Article

Complete Recovery of Intestinal Mucosa Occurs Very Rarely in Adult Coeliac Patients Despite Adherence to Gluten-Free Diet

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  • Institute for Pathology
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Abstract

Expected benefits of gluten-free diet (GFD) in coeliac patients include healing of small intestinal mucosa, but it remains unclear to what extent this benefit is achieved in adults. To assess factors affecting histological outcome of GFD in a large cohort of adult coeliac patients. We extracted information on 465 consecutive coeliac patients studied before and during GFD. Duodenal biopsies at diagnosis were classified as Marsh I in 11, II in 25 and III in 429 cases. After a median 16 months GFD, 38 (8%) patients had histological 'normalization', 300 (65%) had 'remission' with persistent intraepithelial lymphocytosis, 121(26%) had 'no change' and 6 (1%) had 'deterioration'. Coeliac disease related serology was negative in 83% of patients with Marsh III lesion during GFD. Male gender and adherence to GFD were independently associated with histological 'normalization' and 'remission'. Persistence of intraepithelial lymphocytosis was not associated with human lymphocyte antigen gene dose or with Helicobacter pylori infection. Complete normalization of duodenal lesions is exceptionally rare in adult coeliac patients despite adherence to GFD, symptoms disappearance and negative CD related serology. Control biopsies are mandatory to identify lack of response to gluten-free diet.

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... Thirty-one studies were characterized as cohort studies, and one was a randomized clinical trial study (Table 1). Most studies were performed in Italy [9,18,[26][27][28][29][30][31][32][33][34][35] (n = 13; 40.6%), followed by Finland [36][37][38][39] (n = 4; 12.5%), the United Kingdom [35,40,41], and the United States [12,35,42] (n = 3, 9.3%), Argentina [43,44], Australia [45,46], Canada [47,48], Norway [49,50] (n = 2, 6.25%), while Paraguay, Poland, Romania, Spain, and Türkiye had one study each [20,35,[51][52][53]. ...
... Most of them used a biopsy [ The studies included in this review used four different tools to evaluate GFDs: BIAGI scores [26], the Coeliac Dietary Adherence Test (CDAT) [19], self-report questionnaires, and interviews. Most of them used a biopsy [9,18,20,26,27,29,32,[34][35][36][37][38][40][41][42]45,47,49,52] (n = 19; 59.3%), followed by serology [12,18,[26][27][28]30,31,33,36,39,43,44,51,53] (n = 14; 43.7%) and GIPs [9,46,48,50] (n = 4; 12.5%). Of the 32 studies, most (n = 45; 46.8%) used the self-report method to evaluate GFD adherence [27,30,32,34,36,38,39,41,[43][44][45]47,[51][52][53], followed by the CDAT [9,12,20,40,46,[48][49][50] (n = 8; 25%), BIAGI [18,26,31,33,40] (n = 5; 15.6%), and interviews [28,29,37,42] (n = 4; 12.5%), while only one used the Standardized Dietitian Evaluation (SDE) [20] and one of the studies used both the BIAGI and CDAT tools [35]. ...
... Most of them used a biopsy [9,18,20,26,27,29,32,[34][35][36][37][38][40][41][42]45,47,49,52] (n = 19; 59.3%), followed by serology [12,18,[26][27][28]30,31,33,36,39,43,44,51,53] (n = 14; 43.7%) and GIPs [9,46,48,50] (n = 4; 12.5%). Of the 32 studies, most (n = 45; 46.8%) used the self-report method to evaluate GFD adherence [27,30,32,34,36,38,39,41,[43][44][45]47,[51][52][53], followed by the CDAT [9,12,20,40,46,[48][49][50] (n = 8; 25%), BIAGI [18,26,31,33,40] (n = 5; 15.6%), and interviews [28,29,37,42] (n = 4; 12.5%), while only one used the Standardized Dietitian Evaluation (SDE) [20] and one of the studies used both the BIAGI and CDAT tools [35]. Abbreviation: BIAGI = Biagi score; CDAT = Coeliac Dietary Adherence Test; GFD = gluten-free diet; SDE = Standardized Dietician Evaluation; AGA = gliadin antibody; tTG = tissue anti-transglutaminase antibody; EMA = anti-endomysium antibody; DGP = anti-deamidated gliadin peptide; fGIPs = gluten-derived peptides in feces; uGIPs = gluten-derived peptides in urine; RCT = randomized clinical trial; NI = no information. ...
Article
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This systematic review aimed to find the tool that best predicts celiac individuals’ adherence to a gluten-free diet (GFD). The Transparent Reporting of Multivariable Prediction Models for Individual Prognosis or Diagnosis (TRIPOD-SRMA) guideline was used for the construction and collection of data from eight scientific databases (PubMed, EMBASE, LILACS, Web of Science, LIVIVO, SCOPUS, Google Scholar, and Proquest) on 16 November 2023. The inclusion criteria were studies involving individuals with celiac disease (CD) who were over 18 years old and on a GFD for at least six months, using a questionnaire to predict adherence to a GFD, and comparing it with laboratory tests (serological tests, gluten immunogenic peptide—GIP, or biopsy). Review articles, book chapters, and studies without sufficient data were excluded. The Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies (CHARMS) was used for data collection from the selected primary studies, and their risk of bias and quality was assessed using the Prediction Risk of Bias Assessment Tool (PROBAST). The association between the GFD adherence determined by the tool and laboratory test was assessed using the phi contingency coefficient. The studies included in this review used four different tools to evaluate GFD adherence: BIAGI score, Coeliac Dietary Adherence Test (CDAT), self-report questions, and interviews. The comparison method most often used was biopsy (n = 19; 59.3%), followed by serology (n = 14; 43.7%) and gluten immunogenic peptides (GIPs) (n = 4; 12.5%). There were no significant differences between the interview, self-report, and BIAGI tools used to evaluate GFD adherence. These tools were better associated with GFD adherence than the CDAT. Considering their cost, application time, and prediction capacity, the self-report and BIAGI were the preferred tools for evaluating GFD adherence.
... A significant percentage, 42.9%, will still have severe changes with villous atrophy. While mucosal recovery rates lied within a wide range of values (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), these findings are consistent with those from most of the studies reported so far. In our geographical setting a recent study revealed persistent villous atrophy in 46% of patients after 42 months of follow-up on average (28). ...
... In the Mediterranean basin results are more similar to ours with mucosal recovery rates at 8-66% after 1-2 years on GFD (13,14). In contrast, in Scandinavian countries patients where intestinal mucosa returns to normal reach 94-96% with persistent lymphocytic enteritis rates of 13-56% (11,15,23). ...
... According to our data, factors related to mucosal recovery include degree of villous atrophy in baseline biopsy, time with symptoms to diagnosis, and TTGA baseline and follow-up titers. Several prior studies support that histological damage severity at diagnosis plays a role in tissue evolution after GFD onset (13,14,20,29). Thus, total villous atrophy (Marsh 3c) is considered a risk factor for failing to achieve complete mucosal recovery despite appropriate dietary compliance. ...
Article
Unlabelled: Study background and objectives: There is great disparity in mucosal recovery among celiac patients on a gluten-free diet. We report a study to identify associated factors. Methods: Celiac patient cases were collected that had positive celiac serology and villous atrophy at diagnosis, and had undergone a control biopsy after at least 12 months of follow-up. Results: We included 70 celiac patients. They had experienced symptoms for 9.05 ± 9.48 years before being diagnosed. After follow-up for 2.93 ± 1.94 years, 34.3 % had complete mucosal recovery and 57.1 % had partial mucosal recovery. In the comparative analysis we found no relationship between mucosal recovery and sex, age, clinical manifestations or follow-up time from diagnosis to second biopsy. Time with clinical manifestations before diagnosis was associated with a worse outcome: 2.64 years in patients with full recovery, 4.61 years in patients with partial recovery, and 14.26 years in patients with persistent villous atrophy. Higher transglutaminase antibody titers both at diagnosis and during follow-up were associated with poorer histologic outcomes. We observed higher mucosal recovey rates in patients with mild atrophy versus severe atrophy at diagnosis. Conclusions: In spite of gluten-free diet a significant proportion of patients have persistent histologic changes. Time with clinical manifestations before diagnosis is key for histological severity and recovery.
... However, not all patients show mucosal recovery after one year of GFD [27]. Lanzini et al. (2009) suggested that a complete normalization of duodenal lesions is exceptionally rare in adult celiac patients [32]. Similarly, Tursi et al. (2006) observed that older adult patients (>30 years) show incomplete endoscopic and histological recovery even 24 months after starting a GFD [33]. ...
... However, not all patients show mucosal recovery after one year of GFD [27]. Lanzini et al. (2009) suggested that a complete normalization of duodenal lesions is exceptionally rare in adult celiac patients [32]. Similarly, Tursi et al. (2006) observed that older adult patients (>30 years) show incomplete endoscopic and histological recovery even 24 months after starting a GFD [33]. ...
... These discrepancies could be due to differences in compliance with the GFD. On the one hand, some patients admit to take gluten containing foods from time to time [32]. On the other hand, although it is common to find celiac patients who claim to follow a completely strict GFD, the lack of mucosa recovery could indicate that they may involuntarily consume gluten. ...
Article
Full-text available
Celiac disease (CD) is a chronic autoimmune disorder of the small intestine, whose only effective treatment is a gluten-free diet (GFD). It is characterized by the atrophy of the intestinal villi that leads to altered nutrient absorption. This study describes the nutritional imbalances which may be found in adults with CD following a GFD. During the first year of treatment, deficiencies will overcome as the intestinal mucosa recovers. Thus, biochemical data will show this progression, together with the decrease in symptoms. In contrast, in the long term, when a strict GFD is followed and mucosal recovery is achieved, analyzing nutrient intake makes more sense. Macronutrient consumption is characterized by its low complex carbohydrate and fiber intakes, and high fat (especially SFA) and sugar intakes. This profile has been related to the consumption of GFP and their nutritional composition, in addition to unbalanced dietary habits. The most notable deficiencies in micronutrients are usually those of iron, calcium and magnesium and vitamin D, E and some of group B. It is necessary to follow up patients with CD and to promote nutritional education among them, since it could help not only to achieve a gluten free but also a balanced diet.
... The sole effective treatment for CD is maintaining a lifelong gluten-free diet (GFD), leading to clinical improvement and histological recovery in the majority of patients. [4]. ...
... Additionally, many patients with CD follow a strict GFD, which can mitigate systemic inflammation and reduce cardiovascular risk factors such as dyslipidemia, hypertension, and chronic inflammation. Studies have shown that adherence to a GFD can lead to the normalization of lipid profiles, reduce inflammatory markers, and reverse certain risk factors for cardiovascular disease [4]. Cardiovascular disease, including MI, is multifactorial in nature, with established risk factors such as hypertension, smoking, diabetes, dyslipidemia, and obesity playing a crucial role [24]. ...
Article
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Background Celiac disease (CD) is an autoimmune disorder characterized by gluten intolerance, primarily affecting the gastrointestinal system but potentially influencing cardiovascular health. Emerging evidence suggests an association between CD and myocardial infarction (MI), though studies have produced inconsistent results. This study aimed to systematically review and conduct a meta-analysis of existing literature to quantify the risk of MI in individuals diagnosed with CD. Methods A comprehensive literature search was performed across PubMed, Embase, and Web of Science up to August 2024. Studies were included if they investigated the association between CD and MI in adult populations and provided relevant effect estimates. Data from eligible studies were extracted, and a random-effects meta-analysis was conducted to calculate pooled hazard ratios (HRs) and odds ratios (ORs), along with an assessment of heterogeneity. Statistical analysis has been performed by R software (V 4.4). Results A total of 8 studies were included in the systematic review. Pooled HR analysis showed no significant association between CD and MI (HR = 1.143, 95% CI: 0.619–2.109), and pooled OR analysis also revealed non-significant results (OR = 0.879, 95% CI: 0.481–1.606). High heterogeneity was observed (I² = 86% for HR, 99% for OR). Conclusion This meta-analysis found no significant association between CD and MI. However, substantial heterogeneity across studies indicates variability in results, highlighting the need for further research with larger, more homogeneous cohorts to better understand cardiovascular risks in CD patients. Future studies should explore subgroups and the impact of gluten-free diet adherence.
... Within two years, 95% of children achieve a mucosal recovery, while only 34% and 66% of adults obtain it in two and five years, respectively [18][19][20]. However, a complete mucosal recovery is rare, even with a carefully followed GFD: Marsh I and II lesions persist in 65% of patients with atrophy at diagnosis after 6-18 months of GFD, and the Marsh 0 stage is seen in only 8% of patients [21]. Moreover, the persistence of intraepithelial lymphocytosis is independent from cross-contaminations, and it is not eliminated even when all gluten contaminations are strictly excluded from the diet [22]. ...
... Endoscopic examination with duodenal biopsies is the most objective method for evaluating adherence, but it is invasive and expensive and there is no agreement regarding the time to perform it. Additionally, in adults, complete mucosal healing is not always possible, and it can take up to five years [21,22]. Thus, endoscopic control is suggested over this period, especially after three or four years, to avoid unnecessary controls [45]. ...
Article
Full-text available
A lifelong gluten-free diet (GFD) is the only treatment for celiac disease and other gluten-related disorders. Nevertheless, strict adherence to the GFD is often challenging due to concerns about social isolation, risk of gluten contaminations, high cost, poor quality and the taste of gluten-free products. Moreover, although the GFD is effective in achieving mucosal healing, it may lead to dietary imbalances due to nutrient deficiencies over a long period of time. To overcome these issues, several gluten-free wheat flours have been developed to create products that closely resemble their gluten-containing counterparts. Furthermore, given the critical importance of adhering to the GFD, it becomes essential to promote adherence and monitor possible voluntary or involuntary transgressions. Various methods, including clinical assessment, questionnaires, serology for celiac disease, duodenal biopsies and the detection of Gluten Immunogenic Peptides (GIPs) are employed for this purpose, but none are considered entirely satisfactory. Since adherence to the GFD poses challenges, alternative therapies should be implemented in the coming years to improve treatment efficacy and the quality of life of patients with celiac disease. The aim of this narrative review is to explore current knowledge of the GFD and investigate its future perspectives, focusing on technology advancements, follow-up strategies and insights into a rapidly changing future.
... heterogeneous clinical picture and increased morbidity and mortality. [1][2][3][4][5][6][7] A lifelong gluten-free diet (GFD) is the mainstay for treatment in CD, leading to improvement of symptoms and intestinal lesions and preventing poor long-term outcomes associated with CD. 1-3 5 8 9 However, villous atrophy (VA) can persist in some patients despite a GFD, usually due to poor dietary adherence or slow responsiveness to a GFD or hypersensitivity to gluten and, less commonly, premalignant/malignant complications of CD. [10][11][12][13][14][15][16][17][18] Current literature provides contrasting data on the relationship between persistent VA (pVA) and long-term outcomes in patients with CD. pVA in CD has been associated with a significantly increased risk of lymphoproliferative disorders 19 and other comorbidities such as osteoporotic hip fractures, but not with an increased mortality. 7 20-23 Furthermore, few studies have evaluated which factors may be associated with pVA in CD, 16 24 so the clinical phenotype of patients at higher risk of pVA is still poorly defined. ...
... Previous estimates on the prevalence of pVA in the literature have shown variable results, with between 10% and 50% of patients with CD showing pVA even in the absence of symptoms while on a GFD. [10][11][12][13][14][15][16][17][18] pVA was due to malignant complications of CD in 20% of cases, and more commonly due to poor GFD adherence (80%). Overall, the prevalence of complications in the present study was higher than previously reported, although comparisons are difficult to make due to differences in clinical and demographic aspects, and duration of follow-up. ...
Article
Full-text available
Objective Persistent villous atrophy (pVA) in coeliac disease (CD) despite a gluten-free diet (GFD) has unclear meaning. We aimed to (i) study the relationship between pVA and long-term outcomes and (ii) develop a score to identify patients at risk of pVA. Design This is a multicentre retrospective-prospective study consisting of a study cohort (cohort 1) and an external validation cohort (cohort 2) of patients with biopsy-proven CD diagnosed between 2000 and 2021. Cohort 1 was used to (i) compare long-term outcomes between patients with and without pVA (Marsh ≥3a) at follow-up biopsy and (ii) to develop a score to evaluate the risk of pVA, which was validated in cohort 2. Results Of 2211 patients, 694 (31%) underwent follow-up duodenal biopsy and were included in the study cohort (491F, 44±16 years). 157/694 (23%) had pVA. Risk of complications (HR 9.53, 95% CI 4.77 to 19.04, p<0.001) and mortality (HR 2.93, 95% CI 1.43 to 6.02, p<0.01) were increased in patients with pVA. A 5-point score was developed and externally validated (receiver operating characteristic area under the curve 0.78, 95% CI 0.68 to 0.89) to stratify patients by risk of pVA: low (0–1 points, 5% pVA), intermediate (2 points, 16% pVA) and high (3–5 points, 73% pVA). Predictors for pVA used in the score were age at diagnosis ≥45 years (OR 2.01, 95% CI 1.21 to 3.34, p<0.01), classical pattern of CD (OR 2.14, 95% CI 1.28 to 3.58, p<0.01), lack of clinical response to GFD (OR 2.40, 95% CI 1.43 to 4.01, p<0.001) and poor GFD adherence (OR 48.9, 95% CI 26.1 to 91.8, p<0.001). Conclusions Risk of complications and mortality were increased in patients with pVA. We developed a score to identify patients at risk of pVA and in need of histological reassessment and closer follow-up.
... Furthermore wheat flour or purified gluten are largely added by the food industry to naturally gluten-free food, due to its technological properties, particularly the high visco-elasticity. Protracted intake of items contaminated with gluten traces may cause persistent intestinal damage and symptoms in treated CD patients [8]. ...
... Despite the GFD, many treated CD patients frequently show incomplete resolution of the histological intestinal damage at the follow-up intestinal biopsy, suggesting ongoing gluten ingestion [8]. Since our data and other surveys [4] found that gluten contamination of wheat substitutes does not represent a big issue in recent years, this persistent enteropathy is probably related to different sources of contamination, such as voluntary dietary transgressions, particularly in adolescents, or contaminated meals consumed outside home. ...
Poster
Background: Gluten free diet is the only accepted treatment for celiac disease and other gluten related disorders. Lack of gluten contamination is usually ensured by a certified food chain but is not routinely checked in gluten-free food that are available in the Italian market. The aim of this study was to test the level of gluten contamination in Italian gluten-free products, an issue that is frequently enquired by gluten intolerant patients on treatment. Method: We planned to test at least 100 different products. In the initial phase 32 commercially food products (naturally gluten free and/or labeled as gluten free) available in Italian super markets were collected. Gluten content was determined by commercially available sandwich ELISA coated with specifically designed R5 monoclonal antibody that reacts with the gliadin fraction from wheat and the prolamins from rye and barley. Results: So far, 26 (81%) food samples (including naturally gluten free and/or labeled as gluten free ) were detected with a gluten content lower than the accepted threshold (20 mg/kg or ppm). However, 6 (19%) samples including one product labeled as gluten free were found to have gluten level higher than 20 mg/kg. Contamination was observed in buckwheat, oat and lentil-based products, ranging from 30 mg/kg to 53 mg/kg. Conclusion: Preliminary results of this study raise doubts on the reliability of the gluten-free food that are commercially available in the Italian supermarket. Complete absence of gluten is not achieved by some manufacturers. These gluten traces could be responsible for the persistence of mucosal damage in treated celiac patients. Ongoing analysis will be performed on a larger sample of additional products. However many naturally gluten free products remain safe from gluten contamination.
... However, strict compliance to a GFD can be compromised by unnoticed gluten consumption, cross-contamination, or social pressure when eating out and unspecific or even absent symptomatology after transgressions [2]. As a consequence, 30% to 60% of patients with CD are exposed to gluten despite their best efforts [3][4][5]. ...
... Severe mucosal damage (Marsh type 2/3) was found in 6.2% of our cohort, less than expected according to some previous publications [3][4][5]31], but in agreement with other studies reporting ratios of 4-6% after a long-term GFD [32,33]. Patients with mild mucosal damage (Marsh 1 or intraepithelial lymphocytosis) represented 21.6% of our cohort. ...
Article
Full-text available
A lifelong gluten-free diet (GFD) is the only current treatment for celiac disease (CD), but strict compliance is complicated. Duodenal biopsies are the “gold standard” method for diagnosing CD, but they are not generally recommended for disease monitoring. We evaluated the sensitivity and specificity of fecal gluten immunogenic peptides (GIPs) to detect duodenal lesions in CD patients on a GFD and compared them with serum anti-tissue transglutaminase (tTG) IgA antibodies. A prospective study was conducted at two tertiary centers in Spain on a consecutive series of adolescents and adults with CD who maintained a long-lasting GFD. Adherence to a GFD and health-related quality of life were scored with validated questionnaires. Mucosal damage graded according to the Marsh–Oberhüber classification (Marsh 1/2/3) was used as the reference standard. Of the 97 patients included, 27 presented duodenal mucosal damage and 70 had normal biopsies (Marsh 0). The sensitivity (33%) and specificity (81%) of GIPs were similar to those provided by the two assays used to measure anti-tTG antibodies. Scores in questionnaires showed no association with GIP, but an association between GIPs and patients’ self-reported gluten consumption was found (p = 0.003). GIP displayed low sensitivity but acceptable specificity for the detection of mucosal damage in CD.
... Adults with both symptom-and screen-detected CD are considered to experience an improved state of health and QoL with a GFD [70] as the damage to the intestine is relieved [71] and associated symptoms are reversed. ...
... Furthermore, in 65% of CD patients, the remission was linked to intraepithelial lymphocytosis, and in 27% of CD patients there was a lack of histological response [84]. Although this kind of slow response is frequent in adult CD patients over 50 years of age [85], this slow response may happen also in one out of five children after 1 year of a GFD [86]. ...
Article
Full-text available
Celiac disease is a chronic inflammatory condition of the small bowel caused, in genetically predisposed subjects, by the ingestion of gluten and characterised by a broad clinical polymorphism, ranging from patients with an asymptomatic or paucisymptomatic disease. The clinical presentation ranges from the presence of minor, apparently unrelated symptoms or first-degree kinship with known patients to severe intestinal malabsorption and all its clinical consequences and complications. Even if a large body of research improved our understanding of the molecular basis of celiac disease pathophysiology, enhancing the identification of new targets for future new treatments, an accurate gluten-free diet remains the mainstay of the therapy for this condition, restoring a normal absorptive mucosa. It is very rare, nowadays, to deal with patients with severe malabsorption syndrome secondary to celiac disease. Consequently, physicians are currently less prone to search for nutritional deficiencies in celiac disease. To pinpoint the possibility of both a disease-related and a diet-induced vitamin deficiency, we reviewed the literature on vitamin deficiency in this condition and reported the impact both in untreated and treated patients with celiac disease. A gluten-free diet must be tailored for each patient to meet nutritional targets: the pre-existence or diet-induced intake inadequacies should be carefully considered for an effective management of celiac disease.
... 13 Baseline quantitative histology in therapeutic trials revealed villous atrophy in up to half of the patients despite being on a gluten-free diet (GFD) (mean duration of follow-up biopsy after starting GFD: 16 months to 7 years). [14][15][16][17][18][19] Persistent villous atrophy has been associated with an increased risk of lymphoproliferative malignancy 20 and other comorbidities, such as osteoporotic hip fractures, 21 as well as with increased mortality. 22 Symptoms include nausea, diarrhea, abdominal pain, and bloating as well as extraintestinal symptoms such as tiredness and headaches. ...
Article
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Celiac disease (CeD), an autoimmune disorder triggered by gluten, affects around 1% of the global population. Standard treatment is a strict gluten-free diet (GFD), which poses significant challenges due to dietary restrictions, cross-contamination and subsequent persistent intestinal inflammation. This underscores the need for new treatment options addressing the complex pathophysiology of CeD. Recent research focuses on developing drugs that target intestinal barrier regeneration, gluten peptide modification, immune response alteration, and gut microbial ecosystem modulation. These approaches offer potential for more effective management of CeD beyond GFD. Gluten-independent treatments may be particularly relevant under the FDA's draft guidance for CeD, which emphasizes drug development as an adjunct to GFD for patients with ongoing signs and symptoms of CeD despite strict GFD. Teaser Emerging therapies for celiac disease focus on enhanced barrier integrity, enzymatic degradation of gluten, and immunomodulation, addressing gaps where the gluten-free diet falls short and providing new hope to patients.
... Reported rates of mucosal healing after periods of 6 months-10 years of a GFD is highly variable and after 2 years ranges between 12 and 79%. 6,18,[59][60][61][62][63][64][65][66][67] These data are impacted by the histologic reporting method (discussed above), the large number of retrospective studies (which are limited by selection bias), how mucosal recovery was defined, variations in GFD duration or adherence, variations in patient age, incomplete follow-up (many patients are not re-biopsied), and the presence of slow responders. Slowlyresponsive CD describes the important group of patients with enteropathy at 12 months on a GFD who, given enough time (in some cases 2 years or more), eventually achieve full mucosal and serologic remission. ...
Article
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The traditional gut‐centric view of coeliac disease is evolving as immune and genetic insights underscore the central importance of a systemic, T cell immune response to gluten in disease pathogenesis. As the field increasingly recognize the limitations of small intestinal histology as the diagnostic standard, data supporting the accuracy of an immune (serologic) diagnosis of coeliac disease ‐ well demonstrated in children ‐ are growing for adults. Novel biomarkers such as interleukin‐2 that identify the gluten‐specific T cell demonstrate high sensitivity and specificity for coeliac disease and offer the potential for a diagnostic approach that avoids the need for gluten challenge. Asymptomatic disease and manifestations outside the gut pose considerable challenges for diagnosis using a case‐finding strategy and enthusiasm for population screening is growing. The gluten‐free diet remains a highly restrictive treatment and there is a paucity of controlled data to inform a safe gluten intake threshold. Ongoing symptoms and enteropathy are common and require systematic evaluation. Slowly‐responsive disease is prevalent in the older patient diagnosed with coeliac disease, and super‐sensitivity to gluten is an emerging concept that may explain many cases of nonresponsive disease. While there is great interest in developing novel therapies for coeliac disease, no drug has yet been registered. Efficacy studies are generally assessing drugs in patients with treated coeliac disease who undergo gluten challenge or in patients with nonresponsive disease; however, substantial questions remain around specific endpoints relevant for patients, clinicians and regulatory agencies and optimal trial design. Novel immune tools are providing informative readouts for clinical trials and are now shaping their design.
... 2,3 Among many studies, Lanzini, et al. demonstrated that after a median of 16 months on a GFD, only 8% of patients experienced histologic normalization and 26% had no improvement at all. 4 Recent evidence indicates that, despite GFD adherence, CeD patients on average consume unsafe levels of gluten on a GFD, which may account for persistence of histologic inflammation and residual symptoms. 5,6 Low levels of gluten exposure can also lead to both inflammation and morphological changes that can increase the risk of complications including lymphoma, bowel cancer, osteoporosis, anemia, and malnutrition. ...
... In addition, the GFD alone is frequently not sufficient to control symptoms and prevent mucosal damage (Alhassan et al. 2019). Several studies in people with celiac disease have shown that despite adherence to GFD over many years, the intestinal mucosa does not improve completely (Lanzini et al. 2009;Rubio-Tapia et al. 2010;Lebwohl et al. 2014;Newnham et al. 2016). Also, many patients may be unintentionally exposed to gluten due to the contamination of food and drugs, which causes the onset of symptoms and mucosal damage (Tye-Din et al. 2018;Alhassan et al. 2019). ...
Article
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Enzyme therapy for celiac disease (CeD), which digests gliadin into non-immunogenic and non-toxic peptides, can be an appropriate treatment option for CeD. Here, we have investigated the effectiveness of bromelain and ficin on gliadin digestion using in vitro, such as SDS-PAGE, HPLC, and circular dichroism (CD). Furthermore, the cytotoxicity of gliadin and 19-mer peptide before and after digestion with these enzymes was evaluated using the MTT assay in the Caco-2 cell line. Finally, we examined the effect of these treatments along with Larazotide Acetate on the expression of genes involved in cell-tight junctions, such as Occludin, Claudin 3, tight junction protein-1, and Zonulin in the Caco-2 cell line. Our study demonstrated bromelain and ficin digestion effects on the commercial and wheat-extracted gliadin by SDS-PAGE, HPLC, and CD. Also, the cytotoxicity results on Caco-2 showed that toxicity of the gliadin and synthetic 19-mer peptide was decreased by adding bromelain and ficin. Furthermore, the proteolytic effects of bromelain and ficin on gliadin indicated the expression of genes involved in cell-tight junctions was improved. This study confirms that bromelain and ficin mixture could be effective in improving the symptoms of CeD.
... Ciò è corroborato dal fatto che negli adulti spesso, nonostante l'assenza dei sintomi e la negativizzazione della sierologia, è difficile ottenere la guarigione completa della mucosa intestinale. [104][105][106] Ciò potrebbe aumentare il rischio di sviluppare negli anni successivi il linfoma intestinale, malattie secondarie del metabolismo osseo e una forma stabile di celiachia refrattaria. 104,107 Pertanto, è ragionevole pensare ad un follow-up bioptico della mucosa digiunale dopo due anni dall'inizio della dieta priva di glutine in tutti i pazienti con sierologia negativa ed assenza di sintomi per assicurarsi della completa guarigione della mucosa. ...
Article
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p class="titolo"> MANAGEMENT DEL PAZIENTE CON DIARREA, NAUSEA E VOMITO: DALLE EVIDENZE ALLA PRATICA CLINICA La gestione del paziente con diarrea: razionale e obiettivi T.M. Attardo, C. Quarneti, R. Menichella, E. Romualdi La gestione del paziente con nausea e vomito : razionale e obiettivi T.M. Attardo, R. Menichella, C. Quarneti, E. Romualdi MALNUTRIZIONE E MALATTIA CELIACA: LO STATO DELL’ARTE La gestione del paziente con malnutrizione: dalle evidenze alla pratica clinica S. Ciarla, M. Poggiano, P. Gnerre, F. Risaliti, L. Magni, L. Morbidoni, A. Maffettone, A. Paradiso, M. Rondana, A. Schimizzi, R. Risicato La gestione del paziente con malattia celiaca: razionale e obiettivi T.M. Attardo, E. Magnani, C. Casati, D. Cavalieri, P. Crispino, F. Fascì Spurio, S. De Carli, D. Tirotta, P. Gnerre </p
... According to recent evidence, the deficit would persist regardless of the duration and adherence to the GFD, being mainly related to poor intake of the nutrient itself, which in 95% of cases is not added to gluten-free products [88]. Despite this, it has been suggested that vitamin D supplementation is essential in those subjects undergoing dietary treatment, especially during the first year of the GFD [89]. ...
Article
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Celiac disease is a rising disorder and is becoming frequently diagnosed in recent years. To date, the only available treatment is the gluten-free diet (GFD). The role of gluten on components of metabolic syndrome and on related inflammatory response is still unclear due to controversial results. In recent years, scientific focus on this topic has been growing up, in particular regarding the role of the GFD on glycometabolic parameters and diabetes. In addition, studies on the remaining components showed discordant results, which was likely due to heterogeneous and large celiac disease populations and to the lack of prospective studies. Furthermore, knowledge about the role of the GFD on inflammatory cytokines and the relationship among vitamin D and celiac disease, metabolic syndrome (MS) and GFD is needed. In this narrative review, we provided evidence regarding the role of the GFD on glycometabolic parameters, cholesterol, triglycerides, waist circumference, blood pressure and inflammatory cascade, also evaluating the role of vitamin D, trying to summarize whether this nutritional pattern may be a value-added for subjects with dysmetabolic conditions. Finally, due to the limited findings and very low-certainty evidence, predominantly based on observational studies, the real effects of a GFD on different components of MS, however, are unclear; nevertheless, an improvement in HDL levels has been reported, although data on glycemic levels are discordant.
... 27 Coeliac patients show highly variable mucosal healing rates on a GFD in follow-up studies ranging from 6 months to 10 years. [28][29][30][31][32][33][34][35][36][37][38][39][40] Rates of healing after 2 years are between 12% and 79% with variability likely resulting from retrospective studies, how mucosal recovery was defined and histology reported, and variations in GFD duration, GFD adherence and patient age. 41 Mucosal healing in children is also variable but tends to be faster and more complete than in adults (generally >80% at 2 years). ...
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Coeliac disease is a lifelong immune‐mediated enteropathy with systemic features associated with increased morbidity and modestly increased mortality. Treatment with a strict gluten‐free diet improves symptoms and mucosal damage but is not curative and low‐level gluten intake is common despite strict attempts at adherence. Regular follow‐up after diagnosis is considered best‐practice however this is executed poorly in the community with the problem compounded by the paucity of data informing optimal approaches. The aim of dietary treatment is to resolve symptoms, reduce complication risk and improve quality of life. It follows that the goals of monitoring are to assess dietary adherence, monitor disease activity, assess symptoms and screen for complications. Mucosal disease remission is regarded a key measure of treatment success as healing is associated with positive health outcomes. However, persistent villous atrophy is common, even after many years of a gluten‐free diet. As the clinical significance of asymptomatic enteropathy is uncertain the role for routine follow‐up biopsies remains contentious. Symptomatic non‐responsive coeliac disease is common and with systematic follow‐up a cause is usually found. Effective models of care involving the gastroenterologist, dietitian and primary care doctor will improve the consistency of long‐term management and likely translate into better patient outcomes. Identifying suitable treatment targets linked to long‐term health is an important goal.
... Recent data, analyzing serology as a marker of mucosal recovery is equivocal [5,6]. It has been demonstrated that mucosal recovery was usually incomplete in adult patients with CD, and it was poorly correlated with serum titers of serologic tests [11][12][13][14][15]. Moreover, a recent meta-analysis of follow-up biopsies of patients with CD on GFD demonstrated that celiac serology (tTG-IgA and EMA) had a low sensitivity in detecting persistent villous atrophy [16]. ...
Article
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Recent guidelines suggest non-biopsy serology–based approach for the diagnosis of celiac disease; however, there is no evidence-based data regarding noninvasive follow-up of mucosal healing. The aim of this study is to investigate the efficacy of serology in reflecting mucosal status in the follow-up of pediatric patients with celiac disease. This is a validation study conducted at a university hospital. Patients who had biopsy proven celiac disease (Marsh III) at diagnosis, and had been followed-up for at least 12 months, were prospectively evaluated with duodenal biopsies. tTG-IgA and EMA tests were performed on the day of endoscopy. One hundred four patients with a mean age of 7.4 ± 4.02 years were included in the study. The sensitivity and specificity of tTG-IgA were 85.2% and 61% respectively, with a high negative predictive value (NPV) of 92.2% but a very low positive predictive value (PPV) of 43.4%. We found that a cutoff value of 68.5 U/mL for tTG-IgA had a sensitivity, specificity of 85.2% and 85.7% respectively. The AUC was 0.891. The sensitivity and specificity of EMA was 77.8% and 87% respectively, with a high NPV of 91.8% but low PPV of 67.7%. Conclusion: This study suggests that negative tTG-IgA and/or EMA can be used as an indicator of mucosal improvement in the follow-up of pediatric patients with celiac disease. However, positive serology (i.e., < 10 × ULN) may be misleading in reflecting mucosal status in the follow-up of pediatric patients with celiac disease. What is Known: • The tissue transglutaminase IgA (tTG-IgA) and endomysium IgA (EMA) tests are widely used, sensitive and reliable diagnostic tests, but their role in monitoring adherence to dietary treatment in celiac patients has not yet been demonstrated. • There is still no reliable and non-invasive marker of persistent villous atrophy or mucosal recovery. What is New: • Negative celiac serology detected in the follow-up of pediatric patients with celiac disease was successful in demonstrating histopathological mucosal healing. • Positive celiac serology, which is highly reliable in the diagnosis of celiac disease, has not been successful in reflecting mucosal status when used in the follow-up of pediatric patients with celiac disease.
... Это свидетельствует о неполном восстановлении структуры энтероцитов, что согласуется с наблюдениями, указывающими на медленное и неполное восстановление СОТК у больных, соблюдающих АГД [6][7][8]. ...
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Aim. To evaluate the level of serum I-FABP (Fatty-Acid-Binding Protein a protein that binds fatty acids) and fecal zonulin as markers of the permeability of the mucous membrane of the small intestine in celiac patients. Materials and methods. A total of 151 celiac patients (25 men and 126 women) were examined. The median age was 42 years. Group I included 58 patients with newly diagnosed celiac disease; in group 2 38 patients, knowingly or unknowingly violating the gluten-free diet; group 3 consisted of 55 patients strictly observing gluten-free diet. The control group consisted of 20 healthy volunteers: 4 men and 16 women. All patients underwent esophagogastroduodenoscopy by biopsy of the mucous membrane of the small intestine and assessment of duodenobioptates according to Marsh. In the blood serum, the level of antibodies to tissue transglutaminase IgA and IgG was determined by the enzyme-linked immunosorbent assay using kits manufactured by Orgentec Diagnostics GmbH (Germany), the concentration of I-FABP in blood serum was determined using Hycult Biotech kits (Netherlands). The content of zonulin in feces was investigated by enzyme-linked immunosorbent assay using kits from Immundiagnostik AG (Germany). Statistical analysis was performed using the Statistica 13.3 software (StatSoft Inc., USA). Results. There was a significant increase in the level of antibodies to tissue transglutaminase IgA [120.0 (41.1200)] IU/ml and IgG [31.4 (5.578.9)] IU/ml in patients of group 1 compared with group 2 [IgA 9.1 (2.987.6)] and IgG [3.8 (2.219.7)] IU/ml and group 3 [IgA 1.6 (1.03.2)] and IgG [2.2 (1.152.53)] (p0.01). The level of I-FABP in blood serum in patients of group 1 averaged 2045 pg/ml, in patients in group 2 1406 pg/ml, in patients in group 3 1000 pg/ml. All patients showed a significant increase in the mean I-FABP values compared to controls (1, 2 and control p0.01, 3 and control p=0.016). In patients with Marsh grade III AC atrophy, the I-FABP level depended on the degree of damage to the mucosa and significantly differed from the control: March IIIA (median: 1310 pg/ml, interquartile range: 12121461 pg/ml), March IIIB (median: 2090 pg/ml, interquartile range: 18122322 pg/ml) as well as Marsh IIIC (median: 2058 pg/ml, interquartile range 18582678 pg/ml). The concentration of zonulin in feces in patients of group 1 averaged 111.6 pg/mg, in patients of group 2 90.5 pg/mg. In patients of group 3 50 IU/ml. The concentration of zonulin in feces increased as the degree of mucosa atrophy increased (r=0.585, p0.01). However, despite the fact that both of these markers may indicate impaired permeability, each of them indicates damage to a certain level of the intestinal barrier, which is not always associated with the degree of mucosa atrophy. Conclusion. Determination of serum I-FABP and fecal zonulin levels in celiac patients allows for the assessment of intestinal permeability and can serve as non-invasive markers for monitoring ongoing structural changes in the mucosa without the need for endoscopy.
... Gluten elimination from diet should lead to a total remission of symptoms. However, data in the literature indicate that approximately 20-30% of celiac people continue suffering from symptoms even though they follow a strict GFD [25][26][27][28][29]. One of the reasons attributed to these complications is the involuntary ingestion of small amounts of gluten, called dietary transgressions [27]. ...
Article
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The present work aimed to analyze, through the GlutenFreeDiet digital platform, the evolution over one year of the nutritional status, dietary profile and symptoms present among celiac people on a gluten-free diet (GFD) while receiving individualized dietary advice. Twenty-seven adults and thirty-one celiac children/adolescents participated in the study. This was then followed up by three visits, at diagnosis, and after 3 and 12 months (vt0, vt3 and vt12). Participants filled out dietary and gastrointestinal symptoms questionnaires. All patients received written personalized dietary advice from dietitians who interpreted data from the platform. Results obtained indicated that participants consumed proteins and lipids in excess and carbohydrates in defect. Low intakes of cereals, fruit and vegetables and high meat intakes were observed. However, gluten-free product (GFP) consumption and that of ultra-processed foods was reduced after 1 year in adults. Symptoms decreased after vt3 but recurred in vt12. Changes in ultra-processed foods and GFP intake, but lack of changes in the rest of the parameters suggested that the platform support was not effective enough. Even though the platform represents a useful tool for monitoring celiac patients and giving dietary advice, modules that require more continuous attention and nutritional education of patients should be provided for interventions to be more effective.
... We did not observe complete or partial normalization of mucosal atrophy in these patients 5 . These results are persistent with the previous endoscopic studies in which they observed similar macroscopic signs of intestinal atrophy 8 . During the Gluten-free diet, we observed a successful association of serological tests (anti-tissue transglutaminase IgA) with clinical responses but at the same time, both of these were not correlated with mucosal healings (histological improvement). ...
Article
Aim: Evaluate the histological findings of celiac disease and to analyze the variations that occurred in biopsies. We aimed to execute the GFD method which helps us in diagnosing and managing celiac disease during follow-up. Methodology: This retrospective study was conducted at the Rawalpindi Medical University hospital from September 2020 to September 2021. Standard bioptic forceps and flexible endoscopes were used to perform upper GIT endoscopy and biopsies. For every patient, we collected 4 biopsy specimens from the duodenum. We cut 3μm thick sections from each block and stained them in a hematoxylin compound. We counted intraepithelial lymphocytes using anti-CD3 immuno histochemical staining. Results: We recruited 69 celiac patients with a total of 2,760 power fields. Out of these 69 patients, 52 were (76%) females and 17 (24%) were males. Patients from the age range 14 to 69 were recruited. The mean age of patients was reported as 39 ± 15 years. By the EF method, we observed improvement in histological patterns of 8 patients, and one remain unchanged. Only 2 cases reported worsened histological outcomes. Conclusion: Interpretation of duodenal biopsies demands different methods of analysis based on the clinical settings to address the presence of atrophy and improvements in CD patients. Keywords: Celiac disease, Marsh-Oberhuber scale, endoscopy
... Mucosal healing (typically defined as modified Marsh grade 0-1) is believed to occur in 90% of paediatric patients within 2 years after starting a gluten-free diet; however, less than 50% of adult patients experience mucosal healing within this time period 122 . Dedicated prospective studies of mucosal healing are lacking; however, cross-sectional studies suggest that, although rates of healing improve over time, a substantial proportion of adults do not achieve or cannot maintain mucosal remission [122][123][124][125] . Moreover, the results of studies using quantitative histological methods suggest that assessment of mucosal healing by standard qualitative histology might under-report ongoing villous abnormalities 126,127 . ...
Article
Coeliac disease is a systemic disorder characterized by immune-mediated enteropathy, which is caused by gluten ingestion in genetically susceptible individuals. The clinical presentation of coeliac disease is highly variable and ranges from malabsorption through solely extra-intestinal manifestations to asymptomatic. As a result, the majority of patients with coeliac disease remain undiagnosed, misdiagnosed or experience a substantial delay in diagnosis. Coeliac disease is diagnosed by a combination of serological findings of disease-related antibodies and histological evidence of villous abnormalities in duodenal biopsy samples. However, variability in histological grading and in the diagnostic performance of some commercially available serological tests remains unacceptably high and confirmatory assays are not readily available in many parts of the world. Currently, the only effective treatment for coeliac disease is a lifelong, strict, gluten-free diet. However, many barriers impede patients’ adherence to this diet, including lack of widespread availability, high cost, cross-contamination and its overall restrictive nature. Routine follow-up is necessary to ensure adherence to a gluten-free diet but considerable variation is evident in follow-up protocols and the optimal disease management strategy is not clear. However, these challenges in the diagnosis and management of coeliac disease suggest opportunities for future research.
... At least 67% of the patients with CD get exposed to gluten despite best efforts at dietary modifications [10,11]. Perhaps this is a contributing reason why 25-40% of adults with CD still have villous atrophy after 2 years on a GFD [12]. In addition, many gluten-free products tend to be less healthy than their gluten analogs [13]. ...
Article
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Celiac disease (CD) is a genetically predisposed, T cell-mediated and autoimmune-like disorder caused by dietary exposure to the storage proteins of wheat and related cereals. A gluten-free diet (GFD) is the only treatment available for CD. The celiac immune response mediated by CD4+ T-cells can be assessed with a short-term oral gluten challenge. This study aimed to determine whether the consumption of bread made using flour from a low-gluten RNAi wheat line (named E82) can activate the immune response in DQ2.5-positive patients with CD after a blind crossover challenge. The experimental protocol included assessing IFN-γ production by peripheral blood mononuclear cells (PBMCs), evaluating gastrointestinal symptoms, and measuring gluten immunogenic peptides (GIP) in stool samples. The response of PBMCs was not significant to gliadin and the 33-mer peptide after E82 bread consumption. In contrast, PBMCs reacted significantly to Standard bread. This lack of immune response is correlated with the fact that, after E82 bread consumption, stool samples from patients with CD showed very low levels of GIP, and the symptoms were comparable to those of the GFD. This pilot study provides evidence that bread from RNAi E82 flour does not elicit an immune response after a short-term oral challenge and could help manage GFD in patients with CD.
... Good adherence to this diet corrects damage to the intestines and thus corrects the absorption of macros and micronutrients [8]. However, there are several factors that hinder good adhesion. ...
Article
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The prevalence of celiac disease (CD) is increasing in the world. In Morocco, its incidence is also increasing considerably. The gluten-free diet (GFD) remains the only effective treatment so far. Its effectiveness depends essentially on good adherence to this diet. However, several factors hinder adherence by contributing to diet failure. Within this framework, this study aims to evaluate adherence to this diet in celiac children and adolescents continuing in a tertiary health center. The article also looks to identify the different factors influencing adherence to GFD in Morocco. The results show from serological and/or biopsy tests on 238 celiac patients that half had good adherence and 13% had poor adherence. The questionnaire aimed at 127 parents or proxies of celiac children and adolescents shows that several factors are responsible for the failure to adhere to the diet such as the role of the mass media, cultural and psychological factors. The exorbitant price, nutritional quality, and low availability of gluten-free products play a major role in GFD failure. Low socio-economic factors have a negative influence on the adherence to the GFD.
... The weaknesses are the small size of the study group, the impossibility to fully control the complete adherence to the GFD in a real-life scenario, and the use of raw (rather than cooked) gluten for the challenge procedures. It also remains to be clarified whether our findings may extend to patients with CD, although the standardization of the urinary GIP test in patients frequently showing a variable degree of intestinal mucosa damage, as it is the case in subjects with treated CD (25), could prove even more difficult than in healthy controls. In conclusion, this study suggests that the urinary GIP determination may not be an accurate method to assess the adherence to the standard GFD, but the test may find application in monitoring a zero-gluten diet as the GCED. ...
Article
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Introduction: The adherence to a gluten-free diet (GFD) is a trending topic in the management of celiac disease. The aim of our study was to evaluate the diagnostic performance of urinary gluten immunogenic peptides (GIP) determination to detect gluten contamination of the GFD. Methods: In study A, 25 healthy adults on a standard GFD performed 6 gluten challenges (0, 10, 50, 100, 500, and 1,000 mg) with quantification of urinary GIP before (T0) and during the following 24 hours. In study B, 12 participants on a gluten contamination elimination diet underwent urinary GIP determination at T0 and after challenge with 5 or 10 mg gluten. Urine GIP concentration was determined by an immunochromatographic assay. Results: In study A, 51 of 150 baseline urine samples were GIP+ on GFD and 7 of 17 were GIP+ after the zero-gluten challenge, whereas only 55 of 81 were GIP+ after the 10-1,000 mg gluten challenges. There was no significant change in the 24-hour urinary GIP when increasing gluten from 10 to 1,000 mg. In study B, 24 of 24 baseline urine samples were GIP-, whereas 8 of 24 were GIP+ after 5 or 10 mg of gluten. Discussion: Traces of gluten in the standard GFD may cause positivity of urinary GIP determination, whereas a false negativity is common after a gluten intake of 10-1,000 mg. Owing to the impossibility of standardizing the test in normal conditions, it seems unlikely that urinary GIP determination may represent a reliable tool to assess the compliance to the GFD of patients with celiac disease or other gluten-related disorders.
... As was previously reported, we observed that anti-TG2 IgA antibody levels decrease after the beginning of a GFD in most patients. However, seroconversion (negative anti-TG2) in patients on a GFD does not necessarily imply recovery of the damage in the intestinal mucosa [24]. We found that sCD14 was significantly elevated in untreated CD patients compared to those on GFD, independent of the status of anti-TG2 IgA antibody (positive or negative). ...
Article
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Introduction: Celiac disease (CD) is an autoimmune enteropathy triggered by gluten ingestion in genetically susceptible individuals. In CD, activation of the immune response causes damage of the intestinal mucosa, and a gluten-free diet (GFD) is the only available therapy. Intestinal damage can lead to an increase in the circulation of components of bacteria from the intestinal lumen, such as lipopolysaccharide (LPS). Soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP) participate in the recognition of LPS, and their levels are altered in different pathologies. In the present study, the circulating levels of sCD14 and LBP from untreated CD patients were evaluated and compared to CD patients on a GFD and controls. Material and methods: In total seventy-two adult patients with CD, twenty-three untreated CD patients and forty-nine on a GFD were included. In addition, fifty-five healthy individuals were included as controls. Additionally, the effect of LPS on sCD14 production by both normal and inflamed intestinal tissue culture was explored. Results: Serum levels of sCD14 were found to be significantly increased in untreated CD patients compared to patients on a GFD and controls. In addition, we found that LPS induced the production of sCD14 by biopsies of intestinal tissue from untreated CD patients. Conclusions: The data from this study show that circulating levels of sCD14 are increased in the untreated CD patients compared to patients on a GFD. Our data show that LPS induces the production of sCD14 by the intestinal tissue from untreated CD patients.
... CD follow-up is controversial and serological response is often used as a surrogate for histological recovery and GFD adherence [26]. In the literature, there are many studies that show that a complete recovery of the intestinal mucosa occurs rarely in celiac patients on a GFD, and, furthermore, tTGA are not useful predictors of mucosal healing, if mucosal healing represents the reference standard to evaluate the activity or remission of CD [27][28][29][30][31]. Surprisingly, patients with tTGA+ titres presented a lower rate of mucosal atrophy compared to the control group. ...
Article
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Introduction & aim: Anti-tissue transglutaminase antibody (tTGA) titer is used during the follow-up of celiac patients to evaluate gluten-free diet (GFD) responsiveness. However, no clear data are available on this issue. The aim of this study was to evaluate tTGA significance during celiac disease (CD) monitoring. Methods: From January 2017 to January 2020, consecutive CD patients on a GFD with persistent positive tTGA were enrolled. Antibody titres were evaluated on a yearly basis from CD diagnosis to the last follow-up. Urinary gluten detection tests, duodenal histology and capsule enteroscopy (CE) were performed. A tTGA-positive cohort was compared with a control group composed of 212 treated CD patients with negative tTGA. Results: 65 patients (12% males, median age at enrollment and CD diagnosis, 37 (14-86) and 31 (1-76), respectively, median follow up 4 (1-26) years) presented with positive tTGA during follow-up. Overall, the tTGA titres were 3 (1-79) fold increased (ULN). Three different tTGA trends were recognized: (I) 36 (55%) patients with a progressive titres decrease; (II) 16 (25%) patients with a fluctuating behavior; (III) 13 (20%) patients with a steady state or increased titres. tTGA+ patients did not present with different clinical and demographic parameters. Duodenal atrophy was present in 10% vs. 36% of the tTGA positive vs. negative group (p < 0.005), respectively. Gluten detection results were positive in 3 (8%) cases, all in the III group. In tTGA+ patients, CE did not identify any CD-related complications. Conclusions: tTGA positivity during CD follow up did not present a relevant clinical significance without association with autoimmune comorbidities and mucosal damage.
... Interestingly, 83% of patients having baseline modified Marsh 3c changes showed a mismatch of histological and serological response after an average period of 16 months post-GFD. [80] Among all serological tests available only EMA was found to be a fair indicator of mucosal healing, though not routinely performed during the initial screening and diagnosis, especially in India. [81] In the presence of systemic autoimmune inflammation, both the anti-tTG titer and EMA can be falsely elevated/positive despite achieving mucosal healing. ...
Article
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The Indian Association of Pathologists and Microbiologists (IAPM) and Indian Society of Gastroenterology (ISG) decided to make a joint consensus recommendation for handling, processing, and interpretation of SI biopsies for the diagnosis and management of celiac disease (CD) recognizing the inhomogeneous practice of biopsy sampling, orientation, processing, and interpretation. A modified Delphi process was used to develop this consensus document containing a total of 42 statements and recommendations, which were generated by sharing the document draft, incorporating expert's opinion, followed by three cycles of electronic voting as well as a full-day face-to-face virtual ZOOM meeting and review of supporting literature. Of the 42 statements, 7 statements are on small intestinal (SI) biopsy in suspected patients of CD, site and the number of biopsies; 7 on handling, fixative, orientation, processing, and sectioning in pathology laboratories; 2 on histological orientation; 13 statements on histological interpretation and histological grading; 3 on the assessment of follow-up biopsies; 2 statements on gluten-free diet (GFD)-nonresponsive CD; 4 on challenges in the diagnosis of CD; 2 statements each on pathology reporting protocol and training and infrastructure in this area. The goal of this guideline document is to formulate a uniform protocol agreed upon both by the experienced pathologists and gastroenterologists to standardize the practice, improve the yield of small bowel biopsy interpretation, patients' compliance, overall management in CD, and generate unified data for patient care and research in the related field.
... Often studies reporting rate of mucosal healing demonstrate a trend for higher rates of mucosal healing as time from diagnosis increases [19,21]. Previous studies have demonstrated that many patients can be identified as 'slow responders' [19,21,42,43]. The cause of delayed healing in many CD patients is debated. ...
Article
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Background and aims: Methods of assessing gluten-free diet (GFD) adherence in adults with coeliac disease (CD) include serological testing, dietitian evaluation, questionnaires and repeat duodenal biopsies. Persisting villous atrophy (VA) is associated with CD complications, however gastroscopy with biopsies is expensive and invasive. This study aimed to assess the abilities of a duodenal bulb (D1) biopsy and the Celiac Dietary Adherence Test (CDAT) to detect persisting VA in adults with CD. Methods: A prospective observational study of adult CD patients referred for follow-up duodenal biopsies was performed. Quadrantic biopsies were taken from the second part of the duodenum (D2), in addition to a D1 biopsy. Patients underwent follow-up serological testing, and completed the CDAT and Biagi Score. These non-invasive adherence markers were compared against duodenal histology. Results: 368 patients (mean age 51.0 years, 70.1% female) had D1 and D2 biopsies taken at follow-up gastroscopy. Compared to D2 biopsies alone, additional D1 biopsies increased detection of VA by 10.4% (p<0.0001). 201 patients (mean age 50.3 years, 67.7% female) completed adherence questionnaires and serology. When detecting VA, sensitivities and specificities of these markers were 39.7% and 94.2% for IgA- tTG, 38.1% and 96.4% for IgA-EMA, 55.6% and 52.2% for CDAT and 20.6% and 96.4% for the Biagi score. Conclusions: Bulbar biopsies increase detection of persisting VA by 10.4%. Serology, CDAT and Biagi performed poorly when predicting VA. The gold standard for predicting persisting VA remains repeat biopsy.
... Another challenge in the diagnosis of RCDI is that persistent villous atrophy is frequently present in asymptomatic CD patients and those patients are referred to as slow responders and are generally believed not to require additional immunosuppressive treatment. For instance, after one and five years of following a GFD respectively up to 80% and 40% of adult-onset CD patients still display villous atrophy [59][60][61][62][63][64][65]. So distinguishing patients with persistent villous atrophy without symptoms (slow responders) from those with symptoms (RCDI) might sometimes be controversial as for instance abdominal pain or diarrhea could well be caused by concomitant disease. ...
Article
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Immune-mediated enteropathies are caused by excessive reactions of the intestinal immune system towards non-pathogenic molecules. Enteropathy leads to malabsorption-related symptoms and include (severe) chronic diarrhea, weight loss and vitamin deficiencies. Parenteral feeding and immunosuppressive therapy are needed in severe cases. Celiac disease has long been recognized as the most common immune-mediated enteropathy in adults, but the spectrum of immune-mediated enteropathies has been expanding. Histological and clinical features are sometimes shared among these enteropathies, and therefore it may be challenging to differentiate between them. Here, we provide an overview of immune-mediated enteropathies focused on clinical presentation, establishing diagnosis, immunopathogenesis, and treatment options.
... Furthermore, it has been demonstrated that a substantial percentage (ranging from 9% to 43%) of celiac patients do not achieve complete mucosal healing after the start of the GFD [4,12,13]. Conflicting data on histological recovery are mainly dependent on the variability of GFD duration and different GFD adherence assessments used at the time of histological control in different studies [14][15][16][17]. Refractory celiac disease (RCD), a rare complication of CD, is defined as the persistence or recurrence of GI symptoms and signs of malabsorption with persistent villous atrophy despite a strict GFD for more than 12 months when other potentially accountable disorders are excluded [1,18]. ...
Article
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A gluten-free diet (GFD) leads to a rapid improvement in gastrointestinal (GI) symptoms, biochemical alterations and duodenal histological damage in the majority of celiac disease (CD) patients. This study aimed to assess the frequency and factors associated with the persistence of GI symptoms/malabsorption signs and their relationship with duodenal histological findings among CD patients on an adequate GFD (mean duration 16 months, range 12–28 months). This longitudinal cohort study included 102 adult CD patients (median age 38.5 years, range 18–76 years, F = 71.6%) diagnosed between 2012 and 2018. A total of 36.3% of the included patients had persistent GI symptoms and/or malabsorption signs (Group 1), while the remaining patients had complete GI well-being without malabsorption signs (Group 2) at the time of histological re-evaluation. The persistence of GI symptoms/signs was associated with a long duration of symptoms/signs before CD diagnosis (≥5 years) (OR 5.3; 95% CI 1.3–21.8) and the presence of constipation at the time of CD diagnosis (OR 7.5; 95% CI 1.3–42) while for other variables, including age at CD diagnosis, sex, duration of GFD, comorbidities, CD serology positivity and severity of duodenal damage at histological re-evaluation, no association was found. According to our results, the persistence of symptoms/signs is not associated with histological findings, and their relationship could be a gray area in CD management.
... Despite the availability of a wide range of naturally (by origin) and industrially prepared gluten-free (GF) food products, it is hard for patients to maintain a GFD. Approximately 15-40% patients with CeD persist to have enteropathy despite maintaining GFD, one of the reasons being inadvertent intake of gluten [7]. Intake of even 50 mg of gluten/day has been demonstrated to maintain the persistence of enteropathy [8]. ...
Article
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Gluten-free (GF) diet is the only reliable treatment for patients with celiac disease (CeD), but data on the extent of gluten contamination in GF food available in India is scanty. We evaluated gluten content in labeled, imported, and non-labeled GF food products currently available in the Indian market. Overall, 794 processed and commercially available packaged GF products (labeled GF (n = 360), imported GF (n = 80), and non-labeled/naturally GF (n = 354)) were collected from supermarkets of National Capital Region of India. Those unavailable in stores were purchased from e-commerce sites or directly from the manufacturers. Gluten level in them was determined by Ridascreen Gliadin sandwich R5 enzyme-linked immunosorbent assay (R-Biopharm AG, Germany). As per Codex Alimentarius and Food Safety and Standard Authority of India, “gluten free” labeled products must not contain > 20 mg/kg of gluten. Overall, 10.1% of 794 GF products including 38 (10.8%) of 360 labeled and 42 (11.8%) of 354 non-labeled/naturally GF food products had gluten content > 20 mg/kg (range: 24.43–355 and 23.2–463.8 mg/kg, respectively). None of the imported GF products had gluten more than the recommended limits. Contaminated products most commonly belonged to cereal and their products (flours, coarse grains, pasta/macaroni, snack foods) pulse flours, spices, and bakery items. A substantial proportion (10.1%) of GF food products (both labeled and non-labeled) available in India have gluten content greater than the prescribed limits of <20 mg/kg. Physicians, dietitians, support group, and patients with CeD should be made aware of this fact and regulatory bodies should ensure quality assurance.
... For instance, the ranges of cases reported to show improvement of a Marsh 0, 1 or 2 lesion (regarded as a good response) after 1 year are 4-81% (Marsh 0) and 4-71% (Marsh 1/2), whereas the range of cases showing persistence of a Marsh type 3 lesion is 8-62%. [57][58][59][60][61][62][63][64] Paediatric populations generally show a better response. The length of follow-up is also important (see below). ...
Article
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Most absorption of nutrients takes place in the proximal small intestine, and the most common disorders leading to malabsorption are associated with a morphological abnormality in the duodenal mucosa that is appreciable in histological sections of biopsy specimens. Coeliac disease is the most well‐known example, causing intraepithelial lymphocytosis, inflammation and villous atrophy in the duodenum. Remarkably similar inflammatory changes can be induced by other processes, including medications, e.g. angiotensin II receptor blockers and immune checkpoint inhibitors, immune dysregulation disorders, e.g. common variable immunodeficiency and autoimmune enteropathy, infections, collagenous sprue, and tropical sprue. However, there are often subtle histological differences from coeliac disease in the type of inflammatory infiltrate, the presence of crypt apoptosis, and the extent and type of inflammation beyond the duodenum. The clinical setting and serological investigation usually allow diagnostic separation, but some cases remain challenging. Histopathology is also important in assessing the response to treatment, such as the change in villous architecture caused by a gluten‐free diet, or the response to cessation of a potentially causative medication. This review examines the practical role that histopathology of duodenal biopsy specimens plays in the assessment and management of inflammatory malabsorptive processes of the proximal small intestine, with a particular emphasis on coeliac disease.
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Celiac disease (CD) is a chronic autoimmune disorder driven by both genetic and environmental factors, with the HLA DQ2/DQ8 genotypes playing a central role in its development. Despite the genetic predisposition, only a small percentage of individuals carrying these genotypes develop the disease. Gluten, a protein found in wheat, rye, and barley, is the primary environmental trigger, but other factors, such as the intestinal microbiota, may also contribute to disease progression. While the gluten-free diet (GFD) remains the cornerstone of treatment, many CD patients experience persistent inflammation and gut dysbiosis, leading to ongoing symptoms and complications. This chronic inflammation, which impairs nutrient absorption, increases the risk of malnutrition, anemia, and other autoimmune disorders. Recent studies have identified an altered gut microbiota in CD patients, both on and off the GFD, highlighting the potential role of the microbiota in disease pathogenesis. An emerging area of interest is the supplementation of n-3 polyunsaturated fatty acids (PUFAs), known for their anti-inflammatory properties, as a potential therapeutic strategy. n-3 PUFAs, found in fish oil and certain plant oils, modulate the immune cell function and cytokine production, making them a promising intervention for controlling chronic inflammation in CD. This review explores the current understanding of n-3 PUFAs’ effects on the gut microbiota’s composition and inflammation in CD, with the goal of identifying new avenues for complementary treatments to improve disease management.
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Background: Celiac disease (CD) is an autoimmune disease that results from the interaction of genetic, immune, and environmental factors. According to the 2020 European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidelines, an elimination diet (i.e., excluding products that may contain gluten) is the basic method of treating celiac disease. Following a gluten-free diet is extremely problematic, and patients often make unconscious deviations from the diet. According to the current Oslo definitions for celiac disease, depending on the clinical picture and adequate tests, several forms of celiac disease have been identified: typical, atypical, asymptomatic, potential, and refractory. Objective: The aim of the study was to assess the frequency of conscious diet mistakes and unconscious deviations from a gluten-free diet in a group of patients with long-standing celiac disease and their impact on the frequency of typical and atypical symptoms. Methods: The study included 57 people diagnosed with celiac disease between 1980 and 2010. After verifying the history of the disease according to the ESPGHAN guidelines from 2020, we excluded 19 patients who had Marsh grade 1 at the time of diagnosis or those without HLA DQ2 or DQ8 haplotypes detected. After verification, the study included 38 patients, 30 women and 8 men, with a verified diagnosis of typical celiac disease. The effectiveness of the gluten-free diet was assessed in all participants. Blood was collected to determine IgA anti-tissue transglutaminase II antibodies (anti-tTG) and IgG antibodies against deamidated gliadin peptides by ELISA. All survey participants provided data concerning current gastrointestinal and systemic symptoms, bowel habits, comorbidities, dietary habits, physical activity, and socioeconomic conditions. Results: A total of 25 patients (65.78%) declared strict adherence to the gluten-free diet. However, in this group, seven (18.4%) patients had significantly increased levels of anti-tTG antibodies (mean 82.3 RU/mL ± 78.9 SD at N < 20 RU/mL). Among the patients who consciously made dietary mistakes, six (46.2%) demonstrated increased levels of anti-tTG antibodies. The analysis did not reveal any difference between the frequency of intestinal and extraintestinal symptoms in patients making dietary mistakes and following the gluten-free diet. Conclusions: More than half of celiac patients unconsciously or consciously make dietary mistakes, which indicates an urgent need to increase their general knowledge of CD and the appropriate diet. Regardless of whether the gluten-free diet is followed, both typical and atypical symptoms of the disease have been observed among celiac patients.
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Fewer than 1% of patients with celiac disease (CD) will develop refractory CD (RCD). As such, most gastroenterologists might never need to manage patients with RCD. However, all gastroenterologists must be familiarized with the basic concepts of RCD and non-responsive CD (NRCD), since it can present as a severe disease with high mortality, not only due to intestinal failure, but also due to progression to enteropathy-associated T cell lymphoma (EATL) and a higher susceptibility to life-threatening infections. The diagnostic workup and differential diagnosis with other causes of gastrointestinal symptoms and villous atrophy, as well as the differentiation between type I and II RCD, are complex, and may require specialized laboratories and reference hospitals. Immunosuppression is efficient in the milder RCDI; however, the treatment of RCDII falls short, with current options probably only providing transient clinical improvement and delaying EATL development. This review summarizes the current diagnostic and therapeutic approach for patients with RCD that all doctors that manage patients with CD should know.
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Enzyme therapy for Celiac disease (CeD), which digests gliadin into non-immunogenic and non-toxic peptides, can be an appropriate treatment option for CeD. Here we have investigated the effectiveness of Bromelain and Ficin on gliadin digestion using in vitro such as SDS-PAGE, HPLC, and circular dichroism (CD). Furthermore, the cytotoxicity of gliadin and 19-mer peptide before and after digestion with these enzymes was evaluated using the MTT assay in the Caco-2 cell line. Finally, we examined the effect of these treatments along with Larazotide Acetate (LA) on the expression of genes involved in cell tight junctions such as Occludin (OCCL), Claudin 3 (CLDN), Tight junction protein-1 (TGP), and Zonulin (ZON) in the Caco-2 cell line. Our study demonstrated Bromelain and Ficin digestion effects on the commercial and wheat-extracted gliadin by SDS-PAGE, HPLC, and Circular Dichroism (CD). Also, the cytotoxicity results on Caco-2 showed that toxicity of the gliadin and synthetic 19-mer peptide was decreased by adding Bromelain and Ficin. Furthermore, the proteolytic effects of Bromelain and Ficin on gliadin indicated the expression of genes involved in cell-tight junctions was improved. This study confirms that ‌Bromelain and Ficin mixture could be effective in improving the symptoms of CeD.
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Background The gluten-free diet (GFD), the only effective treatment for celiac disease, is usually nutritionally imbalanced. The present work aimed to analyze the evolution of the nutritional status, dietary profile, and symptoms present among celiac people over one year on a GFD while receiving individualized dietary advice. Methods Twenty-seven adults and thirty-one celiac children/adolescents participated in the cohort study. They were followed by 3 visits, at diagnosis (vt0) and after 3 and 12 months (vt3;vt12). Participants filled out dietary and gastrointestinal symptoms questionnaires and received a personalized form from dietitians containing dietary advice and anthropometric and biochemical data evolution. Results Most patients presented normal BMI, fat and muscle mass, and biochemical parameters at diagnosis and vt12. By contrast, all participants consumed protein and lipids in excess and carbohydrates in defect, in both vt0 and vt12. Low intakes of cereals, fruits and vegetables and high of meat were observed, these also remain-ing unchanged after dietary counseling. Symptoms present decreased after vt3 but rebounded in vt12. Conclusions Few changes in dietary pattern and symptom elimination suggested that the intervention was not effective enough. More research is necessary to evaluate whether closer follow up and face-to-face dietary advice improve dietary habits of celiac people. Trial registration Code PI2016069, Ethical Comitee of the Clinical Investigation of the Basque Country. Registered on 15 July 2016.
Article
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Chapter
A small subset of celiac disease (CD) patients is, or becomes, refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. Based on the presence or absence of a clonal expansion of premalignant intra-epithelial lymphocytes in the small intestinal epithelium patients are recognized as either Type I or Type II refractory celiac disease (RCD). While the former generally has a relatively mild disease course, Type II RCD is associated with a high risk of transformation towards an aggressive enteropathy associated T cell lymphoma. Since the first descriptions of RCD in the seventies, a large range of pharmacological approaches have been investigated for both types. In this Chapter, these approaches are extensively reviewed and a roadmap for future treatments is presented.
Chapter
Refractory celiac disease (RCD) is usually divided into two clinical entities: without malignant lymphoma-like T cells (RCD1) and with such cells (RCD2). The former represents a not so well understood inflammatory condition that is usually rather difficult to distinguish from non-compliant CD—a major challenge. The latter is a more severe condition with frequent transition to overt lymphoma. Both conditions appear to affect CD patients that receive their diagnosis later in life, suggesting that long-term untreated CD predisposes. The population frequencies of both conditions are very low, and the rarity of the conditions and lack of effective treatment options calls for centralized care.
Chapter
Celiac is a chronic enteric disease resulted from an abnormal immune response to gluten proteins in patients having a certain genomic constitution. Tissue transglutaminase enzyme 2 converts the glutamine residues of gluten peptides by deamidation reaction into glutamic acid, which binds to human leukocyte antigen (HLA)-DQ2 or -DQ8 molecules and subsequently evokes T cell responses leading to small intestine inflammation. These events lead to the typical symptoms associated with celiac disease. Also, wheat proteins are rich in proline content and are resistant to human pancreatic and gastric enzymes. Different peptidases from microbial and fungal sources can degrade these incompletely digested peptides. While following a gluten-free diet is the best preventive strategy, a combination therapy by using proteases or carboxypeptidases from microbial sources for gluten detoxification or treatment with tissue transglutaminase inhibitors may also be a good option. Intestinal epithelial cell lines (Caco-2) may be used as in vitro model to study trans/paracellular permeability, distortion of intercellular tight junction protein viz., occludin, and ZO-1, and rearrangement of actin filaments.
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EVIDENCE&hyphen;BASED ANSWER After an average of 11 months on a gluten&hyphen;free diet, 81&percnt; of patients with celiac disease and positive tissue transglutaminase IgA &lpar;tTG&hyphen;IgA&rpar; at baseline will revert to negative tTG&hyphen;IgA &lpar;SOR&colon; C, disease&hyphen;oriented evidence from retrospective cohort study&rpar;. The intestinal mucosa of adult patients with celiac disease will return to normal after following a gluten&hyphen;free diet for 16 to 24 months in only 8&percnt; to 18&percnt;. However, in children after 2 years, 74&percnt; will have a return to normal mucosa &lpar;SOR&colon; C, diseaseoriented evidence from longitudinal studies&rpar;.
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Introduction: A substantial proportion of adult patients with celiac disease on a gluten-free diet exhibit persistent villous atrophy, and inadvertent gluten exposure may be one of the causes. The aim of the present study was to evaluate villous atrophy persistence after 2 years on a gluten-free diet in de novo adult patients with celiac disease with strict control of gluten exposure. Methods: Symptomatic de novo adult patients with celiac disease were prospectively included. Clinical visits and dietary surveillance were scheduled every 6 months during a 2-year follow-up period. At each visit, fecal samples were collected and stored at -20 °C until analysis for gluten immunogenic peptides (f-GIPs). A follow-up duodenal biopsy was performed at 2 years. We evaluated the variables associated with persistent villous atrophy. Results: Seventy-six patients completed the study (36.5 ± 1.6 years, 73% women); persistent villous atrophy was observed in 40 (53%), whereas 72.5% were asymptomatic and 75% had negative serology. Detectable f-GIP >0.08 μg/g in at least 1 fecal sample was seen in 69% of patients. There were no significant differences in the median f-GIP at each visit and median area under the curve over the serial measurements between patients with persistent villous atrophy and those who recovered. On multivariate analysis, only older age was associated with persistent villous atrophy (32% for 16-30 years; 67% for >30 years; P = 0.016). Discussion: The rate of persistent villous atrophy after 2 years was high in adult patients with celiac disease on an intentionally strict gluten-free diet. Low-level ongoing inadvertent gluten exposure could be a contributing factor to persistent villous atrophy.
Chapter
Seronegative celiac disease (SNCD) is an uncommon, poorly defined form of celiac disease (CeD) that poses an important diagnostic challenge to clinicians, especially in regard to differential diagnoses. Due to a previous inconsistency in definition and use of celiac serology, data have been limited and contrasting in this condition. The chapter summarizes the current knowledge about SNCD and its pathogenesis, clinical course, and treatment options.
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Sexual dimorphism in anatomical, physiological and behavioural traits are characteristics of many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course and severity of many common diseases, including cardiovascular diseases, autoimmune diseases and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid-responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.
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This article examines associations between gluten, polymorphisms of the major histocompatibility complex, and mucosal pathology representative of the spectrum of gluten sensitivity. Sequences of wheat, rye, and barley prolamins contain recurring tetrapeptide motifs that are predicted to have beta-reverse-turn secondary structure and that, with in vitro assays, appear active. Structural polymorphisms of major histocompatibility complex subloci identify codon switches within the second exon that control the third hypervariable region in the outer domain of the beta chain. Observations of the intestinal response to gluten reveal five interrelated lesions (preinfiltrative, infiltrative, hyperplastic, destructive, and hypoplastic) that are interpretable as cell-mediated immunologic responses. These responses originate in the lamina propria, where a series of antigen-specific inflammatory processes has now been identified. There is no evidence that celiac sprue is a disease of jejunal enterocytes. Furthermore, the role of intraepithelial space lymphocytes in pathogenesis, if relevant, needs further experimental dissection. Also awaiting further definition are polymorphisms of the celiac lymphocyte antigen receptor and their relationship to gliadin oligopeptide(s) and predisposing genes. The nature and basis of nonresponsive celiac sprue require more thoughtful initiatives to elucidate the immunologic mechanism(s) of unresponsiveness and evaluate possible means of reversal. Finally, a more sensible definition of gluten sensitivity (unhampered by qualitative morphological imagery) is ultimately called for in order to accommodate the biomolecular advances addressed in this review.
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Duration of gluten exposure seems to predispose adolescents with coeliac disease to autoimmune diseases. In a retrospective cohort study, we assessed the relationship between autoimmune disorders and actual gluten exposure in patients in whom coeliac disease was diagnosed in adult life (> or = 16 years). We screened for the presence of autoimmunity in 605 controls (16-84 years) and 422 patients (16-84 years), all of whom had been on gluten withdrawal for at least one year (median follow up 9.5 years). A logistic regression analysis, setting the prevalence of autoimmunity as the dependent variable, was employed to control for independent covariates as predictors of the risk of autoimmunity. The prevalence of autoimmunity was threefold higher (p < 0.00001) in patients than in controls. Mean duration of gluten exposure was 31.2 and 32.6 years for patients with or without autoimmunity. Logistic regression showed that increased age at diagnosis of coeliac disease was related to the prevalence of autoimmune disease while "actual gluten exposure" which takes into account diet compliance, follow up, and age at diagnosis of autoimmune disorders were not predictive for the risk of developing autoimmune diseases (odds ratio 0.82 per year). The prevalence of autoimmune diseases in patients with a late coeliac disease diagnosis does not correlate with duration of gluten intake. Early exposure to gluten may modify the immunological response. Gluten withdrawal does not protect patients with a late diagnosis from autoimmune diseases.
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Celiac disease is the most common severe food intolerance in the Western world and is due to gluten ingestion in genetically susceptible children and adults. Intestinal biopsy is the golden standard for evaluation of mucosal damage associated with celiac disease. Gluten-free diet is the key treatment for celiac disease. Data on the long-term control of celiac disease are few and limited to small series of patients. The study reports data on the control of celiac disease and on its correlates in a large cohort of celiac adults during long-term treatment with gluten-free diet. The study cohort comprises 91 men and 299 women having undergone treatment with a gluten-free diet for at least 2 years and with complete records for visits at the time of diagnosis of celiac disease (baseline). Data collection included gender, age, education, weight, bowel habit, blood hemoglobin, plasma albumin and cholesterol, serum antiendomysium antibodies (EMA), dietary compliance to gluten-free diet (coded as good, low, or very low), and intestinal damage at biopsy (coded as absent, mild, or severe). The duration of follow-up was 6.9 +/- 7.5 years (mean +/- SD, range 2-22 years). At follow-up visit, intestinal damage was absent in 170 patients (43.6%), mild in 127 (32.6%), and severe in 93 (23.8%). At follow-up, intestinal damage was significantly associated with dietary compliance, EMA, and plasma albumin (follow-up value and change value from baseline to follow-up). Baseline education significantly predicted dietary compliance and intestinal damage at follow-up. Celiac disease is often poorly controlled in the majority of patients on long-term treatment with a gluten-free diet as demonstrated by intestinal biopsy. Lack of adherence to strict gluten-free diet is the main reason of poorly controlled disease in adults. Laboratory and clinical information have a high positive predictive value and low negative predictive value for intestinal damage on long-term treatment. Dietary compliance as assessed by interview is the best marker of celiac disease control due to low cost, noninvasivity, and strong correlation with intestinal damage.
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Coeliac disease (gluten sensitive enteropathy) is a common, polygenic and multifactorial disorder that serves as a pioneering model for the study of inflammatory disease. A major environmental factor is known (ingested gluten from wheat), and there is unprecedented genetic and functional evidence pinpointing HLA-DQA1*05-DQB1*02 ( DQ2) and DQA1*03-DQB1*0302 ( DQ8) in disease predisposition. We discuss the current state of play in coeliac disease genetics, focussing particularly on the HLA complex. Emerging evidence suggests that additional HLA risk loci exert weak effects, independent of DQA1*05-DQB1*02, on the B8-DR3-DQ2 haplotype. There is also good evidence from linkage studies of disease gene(s) on chromosome 5q. We discuss the role and implications of linkage disequilibrium and haplotype blocks in complex disease gene mapping. We briefly address findings from studies of animal models for chronic inflammatory disease, and consider roles for both common genes associated with multiple inflammatory diseases, and genes unique to coeliac disease. The coeliac genetics research community has established a sound foundation for the identification of additional disease genes in the not-too-distant future. Functional studies will play a critical role, and coeliac disease has a promising future in this respect. Coeliac disease continues to function as a model disorder, facilitating the development and implementation of complex disease gene mapping strategies.
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In patients with celiac disease, inflammatory T cell responses to HLA-DQ2-bound gluten peptides are thought to cause disease. Two types of HLA-DQ2 molecules exist, termed HLA-DQ2.5 and HLA-DQ2.2. Whereas HLA-DQ2.5 predisposes to celiac disease, HLA-DQ2.2 does not. We now provide evidence that the disease-associated HLA-DQ2.5 molecule presents a large repertoire of gluten peptides, whereas the non-disease-associated HLA-DQ2.2 molecule can present only a subset of these. Moreover, gluten presentation by HLA-DQ2 homozygous antigen-presenting cells was superior to presentation by HLA-DQ2/non-DQ2 heterozygous antigen-presenting cells in terms of T cell proliferation and cytokine secretion. Gluten presentation by HLA-DQ2.5/2.2 heterozygous antigen-presenting cells induced intermediate T cell stimulation. These results correlated with peptide binding to the antigen-presenting cells. Finally, we demonstrate that HLA-DQ trans dimers formed in HLA-DQ2.5/2.2 heterozygous individuals have properties identical with HLA-DQ2.5 dimers. Our findings explain the strongly increased risk of disease development for HLA-DQ2.5 homozygous and HLA-DQ2.2/2.5 heterozygous individuals, and they are indicative of a quantitative model for disease development, where HLA-DQ expression and the available number of T cell-stimulatory gluten peptides are critical limiting factors. This model may have important implications for disease prevention.
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Because celiac disease is a female-predominant disease we investigated the influence of gender on clinical manifestations of the disease in the United States. Data were obtained on biopsy-proven adult patients with celiac disease from a database of patients seen between 1981 and 2001 in a University-based referral center. Z scores were calculated to adjust for age, ethnicity and gender using the National Health and Nutrition Examination Survey database as controls. The cohort consisted of 323 patients (211 F, 112 M). Men had a shorter duration of symptoms than women (p=0.006). There was no gender difference in the age at diagnosis or mode of presentation. Body mass index (BMI), mean hemoglobin and ferritin values were lower in women than in men, but the Z scores for these values were not significantly different, indicating that the differences are physiological. All lipid values were low (negative Z scores). Men had lower total cholesterol (162.0+/-46.5mg/dl) compared to women (181.0+/-40.0mg/dl), p=0.02 and lower Z scores (-1.10+/-1.1) compared to women (-0.71+/-0.9), p=0.04. Men had lower bone density T scores at the radius (p=0.07). Autoimmune diseases were present in 30.7% with a female to male ratio of 1:1, compared to the general population in which 3.2% have autoimmune diseases with a female predominance. Most gender differences in celiac disease are physiological. However, men have indirect evidence of greater malabsorption than females and have female-predominant associated diseases when they present with celiac disease.
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We have observed expansions of intraepithelial lymphocytes in duodenal biopsies from patients with Helicobacter pylori gastritis. This study was undertaken to prospectively evaluate, unselected, paired gastric and duodenal biopsies from 50 patients with H. pylori gastritis and a comparison group of 30 patients with other types of gastritis (10 autoimmune and 20 reactive) to: (1) quantify duodenal intraepithelial lymphocytes, determine their distribution patterns, epithelial location, and phenotype, and (2) correlate the intraepithelial lymphocyte elevations with various features of gastric and duodenal pathology. Intraepithelial lymphocytes were analyzed with antibodies including CD3, CD8, and TIA-1. A stain for H. pylori was performed on all gastric and duodenal biopsies. Duodenal intraepithelial lymphocytes from patients with H. pylori gastritis (using CD3) ranged from 3 to 42 lymphocytes/100 epithelial cells (mean 18.5) compared to 3 to 18 lymphocytes/100 epithelial cells (mean 6.6) in the comparison group. Intraepithelial lymphocyte elevations were seen in 44% of the duodenal biopsies from patients with H. pylori gastritis (using CD3). Significant differences in the intraepithelial lymphocyte counts between patients with H. pylori gastritis and the comparison group were seen for all three T-cell antigens (P<0.001 for CD3 and CD8 and P<0.002 for TIA-1). Duodenal intraepithelial lymphocytes in the H. pylori+ cases had a latent cytotoxic phenotype, H. pylori was not visualized in any of the duodenal biopsies from patients with H. pylori gastritis, and no patient had clinical evidence of celiac disease. Our study highlights frequent duodenal intraepithelial lymphocytosis in individuals with H. pylori gastritis and the lymphocyte distribution patterns (and numbers) overlapped with those described for celiac disease patients. H. pylori gastritis must be considered as a possible explanation for duodenal intraepithelial lymphocytosis with normal villous architecture, especially when lymphocytosis is patchy, intraepithelial lymphocytes display a 'latent' cytotoxic phenotype, and the clinical findings and serologic profile does not fit celiac disease.
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Celiac disease (CD) is a common gluten-sensitive enteropathy associated with human leukocyte antigen (HLA)-DQ2 and HLA-DQ8. The aim of this study was to determine if a particular HLA-DQ subtype predisposes to complications such as refractory CD with (RCD II) or without aberrant T cells (RCD I), and enteropathy-associated T-cell lymphomas (EATL). Molecular HLA-DQ typing was performed on 43 RCD I, 43 RCD II, and 30 EATL patients, and compared with age-matched groups of 121 patients with histologically defined uncomplicated CD and 183 healthy controls. All individuals were Dutch Caucasians and were at least 21 years of age. HLA-DQ2 was present in 79% of RCD I, 97.7% of RCD II, and 96.6% of EATL patients. The differences were significant when compared with 28.9% in controls but not with 91.7% in uncomplicated CD. Homozygosity for HLA-DQ2 was observed in 25.5% of RCD I, 44.1% of RCD II, and 53.3% of EATL patients vs 20.7% of uncomplicated CD patients and 2.1% of controls. HLA-DQ8 was present in 10.7% of CD, 16.2% of RCD I, 9.3% of RCD II, and 6.6% of EATL patients vs 20.2% of controls. Homozygosity for HLA-DQ2 is associated with RCD II and EATL. Early identification of HLA-DQ2 homozygous CD patients may help to recognize CD patients at risk for developing these severe complications.
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Published follow-up data on small-intestinal recovery in patients with celiac disease are scarce and contradictory. This is especially the case for adult patients, who often show incomplete histological recovery after starting a gluten-free diet (GFD). We conducted a 2-year prospective study to evaluate the effectiveness of a GFD in improving the endoscopic and histological duodenal findings in adults with celiac disease. We studied 42 consecutive adults with newly diagnosed celiac disease (13 men, 29 women; mean age 32.7 years, range 15 - 72 years). All the patients underwent esophagogastroduodenoscopy and small-bowel biopsy. We devised our own grading system for the endoscopic appearance of the duodenum, which ranged from "normal" appearance to "mild", "moderate", or "severe" alterations. Small-bowel biopsies were obtained from the second part of the duodenum (and from the duodenal bulb when it had a micronodular appearance). The histopathological appearances were described according to modified Marsh criteria. A normal endoscopic appearance in the duodenum was found in 5/42 patients (11.9 %) at entry and in 32/42 patients (76.2 %) after 2 years on a GFD. Subdividing the patients according to age, patients aged from 15 years to 60 years showed significant improvement within 12 months ( P < 0.0001 for patients aged from 15 years to 45 years; P < 0.003 for patients in the 46 years to 60 years group), whereas the improvement in endoscopic findings in patients older than 60 years was not statistically significant, even 24 months after starting the GFD. "Normal" histology was reported in none of the patients at entry, but in 25 patients (59.5 %) after 24 months on a GFD, but this parameter did not show a significant improvement until the patients had been on the GFD for 12 months ( P < 0.0001). Only the younger patients (5 - 30 years) showed significant improvement of histology within 12 months ( P < 0.034); older patients (>30 years) showed histological improvement but this was not statistically significant, even after 24 months on a GFD. This study shows for the first time that endoscopic recovery is faster than histological recovery in adults with celiac disease who go on a GFD. Moreover, older patients showed incomplete endoscopic and histological recovery even 24 months after starting a GFD. We therefore advise, as a minimum recommendation, that follow-up biopsies should be taken 1 - 2 years after starting a GFD in adults with celiac disease.
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Treatment of celiac disease (CD) is based on the avoidance of gluten-containing food. However, it is not known whether trace amounts of gluten are harmful to treated patients. The objective was to establish the safety threshold of prolonged exposure to trace amounts of gluten (ie, contaminating gluten). This was a multicenter, double-blind, placebo-controlled, randomized trial in 49 adults with biopsy-proven CD who were being treated with a gluten-free diet (GFD) for > or =2 y. The background daily gluten intake was maintained at < 5 mg. After a baseline evaluation (t0), patients were assigned to ingest daily for 90 d a capsule containing 0, 10, or 50 mg gluten. Clinical, serologic, and histologic evaluations of the small intestine were performed at t0 and after the gluten microchallenge (t1). At t0, the median villous height/crypt depth (Vh/Cd) in the small-intestinal mucosa was significantly lower and the intraepithelial lymphocyte (IEL) count (x 100 enterocytes) significantly higher in the CD patients (Vh/Cd: 2.20; 95% CI: 2.11, 2.89; IEL: 27; 95% CI: 23, 34) than in 20 non-CD control subjects (Vh/Cd: 2.87; 95% CI: 2.50, 3.09; IEL: 22; 95% CI: 18, 24). One patient (challenged with 10 mg gluten) developed a clinical relapse. At t(1), the percentage change in Vh/Cd was 9% (95% CI: 3%, 15%) in the placebo group (n = 13), -1% (-18%, 68%) in the 10-mg group (n = 13), and -20% (-22%, -13%) in the 50-mg group (n = 13). No significant differences in the IEL count were found between the 3 groups. The ingestion of contaminating gluten should be kept lower than 50 mg/d in the treatment of CD.
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In this paper, we review the histological features of coeliac disease and propose a standardized report scheme based on the Marsh classification. Furthermore, terms used by pathologists are defined. The most important histological differential diagnoses are given, as well as a definition of the different clinical forms of coeliac disease such as symptomatic, silent, latent, potential, treated and refractory coeliac disease.
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Background: Serum antibodies to tissue transglutaminase (tTGA) are reported to have high sensitivity and specificity for coeliac disease and to correlate closely with endomysial antibodies (EmA). We assessed their performance in a coeliac population with a high proportion of EmA-negative patients, who have been under-represented in previous studies. Methods: We used a commercial ELISA kit to test for IgA class tTGA in sera from a population of 73 untreated coeliac patients with normal serum IgA and a high percentage (19%) EmA-negative, taking 58 patients with normal duodenal biopsies as controls. EmA was measured using indirect immunofluorescence. Results: Forty-six (63%) patients with villous atrophy (VA) had both tTGA and EmA. However, when considered separately, sensitivities of tTGA and EmA for VA were similar (75% versus 81%) and both had high specificity (98% versus 97%). As 9 patients were tTGA-positive only and 13 had EmA only, selection of patients for biopsy on the presence of either antibody wo...
Article
The aim of this study was to determine the specificity of increase in intraepithelial lymphocytes (IELs) with normal villous architecture in small bowel biopsy samples for diagnosis of gluten sensitivity (GS) and its significance in the absence of GS.Methods Small bowel biopsy samples from 43 patients with increased IELs and no other pathology were reviewed. Patients with prior diagnosis of GS were excluded. A group of 46 patients with normal duodenal biopsy during the same period served as controls. The clinical records of patients and controls were examined for presenting symptoms, laboratory tests, and final clinicopathological diagnosis. Immunohistochemical characterization of IELs was performed in 13 cases.ResultsFour (9.3%) patients had GS based on positive IgA antiendomysial antibodies (n = 3) and favorable response to gluten-free diet (n = 4). One patient (2.2%) had partially treated tropical sprue; six patients (14%) had disorders of immune regulation including Hashimoto's thyroiditis (n = 2) and one case each of Graves' disease, rheumatoid arthritis, psoriasis, and multiple sclerosis; and six patients (14%) were on nonsteroidal anti-inflammatory drugs (NSAIDs). In contrast, none of the control subjects had GS (p = 0.05), tropical sprue, or immunoregulatory disorders (p = 0.011), and one (2.2%) was on NSAIDs (p = 0.04). Increased IELs were also observed in Crohn's disease, lymphocytic/collagenous colitis, and bacterial overgrowth, but the association did not reach statistical significance. Histological features (number and distribution of IELs, crypt mitoses) and immunophenotypic analysis of IELs did not reliably distinguish GS-related from non–GS-related causes of increased IELs.Conclusions Intraepithelial lymphocytosis in an otherwise normal small bowel biopsy is somewhat nonspecific, but in nearly 10% of cases can be the initial presentation of GS. Therefore all patients with this finding should be investigated for GS. Increased IELs may also be associated with autoimmune disorders and NSAIDs.
Article
The relationship between celiac disease and many autoimmune disorders has been explained by the sharing of a common genetic factor. In a multicenter national study, we examined the relationship between the prevalence of autoimmune disorders in celiac disease and the duration of exposure to gluten. Over a 6-month period, 909 patients with celiac disease (group A; mean age, 16.1 +/- 3.8 years; grouped according to age at diagnosis into three subgroups [group A1, <2 years; group A2, 2-10 years; and group A3, >10 years]), 1268 healthy controls (group B; mean age, 20.8 +/- 4.5 years), and 163 patients with Crohn's disease (group C; mean age, 28.8 +/- 10 years) were evaluated for the presence of autoimmune disorders. Prevalence of autoimmune disorders in group A was significantly higher than in group B (14% vs. 2.8%; P < 0.000001) but not higher than in group C (12.9%). Prevalence of autoimmune disorders in celiac disease increased with increasing age at diagnosis: 5.1% in group A1, 17% in group A2, and 23.6% in group A3 (P = 0.000001). In group A3, the prevalence of autoimmune disorders was significantly higher than in group C. In a logistic regression model, age at diagnosis was the only significant predictor variable of the odds of developing an autoimmune disorder (r = 0.3; P < 0.000001). Our data show for the first time that the prevalence of autoimmune disorders in celiac disease is related to the duration of exposure to gluten.
Article
A substantial minority of patients with coeliac disease (estimated at anything between 7 and 30%) fail to respond to treatment with a gluten-free diet. Non-responsiveness may be primary, that is when the patient fails to respond to treatment following initial diagnosis, or secondary, when a patient who has previously had a documented response to gluten exclusion becomes non-responsive to therapy. The commonest cause of non-responsiveness is continued gluten ingestion, either voluntary or inadvertent. Other causes to be considered include intolerances to dietary constituents other than gluten (e.g. milk, soya), pancreatic insufficiency, enteropathy-associated T-cell lymphoma and ulcerative jejunitis. There is some evidence that ulcerative jejunitis is, in fact, a manifestation of lymphoma. The most important steps in the management of the non-responsive coeliac patient are (a) to determine whether the patient is indeed coeliac, (b) to exclude lymphoma and (c) to establish the cause of the non-responsiveness. In those coeliac patients with no demonstrable cause for non-responsiveness, a variety of therapeutic stratagems (mostly based on small, uncontrolled studies) have been described; these include elimination diets, dietary supplementation with zinc and copper, and pharmacological therapy in the form of steroids, azathioprine and cyclosporin. In a minority of non-responsive patients, the clinical course is characterized by a rapid decline, and total parenteral nutrition is required. None of the therapies described above has been subjected to rigorous controlled studies. The precise mechanisms of non-responsiveness in coeliac patients need to be unravelled before rational therapeutic approaches can be established.
Article
While gluten-free diet is an effective treatment for coeliac disease, the need for and goals of long-term management of patients are poorly defined. To review systematically the complications and associations of coeliac disease, to identify potential risk factors, to define ways of assessing risk factors and to provide a strategy for management. Review of medical literature from 1975. There is an increasing list of potential complications and/or conditions associated with coeliac disease, in particular, autoimmune disease, malignancy and bone disease. Risk factors that may predict or influence long-term outcomes include genetic susceptibility, environmental factors predominantly gluten ingestion, persistent small intestinal inflammation/injury and nutritional deficiencies. Genotyping of patients is yet to have an established clinical role in long-term management. Assessment of adherence to the gluten-free diet largely relies upon skilled dietary history, but the ultimate test is duodenal histopathology, which is the only currently established means of assessing healing. Symptoms, serology or other non-invasive means are poor predictors of healing and the likelihood of complications. Evidence (albeit limited) that adherence to a gluten-free diet and mucosal healing prevent and/or ameliorate complications indicates that a planned long-term strategy for follow-up is essential.
Article
Treatment of patients with coeliac disease with a low gluten containing diet (LGD) remains controversial. We have studied jejunal morphology and antigluten (AG) antibody titres by ELISA in patients on a LGD of 2.5-5 g/day for three to 14 months (median six months) and compared results with patients on a strict gluten free diet (GFD) for six to 27 months (median 13 months). We found no significant difference in villous height or crypt depth (eight LGD v 10 GFD patients) or serum AG-IgA, -IgG, and IgM titres (13 LGD v 12 GFD patients). there was however, a significant increase (p less than 0.05) in intra-epithelial lymphocytes in those patients on a LGD. We conclude that adult coeliac patients can tolerate a LGD without gross morphological change and without initiating significant AG antibody responses.
Article
The structure and ultrastructure of the villi of small intestinal mucosa was examined in 237 duodenal or jejunal biopsies taken from children with active celiac disease and during gluten-free diet. All biopsies were processed for light and scanning electron microscopy. Conventional histology showed four different morphological aspects: total and subtotal villous atrophy in patients on unrestricted diet, partial villous atrophy and normal mucosa during gluten-free diet. Scanning electron microscopy demonstrated that in active celiac disease the severity of the intestinal lesions was related to individual vulnerability to gluten. Our results showed that during dietary treatment the process of mucosal healing was constant and strictly time-dependent. Furthermore, the ultrastructural examination has been relevant in evaluating the evolution of the villous regeneration. In this study a classification regarding the healing process of the small intestinal mucosa correlated with the time of start of dietary therapy is proposed.
Article
Compliance to a gluten-free diet is currently an important issue in the care of both adolescent and adult coeliac patients. The aim of this study was evaluate the compliance to a gluten-free diet and the dietary habits in general of coeliac teenagers and young adults. A total of 306 adolescents and young adults were followed in a coeliac clinic. They were grouped on the basis of: strict compliance to a gluten-free dietary regimen (n = 223, 73%); dietary transgressions 2-3 times/month (n = 46, 15%); and frequent transgressions or a full gluten-containing diet (n = 37, 12%). The physical growth status was optimal in the male patients, and less so in the females, but was not related to compliance. Symptoms were very rare in all groups. Compliance to the diet was related to sex (females better than males), age (younger better than older), good school grades, and good self-esteem. The teen-agers studied consumed an average of about 11.32 kg/month of gluten-free products provided by the Italian Health System. Gluten-free pasta and bread were the daily choices. The mean cost for each patient was estimated to be Italian Lire 242,640 (ECU 124) per month or ECU 1,490/year.
Article
In this paper, we review the histological features of coeliac disease and propose a standardized report scheme based on the Marsh classification. Furthermore, terms used by pathologists are defined. The most important histological differential diagnoses are given, as well as a definition of the different clinical forms of coeliac disease such as symptomatic, silent, latent, potential, treated and refractory coeliac disease, Eur J Gastroenterol Hepatol 11:1185-1194 (C) 1999 Lippincott Williams & Wilkins.
Article
Serum IgA-class tissue transglutaminase antibody has proved effective in screening for coeliac disease. The response to a gluten-free diet has been assessed on the basis of small-intestinal morphology. We investigated whether the tissue transglutaminase antibody test could substitute biopsy in this respect, and whether the test is better than the endomysial antibody test in follow-up. Controlled cross sectional, and follow-up study. Serum IgA-class tissue transglutaminase antibodies and endomysial antibodies were determined in 87 coeliac adults on a gluten-free diet. All underwent small bowel biopsy, and the mucosal morphology was interpreted along with Marsh's grading 0-3. In 30 patients histological and serological data could be analysed before and after adopting the diet; Marsh 3 was considered inadequate mucosal recovery during the diet. Of the 87 coeliac patients 27 showed Marsh 3 villous atrophy on gluten-free diet; of these 27, tissue transglutaminase antibody was within normal limits in 16 (59%) and endomysial antibody in 20 (74%). Two (7%) out of 29 with normal mucosa (Marsh 0) had positive tissue transglutaminase antibodies. Six (55%) out of 11 admitting regular dietary lapses remained tissue transglutaminase antibody negative. In the follow-up, serum IgA-class tissue transglutaminase antibody was initially positive in 28 (93%) out of 30 untreated patients; even a significant decrease in tissue transglutaminase antibody did not guarantee mucosal recovery. A substantial number of coeliac patients with negative tissue transglutaminase or endomysial antibodies may still have manifest mucosal villous atrophy. Small bowel biopsy is therefore still necessary to ensure that the gluten-free diet is adequate.
Article
An increase in intraepithelial lymphocytes (IELs) is mandatory for the histological diagnosis of coeliac disease (CD). Currently, duodenal biopsies are used almost exclusively to establish the diagnosis, yet published work continues to cite an upper limit of 40 lymphocytes/100 epithelial cells, a figure derived from jejunal biopsies over 30 years ago. Aim: To establish the normal range for IEL counts in distal duodenal biopsies. Twenty subjects (seven men, 13 women; median age, 34 years; range, 20-65) with a normal sugar permeability test and concurrent distal duodenal biopsies were identified. The number of IELs and epithelial cell nuclei in an uninterrupted length of surface (villous) epithelium (> 500 cells) was counted. An image analysis system was used to assess villous architecture by calculating the villous height to crypt depth ratio. The range of IEL counts in 20 subjects was 1.8-26/100 villous epithelial cells, with a mean value of 11 and SD of 6.8. The mean villous to crypt ratio was 1.82 (SD, 0.38; range, 1.22-2.46). There was no correlation between IEL counts and villous to crypt ratio (Spearman rank correlation, -0.066; p = 0.80). These results suggest that 25 IELs/100 epithelial cells (mean +2 SD) should be taken as the upper limit of the normal range for duodenal mucosa.
Article
Nonresponse or relapse of symptoms is common in patients with celiac disease treated with gluten free diet. Refractory sprue (RS) is defined as initial or subsequent failure of a strict gluten-free diet to restore normal intestinal architecture and function in patients who have celiac-like enteropathy. The aims of this study were: 1) to identify causes of persistent symptoms in patients referred with presumed diagnosis of nonresponsive celiac disease (NCD); and 2) to characterize patients with true RS. Patients were identified who had been systematically evaluated for NCD between January 1997, and May 2001. Patient records and small bowel biopsy results were reviewed. A total of 55 patients were referred with a presumed diagnosis of NCD. Six did not have celiac disease and had other diseases responsible for their symptoms. Diarrhea, abdominal pain, and weight loss were the most common reasons for evaluation in cases of NCD, whereas weight loss, steatorrhea, and diarrhea were the most common presenting features of RS (nine patients). Of the 49 patients with celiac disease, 25 were identified as having gluten contamination. Additional diagnoses accounting for persistent symptoms included: pancreatic insufficiency, irritable bowel syndrome, bacterial overgrowth, lymphocytic colitis, collagenous colitis, ulcerative jejunitis, T-cell lymphoma, pancreatic cancer, fructose intolerance, protein losing enteropathy, cavitating lymphadenopathy syndrome, and tropical sprue. Based on this study, we conclude the following: 1) gluten contamination is the leading reason for NCD; 2) of NCD cases, 18% are due to RS; and 3) alternative diseases or those coexistent with celiac disease and gluten contamination should be ruled out before a diagnosis of RS is made.
Article
To assess histologic recovery in response to gluten withdrawal in celiac disease, 158 patients seen in our hospital during a 15-year period underwent follow-up small intestine biopsies (SIBs) within 2 years after starting a gluten-free diet; further SIBs were done if villous atrophy was present. A modified Marsh classification was used (IIIA, partial villous atrophy; IIIB, subtotal villous atrophy; IIIC, total villous atrophy). Of patients with Marsh IIIA, IIIB, or IIIC lesions, histologic remission was seen in 65.0% within 2 years, 85.3% within 5 years, and 89.9% in long-term follow-up. Eleven patients (7.0%) with persisting (partial) villous atrophy had symptoms and signs of malabsorption and were considered to have refractory celiac disease; 5 of them developed an enteropathy-associated T-cell lymphoma. Children recovered up to 95% within 2 years and 100% in the long-term. Histologic recovery in celiac disease after starting a gluten-free diet takes time and is incomplete or absent in a substantial subgroup of patients (10.1% villous atrophy after 5 years). Systematic follow-up of patients with celiac disease and the malabsorption syndrome and secondary complications is needed.
Article
The diagnosis of celiac disease requires characteristic histopathologic changes in an intestinal biopsy with clinical improvement in response to a gluten-free diet. Endoscopy with procurement of biopsy specimens is often performed to document response to the diet, but there are little data on the appearance of treated celiac disease. This study examined the endoscopic and histopathologic appearance of the duodenum of patients with celiac disease whose diet was gluten-free. A cohort of 39 adult patients (mean age 52 years, range 20-74 years) with biopsy-proven celiac disease was retrospectively reviewed. All had responded clinically to a gluten-free diet that they had maintained for a mean of 8.5 years (range 1-45 years). The endoscopic and histopathologic appearances of the duodenal mucosa were reviewed. Blinded review of the diagnostic (initial) and post-treatment biopsy specimens was also performed to assess response of individual patients to the diet. The endoscopic appearance was normal in 23%, reduced duodenal folds were present in 46%, scalloping of folds in 33%, mucosal fissures in 44%, and nodularity in 33%. There was more than 1 abnormality present in 46%. Histology was normal in only 21%. The remainder had villous atrophy (69% partial, 10% total). Paired (diagnostic and follow-up) biopsy specimens were reviewed blindly for 12 patients. The mean (SD) intraepithelial lymphocyte count fell from 61 (22) to 38 (17) (normal <30 per 100 epithelial cells) and the crypt-to-villous ratio improved although it did not normalize. Despite a good clinical response, abnormal endoscopic and histopathologic appearances persist in the majority of patients with celiac disease treated with a gluten-free diet.
Article
Coeliac disease is a genetically-determined chronic inflammatory intestinal disease induced by an environmental precipitant, gluten. Patients with the disease might have mainly non-gastrointestinal symptoms, and as a result patients present to various medical practitioners. Epidemiological studies have shown that coeliac disease is very common and affects about one in 250 people. The disease is associated with an increased rate of osteoporosis, infertility, autoimmune diseases, and malignant disease, especially lymphomas. The mechanism of the intestinal immune-mediated response is not completely clear, but involves an HLA-DQ2 or HLA-DQ8 restricted T-cell immune reaction in the lamina propria as well as an immune reaction in the intestinal epithelium. An important component of the disease is the intraepithelial lymphocyte that might become clonally expanded in refractory sprue and enteropathy-associated T-cell lymphoma. Study of the mechanism of the immune response in coeliac disease could provide insight into the mechanism of inflammatory and autoimmune responses and lead to innovations in treatment.
Article
In the mid 1980s the incidence of coeliac disease in Swedish children below 2 years of age increased threefold within a few years, and after a 10-year high incidence period returned equally rapidly to the previous level. Analysing the epidemic with respect to any change in female to male ratio over time, or shift in age at diagnosis, may increase the understanding of coeliac disease aetiology. In a population-based incidence study of childhood coeliac disease, 2151 cases (811 boys/1340 girls) were diagnosed from 1973 to 1997. Incidence rates and relative risks (RRs) were calculated by gender, age at diagnosis and calendar time. Cumulative incidences by age and gender were calculated for different birth cohorts. A twofold higher risk (RR: 1.9, 95% confidence interval (CI) 1.7-2.1) for coeliac disease in girls as compared to boys prevailed throughout the epidemic. Further, during the post-epidemic period there was an upward shift in age at diagnosis. So far, however, a majority of the cases diagnosed at older ages belong to birth cohorts of the epidemic period, i.e. cohorts that already had a high coeliac disease risk before 2 years of age. Our results suggest that girls as compared to boys may be genetically more vulnerable to environmental exposures influencing the immunological processes towards coeliac disease. Further, an increased risk for coeliac disease during the first years of life due to, for example, unfavourable infant dietary habits, may result in an increased total childhood risk for coeliac disease. A longer follow-up, even into adulthood, is needed to determine whether or not the lifetime risk has changed.