Ragnar Hanas, MD, PhD Dept. of Pediatrics, Uddevalla, Sweden Celiac Management Ragnar Hanas, MD, PhD Dept. of Pediatrics, Uddevalla, Sweden CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Why diabetes (type 1) and CD? Allt från Schober Common genetic background (HLA-marker DQ2, DQ8)) Both have increased gut permeability (caused by a protein modulator called zonulin), present even in pre-diabetes (70%), several years before onset (in average 3.5 years). Sapone A. Diabetes 2006;55:1443-49. Early (< 3 months) introduction of gluten increased risk of developing diabetes 6- to 9-fold. Norris, JM. J Am Med Assoc 2003;290:1713-20. Ziegler AG. J Am Med Assoc 2003;290:1721-28. Late (> 6 months) introduction of gluten is a risk factor for developing antibodies preceding diabetes Wahlberg J. Br J Nutrition 2006;95:603-08. 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Zonulin - keeping things in and out of order in the gut Endothelial cells The zonulin system Blood vessel Intestine Zonulin Cholera bacteria 90% of absorbed proteins are converted to peptides that the immune system will not react to Zot toxin Activated by: Prematurity Any bacteria (even dead!) Toxins (food poisoning) Radiation Chemotherapy Tight junction White blood cell Blood vessel Intestine Diarrhea!! ➠ Bacteria are flushed out Diarrhea!! 22;02 Fasano A. Gut 2001;49:159-62. CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Zonulin - role in CD and diabetes Celiac disease Type 1 diabetes Zonulin Unknown substance Cow´s milk??? (insulin in milk) Gliadin from gluten Gliadin enters lamina propria, is deaminated by tissue transglutamase and recognized by antigen presenting cells in HLA-DQ2/DQ8 individuals (Clemente) ➠ Gliadin is presented to immune system ➠ Susceptible persons produce antibodies ➠ ?? is presented to immune system ➠ same persons! Zonulin Tolerance? Food allergy? Autoimmune disease?? 22;02 Clemente, MG. Gut 2003;52:218-23. Tamara W. PNAS 2005;102:2916-21. CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Zonulin - role in the infant 1975 1980 1985 1990 1995 Cases per 1000 births Coeliac disease in Sweden 6 5 4 3 2 1 The zonulin system Food protein Zonulin Official diet recommendations: Before 1982: Gluten from ~ 4 months, no strict rules 1982: Gluten from 6 months 1996: Gluten from 4 months, breast-feeding until 6 months Activated by: Prematurity Infancy? 3-6 months?? Tolerance? Food allergy? Autoimmune disease?? ➠ Many substances are presented to immune system ➠ Tolerance if presented in the right time window, i.e when breast-feeding 22;02 Ivarsson A. Arch Dis Child 2000;89:165-71. CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

How common is celiac disease (CD)? Allt från Schober Symptomatic disease 0.1-0.29% in non-diabetes, 1-6.4% in persons with type 1 diabetes = 2-10 times the risk Schober E, Horm Res 2002;57(suppl 1):97-100. (Austria) 491 persons with diabetes: 5.7% antibody positive (AEA) 1420 first-degree relatives: 1.9% 4000 blood donors: 0.25% Not T. Diabetologia 2001;44:151-5. (Italy) Children with diabetes 4.3% Healthy siblings 3.8% Healthy children 0.69% Healthy adults 0.45% Sumnik Z. Eur J Pediatr 2005;164:9-12 (Czech Republic) 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

The CD Iceberg Model DIAGNOSED Disease awareness Genetic background Diagnostic facilities Gluten intake Gastrointestinal infections Others ? Genetic background CD definition Silent disease (relatives) Others ? UNDIAGNOSED Most cases of CD are undiagnosed 22;02 Slide from E Schoeber CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Onset of celiac disease in first year of life Chronic diarrhoea à Failure to thrive à Abdominal distension Typical symptoms: Height Weight 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Onset of celiac disease in first year of life Height Weight Diagnosis: Biopsy from intestinal cell wall lining with Watson´s capsule Premedication but not general anesthesia 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Atypical symptoms of celiac disease Secondary to malabsorption Anaemia due to iron deficiency Short stature, growth failure Bone loss (osteopenia) Recurrent abdominal pain Flatulence Fatty liver 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Atypical symptoms of celiac disease Independent of malabsorption Dental enamel deficiency Ataxia (unsteady gait) Alopecia (localised hair loss) Infertility Laboratory abnormalities (transaminases) Recurrent aphthous stomatitis Epilepsy (with or without calcifications on CT scan) Polyneuropahty (peripheral neuronal disease) Heart problems (dilative cardiomyopathy) 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

CD and other diseases Skin: Dermatitis herpetiformis Reduced fertility Increased abortion rates Lymfom 20-92 år, 653 pat. Migraine: 4 patients experienced improvements in attacks and CT showed normalization of brain uptake of tracers after diet Gabrielli M. Am J Gastroenterol 2003;98:625-9. Non-Hodgkin lymphoma (in persons > 20 years of age): 0.92 % of patients with lymphoma had CD 0.42 % of patients in control group had CD Catassi C. JAMA 2002;287:1413-19. 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Celiac disease - the clinical reality Tübingen, Germany: 281 patients, 1.4-25 years 18 (6.4%) were positive for EMA, an additional 44 (15.7%) for gliadin antibodies 18 (6.4%) were recommended biopsy 12 accepted biopsy 8 had celiac disease 3 had abdominal symptoms, 2/3 better with diet 3 had iron deficiency anemia, all better with diet All had normal height and weight, but for those complying with diet there was an increase in height HbA1c improved from 8% to 7.3% (p=0.05) 22;02 Sanchez-Albisua I. Diabet Med 2005;22:1079-82.. CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Celiac disease - the clinical reality Multicenter, Italy: 4332 patients, 1.4-25 years 292 (6.8%) were biopsy confirmed CD Higher risk in girls (odds ratio ~2) In 11%, CD was diagnosed before diabetes CD was 3 times more common in children < 4 years age, compared to > 9 years 22;02 Cerutti F. Diabetes Care 2004;27:1294-8. CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

How do we suspect CD? Gliadin antibodies in children < 2 years age ALB rutiner enl. Finkel Y, Hildebrand H. Incitament 2003/2;143-145 Gliadin antibodies in children < 2 years age TGA (transglutaminase antibodies) is a better test than EMA (endomycial antibodies) in persons > 2 years age 22;02 Slide from E Schoeber CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Gastroscopic biopsy in children We do most biopsies with the help of a gastroscope 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Gastroscopic biopsy Gullet Gastro- scope Lower stomach sphincter (pylorus) Stmall intestine Normal intestinal lining (mucosa) Celiac disease 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

A healthy mucosa with villi (“fingers”) DCCT à The purpose of the villi is to increase the absorption area of the intestinal mucosa to ~ 200 square meters (~250 square yards) 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Flat mucosa from patient with celiac disease à When the villi are destroyed by celiac antibodies the absorption area decreases to ~ 2 square meters (~2 square yards) 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

The mucosa seen through a microscope Normal Celiac disease 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Follow-up Gluten-free diet Antibodies ALB rutiner enl. Finkel Y, Hildebrand H. Incitament 2003/2;143-145 Gluten-free diet Antibodies New biopsy: < 2 years at diagnosis: # 2 after 1 year of gluten-free diet # 3 after provocation with gluten-containing diet > 2 years at diagnosis: No re-biopsy if antibodies disappear on diet and the person is without symptoms 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

HbA1c and insulin requirements in children 18 CD & 26 controls HbA1c Insulin, U/kg Decreased insulin requirements the year before diagnosis and slight increase in HbA1c after GFD Mohn A. JPGN 2001;32:37-40. 22;02 Slide from E Schoeber CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Hypoglycemia 18 CD & 26 controls Increase in hypoglycemia 6 months before and up to 6 months after diagnosis Mohn A. JPGN 2001;32:37-40. 22;02 Slide from E Schoeber CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Celiac disease - what happens in the long run? Cork, Ireland: 28-year follow-up of 50 adults with childhood diagnosis of CD (not diabetes) CD for 22-45 years Diet: 50% fully compliant 18% partially compliant 32% not adhering to diet Motivation: Avoidance of symptoms rather than avoidance of complications Iron deficiency: 86% of women, 21% of males Bone mineral density: Normal in 68% 2.6% osteoporosis Quality of life scores were normal 22;02 Sanchez-Albisua I. Diabet Med 2005;22:1079-82.. CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Long-term health risks in untreated CD Normal mortality in children, twofold increase in overall mortality in adults. Logan, RFA Gastroenterology 1989;97:265. ALB rutiner enl. Finkel Y, Hildebrand H. Incitament 2003/2;143-145 Persons with osteoporosis (and no other disease) have more CD than in the general population. Lindh, E J.Intern.Med.1992;231:403 Reduced bone mineralization in asymptomatic CD patients. Mazure, R Am.J.Gastroenterol 1994;89:2130 Bone density and metabolism normal after long-term GFD in young persons with CD. Mora, S Am.J.Gastroenterol.1999;94:389 Only 30% of children and adolescents complied with a strict gluten-free diet, but growth parameters were unaffected by dietary compliance. Westman E. JPEM 1999;12:433-42. 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Cancer risks in untreated CD The risk of developing cancer is not increased when compared with the general population in celiac patients who have taken a GFD for five years or more. Holmes, GKT. Gut 1989;30:333. Ten cases of lymphoma were found in Switzerland, 5 with malabsorption but none had diabetes. Lang-Muritano M. Pediatric Diabetes 2002;3:42-45. Calculated risk: 1/8,000 persons with diabetes will get lymphoma over 60 years – do these have untreated CD? Lang-Muritano M. Pediatric Diabetes 2002;3:42-45. 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Happy without celiac diet? Switzerland: Classical celiac disease – 1/1000 à ”Asymptomatic disease” – 1/137 à Almost 1% of the population has celiac disease??!! Swiss Med Weekly 2002;132:43-47 22;02 Slide from T Battelino CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Risks with the diet? Higher fat/carbohydrate ratio in GFD which can be difficult for a person with diabetes Am J Clin Nutr 2000;72:76-81. à Change in body composition with increased body fat stores Am J Clin Nutr 2000;72:76-81. à Poor vitamin status in 50 % of patients on GFD Aliment Pharmacol Ther 2002;16:1333-9. 22;02 Slide from T Battelino CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Can CD be treated with drugs?? In diabetes-prone rats, intestinal production of zonulin increased at age 50 days. This resulted in a decreased intestinal barrier function Diabetes antibodies appeared after 2-3 weeks This was followed by high blood glucose levels and clinical diabetes Blocking the zonulin receptor decreased diabetes by 70% in spite of continued high release of zonulin into the intestine. à The rats that did not get diabetes produced no diabetes antibodies. 22;02 Watts T. PNAS 2005;102:2916-21. CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

To screen or not to screen for CD? Yes Most cases asymptomatic GFD eliminates most symptoms Several health risks if untreated Increased cancer risk over a lifetime if untreated No Difficult diet that many do not follow strictly anyway Does a GFD really prevent cancer? Our routines First screening 6-12 months after diagnosis Repeated every 2-3 years and if there are symptoms 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden

Celiac disease and diabetes – open questions Whom to screen? When to screen? How often and for how long to screen? Is a second biopsy necessary, or can we rely on antibody results? What is the natural course of potential or silent CD (positive antibodies, positive biopsy)? Shall patients with latent or potential CD (positive antibodies, negative first biopsy) have repeated biopsies? How do we improve acceptance of GFD and compliance to GFD? 22;02 CWD, Orlando 2006. R Hanas, Dept of Pediatrics, Uddevalla Hospital, Sweden