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Celiac Management Ragnar Hanas, MD, PhD Dept. of Pediatrics, Uddevalla, Sweden.

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Presentation on theme: "Celiac Management Ragnar Hanas, MD, PhD Dept. of Pediatrics, Uddevalla, Sweden."— Presentation transcript:

1 Celiac Management Ragnar Hanas, MD, PhD Dept. of Pediatrics, Uddevalla, Sweden

2 2R. Hanas, CWD ;02 Why diabetes (type 1) and CD? àCommon genetic background (HLA-marker DQ2, DQ8) ) àBoth 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: Allt från Schober àEarly (< 3 months) introduction of gluten increased risk of developing diabetes 6- to 9-fold. Norris, JM. J Am Med Assoc 2003;290: Ziegler AG. J Am Med Assoc 2003;290: àLate (> 6 months) introduction of gluten is a risk factor for developing antibodies preceding diabetes Wahlberg J. Br J Nutrition 2006;95:

3 3R. Hanas, CWD ;02 Zonulin - keeping things in and out of order in the gut Blood vesselIntestine Endothelialcells Tightjunction Cholerabacteria Zottoxin Diarrhea!! Bacteria are flushed out The zonulin system Blood vesselIntestine Zonulin Diarrhea!! Activated by: Prematurity Any bacteria (even dead!) Toxins (food poisoning) Radiation Chemotherapy Fasano A. Gut 2001;49: % of absorbed proteins are converted to peptides that the immune system will not react to White blood cell

4 4R. Hanas, CWD ;02 Type 1 diabetes Zonulin Zonulin - role in CD and diabetes Gliadin is presented to immune system Gliadin is presented to immune system Susceptible persons produce antibodies Susceptible persons produce antibodies Zonulin Gliadin from gluten Celiac disease ?? is presented to immune system ?? is presented to immune system same persons! same persons! Clemente, MG. Gut 2003;52: Tamara W. PNAS 2005;102: Tolerance? Food allergy? Autoimmune disease?? Gliadin enters lamina propria, is deaminated by tissue transglutamase and recognized by antigen presenting cells in HLA-DQ2/DQ8 individuals (Clemente) Unknown substance Cow´s milk??? (insulin in milk)

5 5R. Hanas, CWD ;02 Zonulin - role in the infant Many substances are presented to immune system Many substances are presented to immune system Tolerance if presented in the right time window, i.e when breast-feeding Tolerance if presented in the right time window, i.e when breast-feeding Ivarsson A. Arch Dis Child 2000;89: Tolerance? Food allergy? Autoimmune disease?? The zonulin system Zonulin Activated by: Prematurity Infancy? 3-6 months?? Cases per 1000 births Coeliac disease in Sweden 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 Food protein

6 6R. Hanas, CWD ;02 How common is celiac disease (CD)? àSymptomatic disease % 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): (Austria) Allt från Schober àChildren with diabetes4.3% Healthy siblings3.8% Healthy children0.69% Healthy adults0.45% Sumnik Z. Eur J Pediatr 2005;164:9-12 (Czech Republic) à491 persons with diabetes: 5.7% antibody positive (AEA) 1420 first-degree relatives: 1.9% 4000 blood donors: 0.25% à491 persons with diabetes: 5.7% antibody positive (AEA) 1420 first-degree relatives: 1.9% 4000 blood donors: 0.25% Not T. Diabetologia 2001;44: (Italy)

7 7R. Hanas, CWD ;02 The CD Iceberg Model àMost cases of CD are undiagnosed UNDIAGNOSED DIAGNOSED Genetic background CD definition Silent disease (relatives) Others ? Disease awareness Diagnostic facilities Gluten intake Gastrointestinal infections Others ? Slide from E Schoeber

8 8R. Hanas, CWD ;02 Onset of celiac disease in first year of life àChronic diarrhoea àFailure to thrive àAbdominal distension Typical symptoms: Height Weight

9 9R. Hanas, CWD ;02 Onset of celiac disease in first year of life àBiopsy from intestinal cell wall lining with Watson´s capsule àPremedication but not general anesthesia Diagnosis: Height Weight

10 10R. Hanas, CWD ;02 Atypical symptoms of celiac disease Secondary to malabsorption àAnaemia due to iron deficiency àShort stature, growth failure àBone loss (osteopenia) àRecurrent abdominal pain àFlatulence àFatty liver

11 11R. Hanas, CWD ;02 Atypical symptoms of celiac disease Independent of malabsorption àDental enamel deficiency àAtaxia (unsteady gait) àAlopecia (localised hair loss) àInfertility àLaboratory abnormalities (transaminases) àRecurrent aphthous stomatitis àEpilepsy (with or without calcifications on CT scan) àPolyneuropahty (peripheral neuronal disease) àHeart problems (dilative cardiomyopathy)

12 12R. Hanas, CWD ;02 CD and other diseases àSkin: Dermatitis herpetiformis àReduced fertility Increased abortion rates Lymfom år, 653 pat. Lymfom år, 653 pat. àMigraine: 4 patients experienced improvements in attacks and CT showed normalization of brain uptake of tracers after diet Gabrielli M. Am J Gastroenterol 2003;98: àNon-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:

13 13R. Hanas, CWD ;02 Celiac disease - the clinical reality Tübingen, Germany: 281 patients, years à18 (6.4%) were positive for EMA, an additional 44 (15.7%) for gliadin antibodies à18 (6.4%) were recommended biopsy à12 accepted biopsy à8 had celiac disease à3 had abdominal symptoms, 2/3 better with diet à3 had iron deficiency anemia, all better with diet àAll had normal height and weight, but for those complying with diet there was an increase in height àHbA1c improved from 8% to 7.3% (p=0.05) Sanchez-Albisua I. Diabet Med 2005;22:

14 14R. Hanas, CWD ;02 Celiac disease - the clinical reality Multicenter, Italy: 4332 patients, years à292 (6.8%) were biopsy confirmed CD àHigher risk in girls (odds ratio ~2) àIn 11%, CD was diagnosed before diabetes àCD was 3 times more common in children 9 years Cerutti F. Diabetes Care 2004;27:

15 15R. Hanas, CWD ;02 How do we suspect CD? àGliadin antibodies in children < 2 years age àTGA (transglutaminase antibodies) is a better test than EMA (endomycial antibodies) in persons > 2 years age ALB rutiner enl. Finkel Y, Hildebrand H. Incitament 2003/2; Slide from E Schoeber

16 16R. Hanas, CWD ;02 Gastroscopic biopsy in children We do most biopsies with the help of a gastroscope

17 17R. Hanas, CWD ;02 Gastroscopic biopsy Normal intestinal lining (mucosa) Celiac disease Lower stomach sphincter (pylorus) Gastro-scope Gullet Stmallintestine

18 18R. Hanas, CWD ;02 A healthy mucosa with villi (fingers) DCCT àThe purpose of the villi is to increase the absorption area of the intestinal mucosa to ~ 200 square meters (~250 square yards)

19 19R. Hanas, CWD ;02 Flat mucosa from patient with celiac disease àWhen the villi are destroyed by celiac antibodies the absorption area decreases to ~ 2 square meters (~2 square yards)

20 20R. Hanas, CWD ;02 The mucosa seen through a microscope NormalCeliac disease

21 21R. Hanas, CWD ;02 Follow-up àGluten-free diet àAntibodies ALB rutiner enl. Finkel Y, Hildebrand H. Incitament 2003/2; àNew 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 > 2 years at diagnosis: No re-biopsy if antibodies disappear on diet and the person is without symptoms

22 22R. Hanas, CWD ;02 HbA1c and insulin requirements in children àDecreased insulin requirements the year before diagnosis and slight increase in HbA1c after GFD Mohn A. JPGN 2001;32: HbA1c Insulin, U/kg 18 CD & 26 controls Slide from E Schoeber

23 23R. Hanas, CWD ;02 Hypoglycemia àIncrease in hypoglycemia 6 months before and up to 6 months after diagnosis Mohn A. JPGN 2001;32: CD & 26 controls Slide from E Schoeber

24 24R. Hanas, CWD ;02 Celiac disease - what happens in the long run? Cork, Ireland: 28-year follow-up of 50 adults with childhood diagnosis of CD (not diabetes) àCD for years àDiet: 50% fully compliant 18% partially compliant 32% not adhering to diet àMotivation: Avoidance of symptoms rather than avoidance of complications àIron deficiency: 86% of women, 21% of males àBone mineral density: Normal in 68% 2.6% osteoporosis àQuality of life scores were normal Sanchez-Albisua I. Diabet Med 2005;22:

25 25R. Hanas, CWD ;02 Long-term health risks in untreated CD àPersons with osteoporosis (and no other disease) have more CD than in the general population. Lindh, E J.Intern.Med.1992;231:403 àReduced bone mineralization in asymptomatic CD patients. Mazure, R Am.J.Gastroenterol 1994;89:2130 àBone density and metabolism normal after long-term GFD in young persons with CD. Mora, S Am.J.Gastroenterol.1999;94:389 ALB rutiner enl. Finkel Y, Hildebrand H. Incitament 2003/2; àNormal mortality in children, twofold increase in overall mortality in adults. Logan, RFA Gastroenterology 1989;97:265. àOnly 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:

26 26R. Hanas, CWD ;02 Cancer risks in untreated CD àThe 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. àTen cases of lymphoma were found in Switzerland, 5 with malabsorption but none had diabetes. Lang-Muritano M. Pediatric Diabetes 2002;3: àCalculated 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.

27 27R. Hanas, CWD ;02 Happy without celiac diet? Switzerland: àClassical celiac disease – 1/1000 àAsymptomatic disease – 1/137 àAlmost 1% of the population has celiac disease??!! Swiss Med Weekly 2002;132:43-47 Slide from T Battelino

28 28R. Hanas, CWD ;02 Risks with the diet? àHigher fat/carbohydrate ratio in GFD which can be difficult for a person with diabetes Am J Clin Nutr 2000;72: àChange in body composition with increased body fat stores Am J Clin Nutr 2000;72: àPoor vitamin status in 50 % of patients on GFD Aliment Pharmacol Ther 2002;16: Slide from T Battelino

29 29R. Hanas, CWD ;02 Can CD be treated with drugs?? àIn diabetes-prone rats, intestinal production of zonulin increased at age 50 days. àThis resulted in a decreased intestinal barrier function àDiabetes antibodies appeared after 2-3 weeks àThis was followed by high blood glucose levels and clinical diabetes àBlocking the zonulin receptor decreased diabetes by 70% in spite of continued high release of zonulin into the intestine. àThe rats that did not get diabetes produced no diabetes antibodies. Watts T. PNAS 2005;102:

30 30R. Hanas, CWD ;02 To screen or not to screen for CD? Yes àMost cases asymptomatic GFD eliminates most symptoms Several health risks if untreated Increased cancer risk over a lifetime if untreated No àDifficult diet that many do not follow strictly anyway Does a GFD really prevent cancer? Our routines àFirst screening 6-12 months after diagnosis àRepeated every 2-3 years and if there are symptoms

31 31R. Hanas, CWD ;02 Celiac disease and diabetes – open questions àWhom to screen? àWhen to screen? àHow often and for how long to screen? àIs a second biopsy necessary, or can we rely on antibody results? àWhat is the natural course of potential or silent CD (positive antibodies, positive biopsy)? àShall patients with latent or potential CD (positive antibodies, negative first biopsy) have repeated biopsies? àHow do we improve acceptance of GFD and compliance to GFD?


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