Persistent Villous Atrophy Research Articles

Phenotype and Treatment Options for Mesenteric Lymph Node Cavitating Syndrome in Coeliac Disease: A Case Series and Literature Review.

Background: There is a paucity of data on mesenteric lymph node cavitation syndrome (MLNCS), a rare condition associated with coeliac disease (CD), characterized by central necrosis within enlarged mesenteric lymph nodes. The largest case series of MLNCS was completed in 1984, (n = 6) and a poor prognosis was identified. Methods: A case series of all patients was conducted with MLNCS treated at the UK NHS England National Centre for Refractory Coeliac Disease between 2000 and 2023. A further literature review was conducted using PubMed and Google Scholar for patients with MLNCS and coeliac disease until 2023. Results: In total, there were 51 patients (6 from our case series and 45 from the literature review); 57% were female, and the mean age was 52.8 years (SD: 14.01 years). The most common presenting symptoms were weight loss (80%) and diarrhea (65%), and patients often had hyposplenism (80%). Persistent villous atrophy was present in 88% of the patients. Ten patients also had Refractory Coeliac Disease. Most of the patients (90%) were on a GFD, but the effect of this is unclear. Treatment with steroids and immunosuppressants resulted in a 40% survival rate. The overall mortality was 43%, associated with cachexia, sepsis, infectious complications, and lymphoma. Conclusions: MLNCS has a poor prognosis, and its diagnosis should prompt further intervention and careful follow-up. Patients commonly present with weight loss and hyposplenism should prompt further investigation. Current treatment options are inadequate and novel therapies are required.

Role of capsule endoscopy and double-balloon enteroscopy in the management of adult patients with coeliac disease and persisting symptoms

BackgroundSmall bowel capsule endoscopy (CE) and double-balloon enteroscopy (DBE) are recommended for the management of patients with nonresponsive or refractory coeliac disease (CD). However, there is a paucity of data regarding the clinical profiles and outcomes of patients undergoing these investigations. MethodsWe conducted a retrospective analysis of two databases of adult patients with CD who underwent CE and/or DBE between 2017 and 2022 at the National Centre for Refractory CD in England. Patient demographic, clinical and endoscopic data were collected, and clinically relevant outcomes were reported. ResultsA total of 132 patients (median age 53 years, 64.4 % female) underwent 146 CEs and 25 DBEs. The most common symptoms were diarrhoea (51.5 %), abdominal pain (37.8 %), bloating (34.8 %), and weight loss (29.5 %). The overall detection rate of CE and DBE was 87.6 % and 92 %, respectively. Following CE and DBE, 14 patients (10.6 %) were diagnosed with CD-related complications such as ulcerative jejunitis, strictures and malignancy. Seven patients (5.3 %) died during follow-up, with five of these deaths directly attributed to CD. Older age, weight loss and anaemia were associated with poor outcomes. ConclusionsThe sequential approach of CE and DBE identified CD-related complications in almost 1 in 10 patients with nonresponsive or refractory CD. Older patients with persistent villous atrophy, weight loss and anaemia require close monitoring to help with the early diagnosis and management of complications.

Coeliac disease and type 2 diabetes risk: a nationwide matched cohort and Mendelian randomisation study

Aims/hypothesisWhile the association between coeliac disease and type 1 diabetes is well documented, the association of coeliac disease with type 2 diabetes risk remains undetermined. We conducted a nationwide cohort and Mendelian randomisation analysis to investigate this link.MethodsThis nationwide matched cohort used data from the Swedish ESPRESSO cohort including 46,150 individuals with coeliac disease and 219,763 matched individuals in the comparator group selected from the general population, followed up from 1969 to 2021. Data from 9053 individuals with coeliac disease who underwent a second biopsy were used to examine the association between persistent villous atrophy and type 2 diabetes. Multivariable Cox regression was employed to estimate the associations. In Mendelian randomisation analysis, 37 independent genetic variants associated with clinically diagnosed coeliac disease at p<5×10−8 were used to proxy genetic liability to coeliac disease. Summary-level data for type 2 diabetes were obtained from the DIAGRAM consortium (80,154 cases) and the FinnGen study (42,593 cases).ResultsOver a median 15.7 years’ follow-up, there were 6132 (13.3%) and 30,138 (13.7%) incident cases of type 2 diabetes in people with coeliac disease and comparator individuals, respectively. Those with coeliac disease were not at increased risk of incident type 2 diabetes with an HR of 1.00 (95% CI 0.97, 1.03) compared with comparator individuals. Persistent villous atrophy was not associated with an increased risk of type 2 diabetes compared with mucosal healing among participants with coeliac disease (HR 1.02, 95% CI 0.90, 1.16). Genetic liability to coeliac disease was not associated with type 2 diabetes in DIAGRAM (OR 1.01, 95% CI 0.99, 1.03) or in FinnGen (OR 1.01, 95% CI 0.99–1.04).Conclusions/interpretationCoeliac disease was not associated with type 2 diabetes risk.Graphical

Emerging Pharmaceutical Therapies to Address the Inadequacy of a Gluten-Free Diet for Celiac Disease.

Celiac disease (CeD) is a chronic autoimmune disorder triggered by the ingestion of gluten, affecting around 1% of the global population. It is a multifactorial disease involving both genetics and environmental factors. Nowadays, the only available treatment for CeD is a life-long gluten-free diet (GFD), which can cause a significant burden for patients, since symptoms and mucosal injury can persist despite apparent compliance with a GFD. This could also lead to psychological consequences and affect the quality of life of these patients. Thankfully, recent advances in understanding the pathogenesis of CeD and the availability of various targets have made it feasible to explore pharmaceutical treatments specific to CeD. Recently, the FDA has highlighted the unmet needs of adult patients on a GFD who experience ongoing symptoms attributed to CeD and also show persistent duodenal villous atrophy. This review will outline the limitations of a GFD, describe the targets of potential novel treatment of CeD and provide an overview of the primary clinical trials involving oral and injectable agents for a non-dietary treatment of CeD.

Serological Investigation of Persistent Villous Atrophy in Celiac Disease.

Persistent villous atrophy (VA) is not uncommon in celiac disease (CeD) while patients take a gluten-free diet (GFD). We conducted a retrospective study with 122 serum samples collected from controls and patients with CeD either at the initial diagnosis or at the follow-up during endoscopy. These samples were assigned to 3 groups: nonceliac control, non-VA CeD (Marsh score 0-2), and VA CeD (Marsh score 3a-3c). We established an in-house multiplex assay to identify potential serological biomarkers for VA. We assessed autoantibodies reported to affect the small intestine, including IgA and IgG antibodies against tissue transglutaminase (tTG), interferons, villin, actin, autoimmune enteropathy-related 75 kDa antigen (AIE-75), and tryptophan hydroxylase (TPH)-1, as well as 27 cytokines. The apolipoproteins quantified included apo A1, apo B-100, and apo A4, which were produced predominantly by the intestinal epithelium or expressed specifically in villi. Autoantibody levels were high only for tTG antibodies, which performed well in initial CeD diagnosis, but suboptimally for VA prediction during follow-up, because 14.6% of the follow-up patients with VA had low tTG-IgA. Increasing dilution improved tTG-IgA quantification, particularly when the antibody levels were extremely high but did not significantly improve VA detection. Among those with low tTG-IgA and persistent VA, high proinflammatory cytokines were observed in 2 patients. Median low-density lipoprotein cholesterol levels were significantly lower in the VA CeD group ( P = 0.03). Apolipoprotein levels were similar in patients with and without VA but diverged between those on a GFD or not. tTG-IgA as a biomarker is suboptimal for VA prediction while on a GFD. Persistent VA is associated with low low-density lipoprotein cholesterol levels and partially related to persistent high proinflammatory cytokines.

Old and New Adjunctive Therapies in Celiac Disease and Refractory Celiac Disease: A Review.

Celiac disease (CD) is a chronic enteropathy caused by the ingestion of gluten in a genetically susceptible individual. Currently, a gluten-free diet (GFD) is the only recommended treatment. However, unintentional gluten ingestion or a persistent villous atrophy with malabsorption (regardless of a strict GFD) as in the case of Refractory Celiac Disease (RCD) represents a major issue. In this review, we have analysed and discussed data from both randomized controlled trials and observational studies concerning adjunctive therapies as well as novel therapies for the treatment of CD and RCD. The literature search was carried out through Medline and Scopus. In total, 2268 articles have been identified and 49 were included in this review (36 studies resulting from the search strategy and 13 from other sources). Today, GFD remains the only effective treatment, although steroids, mesalamine, and more recently biological therapies have found space in the complex management of RCD. Currently, studies evaluating the effectiveness of novel therapies are still limited and preliminary results have been controversial.

Persistent villous atrophy predicts development of complications and mortality in adult patients with coeliac disease: a multicentre longitudinal cohort study and development of a score to identify high-risk patients

ObjectivePersistent 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)...

Predictors of slow responsiveness and partial mucosal recovery in adult patients with celiac disease.

The present study aims to determine the rate of mucosal recovery and predictors of persistent mucosal damage after gluten free diet (GFD). Celiac disease (CD) is a complex multi-systemic autoimmune disease triggered by exposure to dietary gluten in genetically predisposed individuals. There is still little evidence on the best method for assessing GFD adherence and mucosal recovery during treatment. The retrospective study included only adult patients (age≥18 years old), with biopsy-proven CD evaluated at a tertiary referral centre between 2016 and 2021. We performed a logistic regression analysis to identify factors associated with partial mucosal recovery (MR) after GFD. We included in the multivariate analysis parameters available at the time of CD diagnosis. A total of 102 patients were enrolled, two thirds were females, median age of 39 years (yrs). The initial biopsy analysis showed different stages of villous atrophy (VA) in 79 (77.4%) cases, while in 23(22.5%) cases showed mild enteropathy (Marsh 1, 2). After at least 12 months of GFD, 26 (25.5%) patients had persistent VA despite good or excellent adherence to GFD. Younger patients (< 35yrs), who showed severe mucosal damage (Marsh 3c lesions) and who had increased anti-gliadin antibody (AGA) levels were at risk for failure to obtain mucosal recovery (MR). Logistic regression analysis demonstrated that complete mucosal atrophy (P=0.007) and high AGA antibody levels (cutoff 129 U/ml, P=0.001) were independent risk factors for lack of mucosal improvement after at least 12 months of GFD. Interestingly, genotype, tTG-IgA antibody levels, or duration of GFD levels did not influence the occurrence of MR. Although AGA seropositivity has lost much of their diagnostic significance in recent years due to the introduction of the more sensitive and specific antibody tests, our study reported that patients aged < 35 yrs, who showed severe mucosal damage (Marsh 3c lesions) and who had increased AGA antibody levels at diagnosis were at risk for failure to obtain MR. The elevated AGA levels at diagnosis could be used as a prognostic tool for assessing MR.

Review article: Follow-up of coeliac disease.

SummaryCoeliac 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.

Serum transglutaminase antibodies do not always detect the persistent villous atrophy in patients with celiac disease on a gluten-free diet.

Serum transglutaminase antibodies (tTGs) are used for celiac disease screening and to monitor celiac disease patients on a gluten-free diet (GFD). The need for histology of duodenal biopsies to assess mucosal healing after a GFD is still a matter of debate. We evaluated whether tTGs are adequate to detect the persistence of histological lesions of duodenal mucosa in celiac patients after a GFD. In total 253 patients with histological diagnosis of celiac disease according to Marsh criteria, both at the time of diagnosis (T0) and 18-24 months after starting a GFD (T2), were included. tTGs were evaluated both at T0 and T2; endomysial antibodies (EMAs) only at T0. At T0, 9.2% of patients had both tTG and EMA negative values, despite the evidence of duodenal lesions: 33.3% of Marsh 1, 14.3% of Marsh 2 and 5.2% of Marsh 3. At T2, tTGs were negative in 77.6% of patients: 82.2% of Marsh 0, 79.8% of Marsh 1, 70.0% of Marsh 2 and 59.1% of Marsh 3. At T2, approximately 60% of patients with the persistence of mucosal atrophy had negative tTGs. At T0, tTG median values were lower in patients with Marsh 1 and Marsh 2 than patients with Marsh 3 (P < 0.001), whereas no difference was found at T2 regardless of Marsh's grade (P = 0.4). The results of our study highlight how histologic evaluation of duodenal biopsies remains the gold standard for both celiac disease diagnosis and the evaluation of mucosal recovery after 18-24 months of a GFD.

What is the Optimal Method Assessing for Persistent Villous Atrophy in Adult Coeliac Disease?

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. 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. 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. 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.

Persistent Villous Atrophy in De Novo Adult Patients With Celiac Disease and Strict Control of Gluten-Free Diet Adherence: A Multicenter Prospective Study (CADER Study).

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. 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. 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). 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.

Evaluation of crypt apoptotic bodies and apoptotic indices in pediatric celiac disease by routine staining and H2AX immunostaining.

Celiac disease (CD) is an immune-mediated disorder with premature apoptosis occurring along the entire crypt-villous axis. H2AX is the end product of the intrinsic apoptotic pathway. This is the first study to assess apoptotic body counts (ABC) by H&E and apoptotic indices (AI) by immunohistochemistry (IHC) in pediatric CD. The aim of the current study was to evaluate ABC in pediatric patients with CD prior to and following institution of a gluten free diet (GFD). Sixty-three pediatric endoscopic duodenal samples were assessed and divided into three groups. A total of 21 samples from treatment naïve CD patients, 21 from the same patients after instituting a GFD, and 21 from non-celiac patients as a control group. Histopathological evaluation of ABC by H&E, and immunohistochemistry assessment of apoptotic indices (AI) by H2AX antibody were performed. The mean maximum ABC and AI were significantly higher in treatment naïve CD than in GFD and control samples. These values were also significantly higher in treatment naïve Marsh 3C (flat) than in Marsh 1, 2, 3A, and 3B (non-flat) CD cases. GFD samples with persistent flat lesions had significantly higher ABC and AI than GFD non-flat cases. ROC analysis of the mean maximum ABC and AI of treatment naïve CD cases had a statistically significant predictive potential for persistent villous atrophy at a cut-off level ⩾6.61 (P = 0.008) and ⩾105.4 (P = 0.003), respectively. Histopathological evaluation of crypt apoptotic bodies could provide predictive potential for continued villous atrophy following GFD.

Non-invasive prediction of persistent villous atrophy in celiac disease.

BACKGROUNDCeliac disease (CD) is an immune-mediated enteropathy that is primarily treated with a gluten-free diet (GFD). Mucosal healing is the main target of the therapy. Currently, duodenal biopsy is the only way to evaluate mucosal healing, and non-invasive markers are challenging. Persistent elevation of anti-tissue transglutaminase antibodies (aTTG) is not an ideal predictor of persistent villous atrophy (VA). Data regarding prediction of atrophy using anti-deamidated gliadin peptide antibodies (aDGP) and abdominal ultrasonography are lacking.AIMTo evaluate the ability of aTTG, aDGP, small bowel ultrasonography, and clinical and laboratory parameters in predicting persistent VA determined using histology.METHODSPatients with CD at least 1 year on a GFD and available follow-up duodenal biopsy, levels of aTTG and aDGP, and underwent small bowel ultrasonography were included in this retrospective cohort study. We evaluated the sensitivity, specificity, and positive and negative predictive values of aTTG, aDGP, small bowel ultrasonography, laboratory and clinical parameters to predict persistent VA. A receiver operating characteristic (ROC) curve analysis of antibody levels was used to calculate cut off values with the highest accuracy for atrophy prediction.RESULTSComplete data were available for 82 patients who were followed up over a period of four years (2014-2018). Among patients included in the analysis, women (67, 81.7%) were predominant and the mean age at diagnosis was 33.8 years. Follow-up biopsy revealed persistent VA in 19 patients (23.2%). The sensitivity and specificity of aTTG using the manufacturer’s diagnostic cutoff value to predict atrophy was 50% and 85.7%, respectively, while the sensitivity and specificity of aDGP (using the diagnostic cutoff value) was 77.8% and 75%, respectively. Calculation of an optimal cutoff value using ROC analysis (13.4 U/mL for aTTG IgA and 22.6 U/mL for aDGP IgA) increased the accuracy and reached 72.2% [95% confidence interval (CI): 46.5-90.3] sensitivity and 90% (95%CI: 79.5-96.2) specificity for aDGP IgA and 66.7% (95%CI: 41.0-86.7) sensitivity and 93.7% (95%CI: 84.5-98.2) specificity for aTTG IgA. The sensitivity and specificity of small bowel ultrasonography was 64.7% and 73.5%, respectively. A combination of serology with ultrasound imaging to predict persistent atrophy increased the positive predictive value and specificity to 88.9% and 98% for aTTG IgA and to 90.0% and 97.8% for aDGP IgA. Laboratory and clinical parameters had poor predictive values.CONCLUSIONThe sensitivity, specificity, and negative predictive value of aTTG and aDGP for predicting persistent VA improved by calculating the best cutoff values. The combination of serology and experienced bowel ultrasound examination may achieve better accuracy for the detection of atrophy.

Can individuals with celiac disease identify gluten-free foods correctly?

Patients with celiac disease (CD) often report inadvertent gluten exposures and challenges reading labels. The most common cause of non-responsive CD is gluten exposure. We aimed to assess whether recently diagnosed CD patients can determine whether a food is gluten-free based on labeling, and to assess skills over time. A secondary aim was to identify factors associated with label reading proficiency. Inception cohort with follow-up at 6, 12, and 24 months after diagnosis. Participants were asked to determine whether 25 food items were gluten-free based on labeling information. Diet adherence was assessed using the Celiac Diet Assessment Tool (CDAT) and the Gluten-Free Eating Assessment Tool (GF-EAT). 144 adults with newly diagnosed celiac disease were enrolled. The initial quiz at 6 months was completed by 83%. Quizzes were completed by 72% at 12 months and 70% at 24 months. Median overall accuracy scores were: 23/25, 24/25 and 21/25at 6, 12 and 24 months respectively. Gluten-free products with explicit "gluten-free" claims had the fewest errors. Quiz scores were not correlated with tTG IgA levels, or CDAT or GF-EAT scores. Diet adherence was generally good (>85% with CDAT <13 suggesting adequate GFD adherence); however, at 24 months, only 11% reported no gluten exposure. CD patients may be unable to consistently choose gluten-free foods based on product labeling. Explicit identification of gluten-free products may be helpful. Label reading ability appears stable over time. Further studies are needed to evaluate whether erroneous label reading or misleading labels are associated with persistent villous atrophy.

A Call for Research on the Prognostic Role of Follow-Up Histology in Celiac Disease: A Systematic Review

Background: Convincing evidence is lacking on the benefit of follow-up biopsy in celiac disease. Regardless, achieving mucosal recovery (MR) has remained a desirable goal of therapy. We aimed to conduct a systematic review to determine whether MR is a protective factor and persisting villous atrophy (PVA) has negative consequences on long-term outcomes of celiac disease.Methods: Seven databases were searched for articles discussing celiac patients subjected to a gluten-free diet who had a follow-up biopsy, and clinical and laboratory characteristics were reported by follow-up histology (MR vs. PVA). Outcomes included clinical symptoms, mortality, malignant tumors, nutritional parameters, and metabolic bone disease. Comparative and descriptive studies were included. Since data proved to be ineligible for meta-analysis, the evidence was synthesized in a systematic review.Results: Altogether, 31 studies were eligible for systematic review. Persisting symptoms were more frequently associated with PVA than with MR, although a lot of symptom-free patients had PVA and a lot of symptomatic patients achieved MR. PVA might be a risk factor of lymphomas, but mortality and the overall rate of malignant tumors seemed independent of follow-up histology. Patients with PVA tended to develop metabolic bone disease more often, although fracture risk remained similar in the groups except in hip fractures of which PVA was a risk factor. Reports on nutritional markers are only anecdotal.Conclusions: The limited evidence calls for high-quality prospective cohort studies to be arranged to clarify the exact role of follow-up histology in celiac disease.

2640 Intractable Celiac Disease in IgA Deficiency

INTRODUCTION: Celiac disease is an immune-mediated disorder triggered by a reaction to gluten with elevated levels of IgA antibodies. Symptoms typically resolve with a gluten free diet. However, refractory cases have been reported despite dietary adherence. Our discussion involves an elderly woman with severe, refractory celiac disease with concomitant IgA deficiency. CASE DESCRIPTION/METHODS: An 80-year-old woman presented our clinic with exacerbation of chronic, non-bloody diarrhea. She has a history of celiac disease diagnosed 20 years ago after an episode of acute pancreatitis. She also has IgA deficiency and her total IgA level remains low at 37, despite infusions 3 times per week. She is strictly adherent to a gluten free diet, but continues to have multiple episodes of diarrhea and has lost over 100 pounds since her diagnosis. Patient had bidirectional endoscopy notable for antral gastropathy as well as fissures and flattening of the duodenal mucosa. Biopsies were consistent with celiac sprue. Capsule endoscopy showed diffuse flattening of the small bowel villi with erythema and cracked, scalloped mucosa as well as multiple, small, aphthous ulcers throughout the bowel (Figures 1, 2, and 3). Patient has had an extensive workup, but everything else have been unrevealing. Steroids have been initiated as a last-ditch effort, but she continues to have “more bad days than good days” despite being on a high dose prednisone. DISCUSSION: The diagnosis and treatment of celiac disease can be complicated by coexisting immunodeficiencies. Usually, titers of tissue transglutaminase IgA will be elevated and are involved in the immune reaction that causes damage to the lining of the small bowel with characteristic flattening of the villi as well as chronic diarrhea and malabsorption. A connection between IgA deficiency and celiac disease has been well established and likely contributes to the refractory nature of our patient’s disease. In patients with IgA deficiency it is important to utilize other forms of serologic testing, typically with IgG tissue transglutaminase, in addition to duodenal biopsies. Symptoms typically resolve with a gluten free diet. However, refractory cases have been reported with persistent diarrhea and villous atrophy for over 1–2 years. Symptom management can be difficult for these patients and may require the use of steroids as the last resource.

Anxiety after coeliac disease diagnosis predicts mucosal healing: a population‐based study

Coeliac disease has been linked to anxiety and depression. However, their association with mucosal healing is unknown. To examine the relationship between anxiety, depression and mucosal healing in coeliac disease. Between 1969 and 2008, we collected data on all small intestinal biopsies with villous atrophy from Sweden's 28 pathology departments. We restricted our cohort to individuals with data on follow-up biopsy (either persistent villous atrophy [n=3317] or mucosal healing [n=4331]). Through Cox regression, we estimated hazard ratios (HRs) for anxiety or depression. During follow-up, 123 (2.8/1000 person-years) individuals with mucosal healing had developed anxiety, compared to 94 (2.1/1000 person-years) with persistent villous atrophy. Mucosal healing was hence associated with a higher risk of future anxiety (HR=1.49; 95% CI=1.12-1.96). Similarly, 167 (3.8/1000 person-years) individuals with mucosal healing developed depression, compared to 148 (3.3/1000 person-years) with persistent villous atrophy, corresponding to a HR of 1.25 (95% CI=0.99-1.59). Mucosal healing was more common in individuals with prior diagnoses of anxiety or depression before follow-up biopsy. Anxiety diagnosed between diagnostic and follow-up biopsy for coeliac disease was associated with an almost nine-fold increased chance of mucosal healing (odds ratio=8.94; 95%CI=2.03-39.27). Anxiety and depression are more common in coeliac disease patients with mucosal healing, both before and after follow-up biopsy, an association potentially mediated through more vigilant compliance with a gluten-free diet. This finding raises concern that achieving the goal of mucosal healing may come at a cost of an increased risk of mood disorders.

Persistent mucosal damage and risk of epilepsy in people with celiac disease.

Celiac disease (CD) is associated with an increased risk of developing epilepsy, a risk that persists after CD diagnosis. A significant proportion of patients with CD have persistent villous atrophy (VA) on follow-up biopsy. The objective of this study was to determine whether persistent VA on follow-up biopsy affected long-term epilepsy risk and epilepsy-related hospital emergency admissions. This was a nationwide cohort study. We identified all people in Sweden with histological evidence of CD who underwent a follow-up small intestinal biopsy (1969-2008). We compared those with persistent VA with those who showed histological improvement, assessing the development of epilepsy and related emergency hospital admissions (defined according to relevant International Classification of Diseases codes in the Swedish Patient Register). Cox regression analysis was used to assess outcome measures. Villous atrophy was present in 43% of 7590 people with CD who had a follow-up biopsy. The presence of persistent VA was significantly associated with a reduced risk of developing newly-diagnosed epilepsy (hazard ratio, 0.61; 95% confidence interval, 0.38-0.98). On stratified analysis, this effect was primarily amongst males (hazard ratio, 0.35; 95% confidence interval, 0.15-0.80). Among the 58 patients with CD with a prior diagnosis of epilepsy, those with persistent VA were less likely to visit an emergency department with epilepsy (hazard ratio, 0.37; 95% confidence interval, 0.09-1.09). In a population-based study of individuals with CD, persisting VA on follow-up biopsy was associated with reduced future risk of developing epilepsy but did not influence emergency epilepsy-related hospital admissions. The mechanism as to why persistent VA confers this benefit requires further exploration.

Indications and Use of the Gluten Contamination Elimination Diet for Patients with Non-Responsive Celiac Disease.

For the majority of patients diagnosed with celiac disease, once a gluten-free diet is initiated, symptoms improve within weeks and may completely resolve in months. However, up to 30% of patients may show signs, symptoms or persistent small intestinal damage after one year on a gluten-free diet. These patients require evaluation for other common GI etiologies and assessment of their celiac disease status in order to make a diagnosis and suggest treatment. Here, we propose an approach to evaluating patients with celiac disease with persistent symptoms, persistently elevated serology, and or persistent villous atrophy despite a gluten-free diet. We detail how to diagnose and distinguish between non-responsive and refractory celiac disease. Finally, we introduce the indications for use of the gluten contamination elimination diet and provide information for practitioners to implement the diet when necessary in their practice.