Systematic review: worldwide variation in the frequency of coeliac disease and changes over time

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1 Alimentary Pharmacology and Therapeutics Systematic review: worldwide variation in the frequency of coeliac disease and changes over time J. Y. Kang*, A. H. Y. Kang*, A. Green*, K. A. Gwee &K.Y.Ho *Department of Gastroenterology, St George s Hospital, London, UK. Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Department of Gastroenterology and Hepatology, National University Health System, Singapore. SUMMARY Background Coeliac disease (CD), originally thought to be largely confined to Northern Europe and Australasia and uncommon in North America and the Middle East, is now recognised to be equally common in all these countries. It is still thought to be rare in the Orient and Sub-Saharan Africa. Correspondence to: Dr J. Y. Kang, Department of Gastroenterology, St George s Hospital, Blackshaw Road, London SW17 0QT, UK. jykang@sgul.ac.uk Publication data Submitted 6 October 2012 First decision 28 October 2012 Resubmitted 26 May 2013 Accepted 26 May 2013 EV Pub Online 18 June 2013 This uncommissioned systematic review was subject to full peer-review. Aim To assess geographical differences and time trends in the frequency of CD. Methods Medline and Embase searches were conducted on 10 November 2012, from 1946 and 1980 respectively, using the key words: coeliac disease or celiac disease + prevalence or incidence or frequency. Results There were significant intra- and inter-country differences in the prevalence and incidence of CD. Only 24 ethnic Chinese and Japanese patients have been reported in the English literature. Of CD-associated HLA DQ antigens, DQ2 occurs in 5 10% of Chinese and sub-saharan Africans, compared to 5 20% in Western Europe. DQ8 occurs in 5 10% of English, Tunisians and Iranians, but in <5% of Eastern Europeans, Americans and Asians. The prevalence and incidence of both clinically and serologically diagnosed CD increased in recent years. These geographical and temporal differences seem genuine, although variable indices of suspicion and availability of diagnostic facilities are confounding factors. Conclusions Coeliac disease is increasing in frequency, with significant geographical differences. Although few cases have been described to date in the Orient and Sub-Saharan Africa, there is a significant prevalence of HLA DQ2 and wheat consumption is of the same order as that in Western Europe. CD may therefore become more common in the future in these countries. Aliment Pharmacol Ther 2013; 38: doi: /apt.12373

2 Systematic review: geography and time in coeliac disease INTRODUCTION Coeliac disease (CD) occurs when ingestion of gluten by genetically susceptible persons leads to immunologically induced small intestinal mucosal damage. Until the 1990s, CD was thought to occur mainly among White Europeans 1 and deemed uncommon in the Middle East, North Africa and even North America, whose White population is of European origin. 2 CD has since been shown to be as common in these latter countries as in Western Europe, low levels of clinical suspicion and availability of healthcare resources accounting for the previous underdiagnosis. In the Far East and sub-saharan Africa, CD is still rarely diagnosed. This was thought to be due to a low prevalence of the HLA antigens DQ2 in these populations. 3 Racial and geographical differences in disease frequency highlight the interplay between genetic and environmental factors. We hypothesise that there are indeed significant geographical differences in the frequency of CD and that the incidence and prevalence of CD is increasing. We carried out a systematic review on CD frequency in different populations and at different times to test our hypotheses and to examine possible reasons for any difference found. METHODS Medline and Embase searches were conducted on 10 November 2012, from 1946 and 1980 respectively, limited to the English language, using the key words: coeliac disease or celiac disease + prevalence or incidence or frequency. Data on the frequency of HLA DQ2 and DQ8 were obtained from the allele frequency net database. 4 Abstracts were studied to identify those clearly inappropriate for this review. Full-text articles for the remaining papers were then perused and studies fulfilling any of the following criteria included: (i) Incidence and/or prevalence of clinically diagnosed CD assessed in defined populations. (ii) Screening tests for CD [antiendomysial antibodies (EMA), tissue transglutaminase antibodies (ttg) or duodenal biopsy]applied to all members of an unselected group of individuals, for example, schoolchildren or representative community sample. (iii) Screening tests for CD (EMA, ttg or duodenal biopsy) applied to unselected blood donors and populations in which CD frequency is expected to be high, namely, first-degree relatives of CD sufferers, people with Down syndrome and patients with type I diabetes mellitus. (iv) Case reports and case series of CD in Oriental and sub-saharan African populations. (v) Time trend studies of CD incidence or prevalence in defined populations. Reports published only in abstract form were not included and authors were not contacted personally. For serological prevalence rates, we only considered studies based on IgA EMA or IgA ttg. These tests, introduced in the 1990s, have sensitivities and specificities in excess of 90% for both children and adults except when histological grades less severe than Marsh 3 are considered. They are significantly more sensitive and specific than antigliadin and anti-reticulin antibody tests introduced in the 1980s. 5, 6 In most studies IgA EMA and/or IgA ttg were measured, together with total IgA. If IgA deficiency was found, IgG antibodies may then be tested for. In studies where EMA was only performed when AGA or ttg was positive, the data for EMA were not included in this review, although those for ttg would be. Small intestinal biopsies were usually performed on patients testing positive for EMA, ttg or sometimes AGA or ARA. Among individuals testing positive for ttg, a significant proportion reverted to negative when retested. 7, 8 For studies in which testing was repeated, therefore, we considered only the initial test. In comparing incidence and prevalence rates of clinically diagnosed CD, differences in diagnostic criteria must be considered. The European Society of Paediatric Gastroenterology and Nutrition (ESPGAN) criteria, first published in 1970, required a sequence of three small intestinal biopsies, including abnormal mucosa when taking a diet containing gluten, clear improvement when taking a gluten-free diet and deterioration with rechallenge 9 The revised ESPGAN criteria, 10 by contrast, did not require the third biopsy after gluten challenge provided there was clear-cut clinical improvement on a gluten-free diet. Prevalence rates based on the original ESPGAN criteria would therefore be lower than when the modified ESPGAN criteria are employed. The 2012 ESPGAN guidelines 11 indicated that symptomatic children with ttg levels at least ten times above normal and positive EMA and DQ2/DQ8 do not need duodenal biopsies to make the diagnosis of CD, but these guidelines are too recent to be used in any of the studies included in this review. Marsh 3 lesions, with various degrees of villous atrophy plus inflammatory changes, are considered diagnostic for CD. 5 The Marsh 1 lesion, with increased Aliment Pharmacol Ther 2013; 38:

3 J. Y. Kang et al. intra-epithelial lymphocytes, is nonspecific, while hyperplastic changes, classed as Marsh 2, represent an intermediate stage and require further supportive clinical or serological features for a definitive diagnosis. 12 Alexander grades III and IV enteropathy 13 and villous atrophy or flat small intestinal mucosa were taken to be diagnostic of CD for the purposes of this study. We have separately presented histological data for Marsh 1 and Marsh 2 cases, where available. Histological data were excluded when the diagnostic criteria were not explicitly stated, although serological data from the same studies would still be included if appropriate. The incidence of clinically diagnosed CD is often described conventionally, per persons per year. However, some authors express childhood CD incidence in terms of number/1000 live births, i.e. the number of children up to a certain age, developing CD in a given year, divided by the number of live births in the same year. 14, 15 Incidence rate by birth is the number of children with CD divided by the total number of children born in the same year of birth. 16 Other authors calculated cumulative incidence by dividing the number of cases diagnosed up to a certain age by the number of births in each cohort The data obtained from this literature review are unsuitable for summary statistics. However, where appropriate, we have provided 95% confidence limits of prevalence rates to help assess the significance of numerical differences between various studies. RESULTS The combined Medline and Embase search yielded 5170 abstracts, but 1936 were duplicates, leaving 3234 unique abstracts. Of these, 266 studies fulfilled our criteria and were included in the present analysis. Incidence and prevalence of clinically diagnosed CD (Tables 1 and 2) Most studies on the prevalence and incidence of clinically diagnosed CD were undertaken in Western Europe. Significant inter-country differences are apparent. Considering various time periods together, incidence rates for both sexes combined ranged from 0.9 to 12.9/ /year for all ages combined, /1000 live births for children 15 21,24,26 44 and / /year for adults. 35, Again considering various time periods together, prevalence rates for both sexes ranged from 8.1 to 204/ for all ages, 26, / for children 16, 19, 26, 48, 52, 53 and / for 45, 46, 53, 54 adults. Prevalence and incidence of CD based on serological screening in unselected populations (Tables 3 and 4, Figure 1) There were fifteen reports on CD prevalence using serological screening in unselected adult populations, seropositive subjects then being invited for duodenal biopsy in most of the studies. Nine were European, three Australasian, 7, 8, 63 two Asian 64, 65 and one African. 66 IgA EMA IgA ttg was measured and total IgA levels were usually determined in addition to exclude IgA deficiency. The prevalence of CD in these populations ranged from 0% to 1.56% based on IgA EMA, 0% to 1.87% based on elevated IgA ttg levels and 0.02% to 1.24% based on histology. All 600 randomly selected community subjects in Burkina Faso, Africa tested negative for IgA EMA and had normal levels of IgA ttg, although one subject was IgA deficient. 66 Seventeen studies evaluated the sero-prevalence of CD in unselected children, usually using IgA EMA and/or IgA ttg. Fourteen studies were European, two African 81, 82 and one Asian. 83 The prevalence of positive IgA EMA, elevated IgA ttg levels and biopsy-positive CD in these studies ranged from 0.78% to 5.66%, 0.43% to 2.42% and 0.11% to 1.71% respectively. 81 In Saharawi, sub-saharan Africa, 5.6% of 989 unselected children had elevated ttg levels and also tested positive for IgA EMA. 82 Duodenal biopsies were not taken, but all 16 of a separate cohort of Saharawi children with positive EMA had histological features typical of CD and improved with gluten exclusion. The prevalence of elevation of ttg above the reference range in unselected adult and paediatric populations in different countries is charted in Figure 1, as a proxy for the prevalence of CD. Prevalence of CD in blood donors and high-risk patient groups (Table S1) Blood donors represent a self-selected population with a lower risk of CD compared with the general population, as they are unlikely to be symptomatic or ill. Furthermore, anaemia, a recognised presentation of CD, precludes blood donation. Studies on the prevalence of CD in high-risk groups, including first-degree relatives, patients with Down syndrome and type 1 diabetes mellitus, are also summarised in the Table S1. There were 15 studies on blood donors, which fulfilled our inclusion criteria The prevalence of CD in blood donors based on EMA was %, % based on elevated ttg levels, while % had Marsh 3 lesions. 228 Aliment Pharmacol Ther 2013; 38:

4 Systematic review: geography and time in coeliac disease Table 1 Incidence of coeliac disease in different countries Author/Country Sample size Age group Years of study Minimum criteria for diagnosis Incidence All ages Europe Mylotte 1973, Ireland Corrao 1996, Fowell 2006, UK Angeli 2012, North America Talley 1994, USA Murray 2003, USA Australasia Ussher 1994, New Zealand Cook 2004, New Zealand Children Asia Ashkenazi 1983, Israel 29 All ages VA + improvement on 1:303 births gluten-free diet 270 All ages Abnormal biopsy / /year 159 All ages Not stated 8.7/ /year 330 All ages Prescription charge exemption for CD-related drugs Men 7.66/ /year, women Men 4.52/ /year, women All ages Abnormal biopsy 1.2 per /year 82 All ages VA + improvement on gluten-free diet 2.1 per /year overall 0.9 per /year in per /year in per /year in All ages Abnormal histology and improvement on gluten-free diet 1.78 per /year 416 All ages Marsh type 3 2.2/ /year, rising from 1.4/ /year ( ) to 12.9/ / year ( ) 99 Children Intestinal biopsy performed on all patients 1.80/1000 live births overall, but increasing from 1.20 in 1968 to 4.17 in 1979 Dahan 1984, Israel 111 Children VA 1.71/1000 live births Khuffash 1987, Kuwait Rawashdeh 1996 Jordan Europe Borgfors 1968, Mylotte 1973, Ireland Berg 1979, Stenhammar 1987, 20 Children VA 1:3000 births (33/ ) 34 Children Revised ESPGAN criteria 1:2800 live births NS Children Not all had histology 0.16/1000 live births VA + improvement on gluten-free diet 1: Live births ( / /year) 1/982 live births 34 Children Original ESPGAN criteria 167 Children Original ESPGAN criteria : 1.27/1000 live births : 1.43/1000 live births Aliment Pharmacol Ther 2013; 38:

5 J. Y. Kang et al. Table 1 (Continued) Author/Country Sample size Age group Years of study Minimum criteria for diagnosis Incidence Stirum 1982, Switzerland Maki 1988, Finland Pittschieler 1988, Ceccarelli 1991, Ascher 1991, Weile, 1992 Denmark Weile, 1993 Denmark Al-Obaidy 1993, Magazzu 1994, George 1995, Netherlands Corrao 1996, George 1997, Holland Challacombe 1997, UK Matek 1999, Croatia Ivarsson 2000, Hawkes 2000, Wales, UK Lopez-Rodriguez 2003, Spain Kolek 2003, Czech Steens 2005, Netherlands Olsson 2008, 354 Children Histologically confirmed 1:1165 livebirths 96 Children & adolescents Original ESPGAN criteria or flat mucosa and clinical improvement on gluten withdrawal : 1:1096 live births : 1:3214 live births Original ESPGAN criteria / live births Small bowel biopsy 1:535-1: Children Flat mucosa + response to gluten-free diet Cumulative incidence at 2 years of age/1000 live births 0.31 in first birth cohort to 2.93 in last cohort 22 Children Original ESPGAN criteria Copenhagen County: Incidence rate by birth 0.10 per 1000 live births 176 Children National and local registers, Celiac-Patient Society, data evaluated by authors 122 Children VA + improvement with gluten-free diet Abnormal biopsy and improvement on gluten-free diet Whole of Denmark: Incidence rate by birth 0.09 per 1000 live births 1.58/1000 live births Maximum cumulative incidence rate up to 1989: 1.65/1000 standardised incidence rate: 3/1000 live births Revised ESPGAN criteria 0.18 per 1000 crude incidence rate ( ) At least one abnormal Cumulative incidence rate 15: biopsy / live births Histology / /year Revised ESPGAN criteria Cumulative incidence: 0.68/1000 live births in children born /1000 live births Children Original ESPGAN criteria Cumulative incidence 1.9:1000 live-births over 10-year period 2151 < Revised ESPGAN criteria Cumulative incidence /1000 live births 27 < Revised ESPGAN criteria Children / /year VA 6.87 per /year per /year 205 Children Revised ESPGAN criteria 91/ /year / /year /100,000/year / /year VA 0.81/1000 live births Abnormal biopsy 10 45/ Aliment Pharmacol Ther 2013; 38:

6 Systematic review: geography and time in coeliac disease Table 1 (Continued) Author/Country Sample size Age group Years of study Minimum criteria for diagnosis Incidence Olsson 2009, Dydensborg 2012, Denmark Hurley 2012, Wales, UK North America Hoffenberg 2003, USA Australasia Ussher 1994, New Zealand Cook 2004, New Zealand Adults Europe Bode 1996, Denmark Hawkes 2000, Wales, UK Virta 2009, Finland Hurley 2012, Wales, UK North America Riddle 2012, USA NS Revised ESPGAN criteria 21 40/ /year National patient registry 0.8 per /year in 1996 to 6.9 per in Revised ESPGAN criteria 6.89 per /year ( ) 19 Children Marsh 2 or 3 Adjusted risk estimate for evidence of CD by age 5 years: 0.9% (1:104) Abnormal histology and improvement on gluten-free diet 0.1/1000 live births Marsh type 3 Cumulative incidence over 30-year period: 0.40/1000 births, 0/1000 births ( ) 1.40/1000 births ( ) Revised ESPGAN criteria 1.27 per /year 110 > Revised ESPGAN criteria Adults: / /year Entitlement to dietary 39/ /year reimbursement 305 > per /year in US military Electronic medical encounter data 1.3/ /year in / /year in 2008 VA, villous atrophy; ESPGAN, European Society of Paediatric Gastroenterology and Nutrition. Twenty-nine studies on first-degree relatives fulfilled our inclusion criteria Of these, % were positive for EMA, % had elevated levels of ttg, while % had Marsh 3 changes or villous atrophy on histology. Twenty-three studies on patients with Down syndrome fulfilled our inclusion criteria The prevalence of EMA positivity ranged from 0% to 19.39%. The prevalence of elevated ttg levels ranged from 2.99% to 19.72%, while the prevalence of villous atrophy or Marsh 3 changes ranged from 2.63% to 18.75%. Sixty-two studies on the prevalence of CD in patients 73, with type 1 diabetes were included in this review. The prevalence of EMA positivity ranged from 0% to 13.83%; that of elevated ttg levels ranged from 0.81% to 21.16%, while 0.40% to 12.16% showed villous atrophy, flat biopsies or Marsh 3 histological changes. Temporal changes in the frequency of coeliac disease Six studies from, 17, 18, 27, 30, 41, 44 two each from Holland 15, 19 and 31, 212 and one each from Spain 38 and the Czech Republic 213 investigated time trends in the frequency of clinically diagnosed childhood CD from the 1970s to the 1990s, generally using the original or revised ESPGAN criteria. All showed an increasing trend. Possible reasons include a true increase in CD prevalence, introduction of serological tests, increased awareness about the condition and changes in diagnostic criteria. An epidemic of CD was described in from 1985 to 1995, 17, 41 possibly related to a doubling of gluten content in baby food at that time. Two Canadian studies reported several fold increases in the number of children diagnosed with CD from the 1990s to the 2000s. 214, 215 These increases were attributed to greater awareness and the introduction of serological tests and Aliment Pharmacol Ther 2013; 38:

7 J. Y. Kang et al. Table 2 Prevalence of coeliac disease in different countries Author/Country Sample size Age group Years of study Minimum criteria for diagnosis Prevalence All ages Europe Hallert All 1979 Alexander II IV 58/ Logan 1986 Scotland 469 All 1979 Subtotal VA 50/ men 74/ women Jansen All 1992 Biopsy proven with VA 8.1/ Holland Collin 1997 Finland Angeli 2012 Australasia Carrington 1987 New Zealand Ussher 1994 New Zealand Children Australasia Carrington 1987 New Zealand Ussher 1994 New Zealand Europe Hallert 1983 Weile 1992 Denmark George 1995 the Netherlands George 1997 Holland Gumaa 1997 Ireland 13.1/ All 1994 Histology 111/ men 280/ women 204/ All 330 All Prescription charge exemption for CD-related drugs 20 All Abnormal histology + response 9/ to gluten-free diet 38 All Histology 70/ Children Abnormal histology + response 35/ to gluten-free diet Histology 14/ Men 7.66, Women Men 67.77, women <15 1 July 1981 Original ESPGAN criteria 104/ (1:960) 22 Children Original ESPGAN criteria 9 12/100, Revised ESPGAN criteria Prevalence 4.7(1980) 15.1(1990)/ Histology 7.9 (1990) 17.5 (1995)/ < Abnormal histology + response to gluten-free diet Cumulative population prevalence/ live births: (250); (100); (40) Dydensborg Denmark 1683 < National patient registry 43.2 per in per in 2010 Adults Europe Bode > Revised ESPGAN criteria 45.9/ Denmark Hallert Original ESPGAN criteria 106/ (1:950) Midhagen Histology + clinical features 95.5/ Virta 2009 Finland Histology 550/ (700/ F, 380/ M) VA, villous atrophy; ESPGAN, European Society of Paediatric Gastroenterology and Nutrition. screening. An Italian study, using prescription charge exemption for CD-oriented drugs as proxy for CD, reported a stable incidence from 2002 to 2010, but a consistent increase in prevalence from 2002 to It is possible that rigorous diagnostic criteria may not have been applied in this study. In contrast, there was a marked fall in the incidence of paediatric CD from the 1970s to the 1990s in 232 Aliment Pharmacol Ther 2013; 38:

8 Systematic review: geography and time in coeliac disease Table 3 Community prevalence of CD in unselected adults Author/Country Sample size Subjects Serological screening test % Prevalence by serology EMA unless otherwise stated (95% confidence limits) % Prevalence by histology (95% confidence limits) (minimum criteria) Europe Pittschieler 1996 Corazza 1997 San Marino Riestra 2000 Spain 4615 Healthy adults EMA 0.20 ( ) 0.20 ( ) (VA) 2237 Random sample of the general population EMA 0.18 ( ) 0.18 ( ) (VA) 1170 Random cross-sectional EMA 0.17 ( ) 0.17 ( ) (VA) sample from population register 1894 Random sample of the EMA 0.48 ( ) 0.42 ( ) general population (Alexander III IV) 3483 All Inhabitants in two towns EMA 0.57 ( ) 0.48 ( ) (VA) Ivarsson 1999 Volta 2001 West General population sample England from a previous survey Schweizer Randomised stratified Holland population sample Fabiani Healthy residents and students Roka Healthy individuals recruited by Greece systematic random sampling Mustalahti 2010 Finland 6403 Representative sample of the population Germany 4633 Sera from previous populationbased survey 4173 Sera from previous population-based survey 4781 Cross-sectional samples from 2 surveys Northern Ireland 4656 Sera from previous population-based survey Vippula 2008 Finland Australasia Cook 2000 New Zealand Hovell 2001 Australia Chin 2009 Australia North America Godfrey 2010 USA Rubio-Tapia 2012 USA 2815 People in age groups representative of the general population 1064 Random Sample of electoral rolls 3011 Random sample of the population, Brusselton Health Study, Sera taken 1994/ Random sample of the population, Brusselton Health Study, Sera taken 1994/ Population-based sample of residents 50 years 7798 Representative population sample EMA 1.2 ( ) Not performed EMA 0.42 ( ) Not performed ttg 1.12 ( ) ttg 1.07 ( ) 0.56 ( ) (VA) ttg 0.54 ( ) 0.18( ) (Marsh 3) ttg 1.87 ( ) 0.73 ( ) (Marsh1) ttg 1.36 ( ) 0.02 (0 0.12) (Marsh 1) ttg 0.43 ( ) 0.12( ) (Marsh 1) ttg 1.36 ( ) 0.48( ) (Marsh 1) ttg 1.59 ( ) 0.06 ( ) (Marsh 1) ttg EMA 1.74 ( ) 1.56 ( ) 1.24 ( ) (Marsh 3) EMA 1.13 ( ) 0.94 ( ) (Marsh 3) 1.13 ( ) (Marsh 2) EMA 0.33 ( ) 0.23 ( ) (VA) ttg 1.56 ( ) Criteria not explicitly stated ttg 0.96 ( ) NA ttg 0.51 ( ) Not performed Aliment Pharmacol Ther 2013; 38:

9 J. Y. Kang et al. Table 3 (Continued) Author/Country Sample size Subjects Serological screening test % Prevalence by serology EMA unless otherwise stated (95% confidence limits) % Prevalence by histology (95% confidence limits) (minimum criteria) Asia Akbari 2006 Iran Israeli 2010 Israel Africa Cataldo 2002 Burkina Faso 2799 Stratified random sampling of the population ttg EMA 1.04 ( ) 0.18 ( ) 0.14 ( ) (Marsh 3) 0.32 ( ) (Marsh 2) 0.96 ( ) (Marsh 1) 850 Army recruits ttg 1.06 ( ) 0.71 ( )(Marsh 3) 600 General population randomly selected and unrelated subjects. EMA, ttg, HLA. 0 NA NA, not applicable; AGA, antigliadin antibody; EMA, antiendomysial antibody; ttg, tissue transglutaminase antibody; VA, villous atrophy. England, 32, 216, 217 Scotland 51 and Ireland, 52 although not Wales, 35 attributed to changing infant feeding practices. On the other hand, four British studies, two of them consecutive in the same population, showed an increase in the incidence of adult CD from the 1960s to the 2000s. 22, 35, 47, 218 However, there was no change in Denmark from 1976 to An increasing incidence was reported in Olmsted County, USA from 1950 to and also in India from 1995 to Serological studies on stored specimens provide reliable evidence of an increasing prevalence over time. Two large Finnish population-based studies, twenty years apart, using ttg and EMA antibodies, showed a doubling in CD prevalence from to An American study compared sera collected between 1948 and 1954 with two matched cohorts collected between 1995 and 2003 and between 2006 and 2008 respectively. 221 The prevalence of CD was four times higher in the recent cohorts compared with the earlier one. Another retrospective analysis of matched serum samples taken from US community volunteers in 1974 and 1989 showed a doubling in prevalence. 222 In this study, only one of nine individuals who developed CD had the diagnosis clinically made, 222 highlighting the poor awareness of CD over this time in USA. Comparison between countries and regions Studies from, 42, 223 Holland 34 and 21 showed up to two-fold differences in CD incidence or prevalence in different regions or cities, attributed to varying disease awareness, healthcare behaviour and dietary gluten intake, possibly influenced by socio-economic factors. In a defined area in Kuwait, CD was three times more common among Palestinians, whose staple diet was wheat, compared with Kuwaities who consumed rice. 37 In Israel, CD is commoner among Jews compared with Arabs, possibly due to different levels of clinical suspicion in the two communities. 224 The incidence of clinically diagnosed childhood CD in a German community in was three times that in their Italian counterparts. 43 Sera from adults and children in Finland, Germany, Northern Ireland and were tested for IgA ttg in a centralised laboratory. Subjects with positive or borderline results were tested for IgA EMA and intestinal biopsy recommended for EMA-positive subjects. The overall prevalence of CD was 1% or 1.5% depending on definition. Adult subjects showed 5- to 8-fold inter-country variations, from 2.6 and 2.4% in Finland to 0.5 and 0.3% in Germany. Britain and had intermediate prevalence rates. 106 While clinically diagnosed CD was six times more common in compared with neighbouring Denmark, 225 sero-prevalence in blood donors was similar, 226 suggesting that the difference may be more apparent than real, due to varying indices of suspicion. However, a serological and histological survey performed in adjacent counties in Finland and Russia, 79 using the same diagnostic tests in the same laboratory, demonstrated 2- to 4-fold differences in CD prevalence, depending on the diagnostic criteria used. This is strong evidence for a true difference in CE prevalence in the two communities, unaccounted for by the frequency of relevant HLA haplotypes. Coeliac disease in the Orient Only six biopsy-proven cases of CD were described among ethnic Japanese, although a White Canadian 234 Aliment Pharmacol Ther 2013; 38:

10 Systematic review: geography and time in coeliac disease Table 4 Community prevalence of undiagnosed coeliac disease in unselected children Author/Country Sample size Subjects Screening test % Prevalence by serology (95% confidence limits) % Prevalence by histology (95% confidence limits) (minimum criteria) Europe Csizmadia ,127 Children attending the EMA 1.22 ( ) 0.51 ( ) (VA) Netherlands Health Care Centres Kopornay Healthy nursery EMA 1.41 ( ) 1.17 ( ) (flat) Hungary schoolchildren. Carlsson Healthy children EMA 1.88 ( ) 1.16 ( ) (VA) attending for routine check-up Maki Population-based EMA 1.40 ( ) 0.74 ( ) (VA) Finland screening ttg 1.42 ( ) Tommasini Schoolchildren ttg 1.51 ( ) Criteria not explicitly stated Castano Healthy children ttg 1.20 ( ) 0.84 ( ) (flat) Spain Ertekin 2005, Turkey 1263 Randomly selected ttga 0.87 ( ) 0.55( ) (Marsh III) healthy schoolchildren Ravikumara Subjects randomly selected EMA 0.99 ( ) Biopsy not performed England from previous study Korponay Children aged 6 in one ttg 1.56 ( ) 1.19 ( ) (VA) Hungary county Ress Schoolchildren ttg 0.43 ( ) 0.34 ( ) Estonia Kondra 2009 Russia 1988 Schoolchildren ttg 0.60 ( ) 0.11 ( ) (VA) Finland 3654 Schoolchildren ttg 1.42 ( ) 1.71 ( ) (VA) Szaflarska-Poplawska 3210 Children born in one EMA 0.78 ( ) 0.22( ) (Marsh III) 2009 Poland town over 4 years Mustalahti Secondary school ttg 1.25( ) 0.72 ( ) (Marsh II) population Northern Ireland 1975 Cardiovascular risk ttg 0.91( ) 0.10 ( ) (Marsh II) Dalgic 2011 Turkey Africa Catassi 1999 Western Sahara Ben Hariz 2007 Tunisia Asia Nusier 2010 Jordan North America Galvan 2010 Cuba factor survey Schoolchildren ttg 2.42 ( ) 0.47 ( ) (Marsh 1) 0.38 ( ) (Marsh 2) 0.35 ( ) (Marsh 3) 989 Unselected Children EMA 5.66 ( ) No Biopsies taken 6284 Schoolchildren ttg EMA 2.21 ( ) 0.64 ( ) 0.37 ( ) (VA) 1985 Schoolchildren ttg 1.51 ( ) No biopsies taken 595 Apparently healthy children aged 3 years EMA, antiendomysial antibody; ttg, tissue transglutaminase antibody; VA, villous atrophy. ttg 0.50 ( ) No biopsies taken patient with CD was reported from Japan. 230 Eighteen cases of biopsy-proven CD were described among Chinese One patient of Chinese ethnicity was 227, described in Canada. 227 Four Chinese patients with diarrhoea had CD initially recognised at capsule endoscopy and subsequently confirmed histologically. 231 In another Chinese study, 233 seven of 78 patients with irritable bowel syndrome or insulin-dependent diabetes had positive IgG Aliment Pharmacol Ther 2013; 38:

11 J. Y. Kang et al. U K c Finland c a Holland a Estonia c Germany a Hungary c Russia c United States a Western Sahara c Spain c c a Tunisia c Burkina Faso a Greece a Israel a Jordan c Turkey c Iran a Laos No data < 0.45% 0.50%-0.95% 1.00%-1.95% 2.00% Adults Children a c Australia a Figure 1 Worldwide prevalence of Coeliac disease, expressed as percentage prevalence of elevated tissue transglutaminase antibody levels in unselected adult and paediatric populations. AGA, IgA ttg or both. Small intestinal biopsies were not performed, but diarrhoea and weight loss improved in two patients with gluten exclusion. One hundred and eighteen Chinese children from four cities, who presented with chronic diarrhoea, underwent serological testing with ttg and EMA, proceeding to duodenal biopsy if EMA was positive or ttg, strong positive. Fourteen had histological abnormalities consistent with CD, although only 11 had Marsh III changes. 232 Of 22 Chinese patients with dermatitis herpetiformis, 234 8/16 tested positive for EMA, while 10/16 tested positive for ttg. Small intestinal biopsies were obtained for only two patients, both demonstrating mild-to-moderate villous atrophy. Prevalence of DQ2 and DQ8 in various populations 4 (Figures 2 and 3) Almost all patients with CD carry the DQ2 or DQ8 molecule, compared to 25 40% of the general population of the United States of America. 235 These two HLA haplotypes are therefore considered a necessary, but not sufficient, factor for CD. 236 In Western Europe, the allele frequency of DQ2 is in the region of 5 20% and that of DQ8, 5 10%. Similar frequencies of DQ2 are found in North Africa and the Middle East, while the prevalence of DQ8 is around 5 10% in these countries. The frequency of DQ2 in North Americans is likewise around 10 15%. In China, DQ2 frequency is in the order of 5 10%, although that of DQ8 is below 5%. DQ2 frequency in several countries in sub-saharan Africa is in the order of 5 10%. 4 Most CD patients carry the DQ2 heterodimer formed by DQB1.02 and DQA1.05, denoted DQ , 238 In contrast, DQ2.2, formed by DQA and DQB1.0202, does not predispose to CD unless expressed together with DQA1.05, thus forming the DQA1.05 DQB1.02 heterodimer. The frequency of DQ2.5 is 7.2% in Jiangsu province, Eastern China 233 and 4.5% in Canton, South China, compared to 12.7% in an English population. 4 DISCUSSION The clinical presentation of CD has changed in recent decades, from steatorrhoea, diarrhoea, weight loss and failure to thrive, to atypical gastrointestinal symptoms such as bloating, nongastrointestinal symptoms such as iron deficiency anaemia to asymptomatic patients diagnosed through serological 23, 215 screening. 236 Aliment Pharmacol Ther 2013; 38:

12 Systematic review: geography and time in coeliac disease Canada United States Mexico UK Spain Morocco Belgium Belarus Ukraine Slovenia Croatia Georgia Turkey Greece Iran Tunisia Algeria Jordan India Russia Mongolia China South Korea Cameroon No data 1.0%-4.9% 5.0%-9.9% 10.0%-14.9% 15% Gabon Congo Fiji Figure 2 The prevalence of DQ2 (DQA1*05:01-DQB1*02:01) in various countries (median percentage of available studies). The introduction of EMA and ttg facilitated the diagnosis of CD and allowed screening of family members and patients with conditions like type 1 diabetes and Down syndrome. However, not all eligible subjects take part in serological surveys of community subjects and patient groups. The prevalence rates of histologically confirmed CD in these studies are minimal estimates because not all serologically positive subjects undergo biopsies. We have demonstrated an increasing frequency of CD in recent decades, due in part to the advent of serological testing and increasing awareness, for example, recently in North America. However, evidence for a true increase comes from retrospective analysis of stored sera from community subjects compared with sera collected at a 220, 221, 239 later date. The reasons behind this increase are uncertain, but changing patterns of early childhood infections the hygiene hypothesis is one possibility. 240 Significant geographical variation in CD frequency was also demonstrated in this review, with differences in incidence and prevalence rates frequently greater than their 95% confidence limits. While some of this variation can again be accounted for by different levels of clinical suspicion and availability of healthcare resources, these confounders are less relevant when comparing neighbouring provinces or countries, especially serological studies 79 using the same techniques. The high prevalence of CD in Saharawi, mentioned earlier, may in part be due to a 42.5% frequency of DQ There was also a rapid increase in wheat intake in recent decades, often initiated during the first month of life. CD is rare in the Orient and sub-saharan Africa, areas where the main agricultural crops of rice, maize, millet and sorghum do not contain gluten. In this review, we only encountered 24 ethnic Chinese or Japanese biopsyproven cases. We know of another report in Japanese, but histology was not available. 242 One of five Japanese patients with idiopathic cerebellar ataxia and antigliadin antibodies improved with gluten exclusion, although duodenal histology was not diagnostic of CD. 243 ASwedish study not included in this review found that second-generation immigrant children, particularly those from China, Japan or Korea, were less likely to be hospitalised for CD than children born to Swedish parents. 244 In the Middle East, North Africa, Europe and North America, wheat was always a staple part of the diet and annual per capita consumption is in the order of kg. 245, 246 Wheat consumption increased in Japan Aliment Pharmacol Ther 2013; 38:

13 J. Y. Kang et al. UK Belarus United States Mexico Venezuela Spain Morocco Slovenia Georgia Greece Iran Tunisia Jordan Ethiopia India China South Korea Japan No data 1.0%-4.9% 5.0%-9.9% 10.0%-14.9% 15% Fiji Figure 3 The prevalence of DQ8 (DQA1*03:01-DQB1*0302) in various countries (median percentage of available studies). from a low base after the Second World War to around 50 kg per capita per year in the last decade, comparable to that in western countries. In developing countries, wheat consumption increased greatly in recent decades. 247 In China, per capita wheat consumption, after trebling from the 1960s to the 1980s, remained stable between 80 and 90 kg per year since the 1990s. 248, 249 In Southeast Asia, wheat consumption increased from under 5 kg per capita per annum in 1961 to 15 kg by In Sub-Saharan Africa, wheat consumption increased three-fold between 1960 and 1985, although remaining at relatively low levels and averaging around 10 kg per capita per year. 250 These increases occurred through urbanisation, food aid and government policies, which sometimes made imported cereals more available than domestically produced staples. Wheat consumption is expected to continue to increase, especially in developing countries. 248 Undoubtedly, there would be significant publication bias as studies on CD prevalence are unlikely to be performed in populations where CD is uncommon. However, this does not fully explain the geographical variation. The authors and their colleagues have worked in Asian institutions with excellent diagnostic facilities and have diagnosed CD in Caucasian expatriates, but not in Oriental individuals. A subgroup of patients with diarrhoea-predominant irritable bowel syndrome, but not CD, nevertheless respond to a gluten-free diet. 251, 252 These patients exhibit IgG antigliadin or ttg antibodies and an association with HLA DQ2 suggests a possible link with CD. Such patients have recently been described in Singaporean Chinese 253 with insufficient histological abnormality to diagnose CD. Perhaps this represents a mild form of CD, which may develop into the full-blown form in due course, but another possibility is that gluten sensitivity and CD represent two distinct conditions. Although Cummins pointed out that the frequency of DQ2 is low in Southeast Asia and extremely low in Japan, 3 there is actually a DQ2 prevalence of 5 10% in Southeast Asia, China and sub-saharan Africa, although the prevalence of DQ8 in Asia is generally <5%. As pointed out earlier, the intake of wheat is significant in these populations and increasing in some cases. There is therefore the potential for CD to become more common in the Far East. However, among DQ2- and DQ8-positive individuals, there may be other genetic factors that inhibit the development of CD. The timing of gluten introduction may matter and gluten exposure in infancy may not necessarily be proportionate to total wheat 238 Aliment Pharmacol Ther 2013; 38:

14 Systematic review: geography and time in coeliac disease intake. It is also possible that gluten-induced small intestine damage occurs in a milder form in Oriental populations compared with the west. The frequency of several gastrointestinal diseases, for example, reflux oesophagitis, inflammatory bowel diseases, previously uncommon in the Orient compared with western populations, increased rapidly in recent years, presumably through westernisation and urbanisation. 254, 255 It is possible that the same will occur for CD, as Oriental populations possess the necessary HLA types and consume significant amounts of wheat. If even a tiny proportion of Oriental and African individuals possessing DQ2 and DQ8 alleles were to develop CD, many cases would present in coming decades and lead to a significant public health problem. AUTHORSHIP Guarantor of the article: J. Y. Kang. Author contributions: The study was conceived by JY Kang, with further ideas contributed by KY Ho and KA Gwee. AHY Kang and A Green carried out the literature search and reviewed the papers with J Y Kang. A Green produced the maps. JY Kang drafted the manuscript, which was then approved by all the other authors. All authors approved the final version of the article, including the authorship list. ACKNOWLEDGEMENTS The authors thank Professor Ciclitira and Dr Simon Moodie for their advice. Professor Y H Chan and Dr Poloniecki kindly provided statistical input. Declaration of personal and funding interests: None. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. Prevalence of coeliac disease in blood donors, first-degree relatives of coeliac patients, people with Down syndrome and patients with diabetes mellitus in different countries. REFERENCES 1. Gardiner AJ, Mutton KJ, Walker- Smith JA. A family study of coeliac disease. Aust Paediatr J 1973; 9: Fasano A. Where have all the American celiacs gone? 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