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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Gastroenterol. Author manuscript; available in PMC 2011 March 1.
Published in final edited form as:
PMCID: PMC2830645

Celiac Disease


Purpose of review

To summarize recent advances in celiac disease (CD) published between August 2008 and July 2009.

Recent findings

CD affects ~1% of most populations but remains largely unrecognized. In the last year, work has shown that the prevalence of CD has increased dramatically, not simply due to increased detection. Also, undiagnosed CD may be associated with increased mortality. Significant progress has been made in understanding how gliadin peptides can cross the intestinal border and access the immune system. New genetic loci and candidate genes that may contribute to the risk of CD and its overlap with type 1 diabetes mellitus have been identified. New deamidated gliadin peptides antibodies have better diagnostic accuracy over native gliadin-based tests. The inclusion of duodenal bulb biopsy specimens may increase the rate of CD detection. The spectrum of CD likely includes a minority of patients with mild enteropathy. A practical 7-item instrument may facilitate standardized evaluation of gluten-free diet adherence. Finally, refractory CD, whilst rare, is associated with a poor prognosis.


Celiac disease is a global health problem that requires a multidisciplinary and increasingly cooperative multinational research effort.

Keywords: undiagnosed celiac disease, mortality, autoimmunity, gluten


This review summarizes the basic and clinical advances in CD published between August 2008 and July 2009 including Epub ahead of print listed by July 2009 at the time of PubMed search. During the study period, a total of 557 publications were identified in PubMed using the keyword “Celiac Disease”. We exclude review articles (n=77), case reports (n=67), letters or editorials (n=48), and those articles not written in English language (n=48). Thus, 317 original articles, metaanalysis, or systematic reviews were considered for inclusion. Citations were chosen on relevance by authors’ subjective selection.


Celiac disease (CD) now affects ~1% of most populations. This was not always so. In fact, at least two studies have shown that over time there has been a substantial increase in background prevalence of the disease.1, 2 In addition to an increase in background prevalence, serologic testing for CD has impacted the rate of diagnosis as well as our understanding of the epidemiology of CD. The incidence of CD in children <2 years of age showed an epidemic pattern in Sweden during the period of 1984–1996.3 A population-based incidence register of CD covering epidemic and post-epidemic birth cohorts revealed that the cumulative incidence at 2 years of age was almost 3 times higher during the epidemic, compared to the years before and after the epidemic.4 Also, a significant successive increase in incidence rates among children <2 years of age was once again revealed during the last years of follow-up monitoring rising the question of a new epidemic approaching.4 Furthermore, a study that followed up the fate of children born during the Swedish epidemic of infant CD showed an increasing prevalence of CD in these children reaching 3% by the age of 12.5

Whilst CD was traditionally considered a childhood disease, most patients are diagnosed in adulthood. Indeed, the prevalence of CD in Finland adults aged 52 to 74 years was 2.1%, higher than the prevalence reported in the general population.6 Virta7 reported that the nation-wide point prevalence of adult diagnosed CD in Finland is 0.55%, the highest reported to date for clinically-diagnosed CD. Therefore, awareness of CD diagnosis and active case-finding are encouraged in all ages.

Why the prevalence of celiac disease may have increased over time is not clear. This is too short a time period for substantial changes in human genetics and likely represents some major and pervasive environmental influence. Concepts such as the hygiene hypothesis, perhaps changes in wheat or other cereals may influence this. One study suggesting a pervasive environmental influence identified a higher rate of celiac disease in Finland compared to the adjacent, but less developed, Karelia.8 Immunoreactivity to dietary proteins in CD appears to be age-related; specifically IgA immunoreactivity to bovine milk caseins was lower in CD patients under 2 years of age than older children or young adults suggesting that the proteins in infant formulas and foods could be associated with the risk for CD prevalence.9

Abu-Zekry10 demonstrated that CD is a frequent disorder among not-at risk (general population) and at-risk (type 1 DM, diarrhea) Egyptian children, similar to the rate in Iceland. 11 These data and previous reports of high prevalence of CD in the “Fertile Crescent” challenges the hypothesis of a Middle East-Europe CD prevalence gradient attributable to a lack of exposure to cereals until relatively recently (Simoons’ hypothesis).

Undiagnosed Celiac Disease is not benign

Delay in diagnosis, especially in patients who have severe symptoms at presentation, is associated with increased mortality, primarily because of malignancy. A major question relates to what is the ultimate outcome of undiagnosed, presumed silent CD. Two studies suggested a significantly increased risk of mortality in patients with undiagnosed CD.1, 12 However, the association with increased mortality is not universal nor is the association with increased malignancy.13, 14 For example, CD detected in an older population is not necessarily associated with increased risk of either malignancy or general mortality (author’s unpublished data). However, the longest follow-up study over 45 years showed the accumulated excess mortality does not occur until 25 years after the serum sampling date,1 suggesting that if one got CD later in life it may take much longer follow-up to determine excess mortality if it occurs.


Celiac disease results from innate and adaptive immune system dysregulation. Activation of the adaptive immune system implies that gliadin (the toxic component of gluten) cross the intestinal epithelium. It has been hypothesized that increased intestinal permeability is an early event in CD pathogenesis. Lammers et al15 demonstrated that gliadin bind to the chemokine receptor CXCR3, the interaction gliadin-CXCR3 may induce release of zonulin that may lead to tight junction disassembly and subsequent paracellular passage of gliadin to the gut mucosa. Other mechanisms of gliadin transport in CD have been postulated. Matysiak-Budnik et al16 and Heyman et al17 demonstrated the overexpression of the transferrin receptor CD71 in patients with active CD; this receptor may transport gliadin across the intestinal mucosa through retro-transcytosis of secretory immunoglobulin A-gliadin complexes. Finally, Schumann et al 18 demonstrated that epithelial translocation of the intact or partially degraded α2-gliadin-33mer (an important trigger of CD) occurs by apical-to-basal transcytosis and that this process is stimulated by interferon-γ, a key cytokine involved in CD immunopathogenesis. In summary, these novel findings suggest that gliadin transport through the epithelial barrier in CD may involve paracellular as well as transcellular mechanisms. Better understanding of the complex mechanisms associated to gliadin transport might lead to novel therapeutic strategies for CD in the future.

Fina D et al19 demonstrated a gluten-dependent increased expression of both RNA and protein interleukin 21 in duodenal samples of patients with untreated CD as well as the relevance of this cytokine to sustain T-bet expression and interferon-γ production. Bas et al20 showed that patients with CD may fail to regulate T cell response to gluten because of an impaired capacity for extra-thymic T cell receptor gene rearrangement.

Grose et al21 demonstrated that invariant NK T cells were both systemically deficient and with defective cytokine production in CD, this observation suggest that a deficiency on immunoregulatory NK T cells may play a role in loss of immunological tolerance in CD.

Cytosolic phospholipase A2 is a central molecule in NKG2D-mediated cytolysis in cytotoxic T lymphocytes.22

Di Sabatino23 demonstrated that mucosal addressin cell adhesion molecule 1 (a critical molecule in lymphocyte homing to the gut) is strongly up-regulated in untreated CD dependent on interferon α and may be involved in the mucosal damage in CD.

Serological responses to commensal enteric bacteria (either anti-Saccharomyces cerevisiae antibodies, Pseudomonas fluorescens associated sequence I2 or Bacteroides caccae TonB-linked outer membrane protein) are frequent in CD.24 Serum levels of microbial antigens decreased significantly during GFD, also ASCA levels correlated with the grade of mucosal injury, thus, these markers may be gluten dependent in CD patients.25

Clinical manifestations and Associated conditions

Celiac disease has a wide spectrum of gastrointestinal and extraintestinal manifestations. In a prospective Spanish cohort,26 female preponderance, presence of typical symptoms, marked villous atrophy, and higher titer of tissue transglutaminase antibodies were more frequently observed in children than adults. Time to diagnosis was shorter in children than in adults. 26 Dental enamel defects were more prevalent in celiac children than non-CD controls (83.3% vs. 53.3%, p=.02).27

Many conditions occur in association with CD. CD is associated with diabetes mellitus type 1 (T1DM), although most children had a silent presentation and yearly screening for CD may be necessary to detect the majority of cases. 28 Children and adults with CD may have a modest increased risk of sepsis; however, the risk is higher for pneumococcal-related sepsis.29 Increased risk of pneumococcal infection in CD was also suggested by a British study that included a cohort of 18 928 CD patients, although risk was not as high as for splenectomized subjects.30 The risk of non-Hodgkin lymphoma is higher in patients with CD and also among individuals with a sibling affected with CD.31 Neurologic dysfunction can be the sole presenting feature of gluten sensitivity, antibodies to transglutaminase 6 IgG and IgA are prevalent in gluten ataxia and these antibodies can serve as a marker of CD-associated neurological disorder. 32

The increased risk of autoimmune conditions such as T1DM or juvenile rheumatoid arthritis/juvenile idiopathic arthritis is not limited to CD cases but also present among first-degree relatives of celiacs.33 The risk of CD in first-degree relatives of CD patients may be higher than previously though especially for siblings.34 The prevalence of depression is higher in patients with both T1DM and CD.35

Patients with CD have a 70-fold increased risk to have microscopic colitis compared with the general population.36 Patients with concurrent microscopic colitis and CD frequently required steroids or immunosuppressive drugs to control diarrhea and may have more severe villous atrophy.36

The prevalence of biopsy-proven CD was 2.8% among 251 patients with Turner‘s syndrome.37 Small-bowel bacterial overgrowth diagnosed by quantitative culture of intestinal aspirate was observed in 9.3% patients with symptomatic treated or untreated CD.38

A systematic review and meta-analysis demonstrated that the prevalence of CD in patients meeting diagnostic criteria for irritable bowel syndrome was more than 4-fold that in controls.39


A large genome-wide association study demonstrated that seven chromosome regions are shared between CD and T1DM such as RGS1 (1q31), IL18RAP (2q12), TAGAP (6q25), the 32-bp insertion-deletion variant (3p21), PTPN2 (18p11), CTLA4 (2q33), and SH2B3 (12q24). 40 These data further supports extensive epidemiological evidence of association between CD and type 1 DM and future evaluation of gluten consumption as a shared etiologic factor.

Two novel CD risk regions were identified at chromosomes 6q23.3 (OLIG3-TNFAIP3) and 2p16.1 (REL) by testing large case-control European cohorts, both genes are key mediators in the nuclear factor kappa B pathway, an innate-immunity via that has not been reported to be heritably altered in CD before.41

In the first follow-up study of CD cases from the United States, five of the eight regions identified in a previous large UK GWAS study were strongly associated with CD, including regions on 1q31, 3q25, 3q28, 4q27, and 12q24. In addition, new evidence for association in the region 2q31 (ITGA4) was reported. 42

Although human leukocyte antigen (HLA)-DQ2 is the principal genetic risk factor for CD, Romanos et al 43 demonstrated that CD cases carrying ≥13 non-HLA risk alleles had a higher CD risk compared with those carrying 0–5 risk alleles, this model increased sensitivity by 6.2% in relation to the use of HLA only.


The availability of highly accurate serologic tests greatly facilitates the diagnosis of CD. A large multinational study demonstrated significant variability in sensitivity (69% to 93%) and specificity (96% to 100%) for tTGA assays among 20 laboratories that support the necessity of better standardization of the tTGA assays.44 A changing pattern of CD serology request has been observed in United Kingdom during the last decade with a significant increase on general practitioner requests of CD serologies (from 3.3% to 52%) and a decrease on the proportion of positive serological results (from 5.7% to 2.6%).45 Deamidated gliadin peptides may replace native anti-gliadin antibodies, though they are not necessarily any better than tissue transglutaminase antibodies. 46 In addition, combination testing (such as multiplex immunoassay) provides both opportunities and challenges for improving the accurate diagnosis of celiac disease, though there also may be increased or decreased specificity in this context when tests of intrinsically lower specificity are combined with those of higher specificity.47 Detection of anti-transglutaminase antibodies in human saliva is possible and may be useful to monitor adherence to GFD with a good correlation between saliva and serum titers (r = 0.75, p = 0.0001).48 The diagnostic accuracy of serologic kits (either tTGA or deamidated gliadin peptide) for the detection of CD may be lower in routine clinical practice than that reported in the literature, especially in patients with lower grades of villous atrophy.49 Immunoglobulin A antibodies directed at epidermal transglutaminase (TG3) are elevated in patients with dermatitis herpetiformis (a papulovesicular eruption caused by ingestion of gluten) and adults with CD. 50

Endoscopy and Biopsy of the Small Intestine

Confocal endomicroscopy effectively evaluated CD severity “in vivo” before and after treatment with a gluten-free diet.51 High-resolution magnification with optimal band imaging system had an almost perfect diagnostic accuracy for detection of partial/total villous atrophy or normal mucosa.52 Endocytoscopy at 450x magnification accurately identified villous atrophy but not minimal change CD.53

Despite advances on endoscopic “in vivo” diagnosis, histology examination of the small intestine remains the diagnostic gold standard for CD. In a multicenter study, the lesion was limited to the duodenal bulb in 2.4% of 665 children with CD.54 These data suggests that biopsy specimens should be obtained from both the duodenal bulb and the distal duodenum.

Vande Voort et al55 compared 124 systematically assessed patients with lymphocytic duodenosis (defined as >40 intraepithelial lymphocytes per 100 epithelial nuclei) with 454 CD patients, this study demonstrated that lymphocytic duodenosis differs significantly in terms of HLA type, serology, and clinical features to CD patients, suggesting that the majority (52%) of patients with lymphocytic duodenosis do not belong in the spectrum of CD. Therefore, serologic and HLA genotyping are necessary to determine if mild enteropathy is part of the spectrum of CD.55 Biagi et al56 showed that minimal intestinal lesions in the absence of endomysial antibodies are most often unrelated to CD. IgA anti-tissue transglutaminase 2 antibody deposits in the small-bowel mucosa may suggest gluten-sensitivity in subjects with normal villous architecture and either CD-associated antibodies in serum or greater density of γδ intraepithelial lymphocytes.57 Koskinen et al58 demonstrated that the response of small bowel mucosal transglutaminase 2 IgA deposits after GFD was similar in overt and mild enteropathy CD. Thus, detection of such IgA deposits may improve detection of mild enteropathy CD but ultimately proof would be the clinical response to gluten withdrawal.

Treatment with a Gluten-free diet

The treatment of choice in CD is a lifelong gluten-free diet (GFD). Although expected, complete recovery of intestinal mucosa is rare in adults with CD despite adherence to GFD, clinical response, and disappearance of CD-specific serology.59 The histological spectrum of CD recognizes that mucosal damage develops gradually over time. Kurppa et al60 demonstrated using a randomized, controlled design that patients with mild enteropathy (defined by Marsh type I-II) with positive endomysial antibodies may have a benefit from GFD in terms of improving symptoms, antibody response, and mucosal inflammation. Thus, EMA positivity in the absence of enteropathy may be an early predictor for later development of villous atrophy.61

Identification of CD by mass screening led 10 year later to health improvement in 66% of children (aged 2–4 years) without deterioration of quality of life.62 Quality of life is more severely affected in patients with classical CD than those with atypical/silent CD, treatment with a GFD improved quality of life in symptomatic cases but not in silent patients.63

The ingestion for 24 weeks of wheat-based starch hydrolysates, glucose syrups and maltodextrines did not have harmful effect on histology or inflammation in CD patients in remission as compared with placebo.64

A systematic review concluded that adherence to GFD and mucosal healing may prevent or ameliorate CD-associated complications.65 Serology, dietitian interview, and re-biopsy have been utilized for assessment of adherence to GFD. Leffler et al 66 proposed a 7-item instrument that allows standarized evaluation of GFD adherence with a superior performance than tissue transglutaminase antibodies (areas under the curve of 0.830 vs 0.652 respectively). Compliance to GFD in adolescents represents a particular challenge that may require specific clinical interventions for optimum clinical outcomes.67 Meal appearance and the poor availability of gluten-free food that make their condition obvous in public are recurrent stigma-related themes in adolescents with CD.68 Adherence to GFD may prevent osteopenic status in children and adolescents with CD and concurrent Type 1 DM. 69

A double-blind placebo controlled multicenter trial showed that the supplementation of B vitamins for 6 months normalized total homocysteine and improved general well-being in patients with CD following a GFD.70 Copper deficiency in CD may be associated with neurologic or hematologic abnormalities that can be treated with adequate supplementation.71 Patients with CD and GFD may have inadequate intake of calcium, non-starch polysaccharides, and vitamin D.72

On average, gluten-free products were 242 % more expensive than comparable regular products in Canada.73 This excess cost may affect adherence to the GFD.

Basic Research behind Potential Alternative Therapies for the Future

Huibregtse et al74 demonstrated that oral administration of Lactococcus lactis-delivered DQ8-specific gliadin epitope induced suppression of local and systemic DQ8-restricted T cell response in a NOD AB° DQ8 transgenic mice. These data provides experimental support for potential therapeutic approaches to induce oral tolerance in CD. Gliadin was neutralized by formation of complexes with a linear co-polymer of hydroxyethylmethacrylate and sodium 4-styerne sulfonate; even more, polymeric binders prevent gliadin-induced epithelial toxicity and barrier dysfunction in HLA-HCD4/DQ8 transgenic mice.75 Proteases from germinating wheat degraded gliadin into small peptide fragments that did not increase epithelial permeability or stimulate T-cell proliferation in vitro at the same extent as unprocessed pepsin and trypsin digested gliadin.76 New improved variants of Sphingomonas capsulata prolyl endopeptidases (enzymes that may cleave immunogenic gluten peptides) with as much as 20% enhanced activity at pH 4.5 and 200-fold greater resistance to pepsine were identified by protein engineering.77

Refractory Celiac Disease

Refractory celiac disease is a rare condition characterized by a symptomatic severe enteropathy and villous atrophy despite strict adherence to GFD for at least 6–12 months after exclusion of other causes of non-responsive CD and malignancy.

Refractory CD was associated with poor prognosis in two large cases series from France and US, with clonal (type 2 subtype) having a worse outcome because of progression to overt lymphoma.78, 79 A novel clinically-based staging system based on the additive effect of the following 5 prognostic factors scored at the time of refractory CD has been proposed using single-center data: older age (>65), low albumin (<3.2), low hemoglobin (<11), total villous atrophy on the diagnostic biopsy, and presence of T-cell clone in the intestine.78

Verbeek et al80 demonstrated that aberrant T-lymphocytes, the hallmark of type 2 refractory CD are not strictly confined to a small intestinal intraepithelial localization.


Celiac disease is a global health problem that requires a multidisciplinary and increasingly cooperative multinational research effort.


This article was supported by the National Institutes of Health (NIH) under Ruth L. Kirschstein National Research Service Award/Training Grant in Gastrointestinal Allergy and Immunology (T32 AI-07047) (to ART) and the NIH grant DK-57892 (to JAM).


1** Rubio-Tapia A, Kyle RA, Kaplan EL, et al. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology. 2009;137:88–93. This study demonstrated that undiagnosed CD is associated with a 4-fold increased risk of death during 45 years of follow-up. Also, the prevalence of undiagnosed CD seems to have increased dramatically in the United States during the past 50 years. [PMC free article] [PubMed]
2. Lohi S, Mustalahti K, Kaukinen K, et al. Increasing prevalence of coeliac disease over time. Aliment Pharmacol Ther. 2007;26:1217–25. [PubMed]
3. Ivarsson A, Persson LA, Nystrom L, et al. Epidemic of coeliac disease in Swedish children. Acta Paediatr. 2000;89:165–71. [PubMed]
4. Olsson C, Hernell O, Hornell A, et al. Difference in celiac disease risk between Swedish birth cohorts suggests an opportunity for primary prevention. Pediatrics. 2008;122:528–34. [PubMed]
5** Myleus A, Ivarsson A, Webb C, et al. Celiac disease revealed in 3% of Swedish 12-year-olds born during an epidemic. J Pediatr Gastroenterol Nutr. 2009;49:170–6. This study demonstrated that the prevalence of CD in 12-year old children born during the Swedish epidemic of CD (1993) was 3% higher than the usually suggested screening prevalence of 1%. [PubMed]
6. Vilppula A, Kaukinen K, Luostarinen L, et al. Increasing prevalence and high incidence of celiac disease in elderly people: a population-based study. BMC Gastroenterol. 2009;9:49. [PMC free article] [PubMed]
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8** Kondrashova A, Mustalahti K, Kaukinen K, et al. Lower economic status and inferior hygienic environment may protect against celiac disease. Ann Med. 2008;40:223–31. This study support the hygiene hypothesis in CD by demonstrates a lower prevalence of CD in Russian Karelia characterized by inferior prosperity and standard of hygiene than in Finland. [PubMed]
9. Cabrera-Chavez F, Rouzaud-Sandez O, Sotelo-Cruz N, Calderon de la Barca AM. Bovine milk caseins and transglutaminase-treated cereal prolamins are differentially recognized by IgA of celiac disease patients according to their age. J Agric Food Chem. 2009;57:3754–9. [PubMed]
10. Abu-Zekry M, Kryszak D, Diab M, et al. Prevalence of celiac disease in Egyptian children disputes the east-west agriculture-dependent spread of the disease. J Pediatr Gastroenterol Nutr. 2008;47:136–40. [PubMed]
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12. Metzger MH, Heier M, Maki M, et al. Mortality excess in individuals with elevated IgA anti-transglutaminase antibodies: the KORA/MONICA Augsburg cohort study 1989–1998. Eur J Epidemiol. 2006;21:359–65. [PubMed]
13. Lohi S, Maki M, Montonen J, et al. Malignancies in cases with screening-identified evidence of coeliac disease: a long-term population-based cohort study. Gut. 2009;58:643–7. [PubMed]
14. Lohi S, Maki M, Rissanen H, et al. Prognosis of unrecognized coeliac disease as regards mortality: A population-based cohort study. Ann Med. 2009:1–8. [PubMed]
15. Lammers KM, Lu R, Brownley J, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008;135:194–204 e3. [PMC free article] [PubMed]
16** Matysiak-Budnik T, Moura IC, Arcos-Fajardo M, et al. Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J Exp Med. 2008;205:143–54. This study showed a novel mechanism how gliadin peptides can cross the intestinal border. [PMC free article] [PubMed]
17* Heyman M, Menard S. Pathways of gliadin transport in celiac disease. Ann N Y Acad Sci. 2009;1165:274–8. This study demonstrated a CD71-mediated transcytosis of gliadin peptides to the intestinal mucosa. [PubMed]
18. Schumann M, Richter JF, Wedell I, et al. Mechanisms of epithelial translocation of the alpha(2)-gliadin-33mer in coeliac sprue. Gut. 2008;57:747–54. [PubMed]
19. Fina D, Sarra M, Caruso R, et al. Interleukin 21 contributes to the mucosal T helper cell type 1 response in coeliac disease. Gut. 2008;57:887–92. [PubMed]
20. Bas A, Forsberg G, Sjoberg V, et al. Aberrant extrathymic T cell receptor gene rearrangement in the small intestinal mucosa: a risk factor for coeliac disease? Gut. 2009;58:189–95. [PMC free article] [PubMed]
21. Grose RH, Thompson FM, Cummins AG. Deficiency of 6B11+ invariant NK T-cells in celiac disease. Dig Dis Sci. 2008;53:1846–51. [PubMed]
22* Tang F, Chen Z, Ciszewski C, et al. Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15. J Exp Med. 2009;206:707–19. This study establishes a novel model of NKG2D signaling pathway in cytotoxic T lymphocytes in celiac disease. NKG2D-mediated cytolysis is critically regulated by cytosolic phospholipase A2 in cytotoxic T lymphocytes. [PMC free article] [PubMed]
23. Di Sabatino A, Rovedatti L, Rosado MM, et al. Increased expression of mucosal addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin alpha4beta7-positive T cells in blood. Hum Pathol. 2009;40:699–704. [PubMed]
24. Ashorn S, Raukola H, Valineva T, et al. Elevated serum anti-Saccharomyces cerevisiae, anti-I2 and anti-OmpW antibody levels in patients with suspicion of celiac disease. J Clin Immunol. 2008;28:486–94. [PMC free article] [PubMed]
25. Ashorn S, Valineva T, Kaukinen K, et al. Serological responses to microbial antigens in celiac disease patients during a gluten-free diet. J Clin Immunol. 2009;29:190–5. [PMC free article] [PubMed]
26. Vivas S, Ruiz de Morales JM, Fernandez M, et al. Age-related clinical, serological, and histopathological features of celiac disease. Am J Gastroenterol. 2008;103:2360–5. quiz 2366. [PubMed]
27. Ortega Paez E, Junco Lafuente P, Baca Garcia P, et al. Prevalence of dental enamel defects in celiac patients with deciduous dentition: a pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;106:74–8. [PubMed]
28. Larsson K, Carlsson A, Cederwall E, et al. Annual screening detects celiac disease in children with type 1 diabetes. Pediatr Diabetes. 2008;9:354–9. [PubMed]
29** Ludvigsson JF, Olen O, Bell M, et al. Coeliac disease and risk of sepsis. Gut. 2008;57:1074–80. This study demonstrated a modestly increased risk of sepsis in patients with CD by search Swedish national health registers to identify 15 325 patients with CD and 14 494 inpatient reference individuals. [PubMed]
30. Thomas HJ, Wotton CJ, Yeates D, et al. Pneumococcal infection in patients with coeliac disease. Eur J Gastroenterol Hepatol. 2008;20:624–8. [PubMed]
31. Gao Y, Kristinsson SY, Goldin LR, et al. Increased risk for non-Hodgkin lymphoma in individuals with celiac disease and a potential familial association. Gastroenterology. 2009;136:91–8. [PMC free article] [PubMed]
32. Hadjivassiliou M, Aeschlimann P, Strigun A, et al. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol. 2008;64:332–43. [PubMed]
33. Neuhausen SL, Steele L, Ryan S, et al. Co-occurrence of celiac disease and other autoimmune diseases in celiacs and their first-degree relatives. J Autoimmun. 2008;31:160–5. [PMC free article] [PubMed]
34. Rubio-Tapia A, Van Dyke CT, Lahr BD, et al. Predictors of family risk for celiac disease: a population-based study. Clin Gastroenterol Hepatol. 2008;6:983–7. [PMC free article] [PubMed]
35* Garud S, Leffler D, Dennis M, et al. Interaction between psychiatric and autoimmune disorders in coeliac disease patients in the Northeastern United States. Aliment Pharmacol Ther. 2009;29:898–905. This case control study demonstrated that the prevalence of depression was not increased in CD as compared to controls. However, among CD patients, the presence of type 1 diabetes mellitus was identified as a significant risk factor for depression. [PMC free article] [PubMed]
36. Green PH, Yang J, Cheng J, et al. An association between microscopic colitis and celiac disease. Clin Gastroenterol Hepatol. 2009;7:1210–6. [PubMed]
37. Frost AR, Band MM, Conway GS. Serological screening for coeliac disease in adults with Turner’s syndrome: prevalence and clinical significance of endomysium antibody positivity. Eur J Endocrinol. 2009;160:675–9. [PubMed]
38. Rubio-Tapia A, Barton SH, Rosenblatt JE, Murray JA. Prevalence of small intestine bacterial overgrowth diagnosed by quantitative culture of intestinal aspirate in celiac disease. J Clin Gastroenterol. 2009;43:157–61. [PMC free article] [PubMed]
39** Ford AC, Chey WD, Talley NJ, 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;169:651–8. This systematic review and meta-analysis showed that the prevalence of biospy-proved CD in cases meeting diagnostic criteria for irritable bowel syndrome was more than 4-fold that in controls without irritable bowel syndrome by included 14 studies with a total of 2278 subjects that met diagnostic criteria for irritable bowel syndrome. [PubMed]
40** Smyth DJ, Plagnol V, Walker NM, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med. 2008;359:2767–77. This large genetic study demonstrated that genetic susceptibility to both type 1 diabetes and celiac disease shares common alleles. [PMC free article] [PubMed]
41. Trynka G, Zhernakova A, Romanos J, et al. Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling. Gut. 2009;58:1078–83. [PubMed]
42* Garner CP, Murray JA, Ding YC, et al. Replication of Celiac Disease UK Genome-Wide Association Study Results in a US Population. Hum Mol Genet. 2009 This study represents the first follow-up effort to replicate results of large UK genome-wide association study in patients from the United States. [PMC free article] [PubMed]
43** Romanos J, van Diemen CC, Nolte IM, et al. Analysis of HLA and Non-HLA Alleles Can Identify Individuals at High Risk for Celiac Disease. Gastroenterology. 2009 This study demonstrated the utility of non-HLA risk genotypes for CD to improve identification of high-risk individuals. [PubMed]
44* Li M, Yu L, Tiberti C, Bonamico M, et al. A report on the International Transglutaminase Autoantibody Workshop for Celiac Disease. Am J Gastroenterol. 2009;104:154–63. This multinational study demonstrated a significant variability in sensitivity and specificity for the transglutaminase antibody among 20 participant laboratories. [PMC free article] [PubMed]
45. Evans KE, Malloy AR, Gorard DA. Changing patterns of coeliac serology requests. Aliment Pharmacol Ther. 2009;29:1137–42. [PubMed]
46. Prause C, Ritter M, Probst C, et al. Antibodies against deamidated gliadin as new and accurate biomarkers of childhood coeliac disease. J Pediatr Gastroenterol Nutr. 2009;49:52–8. [PubMed]
47. Rashtak S, Ettore MW, Homburger HA, Murray JA. Combination testing for antibodies in the diagnosis of coeliac disease: comparison of multiplex immunoassay and ELISA methods. Aliment Pharmacol Ther. 2008;28:805–13. [PMC free article] [PubMed]
48. Bonamico M, Nenna R, Luparia RP, et al. Radioimmunological detection of anti-transglutaminase autoantibodies in human saliva: a useful test to monitor coeliac disease follow-up. Aliment Pharmacol Ther. 2008;28:364–70. [PubMed]
49. Naiyer AJ, Hernandez L, Ciaccio EJ, et al. Comparison of commercially available serologic kits for the detection of celiac disease. J Clin Gastroenterol. 2009;43:225–32. [PubMed]
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51* Leong RW, Nguyen NQ, Meredith CG, et al. In vivo confocal endomicroscopy in the diagnosis and evaluation of celiac disease. Gastroenterology. 2008;135:1870–6. This study demonstrated that confocal endomicroscopy can effectively diagnosed and evaluate CD severity in vivo. [PubMed]
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