 United Kingdom 1:100 Saudi Arabia (Type1 diabetes) 12:100 Switzerland 1:132 Japan 1:20,000 Spain 1:118

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10 Differential Diagnosis of Celiac Disease Anorexia nervosa Autoimmune enteropathy Bacterial overgrowth Collagenous sprue Crohn's disease Giardiasis Human immunodeficiency virus enteropathy Hypogammaglobulinemia Infective gastroenteritis Intestinal lymphoma Irritable bowel syndrome Ischemic enteritis Lactose intolerance Pancreatic insufficiency Soy protein intolerance Tropical sprue Tuberculosis Whipple's disease Zollinger-Ellison syndrome

11 Signs and Symptoms Typical - Abdominal pain - Chronic diarrhea - Vomiting - Weight loss - Foul smelling stool - Tiredness - Failure to thrive - Delayed puberty - Osteoporosis - Anaemia - Iron deficiency Anaemia Atypical - Abnormal liver function - Neurologic dysfunction - Constipation - Obesity - Dyspepsia - Depression and anxiety - Infertility - Obesity - Dyspepsia - anxiety Up to 38 % Asymptomatic

12 Diagnosis of celiac disease Clinical Presentation Serology Histology Genetic

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14 Presentation at diagnosis >50% without significant diarrhea >10% with overweight 20% diagnosed at birth and after 60 years old Shahbazkhani B, Malekzadeh R, et al. Coeliac disease is the most common cause of chronic diarrhoea in Iran. Eur J Gastroenterol Hepatol Jul;16(7): Pourhoseingholi MA, et al. Underweight in adult celiac patients in the community: is screening program necessary in low weight individuals? J Gastrointestin Liver Dis Dec;18(4):516-7.

15 Presentation of celiac disease in adults Anemia (13%) Diarrhea (36%) Diarrhea Incidental Endoscopy Screening Bone Disease Anemia Other Bone disease (5%) Screening (8%) Incidental at EGD (4%) N = 1499

16 vomiting 14% GI symptoms in Khuzestan province constipation 7% diarrhea 32% abdominal pain 13% bloating 16% reflux 18% diarrhea reflux bloating abdominal pain vomiting constipation Alavinejad P, Hajiani E, Masjedizadeh R, et al. Epidemiologic and demographic survey of celiac disease in Khuzestan province. Middle East J Dig Dis Apr;6(2):

17 Presentation of CD in pediatrics Green PH. Celiac disease in normal-weight and overweight children: clinical features and growth outcomes following a gluten-free diet. J Pediatr Gastroenterol Nutr Nov;53(5):528-31

18 Modes of Presentation by Age 100% n=186 n=78 90% 80% 70% 60% 50% 40% 30% Growth Issues+ Screening Abdominal Pain Diarrhea Anemia Constipation Abdominal Distension Other++ 20% 10% 0% 0-2 Yrs >2-12 Yrs >12 Yrs Green PH. Celiac disease in children: an old disease with new features. Minerva Pediatr Feb;64(1):71-81

19 Who should be tested? Rubio Tapia R et al: Am J Gastro 2013: 108: American Gastroenterology Society Recommendations Consider testing in symptomatic patients at high risk of Autoimmune Hepatitis Premature onset osteoporosis Primary Biliary cirrhosis Unexplained increase in liver transaminases Unexplained iron deficiency anemia Consider testing for CD when following are present: Autoimmune Thyroid disease Cerebellar Ataxia 1 st & 2 nd degree relatives IBS Peripheral neuropathies Selective IgA deficiency Type 1 diabetes Turner & Down syndrome

20 Who should be tested? ESPGHAN Guidelines for Celiac Disease 2012 European Society for pediatric gastroenterology, hepatology and nutrition Group 1 - Children & adolescents with otherwise unexplained symptoms & signs of: Chronic or intermittent diarrhea Failure to thrive / Weight loss/ Stunted growth Delayed puberty / Amenorrhea Iron deficiency anemia Nausea or vomiting Abdominal pain, cramping or distention Chronic fatigue Recurrent aphthous ulcer Group 2 Asymptomatic children & adolescent with Type 1 diabetes Down syndrome Autoimmune thyroid disease Turner syndrome Selective IgA deficiency Autoimmune liver disease First degree relatives of Celiac disease patients

21 Laboratory Diagnosis of Celiac Disease Milestones Before 1960: based on clinical suspicion & biopsy 1982: Anti gliadin; Sensitivity: 70%; Specificity 70% 1985: Endomysial IFA; Sen: 70 90%; Specificity 100% 1997: Anti ttg by ELISA; Sen & Spec: 90 95% 2005: Anti deamidated Gliadin: Sen: 85%, Spec 90%

22 Serologic tests for celiac disease 2014 Tissue transglutaminase antibodies IgA and IgG isotypes [ELISA] Deamidated gliadin antibodies IgA and IgG isotypes [ELISA] Endomysial antobodies IgA isotype only by IFA

23 Serologic diagnostic accuracy Fasano A, Catassi C. Celiac Disease. The New England Journal of Medicine. 2012;367:

24 1. Normal Total IgA ttg IgA < 4 U/ml Equivocal > 10 U/ml CD unlikely HLA DQ2 & DQ8 Negative Deamidated Gliadin IgA & IgG EMA IgA -/- Positive CD unlikely +/+, +/-,-/+ S.I Biopsy

25 2. Undetectable Total IgA Selective IgA deficiency Test for ttg Test for Deamidated Gliadin Both for IgG isotype only If positive advice small intestinal biopsy

26 Endoscopic evaluation Gross Findings Scalloping Fold flattening Fissuring Nodular mucosa NOTE: Absence of visual endoscopic findings does not exclude the disease Setty M, Hormaza L, Guandalini S. Celiac Disease Risk Assessment, Diagnosis, and Monitoring. Molecular Diagnosis & Therapy. 2008;12(5):

27 SMALL BOWEL BIOPSY Required to confirm the diagnosis of celiac disease for most patients. Should also be considered in patients with negative serologic test results who are at high risk or in whom the physician strongly suspects celiac disease. Mucosal changes may vary from partial to total villous atrophy, or may be characterized by subtle crypt lengthening or increased epithelial lymphocytes. To avoid false-negative results on endoscopic biopsy, most authorities recommend obtaining at least four tissue samples, which increases the sensitivity of the test.

28 Marsh 3a

29 When diagnosis still remains uncertain? Asymptomatic individuals with a FH or autoimmune disease Borderline serology/biopsies Discordance between symptoms, serology and biopsies Rostom A, Murry J, Kagnoff M. Medical Position Statement on Celiac Disease. Gastroenterology. 2006;131(6):

30 Utility of HLA genotyping HLA-DQ2 and HLA-DQ8 HLA-DQ2: 90-95% of celiac HLA-DQ8: 5% of celiac High negative predicative value Note: 30-40% of the general population has either HLA DQ2 or DQ8 Rostom A, Murry J, Kagnoff M. Medical Position Statement on Celiac Disease. Gastroenterology. 2006;131(6):

31 Proposed Algorithm for the Differential Diagnosis of Gluten-Related Disorders. Fasano A, Catassi C. N Engl J Med 2012;367:

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34 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. In asymptomatic patients with low antibody levels there no urgency to perform biopsies compared to symptomatic patients with the same low levels.

35 Additional tests that need to be carried out CBC TSH LFT Vitamins: D, A, E, K, Folate, B12 Calcium, Phosphate, Zinc PTH Iron studies Bone Mineral Density Scan

36 Celiac disease overview in Iran

37 Estimation of epidemiology of CD around the world Last Decades 1/6000 Today 1/100 to 1/250 Europe ~ 3 million USA ~ 3 million Iran ~ 700,000 For each known Iranian CD there are 89 undiagnosed patients.

38 Prevalence of CD in Iranian healthy blood donor Healthy populations Prevalence Tehran 1:166 Kerman 1:91 Sari 1:120 Shiraz 1:374 Goulestan 1:100 Sistan and Balouchestan 1:75 Shahbazkhani B, Malekzadeh R, et al. High prevalence of coeliac disease in apparently healthy Iranian blood donors. Eur J Gastroenterol Hepatol May;15(5):475-8.

39 Prevalence of celiac disease among at risk groups in Iran (serological screenings) Disease groups Prevalence (%) Normal population 1 Chronic diarrhea (children) Inflammatory bowel disease 7.8 Autoimmune hepatitis Chronic psychiatric disorders 1.5 Irritable bowel syndrome Short stature Type 1 diabetes mellitus 2.4 hypothyroidism 0.4 Dyspepsia 2.5 Infertility 1.5 Patients with atypical GI symptoms 3.3 Iron deficiency anemia of unknown origin Recurrent aphthous stomatitis 2.84 Behcet's 1.32 Mental retardation 1 Epilepsy 2.7

40 Gastrointestinal and non-gastrointestinal symptoms in different countries GI Diseases or Country (%) Symptoms Iran Italy Romania Abdominal pain 3 (3) 8 (32) 6 (6) Diarrhea 32 (32) 21 (8.4) 8 (8) Constipation 8 (8) 9 (3.6) 1 (1) Weight loss 5 (5) 6 (2.4) 5 (5) IBS 0 (0) 5 (2) 0 Malabsorption 0 4 (1.6) 2 (2) Bloating 11 (11) 1 (0.4) 0 Dyspepsia 3 (3) 36 (14) 0 Gastritis 7 (7) 6 (2.4) 0 Gastrointestinal symptoms Non-Gastrointestinal Signs Country (%) or Symptoms Iran Italy Romania Anemia 55(55) 38(15.2) 1 (1) Dermatitis herpetiformis 3 (3) 4 (1.6) 0 Osteoporosis 2 (2) 10 (4) 0 Osteopenia 25(25) 2 (0.8) 2 (2) Hypertransaminasemia 4 (4) 7 (2.8) 0 Thyroiditis 1 (1) 10 (4) 0 Aphtosis 3 (3) 7 (2.8) 0 Diabetes Mellitus 0 4 (1.6) 2 (2) Food allergy 1 (1) 1 (0.4) 1 (1) IgA deficiency 0 3 (1.2) 0 Neurological symptoms 21(21) 2 (0.8) 0 Menstrual abnormality 14(14) 0 (0.0) 0 Asthenia 0 4 (1.6) 2(2) Failure to thrive 7 (7) 4 (1.6) 0 Low B12/Acid folic 0 3 (1.2) 0 Non-Gastrointestinal symptoms Ehsani-Ardakani MJ, Rostami Nejad M, et al. Gastrointestinal and non-gastrointestinal signs and symptoms in a large cohort of symptomatic patients with CD. Arch Iran Med. 2013; 16(2): 78 82

41 Genetics of Celiac Disease in Iran In this study 97% of CD cases and 58% of controls were carriers of HLADQ2 and/or HLA-DQ8 heterodimers, either in the homozygous or heterozygous state. HLA haplotype frequencies in different ethnicities of Iran M. Rostami Nejad, et al. The frequency of HLA DQ haplotypes in Iranian celiac disease patients. World J Gastroenterol 2014 May 28; 20(20).

42 Guideline and Practice The number of duodenal biopsies taken were inadequate in clinical practices

43 Number of biopsies taken in different countries per 100 cases Country No of Biopsy percent Romania 1 52 Iran 2 56 Lithuania UK 3 65 Italy 4 and more 48.3 Rostami Nejad M, et al. Endoscopy and histological Pitfalls in Celiac disease diagnosis: Assessment of current practice, A Multicentre Study. Rev Esp Enferm Dig 2013;105:

44 Epidemiology of CD in Iran High P Int. P Low P

45 Caution ESPGHAN Guidelines for Celiac Disease 2012 European Society for pediatric gastroenterology, hepatology and nutrition A gluten free diet (GFD) should be introduced only after the completion of the diagnostic process and when a conclusive diagnosis has been made. Healthcare professionals should be advised that starting patients on a GFD, when CD has not been excluded or confirmed, may be detrimental.

46 Management of Celiac Disease C E L I A C Consultation with a skilled dietitian Education about the disease Lifelong adherence to a gluten-free diet Identification and treatment of nutritional deficiencies Access to an advocacy group Continuous long-term follow-up by a multidisciplinary team Milito T, Muri M, Oakes J, et al. Celiac disease: Early diagnosis leads to the best possible outcome. Journal of the American Academy of Physician Assistants. 2012;25(11):43-47.

47 Iranian celiac disease registry: under construction RCGLD, SBMU