Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet

BACKGROUND The gluten-free diet(GFD)has limitations,and there is intense research in the development of adjuvant therapies.AIM To examine the effects of orally administered Aspergillus niger prolyl endopeptidase protease(AN-PEP)on inadvertent gluten exposure and symptom prevention in adult celiac disease(CeD)patients following their usual GFD.METHODS This was an exploratory,double-blind,randomized,placebo-controlled trial that enrolled CeD patients on a long-term GFD.After a 4-wk run-in period,patients were randomized to 4 wk of two AN-PEP capsules(GliadinX;AVI Research,LLC,United States)at each of three meals per day or placebo.Outcome endpoints were:(1)Average weekly stool gluten immunogenic peptides(GIP)between the run-in and end of treatments and between AN-PEP and placebo;(2)celiac symptom index(CSI);(3)CeD-specific serology;and(4)quality of life.Stool samples were collected for GIP testing by ELISA every Tuesday and Friday during run-ins and treatments.RESULTS Forty patients were randomized for the intention-to-treat analysis,and three were excluded from the per-protocol assessment.Overall,628/640(98.1%)stool samples were collected.GIP was undetectable(<0.08μg/g)in 65.6%of samples,and no differences between treatment arms were detected.Only 0.5%of samples had GIP concentrations sufficiently high(>0.32μg/g)to potentially cause mucosal damage.Median GIP concentration in the AN-PEP arm was 44.7%lower than in the run-in period.One-third of patients exhibiting GIP>0.08μg/g during run-in had lower or undetectable GIP after AN-PEP treatment.Compared with the run-in period,the proportion of symptomatic patients(CSI>38)in the AN-PEP arm was significantly lower(P<0.03).AN-PEP did not result in changes in specific serologies.CONCLUSION This exploratory study conducted in a real-life setting revealed high adherence to the GFD.The AN-PEP treatment did not significantly reduce the overall GIP stool concentration.However,given the observation of a significantly lower prevalence of patients with severe symptoms in the AN-PEP arm,further clinical research is warranted.

Celiac disease screening in patients with cryptogenic cirrhosis

We write a letter to the editor commenting the article“Who to screen and how to screen for celiac disease”.We discuss the present literature on cirrhosis and celiac disease(CD)and recommend screening and treating CD in individuals with cryptogenic cirrhosis.

Risk of pancreatic cancer in individuals with celiac disease in the United States:A population-based matched cohort study

BACKGROUND Celiac disease(CD)has been associated with gastrointestinal malignancies.However,the magnitude of the risk of pancreatic cancer(PC)associated with CD is much less clear,and risks have not been estimated from large populations.AIM To assess the risk of PC in CD patients.METHODS We conducted a population-based,multicenter,propensity score-matched cohort study with consecutive patients diagnosed with CD using the TriNeTx research network platform.We examined the incidence of PC in patients with CD compared with a matched cohort of patients without CD(non-CD,controls).Each patient in the main group(CD)was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding effects.The incidence of PC was estimated using a Cox proportional hazards model with a hazard ratio(HR)and 95%confidence interval(CI).RESULTS A total of 389980 patients were included in this study.Among them,155877 patients had a diagnosis of CD,and the remaining 234103 individuals without CD were considered a control cohort.The mean duration of follow-up for patients in the CD and control cohorts was 5.8±1.8 and 5.9±1.1 years,respectively.During the follow-up,309 patients with CD developed PC,whereas 240 patients developed PC in the control group(HR=1.29;95%CI:1.09-1.53).In the secondary analyses in the first year after diagnosis of CD,patients with CD were at a significant increase in risk for PC;151 patients with CD had an incidence of PC compared with 96 incidences of PC among the patients in the non-CD control group(HR=1.56;95%CI:1.20-2.01)and sensitivity analysis showed similar magnitude to the one generated in the primary and secondary analysis.CONCLUSION Patients with CD are at increased risk of PC.Risk elevation persists beyond the first year after diagnosis to reference individuals without CD from the general population.

Gut microbiota predicts the diagnosis of celiac disease in Saudi children

BACKGROUND Celiac disease(CeD)is a multisystem immune-mediated multifactorial condition strongly associated with the intestinal microbiota.AIM To evaluate the predictive power of the gut microbiota in the diagnosis of CeD and to search for important taxa that may help to distinguish CeD patients from controls.METHODS Microbial DNA from bacteria,viruses,and fungi,was isolated from mucosal and fecal samples of 40 children with CeD and 39 controls.All samples were sequenced using the HiSeq platform,the data were analyzed,and abundance and diversities were assessed.For this analysis,the predictive power of the microbiota was evaluated by calculating the area under the curve(AUC)using data for the entire microbiome.The Kruskal-Wallis test was used to evaluate the significance of the difference between AUCs.The Boruta logarithm,a wrapper built around the random forest classification algorithm,was used to identify important bacterial biomarkers for CeD.RESULTS In fecal samples,AUCs for bacterial,viral,and fungal microbiota were 52%,58%,and 67.7%respectively,suggesting weak performance in predicting CeD.However,the combination of fecal bacteria and viruses showed a higher AUC of 81.8%,indicating stronger predictive power in the diagnosis of CeD.In mucosal samples,AUCs for bacterial,viral,and fungal microbiota were 81.2%,58.6%,and 35%,respectively,indicating that mucosal bacteria alone had the highest predictive power.Two bacteria,Bacteroides intestinalis and Burkholderiales bacterium 1-1-47,in fecal samples and one virus,Human_endogenous_retrovirus_K,in mucosal samples are predicted to be“important”biomarkers,differentiating celiac from nonceliac disease groups.Bacteroides intestinalis is known to degrade complex arabinoxylans and xylan which have a protective role in the intestinal mucosa.Similarly,several Burkholderiales species have been reported to produce peptidases that hydrolyze gluten peptides,with the potential to reduce the gluten content of food.Finally,a role for Human_endogenous_retrovirus_K in immune-mediated disease such as CeD has been reported.CONCLUSION The excellent predictive power of the combination of the fecal bacterial and viral microbiota with mucosal bacteria alone indicates a potential role in the diagnosis of difficult cases of CeD.Bacteroides intestinalis and Burkholderiales bacterium 1-1-47,which were found to be deficient in CeD,have a potential protective role in the development of prophylactic modalities.Further studies on the role of the microbiota in general and Human_endogenous_retrovirus_K in particular are needed.

Efficacy of probiotics supplementation in amelioration of celiac disease symptoms and enhancement of immune system

Patients with celiac disease(CD)have a mucosal layer that is unable to regulate the gut microbiota,leaving the host vulnerable to dangerous infections and antigens.When compared to healthy people,this dysbiosis is marked by a decrease in intra-and intergeneric biodiversity,which demonstrates an imbalance between helpful bacteria and possibly harmful or proinflammatory species.The early gut microbiota is influenced by the genotype of newborns with the HLADQ2 haplotypes,and this may modify how gluten is handled in the intestinal lumen,polarize innate or adaptive immune responses,and result in glutensensitive enteropathy.The outcome of gluten digestion can vary depending on the composition of the intestinal gut bacteria and the partial conversion of gluten into peptides larger than ten amino acids in the small intestines,which can be immunogenic.In the small intestine,114 different bacterial strains belonging to 32 different species have 27 of them exhibiting peptidolytic activity.Thus,the individual risk of developing a gluten-related illness is further influenced by microbial composition and gluten degrading capacity.The conclusion that lactobacilli and Bifidobacterium spp.may be used as a probiotic supplement in CD patients is based on their shared possession of the most extensive peptidolytic and proteolytic activity thought to be engaged in the breakdown of gluten among all potential bacterial genera present in the gut microbiota.In children with CD autoimmunity,daily oral dose of Lactobacillus.plantarum HEAL9 and Lactobacillus.paracasei 8700:2 was found to modify the peripheral immune response.Bifidobacterium.breve strains have demonstrated a beneficial effect on reducing pro-inflammatory cytokine TNF-production in CD children on gluten-free diets.

Non-responsive celiac disease in children on a gluten free diet

BACKGROUND Non-responsive celiac disease(NRCD) is defined as the persistence of symptoms in individuals with celiac disease(CeD) despite being on a gluten-free diet(GFD). There is scant literature about NRCD in the pediatric population.AIM To determine the incidence, clinical characteristics and underlying causes of NRCD in children.METHODS Retrospective cohort study performed at Boston Children’s Hospital(BCH). Children < 18 years diagnosed with CeD by positive serology and duodenal biopsies compatible with Marsh Ⅲ histology between 2008 and 2012 were identified in the BCH’s Celiac Disease Program database. Medical records were longitudinally reviewed from the time of diagnosis through September 2015. NRCD was defined as persistent symptoms at 6 mo after the initiation of a GFD and causes of NRCD as well as symptom evolution were detailed. The children without symptoms at 6 mo(responders) were compared with the NRCD group. Additionally, presenting signs and symptoms at the time of diagnosis of CeD among the responders and NRCD patients were collected and compared to identify any potential predictors for NRCD at 6 mo of GFD therapy.RESULTS Six hundred and sixteen children were included. Ninety-one(15%) met criteria for NRCD. Most were female(77%). Abdominal pain [odds ratio(OR) 1.8 95% confidence interval(CI) 1.1-2.9], constipation(OR 3.1 95%CI 1.9-4.9) and absence of abdominal distension(OR for abdominal distension 0.4 95%CI 0.1-0.98) at diagnosis were associated with NRCD. NRCD was attributed to a wide variety of diagnoses with gluten exposure(30%) and constipation(20%) being the most common causes. Other causes for NRCD included lactose intolerance(9%), gastroesophageal reflux(8%), functional abdominal pain(7%), irritable bowel syndrome(3%), depression/anxiety(3%), eosinophilic esophagitis(2%), food allergy(1%), eating disorder(1%), gastric ulcer with Helicobacter pylori(1%), lymphocytic colitis(1%), aerophagia(1%) and undetermined(13%). 64% of children with NRCD improved on follow-up.CONCLUSION NRCD after ≥ 6 mo GFD is frequent among children, especially females, and is associated with initial presenting symptoms of constipation and/or abdominal pain. Gluten exposure is the most frequent cause.

Classical and Non-Classical Celiac Disease Comparison: Ten Years of Study

Objective: Celiac disease (CD) is an immune-mediated systemic disorder triggered by gluten. It has a variable combination of clinical manifestations and changes that have been occurring in recent decades however they are not known in detail. The purpose of the article is to compare Classical and Non-Classical CD cases in terms of demographic characteristics, duodenal biopsy, extraintestinal manifestations, and associated comorbidities. Materials and Methods: A comparative retrospective cohort study from January 2008 to December 2018. Results: A total of 128 cases were included: 84 Classical (66%) and 44 Non-Classical CD (34%). The family history of CD was identified in 14% of cases without differences between groups. The age at diagnosis was distinct for Classical and Non-Classical CD (4.9 ± 4 and 8.3 ± 4 years old;p 0.001), respectively. Important changes were found within the classical presentation, including mono symptoms and a significantly higher rate of intestinal atrophy;p = 0.04. The main Non-Classical CD symptom was recurrent abdominal pain. The extraintestinal manifestations (EIM) were identified in 42% and occurred in both groups. The comparison between groups showed differences in rates of migraine and vitamin D deficiency and was higher for Non-Classical CD (p 0.05). Associated diseases occurred in 10.9%, and type 1 diabetes was significant for the Non-Classical CD group (p = 0.04). Conclusion: The classical CD was the most prevalent profile and presented a decrease in the severity of symptoms however remain a higher rate of intestinal atrophy. Recurrent abdominal pain was the main symptom of Non-Classical CD. Extraintestinal manifestations and associated diseases presented an increasing trend of occurrence among cases of Non-Classical CD.

Intestinal epithelium, intraepithelial lymphocytes and the gut microbiota-Key players in the pathogenesis of celiac disease

Celiac disease(CD) is a chronic immune-mediated disorder triggered by the ingestion of gluten in genetically predisposed individuals. Before activating the immune system, gluten peptides are transferred by the epithelial barrier to the mucosal lamina propria, where they are deamidated by intestinal tissue transglutaminase 2. As a result, they strongly bind to human leucocyte antigens(HLAs), especially HLA-DQ2 and HLA-DQ8, expressed on antigen-presenting cells. This induces an inflammatory response, which results in small bowel enteropathy. Although gluten is the main external trigger activating both innate and adaptive(specific) immunity, its presence in the intestinal lumen does not fully explain CD pathogenesis. It has been hypothesized that an early disruption of the gut barrier in genetically susceptible individuals, which would result in an increased intestinal permeability, could precede the onset of gluten-induced immune events. The intestinal barrier is a complex functional structure, whose functioning is dependent on intestinal microbiotahomeostasis, epithelial layer integrity, and the gutassociated lymphoid tissue with its intraepithelial lymphocytes(IELs). The aim of this paper was to review the current literature and summarize the role of the gut microbiota, epithelial cells and their intercellular junctions, and IELs in CD development.

Celiac disease serology in patients with different pretest probabilities: Is biopsy avoidable?

AIM: To establish the diagnostic performance of sev-eral serological tests, individually and in combination, for diagnosing celiac disease (CD) in patients with different pretest probabilities, and to explore potential se- rological algorithms to reduce the necessity for biopsy. METHODS: We prospectively performed duodenal biopsy and serology in 679 adults who had either high risk (n = 161) or low risk (n = 518) for CD. Blood samples were tested using six assays (enzyme-linked immunosorbent assay) that detected antibodies to tissue transglutaminase (tTG) and deamidated gliadin peptide (DGP). RESULTS: CD prevalence was 39.1% in the high-risk population and 3.3% in the low-risk group. In high-risk patients, all individual assays had a high diagnostic efficacy [area under receiving operator characteristic curves (AU ROC): 0.968 to 0.999]. In contrast, assays had a lower diagnostic efficacy (AU ROC: 0.835 to 0.972) in the low-risk group. Using assay combinations, it would be possible to reach or rule out diagnosis of CD without biopsy in 92% of cases in both pretest populations. We observed that the new DGP/tTG Screen assay resulted in a surplus compared to more conventional assays in any clinical situation. CONCLUSION: The DGP/tTG Screen assay could be considered as the best initial test for CD. Combinations of two tests, including a DGP/tTG Screen, might be able to diagnose CD accurately in different clinical scenarios making biopsy avoidable in a high proportion of subjects.

Risk factors in familial forms of celiac disease

Celiac disease has been reported in up to 2% of some European populations. A similar risk has been identified in the America and Australia where immigration of Eu-ropeans has occurred. Moreover, an increasing number of celiac disease patients are being identified in many Asian countries, including China and India. Finally, celiac disease has also been detected in Asian immigrants and their descendants to other countries, such as Canada. Within these so-called "general" celiac populations, however, there are specific high risk groups that have an even higher prevalence of celiac disease. Indeed, the single most important risk factor for celiac disease is having a first-degree relative with already-defined celiac disease, particularly a sibling. A rate up to 20% or more has been noted. Risk is even greater if a specific family has 2 siblings affected, particularly if a male carries the human leukocyte antigen-DQ2. Both structural changes in the small bowel architecture occur along with func-tional changes in permeability, even in asymptomatic first-degree relatives. Even if celiac disease is not evident, the risk of other autoimmune disorders seems significantly increased in first-degree relatives as well as intestinal lymphoma. Identification of celiac disease is important since recent long-term studies have shown that the mortality of celiac disease is increased, if it is unrecognized and untreated.

Effect of the timing of gluten introduction on the development of celiac disease

Celiac disease(CD) is a permanent auto-immune enteropathy,triggered in genetically predisposed individuals by the ingestion of dietary gluten.Gluten is the alcohol-soluble protein component of the cereals wheat,rye and barley.CD is a multifactorial condition,originating from the interplay of genetic and environmental factors.The necessary environmental trigger is gluten,while the genetic predisposition has been identified in the major histocompatibility complex region on chromosome 6p21,with over 90% of CD patients expressing HLA DQ2 and the remaining celiac patients express DQ8.The fact that only about 4% of DQ2/8positive individuals exposed to gluten develop CD,has led to the recognition that other genetic and environmental factors are also necessary.In the last few years,several epidemiological studies have suggested that the timing of the introduction of gluten,as well as the pattern of breastfeeding,may play an important role in the subsequent development of CD.Here,we present and review the most recent evidences regarding the effect of timing of gluten introduction during weaning,the amount of gluten introduced and simultaneous breastfeeding,on the development of CD.

Celiac Disease in Asia beyond the Middle East and Indian subcontinent:Epidemiological burden and diagnostic barriers

Celiac Disease(CD)had been considered uncommon in Asia for a long time.However,several studies suggested that,in the Indian subcontinent and Middle East countries,CD is present and as prevalent as in Western countries.Outside these Asian regions,the information about the epidemiology of CD is still lacking or largely incomplete for different and variable reasons.Here,we discuss the epidemiological aspects and the diagnostic barriers in several Asian regions including China,Japan,Southeast Asia and Russia/Central Asia.In some of those regions,especially Russia and Central Asia,the prevalence of CD is very likely to be underestimated.Several factors may,to a different extent,contribute to CD underdiagnosis(and,thus,underestimation of its epidemiological burden),including the poor disease awareness among physicians and/or patients,limited access to diagnostic resources,inappropriate use or interpretation of the serological tests,absence of standardized diagnostic and endoscopic protocols,and insufficient expertise in histopathological interpretation.

Current guidelines for the management of celiac disease:A systematic review with comparative analysis

BACKGROUND Wheat and other gluten-containing grains are widely consumed,providing approximately 50%of the caloric intake in both industrialised and developing countries.The widespread diffusion of gluten-containing diets has rapidly led to a sharp increase in celiac disease prevalence.This condition was thought to be very rare outside Europe and relatively ignored by health professionals and the global media.However,in recent years,the discovery of important diagnostic and pathogenic milestones has led to the emergence of celiac disease(CD)from obscurity to global prominence.These modifications have prompted experts worldwide to identify effective strategies for the diagnosis and follow-up of CD.Different scientific societies,mainly from Europe and America,have proposed guidelines based on CD's most recent evidence.AIM To identify the most recent scientific guidelines on CD,aiming to find and critically analyse the main differences.METHODS We performed a database search on PubMed selecting papers published between January 2010 and January 2021 in the English language.PubMed was lastly accessed on 1 March 2021.RESULTS We distinguished guidelines from 7 different scientific societies whose reputation is worldwide recognized and representative of the clinical practice in different geographical regions.Differences were noted in the possibility of a no-biopsy diagnosis,HLA testing,follow-up protocols,and procedures.CONCLUSION We found a relatively high concordance between the guidelines for CD.Important modifications have occurred in the last years,especially about the possibility of a no-biopsy diagnosis in children.Other modifications are expected in the next future and will probably involve the extension of the non-invasive diagnosis to the adult population and the follow-up modalities.

Celiac disease in Middle Eastern and North African countries:A new burden?

Celiac disease(CD) is now recognized as a common disorder among Middle Eastern(ME) and North African(NA) populations.The aim of this review is to assess the available data regarding CD in the ME and NA and to compare this information with that of Western countries.A literature review was performed using the electronic databases PubMed and Medline(1950-2008) as search engines,and "celiac disease" was used as a Mesh term.The search was limited to ME and NA countries.The prevalence of CD in ME and NA countries among low risk populations is similar to that of Western countries,but is higher in high risk populations such as those with type 1 diabetes.It is underestimated because of lack of clinical suspicion and lack of patient awareness.Clinical presentations in term of gastrointestinal,hematologic,skeletal,and liver manifestations are similar between both populations except for a high prevalence of short stature in some ME and NA countries.Few studies have addressed atypical or silent CD.As in the West,diagnosis is initially made by serological tests and is confirmed by small intestinal biopsies.Gluten-free diet is the main mode of treatment with a higher apparent adherence rate than in the West.Most disease complications result from malabsorption.The disease is strongly associated with HLA DQ2 and to a lesser extent with HLA DQ8 alleles.In conclusion,CD prevalence is underestimated,with little data available about its malignant complications.Disease parameters in the ME and NA are otherwise similar to those in Western countries.

Celiac disease:Overview and considerations for development of gluten-free foods

Celiac disease is a genetically-determined chronic inflammatory intestinal disease induced by gluten in wheat,barley,rye etc.Celiac disease affects approximately one percent of people in the world and strict gluten-free diet(GFD)for a lifetime is the only available treatment.As gluten-free products available in the market are known to have low nutritional quality as well as are more expensive than gluten-containing food products,there is a strong need to develop gluten-free products that are nutritionally complete as well as economical.This review focuses on the special considerations during developing gluten-free products viz.,finding an alternate non-gluten source,ensuring nutrition and sensory quality characteristics,compliance with the regulatory guidelines,economics and product.

Association between intestinal neoplasms and celiac disease:A review

Celiac disease(CD)is a chronic immune-mediated intestinal disease with genetic susceptibility.It is characterized by inflammatory damage to the small intestine after ingestion of cereals and products containing gluten protein.In recent years,the global prevalence rate of CD has been approximately 1%,and is gradually increasing.CD patients adhere to a gluten-free diet(GFD)throughout their entire life.However,it is difficult to adhere strictly to a GFD.Untreated CD may be accompanied by gastrointestinal symptoms,such as diarrhea,abdominal pain,and extraintestinal symptoms caused by secondary malnutrition.Many studies have suggested that CD is associated with intestinal tumors such as enteropathyassociated T-cell lymphoma(EATL),small bowel cancer(SBC),and colorectal cancer.In this study,we reviewed related studies published in the literature to provide a reference for the prevention and treatment of intestinal tumors in patients with CD.Compared with the general population,CD patients had a high total risk of SBC and EATL,but not colorectal cancer.The protective effect of GFD on CD-related malignancies is controversial.Further studies are needed to confirm whether GFD treatment can reduce the risk of intestinal neoplasms in CD.

Erythrocytic transglutaminase inhibition hemolysis at presentation of celiac disease

Celiac disease (CD) is a common autoimmune condition.Previously it was considered to be a rare childhood disorder,but is actually considered a relatively common condition,present at any age,which may have multiple complications and manifestations.Hematological disorders of the disease are not uncommon.Among these disorders,the most frequently reported are anemias as a result of iron deficiency,often associated with folate and/or B12 deficiency.Anemias caused by hemolysis are very rarely reported in celiac patients.An 11-year-old girl with a previous uneventful medical history presented with severe hemolytic anemia.Hemolysis was Coombs negative,accompanied by inappropriate low reticulocyte count,despite exaggerated bone marrow hyperplasia of the erythroid precursors which showed normal maturation.Serology for recent infections,including EpsteinBarr virus,parvovirus B19,cytomegalovirus and mycoplasma,were all negative.Levels of serum IgA,IgG and IgM,were all within normal ranges for age.Screeningfor anti-DNA,antinuclear,antineutrophil cytoplasmic,antimicrosomal,antithyroglobulin,and antimitochondrial antibodies and lupus anticoagulants,was negative.She was also negative for human immunodeficiency virus.Conventional therapy with corticosteroids and intravenous immunoglobulin failed.CD was serendipitously discovered upon screening for anti-tissue transglutaminase autoantibodies.The disease was confirmed by biopsy of the small intestine mucosa.The patient recovered with gluten-free diet.A unique case of CD is presented.CD should be serologically screened in each patient with Coombs negative "immune"hemolytic anemia,particularly if accompanied by "reticulocytopenia".A new hemolytic mechanism and very speculative explanation for "reticulocytopenia"are discussed.

Pancreatic involvement in celiac disease

Celiac disease(CD)is well recognized as a systemic,chronic autoimmune disease mainly characterized by gluten-sensitive enteropathy in genetically predisposed individuals but with various extraintestinal features.One of the affected organs in CD is the pancreas,consisting of both endocrine and exocrine alterations.Over the last decades there has been increasing interest in the pancreatic changes in CD,and this has been reflected by a great number of publications looking at this extraintestinal involvement during the course of CD.While pancreatic endocrine changes in CD,focusing on type 1 diabetes mellitus,are well documented in the literature,the relationship with the exocrine pancreas has been less studied.This review summarizes currently available evidence with regard to pancreatic exocrine alterations in CD,focusing on risk of pancreatitis in CD patients,association with autoimmune pancreatitis,prevalence and outcomes of pancreatic exocrine insufficiency in newly diagnosed and gluten-free diet treated CD patients,and the link with cystic fibrosis.In addition,we discuss mechanisms behind the associated pancreatic exocrine impairment in CD and highlight the recommendations for clinical practice.

Determination of gluten immunogenic peptides for the management of the treatment adherence of celiac disease: A systematic review

BACKGROUND Gluten is a complex mixture of proteins with immunogenic peptide sequences triggering the autoimmune activity in patients with celiac disease(CeD).Gluten immunogenic peptides(GIP)are resistant to gastrointestinal digestion and are then excreted via the stool and urine.Most common detection methods applied in the follow-up visits for CeD patients such as serology tests,dietetic interviews,questionnaires,and duodenal biopsy have been proved to be inefficient,invasive,or inaccurate for evaluating gluten-free diet(GFD)compliance.Determination of excreted GIP in stool and urine has been developed as a non-invasive,direct,and specific test for GFD monitoring.AIM To summarize published literature about the clinical utility of GIP determination in comparison to the tools employed for GFD monitoring.METHODS PubMed and Web of Science searches were performed using the keywords“gluten immunogenic peptides”or“gluten immunogenic peptide”and a combination of the previous terms with“feces”,“stools”,“urine”,“celiac disease”,“gluten-free diet”,and“adherence”to identify relevant clinical studies published in English and Spanish between 2012 to January 2021.Reference lists from the articles were reviewed to identify additional pertinent articles.Published articles and abstracts reporting the clinical use of GIP determination in stool and/or urine for the follow-up of patients with CeD in comparison with other tools in use were included.Case reports,commentaries,reviews,conference papers,letters,and publications that did not focus on the aims of this review were excluded.RESULTS Total of 15 publications were found that involved the use of GIP determination in stool and/or urine to monitor the adherence to the GFD in comparison to other tools.Studies included both children and adults diagnosed with CeD and healthy volunteers.Overall,these preliminary studies indicated that this novel technique was highly sensitive for the detection of GFD transgressions and therefore could facilitate the follow-up of patients with CeD.Tools identified in this work included the CeD-specific serology,dietetic questionnaires,symptomatology,and the duodenal biopsy.Review of the literature revealed that the rates of GFD adherence may vary between 30%-93%using either stool or urine GIP determination,49%-96%by the serology,59%-94%using the dietetic questionnaires,56%-95%by the reported symptoms and 44%-76%with the duodenal biopsy.In addition,the association between the different methods and histological abnormalities(Marsh II-III)was found to be 33%-100%for GIP determination(stool and urine),25%-39%for CeD-specific serology,3%-50%for dietetic questionnaires,and 22%-28%for the symptomatology.CONCLUSION Excreted GIP detection is the precise approach for determining voluntary or involuntary gluten consumption in CeD patients preventing future complications arising from gluten exposure.

HLA-DQ:Celiac disease vs inflammatory bowel disease

AIM To determine the genetic predisposition to celiacdisease(Ce D) in inflammatory bowel disease(IBD) patients by quantifying the frequency of Ce D-related human leucocyte antigen(HLA)(HLA-Ce D: HLA-DQ2 and-DQ8) in IBD patients globally, by type of IBD and gender, and by calculating the protective/risk contribution of these haplotypes in the development of the IBD disease.METHODS We conducted a prospective study with IBD patients from our Unit. Clinical information was gathered and blood was tested for HLA-CeD. The control group was made up of unrelated Valencian organ donors.RESULTS1034 subjects were analyzed: 457 IBD [207 ulcerative coliti(UC) and 250 Crohn's disease(CD)] patients and 577 healthy controls. 39% of the controls and 34% of the patients had HLA-Ce D(P = 0.0852). HLA-DQ2 was less frequent in UC patients(P = 0.0287), and HLA-DQ8 in CD(P = 0.0217). In women with UC, the frequency of DQ2.5 cis(DQB1*02:01-DQA1*05:01) was reduced ≥ 50% [P = 0.0344; preventive fraction(PF) = 13%]. PFs(7%-14%) were obtained with all HLACe D haplotypes. HLA DQB1*02:02-DQA1*02:01(HLADQ2.2) was more frequent in CD patients with respect to controls(P = 0.001) and UC patients(etiological fraction = 15%).CONCLUSION HLA-CeD is not more frequent in IBD patients, with an even lower frequency of HLA-DQ2 and-DQ8 in UC and CD respectively. HLA-DQ2.5 confers protection from the development of UC, especially in women, and HLADQ8 does so for the appearance of CD. HLA-DQ2.2 is present in 34% of the CD patients and may constitute a genetic risk factor for CD development.