Portal de Periódicos da CAPES

Epidemiology of celiac disease: What are the prevalence, incidence, and progression of celiac disease?

2005; Elsevier BV; Volume: 128; Issue: 4 Linguagem: Inglês

10.1053/j.gastro.2005.02.030

1528-0012

Marian Rewers,

Digestive system and related health

Celiac disease (CD) is a chronic systemic autoimmune disorder induced by gluten proteins present in wheat, barley, and rye. Contrary to common belief, gluten enteropathy is a systemic disease rather than merely an ailment of the alimentary tract. Genetically susceptible persons develop autoimmune injury to the gut, skin, liver, joints, uterus, brain, heart, and other organs (Figure 1). The classical definition of CD included gastrointestinal manifestations (chronic diarrhea, failure to grow, weight loss, vomiting, abdominal pain, bloating, distention, and constipation), confirmed by a small bowel biopsy (SBB) with findings of villous atrophy, crypt hyperplasia, and normalization of the villous architecture in response to a gluten-free diet.1Walker-Smith J. Guandalini S. Schmitz J. Shmerling D. Visakorpi J. Revised 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 (28) Google Scholar, 2Catassi C. Cellier C. Cerf-Bensussan N. Ciclitira P.J. Collin P. Corazza G.R. Dickey W. Fasano A. Holmes G.K.T. Klincewicz P. Mearin M.L. Mulder C.J.J. Murray J.A. Pena A.S. Schuppan D. Sollid L.M. Uil J.J. Wahab P.J. Walker-Smith J.A. Watson P. Van Belzen M. von Blomberg B.M.E. Bouquet J. Bijleveldt C.M.A. Crusius J.B.A. Douwes A.C. George E.K. Hamer R.J. Janssen F.W. Meyer J.W.R. Sinaasappel M. Rostami K. Taminiau J.A.J.M. Vader L.W. Wijmenga C. When is a coeliac a coeliac?.Eur J Gastroenterol Hepatol. 2001; 13 (Report of a working group of the United European Gastroenterology Week in Amsterdam, 2001): 1123-1128Crossref PubMed Scopus (204) Google Scholar Previously, CD was thought to be a disease primarily of infancy; however, with the widespread delay in introduction of wheat into the infant diet, the clinical manifestations have become more subtle, and diagnosis is now typically made in older children and adults.3Maki M. Kallonen K. Lahdeaho M.L. Visakorpi J.K. Changing pattern of childhood coeliac disease in Finland.Acta Paediatr Scand. 1988; 77: 408-412Crossref PubMed Scopus (176) Google Scholar, 4Murray J.A. Van Dyke C. Plevak M.F. Dierkhising R.A. Zinsmeister A.R. Melton III, L.J. Trends in the identification and clinical features of celiac disease in a North American community, 1950–2001.Clin Gastroenterol Hepatol. 2003; 1: 19-27Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 5Fasano A. Catassi C. Current approaches to diagnosis and treatment of celiac disease an evolving spectrum.Gastroenterology. 2001; 120: 636-651Abstract Full Text Full Text PDF PubMed Scopus (1101) Google Scholar SBB is poorly accepted by a majority of patients with mild or no symptoms, and the pathologic examination of biopsy material is suboptimal in most settings. The use of SBB as a "gold standard" for diagnosis has significant limitations. It is occasionally false-negative because of patchy mucosal changes. Villous atrophy is often most severe in the proximal jejunum, typically not reached by endoscopic biopsy. This has led some to propose a new definition of CD, based on the presence of serum IgA autoantibodies to tissue transglutaminase (IgA TG) and HLA-DQB1*0201 or *0302 alelles.6Maki 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 These markers are increasingly used in screening for CD, but their true sensitivity and specificity are debatable. Although efforts to standardize IgA TG assays have been undertaken,7Wong R.C. Wilson R.J. Steele R.H. Radford-Smith G. Adelstein S. A comparison of 13 guinea pig and human anti-tissue transglutaminase antibody ELISA kits.J Clin Pathol. 2002; 55: 488-494Crossref PubMed Scopus (132) Google Scholar, 8Van M.B. Hiele M. Hoffman I. Vermeire S. Rutgeerts P. Geboes K. Bossuyt X. Diagnostic accuracy of ten second-generation (human) tissue transglutaminase antibody assays in celiac disease.Clin Chem. 2004; 50: 2125-2135Crossref PubMed Scopus (106) Google Scholar previous reports have likely overestimated the sensitivity and underestimated the specificity because of verification bias9Punglia R.S. D'Amico A.V. Catalona W.J. Roehl K.A. Kuntz K.M. Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen.N Engl J Med. 2003; 349: 335-342Crossref PubMed Scopus (284) Google Scholar caused by the lack of SBB studies in patients negative on TG screening. The current model of the natural history of CD (Figure 2) recognizes that, at certain points in time, the disease is not associated with obvious clinical signs and symptoms. Latent CD precedes diagnosis of CD or follows successful treatment of active disease with a gluten-free diet (GFD). The SBB does not show villous atrophy and crypt hyperplasia, but there are increased γ/δ intraepithelial T cells, higher proportion of dividing epithelial crypt cells,10Mustalahti K. Collin P. Sievanen H. Salmi J. Maki M. Osteopenia in patients with clinically silent coeliac disease warrants screening.Lancet. 1999; 354: 744-745Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar and subtle morphometric abnormalities of the enterocytes,11Maki M. Holm K. Lipsanen V. Hallstrom O. Viander M. Collin P. Savilahti E. Koskimies S. Serological markers and HLA genes among healthy first-degree relatives of patients with coeliac disease.Lancet. 1991; 338: 1350-1353Abstract PubMed Scopus (185) Google Scholar pointing to a low-grade ongoing inflammation in the gut wall. IgA TG or endomysial autoantibodies can be detected in many of these patients. Prospective studies have shown that individuals with latent CD develop symptoms and positive SBB while on gluten-containing diet.12Maki M. Holm K. Koskimies S. Hallstrom O. Visakorpi J.K. Normal small bowel biopsy followed by coeliac disease.Arch Dis Child. 1990; 65: 1137-1141Crossref PubMed Scopus (150) Google Scholar, 13Collin P. Helin H. Maki M. Hallstrom O. Karvonen A.L. Follow-up of patients positive in reticulin and gliadin antibody tests with normal small-bowel biopsy findings.Scand J Gastroenterol. 1993; 28: 595-598Crossref PubMed Scopus (150) Google Scholar, 14Troncone R. The SIGEP Working Group on Latent Coeliac DiseaseItalian Society for Paediatric Gastroenterology and HepatologyLatent coeliac disease in Italy.Acta Paediatr. 1995; 84: 1252-1257Crossref PubMed Scopus (64) Google Scholar Active CD is characterized by intestinal and/or extraintestinal symptoms, villous atrophy and crypt hyperplasia, and strongly positive IgA TG and endomysial autoantibodies. However, the latter can be undetectable in occasional patients with coexisting IgA deficiency. Atypical presentation has become increasingly frequent, with nonspecific abdominal discomfort or extraintestinal symptoms5Fasano A. Catassi C. Current approaches to diagnosis and treatment of celiac disease an evolving spectrum.Gastroenterology. 2001; 120: 636-651Abstract Full Text Full Text PDF PubMed Scopus (1101) Google Scholar such as dermatitis herpetiformis, iron-deficiency anemia, hepatitis, cholangitis, hypertransaminasemia, coagulopathy, short statue, pubertal delay, osteopenia, arthralgia, aphthous stomatitis, dental enamel defects, alopecia, edema, infertility, depressive symptoms, and cerebellar ataxia. Dermatitis herpetiformis—an extremely itchy, bullous skin rash of the extensor surface of the limbs, trunk, and scalp—is a good example of a predominantly extraintestinal form of CD. Patients with dermatitis herpetiformis have IgA TG (80%–95%), HLA-DQB1*0201 (90%), and villous atrophy (75%, the remaining 25% have increased intraepithelial lymphocytes) and respond to GFD, yet they are often treated as if they had a different disease (eg, using Dapsone and not GFD).15Reunala T.L. Dermatitis herpetiformis.Clin Dermatol. 2001; 19: 728-736Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Silent CD is characterized by the presence of IgA TG and endomysial autoantibodies, histologic lesions on SBB typical for CD, and CD-associated HLA-DQ genotypes in an asymptomatic individual. In retrospect, however, many patients or their relatives recollect typical symptoms.16Hoffenberg E.J. Emery L.M. Barriga K.J. Bao F. Taylor J. Eisenbarth G.S. Haas J.E. Sokol R.J. Taki I. Norris J.M. Rewers M. Clinical features of children with screening-identified evidence of celiac disease.Pediatrics. 2004; 113: 1254-1259Crossref PubMed Scopus (72) Google Scholar, 17Bingley P.J. Williams A.J. Norcross A.J. Unsworth D.J. Lock R.J. Ness A.R. Jones R.W. Undiagnosed coeliac disease at age seven population based prospective birth cohort study.BMJ. 2004; 328: 322-323Crossref PubMed Scopus (221) Google Scholar, 18Tommasini A. Not T. Kiren V. Baldas V. Santon D. Trevisiol C. Berti I. Neri E. Gerarduzzi T. Bruno I. Lenhardt A. Zamuner E. Spano A. Crovella S. Martellossi S. Torre G. Sblattero D. Marzari R. Bradbury A. Tamburlini G. Ventura A. Mass screening for coeliac disease using antihuman transglutaminase antibody assay.Arch Dis Child. 2004; 89: 512-515Crossref PubMed Scopus (201) Google Scholar Children with silent disease had decreased height z-scores that correlated with the degree of intestinal injury.16Hoffenberg E.J. Emery L.M. Barriga K.J. Bao F. Taylor J. Eisenbarth G.S. Haas J.E. Sokol R.J. Taki I. Norris J.M. Rewers M. Clinical features of children with screening-identified evidence of celiac disease.Pediatrics. 2004; 113: 1254-1259Crossref PubMed Scopus (72) Google Scholar, 19Hoffenberg 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 Silent CD has been suggested to cause nutritional deficiency of iron; zinc; folate; vitamins D, K, and E; osteoporosis20Kemppainen T. Kroger H. Janatuinen E. Arnala I. Lamberg-Allardt C. Karkkainen M. Kosma V.M. Julkunen R. Jurvelin J. Alhava E. Uusitupa M. Bone recovery after a gluten-free diet a 5-year follow-up study.Bone. 1999; 25: 355-360Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar; lymphoma21Catassi C. Fabiani E. Corrao G. Barbato M. De Renzo A. Carella A.M. Gabrielli A. Leoni P. Carroccio A. Baldassarre M. Bertolani P. Caramaschi P. Sozzi M. Guariso G. Volta U. Corazza G.R. Risk of non-Hodgkin lymphoma in celiac disease.JAMA. 2002; 287: 1413-1419Crossref PubMed Scopus (277) Google Scholar; and neurological disease,22Hadjivassiliou M. Grunewald R. Sharrack B. Sanders D. Lobo A. Williamson C. Woodroofe N. Wood N. Davies-Jones A. Gluten ataxia in perspective epidemiology, genetic susceptibility and clinical characteristics.Brain. 2003; 126: 685-691Crossref PubMed Scopus (248) Google Scholar but the evidence is not very strong. There are no clear guidelines concerning the GDF in people with silent CD, especially those detected through serologic screening. However, preliminary reports appear to confirm that a GFD in silent cases prevents or reverses systemic complications such as delayed growth, weight loss,23Acerini C.L. Ahmed M.L. Ross K.M. Sullivan P.B. Bird G. Dunger D.B. Coeliac disease in children and adolescents with IDDM clinical characteristics and response to gluten-free diet.Diabet Med. 1998; 15: 38-44Crossref PubMed Scopus (128) Google Scholar, 24Fabiani E. Catassi C. Villari A. Gismondi P. Pierdomenico R. Ratsch I.M. Coppa G.V. Giorgi P.L. Dietary compliance in screening-detected coeliac disease adolescents.Acta Paediatr Suppl. 1996; 412: 65-67Crossref PubMed Google Scholar or osteopenia.10Mustalahti K. Collin P. Sievanen H. Salmi J. Maki M. Osteopenia in patients with clinically silent coeliac disease warrants screening.Lancet. 1999; 354: 744-745Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar The proportion of people in a population who have CD at a specified time (prevalence rate) depends of course on definition of the disease. Figure 3 illustrates prevalence of preclinical (latent), undiagnosed (largely silent), and diagnosed (mostly active) CD in several European and US populations. Although the prevalence of diagnosed CD varied widely among these populations, the estimates of combined undiagnosed and diagnosed (or silent and active) CD were remarkably similar, between 0.7%–2.0% in most of the populations, including the United States. The prevalence of childhood CD has been reported to be between 1:285 and 1:77 in Sweden,25Cavell B. Stenhammar L. Ascher H. Danielsson L. Dannaeus A. Lindberg T. Lindquist B. Increasing incidence of childhood coeliac disease in Sweden. Results of a national study.Acta Paediatr. 1992; 81: 589-592Crossref PubMed Scopus (123) Google Scholar, 26Carlsson A.K. Axelsson I.E. Borulf S.K. Bredberg A.C. Ivarsson S.A. Serological screening for celiac disease in healthy 2.5-year-old children in Sweden.Pediatrics. 2001; 107: 42-45Crossref PubMed Scopus (154) Google Scholar 1:99 (positive SBB) and 1:67 (presence of IgA TG and HLA- DQB1*0201 or *0302) in Finland,6Maki 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 and 1:23027Catassi 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 and 1:10618Tommasini A. Not T. Kiren V. Baldas V. Santon D. Trevisiol C. Berti I. Neri E. Gerarduzzi T. Bruno I. Lenhardt A. Zamuner E. Spano A. Crovella S. Martellossi S. Torre G. Sblattero D. Marzari R. Bradbury A. Tamburlini G. Ventura A. Mass screening for coeliac disease using antihuman transglutaminase antibody assay.Arch Dis Child. 2004; 89: 512-515Crossref PubMed Scopus (201) Google Scholar in Italian schoolchildren. Generally, similar rates have been reported for non-European white populations, such as New Zealand,28Cook H.B. Burt M.J. Collett J.A. Whitehead M.R. Frampton C.M. Chapman B.A. Adult coeliac disease prevalence and clinical significance.J Gastroenterol Hepatol. 2000; 15: 1032-1036Crossref PubMed Scopus (118) Google Scholar Australia,29Hovell C.J. Collett J.A. Vautier G. Cheng A.J.P. Sutanto E. Mallon D.F. Olynyk J.K. Cullen D.J.E. High prevalence of coeliac disease in a population-based study from Western Australia a case for screening?.Med J Aust. 2001; 175: 247-250PubMed Google Scholar Argentina,30Gomez J.C. Selvaggio G.S. Viola M. Pizarro B. la Motta G. de Barrio S. Castelletto R. Echeverria R. Sugai E. Vazquez H. Maurino E. Bai J.C. Prevalence of celiac disease in Argentina screening of an adult population in the La Plata area.Am J Gastroenterol. 2001; 96: 2700-2704Crossref PubMed Google Scholar and Israel.31Shamir R. Lerner A. Shinar E. Lahat N. Sobel E. Bar-or R. Kerner H. Eliakim R. The use of a single serological marker underestimates the prevalence of celiac disease in Israel a study of blood donors.Am J Gastroenterol. 2002; 97: 2589-2594Crossref PubMed Google Scholar In the United States, cumulative incidence of persistent IgA TG positivity by the age of 5 years was 1:104 (95% CI: 1:49–221).32Hoffenberg E.J. Mackenzie T. Barriga K.J. Eisenbarth G.S. Bao F. Haas J.E. Erlich H. Bugawan T.L. 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 US adults, the prevalence varied from 1:17504Murray J.A. Van Dyke C. Plevak M.F. Dierkhising R.A. Zinsmeister A.R. Melton III, L.J. Trends in the identification and clinical features of celiac disease in a North American community, 1950–2001.Clin Gastroenterol Hepatol. 2003; 1: 19-27Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar (clinically diagnosed CD, including dermatitis herpetiformis) to 1:10533Fasano A. Berti I. Gerarduzzi T. Not T. Colletti R.B. Drago S. Elitsur Y. Green P.H. Guandalini S. Hill I.D. Pietzak M. Ventura A. Thorpe M. Kryszak D. Fornaroli F. Wasserman S.S. Murray J.A. Horvath K. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States a large multicenter study.Arch Intern Med. 2003; 163: 286-292Crossref PubMed Scopus (1495) Google Scholar (presence of IgA endomysial antibodies). Ethnic-specific data for the US population are scarce; the cumulative incidence of persistent IgA TG in Hispanic children was reported to be more than 3 times lower than in non-Hispanic whites,32Hoffenberg E.J. Mackenzie T. Barriga K.J. Eisenbarth G.S. Bao F. Haas J.E. Erlich H. Bugawan T.L. 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 probably because of the low frequency of the HLA-DR3, DQB1*0201 haplotype in this population. CD is virtually unknown in East Asian populations who also lack this HLA haplotype; however, rates close to those in Europe have been reported from the Middle East and India. Although the disease is believed to be rare in Africa (and in African Americans), the highest prevalence has been reported for Saharavi in North Africa.34Catassi C. Ratsch I.M. Gandolfi L. Pratesi R. Fabiani E. El Asmar R. Frijia M. Bearzi I. Vizzoni L. Why is coeliac disease endemic in the people of the Sahara?.Lancet. 1999; 354: 647-648Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar The estimates based on seroepidemiologic studies suggest that, for each diagnosed case of CD, there may be 3–7 undiagnosed cases and that 1%–3% of the general population in Europe and the United States becomes affected at some point in life. Most studies point to a secular increase in the prevalence of CD (Figure 4) that is largely due to increasing index of clinical suspicion and availability of highly sensitive and specific serologic screening tests. Population-based estimates of the incidence of SBB-confirmed CD in adults vary from 2–13/100,000 per year.4Murray J.A. Van Dyke C. Plevak M.F. Dierkhising R.A. Zinsmeister A.R. Melton III, L.J. Trends in the identification and clinical features of celiac disease in a North American community, 1950–2001.Clin Gastroenterol Hepatol. 2003; 1: 19-27Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 35Cook B. Oxner R. Chapman B. Whitehead M. Burt M. A thirty-year (1970–1999) study of coeliac disease in the Canterbury region of New Zealand.N Z Med J. 2004; 117: U772PubMed Google Scholar These rates have to be interpreted with caution because many patients diagnosed as adults likely have had 20–60 years of untreated CD, thus hardly represent truly incident (new) disease. The recent increase in the incidence rates (Figure 5) is likely due to increasing use of serologic screening leading to diagnosis in milder cases. However, there is a paucity of incidence data that would represent the full spectrum of disease, including silent and latent cases. Infant and early childhood nutrition varies among populations. Differences in the prevalence of susceptibility HLA alleles may explain interpopulation variation in the incidence of CD. The effects of nutritional practices on the risk and severity of CD may also account for geographic and temporal variation in the incidence of CD and be of great public health importance. Over time, individuals progress from latent to silent or active disease (Figure 2) and can reverse to the latent subclinical state on a strict GFD. It is not entirely clear how strict the GFD has to be in a given patient to avoid symptoms and long-term complications. Although there is growing evidence for a remitting-relapsing pattern of CD autoimmunity in some patients,6Maki 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, 36Liu 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 the disease process defined by current serologic and histopathologic techniques is remarkably persistent in the absence of a GFD. A 2- to 3-fold excess in all-cause mortality among CD patients, compared with the general population, has been reported in some studies37Ferguson A. Kingstone K. Coeliac disease and malignancies.Acta Paediatr Suppl. 1996; 412: 78-81Crossref PubMed Google Scholar, 38Corrao G. Corazza G.R. Bagnardi V. Brusco G. Ciacci C. Cottone M. Guidetti C.S. Usai P. Cesari P. Pelli M.A. Loperfido S. Volta U. Calabro A. Certo M. Mortality in patients with coeliac disease and their relatives a cohort study.Lancet. 2001; 358: 356-361Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar but not all.39Collin P. Reunala T. Pukkala E. Laippala P. Keyrilainen O. Pasternack A. Coeliac disease—associated disorders and survival.Gut. 1994; 35: 1215-1218Crossref PubMed Scopus (438) Google Scholar, 40Johnston S.D. Watson R.G. McMillan S.A. Sloan J. Love A.H. Coeliac disease detected by screening is not silent—simply unrecognized.QJM. 1998; 91: 853-860Crossref PubMed Scopus (124) Google Scholar The increased mortality has been attributed to gastrointestinal tract malignancies, especially lymphoma.21Catassi C. Fabiani E. Corrao G. Barbato M. De Renzo A. Carella A.M. Gabrielli A. Leoni P. Carroccio A. Baldassarre M. Bertolani P. Caramaschi P. Sozzi M. Guariso G. Volta U. Corazza G.R. Risk of non-Hodgkin lymphoma in celiac disease.JAMA. 2002; 287: 1413-1419Crossref PubMed Scopus (277) Google Scholar, 41O'Connor T.M. Cronin C.C. Loane J.F. O'Meara N.M. Firth R.G. Shanahan F. O'Halloran D.J. Type 1 diabetes mellitus, coeliac disease, and lymphoma a report of four cases.Diabet Med. 1999; 16: 614-617Crossref PubMed Scopus (36) Google Scholar, 42Askling 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, 43Green P.H.R. Fleischauer A.T. Bhagat G. Goyal R. Jabri B. Neugut A.I. Risk of malignancy in patients with celiac disease.Am J Med. 2003; 115: 191-195Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar Patients with CD-associated T-cell lymphomas express the HLA-DR3/4 genotype (40%) more often than other CD patients (7%) or controls (2%).44Howell W.M. Leung S.T. Jones D.B. Nakshabendi I. Hall M.A. Lanchbury J.S. Ciclitira P.J. Wright D.H. HLA-DRB, -DQA, and -DQB polymorphism in celiac disease and enteropathy-associated T-cell lymphoma. Common features and additional risk factors for malignancy.Hum Immunol. 1995; 43: 29-37Crossref PubMed Scopus (98) Google Scholar Although the HLA class II genes are clearly important, they account for only approximately 30%–40% of the familial clustering of CD.45Petronzelli F. Bonamico M. Ferrante P. Grillo R. Mora B. Mariani P. Apollonio I. Gemme G. Mazzilli M.C. Genetic contribution of the HLA region to the familial clustering of coeliac disease.Ann Hum Genet. 1997; 61: 307-317Crossref PubMed Scopus (126) Google Scholar Additional loci, eg, CD28/CTLA4/ICOS 2q33,46Djilali-Saiah I. Schmitz J. Harfouch-Hammoud E. Mougenot J.F. Bach J.F. Caillat-Zucman S. CTLA-4 gene polymorphism is associated with predisposition to coeliac disease.Gut. 1998; 43: 187-189Crossref PubMed Scopus (205) Google Scholar 15q26,47Zhong F. McCombs C.C. Olson J.M. Elston R.C. Stevens F.M. McCarthy C.F. Michalski J.P. An autosomal screen for genes that predispose to celiac disease in the western counties of Ireland.Nat Genet. 1996; 14: 329-333Crossref PubMed Scopus (164) Google Scholar IDDM17,48Redondo M.J. Eisenbarth G.S. Genetic control of autoimmunity in type I diabetes and associated disorders.Diabetologia. 2002; 45: 605-622Crossref PubMed Scopus (127) Google Scholar and 5qter49Greco L. Corazza G. Babron M.C. Clot F. Fulchignoni-Lataud M.C. Percopo S. Zavattari P. Bouguerra F. Dib C. Tosi R. Troncone R. Ventura A. Mantavoni W. Magazzu G. Gatti R. Lazzari R. Giunta A. Perri F. Iacono G. Cardi E. De Virgiliis S. Cataldo F. De Angelis G. Musumeci S. Clerget-Darpoux F. Genome search in celiac disease.Am J Hum Genet. 1998; 62: 669-675Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar may be related to progression of CD and development of long-term complications. Additional nongenetic candidate factors associated with progression to CD include early exposure to gliadins in utero or via breast milk,3Maki M. Kallonen K. Lahdeaho M.L. Visakorpi J.K. Changing pattern of childhood coeliac disease in Finland.Acta Paediatr Scand. 1988; 77: 408-412Crossref PubMed Scopus (176) Google Scholar, 50Auricchio S. Follo D. De Ritis G. Giunta A. Marzorati D. Prampolini L. Ansaldi N. Levi P. Dall'Olio D. Bossi A. Does breast feeding protect against the development of clinical symptoms of celiac disease in children?.J Pediatr Gastroenterol Nutr. 1983; 2: 428-433Crossref PubMed Scopus (107) Google Scholar dose, and age at introduction51Ivarsson A. Persson L.A. Nystrom L. Hernell O. The Swedish coeliac disease epidemic with a prevailing twofold higher risk in girls compared to boys may reflect gender specific risk factors.Eur J Epidemiol. 2003; 18: 677-684Crossref PubMed Scopus (62) Google Scholar, 52Norris J.M. Barriga K. Hoffenberg E.J. Taki I. Emery L.M. Eisenbarth G.S. Sokol R.J. Bugawan T.L. Erlich H.A. Rewers M. Timing of gluten introduction in the infant diet affects risk of coeliac disease autoimmunity. The 11th International Symposium: Coeliac Disease. 2004Google Scholar and intestinal infections53Howdle P.D. Blair Zajdel M.E. Smart C.J. Trejdosiewicz L.K. Blair G.E. Losowky M.S. Lack of a serologic response to an E1B protein of adenovirus 12 in coeliac disease.Scand J Gastroenterol. 1989; 24: 282-286Crossref PubMed Scopus (33) Google Scholar, 54Mahon J. Blair G.E. Wood G.M. Scott B.B. Losowsky M.S. Howdle P.D. Is persistent adenovirus 12 infection involved in coeliac disease? A search for viral DNA using the polymerase chain reaction.Gut. 1991; 32: 1114-1116Crossref PubMed Scopus (37) Google Scholar with gut hyperpermeability. Infant and early childhood nutrition varies among populations. Although the effects of nutritional practices on the risk and severity of CD may be of great public health importance, these are largely unknown and need to be assessed in large prospective studies. In summary, CD is a protean systemic disease affecting up to 1% of the general population. Appropriate screening, diagnosis, and treatment guidelines are being redefined, using improved diagnostic methods that include IgA TG testing and HLA-DQB1 typing, in addition to SBB.