Diagnostic Accuracy of IgA Anti-Transglutaminase and IgG Anti-Deamidated Gliadin for Diagnosis of Celiac Disease in Children under Two Years of Age: A Systematic Review and Meta-Analysis

The need of adding the determination of anti-deamidated gliadin peptide (DGP) IgG to anti-transglutaminase (TTG) IgA antibodies for diagnosis of celiac disease (CD) in children <2 years of age is controversial. We performed a systematic review and meta-analysis to evaluate, by head-to-head comparison, the diagnostic accuracy of TTG IgA and DGP IgG antibodies. We searched PubMed, MEDLINE, and Embase databases up to January 2021. The diagnostic reference was intestinal biopsy. We calculated the sensitivity and specificity of these tests and the odds ratio (OR) between the tests. Fifteen articles were eligible for the systematic review and ten were eligible for the meta-analysis. Sensitivity and specificity were 0.96 (95% confidence interval (CI), 0.91–0.98) and 0.96 (95% CI, 0.85–0.99) for DGP IgG and 0.93 (95% CI, 0.88–0.97) and 0.98 (95% CI, 0.96–0.99) for TTG IgA, respectively. TTG IgA specificity was significantly higher (OR 9.3 (95% CI, 2.3–37.49); p < 0.001) while the sensitivity of DGP IgG was higher without reaching statistical significance (OR: 0.6 (95% CI, 0.24–1.51); p = 0.28). Both the meta-analysis and the systematic review showed that some children with early CD are missed without the DGP IgG test. In children <2 years of age, TTG IgA is the best CD screening test; however, the addition of DGP IgG may increase the diagnostic sensitivity.

Transcriptional and Cytotoxic Responses of Human Intestinal Organoids to Interferon Types I, II, and III

The three types of interferon (IFN) have roles in antimicrobial immunity and inflammation that must be properly balanced to maintain tissue homeostasis. For example, IFNs are elevated in the context of inflammatory bowel disease and may synergize with inflammatory cytokines such as tumor necrosis factor alpha (TNFα) to promote tissue damage. Prior studies suggest that in mouse intestinal epithelial cells (IECs), type III IFNs are preferentially produced during viral infections and are less cytotoxic than type I IFN. Here, we generated human IEC organoid lines from biopsies of ileum, ascending colon, and sigmoid colon of three healthy subjects to establish the baseline responses of normal human IECs to types I, II, and III IFN. We found that all IFN types elicited responses that were qualitatively consistent across intestinal biopsy sites. However, IFN types differed in magnitude of STAT1 phosphorylation and identity of genes in their downstream transcriptional programs. Specifically, there was a core transcriptional module shared by IFN types, but types I and II IFN stimulated unique transcriptional modules beyond this core gene signature. The transcriptional modules of type I and II IFN included pro-apoptotic genes, and expression of these genes correlated with potentiation of TNFα cytotoxicity. These data define the response profiles of healthy human IEC organoids across IFN types, and suggest that cytotoxic effects mediated by TNFα in inflamed tissues may be amplified by a simultaneous high-magnitude IFN response.

A Novel Approach Towards Less Invasive Multi ‘Omics Gut Analyses: A Pilot Study

Newer ‘omics approaches such as metatranscriptomics and metabolomics allow functional assessments of the interaction(s) between the gut microbiome and the human host. In order to generate meaningful data with these approaches, though, the method of sample collection is critical. Prior studies have relied upon expensive and invasive means towards sample acquisition such as intestinal biopsy, while other studies have relied upon easier methods of collection such as fecal samples that do not necessarily represent those microbes in contact with the host. In this pilot study, we attempt to characterize a novel, minimally invasive method towards sampling the human microbiome using mucosal cytology brush sampling compared to intestinal gut biopsy on 5 healthy participants undergoing routine screening colonoscopy. We compared metatranscriptomic analyses between the two collection methods, identifying increased taxonomic evenness and beta diversity in the cytology brush samples, and similar community transcriptional profiles between the two methods. Metabolomics assessment demonstrated striking differences between the two methods, implying a difference in bacterial-derived versus human absorbed metabolites. Put together, this study supports the use of a less invasive method of microbiome sampling with cytology brushes, but caution must be exercised when performing metabolomics assessment as this represents differential metabolite production but not absorption by the host.

GGLUTEN-SENSITIVE ENTEROPATHY - NEW VIEW ON PROBLEM

Gluten sensitive enteropathy-celiac disease is an immune-mediated disorder caused by permanent sensitivity to gluten in genetically susceptible individuals. Epidemiologic studies of last years suggest that it is common and may occur in 0,5-1% of the general population. The bowel inflammatory and immunologic response results in atrophy and damage in the small bowel and secondary malabsorbtion. The mode of presentation can be quite variable. Celiac disease is generally defined as chronic diarrea and failure to thrive in infants and toddlers, diarrhea is still the most common symptom, but disease may occure in different age groups and with exstraintestinal, sometimes monosymptomic clinic. Clinical forms of celiac disease are: classic, atypical, silent, latent and potential. Definitive diagnose of Celiac disease requires serrologic screening, small intestinal biopsy and effectiveness of elimination diet. Anti-tissue transglutaminase antybody test (TTG IgA and TTG IgG) is highly sensitive, specific and less expensive, thus is recommended for general practice. None of serologic tests are 100% reliable. Definitive diagnosis requires characteristic histologic changes in intestine mucus. Tissue for investigation may be taken from duodenum during gastro endoscopy. Diagnosing only by results of gluten-free diet is not correct. The only treatment for celiac disease is lifelong exclusion of gluten. Early diagnosis and strict dietary restrictions appear to be the only possibility of prevention risk for failure to thrive, delay of sexual maturity, autoimmune disorders, adenocarcinoma of gastrointestinal tract and lymphoma.

Predictive Value of NKILA and lnc13 lnc RNAs for Distinguishing of Celiac Disease and IBD: A Case-Control Study

Long-noncoding RNA 13 (lnc13) and NF-κB-interacting lncRNA (NKILA) are long noncoding RNAs (lncRNAs) that play a role in inflammatory disorders pathogenesis. This study aimed at investigating the expression of these lncRNAs in inflammatory bowel disease (IBD) and celiac disease (CeD) patients compared to controls. We evaluated mRNA expression of lnc13 and NKILA in peripheral blood and intestinal biopsy samples of 50 CeD, 46 IBD patients, and 20 controls using qRT- PCR method. Compared to the controls, CeD and IBD patients had a significantly higher PBMC mRNA level of Lnc13 (p < 0.0001 for both of them) and NKILA (p < 0.0001 and p=0.0174, respectively). NKILA mRNA level was significantly higher in CeD than in IBD patients (p < 0.0001). IBD subjects had significantly increased colonic NKILA expression (p=0.004). In UC, NKILA, and CD, lnc13 colonic expression was significantly increased compared to others (p=0.002 and p=0.0111 respectively for UC, p = 0.0075 and p = 0.002, respectively for CD). Collectively, increased peripheral expression of lnc13 and NKILA along with their decreased duodenal expression demonstrates CeD. Moreover, suppose the increased peripheral expression of lnc13 and NKILA is associated with increased lnc13 colonic expression. In that case, it indicates CD, and if it is associated with increased NKILA colonic expression, it indicates UC.

Associated factors for celiac disease, and utility of tissue transglutaminase antibody tests for diagnosis: a matched case-control study

Background Prevalence of Celiac disease (CD) increased worldwide in recent decades. Approximately 53% of the 33.4 million Saudi population are genetically susceptible and 1.5% develop CD. This underscores the importance of identification of factors associated with CD and the diagnostic accuracy of CD screening tests. Methods In this case-control study records of patients managed between January 2016 and July 2019 at Gastroenterology Department, King Abdul-Aziz Medical City, Riyadh, Saudi Arabia were reviewed. CD cases with confirmed intestinal biopsy were matched (1:1) by age with biopsy negative controls free of CD. Area under the curve (AUC) for anti-tissue transglutaminase IgA (TTG-IgA) and IgG (TTG-IgG) CD diagnostic tests were calculated and compared. Results The study included 270 cases and 270 controls. Sex distribution was similar in both groups. In a stepwise conditional logistic regression analysis, factors significantly associated with CD were family history (odds ratio (OR)=7.76, 95% confidence interval (CI): 2.26-26.63, P=0.001), Helicobacter pylori infection (OR=1.72, 95% CI: 1.10-2.71, P=0.018), diabetes mellitus (OR=3.37, 95% CI: 1.68-6.74, P=0.001), hypothyroidism (OR=2.46, 95% CI: 1.15-5.28, P=0.02) and respiratory infections (OR=4.89,95% CI 2.26-10.56, P<0.001). AUC for TTG-IgA test was 0.934 and for TTG-IgG was 0.787, P<0.001. The optimal cut-off for TTG-IgA was >=12.7 U/ml, with 89% sensitivity and 86% specificity, and for TTG-IgG was >=3.5 U/ml, with 70% sensitivity and 77% specificity.Conclusion The findings of this study can inform strategies for CD screening and prevention. Public awareness campaigns for CD are urgently needed, particularly, for high-risk groups.

Telomere dysfunction instigates inflammation in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn’s disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.

Response of Hepatitis B Vaccine in Children with Celiac Disease – An Experience at Ayub Teaching Hospital, Abbottabad Pakistan

Background: Celiac Disease (CD), characterized by chronic small intestinal inflammation, is an immune-mediated disorder, with a strong family history and association with DQ2 HLA haplotype. It has been postulated that children with CD show less response to hepatitis B vaccine due to overexpression of HLA-DQ2 haplotype. This study was done to determine the response of hepatitis B vaccine in children with CD in our tertiary care setting in the Hazara region of eastern Khyber Pakhtunkhwa, Pakistan.Material and Methods: This cross-sectional study was conducted in the Pediatrics outpatient department (OPD) of Ayub Teaching Hospital, Abbottabad Pakistan from April 2018 till March 2020. Children with CD (n=38) aged 1-14 years with completed HBV vaccination, anti-tissue transglutaminase IgA antibody (tTG-IgA) >150 IU/ml and/or typical histological findings of CD on small-bowel biopsy, were included in the study. Hepatitis B surface antibody (HbsAb) titer of ≥10 mIU/ml was taken as antibody positive, while HbsAb levels < 10 mIU/ml were considered as vaccine non-responsive. Data was analyzed using SPSS version 20.0. Chi square test was applied for comparison with P-value < .05 taken as significant.Results: Out of 38 diagnosed cases of CD, 15 (39.5%) were males and 23 (60.5%) were females. Mean age of children was 8.32±3.26 years with an age range of 3-14 years. HbsAb levels ranged from 0.10 to 62.7 mIU/ml with a mean of 11.2+17.42 mIU/ml. HbsAb levels were less than 10.0 IU/ml in 73.7% of children with CD. Small intestinal biopsy was performed in 11 (28.9%) patients. There was a significant relationship between anti tTG-IgA levels and histopathology findings with P-value of .001.Conclusions: In children having celiac disease, there was low rate of protective antibody response to hepatitis B vaccine.

Case Report: Severe Hypocalcemic Episodes Due to Autoimmune Enteropathy

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic disorder, associated with endocrine deficiencies and non-endocrine involvement. Gastrointestinal (GI) manifestations appear in approximately 25% of patients and are the presenting symptom in about 10% of them. Limited awareness among pediatricians of autoimmune enteropathy (AIE) caused by destruction of the gut endocrine cells in APECED patients delays diagnosis and appropriate therapy. We describe an 18-year-old female presenting at the age of 6.10 years with hypoparathyroidism, oral candidiasis and vitiligo. The clinical diagnosis of APECED was confirmed by sequencing the autoimmune regulator-encoding (AIRE) gene. Several characteristics of the disease—Hashimoto’s thyroiditis, Addison’s disease, diabetes mellitus type 1 and primary ovarian insufficiency—developed over the years. She had recurrent episodes of severe intractable hypocalcemia. Extensive GI investigations for possible malabsorption, including laboratory analyses, imaging and endoscopy with biopsies were unremarkable. Revision of the biopsies and chromogranin A (CgA) immunostaining demonstrated complete loss of enteroendocrine cells in the duodenum and small intestine, confirming the diagnosis of AIE. Management of hypocalcemia was challenging. Only intravenous calcitriol maintained calcium in the normal range. Between hypocalcemic episodes, the proband maintained normal calcium levels, suggesting a fluctuating disease course. Repeated intestinal biopsy revealed positive intestinal CgA immunostaining. The attribution of severe hypocalcemic episodes to AIE emphasizes the need for increased awareness of this unique presentation of APECED. The fluctuating disease course and repeated intestinal biopsy showing positive CgA immunostaining support a reversible effect of GI involvement. CgA immunostaining is indicated in patients with APECED for whom all other investigations have failed to reveal an explanation for the malabsorption.