The Spectrum of Celiac Disease: Epidemiology, Clinical Aspects and Treatment

Greetje J. Tack; Wieke H. M. Verbeek; Marco W. J. Schreurs; Chris J. J. Mulder

Disclosures
In This Article

Epidemiology

Global Population Trends

Until the 1970s the estimated global prevalence of celiac disease in the general population was 0.03%.[6] The currently estimated prevalence is 1%, with a statistical range of probability of 0.5–1.26% in the general population in Europe and the USA.[7] Even taking into account that the actual occurrence rate of celiac disease has been underestimated for many decades, the prevalence of this disease is increasing. Advances in diagnostic methods and improvement in screening have played a part in the increase observed, but environmental factors have also been important.

Trends in Diagnosis and Screening

The introduction of gastrointestinal endoscopic techniques—which provided the opportunity to take routine biopsy samples—in the 1970s opened new horizons in celiac disease case-finding and diagnosis. In addition, identification of two human leukocyte antigen (HLA) molecules typically associated with celiac disease, HLA-DQ2 and HLA-DQ8, in the late 1980s and early 1990s, respectively,[8] and development of highly sensitive and specific serologic tests have also been important. Furthermore, the implementation, since the late 1980s, of screening programs for detecting celiac disease has contributed to a more realistic estimate of the actual disease prevalence.[9] The recognition that atypical, minor or extraintestinal complaints can be associated with celiac disease in patients of all ages and the detection of a range of histological abnormalities in the small intestine of patients with the disease have also contributed to improved diagnosis.[10–12]

Despite the advances in screening for celiac disease, it remains underdiagnosed.[13] In the general population, the ratio between patients with celiac disease who received an accurate diagnosis and those who were never diagnosed as having the disease was reported to range from 1:5.5[13] up to 1:10.[14] Since the 1980s, a trend towards earlier diagnosis of celiac disease has been observed.[15] Unawareness of celiac disease by physicians probably still underlies misdiagnosis and diagnostic delay.

Environmental Risk Factors

A Finish population-based study has shown that the almost doubled prevalence of celiac disease observed from 1980 (1.03%) to 2001 (1.99%) could not be ascribed only to screening and improved diagnostics, but was rather most probably attributable to environmental changes.[6,16]

Infant Feeding The role of infant feeding on the development of celiac disease has been intensely debated since the late 1980s, which has resulted in a recommendation by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) committee.[17] This committee currently recommends that small amounts of gluten are gradually introduced between 4 and 7 months of age during breastfeeding.[17] This recommendation is strongly supported by a meta-analysis[18] and, moreover, by lessons learned from the Swedish epidemic of celiac disease (1984–1996), which arose as a consequence of changes in infant feeding.[19] In this birth cohort, gluten was mainly introduced abruptly after discontinuing breastfeeding at 6 months of age. At the same time, the gluten content of commercial infant food was increased. The prevalence of celiac disease was almost threefold higher in this birth cohort compared with that in infants born after the epidemic, in whom gluten was introduced gradually while continuing breastfeeding.[19] Although dietary gluten exposure in children under the age of two seems more important with respect to celiac disease risk when compared with exposure in older children,[19] whether breastfeeding only delays clinical onset or whether it leads to permanent protection against celiac disease remains to be elucidated. Interestingly, one study has suggested that breastfeeding during gluten introduction, which slightly delays onset of celiac disease, also influences clinical appearance as well. Among children who develop celiac disease during gluten introduction, those who were breastfed at the same time can present the typical (49%) or atypical (51%) form of disease, whereas the ones in which gluten introduction occurred after breastfeeding was stopped more frequently develop typical gastrointestinal symptoms (90%).[20]

Infections Infections after birth have been proposed to contribute to the development of celiac disease. Whereas the role of infection with adenovirus type 12 in this process remains controversial, the association of HCV infection and celiac disease is well documented.[21] A prospective study showed that frequent rotavirus infections, the most common cause of childhood gastroenteritis, represent an independent risk factor for celiac disease in genetically susceptible individuals.[22] Rotavirus infection changes the permeability of and the cytokine balance in the intestinal mucosa, potentially enhancing penetration of gluten peptides.[22] If this is the case, worldwide implementation of a rotavirus vaccine might diminish the occurrence of celiac disease. The influence of infections with other common intestinal microorganisms, including Campylobacter jejuni, Giardia lamblia and enterovirus has not yet been clarified.[23]

Socioeconomic Features An epidemiological survey where comparisons were made between schoolchildren living in a prosperous area of Finland and children living in an adjacent poor region of Russia, whom in part shared genetic susceptibility and gluten intake, has suggested that worse socioeconomic conditions might protect against celiac disease development.[24] Variation in gut flora, infections and differences in diet, which are factors involved in the maturation of immunoregulatory functions, may in turn precipitate celiac disease development.[24]

Genetic Risk Factors

HLA Genes Celiac disease is a multigenic disorder, in which the most dominant genetic risk factors are the genotypes encoding the HLA class II molecules HLA-DQ2 (encoded by HLA-DQA1*0501 and HLA-DQB1*02) and HLA-DQ8 (encoded by HLA-DQA1*0301 and HLA-DQB1*0302). About 90% of individuals with celiac disease carry the DQ2 heterodimer encoded either in cis or in trans, and practically all of the remaining patients express DQ8.[8] Deamidated gliadin peptides have a high binding affinity to HLA-DQ2 and HLA-DQ8 molecules, but not to other HLA class II molecules, which explains the immunogenicity of gluten in carriers of HLA-DQ2 and HLA-DQ8. A correlation has been found between homozygosity for the genes encoding the HLA-DQ2 molecule and the development of serious complications of celiac disease, in particular RCD and EATL, which implies a gene–dose effect.[25] These HLA-encoding genes are associated with approximately 40% of the heritable risk of developing celiac disease.[26]

Non-HLA Genes Currently, several susceptibility loci not related to HLA have been identified by genome-wide association studies, each of which is estimated to be associated with only a small risk of developing celiac disease. Most of these loci contain immune-related genes, in particular genes implicated in the control of the adaptive immune response. The proteins encoded by these genes include an integrin (encoded by ITGA4 at 2q31),[27] chemokines, cytokines and their receptors (IL2 and IL21 at 4q27, IL18RAP at 2q11–2q12, IL12A at 3q25–3q26, the CCR1 and CCR3 cluster locus at 3p21), and proteins involved in several signaling pathways (RGS1 at 1q31, SH2B3 at 12q24, ATXN2 at 12q24, TNFAIP3 at 6q23.3, REL at 2p16.1), in regulating B-cell (RGS1) and T-cell activation (TAGAP at 6q25), and in maintaining cell adhesion and motility (LPP at 3q28).[28,29] However, association between the risk of celiac disease development and CCR3 and IL18RAP could not be confirmed in other studies.[27,30] The 4q27 region, which harbors the IL2 and IL21 genes, showed the strongest association.[27,29] The latter association, however, accounted for less than 1% of the familial risk of celiac disease and genetic variation in all currently known non-HLA genes together accounts for less than 10%.[27,29] This indicates that many contributing polymorphisms in non-HLA genes still have to be discovered. An association between MYO9B polymorphisms and an increased risk for RCD and EATL has been found, however for uncomplicated celiac disease this association remains controversial.[31] Further research is needed to determine the functions of the proteins that these genes encode and their involvement in the pathogenesis of celiac disease.

Population, Gender and Age Distribution

Variety in genetic factors including the frequency of non-HLA alleles, and environmental factors including dietary habits underlie the variations in the frequency of celiac disease observed in different world regions (Table 1). The HLA-DQ2 heterodimer is frequently found in white populations in Western Europe (20–30%), Northern and Western Africa, the Middle East and central Asia, whereas HLA-DQ8 is more prevalent in Latin America and Northern Europe.[32] Gluten consumption is widespread in Northern Africa, South America and the northern wheat-eating parts of India. The Saharawi population of Arab-Berber origin living in Algeria has the highest prevalence of celiac disease (5.6%) among all world populations.[33] High levels of consanguinity, high frequencies of HLA-DQ2 and gluten being used as staple food in this population may potentially explain this finding.[33] By contrast, celiac disease seems to be rare in individuals of Japanese and Chinese ancestry, for whom the frequency of HLA-DQ2 is negligible.[32] The occurrence of celiac disease may vary within individual countries, for instance in different parts of India.[34,35] This variation is probably attributable to differences in dietary habits and to associations between specific genetic clusters and particular regions. Middle Eastern countries, including Iran, Turkey, Israel and Syria, seem to have similar frequency rates of celiac disease to those of Western countries.[36]

As expected, in high-risk populations the prevalence of celiac disease is much higher than that in the general population. A multicenter study conducted in the USA revealed that the prevalence of serotypes associated with risk of disease was 1:56 in individuals with clinical features of celiac disease or celiac-disease-associated extraintestinal disorders.[37] Furthermore, the prevalence of risk-associated serotypes in first-degree and second-degree relatives of these patients was 1:22 and 1:39, respectively. In adults and children with symptoms that raise suspicion of celiac disease, prevalence rates of 1:68 and 1:25, respectively, were observed.

As with many other autoimmune diseases, celiac disease is more common in women,[38] with a female to male ratio of between 2:1 and 3:1. Some genetic loci are gender-influenced and immunoregulation is subject to hormones, which might explain these differences. By contrast, patients over the age of 60 who are diagnosed as having celiac disease are more frequently male.[39]

Celiac disease can be diagnosed at any age, with a peak at early childhood and at the fourth and fifth decade of life for women and men, respectively. Currently, the reported global prevalence of celiac disease in children ranges from 0.31% to 0.9%.[7,40] The prevalence of celiac disease in adults is approximately 1–2% in Europe[6] and 0.4–0.95% in the USA.[7] Whether diagnosing celiac disease at advanced age is the result of diagnostic delay or of a true late onset of the disease is still debated. Whereas several studies reported a diagnostic delay in the elderly population,[41] other reports suggest that celiac disease may indeed develop later in life.[12,16]

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