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1.  Increased use of hypnotics in individuals with celiac disease: a nationwide case-control study 
BMC Gastroenterology  2015;15:10.
Background
Although poor sleep is common in numerous gastrointestinal diseases, data are scarce on the risk of poor sleep in celiac disease. The objective of this study was to estimate the risk of repeated use of hypnotics among individuals with celiac disease as a proxy measure for poor sleep.
Methods
This is a nationwide case–control study including 2933 individuals with celiac disease and 14,571 matched controls from the general Swedish population. Poor sleep was defined as ≥2 prescriptions of hypnotics using prospective data from the National Prescribed Drug Register (data capture: July 2005-January 2008). We estimated odds ratios and hazard ratios for poor sleep before and after celiac disease diagnosis respectively.
Results
In this study, poor sleep was seen in 129/2933 individuals (4.4%) with celiac disease, as compared with 487/14,571 controls (3.3%) (odds ratio = 1.33; 95% CI = 1.08-1.62). Data restricted to sleep complaints starting ≥1 year before celiac disease diagnosis revealed largely unchanged risk estimates (odds ratio = 1.23; 95% CI = 0.88-1.71) as compared with the overall risk (odds ratio 1.33). The risk of poor sleep in celiac disease was essentially not influenced by adjustment for concomitant psychiatric comorbidity (n = 1744, adjusted odds ratio =1.26; 95% CI = 1.02-1.54) or restless legs syndrome (n = 108, adjusted odds ratio = 1.33; 95% CI = 1.08-1.63). Poor sleep was also more common after celiac disease diagnosis as compared with matched controls (hazard ratio = 1.36; 95% CI = 1.30-1.41).
Conclusions
In conclusion, individuals with celiac disease suffer an increased risk of poor sleep, both before and after diagnosis. Although we cannot rule out that surveillance bias has contributed to our findings, our results are consistent with previous data suggesting that sleep complaints may be a manifestation of celiac disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s12876-015-0236-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12876-015-0236-z
PMCID: PMC4322544  PMID: 25649738
Coeliac; Immune-mediated; Insomnia; Sleep disorders; Small intestine
2.  Risk of lymphoproliferative malignancy in celiac patients with a family history of lymphoproliferative malignancy 
Journal of gastroenterology  2013;48(12):10.1007/s00535-013-0757-6.
Background and aims
Individuals with celiac disease (CD) are at increased risk of lymphoproliferative malignancy (LPM). We examined if a family history of LPM or any cancer influenced the risk of LPM in individuals with CD.
Methods
We identified 28,996 individuals with biopsy-verified CD (equal to villous atrophy, Marsh histopathology stage 3), of whom 616 had family history of LPM. Cox regression then estimated hazard ratios (HRs) for LPM in these 616 compared with two control groups. We also examined the risk of LPM in CD individuals with a family history of any cancer (n=8,439).
Results
During follow-up, 2/616 CD individuals with a family history of LPM, and 235/28,380 CD individuals without a family history of LPM developed LPM themselves. CD individuals with a family history of LPM were not at increased risk of LPM compared to general population controls (HR=1.18; 95%CI=0.27–5.10), or compared to CD individuals without a family history of LPM (adjusted HR=0.31; 95%CI=0.08–1.23). We found no increased risk of LPM in CD individuals with a family history of any cancer.
Conclusion
This study found no evidence that a family history of LPM or any cancer increases the risk of future LPM in individuals with CD. Despite the large number of study participants, this study is however limited by few positive events due to a low absolute risk of LPM even in individuals with CD.
doi:10.1007/s00535-013-0757-6
PMCID: PMC3664649  PMID: 23440554
cancer; celiac; coeliac; lymphoma; lymphoproliferative; malignancy
3.  Use of computerized algorithm to identify individuals in need of testing for celiac disease 
Background and aim
Celiac disease (CD) is a lifelong immune-mediated disease with excess mortality. Early diagnosis is important to minimize disease symptoms, complications, and consumption of healthcare resources. Most patients remain undiagnosed. We developed two electronic medical record (EMR)-based algorithms to identify patients at high risk of CD and in need of CD screening.
Methods
(I) Using natural language processing (NLP), we searched EMRs for 16 free text (and related) terms in 216 CD patients and 280 controls. (II) EMRs were also searched for ICD9 (International Classification of Disease) codes suggesting an increased risk of CD in 202 patients with CD and 524 controls. For each approach, we determined the optimal number of hits to be assigned as CD cases. To assess performance of these algorithms, sensitivity and specificity were calculated.
Results
Using two hits as the cut-off, the NLP algorithm identified 72.9% of all celiac patients (sensitivity), and ruled out CD in 89.9% of the controls (specificity). In a representative US population of individuals without a prior celiac diagnosis (assuming that 0.6% had undiagnosed CD), this NLP algorithm could identify a group of individuals where 4.2% would have CD (positive predictive value). ICD9 code search using three hits as the cut-off had a sensitivity of 17.1% and a specificity of 88.5% (positive predictive value was 0.9%).
Discussion and conclusions
This study shows that computerized EMR-based algorithms can help identify patients at high risk of CD. NLP-based techniques demonstrate higher sensitivity and positive predictive values than algorithms based on ICD9 code searches.
doi:10.1136/amiajnl-2013-001924
PMCID: PMC3861918  PMID: 23956016
algorithm; artificial intelligence; celiac; decision support system, clinical; inflammation
4.  BL-7010 Demonstrates Specific Binding to Gliadin and Reduces Gluten-Associated Pathology in a Chronic Mouse Model of Gliadin Sensitivity 
PLoS ONE  2014;9(11):e109972.
Celiac disease (CD) is an autoimmune disorder in individuals that carry DQ2 or DQ8 MHC class II haplotypes, triggered by the ingestion of gluten. There is no current treatment other than a gluten-free diet (GFD). We have previously shown that the BL-7010 copolymer poly(hydroxyethyl methacrylate-co-styrene sulfonate) (P(HEMA-co-SS)) binds with higher efficiency to gliadin than to other proteins present in the small intestine, ameliorating gliadin-induced pathology in the HLA-HCD4/DQ8 model of gluten sensitivity. The aim of this study was to investigate the efficiency of two batches of BL-7010 to interact with gliadin, essential vitamins and digestive enzymes not previously tested, and to assess the ability of the copolymer to reduce gluten-associated pathology using the NOD-DQ8 mouse model, which exhibits more significant small intestinal damage when challenged with gluten than HCD4/DQ8 mice. In addition, the safety and systemic exposure of BL-7010 was evaluated in vivo (in rats) and in vitro (genetic toxicity studies). In vitro binding data showed that BL-7010 interacted with high affinity with gliadin and that BL-7010 had no interaction with the tested vitamins and digestive enzymes. BL-7010 was effective at preventing gluten-induced decreases in villus-to-crypt ratios, intraepithelial lymphocytosis and alterations in paracellular permeability and putative anion transporter-1 mRNA expression in the small intestine. In rats, BL-7010 was well-tolerated and safe following 14 days of daily repeated administration of 3000 mg/kg. BL-7010 did not exhibit any mutagenic effect in the genetic toxicity studies. Using complementary animal models and chronic gluten exposure the results demonstrate that administration of BL-7010 is effective and safe and that it is able to decrease pathology associated with gliadin sensitization warranting the progression to Phase I trials in humans.
doi:10.1371/journal.pone.0109972
PMCID: PMC4217726  PMID: 25365555
5.  A nationwide study of small intestinal histopathology and risk of autistic spectrum disorders 
JAMA psychiatry  2013;70(11):10.1001/jamapsychiatry.2013.2048.
Context and objective
Most case reports suggest an association between autistic spectrum disorders (ASD) and celiac disease (CD) or positive CD serology, but larger studies are contradictory. We examined the association between ASD and CD according to small intestinal histopathology.
Setting
Sweden.
Design
Nationwide case-control study.
Participants and outcome measure
Through 28 Swedish biopsy registers, we collected data on 26,995 individuals with CD (equal to villous atrophy, Marsh histopathology stage 3), 12,304 individuals with inflammation (Marsh 1–2), and 3,719 individuals with normal mucosa (Marsh 0) but positive CD serology (IgA/IgG gliadin, endomysium, tissue transglutaminase) and compared them with 213,208 age-and sex-matched controls. Conditional logistic regression estimated odds ratios (ORs) for having a prior diagnosis of ASD according to the Swedish Patient Register. In a second analysis we used Cox regression to estimate hazard ratios (HRs) for future ASD in individuals undergoing small intestinal biopsy.
Results
Prior ASD was not associated with CD (OR=0.93; 95% CI=0.51–1.68) or inflammation (OR=1.03; 95% CI=0.40–2.64) but was associated with a markedly increased risk of having a normal mucosa but positive CD serology (OR=4.57; 95% CI=1.58–13.22).
Restricting our data to individuals without a diagnosis of ASD at the time of biopsy, CD (HR=1.39; 95% CI=1.13–1.71) and inflammation (HR=2.01; 95% CI=1.29–3.13) were both associated with moderate excess risks of later ASD, whereas the HR for later ASD in individuals with normal mucosa but positive CD serology was 3.09 (95% CI=1.99–4.80).
Conclusion
Although this study found no association between CD or inflammation and earlier ASD, there was a markedly increased risk of ASD in individuals with a normal mucosa but positive CD serology.
doi:10.1001/jamapsychiatry.2013.2048
PMCID: PMC3884520  PMID: 24068245
autism; autistic spectrum disorder; autoimmunity; celiac; coeliac; inflammation
6.  HLA Genetics and Clinical Features of Self-Treated Patients on a Gluten-Free Diet 
Background and Aims
Increasingly, persons start a gluten-free diet (GFD) without a clear celiac disease (CD) diagnosis. Human leukocyte antigen (HLA) genotyping is useful in ruling out CD in patients with equivocal results of serologic testing or small-bowel biopsy (SBB), but its utility and the clinical features of patients on self-treated GFD (ST-GFD) are largely unknown.
Methods
Retrospective study of single tertiary care center cohort compared 137 patients on ST-GFD and 443 patients with well-defined CD. We compared HLA genotype, symptoms, serologic and SBB results, and response to GFD between the 2 groups. Analysis used univariate logistic regression modeling, adjusted for age and sex.
Results
Patients with ST-GFD presented more often with diarrhea (P<.001), abdominal distention (P<.001), flatulence (P=.002), cramping (P=.02), itchy skin (P=.02), oral inflammation (P=.04), and constipation (P=.01) and less often with anemia (P<.001) or malaise (P=.02) than CD patients. In addition, 41% did not carry DQ2.5 and DQ8 vs 6% of CD patients (P<.001). Only 2% of ST-GFD patients had SBB clearly consistent with CD. Family history of CD showed no difference between groups (P=.77). Although CD patients had a statistically higher rate of GFD benefit, both groups had a high responsiveness rate (98% vs 94%; P=.03).
Conclusions
HLA genotyping is useful in evaluating patients on a ST-GFD. Although confirmed CD is rare in self-treated patients, most still report benefit from GFD regardless of DQ2 and DQ8 status. Nonceliac gluten sensitivity may play a role.
doi:10.1097/MCG.0b013e31828f531c
PMCID: PMC3735773  PMID: 23632357
celiac disease; diet; food intolerance; gluten-sensitive enteropathy
7.  Does urticaria risk increase in patients with celiac disease? A large population-based cohort study 
Background
Case reports and smaller case-control studies suggest an association between celiac disease (CD) and urticaria, but risk estimates have varied considerably across studies and as yet there are no studies on CD and the risk of future urticaria.
Objective
To examine the association between CD and urticaria.
Methods
We identified 28,900 patients with biopsy-verified CD (equal to Marsh stage 3) and compared them with 143,397 age- and sex-matched controls with regards to the risk of urticaria and chronic urticaria (duration ≥6 weeks). Hazard ratios (HRs) were estimated using a Cox regression model.
Results
During follow-up, 453 patients with CD and no previous diagnosis of urticaria developed urticaria (expected n=300) and 79 of these 453 had chronic urticaria (expected n=41). The corresponding HRs were 1.51 for any urticaria (95%CI=1.36–1.68) and 1.92 for chronic urticaria (95%CI=1.48–2.48). The absolute risk for urticaria in CD was 140/100,000 person-years (excess risk=47/100,000 person-years). Corresponding figures for chronic urticaria were 24/100,00 person-years and 12/100,000 person-years. Patients with CD were also at increased risk of having both urticaria (odds ratio, OR=1.31; 95%CI=1.12–1.52) and chronic urticaria (OR=1.54; 95%CI=1.08–2.18) prior to the CD diagnosis.
Conclusion
This study suggests that CD is associated with urticaria, especially chronic urticaria.
doi:10.1684/ejd.2013.2158
PMCID: PMC3896876  PMID: 24135663
autoimmunity; celiac; coeliac; gluten; inflammation; population-based; skin; urticaria
8.  Mucosal Healing and Risk of Lymphoproliferative Malignancy in Celiac Disease 
Annals of internal medicine  2013;159(3):169-175.
Background
Celiac disease (CD) is associated with an increased risk of lymphoproliferative malignancy (LPM). It is unknown whether this risk is affected by the results of the follow-up intestinal biopsy, performed to document mucosal healing.
Objective
To examine the association between mucosal healing in CD and later LPM.
Design
Population-based cohort study
Setting
We identified patients with CD from all of Sweden’s 28 pathology departments.
Patients
Individuals with CD who had a follow-up biopsy after initial diagnosis.
Measurements
We compared the risk of LPM to that of the general population using expected rates; and through Cox regression we compared the rate of LPM in those with persistent villous atrophy to those with mucosal healing.
Results
Among 7,625 patients with CD and a follow-up biopsy, persistent villous atrophy was present in 3,308 (43%). The overall risk of LPM was increased compared to the general population (Standardized incidence ratio, SIR 2.81; 95%CI 2.10–3.67), but this increase was greater among those with persistent villous atrophy (SIR 3.78; 95%CI 2.71–5.12) as compared to those with mucosal healing (SIR 1.50; 95%CI 0.77–2.62). Persistent villous atrophy compared to mucosal healing was associated with an increased risk of LPM (Hazard ratio, HR 2.26; 95%CI 1.18–4.34). We found an increased risk of T cell lymphoma (HR 3.51; 95%CI 0.75–16.34), but no excess risk of B cell lymphoma (HR 0.97; 95%CI 0.21–4.49).
Limitation
We had no data on dietary compliance.
Conclusions
The increased LPM risk in CD is associated with the results of the follow-up biopsy, with a higher risk among those with persistent villous atrophy. Follow-up biopsy may be a means to effectively stratify CD patients regarding subsequent LPM risk.
Primary funding source
the National Center for Advancing Translational Sciences, National Institutes of Health, The American Scandinavian Foundation, the Celiac Sprue Association, Örebro University Hospital, Karolinska Institutet, the Swedish Society of Medicine, the Swedish Research Council, and the Swedish Celiac Society.
doi:10.7326/0003-4819-159-3-201308060-00006
PMCID: PMC3788608  PMID: 23922062
9.  Risk of Thyroid Cancer in a Nationwide Cohort of Patients with Biopsy-Verified Celiac Disease 
Thyroid  2013;23(8):971-976.
Background
In earlier studies based on selected populations, the relative risk for thyroid cancer in celiac disease has varied between 0.6 and 22.5. We aimed to test this relationship in a population-based setting.
Methods
We collected small intestinal biopsy report data performed in 1969–2008 from all 28 Swedish pathology departments. 29,074 individuals with celiac disease (villous atrophy; Marsh histopathology stage III) were matched for sex, age, calendar year, and county to 144,440 reference individuals from the Swedish general population. Through Cox regression, we then estimated hazard ratios (HRs) and confidence intervals (CIs) for any thyroid cancer and papillary thyroid cancer (defined according to relevant pathology codes in the Swedish Cancer Register) in patients with celiac disease.
Results
During follow-up, any thyroid cancer developed in seven patients with celiac disease (expected=12) and papillary thyroid cancer developed in five patients (expected=7). Celiac disease was not associated with an increased risk of any thyroid cancer (HR 0.6 [CI 0.3–1.3]) or of papillary thyroid cancer (HR 0.7 [CI 0.3–1.8]). All cases of thyroid cancer in celiac disease occurred in female patients. Risk estimates were similar before and after the year 2000 and independent of age at celiac diagnosis (≤24 years vs. ≥25 years).
Conclusions
We conclude that, in the Swedish population, there is no increased risk of thyroid cancer in patients with celiac disease. This differs from what has been reported in smaller studies in Italy and the United States.
doi:10.1089/thy.2012.0306
PMCID: PMC3752514  PMID: 23281890
10.  Genome-Wide Association Study of Celiac Disease in North America Confirms FRMD4B as New Celiac Locus 
PLoS ONE  2014;9(7):e101428.
We performed a genome-wide association study (GWAS) of 1550 North American celiac disease cases and 3084 controls. Twelve SNPs, distributed across four regions (3p21.31, 4q27, 6q15, 6q25), were significantly associated with disease (p-value <1.0×10−7), and a further seven SNPs, across four additional regions (1q24.3, 10p15.1, 6q22.31, 17q21.32) had suggestive evidence (1.0×10−7 < p-value < 1.0×10−6). This study replicated a previous suggestive association within FRMD4B (3p14.1), confirming it as a celiac disease locus. All four regions with significant associations and two regions with suggestive results (1q24.3, 10p15.1) were known disease loci. The 6q22.31 and 10p11.23 regions were not replicated. A total of 410 SNPs distributed across the eight significant and suggestive regions were tested for association with dermatitis herpetiformis and microscopic colitis. Preliminary, suggestive statistical evidence for association with the two traits was found at chromosomes 3p21.31, 6q15, 6q25, 1q24.3 and 10p11.23, with future studies being required to validate the reported associations.
doi:10.1371/journal.pone.0101428
PMCID: PMC4084811  PMID: 24999842
11.  Coeliac disease, eosinophilic oesophagitis and gastro-oesophageal reflux disease, an adult population-based study 
Objective
Coeliac disease (CD) has been linked to gastro-oesophageal reflux disease (GORD) and eosinophilic oesophagitis (EoE), but population-based studies of the prevalence of CD in these conditions are lacking, that is, the aim of this study.
Materials and methods
An endoscopic study of 1000 randomly selected adults from the general population. CD was defined on the basis of positive serology in parallel with mucosal abnormalities of the small intestine. Any eosinophil infiltration of the oesophageal epithelium was defined as oesophageal eosinophilia and EoE was defined as having at least 15 eosinophils/high power field in biopsies from the distal oesophagus. We used Fisher’s exact test to compare the prevalence of GORD, oesophageal eosinophilia and EoE in subjects with CD vs. controls.
Results
400 subjects (40%) had gastro-oesophageal reflux symptoms (GORS), 155 (15.5%) had erosive oesophagitis, 16 (1.6%) had Barrett’s oesophagus, 48 (4.8%) had oesophageal eosinophilia and 11 (1.1%) had EoE. CD was diagnosed in 8/400 (2.0%) individuals with GORS (vs. controls: 10/600 (1.7%), p=0.81), in 3/155 (1.9%) with erosive oesophagitis (vs. 15/845 controls (1.8%), p=0.75) and in 2/48 (4.2%) individuals with oesophageal eosinophilia (controls: 16/952 (1.7%) p=0.21), but in none of those 16 with Barrett’s oesophagus (vs. 18/984 controls (1.8%), p=1.0) or of the 11 individuals with EoE (controls: 18/989 (1.8%), p=1.0).
Conclusions
This population-based study found no increased risk of CD among individuals with GORD, oesophageal eosinophilia or EoE. CD screening of individuals with GORD or EoE of individuals with CD cannot be recommended.
doi:10.3109/00365521.2013.792389
PMCID: PMC3778444  PMID: 23672638
Barrett’s oesophagus; coeliac disease; eosinophilic oesophagitis; erosive oesophagitis; gastro-oesophageal reflux disease
12.  Association Between Celiac Disease and Iron Deficiency in Caucasians, but not Non-Caucasians 
Background & Aims
Celiac disease is an increasingly recognized disorder in Caucasian populations of European origin. Little is known about its prevalence in non-Caucasians. Although it is thought to be a cause of iron deficiency anemia, little is known about the extent to which celiac disease contributes to iron deficiency in Caucasians, and especially non-Caucasians. We analyzed samples collected from participants in the Hemochromatosis and Iron Overload Screening (HEIRS) study to identify individuals with iron deficiency and assess the frequency of celiac disease.
METHODS
We analyzed serum samples from white men (25 y old or older) and women (50 y old or older) who participated the HEIRS study; cases were defined as individuals with iron deficiency (serum level of ferritin ≤12 mg/L) and controls were those without (serum level of ferritin >100 mg/L in men and >50 mg/L in women). All samples were also analyzed for human recombinant tissue transglutaminase immunoglobulin A; positive results were confirmed by an assay for endomysial antibodies. Patients with positive results from both celiac disease tests were presumed to have untreated celiac disease, and those with a positive result from only 1 test were excluded from analysis. We analyzed HLA genotypes and frequencies of celiac disease between Caucasians and non-Caucasians with iron deficiency.
RESULTS
Celiac disease occurred in 14 of 567 of cases (2.5%) and in only 1 of 1136 controls (0.1%; Fisher’s exact test, P=1.92 × 10−6). Celiac disease was more common in Caucasian cases (14/363, 4%) than non-Caucasian cases (0/204; P=.003). Only 1 Caucasian control and no non-Caucasian controls had celiac disease. The odds of celiac disease in individuals with iron deficiency was 28-fold (95% confidence interval, 3.7–212.8) that of controls; 13/14 cases with celiac disease carried the DQ2.5 variant of the HLA genotype.
CONCLUSIONS
Celiac disease is associated with iron deficiency of Caucasians. Celiac disease is rare among non-Caucasians—even among individuals with features of celiac disease, such as iron deficiency. Celiac disease is also rare among individuals without iron deficiency. Men and post-menopausal women with iron deficiency should be tested for celiac disease.
doi:10.1016/j.cgh.2013.02.009
PMCID: PMC3843318  PMID: 23416278
SNP; risk factor; gluten allergy; intestine; absorption
13.  Does celiac disease influence survival in lymphoproliferative malignancy? 
European journal of epidemiology  2013;28(6):10.1007/s10654-013-9789-8.
Celiac disease (CD) is associated with both lymphoproliferative malignancy (LPM) and increased death from LPM. Research suggests that co-existing autoimmune disease may influence survival in LPM. Through Cox regression we examined overall and cause-specific mortality in 316 individuals with CD+LPM vs. 689 individuals with LPM only. CD was defined as having villous atrophy according to biopsy reports at any of Sweden’s 28 pathology departments, and LPM as having a relevant disease code in the Swedish Cancer Register. During follow-up, there were 551 deaths (CD: n=200; non-CD: n=351). Individuals with CD+LPM were at an increased risk of death compared with LPM-only individuals (adjusted hazard ratio (aHR)=1.23; 95% confidence interval (CI)=1.02–1.48). However, this excess risk was only seen in the first year after LPM diagnosis (aHR=1.76), with HRs decreasing to 1.09 in years 2–5 after LPM diagnosis and to 0.90 thereafter. Individuals with CD and non-Hodgkin lymphoma (NHL) were at a higher risk of any death as compared with NHL-only individuals (aHR=1.23; 95%CI=0.97–1.56). This excess risk was due to a higher proportion of T-cell lymphoma in CD patients. Stratifying for T- and B-cell status, the HR for death in individuals with CD+NHL was 0.77 (95%CI=0.46–1.31
In conclusion, we found no evidence that co-existing CD influences survival in individuals with LPM. The increased mortality in the first year after LPM diagnosis is related to the predominance of T-NHL in CD individuals. Individuals with CD+LPM should be informed that their prognosis is similar to that of individuals with LPM only. However, this study had low statistical power to rule our excess mortality in patients with CD and certain LPM subtypes.
doi:10.1007/s10654-013-9789-8
PMCID: PMC3886816  PMID: 23463575
cancer; celiac; coeliac; death; lymphoproliferative; malignancy mortality
14.  A Controlled Trial of Gluten-Free Diet in Patients with Irritable Bowel Syndrome-Diarrhea: Effects on Bowel Frequency and Intestinal Function 
Gastroenterology  2013;144(5):903-911.e3.
Background & Aims
Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD).
Methods
We performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8–negative and 11 HLA-DQ2/8–positive) and 23 on the GFD (12 HLA-DQ2/8−negative and 11 HLA-DQ2/8–positive. We measured bowel function daily, small bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells (PBMCs) following exposure to gluten and rice. We collected rectosigmoid biopsies from 28 patients, analyzed levels of mRNAs encoding tight junction proteins, and performed hematoxylin and eosin staining and immunohistochemical analyses. Analysis of covariance models was used to compare data from the GCD and GFD groups.
Results
Subjects on the GCD had more bowel movements/day (P=.04); the GCD had a greater effect on bowel movements/day of HLA-DQ2/8–positive than −negative patients (P=.019). The GCD was associated with higher SB permeability (based on 0–2 hr levels of mannitol and lactulose:mannitol ratio); SB permeability was greater in HLA-DQ2/8–positive than −negative patients (P=.018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of ZO-1 in SB mucosa and significant decreases in expression of ZO-1, claudin-1, and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8–positive patients. GCD vs GFD had no significant effects on transit or histology. PBMCs produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-a in response to gluten than rice (unrelated to HLA genotype).
Conclusion
Gluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8–positive patients. These findings reveal a reversible mechanism for the disorder.
doi:10.1053/j.gastro.2013.01.049
PMCID: PMC3633663  PMID: 23357715
permeability; transit; immunity; cytokines
15.  AMERICAN COLLEGE OF GASTROENTEROLOGY CLINICAL GUIDELINE: DIAGNOSIS AND MANAGEMENT OF CELIAC DISEASE 
This guideline presents recommendations for the diagnosis and management of patients with celiac disease. Celiac disease is an immune-based reaction to dietary gluten (storage protein for wheat, barley and rye) that primarily affects the small intestine in those with a genetic predisposition and resolves with exclusion of gluten from the diet. There has been a substantial increase in the prevalence of celiac disease over the last 50 years and an increase in the rate of diagnosis in the last 10 years. Celiac disease can present with many symptoms, including typical gastrointestinal symptoms (e.g. diarrhea, steatorrhea, weight loss, bloating, flatulence, abdominal pain) and also non-gastrointestinal abnormalities (e.g. abnormal liver function tests, iron deficiency anemia, bone disease, skin disorders, and many other protean manifestations). Indeed, many individuals with celiac disease may have no symptoms at all. Celiac disease is usually detected by serologic testing of celiac-specific antibodies. The diagnosis is confirmed by duodenal mucosal biopsies. Both serology and biopsy should be performed on a gluten-containing diet. The treatment for celiac disease is primarily a gluten-free diet (GFD), which requires significant patient education, motivation, and follow-up. Non-responsive celiac disease occurs frequently, particularly in those diagnosed in adulthood. Persistent or recurring symptoms should lead to a review of the patient’s original diagnosis to exclude alternative diagnoses, a review of the GFD to ensure there is no obvious gluten contamination, and serologic testing to confirm adherence with the GFD. In addition, evaluation for disorders associated with celiac disease that could cause persistent symptoms, such as microscopic colitis, pancreatic exocrine dysfunction, and complications of celiac disease, such as enteropathy-associated lymphoma or refractory celiac disease, should be entertained. Newer therapeutic modalities are being studied in clinical trials, but are not yet approved for use in practice. Given the incomplete response of many patients to a GFD free diet as well as the difficulty of adherence to the GFD over the long term, development of new effective therapies for symptom control and reversal of inflammation and organ damage are needed. The prevalence of celiac disease is increasing worldwide and many patients with celiac disease remain undiagnosed, highlighting the need for improved strategies in the future for the optimal detection of patients.
doi:10.1038/ajg.2013.79
PMCID: PMC3706994  PMID: 23609613
16.  Increasing incidence of celiac disease in a North American population 
OBJECTIVES
The prevalence of celiac disease (CD) varies greatly, potentially because of incomplete ascertainment of cases and small study samples with limited statistical power. Previous reports indicate that the incidence of CD is increasing. We examined the prevalence of CD in a well-defined US county.
METHODS
Population-based study in Olmsted County, Minnesota, US. Using the infrastructure of the Rochester Epidemiology Project, medical, histopathology, and CD serology records were used to identify all new cases of CD in Olmsted County since 2000. Age- and sex-specific and adjusted (to the US white 2000 population) incidence rates for CD were estimated. Clinical presentation at diagnosis was also assessed.
RESULTS
Between 2000 and 2010, 249 individuals (157 female or 63%, median age 37.9 years) were diagnosed with CD in Olmsted County. The overall age- and sex-adjusted incidence of CD in the study period was 17.4 (95% confidence interval [CI] = 15.2–19.6) per 100,000 person-years, increasing from 11.1 (95% CI=6.8–15.5) in 2000–2001 to 17.3 (95% CI=13.3–21.3) in 2008–2010. The temporal trend in incidence rates was modeled as a two-slope pattern, with the incidence leveling off after 2004. Based on the two classic CD symptoms of diarrhea and weight loss, the relative frequency of classical CD among incident cases decreased over time between 2000 and 2010 (p=0.044).
CONCLUSION
The incidence of CD has continued to increase in the past decade in a North American population.
doi:10.1038/ajg.2013.60
PMCID: PMC3686116  PMID: 23511460
autoimmunity; celiac; coeliac; epidemiology; prevalence
17.  Latest In vitro and in vivo models of celiac disease 
Expert opinion on drug discovery  2013;8(4):445-457.
Introduction
Currently, the only treatment for celiac disease is a gluten free diet, and there is an increased desire for alternative therapies. In vitro and in vivo models of celiac disease have been generated in order to better understand the pathogenesis of celiac disease, and this review will discuss these models as well as the testing of alternative therapies using these models.
Areas Covered
The research discussed describes the different in vitro and in vivo models of celiac disease that currently exist and how they have contributed to our understanding of how gluten can stimulate both innate and adaptive immune responses in celiac patients. We also provide a summary on the alternative therapies that have been tested with these models and discuss whether subsequent clinical trials were done based on these tests done with these models of celiac disease.
Expert Opinion
Only a few of the alternative therapies that have been tested with animal models have gone on to clinical trials; however, those that did go on to clinical trial have provided promising results from a safety standpoint. Further trials are required to determine if some of these therapies may serve as an effective adjunct to a gluten free diet to alleviate the adverse affects associated with accidental gluten exposure. A “magic-bullet” approach may not be the answer to celiac disease, but possibly a future cocktail of these different therapeutics may allow celiac patients to consume an unrestricted diet.
doi:10.1517/17460441.2013.761203
PMCID: PMC3605231  PMID: 23293929
celiac; gliadin; gluten; in vitro; in vivo; model; monkey; mouse; nondietary; rat; T cell; therapy; treatment
18.  LIVER INVOLVEMENT IN CELIAC DISEASE 
Minerva medica  2008;99(6):595-604.
Celiac disease is a chronic immune-mediated multisystem disorder that may affect several organs. Liver abnormalities are common extraintestinal manifestations of celiac disease. Isolated hypertransaminasemia, with mild or nonspecific histologic changes in the liver biopsy, also known as “celiac hepatitis”, is the most frequent presentation of liver injury in celiac disease. Both, histologic changes and liver enzymes reverse to normal after treatment with a gluten-free diet in most patients. Celiac disease may also be associated with severe forms of liver disease and/or coexist with other chronic liver disorders (i.e., autoimmune liver diseases). The mechanisms underlying liver injury in celiac disease are poorly understood. Predisposition to autoimmunity by shared genetic factors (i.e., HLA genes) as well as the systemic effects of abnormal intestinal permeability, cytokines, autoantibodies, and/or other yet undefined biologic mediators induced by gluten exposure in susceptible persons may play a pathogenic role. The aims of this article are 1) to review the spectrum of liver injury related to celiac disease and 2) to understand the clinical implications of celiac disease in patients with chronic liver disorders.
PMCID: PMC3941070  PMID: 19034257
autoimmune; hepatitis; cirrhosis; serology; liver
19.  Review Article: Celiac Disease, New Approaches to Therapy 
STRUCTURED SUMMARY
Background
Celiac disease is managed by life-long gluten withdrawal from the diet. However strict adherence to a gluten-free diet is difficult and is not always effective. Novel therapeutic approaches are needed to supplement or even replace the dietary treatment.
Aims
To review recent advances in new therapeutic options for celiac disease.
Methods
A literature search was performed on MEDLINE, EMBASE, Web of Science, Scopus, DDW.org and ClinicalTrial.gov for English articles and abstracts. The search terms used include but not limited to “Celiac disease”, “new”, “novel”, Advances”, “alternatives” and “Drug therapy”. The cited articles were selected based on the relevancy to the review objective.
Results
Several new therapeutic approaches for celiac disease are currently under development by targeting its underlying pathogenesis. Alternative therapies range from reproduction of harmless wheat strains to immunomodulatory approaches. Some of these therapies such as enzymatic cleavage of gluten and permeability inhibitors have shown promise in clinical studies.
Conclusion
Gluten-free diet is still the only practical treatment for patients with celiac disease. Novel strategies provide promise of alternative adjunctive approaches to diet restriction alone for patients with this disorder.
doi:10.1111/j.1365-2036.2012.05013.x
PMCID: PMC3912561  PMID: 22324389
gluten; zonulin; inflammation; malabsorption
20.  Autoimmune Enteropathy: A Review and Update of Clinical Management 
Current gastroenterology reports  2012;14(5):380-385.
Autoimmune Enteropathy (AIE) is a rare condition characterized by intractable diarrhea, histologic changes on small intestinal biopsy, failed response to dietary manipulation that also may present with extra-intestinal manifestations. In many patients, immunosuppressive therapies are necessary. Although AIE is more common in infants, adult involvement has also been documented. Much of what is known about AIE has been gathered from case reports and small case series; therefore more research in this evolving field is needed. IPEX (Immunodysregulation Polyendocrinopathy Enteropathy X-linked Syndrome) or APECED (Autoimmune Phenomena, Polyendocrinopathy, Candidiasis, and Ectodermal Dystrophy) are systemic forms of AIE.
doi:10.1007/s11894-012-0276-2
PMCID: PMC3912565  PMID: 22810979
Autoimmune Enteropathy (AIE); Immunodysregulation Polyendocrinopathy Enteropathy X-linked Syndrome (IPEX); Autoimmune Phenomena Polyendocrinopathy Candidiasis and Ectodermal Dystrophy (APECED); intractable diarrhea
21.  Mucosal Healing and Mortality in Celiac Disease 
BACKGROUND AND OBJECTIVES
Celiac disease (CD), characterized by the presence of villous atrophy (VA) in the small intestine, is associated with increased mortality, but it is unknown if this excess mortality is influenced by mucosal recovery. We examined overall mortality according to mucosal recovery in CD.
METHODS
Through biopsy reports from all pathology departments (n=28) in Sweden we identified 7,648 individuals with CD (defined as VA) who had undergone a follow-up biopsy within 5 years following diagnosis. We then used Cox regression to examine overall mortality according mucosal recovery in the follow-up biopsy (persistence of VA vs. recovery).
RESULTS
The mean age of CD diagnosis was 28.4, 63% were female, and the median follow-up after diagnosis was 11.5 years. Of the 7,648 patients, persistent VA was present in 3,317 (43%). There were 606 (8%) deaths. Patients with persistent VA were not at increased risk of death compared to those with mucosal healing (Hazard Ratio 1.01; 95% Confidence Interval 0.86-1.19). Mortality was not increased in children with persistent VA (HR 1.09 95% CI 0.37-3.16) or adults (HR 1.00 95% CI 0.85-1.18), including adults older than age 50 years (HR 0.96 95% CI 0.80-1.14).
CONCLUSION
Persistent VA was not associated with increased mortality in CD in this population followed for a median of 11.5 years. While a follow-up biopsy will determine if there is improvement in histology and allow detection of refractory disease in symptomatic patients, our study suggests that early routine follow up biopsies performed within 5 years does not predict long-term mortality risk.
doi:10.1111/apt.12164
PMCID: PMC3566869  PMID: 23190299
coeliac; death; inflammation; serial biopsy (British spelling of coeliac)
22.  Does haemochromatosis predispose to coeliac disease? A study of 29,096 coeliac disease patients 
Background and aim
Case reports suggest an association between hereditary haemochromatosis (HH) and coeliac disease (CD), but estimates of association are lacking. We estimated the association between HH and CD in a population-based study.
Materials and methods
Case-control study. We identified 29,096 individuals with biopsy-verified CD (equal to villous atrophy, Marsh stage III) through biopsy reports from all 28 pathology departments in Sweden. We then investigated the risk of a clinical diagnosis of HH in CD and in 144,522 controls matched for age, sex, county and calendar year. Conditional logistic regression was used to calculate odds ratios (ORs) for CD in patients with HH.
Results
HH was seen in 30 patients with CD and in 60 matched controls. HH was hence associated with an increased risk of CD (OR=2.30; 95%CI=1.53–3.25). Restricting HH to individuals with at least 2 records of HH, the OR for CD was 2.54 (95%CI=1.57–4.11), with a similar risk estimate when we only looked at HH diagnosed before CD (and matched date in controls) (OR=2.64; 95%CI=1.24–5.60).
Conclusion
HH seems to be associated with an increased risk of CD.
doi:10.3109/00365521.2012.749511
PMCID: PMC3576703  PMID: 23256862
autoimmunity; celiac; coeliac; hemochromatosis; haemochromatosis; inflammation
23.  Antibody repertoire profiling using bacterial display identifies reactivity signatures of celiac disease 
Analytical chemistry  2012;85(2):1215-1222.
A general strategy to identify serum antibody specificities associated with a given disease state, and peptide reagents for their detection was developed using bacterial display peptide libraries and multiparameter flow cytometry (MPFC). Using sera from patients with celiac disease (CD) (n = 45) or healthy subjects (n = 40), bacterial display libraries were screened for peptides that react specifically with antibodies from CD patients and not those from healthy patients. The libraries were screened for peptides that simultaneously cross-react with CD patient antibodies present in two separate patient groups labeled with spectrally distinct fluorophores, but do not react with unlabeled non-CD antibodies, thus affording a quantitative separation. A panel of six unique peptide sequences yielded 85% sensitivity and 91% specificity (AUC = 0.91) on a set of 60 samples not used for discovery, using leave-one-out cross-validation (LOOCV). Individual peptides were dissimilar with known CD specific antigens tissue transglutaminase (tTG) and deamidated gliadin, and classifier accuracy was independent of anti-tTG antibody titer. These results demonstrate that bacterial display/MPFC provides a highly effective tool for the unbiased discovery of disease-associated antibody specificities and peptide reagents for their detection that may have broad utility for diagnostic development.
doi:10.1021/ac303201d
PMCID: PMC3903178  PMID: 23234559
serum antibody; diagnostic; peptide
25.  Celiac disease: Diagnosis of celiac disease in pediatric patients 
Children and adolescents with untreated celiac disease display disease-related, histological alterations in the duodenal bulb, according to a new study. In 16 of the 665 patients enrolled in the study, lesions were confined to the duodenal bulb.
doi:10.1038/nrgastro.2009.58
PMCID: PMC3896877  PMID: 19404264

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