Celiac Disease Affects 1% of Global Population: Who Will Manage All These Patients?

Celiac disease is a common gastrointestinal condition with an estimated global prevalence of up to 1%. Adequate long-term surveillance of patients is imperative to ensure strict adherence to treatment with a gluten-free diet and the ensuing clinical and histologic recovery. Traditionally, this has been accomplished by means of regular on-site attendance at specialist health care facilities, accompanied for most patients by follow-up endoscopic and laboratory tests. However, the rapidly increasing prevalence of celiac disease and the limited health care resources challenge the current centralized and nonindividualized follow-up strategies. The improved noninvasive surveillance tools and online health care services are further changing the landscape of celiac disease management. There is a clear need for more personalized and on-demand follow-up based on early treatment response and patient-related factors associated with long-term prognosis. Additional scientific evidence on the optimal implementation of follow-up for pediatric and adulthood celiac disease is nevertheless called for.

Measured levels of positive transglutaminase 2 antibodies are not associated with presentation or incidental endoscopic findings at celiac disease diagnosis.

OBJECTIVES: It has been suggested that celiac disease could be diagnosed non-invasively in adults with transglutaminase antibody (TGA) levels >10x upper limit of normal (ULN). It is, however, unclear if high values signify more advanced disease and higher risk of co-morbidities. We investigated the association between the TGA levels, clinical characteristics and non-celiac endoscopic findings. METHODS: Medical data on 450 celiac disease patients at diagnosis were collected. They were further divided into those with high positive (>10x ULN, n = 164), moderately positive (1-10x ULN, n = 219), and negative (n = 67) TGA. RESULTS: Median age of patients was 50 years and 60% were women. Patients with negative TGA were older (median age 58 vs. 51 vs. 46 years respectively, p = 0.002) and had more often weight loss (27% vs. 10% vs. 9%, p < 0.001) and abdominal pain or dyspepsia (40% vs 27% vs. 22%, p = 0.017) than did those with moderately positive/high TGA. The groups did not differ in sex, BMI, or other symptoms. Major endoscopic findings included one esophageal adenocarcinoma presenting with dysphagia, six esophagitis, three gastric ulcers, and 39 H. Pylori or other active gastritis. High, moderately positive or negative TGA levels were not associated with these findings in crude or age-adjusted analyses. CONCLUSIONS: Presentation was similar in patients with moderate or high levels of TGA, whereas patients with negative TGA were different. The level of TGA was not associated with incidental endoscopic findings and the only malignancy presented with an alarm symptom atypical to celiac disease.

Patient-reported burden of skin disorders in coeliac disease.

OBJECTIVES: The current knowledge on the associations between coeliac disease and different skin diseases is contradictory and the patient's perspective on the burden of these is lacking. This study aimed to investigate patient-reported frequency, severity and quality of life effects of skin disorders in coeliac disease patients compared to controls and moreover to study the impacts of gluten-free diet on these skin diseases. MATERIALS AND METHODS: A study questionnaire designed for the purposes of this study and a validated Dermatology Life Quality Index (DLQI) questionnaire were posted to 600 adult members of the Finnish Coeliac Society and 1173 matched controls. Responses from 327 coeliac disease patients and 382 non-coeliac controls were compared. RESULTS: Coeliac disease patients were shown to be at no increased risk of atopic dermatitis, acne, rosacea, psoriasis, alopecia areata, vitiligo or chronic urticaria. The severity of these skin diseases did not differ between study groups, but the risk for at least moderate effects on quality of life caused by dermatological diseases was increased among those with coeliac disease. Positive response from gluten-free diet was most commonly experienced by coeliac disease patients with atopic dermatitis. CONCLUSIONS: Even though the risk for skin diseases was shown not to be increased among coeliac disease patients, there is still an increased burden related to experienced skin symptoms among these patients, which non-dermatologists treating coeliac disease patients should acknowledge.

Prevalence of vomiting and nausea and associated factors after chronic and acute gluten exposure in celiac disease.

BACKGROUND: Vomiting and nausea seem to be relatively specific symptoms related to gluten ingestion in treated celiac disease. However, the overall prevalence and associated factors of these symptoms after chronic gluten exposure at celiac disease diagnosis and acute re-exposure during gluten challenge remain obscure. METHODS: Medical data on 815 adult celiac disease patients were collected at diagnosis from the medical records and through supplementary interviews. An additional 74 patients underwent a three-day (10 g/day) gluten challenge (wheat, barley, rye or a combination of the three grains) while in remission. Prevalence of vomiting/nausea and associated factors were evaluated in both cohorts. A literature review was conducted to summarize earlier studies. RESULTS: Twenty-eight (3%) patients presented with vomiting at diagnosis. They were less often screen-detected and suffered from extra-intestinal symptoms, and had more often abdominal pain (71% vs. 49%, p = 0.021), diarrhea (61% vs. 40%, p = 0.031), weight loss (36% vs. 17%, p = 0.019) and childhood symptoms (61% vs. 33%, p = 0.002) than those without vomiting (n = 787). The groups were comparable in other clinical-demographic data and in genetic, serological, and histological findings. Short-term gluten challenge provoked vomiting/nausea in 14/74 (19%) patients. They consumed gluten-free oats less often than those without these symptoms (64% vs. 92%, p = 0.017), whereas the groups did not differ in clinical-demographic features at diagnosis, presence of comorbidities, duration of gluten-free diet, or in other symptoms or grain used ingested during the challenge. According to the literature, prevalence of vomiting/nausea at celiac disease diagnosis has varied 3-46% and during gluten challenge 13-61%. CONCLUSIONS: In chronic gluten exposure at celiac disease diagnosis, vomiting was associated with other gastrointestinal symptoms and onset of symptoms already in childhood, whereas regular consumption of oats may increase the tolerance against vomiting/nausea after acute re-exposure in treated celiac disease.

Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus.

OBJECTIVE: Differential diagnosis of villous atrophy (VA) without coeliac antibodies in adults includes seronegative coeliac disease (CD) and chronic enteropathies unrelated to gluten, ie. non-coeliac enteropathies (NCEs). There is currently no international consensus on the nomenclature and diagnostic criteria for these enteropathies. In this work, a Delphi process was conducted to address this diagnostic and clinical uncertainty. DESIGN: An international task force of 13 gastroenterologists from six countries was recruited at the 16th International Coeliac Disease Symposium, Paris, 2019. Between September 2019 and July 2021, a Delphi process was conducted through mail surveys to reach a consensus on which conditions to consider in the differential diagnosis of VA with negative coeliac serology and the clinical diagnostic approaches required for these conditions. A 70% agreement threshold was adopted. RESULTS: Chronic enteropathies characterised by VA and negative coeliac serology can be attributed to two main clinical scenarios: forms of CD presenting with negative serology, which also include seronegative CD and CD associated with IgA deficiency, and NCEs, with the latter recognising different underlying aetiologies. A consensus was reached on the diagnostic criteria for NCEs assisting clinicians in differentiating NCEs from seronegative CD. Although in adults seronegative CD is the most common aetiology in patients with VA and negative serology, discriminating between seronegative CD and NCEs is key to avoid unnecessary lifelong gluten-free diet, treat disease-specific morbidity and contrast poor long-term outcomes. CONCLUSION: This paper describes the Paris consensus on the definitions and diagnostic criteria for seronegative CD and chronic NCEs in adults.

Significance of low ferritin without anaemia in screen-detected, adult coeliac disease patients.

BACKGROUND: Low ferritin without anaemia has been linked to adverse health effects. OBJECTIVES: To investigate the prevalence and clinical significance of low ferritin in screen-detected coeliac disease. METHODS: Seventy-six screen-detected coeliac disease patients were enrolled in the prospective collection of comprehensive clinical, laboratory and histological data at diagnosis and after 1-2 years on a gluten-free diet (GFD). All variables were compared between patients with different ferritin levels. RESULTS: At coeliac disease diagnosis, six patients had anaemia. Of the 70 nonanaemic patients, ferritin levels were <15 µg/L in 21%, 15-29 µg/L in 19%, 30-99 µg/L in 36% and ≥100 µg/L in 24%. Those with lower ferritin were more often females, had lower body mass index, haemoglobin and villous height-crypt depth ratio and also had higher intra-epithelial lymphocyte CD3+ levels in duodenal biopsies. The groups did not differ in neurological or gastrointestinal symptoms, health-related quality of life, bone mineral density, liver values, vitamin, albumin or coeliac autoantibody levels or the prevalence of comorbidities. Median ferritin levels increased from 41.5 µg/L to 86.0 µg/L on GFD (p < 0.001). Ferritin remained <30 µg/L in 21% of patients but was not associated with dietary compliance, nor was any correlation between changes in ferritin and quality of life, gastrointestinal symptoms, autoantibody levels or degree of histological damage detected. CONCLUSION: Decreased ferritin is a frequent finding in screen-detected coeliac disease and may not be fully restored on a GFD. However, low ferritin levels are not associated with more severe symptoms or poorer quality of life.

The risk of renal comorbidities in celiac disease patients depends on the phenotype of celiac disease.

BACKGROUND: An increased risk of kidney disease in patients with celiac disease has been reported, but the association has remained obscure. Only few studies have investigated the association between renal comorbidities and dermatitis herpetiformis, a cutaneous manifestation of celiac disease. OBJECTIVES: We investigated whether patients with different phenotypes of celiac disease are at higher risk of kidney diseases than age- and sex-matched references. METHODS: The diagnoses of glomerulonephritis, diabetic nephropathy, interstitial nephritis, and end-stage renal disease obtained from the National Hospital Discharge Register between 1970 and 2015 were identified in celiac disease (Marsh III, n = 1072) and dermatitis herpetiformis (n = 368) patients diagnosed at Tampere University Hospital catchment region and in 4296 reference subjects. Using the Cox proportional hazards model, we compared the risk of kidney diseases between patients and references. The study protocol was approved by the Regional Ethics Committee of Tampere University Hospital (R16090). As the study was register based, no consent from patients was required. RESULTS: Even after adjusting for type 1 diabetes, celiac disease was associated with an elevated risk of kidney disease (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.12-3.03), glomerulonephritis (HR 3.37, 95% CI 1.64-6.95), and IgA nephropathy (IgAN) (HR 18.98, 95% CI 2.29-157.63). No similarly elevated risk was found among dermatitis herpetiformis patients (HR 1.50, 95% CI 0.63-3.55; HR 2.21, 95% CI 0.77-6.38; and HR 5.87, 95% CI 0.53-64.79, respectively). CONCLUSION: Celiac disease patients were at increased risk of kidney diseases, notably IgAN. The risk was dependent on the celiac disease phenotype and was not seen in patients with dermatitis herpetiformis. Awareness of possible renal manifestations is recommended when treating celiac disease patients.

Sex-differences in Gluten-free Dietary Adherence and Clinical Symptoms in Patients with Long-term Treated Dermatitis Herpetiformis.

Dermatitis herpetiformis is a blistering autoimmune skin disease, and a cutaneous manifestation of coeliac disease. The burden of coeliac disease is increased especially in females, but studies concerning sex differences in patients with long-term treated dermatitis herpetiformis are scarce. This questionnaire study compared adherence to a gluten-free diet, clinical symptoms and well-being between females and males in a cohort of 237 long-term treated (median 24 years) patients with dermatitis herpetiformis. Females had better adherence to a gluten-free diet (p = 0.022) and they used dapsone significantly less often at the time of the study than did males (4% vs 13%, p = 0.017). The occurrence of skin symptoms was equal in both sexes, but dermatological quality of life was lower in females (p = 0.024), and gastrointestinal symptoms were more severe among females with dermatitis herpetiformis than among males (p = 0.027). In conclusion, long-term treated female patients with dermatitis herpetiformis have better adherence to a gluten-free diet, but they also experience more severe clinical symptoms compared with males.

Presence of gastrointestinal symptoms in IgA nephropathy: a cross-sectional study.

BACKGROUND: Gastrointestinal (GI) symptoms are common in end-stage kidney disease. Mounting evidence indicates that the intestine plays an important role in the pathogenesis of IgA nephropathy (IgAN). However, no studies have addressed the obvious question; do IgAN patients suffer from GI symptoms? METHODS: Presence of GI symptoms and health-related quality of life were evaluated using the validated Gastrointestinal Symptom Rating Scale (GSRS) and Psychological General Well-Being (PGWB) questionnaires in 104 patients with kidney biopsy-verified IgAN and in 147 healthy controls. A person was regarded to experience 'increased GI symptoms' if the GSRS score exceeded plus 1 standard deviation of the mean of the corresponding score in the healthy controls. RESULTS: According to the GSRS total score, the IgAN patients had more GI symptoms than the healthy controls (2.0 vs. 1.7, p < 0.001). Female IgAN patients had higher GSRS total score than male patients (2.2 vs. 1.7, p = 0.001). More IgAN patients with preserved kidney function (eGFR > 60ml/min/1.73m2) suffered from increased symptoms of diarrhoea (76 vs. 25%, p = 0.028), constipation (81 vs. 19%, p = 0.046) and reflux (85 vs. 15%, p = 0.004) than did IgAN patients with reduced kidney function (eGFR < 60ml/min/1.73m2). CONCLUSIONS: IgAN patients and especially female IgAN patients experienced more GI symptoms than healthy controls. More prevalent GI symptoms were already observed before kidney function was clearly reduced. Systematic enquiry of GI symptoms might increase the standard of care among IgAN patients. Moreover, GI symptoms may provide clues for future studies that examine the pathophysiology of IgAN.

Toward Xeno-Free Differentiation of Human Induced Pluripotent Stem Cell-Derived Small Intestinal Epithelial Cells.

The small intestinal epithelium has an important role in nutrition, but also in drug absorption and metabolism. There are a few two-dimensional (2D) patient-derived induced pluripotent stem cell (iPSC)-based intestinal models enabling easy evaluation of transcellular transport. It is known that animal-derived components induce variation in the experimental outcomes. Therefore, we aimed to refine the differentiation protocol by using animal-free components. More specifically, we compared maturation of 2D-cultured iPCSs toward small intestinal epithelial cells when cultured either with or without serum, and either on Geltrex or on animal-free, recombinant laminin-based substrata. Differentiation status was characterized by qPCR, immunofluorescence imaging, and functionality assays. Our data suggest that differentiation toward definitive endoderm is more efficient without serum. Both collagen- and recombinant laminin-based coating supported differentiation of definitive endoderm, posterior definitive endoderm, and small intestinal epithelial cells from iPS-cells equally well. Small intestinal epithelial cells differentiated on recombinant laminin exhibited slightly more enterocyte specific cellular functionality than cells differentiated on Geltrex. Our data suggest that functional small intestinal epithelial cells can be generated from iPSCs in serum-free method on xeno-free substrata. This method is easily converted to an entirely xeno-free method.

Clustering based approach for population level identification of condition-associated T-cell receptor ß-chain CDR3 sequences.

BACKGROUND: Deep immune receptor sequencing, RepSeq, provides unprecedented opportunities for identifying and studying condition-associated T-cell clonotypes, represented by T-cell receptor (TCR) CDR3 sequences. However, due to the immense diversity of the immune repertoire, identification of condition relevant TCR CDR3s from total repertoires has mostly been limited to either "public" CDR3 sequences or to comparisons of CDR3 frequencies observed in a single individual. A methodology for the identification of condition-associated TCR CDR3s by direct population level comparison of RepSeq samples is currently lacking. RESULTS: We present a method for direct population level comparison of RepSeq samples using immune repertoire sub-units (or sub-repertoires) that are shared across individuals. The method first performs unsupervised clustering of CDR3s within each sample. It then finds matching clusters across samples, called immune sub-repertoires, and performs statistical differential abundance testing at the level of the identified sub-repertoires. It finally ranks CDR3s in differentially abundant sub-repertoires for relevance to the condition. We applied the method on total TCR CDR3ß RepSeq datasets of celiac disease patients, as well as on public datasets of yellow fever vaccination. The method successfully identified celiac disease associated CDR3ß sequences, as evidenced by considerable agreement of TRBV-gene and positional amino acid usage patterns in the detected CDR3ß sequences with previously known CDR3ßs specific to gluten in celiac disease. It also successfully recovered significantly high numbers of previously known CDR3ß sequences relevant to each condition than would be expected by chance. CONCLUSION: We conclude that immune sub-repertoires of similar immuno-genomic features shared across unrelated individuals can serve as viable units of immune repertoire comparison, serving as proxy for identification of condition-associated CDR3s.

Independent and cumulative coeliac disease-susceptibility loci are associated with distinct disease phenotypes.

The phenotype of coeliac disease varies considerably for incompletely understood reasons. We investigated whether established coeliac disease susceptibility variants (SNPs) are individually or cumulatively associated with distinct phenotypes. We also tested whether a polygenic risk score (PRS) based on genome-wide associated (GWA) data could explain the phenotypic variation. The phenotypic association of 39 non-HLA coeliac disease SNPs was tested in 625 thoroughly phenotyped coeliac disease patients and 1817 controls. To assess their cumulative effects a weighted genetic risk score (wGRS39) was built, and stratified by tertiles. In our PRS model in cases, we took the summary statistics from the largest GWA study in coeliac disease and tested their association at eight P value thresholds (PT) with phenotypes. Altogether ten SNPs were associated with distinct phenotypes after correction for multiple testing (PEMP2 ≤ 0.05). The TLR7/TLR8 locus was associated with disease onset before and the SH2B3/ATXN2, ITGA4/UBE2E3 and IL2/IL21 loci after 7 years of age. The latter three loci were associated with a more severe small bowel mucosal damage and SH2B3/ATXN2 with type 1 diabetes. Patients at the highest wGRS39 tertiles had OR > 1.62 for having coeliac disease-related symptoms during childhood, a more severe small bowel mucosal damage, malabsorption and anaemia. PRS was associated only with dermatitis herpetiformis (PT = 0.2, PEMP2 = 0.02). Independent coeliac disease-susceptibility loci are associated with distinct phenotypes, suggesting that genetic factors play a role in determining the disease presentation. Moreover, the increased number of coeliac disease susceptibility SNPs might predispose to a more severe disease course.

Celiac disease antibody levels reflect duodenal mucosal damage but not clinical symptoms.

OBJECTIVES: This study aimed to investigate, in a real-world population, whether the histological and clinical phenotype differ at baseline and during follow-up in patients with high and low CD (celiac disease) antibody titers. MATERIALS AND METHODS: The study cohort consisted of 96 consecutive patients diagnosed to have CD during the years 2010-2018. The clinical parameters, symptoms and laboratory results were registered and histomorphometry was analyzed from the available duodenal biopsies taken during the primary and follow-up esophageal-gastricduodenoscopies. Patients having immunoglobulin A transglutaminase antibody (tTG-ab) levels above 70 U/mL were classified as high titer patients. RESULTS: Measured by the villous-crypt ratio, the duodenal mucosa was more severely damaged in the high tTG-ab group than in the low tTG-group at baseline (n = 70, 0.61 ± 0.63 vs. 1.02 ± 0.87, p = .003) and during the follow-up when the patients were on gluten-free diet (n = 27, 1.80 ± 0.72 vs. 2.35 ± 0.64, p = .041). Interestingly, the high tTG-ab group members had fewer gastrointestinal symptoms at baseline than those in the low tTG-ab group (43% vs. 68%, p = .013) but lower vitamin D levels (68 ± 34 nmol/L vs. 88 ± 29 nmol/L, p = .034) and more often microcytosis (28% vs. 10%, p = .040). During the follow-up, these differences were no longer detected. CONCLUSIONS: At baseline, CD patients with high tTG-ab have more severe duodenum injury and signs of malabsorption but fewer symptoms. After gluten-free diet has been initiated, the mucosal healing in the high tTG-ab group is prolonged, but symptoms and signs of malabsorption recover equally in both groups.

Differences Between Familial and Sporadic Celiac Disease.

BACKGROUND: It is not known if genetic background, characteristics at diagnosis, physical and psychological well-being, and adherence to a gluten-free diet are comparable between patients with familial or sporadic celiac disease. These issues were investigated in a follow-up study. METHODS: Altogether 1064 patients were analyzed for celiac disease-associated serology, predisposing HLA-DQ, and non-HLA genotypes. Medical data were collected from patient records and supplementary interviews. Current symptoms and quality of life were further evaluated with the Gastrointestinal Symptom Rating Scale (GSRS), the Psychological General Well-Being questionnaire (PGWB), and Short Form 36 (SF-36) questionnaires. RESULTS: Familial and sporadic groups differed (P < 0.001) in the reason for diagnosis and clinical presentation at diagnosis, familial patients being more often screen-detected (26% vs. 2%, P < 0.001) and having less often gastrointestinal (49% vs. 69%) and severe symptoms (47% vs. 65%). The groups were comparable in terms of histological damage, frequency of malabsorption, comorbidities, childhood diagnoses, and short-term treatment response. At the time of the study, familial cases reported fewer symptoms (21% vs. 30%, P = 0.004) and lower prevalence of all (78% vs. 86%, P = 0.007), neurological (10% vs. 15%, P = 0.013), and dermatological (9% vs. 17%, P = 0.001) comorbidities. Dietary adherence and GSRS scores were comparable, but familial cases had better quality of life according to PGWB and SF-36. High-risk genotype HLA-DQ2.5/DQ2.5 was more frequent among familial cases, and four non-HLA SNPs were associated with familial celiac disease. CONCLUSIONS: Despite the greater proportion of high-risk genotypes, familial cases had milder symptoms at presentation than did sporadic cases. Worse experience of symptoms and poorer quality of life in sporadic disease indicate a need for intensified support.

Persistent Skin Symptoms after Diagnosis and on a Long-term Gluten-free Diet in Dermatitis Herpetiformis.

Dermatitis herpetiformis is a cutaneous manifestation of coeliac disease treated with a gluten-free diet. However, the itching and blistering rash alleviates slowly after gluten withdrawal and occasionally persists despite a long-term gluten-free diet. This study investigated the prevalence and factors associated with prolonged (i.e. >2 years) and ongoing skin symptoms in 237 patients with dermatitis herpetiformis. Data were gathered from medical records and via questionnaires. Among patients with dermatitis herpetiformis, 38% had prolonged symptoms after diagnosis, and 14% had ongoing skin symptoms at follow-up (median duration of gluten-free diet 24 years). A severe rash at diagnosis was associated with both prolonged and ongoing cutaneous symptoms. In addition, patients with dermatitis herpetiformis with ongoing skin symptoms at follow-up had been on the dietary treatment for a shorter time (median duration 16 vs 25 years) and were less often on a strict diet (53% vs 78%) compared with patients with dermatitis herpetiformis without ongoing skin symptoms.

Anaemia in Dermatitis Herpetiformis: Prevalence and Associated Factors at Diagnosis and One-year Follow-up.

Dermatitis herpetiformis is a cutaneous manifestation of coeliac disease. Anaemia is a common finding in patients with untreated coeliac disease, but little is known about the occurrence of anaemia in those with dermatitis herpetiformis. This study investigated the prevalence of anaemia and factors associated with anaemia in 250 patients with dermatitis herpetiformis, at diagnosis and one year after diagnosis. As controls, 139 patients with coeliac disease were included. Patient records were reviewed to gather baseline clinical, histological, and laboratory data. Follow-up data for patients with dermatitis herpetiformis were collected from patient records and via questionnaires or at follow-up visits. The prevalence of anaemia was 12% in patients with dermatitis herpetiformis and 17% in patients with coeliac disease at diagnosis (p = 0.257). Anaemia in patients with dermatitis herpetiformis was not associated with the severity of skin symptoms or small bowel damage. The prevalence of anaemia at a 1-year follow-up had increased to 19%, but it was associated mainly with dapsone treatment.

Overall and Cause-Specific Mortality in Adult Celiac Disease and Dermatitis Herpetiformis Diagnosed in the 21st Century.

INTRODUCTION: We assessed whether celiac disease-associated mortality is increased in Finland among patients diagnosed in the 21st century, given recent improvements in diagnostic and treatment facilities. METHODS: Biopsy-proven patients with celiac disease (Marsh III) and dermatitis herpetiformis aged 20-79 years (median 50 years) diagnosed 2005-2014 (n = 12,803) were identified from the national dietary grant registry. Dates and causes of death were obtained from Statistics Finland. Overall mortality and causes of death were compared with reference individuals (n = 38,384) matched for age, sex, and area of residence (at the time of celiac disease diagnosis) selected from the Population Information System. RESULTS: During a mean follow-up of 7.7 years (SD ±3.0 years), 884 (6.9%) and 2,613 (6.8%) deaths occurred among the celiac cohort and reference group, respectively. Overall mortality (hazard ratio [HR] 1.01, 95% confidence intervals [CIs] 0.94-1.09), mortality from all malignancies (HR 1.11, 95% CI 0.96-1.27), gastrointestinal tract malignancies (HR 1.21, 95% CI 0.56-1.71), or cardiovascular diseases (HR 0.91, 95% CI 0.77-1.07) were not increased among patients with celiac disease. Overall, mortality from lymphoproliferative diseases (HR 2.36, 95% CI 1.65-3.39) and nonmalignant digestive diseases (HR 2.19, 95% CI 1.40-3.43) was increased, but HRs decreased after the exclusion of the first 2 years of follow-up (HR 1.71, 95% CI 1.10-2.66 and HR 1.75, 95% CI 1.01-3.05, respectively). DISCUSSION: The overall mortality in adult celiac disease diagnosed 2005-2014 was not increased. Mortality from lymphoproliferative diseases was increased but lower than previously reported.

Diagnostic findings and long-term prognosis in children with anemia undergoing GI endoscopies.

BACKGROUND AND AIMS: Intestinal diseases are regarded as a common cause of anemia, but the diagnostic outcomes of children with anemia undergoing endoscopic investigations are unclear. We investigated this issue in a large cohort of children. METHODS: Indications for and findings of consecutive gastrointestinal (GI) endoscopies were collected. Clinical presentation and diagnostic outcomes were compared between anemic and nonanemic patients and between anemic patients with and without a diagnosis. Diagnoses received during follow-up were collected. RESULTS: Of 2395 consecutive endoscopies, 251 children with and 613 children without anemia had undergone either diagnostic esophagogastroduodenoscopy (EGD) (51.4% and 51.4%, respectively), colonoscopy (4.0% and 11.4%), or both (45.8% and 37.8%). Children with anemia more often received diagnoses (72.9% vs 39.3%; odds ratio [OR], 4.18; 95% confidence interval [CI], 3.03-5.77), particularly of celiac disease (26.3% vs 15.5%, P < .001) and of inflammatory bowel disease (31.1% vs 9.1%, P < .001), than did nonanemic children. The diagnosis in anemic patients was predicted by age 5 to 12 years (OR, 3.52; 95% CI, 1.27-9.75), presence of diarrhea (OR, 2.04; 95% CI, 1.07-3.90), melena/hematochezia (OR, 2.40; 95% CI, 1.17-4.92), poor growth (OR, 3.94; 95% CI, 1.70-9.15), positive celiac serology (OR, 11.81; 95% CI, 3.47-40.12), high calprotectin (OR, 12.86; 95% CI, 4.00-41.32), hypersedimentation (OR, 2.65; 95% CI, 1.29-5.44), and hypoalbuminemia (OR, 5.05; 95% CI, 1.56-16.34). Thirty children with anemia (12.0%) had no GI symptoms, and 22 of them (73.3%) were given diagnoses at the time of the endoscopies. All 22 had additional laboratory abnormalities, whereas these were present in only 2 of 8 undiagnosed children. None of them was diagnosed later in the follow-up of up to 11 years, in contrast to 4 (6.7%) of all anemic and 33 (8.9%) of all nonanemic patients. CONCLUSIONS: Anemia increased the probability of being given a diagnosis, emphasizing its importance as an alarm symptom. However, endoscopies in anemic patients without additional symptoms or laboratory abnormalities seldom improved the diagnostic yield.

Severity of Villous Atrophy at Diagnosis in Childhood Does Not Predict Long-term Outcomes in Celiac Disease.

OBJECTIVES: Current pediatric guidelines allow noninvasive diagnosis of celiac disease in selected children. We investigated in a large cohort study whether the severity of villous atrophy at diagnosis is associated with clinical characteristics or long-term health outcomes, thus having a prognostic significance. METHODS: Comprehensive medical data on 906 children with celiac disease were analyzed. Long-term health outcomes of 503 adult patients diagnosed in childhood were moreover assessed with a specific study questionnaire and validated Gastrointestinal Symptom Rating Scale (GSRS) and Psychological General Well-Being (PGWB) questionnaires. Patients were classified into 3 groups according to the severity of villous atrophy at diagnosis, and all variables were compared. RESULTS: Altogether 34% of the patients had partial, 40% subtotal, and 26% total villous atrophy. Children with milder lesions were diagnosed more recently (median year 2007 vs 2006 vs 2001, respectively, P < 0.001), more often by screening (30% vs 25% vs 17%, P < 0.001) and they suffered less often from anemia (16% vs 21% vs 32%, P < 0.001) and growth disturbances (22% vs 36% vs 54%, P < 0.001) and had lower transglutaminase-2 antibody levels (median 64 U/L vs 120 U/L vs 120 U/L, P < 0.001). There was no difference in other disease features.Altogether 212 adults diagnosed in childhood completed the questionnaires. Severity of villous atrophy at childhood diagnosis did not predict presence of complications or comorbidities, persistent symptoms, and self-perceived health, quality of life or adherence to a gluten-free diet in adulthood. CONCLUSION: Presence of advanced villous atrophy at diagnosis is associated with more severe clinical characteristics but not with poorer long-term health and treatment outcomes.