Epidemiology, Presentation, and Diagnosis of Celiac Disease

The incidence of celiac disease is increasing, partly because of improved recognition of, and testing for, the disease. The rise in incidence is also due to a real increase of this immune-based disorder, independent of disease detection. The reasons for this true rise in recent decades are unknown but may be related to environmental factors that may promote loss of tolerance to dietary gluten. Strategies to reduce the development of celiac disease have not been proven successful in randomized trials, but the quantity of early-life gluten exposure has been a major focus of prevention efforts. The criteria for the diagnosis of celiac disease are changing, but in adults, diagnosis still depends on the presence of duodenal villous atrophy while the patient is on a gluten-containing diet, along with findings from serology analysis. Although guidelines in the United States continue to mandate a biopsy at all ages, some children receive a diagnosis of celiac disease without a biopsy. If proven accurate and scalable, assays that detect gluten–HLA tetramer complexes might be used in diagnosis to be made in the context of a gluten-free diet without intestinal biopsy. The incidence of celiac disease is increasing, partly because of improved recognition of, and testing for, the disease. The rise in incidence is also due to a real increase of this immune-based disorder, independent of disease detection. The reasons for this true rise in recent decades are unknown but may be related to environmental factors that may promote loss of tolerance to dietary gluten. Strategies to reduce the development of celiac disease have not been proven successful in randomized trials, but the quantity of early-life gluten exposure has been a major focus of prevention efforts. The criteria for the diagnosis of celiac disease are changing, but in adults, diagnosis still depends on the presence of duodenal villous atrophy while the patient is on a gluten-containing diet, along with findings from serology analysis. Although guidelines in the United States continue to mandate a biopsy at all ages, some children receive a diagnosis of celiac disease without a biopsy. If proven accurate and scalable, assays that detect gluten–HLA tetramer complexes might be used in diagnosis to be made in the context of a gluten-free diet without intestinal biopsy. Celiac disease is an immune-mediated condition characterized by small intestinal enteropathy, systemic symptoms related to malabsorption and/or immune activation, and autoantibodies to tissue transglutaminase (TTG). It is unique among the autoimmune diseases in that the trigger, dietary gluten, has been identified, and its removal results in resolution of symptoms and enteropathy in the majority of patients. Rising awareness and the development of serologic testing have resulted in a rise in disease incidence and a change in the distribution of clinical features. We review the epidemiology, presentation, and diagnosis of celiac disease, the latest research findings, and trends to follow in the coming decade. Previously thought to occur only (or predominantly) in Northern and Western Europe, celiac disease is now recognized to be present worldwide. A systematic review of the global prevalence of celiac disease found a seroprevalence rate of 1.4%, with prevalence varying by continent from 1.3% (South America, 11 studies) to 1.8% (Asia, 20 studies).1Singh P. Arora A. Strand T.A. et al.Global prevalence of celiac disease: systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2018; 16: 823-836Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar This might be an overestimate of the true prevalence of celiac disease, given the imperfect specificity of celiac disease serologies (see section on Diagnosis: Serology Performance). The prevalence of biopsy-diagnosed celiac disease was also measured in this study and was 0.7%; this likewise varied by continent and region. Although seroprevalence may be an overestimate, biopsy-proven celiac disease may be an underestimate of the condition, because not all individuals tested via serology agree to undergo full endoscopic evaluation. One consistent observation across geographic regions is that the incidence and prevalence of celiac disease are increasing over time. A systematic review and meta-analysis of celiac disease incidence found that in 33 studies that measured incidence at more than 1 timepoint, 24 (73%) showed significant increases in diagnosis rates over time.2King J.A. Jeong J. Underwood F.E. et al.Incidence of celiac disease is increasing over time: a systematic review and meta-analysis.Am J Gastroenterol. 2020; 115: 507-525Crossref PubMed Google Scholar In Olmsted County, Minnesota, diagnosis rates increased by 8.1% per year from 1950 through 2010.2King J.A. Jeong J. Underwood F.E. et al.Incidence of celiac disease is increasing over time: a systematic review and meta-analysis.Am J Gastroenterol. 2020; 115: 507-525Crossref PubMed Google Scholar, 3Murray J.A. Van Dyke C. Plevak M.F. et al.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 (255) Google Scholar, 4Ludvigsson J.F. Rubio-Tapia A. van Dyke C.T. et al.Increasing incidence of celiac disease in a North American population.Am J Gastroenterol. 2013; 108: 818-824Crossref PubMed Scopus (187) Google Scholar Discrete rises in diagnosis rates have been documented in relation to the availability of serologic tests in the 1990s3Murray J.A. Van Dyke C. Plevak M.F. et al.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 (255) Google Scholar and have also been seen in response to incentives. For example, in Finland, after a policy was introduced requiring patients to have a physician-confirmed diagnosis of celiac disease to qualify for a government-subsidized dietary provision, diagnosis rates increased.5Virta L.J. Kaukinen K. Collin P. Incidence and prevalence of diagnosed coeliac disease in Finland: results of effective case finding in adults.Scand J Gastroenterol. 2009; 44: 933-938Crossref PubMed Scopus (83) Google Scholar Nevertheless, there is accumulating evidence that, beyond increased awareness, the true incidence of celiac disease has increased, which is affecting the prevalence of celiac disease. This has been shown by cohort studies that included celiac disease screening, such as the Diabetes Autoimmunity Study in the Young study. In that study, 1339 infants born with a celiac disease–compatible HLA haplotype at a hospital in Denver, Colorado, from 1993 through 2004 were tested for celiac disease antibodies at 9, 15, and 24 months and then annually. Participants with persistent increases in antibodies were offered duodenal biopsy analysis. Celiac disease was diagnosed in 66 children (4.9%); using population HLA distribution data, the researchers extrapolated the prevalence of celiac disease in the greater Denver area, by age 15 years, to be 3.1%.6Liu E. Dong F. Barón A.E. et al.High incidence of celiac disease in a long-term study of adolescents with susceptibility genotypes.Gastroenterology. 2017; 152: 1329-1336Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Celiac disease can develop at any age, including in geriatric populations.7Collin P. Vilppula A. Luostarinen L. et al.Review article: coeliac disease in later life must not be missed.Aliment Pharmacol Ther. 2018; 47: 563-572Crossref PubMed Scopus (16) Google Scholar Such diagnoses do not necessarily indicate late discovery of longstanding celiac disease—they could result from de novo loss of tolerance of gluten. Studies of serial serum samples have reported loss of gluten tolerance in adulthood.8Catassi C. Kryszak D. Bhatti B. et al.Natural history of celiac disease autoimmunity in a USA cohort followed since 1974.Ann Med. 2010; 42: 530-538Crossref PubMed Scopus (245) Google Scholar Nevertheless, recent prospective cohort studies have found that most patients develop celiac disease before age 10 years.6Liu E. Dong F. Barón A.E. et al.High incidence of celiac disease in a long-term study of adolescents with susceptibility genotypes.Gastroenterology. 2017; 152: 1329-1336Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar,9Andrén Aronsson C. Lee H.-S. Hård Af Segerstad E.M. et al.Association of gluten intake during the first 5 years of life with incidence of celiac disease autoimmunity and celiac disease among children at increased risk.JAMA. 2019; 322: 514-523Crossref PubMed Scopus (19) Google Scholar The incidence of celiac disease is higher in women than men (17.0 vs 7.8 per 100,000 person-years in a pooled analysis2King J.A. Jeong J. Underwood F.E. et al.Incidence of celiac disease is increasing over time: a systematic review and meta-analysis.Am J Gastroenterol. 2020; 115: 507-525Crossref PubMed Google Scholar), but this might be because men are more likely to remain undiagnosed. A systematic review and meta-analysis found a slight increase in seropositivity among female participants in screening studies,10Jansson-Knodell C.L. Hujoel I.A. West C.P. et al.Sex difference in celiac disease in undiagnosed populations: a systematic review and meta-analysis.Clin Gastroenterol Hepatol. 2019; 17: 1954-1968Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar although some studies of adults found that men and women have similar seroprevalences.11Rubio-Tapia A. Kyle R.A. Kaplan E.L. et al.Increased prevalence and mortality in undiagnosed celiac disease.Gastroenterology. 2009; 137: 88-93Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar,12Katz K.D. Rashtak S. Lahr B.D. et al.Screening for celiac disease in a North American population: sequential serology and gastrointestinal symptoms.Am J Gastroenterol. 2011; 106: 1333-1339Crossref PubMed Scopus (92) Google Scholar Men are less likely to undergo duodenal biopsy examination during upper endoscopy for indications such as diarrhea and weight loss, which might contribute to underdiagnosis.13Lebwohl B. Tennyson C.A. Holub J.L. et al.Sex and racial disparities in duodenal biopsy to evaluate for celiac disease.Gastrointest Endosc. 2012; 76: 779-785Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar The risk of celiac disease varies within countries. In India, the prevalence of celiac disease is greater in the Punjab region (1.2%) and elsewhere in the north compared with the south (0.1%), despite similar prevalences of the HLA-permissive haplotypes DQ2 and DQ8.14Ramakrishna B.S. Makharia G.K. Chetri K. et al.Prevalence of adult celiac disease in India: regional variations and associations.Am J Gastroenterol. 2016; 111: 115-123Crossref PubMed Scopus (69) Google Scholar Celiac disease did not vary by urban vs rural areas or with socioeconomic status in that study. Similarly, an analysis of duodenal biopsy specimens submitted during upper endoscopy to pathology laboratories throughout the United States showed that persons of Punjab ethnicity had the highest prevalence of villous atrophy—far higher than from persons of Indian ethnicity from outside of that region.15Krigel A. Turner K.O. Makharia G.K. et al.Ethnic variations in duodenal villous atrophy consistent with celiac disease in the United States.Clin Gastroenterol Hepatol. 2016; 14: 1105-1111Abstract Full Text Full Text PDF PubMed Google Scholar The reasons for these regional and ethnic differences are unknown, but they might be related to mean daily wheat intake, which is greater in the Punjab region.14Ramakrishna B.S. Makharia G.K. Chetri K. et al.Prevalence of adult celiac disease in India: regional variations and associations.Am J Gastroenterol. 2016; 111: 115-123Crossref PubMed Scopus (69) Google Scholar It is also possible that more than 1 environmental factor can account for regional differences. There are also racial and ethnic differences in celiac disease prevalence, even in screening studies, independent of differences in testing rates. In the United States, celiac disease was less common in non-Hispanic black and Hispanic vs white individuals. Based on data from the National Health and Nutrition Examination Survey (NHANES), seroprevalence was 0.2% in non-Hispanic black and 0.3% Hispanic individuals, compared with 1.0% in white individuals.16Choung R.S. Ditah I.C. Nadeau A.M. et al.Trends and racial/ethnic disparities in gluten-sensitive problems in the United States: findings from the National Health and Nutrition Examination Surveys from 1988 to 2012.Am J Gastroenterol. 2015; 110: 455-461Crossref PubMed Google Scholar Likewise, the prevalence of celiac disease can vary widely among countries despite geographic proximity. A screening study found serologic evidence of celiac disease in 1.4% of individuals in Finland, but only 0.6% of people in the adjacent Russian Karelia, again without significant differences in compatible HLA haplotypes.17Kondrashova A. Mustalahti K. Kaukinen K. et al.Lower economic status and inferior hygienic environment may protect against celiac disease.Ann Med. 2008; 40: 223-231Crossref PubMed Scopus (98) Google Scholar Such differences have led investigators to test environmental exposures as possible risk factors for the development of celiac disease. A feature of celiac disease that affects epidemiology studies is that a substantial proportion of individuals remains undiagnosed. There are many reasons for this. Some patients are minimally symptomatic or asymptomatic.18Aggarwal S. Lebwohl B. Green P.H.R. Screening for celiac disease in average-risk and high-risk populations.Therap Adv Gastroenterol. 2012; 5: 37-47Crossref PubMed Scopus (0) Google Scholar Others may have longstanding symptoms attributed to irritable bowel syndrome and are not tested for celiac disease.19Ford A.C. Chey W.D. Talley N.J. et al.Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: systematic review and meta-analysis.Arch Intern Med. 2009; 169: 651-658Crossref PubMed Scopus (184) Google Scholar Patients may even undergo upper endoscopy to evaluate symptoms, but duodenal biopsy samples are not collected and analyzed, because of a normal-appearing duodenum—the endoscopic appearance may be normal, but there is microscopic evidence of villous atrophy.13Lebwohl B. Tennyson C.A. Holub J.L. et al.Sex and racial disparities in duodenal biopsy to evaluate for celiac disease.Gastrointest Endosc. 2012; 76: 779-785Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar,20Pitman M. Sanders D.S. Green P.H.R. Lebwohl B. Rates of duodenal biopsy during upper endoscopy differ widely between providers: implications for diagnosis of celiac disease.J Clin Gastroenterol. 2019; 53: e61-e67Crossref PubMed Scopus (4) Google Scholar,21Lebwohl B. Bhagat G. Markoff S. et al.Prior endoscopy in patients with newly diagnosed celiac disease: a missed opportunity?.Dig Dis Sci. 2013; 58: 1293-1298Crossref PubMed Scopus (23) Google Scholar Prior low estimates of celiac disease, dating to the 1960s (based on diagnosis rates), have led some clinicians to believe that celiac disease is a rare condition. This results in the testing of only patients with characteristics such as chronic diarrhea and a family history of celiac disesae.22Talley N.J. Valdovinos M. Petterson T.M. et al.Epidemiology of celiac sprue: a community-based study.Am J Gastroenterol. 1994; 89: 843-846PubMed Google Scholar Regardless of the reasons, celiac disease has remained largely hidden in the United States. In a screening study in 2001, 95% of individuals in Olmsted County were undiagnosed.3Murray J.A. Van Dyke C. Plevak M.F. et al.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 (255) Google Scholar With the publication of prevalence data indicating that almost 1% of individuals have celiac disease,23Fasano A. Berti I. Gerarduzzi T. et al.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 (1341) Google Scholar together with the widespread availability of serologic tests, the proportion of undiagnosed individuals began to decrease, from 95% in 20013Murray J.A. Van Dyke C. Plevak M.F. et al.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 (255) Google Scholar and 90% in Wyoming in 200312Katz K.D. Rashtak S. Lahr B.D. et al.Screening for celiac disease in a North American population: sequential serology and gastrointestinal symptoms.Am J Gastroenterol. 2011; 106: 1333-1339Crossref PubMed Scopus (92) Google Scholar to 83% in 2009 to 2010, based on data from NHANES.24Rubio-Tapia A. Ludvigsson J.F. Brantner T.L. et al.The prevalence of celiac disease in the United States.Am J Gastroenterol. 2012; 107: 1538-1544Crossref PubMed Scopus (446) Google Scholar The most recent analysis of celiac disease prevalence in the United States, based on NHANES, found that the prevalence of celiac disease remained stable from 2009 to 2014, at 0.7%, but that the proportion of patients with celiac disease who remain undiagnosed has decreased over time.25Choung R.S. Unalp-Arida A. Ruhl C.E. et al.Less hidden celiac disease but increased gluten avoidance without a diagnosis in the United States: findings from the National Health and Nutrition Examination Surveys from 2009 to 2014.Mayo Clin Proc. 2017; 92: 30-38Abstract Full Text Full Text PDF Scopus (48) Google Scholar This might be due to increased awareness of the clinical manifestations of celiac disease, but it might also be related to widespread interest in, and adoption of, the gluten-free diet in the general population. Interest in a gluten-free diet has indirectly increased testing for celiac disease. The prevalence of the gluten-free diet, based on data from NHANES, increased from 0.5% in 2009 to 1.7% in 2014, whereas the prevalence of celiac disease remained stable during that same period.25Choung R.S. Unalp-Arida A. Ruhl C.E. et al.Less hidden celiac disease but increased gluten avoidance without a diagnosis in the United States: findings from the National Health and Nutrition Examination Surveys from 2009 to 2014.Mayo Clin Proc. 2017; 92: 30-38Abstract Full Text Full Text PDF Scopus (48) Google Scholar Reasons for the avoidance of gluten in the absence of celiac disease vary, but they include symptoms that improve on this diet (nonceliac wheat or gluten sensitivity),26Krigel A. Lebwohl B. Nonceliac gluten sensitivity.Adv Nutr. 2016; 7: 1105-1110Crossref PubMed Scopus (6) Google Scholar and the belief, based on unproven notions, that gluten avoidance carries cardiovascular or neurologic health benefits.27Lerner B.A. Green P.H.R. Lebwohl B. Going against the grains: gluten-free diets in patients without celiac disease-worthwhile or not?.Dig Dis Sci. 2019; 64: 1740-1747Crossref PubMed Scopus (8) Google Scholar Gluten avoidance in the absence of celiac disease is associated with higher socioeconomic status28Laszkowska M. Shiwani H. Belluz J. et al.Socioeconomic vs health-related factors associated with google searches for gluten-free diet.Clin Gastroenterol Hepatol. 2018; 16: 295-297Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar and appears more common in higher-income countries.29Zylberberg H.M. Yates S. Borsoi C. et al.Regional and national variations in reasons for gluten avoidance.J Clin Gastroenterol. 2018; 52: 696-702Crossref PubMed Scopus (5) Google Scholar Regardless of the reason, widespread adoption of a gluten-free diet can affect efforts to measure celiac disease prevalence, because serologic assays do not detect celiac disease with high levels of sensitivity in groups with gluten avoidance. The prevalence of undiagnosed celiac disease might be more difficult to quantify if substantial proportions of the population are avoiding gluten at the time of testing. The enteropathy associated with celiac disease results from the presentation of gliadin peptide fragments, deamidated by TTG, by antigen-presenting cells via HLA proteins. HLA proteins are encoded by genes in the major histocompatibility complex locus on chromosome 6 and are expressed on the surface of antigen-presenting cells.30Brown N.K. Guandalini S. Semrad C. Kupfer S.S. A clinician’s guide to celiac disease HLA genetics.Am J Gastroenterol. 2019; 114: 1587-1592Crossref PubMed Scopus (3) Google Scholar Specific haplotypes encode proteins with affinities for specific antigens. The haplotypes DQ2 and DQ8 allow for the presentation of gluten antigens by antigen-presenting cells, which can result in activation of an immune response and development of celiac disease. The presence of at least 1 of these haplotypes is necessary but insufficient for development of celiac disease. Approximately 35% of people in the United States population are carriers of a DQ2 or DQ8 haplotype, yet most never develop celiac disease.30Brown N.K. Guandalini S. Semrad C. Kupfer S.S. A clinician’s guide to celiac disease HLA genetics.Am J Gastroenterol. 2019; 114: 1587-1592Crossref PubMed Scopus (3) Google Scholar Genome-wide association studies have identified additional (relatively minor) genetic risk factors for celiac disease, but DQ2 and DQ8 are the genetic features most strongly associated with celiac disease development.31Romanos J. van Diemen C.C. Nolte I.M. et al.Analysis of HLA and non-HLA alleles can identify individuals at high risk for celiac disease.Gastroenterology. 2009; 137: 834-840Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 32Hunt K.A. Zhernakova A. Turner G. et al.Newly identified genetic risk variants for celiac disease related to the immune response.Nat Genet. 2008; 40: 395-402Crossref PubMed Scopus (468) Google Scholar, 33Romanos J. Rosén A. Kumar V. et al.Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants.Gut. 2014; 63: 415-422Crossref PubMed Scopus (79) Google Scholar Two twin studies have found concordance rates of only 49%–83% among monozygotic twins, indicating the existence of environmental risk factors.34Nisticò L. Fagnani C. Coto I. et al.Concordance, disease progression, and heritability of coeliac disease in Italian twins.Gut. 2006; 55: 803-808Crossref PubMed Scopus (0) Google Scholar,35Kuja-Halkola R. Lebwohl B. Halfvarson J. et al.Birth weight, sex, and celiac disease: a nationwide twin study.Clin Epidemiol. 2017; 9: 567-577Crossref PubMed Scopus (2) Google Scholar Also, in multiple countries, the seroprevalence of celiac disease has increased in recent decades. A comparison of serum samples collected at the Warren Air Force Base in 1950 with samples collected from age-matched individuals in 2006 found the prevalence of celiac disease serologies to increase from 0.2% to 0.9%.11Rubio-Tapia A. Kyle R.A. Kaplan E.L. et al.Increased prevalence and mortality in undiagnosed celiac disease.Gastroenterology. 2009; 137: 88-93Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar A similar study in Finland, with a higher baseline prevalence of celiac disease, reported an increase from 1.05% in 1978 to 1.99% in 2000.36Lohi S. Mustalahti K. Kaukinen K. et al.Increasing prevalence of coeliac disease over time.Aliment Pharmacol Ther. 2007; 26: 1217-1225Crossref PubMed Scopus (519) Google Scholar This rapid increase in prevalence would be due to environmental, rather than genetic, risk factors. Infant feeding practices, particularly regarding the introduction of gluten, have been the focus of prevention strategies. Studies of the acute increase of celiac disease incidence in Sweden in the 1980s led to the hypothesis that early introduction of high quantities of gluten, without concurrent breastfeeding, were responsible for the epidemic observed in that country.37Ivarsson A. Persson L.A. Nyström L. et al.Epidemic of coeliac disease in Swedish children.Acta Paediatr. 2000; 89: 165-171Crossref PubMed Google Scholar An analysis of the Diabetes Auto Immunity Study in the Young (DAISY) study found celiac disease-associated antibodies in a higher proportion of infants whose introduction to gluten occurred before age 3 months or beyond age 6 months.38Norris J.M. Barriga K. Hoffenberg E.J. et al.Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease.JAMA. 2005; 293: 2343-2351Crossref PubMed Scopus (348) Google Scholar These observational studies led to trials to test strategies to prevent celiac disease in infants at increased risk—such as those with a family history and a compatible HLA haplotype. In a multicenter trial conducted throughout Italy, 533 infants were randomly assigned to groups that were introduced to gluten at age 12 months or at age 6 months. By age 10 years, 16.8% developed celiac disease, with no significant difference between groups in disease development, apart from a slightly delayed risk of celiac disease in the 12-month group.39Lionetti E. Castellaneta S. Francavilla R. et al.Introduction of gluten, HLA status, and the risk of celiac disease in children.N Engl J Med. 2014; 371: 1295-1303Crossref PubMed Scopus (261) Google Scholar In a multicenter randomized trial, 944 infants were randomly assigned to groups given low-dose daily gluten or placebo at age 4 months, followed by full introduction of gluten at age 6 months in both groups. The prevalence of celiac disease was 12.1% at 5 years, with no significant difference between groups.40Vriezinga S.L. Auricchio R. Bravi E. et al.Randomized feeding intervention in infants at high risk for celiac disease.N Engl J Med. 2014; 371: 1304-1315Crossref PubMed Scopus (254) Google Scholar The results of these trials overturned longstanding beliefs, based on observational studies, that the timing of gluten exposure affected the risk of celiac disease development. These results led to liberalization of feeding recommendations by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition, which issued guidelines that advised introducing gluten any time between 4 months and 12 months.41Szajewska H. Shamir R. Mearin L. et al.Gluten introduction and the risk of coeliac disease: a position paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.J Pediatr Gastroenterol Nutr. 2016; 62: 507-513Crossref PubMed Scopus (79) Google Scholar Despite the negative results from these studies, there is still interest in the effects of gluten exposure early in life and its effects on celiac disease risk. It is possible that the interventions that were tested in this high-risk population have beneficial effects in lower-risk populations, although this would be difficult to study because of the low numbers of reported outcomes. The prevalence of celiac disease correlates with the amount of consumed gluten,14Ramakrishna B.S. Makharia G.K. Chetri K. et al.Prevalence of adult celiac disease in India: regional variations and associations.Am J Gastroenterol. 2016; 111: 115-123Crossref PubMed Scopus (69) Google Scholar so quantity, rather than timing, might affect risk of celiac disease. This hypothesis has recently gained support—3 cohort studies concluded that children consuming higher quantities of gluten had an increased risk of celiac disease.9Andrén Aronsson C. Lee H.-S. Hård Af Segerstad E.M. et al.Association of gluten intake during the first 5 years of life with incidence of celiac disease autoimmunity and celiac disease among children at increased risk.JAMA. 2019; 322: 514-523Crossref PubMed Scopus (19) Google Scholar,42Lund-Blix N.A. Mårild K. Tapia G. et al.Gluten intake in early childhood and risk of celiac disease in childhood: a nationwide cohort study.Am J Gastroenterol. 2019; 114: 1299-1306Crossref PubMed Scopus (4) Google Scholar,43Mårild K. Dong F. Lund-Blix N.A. et al.Gluten intake and risk of celiac disease: long-term follow-up of an at-risk birth cohort.Am J Gastroenterol. 2019; 114: 1307-1314Crossref PubMed Scopus (9) Google Scholar These studies were performed in different countries (Norway42Lund-Blix N.A. Mårild K. Tapia G. et al.Gluten intake in early childhood and risk of celiac disease in childhood: a nationwide cohort study.Am J Gastroenterol. 2019; 114: 1299-1306Crossref PubMed Scopus (4) Google Scholar; the United States43Mårild K. Dong F. Lund-Blix N.A. et al.Gluten intake and risk of celiac disease: long-term follow-up of an at-risk birth cohort.Am J Gastroenterol. 2019; 114: 1307-1314Crossref PubMed Scopus (9) Google Scholar; and an international cohort including Finland, Germany, Sweden, and the United States9Andrén Aronsson C. Lee H.-S. Hård Af Segerstad E.M. et al.Association of gluten intake during the first 5 years of life with incidence of celiac disease autoimmunity and celiac disease among children at increased risk.JAMA. 2019; 322: 514-523Crossref PubMed Scopus (19) Google Scholar) with prevalences of celiac disease ranging from 1.1%42Lund-Blix N.A. Mårild K. Tapia G. et al.Gluten intake in early childhood and risk of celiac disease in childhood: a nationwide cohort study.Am J Gastroenterol. 2019; 114: 1299-1306Crossref PubMed Scopus (4) Google Scholar to 7%.9Andrén Aronsson C. Lee H.-S. Hård Af Segerstad E.M. et al.Association of gluten intake during the first 5 years of life with incidence of celiac disease autoimmunity and celiac disease among children at increased risk.JAMA. 2019; 322: 514-523Crossref PubMed Scopus (19) Google Scholar The studies included screen-det