Celiac Management. Ragnar Hanas, MD, PhD Dept. of Pediatrics, Uddevalla, Sweden. Why diabetes (type 1) and CD?. Allt från Schober. Common genetic backgroun d (HLA-marker DQ2, DQ8) )
Celiac Management Ragnar Hanas, MD, PhDDept. of Pediatrics, Uddevalla, 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 diabetesWahlberg J. Br J Nutrition 2006;95:603-08.
The zonulin system Cholera bacteria Zonulin Zot toxin 90% of absorbed proteins are converted to peptides that the immune system will not react to Tight junction White blood cell Blood vessel Intestine Diarrhea!!➠ Bacteria are flushed out Diarrhea!! Zonulin - keeping things in and out of order in the gut Endothelial cells Activated by:PrematurityAny bacteria(even dead!) Toxins (food poisoning)Radiation Chemotherapy Blood vessel Intestine Fasano A. Gut 2001;49:159-62.
Type 1 diabetes Unknown substanceCow´s milk???(insulin inmilk) Gliadin from gluten Zonulin ➠Gliadin is presented to immune system ➠ Susceptible persons produce antibodies ➠?? is presented to immune system ➠ same persons! Zonulin - role in CD and diabetes Celiac disease Gliadin enters lamina propria, is deaminated by tissue transglutamase and recognized by antigen presenting cells in HLA-DQ2/DQ8 individuals (Clemente) Zonulin Tolerance? Food allergy? Autoimmunedisease?? Clemente, MG. Gut 2003;52:218-23. Tamara W. PNAS 2005;102:2916-21.
Coeliac disease in Sweden Cases per 1000 births 654321 Zonulin 1975 1980 1985 1990 1995 Official diet recommendations: Before 1982: Gluten from ~ 4 months, no strict rules1982: Gluten from 6 months1996: Gluten from 4 months, breast-feeding until 6 months Zonulin - role in the infant The zonulin system Food protein Activated by:PrematurityInfancy? 3-6 months?? Tolerance? Food allergy? Autoimmunedisease?? ➠Many substances are presented to immune system ➠ Tolerance if presented in the right time window, i.e when breast-feeding Ivarsson A. Arch Dis Child 2000;89:165-71.
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 riskSchober 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)
The CD Iceberg Model DIAGNOSED Disease awareness Diagnostic facilities Gluten intake Gastrointestinal infections Others ? Genetic background CD definition Silent disease(relatives) Others ? UNDIAGNOSED • Most cases of CD are undiagnosed Slide from E Schoeber
Typical symptoms: • Chronic diarrhoea à Failure to thrive à Abdominal distension Onset of celiac disease in first year of life Height Weight
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
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
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)
CD and other diseases • Skin: Dermatitis herpetiformis • Reduced fertilityIncreased 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 dietGabrielli M. Am J Gastroenterol 2003;98:625-9. • Non-Hodgkin lymphoma (in persons > 20 years of age):0.92 % of patients with lymphoma had CD0.42 % of patients in control group had CDCatassi C. JAMA 2002;287:1413-19.
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) Sanchez-Albisua I. Diabet Med 2005;22:1079-82..
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 Cerutti F. Diabetes Care 2004;27:1294-8.
How do we suspect CD? 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 Slide from E Schoeber
Gastroscopic biopsy in children We do most biopsies with the help of a gastroscope
Normal intestinal lining(mucosa) Lower stomach sphincter(pylorus) Celiac disease Gastroscopic biopsy Gullet Gastro- scope Stmall intestine
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)
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)
The mucosa seen through a microscope Normal Celiac disease
Follow-up 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 disappearon diet and the person is without symptoms
HbA1c Insulin, U/kg HbA1c and insulin requirements in children 18 CD & 26 controls • Decreased insulin requirements the year before diagnosis and slight increase in HbA1c after GFD Mohn A. JPGN 2001;32:37-40. Slide from E Schoeber
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. Slide from E Schoeber
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 Sanchez-Albisua I. Diabet Med 2005;22:1079-82..
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 withosteoporosis (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.
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.
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 Slide from T Battelino
Risks with the diet? • Higher fat/carbohydrate ratio in GFD which can be difficult for a person with diabetesAm J Clin Nutr 2000;72:76-81. à Change in body composition with increased body fat storesAm J Clin Nutr 2000;72:76-81. à Poor vitamin status in 50 % of patients on GFDAliment Pharmacol Ther 2002;16:1333-9. Slide from T Battelino
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 receptordecreased 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. Watts T. PNAS 2005;102:2916-21.
To screen or not to screen for CD? Yes • Most cases asymptomaticGFD eliminates most symptomsSeveral health risks if untreatedIncreased cancer risk over a lifetime if untreated No • Difficult diet that many do not follow strictly anywayDoes a GFD really prevent cancer? Our routines • First screening 6-12 months after diagnosis • Repeated every 2-3 years and if there are symptoms
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?