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ABSTRACTBackground:Lymphocytic duodenosis (LD) defined as increased intraepithelial lymphocytes >25 intraepithelial lymphocytes (IELs) per 100 epithelial cells with normal villous architecture is associated with many gastrointestinal (GI) disorders. We aim to assess the rate and outcome of LD in children and perform a systematic review.Method:We reviewed all children (<18 years) who underwent esophagogastroduodenoscopy (EGD) with duodenal biopsy between January 2000 and June 2019 to identify LD cases and control group. Demographics, clinical, and pathologic information were reviewed and recorded. A systematic review including our findings was performed.Results:During the study period 12,744 children underwent an EGD with biopsies. Of those, we identified 426 children with LD (3%) and 474 controls. The median age in years was 10.7 and 12.6 and there were 254 (60%) and 278 (59%) girls in the LD and control group, respectively. The most common presenting symptoms in both groups were abdominal pain (52%), gastroesophageal acid reflux disease (18%), diarrhea (16%), and vomiting (12%). Diarrhea (21% vs 12%, P < 0.001) and constipation (2% vs 0.4%, P = 0.021) were statistically different between the LD and control group, respectively. Median follow‐up (range) is 3.6 (0.0, 190.9) and 3.1 (0.0, 194.2) in the LD and control group, respectively. CD (5% vs 0%, P < 0.001), Crohn disease (9% vs 3%, P = 0.003) and Helicobacter pylori gastritis (3% vs 1%, P = 0.021) were more common in the LD group.Conclusions:The Rate of LD in children is similar to reported rate in adults. In the absence of Crohn disease, CD or H. Pylori, LD seems to be a benign and transient histologic finding in children.

Goal: The goal of this study was to estimate the impact of verification bias on the diagnostic accuracy of immunoglobulin A tissue transglutaminase (IgA tTG) in detecting celiac disease as reported by an authoritative meta-analysis, the 2016 Comparative Effectiveness Review (CER). Background: Verification bias is introduced to diagnostic accuracy studies when screening test results impact the decision to verify disease status. Materials and Methods: We adjusted the sensitivity and specificity of IgA tTG reported by the 2016 CER with the proportion of IgA tTG positive and negative individuals who are referred for confirmatory small bowel biopsy. We performed a systematic review from January 1, 2007, to July 19, 2017, to determine these referral rates. Results: The systematic review identified 793 articles of which 9 met inclusion criteria (n=36,477). Overall, 3.6% [95% confidence interval (CI): 1.1%-10.9%] of IgA tTG negative and 79.2.2% (95% CI: 65.0%-88.7%) of IgA tTG positive individuals were referred for biopsy. Adjusting for these referral rates the 2016 CER reported sensitivity of IgA tTG dropped from 92.6% (95% CI: 90.2%-94.5%) to 57.1% (95% CI: 35.4%-76.4%) and the specificity increased from 97.6% (95% CI: 96.3%-98.5%) to 99.6% (95% CI: 98.4%-99.9%). Conclusions: The CER may have largely overestimated the sensitivity of IgA tTG due to a failure to account for verification bias. These findings suggest caution in the interpretation of a negative IgA tTG to rule out celiac disease in clinical practice. More broadly, they highlight the impact of verification bias on diagnostic accuracy estimates and suggest that studies at risk for this bias be excluded from systematic reviews.

19561 Background: Diarrhea is a common side effect of chemotherapy (CT). At times, often unpredictably, patients develop profound diarrhea during CT. Though the clinical diagnosis of celiac disease (CD) is relatively rare, (1/ 2000), the serologic prevalence is much higher (1/ 133), suggesting a large number of undiagnosed cases. Latent CD may be unmasked by stressors, such as CT. We hypothesized that undiagnosed CD may account for some cases of severe diarrhea from CT. Methods: We performed a retrospective chart review at the Mayo Clinic (1980–2006) for patients with diagnoses of cancer and CD that received CT at our center. CD cases were confirmed by biopsy (n= 25) or serologic studies. Data analyzed included severe (grade ≥ 3,) diarrhea while on CT, site of primary cancer, diagnosis of CD prior to or after CT, and specific CT agents received. Results: We identified 27 patients with CD and cancer (12 lymphoma, 6 gastrointestinal, 2 leukemia, 2 breast, 1 brain, bladder, lung, uterine, sarcoma) who received CT at our center. Fifteen were diagnosed with CD prior to receiving CT and 12 after, with the former group presumably on a gluten-free diet. One patient was excluded for lack of clinical data. Five of remaining 14 patients (35%) managed for their CD prior to CT had diarrhea, though 4 of these 5 had only mild diarrhea (gr. 1). One patient suffered gr. 3 diarrhea, though was reported to be poorly compliant with his diet. Three patients received treatment with 5- fluorouracil (5FU), and 2 had gr. 1 diarrhea. Five of the 12 patients (42%) with celiac disease undiagnosed prior to CT were reported to have diarrhea during treatment (3 gr. 4; 2 gr. 1). Of those receiving 5FU, 3 out of 4 had severe (gr. 4) diarrhea. The small numbers of patients precluded meaningful statistical analysis. Conclusion: Patients with known CD compliant with a gluten-free diet tolerated CT well. However, in a subset of undiagnosed patients, severe diarrhea developed during CT, most notably with 5FU-based regimens. We propose that when patients have diarrhea disproportionate to other effects, CD should be considered. Also, in malignancies with a high incidence of CD such as lymphoma and small bowel cancer, underlying CD should be considered before CT is given. No significant financial relationships to disclose.

HLA‐DQ8 is associated with certain autoimmune diseases including celiac disease, juvenile diabetes mellitus, and rheumatoid arthritis. These diseases have significantly high morbidity and mortality rates and often require chronic, life‐long immunosuppressive therapy, especially in the case of rheumatoid arthritis. Recent studies have determined that commensal microorganisms from the gut flora can modulate the development of autoimmune diseases although the mechanism of action remains elusive. We examined the systemic immunological effects following oral exposure to live commensal bacteria within naive AEoDQ8 mice. Specifically, Prevotella species was isolated and cultured from the small intestine of celiac patients and administered by oral gavages every 48 hours for 2 weeks to AEo DQ8 mice. Significant decreases in serum IL‐17 expressed in pg/ml (2406 to 1662, □33%) and GM‐CSF (15.5 to 9.7, □40%) were detected in the sera of the group administered live bacteria as compared to the group administered sham gavages. The decrease in serum IL‐6, G‐CSF, MIP1a, and MIP1b levels did not reach statistical significance. Also, no difference in serum TGFbeta levels was observed between the two groups. However, FACS analysis revealed an increase in splenic CD4+CD25+FoxP3+ regulatory T‐cells in the group administered live bacteria as compared to the control group, 11.4% vs. 8.0%, respectively. These findings suggest that gram negative, commensal bacteria can suppress the expression of pro‐inflammatory IL‐17 at a systemic level.

Background: Celiac disease (CD) often presents with symptoms of diarrhea and malabsorption, termed classical CD. However, it can also present as nonclassical CD, which is commonly associated with nongastrointestinal symptoms. Studies suggest that nonclassical CD tends to have less severe symptoms than classical CD, which may affect both adherence to a gluten-free diet (GFD) and psychological stress. Therefore, we compared adherence to a GFD and psychological measures, including quality of life (QOL) and somatization, between patients with nonclassical and classical presentations of CD. Methods: Patients at a tertiary care center with biopsy-proven CD, who completed a Talley Bowel Disease Questionnaire and the Short Form-36 at diagnosis and who had been on a GFD for at least 1 year, were included in this study. Patients were further surveyed to assess gastrointestinal symptoms, QOL, Somatization Symptom Checklist (SSC), and adherence to a GFD. Results were compared between patients with classical versus nonclassical CD presentation. Results: Among 122 patients included in this study, 62 had classical CD and 60 had nonclassical CD. At diagnosis, health-related QOL was lower in the classical CD group than in the nonclassical CD group. After following a GFD, both groups had improved QOL after following a GFD, and body mass index significantly increased in both groups. Most subscales of QOL, SSC scores, and adherence to the GFD were similar between the groups, except the Short Form-36 Mental Component summary scores that were still lower in the classical CD (48.4 vs. 52.6 nonclassical CD group; P=0.03). Conclusions: Despite QOL at diagnosis being higher in those with nonclassical CD versus lower in those with classical CD, both groups had improved QOL and achieved a similar QOL after following a GFD.

Abstract Abstract 4048 Poster Board III-983 Introduction Iron deficiency is the most common nutritional disorder in the world with an estimated two billion affected persons. Although commonly considered environmental in origin, the existence of multiple genetic disorders of iron metabolism in man, rodents and other vertebrates suggest a genetic contribution to iron deficiency. Methods: The Hemochromatosis and Iron Overload Screening (HEIRS) Study is a multi-center, multi-ethnic study in which transferrin saturation (TS), serum ferritin (SF), and HFE mutations were determined in 101,168 adults. To identify genomic locations associated with iron deficiency, we performed a genome-wide association study (GWAS) using DNA collected from white HEIRS Study participants who had SF ≤ 12 μg/L (cases) and an equal number of white controls (SF > 100 μg/L in men, SF > 50 μg/L in women) frequency-matched to cases by sex and geographic location. Men aged ≥ 25 y and women ≥ 50 y were included in both groups. Tissue body iron, an index of iron deficiency, was estimated from serum transferrin receptor (sTfR) and SF. Genotyping was performed with the Illumina HumanCNV370K Beadchip platform. Quality control filters excluded single nucleotide polymorphisms (SNPs) or samples with > 5% missing genotypes, SNPs showing heterozygosity or Hardy-Weinberg deviations (P<10−7), and SNPs with minor allele frequency < 0.02. Population admixture/structure was assessed using principal component analysis. Regression analysis was used to examine the association between outcomes (case-control status, tissue body iron, serum ferritin, transferrin receptor, serum iron, total iron-binding capacity [TIBC], and unsaturated iron-binding capacity [UIBC]) and each SNP genotype variable; covariates included age, sex, and geographic location. Replication for 56 SNPs was conducted in a population attending primary care clinics at a Veterans Affairs (VA) medical center using the iPlex platform. Eligibility within the VA replication population was restricted to age and self-reported white ethnicity as for the HEIRS subset from a total of 2559 people (138 women). VA participants with SF ≤ 20 μg/L were classified as iron-deficient cases and frequency matched 1:2 with controls (men with SF > 100 μg/L and women with SF > 50 μg/L). Results The GWAS genomic control parameter was not significantly different from 1.0. There were 392 cases (96 men) and 390 controls (96 men) in the HEIRS subset GWAS with average age (SD) of 59 (10) y and 61 (11) y, respectively. Geometric mean SF (minimum, maximum), and mean (SD) for sTfR and tissue body iron in the HEIRS subset were 7.5 (1.2, 12) μg/L, 6.4 (3.77) mg/kg and -2.0 (2.50) for cases and 141 (51, 881) μg/L, 3.0 (0.98) mg/kg and 10.8 (2.5) for controls. After quality control tests, GWAS analysis included genotype data for 331,060 SNPs in 734 individuals (364 cases, 370 controls). For the VA replication population there were 67 male and 11 female cases, and 136 male and 27 female controls for whom DNA was successfully prepared; the average age (SD) was 68 (12) y for cases and 65 (11) y for controls. Regression analysis identified seven SNPs within four independent regions that replicated associations found in the GWAS (GWAS P<1×10-4 and VA P<0.05).The SNP rs6735681 on chromosome 2p24 was associated with serum iron (GWAS P<3.9×10-5, VA P=0.038). Three SNPs on chromosome 2p14 (rs6750096, rs2698541 and rs2698530) significantly influenced both TIBC and UIBC (GWAS P<2.9×10-5, VA P< 0.04 for all). Two SNPs in the TF gene region on chromosome 3q22 also showed significant effects on TIBC and UIBC (GWAS P<4.7×10-6, VA P<0.03 for all). The SNP rs10512064 on chromosome 9q21 was associated with serum ferritin concentration and tissue body iron (GWAS P<2.5×10-5, VA P<0.05 for both). Conclusion: From these GWAS and replication studies, we have identified three new genetic loci and one known iron gene, TF, associated with iron phenotype variability. These results point to specific loci as targets for gene identification and TF polymorphisms as determinants of iron metabolism, which in turn may play a role in regulation of body iron status. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2105 The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. We hypothesized that common variants in genes involved in iron metabolism may modulate susceptibility or resistance to the development of iron deficiency in humans. To examine the association between single nucleotide polymorphisms (SNPs) in key genes involved in iron metabolism pathways, we previously performed a genome-wide association study using DNA collected from white men aged ≥25 y and women ≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤12 μg/L (cases) and controls (SF >100 μg/L in men, SF >50 μg/L in women). We now report on a multiethnic follow-up association study of HEIRS participants. Candidate SNPs were identified from our GWAS and the scientific literature. Population samples of whites, African Americans, Hispanics, and Asians from the U.S. and Canada were analyzed separately for association between SNPs and case-control status and each of seven quantitative outcomes including serum iron, total iron-binding capacity (TIBC), unsaturated iron-binding capacity (UIBC), transferrin saturation, SF, serum transferrin receptor, and body iron. There were 1084 white (357 cases, 727 controls), 153 Asian (51 cases, 102 controls), 221 African American (77 cases, 144 controls) and 233 of 239 Hispanic individuals (79 cases, 160 controls) that passed quality control. For the African-American and Hispanic samples, ancestry proportions were estimated based on genotypes of ancestry informative markers. Regression analysis was used to examine the association between case-control status and quantitative serum iron measures and 1134, 1115, 1113 and 1134 SNP genotypes in the white, African-American, Hispanic, and Asian population samples, respectively. Model predictors included age, sex, the estimated ancestry proportion (for African American and Hispanic only), genotype, and measured covariates that showed nominally significant associations with the outcome. Three chromosomal regions showed evidence of association across multiple populations, including SNPs in the TF gene on chromosome 3q22, the TMPRSS6 gene on chromosome 22q12, and loci on chromosome 18q21. SNP rs1421312 in TMPRSS6 was associated with serum iron in whites (p=4.7×10−7) and was replicated in African Americans (p=0.0012).Twenty SNPs in the TF gene region were significantly associated with TIBC in the white sample (p<4.4×10−5); six SNPs were replicated in other ethnicities (p< 0.01). SNP rs10904850 in the CUBN gene on 10p13 was significantly associated with serum iron in the African-American sample (P=1.0×10−5). Mutations in the TMPRSS6 gene have been implicated in iron-refractory iron deficiency anemia through linkage studies. We found a novel SNP in TMPRSS6 that was associated with serum iron in whites and replicated in African Americans, suggesting a role for this SNP in increasing the risk of iron deficiency in affected persons. Our results confirm known associations with iron measures and give evidence of their role in different ethnic groups, a unique aspect of this study, suggesting origins in a common founder. Disclosures: No relevant conflicts of interest to declare.

Abstract Background : Celiac disease (gluten sensitive enteropathy) is a systemic disease with hematological manifestations including; iron deficiency anemia, vitamin B12 and folate deficiency, leukopenia/neutropenia, hyposplenism, venous thromboembolism, and the enteropathy associated T cell lymphoma (E-TCL). Leukopenia/neutropenia is rare, and can result from folate or copper deficiency, but in many cases remains idiopathic. The consequences of neutropenia and neutrophil responses to a gluten free diet are not well described. We carried out this study to assess the incidence and outcomes of neutropenia in patients with celiac disease. Methods : The Mayo clinic celiac disease database (n=1729) was retrospectively analyzed for all patients with a confirmed diagnosis of celiac disease that had leukopenia (<3.5 x10(9)/L) and/or neutropenia (<1.5 x 10(9)/L). The diagnosis of celiac disease was established by positive tissue transglutaminase antibodies (TTG) and confirmatory small bowel biopsy findings. Additional causes of neutropenia such as copper and folate deficiency, drugs, benign ethnic and cyclic neutropenia, chemotherapy, hematological malignancies, combined variable immunodeficiency (CVID), and autoimmune diseases were meticulously excluded. Data abstracted included demographics, temporal association with diagnosis, nadir counts, associated hematological findings, relationship with infections, the use and effect of G-CSF, response to gluten free diet and survival outcomes. Results: 21(1.2%) of 1729 cases screened had idiopathic-celiac related neutropenia; 17 (81%) Caucasian, 15 (48%) females. In 12(57%) patients the neutropenia preceded or occurred near the time of the diagnosis of celiac disease, while in 7 (33.3%) it occurred subsequently. In 2 cases the temporal association could not be established. The median age at diagnosis of celiac disease was 46 years (10-67) and the median follow up for this group was 41.7 months (0-207.3). At last follow up 1 (4.8%) death has been documented; 0 from infectious complications, with no cases of E-TCL. The median laboratory values at diagnosis of celiac disease were available in 11 (52%) patients and included; hemoglobin 12.9 g/dL (10.5-16.8), MCV 91.5 fl (79.6-102.8), WBC 3.2 x109/L (2.3-5.2), ANC 1.29x109/L (0.33-3.24), ALC 1.34x109/L (0.75-2.17), AMC 0.39x109/L (0.15-0.71), and platelet counts 225x109/L (168-711). Anti-granulocyte antibodies were assessed in 7 patients and were negative in all cases. None of these patients had coexistent hyposplenism and three cases of neutropenia that occurred in the setting of celiac disease and CVID were excluded. In 15 (71%) patients the neutropenia was incidentally detected during routine laboratory work and in 4 (19%) it came to light secondary to infections. Ten (48%) patients had recurrent infections (≥1) as documented by their providers, including 7 with sinopulmonary infections, 1 with urinary tract infections, and 1 with skin and soft tissue infections. Additional immunological assessments were not available in these patients. Three (14%) patients had an ANC <500 (significant neutropenia); of which 2 had recurrent sinopulmonary infections. The third patient remained largely asymptomatic. Two of the 3 patients received G-CSF support during infections and responded adequately (ANC improvement > 1 x 10(9)/L). The ANC in patients in this cohort did not correlate with severity of infections. Five (23%) of 21 patients had improvement in neutrophil counts after adopting a gluten free diet, while there was no response in 10 and data was unavailable in 6. The median time to ANC response was 14.5 months (10-15.3) and the median increment in ANC was 0.67 x 10(9)/L (0.48-0.98). Conclusions: Celiac disease associated neutropenia, especially significant neutropenia (ANC <500) is a rare occurrence (~1%). It can often pre-date the diagnosis of celiac disease or occur subsequently. It is potentially associated with an increased incidence of infections, with-out good correlation with the severity of neutropenia. Less than half the patients do seem to respond to a gluten free diet. G-CSF responses seem to be adequate and G-CSF can be used in the setting of severe infections. Disclosures No relevant conflicts of interest to declare.