Title: Should all children be screened for celiac disease?
Abstract: To address the issue of screening children for celiac disease, current evidence has been summarized and placed within the context of 8 established criteria for childhood screening. Screening all children for celiac disease is not recommended at this time. Areas with gaps in knowledge are identified as areas in need of further study. These include the timing of screening, defining the natural history of screening-identified celiac disease, developing tools to predict disease onset and disease remission, and the risks of screening. To address the issue of screening children for celiac disease, current evidence has been summarized and placed within the context of 8 established criteria for childhood screening. Screening all children for celiac disease is not recommended at this time. Areas with gaps in knowledge are identified as areas in need of further study. These include the timing of screening, defining the natural history of screening-identified celiac disease, developing tools to predict disease onset and disease remission, and the risks of screening. The development of accurate serologic markers provides a tool for evaluating at-risk groups, as well as whole populations, for autoantibodies related to celiac disease (CD). The majority of those individuals who express CD-related autoantibodies consider themselves healthy and do not seek medical attention. These individuals are identifiable only by screening. Many will have small bowel biopsy histologic changes typical of CD. The possibility of conducting widespread screening raises the question of whether all children should be screened for CD.1Catassi C. Fabiani E. Ratsch I.M. Coppa G.V. Giorgi P.L. Celiac disease in the general population should we treat asymptomatic cases?.J Pediatr Gastroenterol Nutr. 1997; 24: S10-S13Crossref PubMed Google Scholar, 2Freemark M. Levitsky L.L. Screening for celiac disease in children with type 1 diabetes two views of the controversy.Diabetes Care. 2003; 26: 1932-1939Crossref PubMed Scopus (102) Google Scholar However, the benefits, risks, and costs merit careful consideration before deciding on the wisdom of widespread screening. Guides published 30 to 40 years ago provide a relevant framework adaptable to today's issue of screening children for CD.3Wilson J.M. Jungner Y.G. Principles and practice of screening for disease. WHO, Geneva1968: 34Google Scholar, 4Frankenburg W.K. Selection of diseases and tests in pediatric screening.Pediatrics. 1974; 54: 612-616PubMed Google Scholar Wilson and Jungner discussed population-based screening, primarily for diseases of adults, such as hypertension and diabetes.3Wilson J.M. Jungner Y.G. Principles and practice of screening for disease. WHO, Geneva1968: 34Google Scholar Their approach was modified for screening in childhood by Frankenburg.4Frankenburg W.K. Selection of diseases and tests in pediatric screening.Pediatrics. 1974; 54: 612-616PubMed Google Scholar Adapting from these sources, 8 criteria needing fulfillment to consider screening for CD will be addressed (Table 1).Table 1Criteria for Screening Children for CD1. Important health problem: prevalence, serious2. Diagnostic criteria accepted3. Screening tests available and acceptable to the public4. Natural history understood, with advantage to earlier treatment and agreement on who needs treatment and when5. Treatment accepted and available6. Cost-benefit favorable7. Repeat testing needs clear8. Predictors of response to treatmentAdapted from Wilson and Jungner3Wilson J.M. Jungner Y.G. Principles and practice of screening for disease. WHO, Geneva1968: 34Google Scholar and Frankenburg.4Frankenburg W.K. Selection of diseases and tests in pediatric screening.Pediatrics. 1974; 54: 612-616PubMed Google Scholar Open table in a new tab Adapted from Wilson and Jungner3Wilson J.M. Jungner Y.G. Principles and practice of screening for disease. WHO, Geneva1968: 34Google Scholar and Frankenburg.4Frankenburg W.K. Selection of diseases and tests in pediatric screening.Pediatrics. 1974; 54: 612-616PubMed Google Scholar A number of studies have assessed the prevalence of CD in Western Europe and, more recently, in the United States, and new information is forthcoming from developing countries and other parts of the world. These studies are generally of 2 types: most are cross-sectional studies of villages,5Maki M. Mustalahti K. Kokkonen J. Kulmala P. Haapalahti M. Karttunen T. Ilonen J. Laurila K. Dahlbom I. Hansson T. Hopfl P. Knip M. Prevalence of celiac disease among children in Finland.N Engl J Med. 2003; 348: 2517-2524Crossref PubMed Scopus (853) Google Scholar schools,6Catassi C. Ratsch I.M. Fabiani E. Rossini M. Bordicchia F. Candela F. Coppa G.V. Giorgi P.L. 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Celiac disease risk in USA high prevalence of antiendomyseum antibodies in healthy blood donors.Scand J Gastroenterol. 1998; 33: 494-498Crossref PubMed Scopus (359) Google Scholar A few are population-based prospective studies; 1 study from Denver has been published,15Hoffenberg E.J. MacKenzie T. Barriga K.J. Eisenbarth G.S. Bao F. Haas J.E. Erlich H. Bugawan T.L.T. Sokol R.J. Taki I. Norris J.M. Rewers M. A prospective study of the incidence of childhood celiac disease.J Pediatr. 2003; 143: 308-314Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar and 1 study from Leeds, the United Kingdom, was presented in April 2004.16Bigley P. Williams A. Norcross A. Unsworth D.J. Lock R.J. Ness A. Jones R. Team A.S. Undetected coeliac disease at age seven. 2004; (11th International Symposium on Coeliac Disease, Belfast, Northern Ireland. April; PT1): 28-30Google Scholar The results of these studies show remarkably consistent results, suggesting that the frequency of CD in Western populations is in the range of 1:50 to 1:300 (0.3% to 2%). In one prospective study, seropositivity was detected only after approximately 3 years of age.15Hoffenberg E.J. MacKenzie T. Barriga K.J. Eisenbarth G.S. Bao F. Haas J.E. Erlich H. Bugawan T.L.T. Sokol R.J. Taki I. Norris J.M. Rewers M. A prospective study of the incidence of childhood celiac disease.J Pediatr. 2003; 143: 308-314Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar In addition to general population studies, risk groups have also been evaluated. Table 2 shows the frequency of CD in a number of these groups.Table 2Estimated Frequency of CD in Selected High-Risk GroupsGeneral population0.3%–2%Type 1 diabetes∼4%17Aktay A.N. Lee P.C. Kumar V. Parton E. Wyatt D.T. Werlin S.L. 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Bredberg A. Alm J. Aronsson S. Gustafsson J. Hagenas L. Hager A. Kristrom B. Marcus C. Moell C. Nilsson K.O. Tuvemo T. Westphal O. Albertsson-Wikland K. Aman J. Prevalence of coeliac disease in Turner syndrome.Acta Paediatr. 1999; 88: 933-936Crossref PubMed Google ScholarIgA deficiency∼2%50Meini A. Pillan N.M. Villanacci V. Monafo V. Ugazio A.G. Plebani A. Prevalence and diagnosis of celiac disease in IgA-deficient children.Ann Allergy Asthma Immunol. 1996; 77: 333-336Abstract Full Text PDF PubMed Scopus (116) Google ScholarNOTE. Superscript numbers identify reference sources. Open table in a new tab NOTE. Superscript numbers identify reference sources. The majority of childhood cases, as in adulthood, are identifiable only on screening because most have no or mild symptoms. If present, symptoms are not specific, and parents usually do not view seropositive children as ill enough to seek medical attention.51Hoffenberg E. Emery L. Barriga K. Bao F. Eisenbarth G. Haas J. Sokol R. Taki I. Norris J. Taylor J. Rewers M. Clinical features of children with screening-identified evidence of celiac disease.Pediatrics. 2004; 113: 1254-1259Crossref PubMed Scopus (72) Google Scholar Some children do have significant disease and seek medical attention. At our institution, 1 or 2 children each year require hospitalization for initial diagnosis and treatment of CD. There is good evidence for a variety of manifestations of CD in children, mostly related to malabsorption (abdominal pain, diarrhea, failure to thrive, abdominal distention, irritability, growth and pubertal delay, nutritional deficiencies) but also decreased bone mineralization and dermatitis herpetiformis.52Hill I.D. Dirks M. Liptak G. Colletti R.B. Fasano A. Guandalini S. Hoffenberg E.J. Horvath K. Murray J.A. Pivor M. Seidman E. Guideline for the diagnosis and treatment of celiac disease in children recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.J Pediatr Gastroenterol Nutr. 2005; 40: 1-19Crossref PubMed Scopus (1019) Google Scholar There are no studies assessing the burden to society of pediatric CD in the United States. In considering how serious CD is in childhood, its impact on associated conditions should be assessed to determine whether early detection and treatment of CD affects outcome of the associated conditions. Because approximately 4% of children with type 1 diabetes have CD, if untreated, it may potentially cause erratic glucose absorption and consequently increase the risk for hypoglycemia episodes.2Freemark M. Levitsky L.L. Screening for celiac disease in children with type 1 diabetes two views of the controversy.Diabetes Care. 2003; 26: 1932-1939Crossref PubMed Scopus (102) Google Scholar, 53Iafusco D. Rea F. Prisco F. Hypoglycemia and reduction of the insulin requirement as a sign of celiac disease in children with IDDM.Diabetes Care. 1998; 21: 1379-1381Crossref PubMed Scopus (52) Google Scholar, 54Mohn A. Cerruto M. Lafusco D. Prisco F. Tumini S. Stoppoloni O. Chiarelli F. Celiac disease in children and adolescents with type I diabetes importance of hypoglycemia.J Pediatr Gastroenterol Nutr. 2001; 32: 37-40Crossref PubMed Scopus (121) Google Scholar Similarly, in genetic disorders such as Trisomy 21, Williams and Turner syndromes, short stature, vomiting, abdominal distention, constipation, diarrhea, and other problems might be related to unrecognized CD.43Book L. Hart A. Black J. Feolo M. Zone J.J. Neuhausen S.L. Prevalence and clinical characteristics of celiac disease in Down's syndrome in a US study.Am J Med Genet. 2001; 98: 70-74Crossref PubMed Scopus (98) Google Scholar Based on these considerations, many centers caring for children with these disorders routinely screen for CD at least once. However, there are few studies evaluating the impact of CD on diabetes or on associated genetic disorders.44Carnicer J. Farre C. Varea V. Vilar P. Moreno J. Artigas J. Prevalence of coeliac disease in Down's syndrome.Eur J Gastroenterol Hepatol. 2001; 13: 263-267Crossref PubMed Scopus (66) Google Scholar, 45Csizmadia C.G. Mearin M.L. Oren A. Kromhout A. Crusius J.B. von Blomberg B.M. Pena A.S. Wiggers M.N. Vandenbroucke J.P. Accuracy and cost-effectiveness of a new strategy to screen for celiac disease in children with Down syndrome.J Pediatr. 2000; 137: 756-761Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar These studies are small and underpowered and provide conflicting preliminary conclusions. The following conclusions summarize current knowledge on whether pediatric CD is an important health problem and how prevalent and serious it might be: (1) There are consistent data on the frequency of CD in general populations (0.3%–2%) and in risk groups; (2) CD autoimmunity develops in childhood; (3) high-risk groups currently undergo screening for CD; (4) in majority of children, CD is associated with absent or mild clinical features; (5) screening before age 3 years does not seem warranted. In 1990, revised criteria (the ESPGN criteria) for the clinical diagnosis of CD summarized evidence that the diagnosis could be made accurately in children with a clinical suspicion of CD when a single small bowel biopsy showed characteristic changes of villous atrophy, and treatment with a gluten-free diet led to improvement in either symptoms or intestinal morphology on repeat biopsy.55Revised criteria for diagnosis of coeliac disease. Report of Working Group of European Society of Paediatric Gastroenterology and Nutrition.Arch Dis Child. 1990; 65: 909-911Crossref PubMed Scopus (1824) Google Scholar Although widely accepted and useful, these criteria have limitations. First, intestinal biopsy changes may be patchy, and are subject to variable orientation and interpretation.56Bonamico M. Mariani P. Thanasi E. Ferri M. Nenna R. Tiberti C. Mora B. Mazzilli M.C. Magliocca F.M. Patchy villous atrophy of the duodenum in childhood celiac disease.J Pediatr Gastroenterol Nutr. 2004; 38: 204-207Crossref PubMed Scopus (166) Google Scholar Second, the response to therapy requirement is difficult to meet because children and teenagers do not comply with a gluten-free diet (or achieve a strict gluten-free diet only after months of effort), symptomatic response is a subjective measure, and acceptance of repeat biopsy is often low.57Fabiani E. Taccari L.M. Ratsch I.M. Di Giuseppe S. Coppa G.V. Catassi C. Compliance with gluten-free diet in adolescents with screening-detected celiac disease a 5-year follow-up study.J Pediatr. 2000; 136: 841-843PubMed Google Scholar Finally, improved serologic testing, is now available and widely used and should be incorporated in the diagnostic algorithm. For all these reasons, the definition of clinical CD needs updating. The utility of DQ2/8 testing may also be considered in ruling in or out the possibility of CD. The definition of screening-identified CD (sCD) is even more problematic. The ESPGN criteria were developed for clinically suspected cases (cCD), not screening-identified cases. Individuals identified on screening are unlikely to attempt or comply with a long-term, gluten-free diet.57Fabiani E. Taccari L.M. Ratsch I.M. Di Giuseppe S. Coppa G.V. Catassi C. Compliance with gluten-free diet in adolescents with screening-detected celiac disease a 5-year follow-up study.J Pediatr. 2000; 136: 841-843PubMed Google Scholar In addition, those with sCD seem less likely to agree to a follow-up biopsy and have no or mild symptoms to guide clinical response. A major concern in screening for CD is that a single positive test for transglutaminase antibodies (TG) (IgA tissue transglutaminase antibodies) or endomyseal antibodies (EMA) (IgA endomyseal antibodies) has a positive predictive value for biopsy confirmation of CD (meaning villous atrophy) of only approximately 75%–80%.17Aktay A.N. Lee P.C. Kumar V. Parton E. Wyatt D.T. Werlin S.L. The prevalence and clinical characteristics of celiac disease in juvenile diabetes in Wisconsin.J Pediatr Gastroenterol Nutr. 2001; 33: 462-465Crossref PubMed Scopus (99) Google Scholar, 58Hoffenberg E.J. Bao F. Eisenbarth G.S. Uhlhorn C. Haas J.E. Sokol R.J. Rewers M. Transglutaminase antibodies in children with a genetic risk for celiac disease.J Pediatr. 2000; 137: 356-360Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar There is some selection bias in that only a proportion of screening-identified subjects agree to undergo biopsy. How to interpret seropositivity in the absence of villous atrophy remains unclear, with the possibilities including false-positive serologic tests, a mild disease process, or simply an early phase in an inevitably progressive disease process. Ideally, medical and public acceptance of screening will likely require some resolution to this problem. To deal with this problem, several strategies have been proposed (Table 3). In screening asymptomatic at-risk children, we have taken the approach of requiring at least 2 positive tests at least several months apart and have required a higher titer than for clinically suspected cases.26Rewers M. Liu E. Simmons J. Redondo M.J. Hoffenberg E.J. Celiac disease associated with type 1 diabetes mellitus.Endocrinol Metab Clin North Am. 2004; 33: 197-214Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Another approach is a 2-step process, in which the initially positive sample is then tested for a second antibody (for example a sample positive for antibodies to gliadin or transglutaminase (TG+) is then tested for EMA.9Catassi C. Ratsch I.M. Fabiani E. Ricci S. Bordicchia F. Pierdomenico R. Giorgi P.L. High prevalence of undiagnosed coeliac disease in 5280 Italian students screened by antigliadin antibodies.Acta Paediatr. 1995; 84: 672-676Crossref PubMed Scopus (146) Google Scholar, 52Hill I.D. Dirks M. Liptak G. Colletti R.B. Fasano A. Guandalini S. Hoffenberg E.J. Horvath K. Murray J.A. Pivor M. Seidman E. Guideline for the diagnosis and treatment of celiac disease in children recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.J Pediatr Gastroenterol Nutr. 2005; 40: 1-19Crossref PubMed Scopus (1019) Google Scholar Only those with double-positive serologic tests undergo small bowel biopsy. In my view, this is another strategy to adjust for higher TG titer samples. Titers of antibodies detected on a radioassay using human recombinant TG correlate well with titers of antibodies to EMA, but the TG assay identifies many more individuals than the EMA assay.33Bao F. Yu L. Babu S. Wang T. Hoffenberg E.J. Rewers M. Eisenbarth G.S. One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies.J Autoimmun. 1999; 13: 143-148Crossref PubMed Scopus (204) Google Scholar There is some evidence that in screening-identified children, TG titers fluctuate with time and that the titer obtained at the time of the biopsy correlates with the degree of injury.59Liu E. Bao F. Barriga K. Miao D. Yu L. Erlich H.A. Haas J.E. Eisenbarth G.S. Rewers M.J. Hoffenberg E.J. Fluctuating transglutaminase autoantibodies are related to histologic features of celiac disease.Clin Gastroenterol Hepatol. 2003; 1: 356-362Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar This data might suggest that the early autoimmune process may consist of cycles of injury and healing. Based on prospective data in children screened multiple times throughout early childhood, TG testing was well accepted.15Hoffenberg E.J. MacKenzie T. Barriga K.J. Eisenbarth G.S. Bao F. Haas J.E. Erlich H. Bugawan T.L.T. Sokol R.J. Taki I. Norris J.M. Rewers M. A prospective study of the incidence of childhood celiac disease.J Pediatr. 2003; 143: 308-314Abstract Full Text Full Text PDF PubMed Scopus (191) Google ScholarTable 3Approaches to Increase the Ability of Screening Tests to Predict Biopsy Confirmation of CD1. Persisting autoimmunity on repeated testing at least 3–6 months apart2. Higher cut-offs for screening than for clinically indicated testing3. Stepwise testing (for example, require TG+ and EMA+) prior to biopsy Open table in a new tab The following conclusions summarize current knowledge on the diagnostic criteria for CD: (1) The definition of clinically identified CD needs updating and consistency; (2) the definition of screening-identified CD remains a problem; (3) a single positive serologic test on screening has an approximately 70% positive predictive value for biopsy confirmation of CD; (4) strategies to improve predictive value of screening tests are needed and could include standardizing the available assays, repeat testing, and using higher cut-offs than for clinically suspected cases; and (5) the clinical significance of TG+ (without villous atrophy) remains unclear and may limit public acceptance of screening. There is little data on the natural history of sCD in children, although new information is emerging. There is some debate on whether all identified "cases" of CD should be treated.1Catassi C. Fabiani E. Ratsch I.M. Coppa G.V. Giorgi P.L. Celiac disease in the general population should we treat asymptomatic cases?.J Pediatr Gastroenterol Nutr. 1997; 24: S10-S13Crossref PubMed Google Scholar However, in the absence of natural history studies, it is unknown whether sCD (TG+ with or without villous atrophy) confers the same long-term consequences as clinically identified CD. Treating all cases seems premature. As yet, there are no long-term observational data in children. Evidence supports the view that CD autoimmunity develops in childhood, and that there may be a gene dose effect.15Hoffenberg E.J. MacKenzie T. Barriga K.J. Eisenbarth G.S. Bao F. Haas J.E. Erlich H. Bugawan T.L.T. Sokol R.J. Taki I. Norris J.M. Rewers M. A prospective study of the incidence of childhood celiac disease.J Pediatr. 2003; 143: 308-314Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, 33Bao F. Yu L. Babu S. Wang T. Hoffenberg E.J. Rewers M. Eisenbarth G.S. One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies.J Autoimmun. 1999; 13: 143-148Crossref PubMed Scopus (204) Google Scholar, 60Congia M. Cucca F. Frau F. Lampis R. Melis L. Clemente M.G. Cao A. De Virgiliis S. A gene dosage effect of the DQA10501/DQB10201 allelic combination influences the clinical heterogeneity of celiac disease.Hum Immunol. 1994; 40: 138-142Crossref PubMed Scopus (91) Google Scholar An environmental influence has been proposed for breastfeeding (protective)61Ivarsson A. Hernell O. Stenlund H. Persson L.A. Breast-feeding protects against celiac disease.Am J Clin Nutr. 2002; 75: 914-921PubMed Scopus (397) Google Scholar but not confirmed in a prospective study.62Norris J.M. Barriga K. Hoffenberg E. Taki I. Emery L.M. Eisenbarth G. Sokol R. Bugawan T. Erlich H. Rewers M. Timing of gluten introduction in the infant diet affects risk of coeliac disease autoimmunity. 2004: P51Google Scholar In this study, early introduction of gluten before 4 months of age, and possibly late introduction after 7 months of age, increases risk of developing TG,62Norris J.M. Barriga K. Hoffenberg E. Taki I. Emery L.M. Eisenbarth G. Sokol R. Bugawan T. Erlich H. Rewers M. Timing of gluten introduction in the infant diet affects risk of coeliac disease autoimmunity. 2004: P51Google Scholar and this risk is higher in those homozygous for DR3, which is in linkage disequilibrium with DQ2. In an overlapping study, at the time of development of TG, children have slightly altered body composition (decreased weight for height or body mass index z-scores) compared with matched TG controls.51Hoffenberg E. Emery L. Barriga K. Bao F. Eisenbarth G. Haas J. Sokol R. Taki I. Norris J. Taylor J. Rewers M. Clinical features of children with screening-identified evidence of celiac disease.Pediatrics. 2004; 113: 1254-1259Crossref PubMed Scopus (72) Google Scholar In summary, (1) there is limited data on the natural history of sCD in children and therefore on the benefit of early treatment; (2) important questions need to be answered, including (a) whether autoimmunity (TG+) equals disease, (b) does villous atrophy predict outcome (need for small bowel biopsy), and (c) does early or preventive treatment alter natural history; (3) needed is a tool to assess transition from autoimmunity to overt disease; (4) prevention strategies may merit further investigation. To date, a gluten-free diet is the only accepted therapy and is effective in children. The diet requires significant effort to follow. There are no data on the cost-benefit of screening for CD in children. The potential harm of screening includes difficulty in obtaining life or health insurance; the impact on psychologic development of the children and their families; the impact of CD in addition to diabetes or other associated conditions. The optimal age at which to begin and to repeat testing is undefined. Testing before age 3 years does not seem warranted. Screening school-age children seems likely to detect most, but not all, cases. Many diabetic TG+ children are identified at first screening, although new seroconversion continues over time.63Barera G. Bonfanti R. Viscardi M. Bazzigaluppi E. Calori G. Meschi F. Bianchi C. Chiumello G. Occurrence of celiac disease after onset of type 1 diabetes a 6-year prospective longitudinal study.Pediatrics. 2002; 109: 833-838Crossref PubMed Scopus (233) Google Scholar We have taken the approach of rescreening diabetic children at 2-year intervals. The role of DQ2/8 testing has not been studied but may identify those who do not need further testing. A question most families ask is how good of a gluten-free diet is good enough? A major problem in addressing this issue is the inability to quantitatively measure dietary gluten. Studies have focused on monitoring compliance by following diet history, antibody titers, or occasionally repeat small bowel biopsy. With a gluten-free diet, children show normalization of growth,64Rea F. Polito C. Marotta A. Di Toro A. Iovene A. Collini R. Rea L. Sessa G. Restoration of body composition in celiac children after one year of gluten-free diet.J Pediatr Gastroenterol Nutr. 1996; 23: 408-412Crossref PubMed Scopus (64) Google Scholar bone mineralization,65Mora S. Barera G. Beccio S. Menni L. Proverbio M.C. Bianchi C. Chiumello G. A prospective, longitudinal study of the long-term effect of treatment on bone density in children with celiac disease.J Pediatr. 2001; 139: 516-521Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar and symptoms.66Saukkonen T. Vaisanen S. Akerblom H.K. Savilahti E. Coeliac disease in children and adolescents with type 1 diabetes a study of growth, glycaemic control, and experiences of families.Acta Paediatr. 2002; 91: 297-302Crossref PubMed Google Scholar, 67Mearin M. van Geel A. Csizmadia C. Koopman H. Hylkema H. Schweizer J. Verloove-Vanhorick S. Follow-up of children with unrecognized coeliac disease (CD) identified after mass screening. 2004: P62Google Scholar Cancer in childhood is not increased.68Askling J. Linet M. Gridley G. Halstensen T.S. Ekstrom K. Ekbom A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis.Gastroenterology. 2002; 123: 1428-1435Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar However, predictors of remission, meaning normalized risk for long-term complications, have not been developed. Screening all children for CD is problematic at this time. The model shown in Figure 1 is useful in highlighting major areas in need of further study. These include determining the optimal time to initiate and repeat screening, defining the natural history of screening-identified CD (with and without villous atrophy) to determine who to treat, developing methods to detect the transition from autoimmunity to disease to determine when to treat, developing predictors of response to treatment to assess the benefit of treatment, and assessing the risks of screening.